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New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part II Causal Mechanisms and Treatment
Abstract
s described in Part I of this 2-part article, 1 diastolic heart failure is common and causes significant alterations in prognosis. In Part II, experimental studies that have provided insight into the mechanisms that cause diastolic heart failure will be described.2-19 In addition, current treatment strategies and the design of future clinical trials of diastolic heart failure will be discussed. The development of truly effective therapy for diastolic heart failure depends on gaining a clear under- standing of the basic mechanisms that alter diastolic function and the ability to efficiently target these mechanisms to correct these abnormalities in diastolic function.
... One can speculate that the drug exerts tissue-specific actions or its effects may be dose dependent, as the cGMP-PKG pathway has different effectors in the vascular smooth muscle and the myocardium Tsai & Kass, 2009 (Atp2a2) expression in BGP-15-treated murine hearts (Kennedy et al., 2016;Sapra et al., 2014). Besides the dysregulated Ca 2+ homeostasis, alterations in extracellular matrix synthesis also contribute to diastolic dysfunction (Zile & Brutsaert, 2002). Here, Masson's trichrome staining revealed fibrotic remodelling in the LV samples of the hypercholesterolemic group, which was reduced in the hypercholesterolemic + BGP-15 group, in accordance with previous findings (Sapra et al., 2014). ...
... Hence, BGP-15 application seems to counteract the increased stiffness of myocytes, a primary feature of diastolic dysfunction. As an underlying mechanism, we showed that BGP-15 induces favourable changes in phosphorylation state and isoform composition of titin, a sarcomeric giant protein that could directly determine diastolic tension (Kotter et al., 2013;Zile & Brutsaert, 2002). The stiff N2B and the compliant N2BA titin isoforms are co-expressed in the heart, and a low ratio of N2BA/N2B is associated with high passive tension. ...
Background and Purpose
The small molecule BGP‐15 has been reported to alleviate symptoms of heart failure and improve muscle function in murine models. Here, we investigated the acute and chronic effects of BGP‐15 in a rabbit model of atherosclerotic cardiomyopathy.
Experimental Approach
Rabbits were maintained on standard chow (control) or atherogenic diet (hypercholesterolemic) for 16 weeks. BGP‐15 was administered intravenously (once) or orally (for 16 weeks), to assess acute and chronic effects. Cardiac function was evaluated by echocardiography, endothelium‐dependent vasorelaxation was assessed and key molecules in the protein kinase G (PKG) pathway were examined by enzyme‐linked immunosorbent assay (ELISA) and western blot. Passive force generation was investigated in skinned cardiomyocytes.
Key Results
Both acute and chronic BGP‐15 treatments improved the diastolic performance of the diseased heart. However, vasorelaxation and serum lipid markers were unaffected. Myocardial cyclic guanosine monophosphate (cGMP) levels were elevated in the BGP‐15‐treated group, along with preserved PKG activity and increased phospholamban Ser16‐phosphorylation. PDE5 expression decreased in the BGP‐15‐treated group and PDE1 was inhibited. Cardiomyocyte passive tension reduced in BGP‐15‐treated rabbits, the ratio of titin N2BA/N2B isoforms increased and PKG‐dependent N2B‐titin phosphorylation elevated.
Conclusions and Implications
BGP‐15 treatment improves diastolic function, reduces cardiomyocyte stiffness and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP‐PKG pathway. As BGP‐15 has been proven to be safe, it may be clinically useful in the treatment of diastolic dysfunction.
... 3 The mechanisms underlying LVDD may include impaired ventricular relaxation, increased chamber stiffness, and/or elevated ventricular filling pressures. 4 These changes can be measured using echocardiographic parameters, including mitral inflow and tissue Doppler imaging (TDI) velocities, left atrial volume index (LAVI), and the presence of an elevated tricuspid regurgitation velocity (TRV). 5,6 The American Society of Echocardiography (ASE) and ...
Background: Left ventricular diastolic dysfunction (LVDD) is an important predictor of cardiovascular outcomes. LVDD assessment guidelines are valuable in clinical practice, yet a significant proportion of individuals remain indeterminate.
Objectives: We aimed to develop an easy-to-use LVDD score and compare its prognostic value to American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) guidelines.
Methods: Participants in the Project Baseline Health Study (PBHS) were included (n=1,952). Minor and major criteria for the PBHS diastolic score (0-6 points) were defined by percentile deviation from a healthy reference cohort (n=565), including early mitral annular tissue Doppler velocity (e'), the ratio of early diastolic inflow velocity to e' (E/e'), and left atrial volume index. Multivariable Cox regression estimated associations between LVDD assessments and major adverse cardiovascular events (MACE).
Results: At enrollment, mean age was 50±16; 56% were female. LVDD according to ASE/EACVI guidelines was present in 8.4% of participants, of whom 54.3% had an indeterminate grade. PBHS diastolic scores of ≥3 and ≥4 were observed in 14.1% and 5.8%, respectively. ASE/EACVI grades 2-3 corresponded with PBHS scores >3, whereas indeterminate categories corresponded with scores of 1-5. After multivariable adjustment, both LVDD grading systems equally predicted MACE (ASE/EACVI grades 2-3: aHR 5.7 [95%CI: 3.01-10.7]; PBHS scores 4 and 5-6: aHRs 2.3 [95%CI: 1.25-4.33] and 5.3 [95%CI: 2.44-11.56], respectively).
Conclusion: The PBHS diastolic score predicted MACE similarly to the ASE/EACVI. Its simplicity and prognostic value can make it useful in clinical settings, particularly for quantifying abnormalities and risk-stratifying patients with indeterminate LVDD.
... Conventional ultrasound parameters in this study showed that HFpEF patients had LV wall hypertrophy, left atrial enlargement, and LV diastolic dysfunction; these features were consistent with the results of previous studies (29). Zile et al. (30,31) revealed significant abnormalities in the active relaxation and passive stiffness of the LV in patients with HFpEF by means of pathophysiological mechanisms and cardiac catheterization. Higher LVMI and E/e' were independently associated with an increased risk of hospitalization for heart failure and with cardiovascular death in HFpEF patients (29). ...
Background
Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent progressive disease accompanied by poor quality of life, high utilization of medical resources, morbidity, and mortality. However, the role of left ventricular (LV) systolic dysfunction has yet to be well elaborated despite the preservation of the LV ejection fraction. This study aimed to explore the diagnostic value of speckle-tracking stratified strain combined with myocardial work (MW) measurement in evaluating LV systolic dysfunction in patients with HFpEF.
Methods
A total of 125 study consecutive individuals, 64 HFpEF patients, and 61 controls were prospectively enrolled in the Fourth Affiliated Hospital of Harbin Medical University. In addition to the conventional echocardiographic parameters, LV stratified strain and MW parameters were statistically compared between the HFpEF and control groups. The global longitudinal strain (GLS) of the subendocardium, myocardium, and subepicardium (GLSendo, GLSmyo, and GLSepi); the transmural gradient (ΔGLS); the global myocardial work index (GWI), global myocardial work efficiency (GWE), global myocardial constructive work (GCW), and the global myocardial wasted work (GWW) were included. Area under the receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of these univariate and multivariable logistic models in detecting impaired LV systolic function in HFpEF. Ten-fold cross-validation was used to evaluate the generalizability of the predictive model.
Results
Stratified strains values showed a gradient decline from GLSendo to GLSepi in both control and HFpEF patients. Compared with the control group, HFpEF patients had a significantly reduced GLSepi, GLSmyo, GLSendo, ΔGLS, GWI, GWE, and GCW and a significantly increased GWW (all P<0.001). In the derivation set, the optimal logistic model (combined stratified strain and MW variables) demonstrated the highest performance in predicting LV systolic function impairment in HFpEF patients. The best-performing model with a mean area under the curve (AUC) of 0.966 [95% confidence interval (CI): 0.88 to 1] accessed by 10-fold cross-validation. In the validation set, the AUC of the optimal logistic model was 0.933 (95% CI: 0.85 to 1), the sensitivity was 87%, and the specificity was 93%.
Conclusions
Both speck-tracking stratified strain and MW measurement may sensitively detect impairment of LV myocardial function at an early stage for patients with HFpEF. Combining the two techniques may improve the quality of HFpEF diagnosis and may provide a reference value for the early diagnosis of HFpEF in the future.
... Although initial mass enlargement aims to normalize LV wall stress under conditions of higher hemodynamic load while maintaining adequate performance, thus representing a compensatory reaction, maladaptive growth of the hypertensive heart in later periods is associated with worse prognosis and frequently results in the development of overt heart failure (HF). Thus, LV hypertrophy has been a target of therapeutic interventions aimed at mitigating or even reversing pathological heart growth, and novel means of treatment are continuously being searched for [3]. ...
There is ample evidence on the benefit of angiotensin receptor-neprilysin inhibitors (ARNIs) in heart failure, yet data regarding the potential protective action of ARNIs in hypertensive heart disease are sparse. The aim of this study was to show whether an ARNI exerts a protective effect in a model of Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension with a hypertensive heart and to compare this potential benefit with an angiotensin-converting enzyme inhibitor, captopril. Five groups of adult male Wistar rats were studied (14 per group) for four weeks: untreated controls; ARNI (68 mg/kg/day); L-NAME (40 mg/kg/day); L-NAME treated with ARNI; and L-NAME treated with captopril (100 mg/kg/day). L-NAME administration induced hypertension, accompanied by increased left ventricular (LV) weight and fibrotic rebuilding of the LV in terms of increased concentration and content of hydroxyproline in insoluble collagen and in total collagen and with a histological finding of fibrosis. These alterations were associated with a compromised systolic and diastolic LV function. Treatment with either an ARNI or captopril reduced systolic blood pressure (SBP), alleviated LV hypertrophy and fibrosis, and prevented the development of both systolic and diastolic LV dysfunction. Moreover, the serum levels of prolactin and prolactin receptor were reduced significantly by ARNI and slightly by captopril. In conclusion, in L-NAME-induced hypertension, the dual inhibition of neprilysin and AT1 receptors by ARNI reduced SBP and prevented the development of LV hypertrophy, fibrosis, and systolic and diastolic dysfunction. These data suggest that ARNI could provide protection against LV structural remodeling and functional disorders in hypertensive heart disease.
... Normal diastolic function is evaluated by adequate ventricular filling at rest and with exercise without an abnormal increase in diastolic filling pressures. Accordingly, diastolic dysfunction is characterized by: an increased intraventricular diastolic pressure, Delayed relaxation, increased stiffness with prolonged time for returning to presystolic length and force (3). In hypertension, diastolic dysfunction is usually present as asymptomatic finding on noninvasive testing, or as dyspnea and pulmonary edema despite their left ventricular systolic function is normal (4). ...
Background: Left ventricular hypertrophy and diastolic dysfunction are considered to be an important risk factor for cardiovascular morbidity and mortality in asymptomatic hypertensivepatients. At the bedside, left ventricular geometric remodeling and diastolic dysfunction in hypertension can not be diagnosed without echocardiography which is a useful adjunct to the medical history, physical examination, ECG, and chest radiography. Hence, it provides an opportunity for good management and prognosis of what appears to be preclinical hypertensive complication. Subjects and Methods: 127 subjects with essential hypertension of either sex attending echo unit were subjected to medical history, clinical examination, physical measurements, ECG, M-mode and Doppler echocardiography. They were classified as 46 treated hypertensives where they were on regular antihypertensive medication, and 81 untreated hypertensive patients. In addition, they were sex and age matched to 39 healthy subjects who served as control group. Results: The results of this study revealed that hypertensive patients especially those with stage II hypertension were prone to develop left ventricular hypertrophy (LVH) of concentric geometric pattern and diastolic dysfunction. However, small percentage of those patients found to have diastolic dysfunction despite they were without LVH. In addition, Doppler echocardiography clarify that hypertensives with abnormal transmitral inflow profile; of left ventricular impaired relaxation pattern suffered left ventricular systolic dysfunction. Moreover, in this study there was no evidence of pseudonormal transmitral inflow filling pattern which is excluded after Valsalva maneuver.Conclusion: There is a strong association between left ventricular hypertrophy and diastolic dysfunction which was more common in patients with stage II hypertension. However, leftventricular diastolic dysfunction is usually follows left ventricular hypertrophy, but it still may proceed especially in those patients with left ventricular hypertrophy (LVH) of concentric geometric pattern. In addition, left ventricle diastolic dysfunction is not necessary coincide with the development of systolic dysfunction, namely normal ejection fraction and fractional shortening.
... The most important downstream target of cGMP is PKG, which regulates several molecular signal transduction pathways [9]. The proper relaxation of the myocardium is provided by the downstream signaling targets of the NO-cGMP-PKG pathway controlling calcium (Ca 2+ ) homeostasis with the help of the sarcoplasmic reticulum Ca 2+ -APTase (SERCA2a), as well as regulating the giant elastic protein called titin [10]. ...
This study evaluates the potential therapeutic effects of anthocyanin-rich Prunus cerasus (sour cherry) extract (PCE) on atherosclerosis-associated cardiac dysfunction, described by the impairment of the NO-PKG (nitric oxide–protein kinase G) pathway and the antioxidant capacity. Initially, a rabbit model of atherosclerotic cardiovascular disease was established by administering a cholesterol-rich diet, enabling the examination of the impact of 9 g/kg PCE on the pre-existing compromised cardiovascular condition. After that, the animals were divided into four groups for 12 weeks: the (1) untreated control group; (2) PCE-administered healthy rabbits; (3) hypercholesterolemic (HC) group kept on an atherogenic diet; and (4) PCE-treated HC group. Dyslipidemia, impaired endothelial function, and signs of diastolic dysfunction were evident in hypercholesterolemic rabbits, accompanied by a reduced cardiac expression of eNOS (endothelial nitric oxide synthase), PKG, and SERCA2a (sarco/endoplasmic reticulum calcium ATPase 2a). Subsequent PCE treatment improved the lipid profile and the cardiac function. Additionally, PCE administration was associated with elevated myocardial levels of eNOS, PKG, and SERCA2a, while no significant changes in the vascular status were observed. Western blot analysis further revealed hypercholesterolemia-induced increase and PCE-associated reduction in heme oxygenase-1 expression. The observed effects of anthocyanins indicate their potential as a valuable addition to the treatment regimen for atherosclerosis-associated cardiac dysfunction.
... From the same institution, Kim et al. [8] reported that preoperative SCH patients showed higher all-cause mortality and cardiovascular mortality after CABG than their euthyroid counterparts. There were 66 patients with SCH in [12], which was associated with increased morbidity and mortality in the general population [13]. Impaired left ventricular systolic function was also documented by Doppler echocardiography and cardiopulmonary exercise testing in subclinical hypothyroid patients [14]. ...
Objectives:
Subclinical hypothyroidism (SCH) is characterized by an elevated thyroid-stimulating hormone and normal free thyroxine. This study aimed to evaluate the influence of SCH on mid-term outcomes of patients after coronary artery bypass grafting (CABG).
Methods:
From January 2015 to December 2018, 548 SCH patients and 6718 euthyroid patients who underwent CABG were identified. Propensity score matching was used to create two cohorts with similar baseline characteristics (n = 544 in each group). The mid-term follow-up outcomes were compared. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards models.
Results:
The mean follow-up for all patients was 39.7 ± 17.3 months. The unadjusted Kaplan-Meier estimate for mortality at 5-year follow-up was higher in patients with SCH compared with euthyroid patients (5.3% vs 1.6%, log-rank P = 0.03). After adjusting for covariates, the risk of mortality was higher in patients with SCH compared with euthyroid patients (HR, 2.40; 95% confidence interval [CI], 1.03 to 5.58; P = 0.04). The adjusted risk of major adverse cardiovascular and cerebral event (MACCE) (HR, 2.16; 95% CI, 1.51 to 3.08; P < 0.001) and angina (HR, 2.44; 95% CI, 1.41 to 4.24; P = 0.001) was higher in patients with SCH compared with euthyroid patients.
Conclusions:
SCH is associated with an increased risk of mortality, MACCE and angina compared with euthyroidism in patients undergoing CABG.
... Many myocytes are arranged in chaotic 2 of 11 and disorganized architectural patterns. Myocardial fibrosis contributes to heart failure, arrhythmias, and sudden cardiac death [6][7][8]. ...
Background:
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. The hallmark of HCM is myocardial fibrosis which contributes to heart failure, arrhythmias, and sudden cardiac death (SCD).
Objective:
To identify the factors implicated in heart failure symptoms and functional capacity of patients with HCM.
Methods:
In this cohort study, 43 patients with HCM were recruited. According to functional capacity and symptoms presentation, patients were categorized according to New York Heart Association (NYHA) classification, and echocardiographic measurements of left ventricle systolic and diastolic function were conducted. The echocardiographic assessment of right ventriculo-arterial coupling (RVAC) was made by calculating the tricuspid annular peak systolic tissue Doppler velocity (TASV)/estimated RV systolic pressure (RVSP) ratio.
Results:
Almost half (51%) of our study population present symptoms of heart failure and were categorized as the symptomatic group-NYHA 2 or higher. Maximum LVOT gradient, RVSP, and the ratio of E/e' were higher in the symptomatic group compared with the asymptomatic group. TASV was lower in the symptomatic group compared with the asymptomatic group (11 ± 1 cm/s vs. 13 ± 2 cm/s, p = 0.04). However, there was no difference in other potentially influential factors, such as heart rate or systemic blood pressure. The SCD risk score does not differ between the two studied groups. The RVAC (estimated with the TASV/RVSP ratio) was lower in the symptomatic group compared with the asymptomatic group (0.32 ± 0.09 vs. 0.46 ± 0.11, p < 0.001).
Conclusion:
A low RVAC (as estimated with TASV/RVSP ratio) value could represent an echocardiographic marker of right ventricular-arterial uncoupling in patients with HCM and impaired functional status.
... Several structural and functional changes occur within the myocardium due to aging that have been linked to diastolic dysfunction 44 . Active relaxation of cardiomyocytes, a process that involves actin-myosin detachment and calcium reuptake, is a major determinant of diastolic function [45][46][47] . Passive stiffness of the myocardium is another key factor that regulates the diastolic reserve and function 47 . ...
Diastolic dysfunction is a key feature of the aging heart. We have shown that late-life treatment with mTOR inhibitor, rapamycin, reverses age-related diastolic dysfunction in mice but the molecular mechanisms of the reversal remain unclear. To dissect the mechanisms by which rapamycin improves diastolic function in old mice, we examined the effects of rapamycin treatment at the levels of single cardiomyocyte, myofibril and multicellular cardiac muscle. Compared to young cardiomyocytes, isolated cardiomyocytes from old control mice exhibited prolonged time to 90% relaxation (RT90) and time to 90% Ca2+ transient decay (DT90), indicating slower relaxation kinetics and calcium reuptake with age. Late-life rapamycin treatment for 10 weeks completely normalized RT90 and partially normalized DT90, suggesting improved Ca2+ handling contributes partially to the rapamycin-induced improved cardiomyocyte relaxation. In addition, rapamycin treatment in old mice enhanced the kinetics of sarcomere shortening and Ca2+ transient increase in old control cardiomyocytes. Myofibrils from old rapamycin-treated mice displayed increased rate of the fast, exponential decay phase of relaxation compared to old controls. The improved myofibrillar kinetics were accompanied by an increase in MyBP-C phosphorylation at S282 following rapamycin treatment. We also showed that late-life rapamycin treatment normalized the age-related increase in passive stiffness of demembranated cardiac trabeculae through a mechanism independent of titin isoform shift. In summary, our results showed that rapamycin treatment normalizes the age-related impairments in cardiomyocyte relaxation, which works conjointly with reduced myocardial stiffness to reverse age-related diastolic dysfunction.
... Many myocytes are arranged in chaotic and disorganized architectural patterns. Myocardial fibrosis contributes to heart failure, arrhythmias, and sudden cardiac death (7)(8)(9). 2 Concerning the clinical course of the disease, HCM is generally characterized by sudden death risk due to fatal ventricular arrythmias, and LV outflow tract obstruction causing heart failure due to diastolic dysfunction as a consequence of LV hypertrophy, fibrosis, and stiffness (10,11). Another aspect of diastolic dysfunction contributing to functional impairment in patients with HCM is left atrium (LA) enlargement, stiffening, and atrial fibrillation (12). ...
Background: Hypertrophic Cardiomyopathy (HCM) is the most common inherited Cardiomyopathy. The hallmark of HCM is myocardial fibrosis which contributes to heart failure, arrhythmias, and sudden cardiac death (SCD). Objective: To identify the factors implicated in heart failure symptoms and functional capacity of patients with HCM. Methods: In this cohort study, 43 patients with HCM were recruited. According to functional capacity and symptoms presentation, patients were categorized according to NYHA classification, and echocardiographic measurements of left ventricle systolic and diastolic function have been conducted. The echocardiographic assessment of right vetriculo-arterial coupling (RVAC) has been made by calculating the tricuspid annular peak systolic tissue Doppler velocity (TASV)/estimated RV systolic pressure (RVSP) ratio. Results: Almost half, 22 (51%) of our study population present symptoms of heart failure and were categorized as the symptomatic group - NYHA 2 or higher. Maximum LVOT gradient, RVSP, and the ratio of E/e’ were higher in the “symptomatic” compared to the “asymptomatic” group. TASV was lower in the “symptomatic” compared to the asymptomatic group (11±1cm/sex vs. 13±2cm/sec, p=0.04). However, there was no difference in other potentially influential factors, such as heart rate or systemic blood pressure. The SCD risk score does not differ between the two studied groups. The RVAC (estimated with the TASV/RVSP ratio) was lower in the “symptomatic” compared with the “asymptomatic” group (0.32±0.09 vs. 0.46±0.11, p<0.001). Conclusion: A low RVAC (as TASV/RVSP ratio) value could represent an echocardiographic marker of right ventricular-arterial uncoupling in patients with HCM and may impaired functional status.
... Control, normal diastolic function; dysfunction, diastolic dysfunction. calcium reuptake, impaired myocardial energetics, mitochondrial function, or myocardial steatosis, of which some have been shown to cause abnormalities in both active relaxation and stiffness [2,[33][34][35][36][37]. These alterations may lead to a distinct pattern of cardiac dynamics, throughout the cardiac cycle, as observed with the SVL. ...
Background:
Presence of left ventricular diastolic dysfunction (DD) is key in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, non-invasive assessment of diastolic function is complex, cumbersome, and largely based on consensus recommendations. Novel imaging techniques may help detecting DD. Therefore, we compared left ventricular strain-volume loop (SVL) characteristics and diastolic (dys-)function in suspected HFpEF patients.
Method and results:
257 suspected HFpEF patients with sinus rhythm during echocardiography were prospectively included. 211 patients with quality-controlled images and strain and volume analysis were classified according to the 2016 ASE/EACVI recommendations. Patients with indeterminate diastolic function were excluded, resulting in two groups: normal diastolic function (control; n = 65) and DD (n = 91). Patients with DD were older (74.8 ± 6.9 vs. 68.5 ± 9.4 years, p < 0.001), more often female (88% vs 72%, p = 0.021), and more often had a history of atrial fibrillation (42% vs. 23%, p = 0.024) and hypertension (91% vs. 71%, p = 0.001) compared to normal diastolic function. SVL analysis showed a larger uncoupling i.e., a different longitudinal strain contribution to volume change, in DD compared to controls (0.556 ± 1.10% vs. -0.051 ± 1.14%, respectively, P < 0.001). This observation suggests different deformational properties during the cardiac cycle. After adjustment for age, sex, history of atrial fibrillation and hypertension, we found an adjusted odds ratio of 1.68 (95% confidence interval 1.19-2.47) for DD per unit increase in uncoupling (range: -2.95-3.20).
Conclusion:
Uncoupling of the SVL is independently associated with DD. This might provide novel insights in cardiac mechanics and new opportunities to assess diastolic function non-invasively.
... Seven patients enrolled in this study had left ventricular diastolic dysfunction with E/e' > 14.0 and e' < 7.0; surprisingly, six had E/e' normalization after CAR. HFpEF is associated with various pathological conditions and is related to CSNA [26]. In hypertensive patients, cardiac sympathetic hyperactivity may lead not only to elevated blood pressure, but also to the development of left ventricular diastolic dysfunction [27]. ...
Background:
The carotid sinus baroreceptor reflex controls the neural regulation of blood pressure. Baroreceptor disorders due to carotid sinus atherosclerosis have detrimental cardiovascular effects. This study investigated the medium-term effects of carotid artery revascularization (CAR) on sympathetic and cardiac function and systemic blood pressure variability in patients with carotid artery stenosis.
Methods:
This study included 21 consecutive patients (median age 70 years, 18 men) with carotid artery stenosis scheduled for CAR. 123I metaiodobenzylguanidine (MIBG) scintigraphy, echocardiography, brain natriuretic peptide levels, 24-h Holter electrocardiography (ECG), and ambulatory blood pressure monitoring assessed approximately 3 months postoperatively were compared to preoperative data.
Results:
All 21 enrolled patients underwent CAR. Carotid artery stenting was done in three patients with cardiovascular risk or anatomical difficult for carotid endarterectomy. The mean common carotid artery end-diastolic velocity improved significantly (P < 0.01) by 1.6-fold, from 10.8 ± 3.2 to 16.1 ± 7.1 cm/s. In 123I-MIBG scintigraphy, the heart-to-mediastinum (H/M) count ratio was significantly higher than preoperatively (from 2.66 ± 0.48 to 2.86 ± 0.56, P = 0.03). Holter ECG analysis revealed a significant decrease in the low-frequency/high-frequency (LF/HF) ratio compared to preoperatively (from 2.17 ± 1.20 to 1.62 ± 0.68, P = 0.04). These findings suggest decreased myocardial sympathetic activation. In echocardiography, the tissue Doppler-derived e' increased, and E/e' decreased significantly (P < 0.05) from 11.7 ± 5.1 to 10.1 ± 4.0, suggesting an improved left ventricular diastolic capacity. The mean 24-h and nighttime blood pressures were unchanged.
Conclusions:
CAR in patients with carotid stenosis may provide medium-term improvement in cardiac sympathetic nerve activity and left ventricular diastolic dysfunction.
... In addition, there was some apparent thinning of the left ventricular posterior wall in diastole (LVPWd) in male mice exposed to PG/VG without nicotine. Reduced exercise tolerance is one clinical hallmark in patients presenting diastolic heart failure (also known as heart failure with preserved ejection fraction) because diastolic myocardial stiffness prevents the increase in left ventricular filling that is physiologically needed to increase the stroke volume during exercise (67). Further studies will be needed to determine if increasing the stress on the heart with a b-adrenergic stimulus, i.e., dobutamine, which more closely reflects exercise, will reveal greater impairments in cardiac function in E-cigaretteexposed male mice. ...
To date there has been a lag between the rise in E-cigarette use and an understanding of the long-term health effects. Inhalation of E-cigarette aerosol delivers high doses of nicotine, raises systemic cytokine levels, and compromises cardiopulmonary function. The consequences for muscle function have not been thoroughly investigated. The present study tests the hypothesis that exposure to nicotine-containing aerosol impairs locomotor muscle function, limits exercise tolerance and interferes with muscle repair in male mice. Nicotine-containing aerosol reduced the maximal force produced by the extensor digitorum longus (EDL) by 30-40% and, the speed achieved in treadmill running by 8%. Nicotine aerosol exposure also decreased adrenal and increased plasma epinephrine and norepinephrine levels and, these changes in catecholamines manifested as increased muscle and liver glycogen stores. In nicotine aerosol exposed mice, muscle regenerating from overuse injury only recovered force to 80% of non-injured levels. However, the structure of NMJs was not affected by e-cigarette aerosols. Interestingly, the vehicle used to dissolve nicotine in these vaping devices, polyethylene glycol (PG) and vegetable glycerin (VG), decreased running speed by 11% and prevented full recovery from a lengthening contraction protocol (LCP) injury. In both types of aerosol exposures, cardiac left ventricular systolic function was preserved, but left ventricular myocardial relaxation was altered. These data suggest that E-cigarette use may have a negative impact on muscle force and regeneration due to compromised glucose metabolism and contractile function in male mice.
... The beneficial impacts of beta-blocker on LV hypertrophy and fibrosis may positively impact HFpEF because fibrosis and hypertrophy of left ventricles can contribute to the pathogenesis of HFpEF [22]. Finally, the protective effects of beta-blockers on oxidative stress and inflammation may increase the longevity of HFpEF [23]. One experimental study on hypertensive diastolic heart failure in a rat model found that the treatment with beta-blockers (bisoprolol) reduced inflammatory alterations and oxidative stress, which increased survival rates [24]. ...
The beneficial impacts of various drugs on long-term outcomes in patients with heart failure with preserved ejection fraction (HFpEF) have been a matter of controversy. The aim of this meta-analysis was to systematically review randomized control trials (RCTs) involving patients with heart failure with preserved left ventricular ejection fraction (LVEF) and identify the effects of various treatment options [angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, angiotensin receptor blockers, and aldosterone receptor blockers] on all-cause mortality, cardiovascular mortality, and hospitalization due to cardiovascular reasons. The current meta-analysis has been conducted as per the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed without any restrictions on language by using the electronic databases Cochrane Library, EMBASE, and PubMed up to July 20, 2022. The outcomes assessed in this meta-analysis included all-cause mortality, cardiovascular mortality, and hospitalization due to cardiovascular reasons. Overall, 10 articles were included in the current meta-analysis with a pooled sample size of 13,336 patients with HFpEF. In comparison to the placebo, among all four pharmacological agents, beta-blockers were the only agent that decreased the risk of all-cause mortality and cardiovascular outcomes. On the other hand, a significant reduction in hospitalization due to cardiac-related reasons was reported in patients on ACE inhibitors as compared to placebo. No other pharmacological agent had an impact on hospitalization due to cardiac-related reasons. The current meta-analysis indicates the possible benefits of beta-blockers in HFpEF in terms of reducing cardiovascular death and all-cause mortality.
... In the apical 4CH view, pulse-wave TDI was utilized to quantify the lateral peak systolic velocity (RV Smv), lateral early and late diastolic velocities (RV Emv and RV Amv), and the average E/Em ratio [12]. ...
... Similarly, Cases #2, 3, 8, and 9 had co-existence of LV systolic and DD; in these cases, commonly used catecholamineinotropic therapy of the former can lead to worsening of the latter. 16 Moreover, in patients with unresolved shock, clinicians often tend to give more fluid, more inotropes, and more pressors without clear indications, further compounding the continuing circulatory instability and making it exceedingly challenging to tease out the cause and effect of PS. ...
Objective:
Persistent shock (PS) or recurrent shock (RS) after initial fluids and vasoactives can be secondary to myriad complex mechanisms, and these patients can have a high mortality. We developed a noninvasive tiered hemodynamic monitoring approach which included, in addition to basic echocardiography, cardiac output monitoring and advanced Doppler studies to determine the etiology and provide targeted therapy of PS/RS.
Design:
Prospective observational study.
Setting:
Tertiary Care Pediatric Intensive Care Unit, India.
Methods:
A pilot conceptual report describing the clinical presentation of 10 children with PS/RS using advanced ultrasound and noninvasive cardiac output monitoring. Children with PS/RS after initial fluids and vasoactive agents despite basic echocardiography underwent BESTFIT + T3 (Basic Echocardiography in Shock Therapy for Fluid and Inotrope Titration) with lung ultrasound and advanced 3-tiered monitoring (T1-3).
Results:
Among 10/53 children with septic shock and PS/RS over a 24-month study period, BESTFIT + T3 revealed combinations of right ventricular dysfunction, diastolic dysfunction (DD), altered vascular tone, and venous congestion (VC). By integrating information obtained by BESTFIT + T1-3 and the clinical context, we were able to modify the therapeutic regimen and successfully reverse shock in 8/10 patients.
Conclusion:
We present our pilot results with BESTFIT + T3, a novel approach that can noninvasively interrogate major cardiac, arterial, and venous systems that may be particularly useful in regions where expensive rescue therapies are out of reach. We suggest that, with practice, intensivists already experienced in bedside POCUS can use the information obtained by BESTFIT + T3 to direct time-sensitive precision cardiovascular therapy in persistent/recurrent pediatric septic shock.
How to cite this article:
Natraj R, Ranjit S. BESTFIT-T3: A Tiered Monitoring Approach to Persistent/Recurrent Paediatric Septic Shock - A Pilot Conceptual Report. Indian J Crit Care Med 2022;26(7):863-870.
... In terms of improving myocardial compliance, digitalis glycosides can reduce the degree of LV hypertrophy, reduce the collagen content, and increase the dP/dt min index [16]. When applicate in a short-term period, digitalis cardiac glycosides can also produce some benefits, including enhancing mitochondrial function, promoting rapid and complete ventricular diastole, increasing visceral blood flow, and increasing venous volume [17]. Although it is still contentious whether cardiac glycoside can be used in the treatment of HFpEF, increasing research attention investigated the novel therapeutic potential of cardiac glycosides in HFpEF treatment, which provides excellent examples to illustrate our strategy. ...
Heart failure with preserved ejection fraction (HFpEF) is a common public health problem associated with increased morbidity and long-term mortality. However, effective treatment for HFpEF was not discovered yet. In the present study, we aimed to decipher the effects of Periplocin on DOCA-induced heart failure rats and explore the possible underlying mechanisms. We demonstrated that Periplocin could significantly attenuate cardiac structural remodeling and improve cardiac diastolic function. Of note, Periplocin significantly inhibited the recruitment of inflammatory and immune cells and decreased the expression of serum inflammatory cytokines. Meanwhile, Periplocin had the effect of cardiac glycosides to improve cardiomyocyte contractility and calcium transient amplitude. These findings indicate that Periplocin might be a potential medicine to treat HFpEF in patients.
Graphical abstract
... Clinically, cardiomyopathy is characterized by diastolic dysfunction [440], which is an apparent inability of the heart muscle to undergo adequate relaxation and then refilling during the diastolic part of a normal cardiac contract-relaxation cycle. Diastolic dysfunction actually is a common clinical manifestation, observed in up to 40-60% of all heart failure cases [441][442][443], with diabetic individuals over-represented [444]. ...
Hyperglycemia in diabetic patients is associated with abnormally-elevated cellular glucose levels. It is hypothesized that increased cellular glucose will lead to increased formation of endogenous methanol and/or formaldehyde, both of which are then metabolically converted to formic acid. These one-carbon metabolites are known to be present naturally in humans, and their levels are increased under diabetic conditions. Mechanistically, while formaldehyde is a cross-linking agent capable of causing extensive cytotoxicity, formic acid is an inhibitor of mitochondrial cytochrome oxidase, capable of inducing histotoxic hypoxia, ATP deficiency and cytotoxicity. Chronic increase in the production and accumulation of these toxic one-carbon metabolites in diabetic patients can drive the pathogenesis of ocular as well as other diabetic complications. This hypothesis is supported by a large body of experimental and clinical observations scattered in the literature. For instance, methanol is known to have organ- and species-selective toxicities, including the characteristic ocular lesions commonly seen in humans and non-human primates, but not in rodents. Similarly, some of the diabetic complications (such as ocular lesions) also have a characteristic species-selective pattern, closely resembling methanol intoxication. Moreover, while alcohol consumption or combined use of folic acid plus vitamin B is beneficial for mitigating acute methanol toxicity in humans, their use also improves the outcomes of diabetic complications. In addition, there is also a large body of evidence from biochemical and cellular studies. Together, there is considerable experimental support for the proposed hypothesis that increased metabolic formation of toxic one-carbon metabolites in diabetic patients contributes importantly to the development of various clinical complications.
... Importantly, endocardial ischemia due to microvascular dysfunction can impair both active and passive relaxation of the ventricle during diastole. Specifically, myocyte relaxation is an energy-dependent process involving cytosolic calcium uptake by sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA); thus a reduction in myocardial perfusion can impair this phase of diastole (136). On the other hand, chronic ischemia is associated with fibrosis development and increased passive stiffness of the heart (137,138). ...
Obesity has reached epidemic proportions and is a major contributor to insulin resistance (IR) and type 2 diabetes (T2D). Importantly, IR and T2D substantially increase the risk of cardiovascular (CV) disease. Although there are successful approaches to maintain glycemic control, there continue to be increased CV morbidity and mortality associated with metabolic disease. Therefore, there is an urgent need to understand the cellular and molecular processes that underlie cardiometabolic changes that occur during obesity so that optimal medical therapies can be designed to attenuate or prevent the sequelae of this disease. The vascular endothelium is in constant contact with the circulating milieu; thus, it is not surprising that obesity-driven elevations in lipids, glucose, and proinflammatory mediators induce endothelial dysfunction, vascular inflammation, and vascular remodeling in all segments of the vasculature. As cardiometabolic disease progresses, so do pathological changes in the entire vascular network, which can feed forward to exacerbate disease progression. Recent cellular and molecular data have implicated the vasculature as an initiating and instigating factor in the development of several cardiometabolic diseases. This Review discusses these findings in the context of atherosclerosis, IR and T2D, and heart failure with preserved ejection fraction. In addition, novel strategies to therapeutically target the vasculature to lessen cardiometabolic disease burden are introduced.
... Increased LV end-diastolic pressure due to decreased ventricular compliance, in the absence of LV systolic dysfunction, is the hallmark of diastolic dysfunction in HFpEF. Current evidence suggests that HFpEF and diastolic dysfunction represent, in part, a disorder of abnormal energetics, resulting, among others, from mitochondrial dysfunction, and the known role of CoQ10 in mitochondrial bioenergetics provided the pathophysiologic rationale for examining CoQ10 as a possible treatment for HFpEF [9,10,17]. ...
Background
Heart failure with preserved ejection fraction (HFpEF) is common in elderly people and is increasing in prevalence. No specific treatment for this condition exists. Coenzyme Q10 (CoQ10) is an essential cofactor for energy production, with reduced levels being noted in HF. Previous studies have suggested a possible role for CoQ10 in the treatment of HF. This study examined the effect of CoQ10 supplementation on diastolic function in HFpEF patients.Methods
We conducted a prospective, randomized, double-blind, placebo-controlled trial including patients aged > 55 years presenting with New York Heart Association class II–IV heart failure symptoms and left ventricular ejection fraction > 50%, with impaired diastolic function. Echocardiography and levels of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed at baseline and following 4 months of CoQ10 or placebo supplementation.ResultsA total of 39 patients were enrolled—19 in the CoQ10 group and 20 in the placebo group. Baseline clinical characteristics were similar between groups, while compliance was high and also similar between the CoQ10 and placebo groups. There was no significant effect of treatment on indices of diastolic function (difference in the lateral E/e' ratio: −0.86 ± 6.57 in the CoQ10 group, +0.18 ± 3.76 in the placebo group; p = 0.561) or on serum NT-proBNP levels (− 72 pg/mL vs. − 42 pg/mL; p = 0.195).Conclusions
In this pilot trial in elderly patients with HFpEF, treatment with CoQ10 did not significantly affect echocardiographic indices of diastolic function and serum NT-proBNP levels.Trial RegistrationThis trial was registered in the US National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier: NCT02779634).
... Таким образом, неотложная терапия ДДЛЖ в послеоперационном периоде включает контроль АД, контроль ритма, устранение риска развития отека легких. Инотропные агенты, как правило, не используются при изолированной ДДЛЖ, поскольку только обостряют патофизиологические процессы (например, повышение потребления О 2 и тахикардию), при-водящие к ДДЛЖ [37]. Важным является активный мониторинг не только основных параметров гемодинамики, но и свободной воды в легких, поскольку для данной категории больных характерен тонкий баланс между сниженной преднагрузкой и избыточной свободной жидкостью в легких [2]. ...
Despite of the growing number of patients, the understanding of diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF) is still not sufficient. The pathophysiological mechanisms of HFpEF are not fully investigated. The mortality rate among patients suffering from heart failure with preserved ejection fraction is the same as among patients with heart failure and reduced ejection fraction. At the moment, the diagnosis and treatment of patients with HFpEF has not been optimized despite these alarming trends. Echocardiography is the main diagnostic tool. The identification of clinically significant echocardiographic changes, even without an evident clinical picture, can contribute to a change in the patient's treatment plan or a revision of surgical tactics and anesthetic management.
... A decrease in diastolic filling and coronary perfusion during tachycardia causes myocardial hypoxia. This condition increases cardiac irritability (11). The main causes of SVT in this case arose from nCPAP. ...
The use of noninvasive ventilation in the treatment of respiratory failure has increased in recent years. Nasal continuous positive airway pressure, a noninvasive method of ventilation, is thought to decrease the incidence of arrhythmias, but this case report presents supraventricular tachycardia attacks secondary to nasal continuous positive airway pressure. A 15-month-old boy was admitted to the intensive care unit with diagnoses of sepsis, disseminated intravascular coagulopathy, acute renal failure, and myocarditis. Supraventricular tachycardia attacks started after nasal continuous positive airway pressure but became regular after switching to invasive mechanical ventilation.
... All rights reserved. 16 , evoked a secondary left ventricle myocardial velocity variation in Fig. 1B. In Fig. 1B, the handstand peak waives are the myocardial velocity in left ventricle diastole. ...
Force enhancement is one kind of myogenic spontaneous fasciculation in lengthening preload striated muscles. In cardiac muscle, the role of this biomechanical event is not well established. The physiological passive property is an essential part for maintaining normal diastole in the heart. In excessive preload heart, force enhancement relative erratic passive properties may cause muscle decompensating, implicate in the development of diastolic dysfunction. In this study, the force enhancement occurrence in mouse cardiac papillary muscle was evaluated by a microstepping stretch method. The intracellular Ca²⁺ redistribution during occurrence of force enhancement was monitored in real-time by a Flou-3 (2 mM) indicator. The force enhancement amplitude, the enhancement of the prolongation time, and the tension–time integral were analyzed by myography. The results indicated that the force enhancement occurred immediately after active stretching and was rapidly enhanced during sustained static stretch. The presence of the force and the increase in the amplitude synchronized with the acquisition and immediate transfer of Ca²⁺ to adjacent fibres. In highly preloaded fibres, the enhancement exceeded the maximum passive tension (from 4.49 ± 0.43 N/mm² to 6.20 ± 0.51 N/mm²). The occurrence of force enhancement were unstable in each static stretch. The increased enhancement amplitude combined with the reduced prolongation time to induce a reduction in the tension–time integral. We concluded that intracellular Ca²⁺-synchronized force enhancement is one kind of interruption event in excessive preload cardiac muscle. During the cardiac muscle in its passive relaxation period, the occurrence of this interruption affected the rhythmic stability of the cardiac relaxation cycle.
... Although we found no evidence of enhanced myocardial hypertrophy and fibrosis in our diabetic animals, diabetic stress is often detrimental to LV systolic and diastolic function in diabetic hearts (41). To assess cardiac function, echocardiographic parameters were measured 8 wk after STZ injections (Table 1). ...
Underlying molecular mechanisms for the development of diabetic cardiomyopathy remain to be determined. Long-term exposure to hyperglycemia causes oxidative stress, which leads to cardiomyocyte dysfunction. Previous studies established the importance of thioredoxin-Interacting protein (Txnip) in cellular redox homeostasis and glucose metabolism. Txnip is a highly glucose-responsive molecule that interacts with the catalytic center of reduced thioredoxin and inhibits the antioxidant function of thioredoxin. Here, we show that the molecular interaction between Txnip and thioredoxin plays a pivotal role in the regulation of redox balance in the diabetic myocardium. High glucose increased Txnip expression, decreased thioredoxin activities, and caused oxidative stress in cells. The Txnip-thioredoxin complex was detected in cells with overexpressing wild-type Txnip but not Txnip cysteine 247 to serine (C247S) mutant that disrupts the intermolecular disulfide bridge. Then, diabetes was induced in cardiomyocyte-specific Txnip C247S knock-in mice and their littermate control animals by injections of streptozotocin (STZ). Prolonged hyperglycemia up-regulated myocardial Txnip expression in both genotypes. The absence of Txnip's inhibition of thioredoxin in Txnip C247S mutant hearts promoted mitochondrial anti-oxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage by diabetes. Stress hemodynamic analysis uncovered that Txnip C247S knock-in hearts have a greater left ventricular contractile reserve than wild-type hearts under STZ-induced diabetic conditions. These results provide novel evidence that Txnip serves as a regulator of hyperglycemia-induced cardiomyocyte toxicities through direct inhibition of thioredoxin, and identify the single cysteine residue in Txnip as a therapeutic target for diabetic injuries.
... Patients with HFpEF regardless aetiology have been shown to have slightly better prognosis than patients with HFrEF. 20,21 The process transforming AS to HF begins with the pressure overload imposed on the LV by the narrowed valve causing LV hypertrophy as a compensatory mechanism to maintain cardiac output, leading further to impaired blood flow reserve, 22,23 cardiomyocyte apoptosis and replacement fibrosis, linking hypertrophy with HF. 24,25 Hypertrophy affects diastolic function 26 and, finally, systolic function. 27 However, the finding that AS-HFrEF patients have the same prognosis as AS-HFpEF patients challenges this mechanism among patients who had undergone an AVI. ...
Aims
To study clinical phenotype, prognosis for all‐cause and cardiovascular (CV) mortality and predictive factors in patients with incident heart failure (HF) after aortic valvular intervention (AVI) for aortic stenosis (AS).
Methods and results
In this retrospective, observational study we included patients from the Swedish Heart Failure Registry (SwedeHF) recorded 2003–2016, with AS diagnosis and AVI before HF diagnosis. The AS diagnosis was established according to International Classification of Diseases 10th revision (ICD‐10) codes, thus without information concerning clinical or echocardiographical data on the aortic valve disease. The patients were divided into two subgroups: left ventricular ejection fraction (LVEF) ≥ 50% (AS‐HFpEF) and <50% (AS‐HFrEF). We individually matched three controls with HF from the SwedeHF without AS (control group) for each patient. Baseline characteristics, co‐morbidities, survival status and outcomes were obtained by linking the SwedeHF with two other Swedish registries. We used Kaplan–Meier curves to present time to all‐cause mortality, cumulative incidence function for time to CV mortality and Cox proportional hazards model to evaluate the relative difference between AS‐HFrEF and AS‐HFpEF and AS‐HF and controls. The crude all‐cause mortality was 49.0%, CV mortality 27.9% in AS‐HF patients, respectively 44.7% and 26.6% in matched controls. The adjusted risk for all‐cause mortality and CV mortality was similar in HF, regardless of LVEF vs. controls. No significant difference in factors predicting higher all‐cause mortality was observed in AS‐HFrEF vs. AS‐HFpEF, except for diabetes (only in AS‐HFrEF), with statistically significant interaction predicting death between the two groups.
Conclusions
In this nationwide SwedeHF study, we characterized incident HF population after AVI. We found no significant differences in all‐cause and CV mortality compared with general HF population. They had virtually the same predictors for mortality, regardless of LVEF.
... Despite the compensatory increase in LV wall thickness that allows for the normalization of ejection performance with AS, LV hypertrophy also leads to decreased reserve in coronary perfusion and impaired diastolic function. [37][38][39][40][41][42] These in turn can lead to the development of the 3 classic symptoms of AS: angina, dyspnea due to heart failure, and syncope. 43 Myocardial blood flow is unique relative to other vascular beds because it dominantly occurs during diastole, and oxygen extraction is always near maximum. ...
Aortic stenosis is the most common valvular disease requiring valve replacement. Valve replacement therapies have undergone progressive evolution since the 1960s. Over the last 20 years, transcatheter aortic valve replacement has radically transformed the care of aortic stenosis, such that it is now the treatment of choice for many, particularly elderly, patients. This review provides an overview of the pathophysiology, presentation, diagnosis, indications for intervention, and current therapeutic options for aortic stenosis.
Left ventricular (LV) diastolic dysfunction is a common condition in hypertensive patients, characterized by impaired relaxation and compliance of the LV, eventually leading to heart failure (HF). Chronic hypertension causes elevated LV end-diastolic pressure and LV hypertrophy, contributing to diastolic dysfunction. Neurohormonal activation and genetic factors also influence its onset. Diagnosis of diastolic dysfunction involves noninvasive and invasive approaches. Transthoracic echocardiography is commonly used, assessing factors like transmitral flow velocities, mitral annulus deformation, left atrial dimensions, and estimation of pulmonary artery pressures. Speckle-tracking echocardiography detects diastolic dysfunction early by evaluating strain and strain rate. Nuclear cardiology and cardiac magnetic resonance provide additional indices, but their clinical use is limited due to accessibility and processing time. Invasive evaluation through cardiac catheterization is the gold standard, allowing direct measurement of LV end-diastolic pressure and pulmonary capillary wedge pressure. Although noninvasive tests have extensively replaced invasive procedures in clinical practice, cardiac catheterization remains valuable in cases with inconclusive findings or when a differential diagnosis is required.
Hypertension is one of the major risk factors for morbidity and mortality worldwide, while the most common cause of death in hypertensive patients is heart failure. Myocardial ischemia is an important pathophysiologic link between high blood pressure and heart failure. Hypertension can lead to myocardial ischemia through two main mechanisms: by promoting atherosclerosis of the major coronary arteries and by left ventricular hypertrophy with vascular remodeling and microcirculatory dysfunction. A remodeled left ventricle will determine an impaired systolic and/or diastolic performance; consequently, the patients will develop heart failure with either reduced or preserved ejection fraction. In this chapter, we summarize the main pathways in the pathophysiological continuum of hypertension, myocardial ischemia, and heart failure.
BACKGROUND
The effect of sevoflurane on left ventricular diastolic function is not well understood. We hypothesized that parameters of diastolic function may improve under sevoflurane anesthesia in patients with preexisting diastolic dysfunction compared to patients with normal diastolic function.
METHODS
This observational study included 60 patients undergoing breast surgery or laparoscopic cholecystectomy. Patients were assigned to diastolic dysfunction (n = 34) or normal (n = 26) groups of septal e’ < 8 or ≥ 8.0 cm/s on the first thoracic echocardiography (TTE) performed before anesthesia. During anesthesia, sevoflurane was maintained at 1 to 2 minimum alveolar concentration (MAC) to maintain the bispectral index at 40 to 50. At the end of surgery, the second TTE was performed under 0.8 to 1 MAC of sevoflurane with the patient breathing spontaneously without ventilator support. Primary end point was the percentage change (Δ) of e’ on 2 TTEs (Δe’). Secondary end points were ΔE/e’, Δleft atrial volume index (ΔLAVI), and Δtricuspid regurgitation maximum velocity (ΔTR Vmax). These percentage changes (Δ) were compared between diastolic dysfunction and normal groups.
RESULTS
e’ (Δe’: 30 [6, 64] vs 0 [−18, 11]%; P < .001), mitral inflow E wave velocity (E), mitral inflow E/A ratio (E/A), and mitral E velocity deceleration time (DT) improved significantly in diastolic dysfunction group compared to normal group. LAVI decreased in diastolic dysfunction group but did not reach statistical significance between the 2 groups (ΔLAVI:−15 [−31, −3] vs −4 [−20, 10]%, P = .091). ΔE/e’ was not different between the 2 groups (11 [−16, 26] vs 12 [−9, 22]%, P = .853) (all: median [interquartile range, IQR]). TR was minimal in both groups.
CONCLUSIONS
In this study, echocardiographic parameters of diastolic function, including septal e’, E, E/A, and DT, improved with sevoflurane anesthesia in patients with preexisting diastolic dysfunction, but remained unchanged in patients with normal diastolic function.
Background
Although elevated resting heart rate (HR) is associated with a higher risk of cardiovascular events in patients with heart failure with reduced ejection fraction in sinus rhythm (SR), the relationship between HR and outcomes among patients with heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction and in those with atrial fibrillation (AF) is uncertain. The aims of this study were to examine the association between baseline HR and outcomes across the range of left ventricular ejection fraction, in patients with and without AF, and evaluate the effect of dapagliflozin according to HR.
Methods
A patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; heart failure with reduced ejection fraction) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure trial; heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction) trials. The primary outcome of each was the composite of worsening heart failure or cardiovascular death.
Results
Among patients with SR (n=6401, 64%), the rate of the primary outcome was higher in those with higher HR: 16.8 versus 7.7 per 100 person-years for ≥80 bpm versus <60 bpm. The relationship between HR and risk was steeper in heart failure with reduced ejection fraction versus heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. HR was not associated with outcomes in patients in AF for either heart failure phenotype. The benefit of dapagliflozin on the primary outcome was consistent across the HR range in both SR ( P interaction =0.28) and AF ( P interaction =0.56), for example, for SR <60 bpm, hazard ratio for dapagliflozin versus placebo 0.72 (95% CI, 0.55–0.95); 60 to 69 bpm, 0.78 (0.63–0.97); 70 to 79 bpm, 0.73 (0.59–0.91); ≥80 bpm, 0.77 (0.61–0.97). The benefit was consistent across HR range in both heart failure with reduced ejection fraction and heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction.
Conclusions
The risk of worsening heart failure or cardiovascular death increased with increasing baseline HR among patients in SR, but this association was not seen among patients in AF, irrespective of left ventricular ejection fraction. The benefit of dapagliflozin was consistent across HR range, irrespective of left ventricular ejection fraction or rhythm.
REGISTRATION
URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124 and NCT03619213.
Background: Many cardiac diseases can cause cardiac hypertrophy developed by the established cardiac overload, such as long term of uncontrolled hypertension, valvuler disease or congenital anomaly and many more causes. If the cause of hypertrophy persists for long time it will generate heart failure, as a result changes in size, shape and function of the heart which refer as remodeling.Objective: To investigate the types of remodeling in patients with heart failure, and study its relation with cardiac performance.Patients and methods: The study included fifty normal individuals and fifty patients, only those patients who developed hypertrophy and failure were chosen. The study has included the measurements of many cardiac parameters obtained by the echocardiography examination. The measurements have included: Left ventricle internal diameter at diastole (LVIDd), Left ventricle internal diameter at systole ( LVIDs), Peak velocity of early transmitral flow (E), Peak velocity of late transmitral flow (A), Isovolumetric contraction time (ICT), Isovolumetric relaxation time (IRT), Ejection time (ET), Ejection fraction (EF%), myocardial performance Index (MPI), Left ventricle mass index (LVMI ), Posterior wall thickness at diastole ( PWTd), Relative wall thickness ( RWT) and Interventricular septum thickness at diastole (IVSTd).Results: results of remodeling have shown nine patients expressed concentric hypertrophy, thirty seven patients have shown eccentric hypertrophy and only four patients were similar to normal. Many other changes were observed these are an exaggerated ratio of (E/A) goes up to four, an increase in the (LV) volume appeared on its dimension at systole for patients (54.63%), a reduced cardiac output for patients and insignificant small change in relative wall thickness (RWT).Conclusion: In conclusion long term cardiac overload can induce hypertrophy, after a period of time heart failure may ensue. This can influence the shape and size of the heart together with a reduction in its performance.
Left ventricular (LV) diastolic dysfunction results from a combination of impaired relaxation, reduced restoring forces, and increased chamber stiffness. Noninvasive assessment of diastology uses a multiparametric approach involving surrogate markers of increased filling pressures, which include mitral inflow, septal and lateral annular velocities, tricuspid regurgitation velocity, and left atrial volume index. However, these parameters must be used cautiously. This is because the traditional algorithms for evaluating diastolic function and estimation of LV filling pressures (LVFPs), as recommended by the American Society of Echocardiography and European Association of Cardiovascular Imaging 2016 guidelines, do not apply to unique patients with underlying cardiomyopathies, significant valvular disease, conduction abnormalities, arrhythmias, LV assist devices, and heart transplants, which alter the relation between the conventional indexes of diastolic function and LVFP. The purpose of this review is to provide solutions for evaluating LVFP through illustrative examples of these special populations, incorporating supplemental Doppler indexes, such as isovolumic relaxation time, mitral deceleration time, and pulmonary venous flow analysis, as needed to formulate a more comprehensive approach.
Cardiovascular disease is the leading cause of morbidity and mortality in children with chronic kidney disease. Asymmetric dimethylarginine (ADMA) is thought to be related to chronic kidney disease patients' adverse cardiovascular effects. Our study is to assess ADMA concentrations in children on hemodialysis (HD) as a marker of cardiovascular risk and detect the relation to the left ventricular (LV) function by traditional and speckled tracking echo. Forty children with end-stage renal disease on regular HD were enrolled in the study and selected from the nephrology HD unit of Al-Zahraa Hospital, Al-Azhar University. Another group of 40 healthy children matches age and sex with the patient's group as a control. ADMA serum level, traditional echo, and tissue Doppler imaging spackled tracking were performed to assess: LV functions for both groups in the same line with the routine laboratory investigations. Moreover, bioimpedance was assessed after the HD session. Children on regular HD have a significantly higher (ADMA) serum level compared to their controls; the median is (72.5 ng/mL) and (25 ng/mL), respectively (P = 0.001) and a significant increase in high-sensitivity C-reactive protein and the median is (3.6 ng/mL) and (2.5 ng/mL), respectively (P = 0.001). Moreover, conventional echo detects 27 (67.5%) patients out of 40 had an impaired LV function; meanwhile, 33 (82.5%) had a global LV strain (LV GLS) detected by 2D (Speckle echo), a negative correlation between LV ejection fraction with serum (urea, cholesterol, and triglyceride) and a positive correlation between ADMA and LV systolic diameter. LV GLS (Speckle echo) is negatively correlated with LV end-diastolic diameter, LV end-systolic diameter and positively correlated with LV inter ventricular septum in diastole and reduced average systolic velocity (ml). The sensitivity and specificity of (ADMA), high-sensitivity C-reactive protein (hs-CRP), traditional, and Speckle echo for early left ventricular (LV) dysfunction were 92.50, 92, and 67.50, 97 and 67.50, 90.00, and 80.00, 92, respectively. An ADMA emerges as a sensitive and specific marker for early LV dysfunction in children on hemodialysis (HD); drugs targeting ADMA isessential in the future direction after clinical approval, to avoid early LV changes, furthermore (Speckle echo) is superior to the traditional echo for early detection of LV changes in chronic kidney disease (CKD) children.
Objective . The purpose of this review is to highlight the pathophysiological mechanisms of the sequential formation of left ventricular hypertrophy (LVH), left ventricular dysfunction and chronic heart failure (CHF) in patients with hypertension (HTN), diagnostic and therapeutical issues of CHF with both reduced and preserved ejection fraction (EF). HTN is the main risk factor for cardiovascular diseases and is accompanied by damage of target organs, among which LVH is of particular importance. On the one hand, development of LVH is the consequence of increased load on the heart muscle and neurohumoral stimuli, and on the other hand, it is an independent risk factor for myocardial infarction, stroke, cardiac arrhythmias and CHF. HTN precedes newly developed heart failure in 91 % of patients with a predominance of CHF with a preserved EF according to the Framingham Heart Study. To date, different drugs can improve the prognosis of patients with HTN, CHF with reduced EF and to induce LVH regression. However, the issues of effective treatment of patients with CHF with preserved EF are still insufficiently studied.
Зниження гормональної функції ЩЗ – гіпотиреоз – є одним із основних і небезпечних для організму ускладнень автоімунного тиреоїдиту (АІТ). Одним із провідних негативних впливів гіпотиреозу на організм є високий ризик серцево-судинних захворювань. Мета – вивчити вплив АІТ із незміненою функцією ЩЗ та у випадках гіпотиреозу середньої тяжкості на показники артеріального тиску та структуру серця. Матеріал і методи. Обстежено 78 хворих на АІТ та 27 здорових осіб у якості контролю. Вивчали гормональну функцію щитоподібної залози, анатомічні особливості та функцію серцевого м᾽яза за даними ехокардіоскопії та показники артеріального тиску. Результати. У хворих на АІТ визначається діастолічний тиск достовірно вищий, ніж у групі контролю. Встановлені виражені і достовірні зміни структури і функції лівого шлуночка, які, з урахуванням показників артеріального тиску, можна розцінювати як прояви діастолічної гіпертензії. На її прояви вказують збільшення м᾽язової маси та індексу м᾽язової маси лівого шлуночка, товщини міжшлуночкової перегородки. При цьому відмічається зменшення показників фракції викиду. Висновки. У хворих на АІТ, порівняно зі здоровими, структура і функція лівого шлуночка порушені. Ці зміни є достовірними в усіх випадках АІТ, проте більш виражені і вагомі в разі АІТ з гіпотирезом середньої тяжкості. Питання впливу АІТ на серце і ССС до кінця не вивчені. Заслуговують на увагу механізми розвитку діастолічної гіпертензії при АІТ, її запобігання і лікування, особливо у випадках еутиреоїдної функції ЩЗ.
Abstract
Background: Doxorubicin (DOXO) has been used to induce dilated cardiomyopathy (DCM) in experimental models.
Objective: To analyze cardiac changes after DOXO infusion and define the most effective protocol to reproduce an
experimental model of DCM.
Methods: Male Wistar rats were divided into 4 groups and received increasing cumulative doses of DOXO (at a
rate of 2 mg/kg/week) or saline solution: the control group (CTR) received saline solution, Group D-8 received a
total infusion of 8 mg/kg, Group D-12 received 12 mg/kg, and Group D-16 received 6 mg/kg. All animals underwent
echocardiography at baseline and after the end of infusion. The animals were then euthanized and cardiac tissue
was collected for histological analysis.
Results: Mortality rates were 20% (D-8), 30% (D-12), and 67.6% (D-16). The 8 mg/kg dose was not associated with a
significant reduction in left ventricular ejection fraction (LVEF) or an increase in left ventricular end-diastolic diameter
(LVEDD). There was significant LVEF impairment with 12 mg/kg and 16 mg/kg doses compared to the control (68.3±5%
vs 58.4±9%, p < 0.01, for CTR-12 vs D-12; and 66.0±6% vs 47.6±15%, p < 0.01, for CTR-16 vs D-16). Histological
analyses revealed a greater percentage of fibrosis in D-12 (10.6±3.3%) and D-16 (9.8±2.3%) compared to CTR
(2.3±1.0%), p < 0.001.
Conclusions: The DOXO dose of 16 mg/kg was associated with severe cardiac changes and high mortality. Thus, we propose
a DOXO dose of 12 mg/kg as the most appropriate and effective for inducing DCM with an acceptable mortality rate.
Background: Chronic kidney disease (CKD) is common in patients with heart failure, and often results in left ventricular diastolic dysfunction (LVDD). However, the mechanisms responsible for cardiac damage in CKD-LVDD remain to be elucidated. Epigenetic alterations may impose long-lasting effects on cellular transcription and function, but their exact role in CKD-LVDD is unknown. We investigate whether changes in cardiac site-specific DNA methylation profiles might be implicated in cardiac abnormalities in CKD-LVDD. Methods: CKD-LVDD and normal control pigs (n=6 each) were studied for 14 weeks. Renal and cardiac hemodynamics were quantified by multidetector CT and echocardiography. In randomly selected pigs (n=3/group), cardiac site-specific 5-methylcytosine (5mC) immunoprecipitation (MeDIP)- and mRNA-sequencing (seq) was performed, followed by integrated (MeDiP-seq/mRNA-seq analysis), and confirmatory ex vivo studies. Results: MeDIP-seq analysis revealed 261 genes with higher (fold-change>1.4; p<0.05) and 162 genes with lower (fold-change<0.7; p<0.05) 5mC levels in CKD-LVDD versus normal pigs, which were primarily implicated in vascular endothelial growth factor (VEGF)-related signaling and angiogenesis. Integrated MeDiP-seq/mRNA-seq analysis identified a select group of VEGF-related genes in which 5mC levels were higher, but mRNA expression lower in CKD-LVDD versus normal pigs. Cardiac VEGF signaling gene and VEGF protein expression was blunted in CKD-LVDD compared to controls and associated with decreased subendocardial microvascular density. Conclusions: Cardiac epigenetic changes in VEGF-related genes are associated with impaired angiogenesis and cardiac microvascular rarefaction in swine CKD-LVDD. These observations may assist in developing novel therapies to ameliorate cardiac damage in CKD-LVDD.
Background
Shear wave elastography (SWE) has been proposed as a novel noninvasive method for the assessment of myocardial stiffness, a relevant determinant of diastolic function. It is based on tracking the propagation of shear waves, induced, for instance, by mitral valve closure (MVC), in the myocardium. The speed of propagation is directly related to myocardial stiffness, which is defined by the local slope of the nonlinear stress-strain relation. Therefore, the operating myocardial stiffness can be altered by both changes in loading and myocardial mechanical properties.
Objectives
This study sought to evaluate the capability of SWE to quantify myocardial stiffness changes in vivo by varying loading and myocardial tissue properties and to compare SWE against pressure-volume loop analysis, a gold standard reference method.
Methods
In 15 pigs, conventional and high–frame rate echocardiographic data sets were acquired simultaneously with pressure-volume loop data after acutely changing preload and afterload and after inducting an ischemia/reperfusion (I/R) injury.
Results
Shear wave speed after MVC significantly increased by augmenting preload and afterload (3.2 ± 0.8 m/s vs 4.6 ± 1.2 m/s and 4.6 ± 1.0 m/s, respectively; P = 0.001). Preload reduction had no significant effect on shear wave speed compared to baseline (P = 0.118). I/R injury resulted in significantly higher shear wave speed after MVC (6.1 ± 1.2 m/s; P < 0.001). Shear wave speed after MVC had a strong correlation with the chamber stiffness constant β (r = 0.63; P < 0.001) and operating chamber stiffness dP/dV before induction of an I/R injury (r = 0.78; P < 0.001) and after (r = 0.83; P < 0.001).
Conclusions
Shear wave speed after MVC was influenced by both acute changes in loading and myocardial mechanical properties, reflecting changes in operating myocardial stiffness, and was strongly related to chamber stiffness, invasively derived by pressure-volume loop analysis. SWE provides a novel noninvasive method for the assessment of left ventricular myocardial properties.
Background:
Chronic kidney disease (CKD) is an independent risk factor for the development of heart failure, but the underlying mechanisms remain unknown. Using a novel translational swine model of CKD and cardiac dysfunction, we hypothesize that CKD alters the cardiac miRNA and transcriptomic profile that associate with cardiac remodeling and metabolic processes implicated in the development of left ventricular diastolic dysfunction (CKD-LVDD).
Methods:
CKD-LVDD and normal control pigs (n=6 each) were studied for 14 weeks. Renal and cardiac hemodynamics were quantified by multidetector CT and echocardiography. In randomly selected pigs (n=3/group), cardiac miRNA- and mRNA-sequencing (seq) was performed, validated (qPCR), and followed by confirmatory ex vivo studies.
Results:
Differential expression analysis identified 9 miRNAs and 125 mRNAs upregulated and 17 miRNAs and 172 mRNAs downregulated (fold change ≥ 2 and FDR ≤ 0.05) in CKD-LVDD vs. normal controls. Integrated miRNA-/mRNA-seq analysis identified 71 overlapping downregulated mRNA targets of miRNAs upregulated, and 39 overlapping upregulated mRNA targets of miRNAs downregulated in CKD-LVDD vs. controls. Functional analysis showed that these genes were primarily implicated in processes associated with cardiac remodeling, including ubiquitination, ATP and fatty acid synthesis, and extracellular matrix remodeling. In agreement, hearts of CKD-LVDD pigs exhibited abnormal diastolic relaxation, mitochondrial injury, moderate LV fibrosis, and myocardial lipid accumulation.
Conclusions:
Our work comprehensively characterizes the cardiac micro-RNA and transcriptomic profile of a translational model of CKD-LVDD. Our data may set the foundation for new targeted studies to further elucidate LVDD pathophysiology and assist to develop therapeutic interventions.
Background:
Unlike left ventricular (LV) ejection fraction, which provides a precise, reliable, and prognostically valuable measure of systolic function, there is no single analogous measure of LV diastolic function.
Objectives:
We aimed to develop a continuous score to grade LV diastolic function using machine learning modeling of echocardiographic data.
Methods:
Consecutive echo studies performed at a tertiary care centre between February 1, 2010 and March 31, 2016 were assessed, excluding studies containing features that would interfere with diastolic function assessment as well as studies in which one or more parameters within the contemporary diastolic function assessment algorithm were not reported. Diastolic function was graded based on 2016 American Society of Echocardiography (ASE) / European Association of Cardiovascular Imaging (EACVI) guidelines, excluding indeterminate studies. Machine learning models were trained (SVM [support vector machine], DT [decision tree], XGB [XGBoost], and DNN [dense neural network]) to classify studies within the training set by diastolic dysfunction severity, blinded to the ASE/EACVI classification. The DNN model was retrained to generate a regression model (R-DNN) to predict a continuous LV diastolic function score.
Results:
A total of 28,986 studies were included; 23,188 studies were used to train the models and 5798 studies were used for validation. The models were able to reclassify studies with high agreement to the ASE/EACVI algorithm (SVM 83%, DT 100%, XGB 100%, DNN 98%). The continuous diastolic function score corresponded well with ASE/EACVI guidelines, with scores of 1.00 ± 0.01 for studies with normal function; and 0.74 ± 0.05, 0.51 ± 0.06, and 0.27 ± 0.11 for mild, moderate, and severe diastolic dysfunction respectively (mean ± 1 standard deviation). A score of <0.91 predicted abnormal diastolic function (AUC 0.99) while a score of <0.65 predicted elevated filling pressure (AUC 0.99).
Conclusions:
Machine learning can assimilate echocardiographic data and generate an automated continuous diastolic function score that corresponds well with current diastolic function grading recommendations.
Genome-wide association studies of magnetic resonance imaging (MRI) of diastolic heart function shed light on the underlying molecular mechanisms and support a causal role of diastolic function for the development of heart failure.
Aim:
Although the effects of pregnancy on the cardiovascular system have been covered by many studies, permanent changes in the hearts of multiparous women have not been investigated. This study therefore aimed to examine the permanent structural changes in the cardiac structure of multiparous women via transthoracic echocardiography (TTE).
Method:
This case-control study included 366 females who had given birth to 1-21 children, and 218 females with no previous deliveries. Anamnesis, physical examination, electrocardiography (ECG), TTE, and exercise stress tests were used to determine whether the cases had additional systemic pathologies. The structural cardiac parameters of all cases were recorded with TTE.
Results:
The study revealed that LV mass, LV mass index, left ventricular end diastolic volume (LVEDV), left ventricular end diastolic volume index (LVEDVI) were observed higher in women with five or more deliveries when compared to nulliparous women. On the other hand, ejection fraction (EF) was significantly lower in the same group. Receiver operating curve (ROC) analysis demonstrated that the prediction sensitivity for the presence of eccentric hypertrophy was 74% among women who had given >10.5 births, and its specificity was 97.8% (AUC: 0.949, 95% CI 0.905-0.993; p < 0.0001).
Conclusion:
The results showed that women with recurrent births had increased left ventricular end diastolic volume, left ventricular total mass in myocardium and decreased EF due to increased end diastolic volume. The results also showed delivering at frequent intervals (especially the birth of 11 or more) may be one of the causes of eccentric hypertrophy, in women of the low-to-middle income countries.
Background
Study examines the influence of cardiac rehabilitation program (CR) on left ventricular diastolic dysfunction (LVDD), functional capacity and major cardiovascular risk factors (CVRF) in patients after with PCI resolved acute coronary syndrome (ACS).
Methods
We performed a non-randomised study included a total of 85 subjects after resolved ACS, with left ventricular ejection fraction (LVEF) ≥ 45% and LVDD, without heart failure. Subjects were divided into control (N = 29) and intervention group (N = 56), depending on CR program attendance consisted of exercise training sessions for 12 weeks, 3 times per/week, 30 min per session. Initially and after 12 weeks, patients were subjected to echocardiography to assess LV filling pressure (E/e’) as well as CPET to asses improvement in peak VO2.
Results
Initially subjects were similar in CVRF, LVDD and CPET parameters (p > 0.05). Following CR, the intervention group demonstrated a significant improvement in E/e’ (8.0 ± 3.0 vs 7.0 ± 2.2; p < 0.05), compared to the control group (8.4 ± 3.0 vs 9.0 ± 3.1; p > 0.05), as well as a significant improvement in peak VO2 (23.2 ± 5.0 ml/kg/min vs 24.8 ± 5.8 ml/kg/min; p < 0.001). Control group also exhibited significant worsening in peak VO2 without CR (23.0 ± 4.0 vs 21.2 ± 4.1 ml/kg/min; p = 0.02). CVRF improved in both groups, except for glycaemia levels and body mass index, which improved only in the intervention group (p < 0.001).
Conclusions
Following ACS treated with PCI, CR had a positive effect on major CVRFs, the degree of LVDD and exercise capacity and should be considered as effective tool to reduce morbidity in such patients.
Patients with chronic kidney disease (CKD) have a high cardiovascular mortality. CKD and heart failure (HF) coexist in up to 50% of patients and both associates with inflammation. We aim to define the cardiac phenotype of a novel swine model of CKD and test the hypothesis that inflammation of renal origin propels the development of precursors of HF in CKD. CKD was induced in 14 pigs, which were followed for 14 weeks. Renal (multi-detector CT) and cardiac (echocardiography) hemodynamics were quantified before and 8 weeks after single intra-renal administration of placebo or a biopolymer-fused peptide inhibitor of nuclear-factor kappa B (NF-κB) that blocks NF-κB activity and decreases inflammatory activity (SynB1-ELP-p50i). Blood was collected to quantify cytokines (TNF-α, MCP-1, interleukins), markers of inflammation (C-reactive protein), and biomarkers of HF (ANP, BNP). Pigs were then euthanized and kidneys and hearts were studied ex vivo. Normal pigs were used as time-matched controls. Renal dysfunction in CKD was accompanied by cardiac hypertrophy and fibrosis, diastolic dysfunction, increased renal and cardiac expression of TNF-a, MCP-1 and interleukins, canonical and non-canonical mediators of NF-κB signaling, circulating inflammatory factors and biomarkers of HF. Notably, most of these changes were improved after intra-renal SynB1-SynB1-ELP-p50i, although cardiac inflammatory signaling remained unaltered. The translational traits of this model support its use as a platform to test novel technologies to protect the kidney and the heart in CKD. A targeted inhibition of renal NF-κB signaling improves renal and cardiac function, suggesting an inflammatory renal-cardio axis underlying early HF pathophysiology in CKD.
Heart failure (HF) and atrial fibrillation (AF) demonstrate a constantly increasing prevalence during the 21st century worldwide, as a result of the aging population and the successful interventions of the clinical practice in the deterioration of adverse cardiovascular outcomes. HF and AF share common risk factors and pathophysiological mechanisms, creating the base of a constant interrelation. AF impairs systolic and diastolic function, resulting in the increasing incidence of HF, whereas the structural and neurohormonal changes in HF with preserved or reduced ejection fraction increase the possibility of the AF development. The temporal relationship of the development of either condition affects the diagnostic algorithms, the prognosis and the ideal therapeutic strategy that leads to euvolaemia, management of non-cardiovascular comorbidities, control of heart rate or restoration of sinus rate, ventricular synchronization, prevention of sudden death, stroke, embolism, or major bleeding and maintenance of a sustainable quality of life. The indicated treatment for the concomitant HF and AF includes rate or/and rhythm control as well as thromboembolism prophylaxis, while the progress in the understanding of their pathophysiological interdependence and the introduction of the genetic profiling, create new paths in the diagnosis, the prognosis and the prevention of these diseases.
In addition to functional alterations, heart failure has a structural basis as well. This concerns all components of the cardiac myocytes as well as the extracellular space. Proteins of the cardiomyocyte can be subdivided in 5 different categories: 1) Contractile proteins including myosin, actin, tropomyosin and the troponins. 2) Sarcomeric skeleton: titin, myosin binding protein C, -actinin, myomesin, and M-protein. 3) True cytoskeletal proteins: tubulin, desmin and actin. 4) Membrane-associated proteins: dystrophin, spectrin, talin, vinculin, ankyrin and others. 5) Proteins of the intercalated disc: desmosomes consisting of desmoplakin, desmocollin, desmoglein and desmin; adherens junctions with N-cadherin, the catenins and vinculin, and gap junctions with connexin. Failing myocardium obtained from patients undergoing cardiac transplantation exhibits ultrastuctural degeneration and an altered nucleus/cytoplasm relationship. The contractile proteins and those of the sarcomeric skeleton, especially titin, are downregulated, the cytoskeletal proteins desmin and tubulin and membrane-associated proteins such as vinculin and dystrophin are upregulated and those of the intercalated disc are irregularly arranged. Elevation of cytoskeletal proteins correlates well with diastolic and contractile dysfunction in these patients. The enlarged interstitial space contains fibrosis, i.e. accumulations of fibroblasts and extracellular matrix components, in addition to macrophages and microvascular elements. Loss of the contractile machinery and related proteins such as titin and -actinin may be the first and decisive event initiating an adaptive increase in cytoskeleton and membrane associated components. Fibrosis may be stimulated by subcellular degeneration. The hypothesis is put forward that all proteins of the different myocardial compartments contribute to the deterioration of cardiac function in heart failure.
We tested the hypothesis that intracellular Ca++ [( Ca++]i) overload underlies the diastolic dysfunction of patients with hypertrophic cardiomyopathy. Myocardial tissue was obtained at the time of surgery or transplantation from patients with hypertrophic cardiomyopathy and was compared with control myocardium obtained from patients without heart disease. The isometric contractions and electrophysiologic properties of all myocardial specimens were recorded by standard techniques and [Ca++]i was measured with the bioluminescent calcium indicator aequorin. In contrast to the controls, action potentials, Ca++ transients, and isometric contraction and relaxation were markedly prolonged in the hypertrophic myocardium, and the Ca++ transients consisted of two distinct components. At 38 degrees C and 1 Hz pacing frequency, a state of relative Ca++ overload appeared develop, which produced a rise in end-diastolic [Ca++]i, incomplete relaxation, and fusion of twitches with a resultant decrease in active tension development. We also found that drugs with increase [Ca++]i, such as digitalis, exacerbated these abnormalities, whereas drugs that lower [Ca++]i, such as verapamil, or agents that increase cyclic AMP, such as forskolin, prevented them. These results may explain why patients with hypertrophic cardiomyopathy tolerate tachycardia poorly, and may have important implications with regard to the pharmacologic treatment of patients with hypertrophic cardiomyopathy.
There is growing recognition that congestive heart failure (CHF) caused by a predominant abnormality in diastolic function (ie, diastolic heart failure) is both common and causes significant morbidity and mortality. However, there is continued controversy surrounding the definition of diastolic dysfunction and the diagnostic criteria for diastolic heart failure. As a result, clinical therapeutic trials have been slow to develop and difficult to design. Fortunately, these controversies are yielding to an emerging consensus. Recent clinical studies have provided sufficient data to develop standardized diagnostic criteria to define diastolic heart failure. 1– 4 Experimental studies have provided increased insight into the mechanisms that cause diastolic heart failure. 5–22 Together, these clinical and experimental studies are being used to design targeted clinical trials to test effective treatments for diastolic heart failure. The purpose of this 2-part article is to provide a perspective on these issues, highlight new research, and introduce emerging ideas. Part 1 will focus on the criteria used to diagnose diastolic heart failure, the effects of diastolic heart failure on prognosis, and measurements used to assess diastolic function. Part 2 will describe the mechanisms that cause diastolic heart failure and discuss approaches to treatment.
Background
The role of cardiac glycosides in treating patients with chronic heart failure and normal sinus rhythm remains controversial. We studied the effect of digoxin on mortality and hospitalization in a randomized, double-blind clinical trial.
Methods
In the main trial, patients with left ventricular ejection fractions of 0.45 or less were randomly assigned to digoxin (3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-converting–enzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo.
Results
In the main trial, mortality was unaffected. There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P = 0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P = 0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure (26.8 percent vs. 34.7 percent; risk ratio, 0.72; 95 percent confidence interval, 0.66 to 0.79; P<0.001). In the ancillary trial, the findings regarding the primary combined outcome of death or hospitalization due to worsening heart failure were consistent with the results of the main trial.
Conclusions
Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure.
The diagnosis of diastolic heart failure (DHF) can be made when a patient has both symptoms and signs on physical exam of congestive heart failure (CHF), and normal left ventricular volume and ejection fraction. Documentation of abnormal diastolic function is confirmatory but not mandatory.
Diastolic heart failure is a frequent cause of CHF (prevalence is 35% to 50%) and has a significant effect on mortality (5-year mortality rate is 25% to 35%) and morbidity (1-year readmission rate is 50%).
Treatment should be targeted at symptoms, causal clinical disease, and underlying basic mechanisms.
Symptom-targeted therapy: decrease pulmonary venous pressure using diuretics and long-acting nitrates, maintain atrial contraction and atrial ventricular synchrony, reduce heart rate using beta-adrenergic blockers and calcium channel blockers; increase exercise tolerance by reducing exerciseinduced increases in blood pressure and heart rate using angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and calcium channel blockers.
Disease-targeted therapy: prevent or treat myocardial ischemia, prevent or regress left ventricular hypertrophy.
Mechanism-targeted therapy (future directions): modify neurohumoral activation using renin, angiotensin, and aldosterone system antagonists (ACE inhibitors, angiotensin II receptor blockade, aldosterone and renin antagonist); endothelin antagonists; nitric oxide agonists; and atrial natruretic peptide agonists; alter intracellular mechanisms; alter extracellular matrix structures.
Adenosine triphosphate (ATP) is the high-energy phosphate-containing compound directly used for excitation and contraction in muscle cells. The distinction between the amount and concentration of ATP versus its turnover rare is central to the understanding of bioenergetics. In the normal heart, [ATP] remains constant but its rate of synthesis and degradation (turnover rate) varies. The energetics of increasing cardiac work illustrates this principle. As the workload of the heart increases, oxygen consumption proportionately increases; yet, ATP content is essentially unchanged. Another important principle essential for our understanding of bioenergetics is that the chemical reactions that use ATP are “driven” by high ratios of ATP to ADP whereas ATP synthesis reactions are inhibited by high ATP/ADP ratios. One expression that defines the energy state of the cell is the adenylate energy charge. Given the critical need to maintain both a constant and high level of ATP and the ATP/[ADPxPi] ratio, it is not surprising that the cell uses many reactions and pathways to synthesize ATP and to regulate ADP and Pi levels. This chapter is the enzyme that transfers the phosphoryl group the most rapidly—namely creatine kinase (CK).
Human heart failure carries with it high mortal risks. The deficit in ventricular function results from a depression in power along with a blunting of the force-frequency relationship. Mechanical, myothermal and molecular biological analysis are used to uncover the mechanistic basis for the deficit in performance. At the cross-bridge level the average isometric force-time integral is increased in failing hearts. Despite this increase, the isometric peak force and rate of relaxation are markedly depressed and correlate with a substantial decrease in the amount and rate of calcium cycling per beat. The blunting of the force frequency relationship is shown to be directly related to the frequency dependence of the calcium concentration which in turn can be accounted for by alterations in the SERCA 2 calcium pump and the sarcolemmal Na/Ca exchange protein. There is a positive correlation between sarcoplasmic reticular calcium ATPase and frequency dependent changes in twitch tension and an inverse correlation between Na/Ca exchange protein and diastolic force. This analysis allows the hearts to be divided into two groups based on the Na/Ca exchange and SR calcium ATPase levels that separates the hearts that develop increased diastolic force from those that do not. In both groups of failing hearts the ratio of the Na/Ca exchange protein to the SERCA 2 pump is substantially increased. The phenotypic alterations in Na/Ca exchange protein, SERCA 2 calcium pump and the TnT isoform shift can account for the depression in power output and the associated ventricular dysfunction found in heart failure.
Objectives:
The purpose of this study was to evaluate left ventricular structure-function interplay in aortic valve disease.
Background:
An increase in myocardial fibrosis has been demonstrated in aortic valve disease, but changes in the collagen network and their effect on ventricular function have not been defined.
Methods:
Left ventricular structure was assessed from left ventricular endomyocardial biopsy specimens obtained in 32 patients with aortic valve disease (aortic stenosis in 25, aortic regurgitation in 7). Total collagen volume fraction, orthogonal collagen fiber meshwork (cross-hatching), endocardial fibrosis, muscle fiber diameter and volume fraction of myofibrils were determined by morphologic-morphometric evaluation. Control biopsy data were obtained from six donor hearts before transplantation. Eleven other patients with normal left ventricular function served as hemodynamic status control subjects. Left ventricular biplane cineangiography and high fidelity pressure measurements were carried out in all patients. Systolic function was assessed from ejection fraction. Diastolic function was evaluated by the time constant of relaxation, early and late peak filling rates and the constant of passive myocardial stiffness. Patients were assigned to three groups according to increasing severity of nonmyocyte tissue alterations. Group 1 comprised 10 patients with elevated total collagen volume fraction. Group 2 comprised 6 patients with normal total collagen volume fraction and the presence of increased cross-hatching or endocardial fibrosis, or both. Group 3 comprised 16 patients with elevated total collagen volume fraction and the presence of cross-hatching or endocardial fibrosis, or both.
Results:
Muscle fiber diameter was increased in the three groups with aortic valve disease, whereas the volume fraction of myofibrils was comparable in all four study groups. Ejection fraction was depressed in groups 2 and 3 compared with the control group. The time constant of relaxation was prolonged in the three groups with aortic valve disease. No differences in early and late peak filling rate were observed in the four study groups, but the constant of myocardial stiffness increased in groups 2 and 3.
Conclusions:
In aortic valve disease, changes in collagen architecture are associated with altered systolic function and passive diastolic properties. The sole increase in total collagen volume fraction without a change in architecture leaves systolic and passive diastolic function unaltered.
In congestive heart failure (idiopathic dilated cardiomyopathy), exercise is accompanied by a smaller-than-normal decrease in end-diastolic left ventricular volume, depressed peak rates of left ventricular pressure rise and fall, and depressed heart-rate-dependent potentiation of contractility (bowditch treppe). We studied contractile function of isolated left ventricular myocardium from New York Heart Association class IV-failing and nonfailing hearts at physiological temperature and heart rates in order to identify and quantitate abnormalities in myocardial function that underlie abnormal ventricular function.
The isometric tension-generating ability of isolated left ventricular strips from nonfailing and failing human hearts was investigated at 37 degrees C and contraction frequencies ranging from 12 to 240 per minute (min-1). Strips were dissected using a new method of protection against cutting injury with 2,3-butanedione monoxime (BDM) as a cardioplegic agent. In nonfailing myocardium the twitch tension-frequency relation is bell-shaped developing 25 +/- 2 mN/mm2 at a contraction frequency of 72 min-1 and peaking at 44 +/- 3.7 mN/mm2 at a contraction frequency of 174 +/- 4 min-1. In failing myocardium the peak of the curve occurs at lower frequencies between 6 and 120 min-1 averaging 81 +/- 22 min-1, and it develops 48% (p less than 0.001) and 80% (p less than 0.001) less tension than in nonfailing myocardium at 72 and 174 min-1, respectively. Between 60 and 150 min-1 tension increases by 107% in nonfailing myocardium, but it does not change significantly in failing myocardium. Peak rates of rise and fall of isometric twitch tension vary in parallel with twitch tension as stimulation frequency rises in nonfailing myocardium but not in failing myocardium.
The quantitative agreement between these results from isolated myocardium and those from catheterization laboratory measurements on intact humans suggest that alterations of myocardial origin, independent of systemic factors, may contribute to the above mentioned abnormalities in left ventricular function seen in dilated cardiomyopathy.
Left ventricular hypertrophy (LVH) is the major risk factor associated with myocardial failure. An explanation for why a presumptive adaptation such as LVH would prove pathological has been elusive. Insights into the impairment in contractility of the hypertrophied myocardium have been sought in the biochemistry of cardiac myocyte contraction. Equally compelling is a consideration of abnormalities in myocardial structure that impair organ contractile function while preserving myocyte contractility. For example, in the LVH that accompanies hypertension, the extracellular space is frequently the site of an abnormal accumulation of fibrillar collagen. This reactive and progressive interstitial and perivascular fibrosis accounts for abnormal myocardial stiffness and ultimately ventricular dysfunction and is likely a result of cardiac fibroblast growth and enhanced collagen synthesis. The disproportionate involvement of this nonmyocyte cell, however, is not a uniform accompaniment to myocyte hypertrophy and LVH, suggesting that the growth of myocyte and nonmyocyte cells is independent of each other. This has now been demonstrated in in vivo studies of experimental hypertension in which the abnormal fibrous tissue response was found in the hypertensive, hypertrophied left ventricle as well as in the normotensive, nonhypertrophied right ventricle. These findings further suggest that a circulating substance that gained access to the common coronary circulation of the ventricles was involved. This hypothesis has been tested in various animal models in which plasma concentrations of angiotensin II and aldosterone were varied. Based on morphometric and morphological findings, it can be concluded that arterial hypertension (i.e., an elevation in coronary perfusion pressure) together with elevated circulating aldosterone are associated with cardiac fibroblast involvement and the resultant heterogeneity in tissue structure. Nonmyocyte cells of the cardiac interstitium represent an important determinant of pathological LVH. The mechanisms that invoke short- (e.g., collagen metabolism) and long-term (e.g., mitosis) responses of cardiac fibroblasts require further investigation and integration of in vitro with in vivo studies. The stage is set, however, to prevent pathological LVH resulting from myocardial fibrosis as well as to reverse it.
Most research in the field of chronic heart failure during the last 20 years has been directed toward defining and understanding the abnormalities of systolic function seen in this disorder, but systolic performance is not a determinant of effort tolerance. Several lines of evidence, however, suggest a strong relation between exercise capacity and abnormalities of diastolic function in chronic heart failure. Of all the commonly measured hemodynamic variables, effort tolerance (whether limited by dyspnea or fatigue) varies more closely with the level of left ventricular filling pressure than the left ventricular ejection fraction. Consequently, drugs that lower ventricular filling pressures are more likely to enhance exercise capacity than drugs that primarily increase cardiac output and left ventricular ejection phase indexes. Vasodilator drugs do not reduce left ventricular filling pressure, however, by simply redistributing central blood volume to the peripheral capacitance circuits because these agents do not predictably decrease left ventricular volumes. Instead, clinically effective drugs seem to reduce left ventricular filling pressure primarily by producing a favorable shift in the left ventricular diastolic pressure-volume relation. Conversely, agents that adversely affect the diastolic pressure-volume relation frequently cause clinical deterioration. These findings suggest that abnormalities of diastolic rather than systolic performance may be the most important determinants of the clinical status and exercise intolerance of patients with chronic heart failure.
Invasive cardiopulmonary exercise testing was performed in 7 patients who presented with congestive heart failure, normal left ventricular ejection fraction and no significant coronary or valvular heart disease and in 10 age-matched normal subjects. Compared with the normal subjects, patients demonstrates severe exercise intolerance with a 48% reduction in peak oxygen consumption (11.6 +/- 4.0 versus 22.7 +/- 6.1 ml/kg per min; p less than 0.001), primarily due to a 41% reduction in peak cardiac index (4.2 +/- 1.4 versus 7.1 +/- 1.1 liters/min per m2; p less than 0.001). In patients compared with normal subjects, peak left ventricular stroke volume index (34 +/- 9 versus 46 +/- 7 ml/min per m2; p less than 0.01) and end-diastolic volume index (56 +/- 14 versus 68 +/- 12 ml/min per m2; p less than 0.08) were reduced, whereas peak ejection fraction and end-systolic volume index were not different. In patients, the change in end-diastolic volume index during exercise correlated strongly with the change in stroke volume index (r = 0.97; p less than 0.0001) and cardiac index (r = 0.80; p less than 0.03). Pulmonary wedge pressure was markedly increased at peak exercise in patients compared with normal subjects (25.7 +/- 9.1 versus 7.1 +/- 4.4 mm Hg; p less than 0.0001). Patients demonstrated a shift of the left ventricular end-diastolic pressure-volume relation upward and to the left at rest. Increases in left ventricular filling pressure during exercise were not accompanied by increases in end-diastolic volume, indicating a limitation to left ventricular filling.(ABSTRACT TRUNCATED AT 250 WORDS)
Left ventricular ejection fraction is normal at rest but may respond abnormally to exercise in many patients with essential hypertension. To assess the determinants of the abnormal ejection fraction response to exercise, we performed radionuclide angiography at rest and during exercise in 41 hypertensive patients without coronary artery disease. In 22 patients (group 1), the ejection fraction increased more than 5% during exercise; in the other 19 patients (group 2), the ejection fraction either increased by less than 5% or decreased with exercise. Left ventricular diastolic filling was impaired at rest in patients in group 2 compared with group 1, with reduced peak filling rate (2.5 +/- 0.4 vs. 3.1 +/- 0.7 end-diastolic volume/sec; p less than 0.01) and prolonged time to peak filling rate (175 +/- 28 vs. 153 +/- 22 msec; p less than 0.01). Impaired diastolic filling in group 2 was associated with less augmentation in end-diastolic volume during exercise compared with group 1 (p less than 0.01). These observations were not dependent on the threshold value that was arbitrarily chosen to define an abnormal ejection fraction response, as there were significant correlations for the entire group between the magnitude of change in ejection fraction with exercise and both the resting peak filling rate (r = 0.46) and the change in end-diastolic volume with exercise (r = 0.62).(ABSTRACT TRUNCATED AT 250 WORDS)
An abnormal elevation in collagen concentration or myocardial fibrosis occurs in the hypertrophied left ventricle of the rat with renovascular hypertension (RHT). The structural nature and functional consequences of this fibrosis and the mechanisms involved in its appearance were reviewed for various phases of hypertrophy. Within days after the onset of renal ischemia, type I collagen messenger ribonucleic acid is expressed. An interstitial fibrosis follows, characterized by an increased dimension of existing perimysial fibers and the appearance of fibrillar collagen in spaces previously devoid of collagen, together with a perivascular fibrosis of intramyocardial coronary arteries. These expressions of myocardial fibrosis are associated with an increase in diastolic and systolic myocardial stiffness. Endomyocardial fibrosis serves to further increase diastolic stiffness while myocytes encircled by fibrillar collagen become atrophic. Each of these consequences of myocardial fibrosis reduce myocyte length-dependent force generation. At 32 weeks of RHT there is an obvious diastolic and systolic dysfunction of the ventricle together with heart failure that includes ventricular dilatation, wall thinning and reduced ejection fraction. The mechanisms involved in mediating fibrosis in RHT appear to be multiple. Myocyte necrosis and fibroblast proliferation have been associated with elevated circulating angiotensin II. Necrosis in RHT was not seen with captopril pretreatment or in the hypertension and hypertrophy that accompanied infrarenal aorta banding. An alteration in coronary artery permeability may be responsible for the perivascular fibrosis that is not seen with captopril pretreatment. Thus in RHT, the hemodynamic status of the ventricle determines myocyte hypertrophy while the elevation in circulating angiotensin II is responsible for the remodeling of nonmyocyte compartments, including the appearance of myocardial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Normal left ventricular systolic performance with impaired left ventricular diastolic filling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 +/- 5 years) with CHF, intact left ventricular function (ejection fraction greater than 45%) and abnormal diastolic filling (peak filling rate less than 2.5 end-diastolic volumes per second [edv/s]) were studied in a placebo-controlled, double-blind 5-week crossover trial. All patients underwent echocardiography to rule out significant valvular disease, and thallium-201 stress scintigraphy to exclude major active ischemia. Compared to baseline values, verapamil significantly improved exercise capacity by 33% (13.9 +/- 4.3 vs 10.7 +/- 3.4 minutes at baseline) and peak filling rate by 30% (2.29 +/- 0.54 vs 1.85 +/- 0.45 edv/s at baseline) (all p less than 0.05). Placebo values were 12.3 +/- 4.0 minutes and 2.16 +/- 0.48 edv/s, respectively (difference not significant for both). Improvement from baseline in an objective clinico-radiographic heart failure score (scale 0 to 13) was significantly greater with verapamil compared to placebo (median improvement in score: 3 vs 1, p less than 0.01). Mean ejection fraction and systolic blood pressure were unchanged from baseline; diastolic blood pressure and heart rate decreased to a small degree. Verapamil may have therapeutic efficacy in patients with CHF, preserved systolic function and impaired diastolic filling.
This study tested the hypothesis that with hypertrophy, the proportion, distribution, and structural alignment of fibrillar collagen are important determinants of myocardial stiffness. Toward this end, the collagen volume fraction (morphometry), the transmural or subendocardial distribution of collagen, and the structural arrangement of fibrillar collagens (picrosirius red) were examined in the hypertrophied ventricle secondary to pressure overload (abdominal aorta banding or perinephritis), isoproterenol, and pressure overload plus isoproterenol. In the same hearts, the slopes of the systolic and diastolic stress-strain relations of the left ventricle, representing its active and passive stiffness, respectively, were obtained. In comparison with controls, we found 1) for a moderate rise in transmural collagen, active and passive stiffness increased with pressure-overload hypertrophy; 2) following isoproterenol alone there was a marked increase in subendocardial collagen, and active and passive stiffness increased; 3) in pressure-overload hypertrophy plus isoproterenol, active stiffness declined. Passive stiffness was increased except when fibrosis and thinning of the interventricular septum occurred, in which case it decreased; and 4) fibrillar collagens involved in remodeling included the formation of either collagen strands and fibers in a greater number of previously collagen-free intermuscular spaces in pressure-overload hypertrophy, or a dense crisscrossing latticework of fibers that encircled muscle fibers after isoproterenol. Thus, an increase in fibrillar collagen in pressure-overload hypertrophy is partially adaptive in that it enhances the tensile strength and three-dimensional delivery of force by the myocardium, but at the expense of reducing distensibility. The appearance of a dense collagen meshwork within the subendocardium after isoproterenol can be considered pathological in that it entraps muscle fibers causing active stiffness to fall while impairing distensibility. Finally, fibrosis may paradoxically reduce passive stiffness if it leads to a thinning of the interventricular septum.
Impaired left ventricular relaxation and filling is an important pathophysiologic mechanism in hypertrophic cardiomyopathy. To determine whether isoproterenol, known to improve relaxation in isolated cardiac muscle, could favorably modify this effect, we assessed simultaneous left ventricular volume and regional systolic asynchrony (by radionuclide angiography), left ventricular pressure (by micromanometer catheters), and lactate metabolism in 12 patients with hypertrophic cardiomyopathy. Pressure-volume relations were studied during atrial pacing stress to induce myocardial ischemia and during isoproterenol infusion to similar heart rates. Angina occurred in 10 patients with pacing and in 11 patients during isoproterenol infusion; lactate consumption was reduced in nine patients during isoproterenol compared with pacing, including five patients who produced lactate with isoproterenol. During isoproterenol compared with pacing, peak left ventricular pressure was higher (205 +/- 33 vs. 142 +/- 21 mm Hg, p less than 0.001), ejection fraction was higher (77 +/- 10% vs. 71 +/- 12%, p less than 0.02), and regional systolic nonuniformity was diminished. Despite ischemia, these changes in load and nonuniformity during isoproterenol were associated with enhanced diastolic function compared with pacing tachycardia: isoproterenol reduced T 1/2, the half-time of pressure decline after peak negative dP/dt (from 46 +/- 10 to 33 +/- 6 msec, p less than 0.001), shifted the diastolic pressure-volume curve downward and rightward in 10 of 12 patients, and increased end-diastolic volume (from 77 +/- 18% to 100 +/- 11% of control values, p less than 0.001) with no change in end-diastolic pressure (19 +/- 7 to 19 +/- 5 mm Hg, p = NS). Thus, despite ischemia, isoproterenol improved left ventricular relaxation and filling compared with tachycardia in the absence of beta-adrenergic stimulation. Although isoproterenol is detrimental in hypertrophic cardiomyopathy by provoking ischemia, these data suggest that the adverse effects of ischemia on ventricular relaxation and distensibility may be alleviated by beta-adrenergic stimulation, possibly as a result of enhanced inactivation and restored load sensitivity.
Composed of type I and III collagens, the valve leaflets, chordae tendineae and collagen matrix of the myocardium form a structural continuum. Synthesized by cardiac fibroblasts, these fibrillar collagens support and tether myocytes to maintain their alignment, whereas their respective tensile strength and resilience resist the deformation, maintain the shape and thickness, prevent the rupture and contribute to the passive and active stiffness of the myocardium. An acquired or congenital defect in this collagen network can lead to abnormalities in myocardial architecture, mechanics or valve function. In the hypertrophic process that accompanies a pressure overload, for example, increased collagen synthesis, fibroblast proliferation and a structural and biochemical remodeling of the matrix are seen. This includes distinctive patterns of reparative and reactive myocardial fibrosis, each of which alters diastolic and systolic myocardial stiffness and may lead to pathologic hypertrophy. Alternatively, a loss of collagen tethers or decline in matrix tensile strength can be responsible for regional or global transformations in myocardial architecture and function seen in the reperfused ("stunned") myocardium and in dilated (idiopathic) cardiopathy. Inherited disorders in the transcriptional and posttranslational processing of collagen can also alter the biophysical properties of the network. Future studies into collagen gene regulation, gene switching events and the control of collagen synthesis and degradation are needed to develop a more complete understanding of the relation between the collagen network and acquired and inherited forms of heart disease and to utilize therapeutics that will prevent, retard or regress abnormal collagen matrix remodeling.
We studied the influence of inotropic agents on prompt and transient left ventricular (LV) diastolic relaxation dysfunction produced by superimposition of pacing tachycardia on low-flow ischemia, using an isolated, blood-perfused and isovolumic (balloon-in-LV) rabbit heart preparation. The LV balloon volume was adjusted to produce an LV end-diastolic pressure (EDP) of 15 mmHg and was held constant thereafter. Coronary perfusion pressure was adjusted to 100 mmHg during baseline and to 20 mmHg during low-flow ischemia of 6 min. At baseline, isoproterenol and ouabain were administered to cause moderate and similar rises (14 +/- 3 and 16 +/- 4% above baseline values, respectively) in maximum + dp/dt of LVP with no change in LVEDP. In control hearts which received no drug, superimposition of 5-min pacing tachycardia on low-flow ischemia produced a significant and transient increase in LVEDP under constant LV volume (from 13.4 +/- 0.4 to 24.7 +/- 3.3 mmHg, p less than 0.01). In the hearts which received isoproterenol it did not change LVEDP (from 14.0 +/- 0.4 to 16.2 +/- 1.0 mmHg, NS). In contrast, the ouabain hearts showed a further increase in LVEDP (from 13.7 +/- 0.8 to 29.9 +/- 4.6 mmHg, p less than 0.01). LV developed pressure, myocardial oxygen consumption or myocardial lactate production during pacing tachycardia superimposed on the low-flow ischemia did not differ significantly among the 3 groups. Thus, isoproterenol markedly improved transient LV relaxation dysfunction produced by superimposition of pacing tachycardia on low-flow ischemia, in which an equipotent inotropic dose of ouabain exaggerated the relaxation dysfunction. These results suggest that calcium overload rather than ATP depletion per se contributes to transiently impaired diastolic relaxation by pacing tachycardia and low-flow ischemia.
Although both dopamine and dobutamine are potent positive inotropic agents, multiple studies indicate that dopamine may produce a rise in left ventricular (LV) filling pressure, while dobutamine often has the opposite effect. To ascertain the pharmacological and hemodynamic mechanisms responsible for the elevation in LV filling pressure observed with dopamine, we administered incremental infusions (2, 4, and 6 micrograms/kg/min) of dopamine to 18 open-chest, anesthetized dogs in the presence and absence of rauwolscine (selective alpha 2-adrenoceptor antagonist) (n = 7), terazosin (selective alpha 1-antagonist) (n = 6), and domperidone (selective dopamine2 antagonist) (n = 5), while measuring pressures in the LV and left atrium and changes in dimension in the LV short-axis (with ultrasonic piezo crystals). Dobutamine (2, 4, and 6 micrograms/kg/min) was infused in five additional dogs before and after administration of rauwolscine. The time constant of isovolumic pressure decay, peak lengthening rate (mm/sec), LV end-diastolic pressure, and diastolic pressure-dimension relation were computed. A significant elevation in LV end-diastolic pressure and a parallel increase in LV end-diastolic chamber size was observed with dopamine, while a decline in LV end-diastolic pressure occurred with dobutamine. Yet both dopamine and dobutamine caused a dose-related acceleration of pressure decay and augmentation of peak lengthening rate. Furthermore, heart rate declined during the administration of dopamine but rose with dobutamine. In the presence of either rauwolscine or terazosin, dopamine infusion resulted in a positive chronotropic effect and dose-dependent reductions in LV end-diastolic pressure and end-diastolic chamber dimension; arterial pressure fell only after terazosin administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Myocardial ischemia causes both systolic and diastolic dysfunction. A variety of positive inotropic agents with different subcellular mechanisms may be used clinically in an attempt to reverse ischemic contractile failure. We tested the hypothesis that two inotropic agents, isoproterenol (a beta-adrenergic agonist) and ouabain (a sodium pump inhibitor), might have different effects on left ventricular (LV) diastolic function during ischemic failure despite an equivalent inotropic effect. Isolated isovolumic (balloon-in-LV) blood perfused rabbit hearts were paced at constant physiological heart rate (4 Hz), given either no drug (controls, n = 7), isoproterenol (n = 7), or ouabain (n = 7), and then subjected to 6 minutes of low flow ischemia (75% reduction of baseline coronary flow). The doses of isoproterenol and ouabain were selected to produce equivalent modest inotropic effects (15% increase in LV + dP/dt) in each heart during baseline perfusion conditions. During the ischemic period, there was a marked decrease in contractility, and neither isoproterenol nor ouabain demonstrated a positive inotropic effect relative to the control group. However, these agents had markedly different effects on diastolic chamber distensibility (assessed by end-diastolic pressure at constant LV volume) during ischemia. In the control and isoproterenol groups, diastolic chamber distensibility did not change during the ischemic period. In contrast, ouabain treatment resulted in a marked decrease in diastolic chamber distensibility during ischemia; this change was not completely reversible during the 10-minute reperfusion period. The mechanism by which ouabain decreased diastolic chamber distensibility relative to isoproterenol was assessed indirectly. The ouabain and isoproterenol groups were subjected to equivalent degrees of ischemia as assessed by oxygen supply/demand imbalance; during ischemia, each drug group did not differ with regard to myocardial perfusion rates, determinants of myocardial oxygen demand (heart rate, LV developed pressure, LV + dP/dt), myocardial oxygen consumption, lactate production, and ATP and creatine phosphate content. We therefore inferred that the greater decrease in diastolic distensibility in the ouabain group was not due to a greater metabolic severity of ischemia. These observations are consistent with a mechanism of cytosolic calcium overload induced by ouabain, resulting in persistent active myofilament tension development throughout diastole, to cause the observed decrease in diastolic chamber distensibility during ischemia in the ouabain group.(ABSTRACT TRUNCATED AT 400 WORDS)
Verapamil improves exercise tolerance and decreases symptoms in many patients with hypertrophic cardiomyopathy. The mechanisms responsible for these effects are not completely understood, although previous studies indicate that verapamil enhances left ventricular relaxation and diastolic filling in such patients. To investigate the association between changes in left ventricular filling and exercise tolerance after verapamil, we studied 55 patients with hypertrophic cardiomyopathy by radionuclide angiography and graded treadmill testing before and after 1 to 4 weeks of therapy with orally administered verapamil, 320 to 640 mg/d. The verapamil-induced increase in peak left ventricular filling rate at rest (from 3.1 +/- 1.3 to 3.7 +/- 1.3 end-diastolic volumes/sec; p less than .001) was associated with an increase in exercise tolerance (from 5.9 +/- 3.6 to 8.7 +/- 4.7 min; p less than .001); exercise capacity increased in 34 of 43 patients (79%) manifesting an increase in peak filling rate but only one of 12 patients (8%) with unchanged or decreased peak filling rate (p less than .001). This initial trend persisted in 25 patients studied after 1 year of therapy; 11 of 16 patients (69%) with a persistent increase in peak filling rate had persistent improvement in exercise tolerance relative to preverapamil values, compared with only one of nine patients (11%) in whom peak filling rate was unchanged or decreased relative to preverapamil levels (p less than .02). Verapamil withdrawal after 1 to 2 years in 24 patients resulted in reduction in peak filling rate (p less than .001) and was associated with deterioration in exercise tolerance in 17 patients (71%). Hence, verapamil-induced changes in left ventricular peak filling rate were associated significantly with objective symptomatic improvement. These data support the concept that enhanced left ventricular diastolic filling is an important mechanism contributing to the clinical improvement experienced by many patients with hypertrophic cardiomyopathy during therapy with verapamil.
To elucidate the mechanisms by which the new bipyridine inotropic agent milrinone improves cardiac function, we examined multiple indexes of left ventricular diastolic function before and after administration of milrinone to patients with advanced (NYHA class III or IV) congestive heart failure. In 13 patients left ventricular pressure measurements were made with a micromanometer to permit assessment of peak negative dP/dt and the time constant of left ventricular isovolumic relaxation, T, before and after milrinone. In nine patients radionuclide ventriculographic studies were performed during left heart catheterization, allowing calculation of left ventricular peak filling rate, volumes, and the diastolic pressure-volume relationship before and after milrinone. After intravenous administration of milrinone, peak negative dP/dt increased (+ 18%; p less than .01) and T decreased (-30%; p less than .01), while heart rate increased by only 8% (87 +/- 12 to 94 +/- 15 beats/min; p less than .01), left ventricular systolic pressure did not change, and mean aortic pressure fell by 11% (p less than .01). Left ventricular peak filling rate increased (1.2 +/- 0.6 to 1.7 +/- 0.7 end-diastolic volumes/sec; p less than or equal to .02) despite a decrease in left ventricular filling pressure (mean pulmonary wedge pressure 27 +/- 7 to 18 +/- 9 mm Hg; p less than .01). There was a fall in left ventricular end-diastolic pressure (28.6 +/- 6 to 19 +/- 7 mm Hg; p less than or equal to .01), with no significant change in left ventricular end-diastolic volume. This was associated with a downward shift in the left ventricular diastolic pressure-volume relationship in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)
Scanning electron microscopy demonstrates an extensive and highly organized network of collagen in the left ventricle of all species examined. This system is arbitrarily divisible into three major components: a collagen weave network that surrounds groups of myocytes; an extensive array of collagen struts measuring 120 to 150 nm in diameter that extend from the basal lamina of a myocyte to the basal laminae of all contiguous myocytes; and an array of similar sized collagen struts that extend from the basal lamina of all capillaries to the basal laminae of all contiguous myocytes. The functions of the individual components of this complicated network are not well-defined. The weave network certainly contributes to the viscous and elastic properties of the heart. Myocyte-to-myocyte struts can prevent slippage of adjacent cells during the cardiac cycle and would ensure equal stretch of adjacent myocytes during diastole. Myocyte to capillary struts may be important in maintaining capillary patency during the early phases of systole. In rats. rabbits and hamsters this entire system is virtually absent at birth and develops rapidly to the adult form by 15 days.
The role of K+ channels and intracellular [Ca2+] in flow-induced nitric oxide (NO) production was investigated in bovine aortic endothelial cells in culture. NO release (measured as nitrite production) and K+ channel activity (measured as 86Rb+ efflux) were measured in cells grown on collagen-coated microcarrier beads and perfused in a column. An eightfold increase in flow produced a rapid (within 1 min), sustained, and reversible sixfold increase in NO release. Efflux of 86Rb+ also increased but rapidly returned to baseline and then transiently decreased when flow was decreased. This was probably due to boundary layer washout rather than to K+ channel activation, because an identical pattern was seen for release of [3H]ouabain. Neither tetraethylammonium nor increasing medium [K+] to block K+ currents prevented flow-induced NO release. Removal of medium Ca2+ or chelation of intracellular Ca2+ also did not block flow-mediated NO release. The results demonstrate that flow rapidly increases NO release from endothelial cells but that this increase in NO release is not dependent on activation of K+ channels or changes in intracellular [Ca2+].
The fibrillar collagen network is postulated to be a primary determinant of left ventricular diastolic stiffness. This hypothesis was tested by examining the structural and physiological effects of a reduction in fibrillar collagen content and cross-linking in the intact left ventricle. Collagen cross-linking was inhibited by treating five normal adult pigs with beta-aminopropionitrile (BAPN; 10 g/day po) for 6 wk; five normal untreated pigs served as controls. Left ventricular volume, mass, and function were determined by simultaneous echocardiography and catheterization. Chamber stiffness, defined by pressure vs. volume data, and myocardial stiffness, defined by stress vs. dimension data, were determined from variably loaded beats during dextran infusion. Collagen distribution (% area) and integrity (% confluence) were determined by light microscopy. Collagen content was measured by hydroxyproline assay, and collagen cross-linking was measured by salt extraction. BAPN decreased collagen distribution (% area decreased from 12 +/- 1% in control to 7 +/- 1% in BAPN, P < 0.05), collagen integrity (% confluence decreased from 8 +/- 1% in control to 4 +/- 1% in BAPN, P < 0.05), collagen content (from 36 +/- 2 mg/g dry wt in control to 27 +/- 2 mg/g dry wt in BAPN, P < 0.05), and collagen cross-linking (extractable collagen increased from 21 +/- 2% in control to 28 +/- 2% in BAPN, P < 0.05). BAPN decreased chamber stiffness (0.13 +/- 0.02 in control to 0.06 +/- 0.01 in BAPN, P < 0.05) and myocardial stiffness (10.4 +/- 0.5 in control to 6.6 +/- 0.5 in BAPN, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
The remodeling of the left ventricle in patients with aortic stenosis after aortic valve replacement (AVR) is a complex process involving structural and functional changes.
Twenty-two patients were included in the present analysis. Twelve patients with severe aortic stenosis were studied before surgery, early (22 +/- 8 months) and late (81 +/- 22 months) after AVR using left ventricular biplane angiograms, high-fidelity pressure measurements, and endomyocardial biopsies. Ten healthy subjects were used as controls. Left ventricular systolic function was assessed from biplane ejection fraction; and diastolic function from the time constant of relaxation, the peak filling rate, and the myocardial stiffness constant. Left ventricular structure was evaluated from interstitial fibrosis, fibrous content, and muscle fiber diameter. Left ventricular muscle mass was significantly increased before surgery in patients with aortic stenosis and remained increased early after surgery, although there was a 35% decrease. Late after AVR, muscle mass decreased significantly but remained slightly (P = NS) elevated. Left ventricular ejection fraction increased slightly after AVR. Left ventricular relaxation was significantly prolonged before surgery and returned toward normal early and late after AVR. Peak filling rates remained unchanged before and after surgery. Myocardial stiffness constant was increased before surgery in patients with aortic stenosis compared with controls and increased even further early after AVR but was normalized late after surgery. Muscle fiber diameter was elevated in patients with aortic stenosis before and after surgery compared with controls; however, it decreased significantly early and late after AVR with respect to preoperative data but remained hypertrophied even late after surgery. Interstitial fibrosis and fibrous contents were larger before surgery than in control subjects and increased even more early but decreased significantly late after AVR.
Diastolic stiffness increases in aortic stenosis early after AVR parallel to the increase in interstitial fibrosis, whereas relaxation rate decreases with a reduction in left ventricular muscle mass. Late after AVR, both diastolic stiffness and relaxation are normalized due to the regression of both muscular and nonmuscular tissue. Thus, reversal of diastolic dysfunction in aortic stenosis takes years and is accompanied by a slow regression of interstitial fibrosis.
In hypertension, the risk of adverse cardiovascular events, including heart failure, is increased in the presence of left ventricular hypertrophy. Morphological studies suggest that it is not the quantity but rather the quality, or structure, of myocardium that confers such risk. Iterations in tissue structure that appear in hypertensive heart disease include a remodeling of intramyocardial coronary arterioles, similar to that found in systemic organs, and a disproportionate accumulation of fibrillar collagen within their adventitia and neighboring interstitial space. Microscopic scars replacing necrotic cardiac myocytes are also evident. These expressions of fibrosis appear in the normotensive, nonhypertrophied right and hypertensive, hypertrophied left ventricles and are linked to the renin-angiotensin-aldosterone system. Cardiac myocyte growth, the major determinant of myocardial mass, is related to ventricular loading. Mechanisms responsible for the reactive and reparative fibrosis with renin-angiotensin-aldosterone system activation are under investigation. In vitro quantitative autoradiography has identified angiotensin II, aldosterone, endothelin, and bradykinin receptors in the myocardium. A nonendothelial tissue angiotensin-converting enzyme, whose binding density is marked in the matrix of heart valves, adventitia, and sites of fibrosis, irrespective of its pathogenic basis, has also been found. This angiotensin-converting enzyme may be responsible for regulating local concentrations of angiotensin II and bradykinin that govern fibroblast collagen turnover. Based on a paradigm of discordant reciprocal regulation, in which a relative abundance of stimulators (eg, angiotensin II, aldosterone, and endothelins) of collagen synthesis exceeds inhibitors (eg, bradykinin, prostaglandins, and glucocorticoids), fibrous tissue appears.(ABSTRACT TRUNCATED AT 250 WORDS)
Experimental studies indicate that in addition to diastolic dysfunction, hypertrophied myocardium can display depressed contractile responses, particularly at rapid heart rates, compounding reserve limitations. This study tests whether such abnormalities exist in intact human subjects at physiological paced rates and, if so, whether they are linked to simultaneous rate-dependent deterioration in diastolic function.
Ten subjects with left ventricular hypertrophy (LVH) and 8 normal control subjects were studied. Most LVH patients presented with dyspnea and/or pulmonary edema and had concentric hypertrophy. Since rapid pacing simultaneously alters cardiac filling volumes and pressures, pressure-volume relation analysis was used to better define changes in contractile response. Patients were instrumented with a conductance catheter and micromanometer for pressure-volume data recording and a balloon occluder at the right atrial-inferior vena caval junction to vary filling and thus generate function relations. Data were obtained at baseline and at three atrial pacing rates (100, 120, 150 min-1). In addition, single-beat force-interval data were used to indirectly examine calcium cycling kinetics. LVH subjects demonstrated baseline diastolic abnormalities, including prolonged relaxation, elevated end-diastolic pressure, and reduced chamber compliance. However, systolic function was similar to that in control subjects. With rapid pacing, normal subjects displayed a positive contractile response, whereas this was markedly diminished in LVH subjects. With abrupt termination of pacing and return to slower sinus rhythm, LVH subjects displayed greater initial potentiation followed by a more rapid decline than control subjects, suggesting abnormalities of calcium handling. Despite contractile abnormalities, diastolic function did not further deteriorate with rapid pacing and thus did not appear to be tightly linked to the systolic changes.
Pacing stress in intact human LVH can result in systolic impairment superimposed on preexisting but not worsened diastolic dysfunction. Abnormal calcium handling probably contributes prominently to this response.
We have shown that the cellular contractile dysfunction characteristic of pressure-overload cardiac hypertrophy results not from an abnormality intrinsic to the myofilament portion of the cardiocyte cytoskeleton but rather from an increased density of the microtubule component of the extramyofilament portion of the cardiocyte cytoskeleton. To determine how, in physical terms, this increased microtubule density mechanically overloads the contractile apparatus at the cellular level, we measured cytoskeletal stiffness and apparent viscosity in isolated cardiocytes via magnetic twisting cytometry, a technique by which magnetically induced force is applied directly to the cytoskeleton through integrin-coupled ferromagnetic beads coated with Arg-Gly-Asp (RGD) peptide. Measurements were made in two groups of cardiocytes from cats with right ventricular (RV) hypertrophy induced by pulmonary artery banding: (1) those from the pressure-overloaded RV and (2) those from the normally loaded same-animal control left ventricle (LV). Cytoskeletal stiffness increased almost twofold, from 8.53 +/- 0.77 dyne/cm2 in the normally loaded LV cardiocytes to 16.46 +/- 1.32 dyne/cm2 in the hypertrophied RV cardiocytes. Cytoskeletal apparent viscosity increased almost fourfold, from 20.97 +/- 1.92 poise in the normally loaded LV cardiocytes to 87.85 +/- 6.95 poise in the hypertrophied RV cardiocytes. In addition to these baseline data showing differing stiffness and, especially, apparent viscosity in the two groups of cardiocytes, microtubule depolymerization by colchicine was found to return both the stiffness and the apparent viscosity of the pressure overload-hypertrophied RV cells fully to normal. Conversely, microtubule hyperpolymerization by taxol increased the stiffness and apparent viscosity values of normally loaded LV cardiocytes to the abnormal values given above for pressure-hypertrophied RV cardiocytes. Thus, increased microtubule density constitutes primarily a viscous load on the cardiocyte contractile apparatus in pressure-overload cardiac hypertrophy.
Mechanisms in addition to diastolic calcium overload may contribute to diastolic dysfunction in hypertrophied hearts. In this study, we tested the hypothesis that failure to maintain a low ADP concentration in hypertrophied hearts contributes to diastolic dysfunction by inhibiting the rate of cross-bridge cycling.
By perfusing isolated rat hearts with pyruvate and 2-deoxyglucose (2DG), we were able to perturb [ADP] with minimal changes in [ATP] and [inorganic phosphate] or the contribution of glycolytic ATP to ATP synthesis. The effects of 2DG were compared in aortic-banded (LVH, n=5) and sham-operated (control, n=5) rat hearts. 31P NMR spectroscopy was used to measure the concentrations of phosphorus-containing compounds. We found a threefold increase of left ventricular end-diastolic pressure (LVEDP) in LVH during 2DG perfusion, and this increase was concomitant with a threefold increase in intracellular free [ADP]. The [ADP] in the control hearts was maintained <40 micromol/L, and no change in LVEDP was observed. A linear relationship between increases in [ADP] and LVEDP was found (r2=.66, P=.001). Furthermore, the capacity of the creatine kinase reaction, a major mechanism for maintaining a low [ADP], was decreased in LVH (P=.0001).
Increased [ADP] contributes to diastolic dysfunction in LVH, possibly due to slowed cross-bridge cycling. Decreased capacity of the creatine kinase reaction to rephosphorylate ADP is a likely contributing mechanism to the failure to maintain a low [ADP] in LVH.
Endocardial endothelium and vascular endothelium of myocardial capillaries share common features as modulators of cardiac performance, rhythmicity and growth. Growing evidence suggests differences between these two cardiac endothelial cell types with regard to developmental, morphological and functional properties. A major difference probably resides in the way and extent by which these endothelial cells perceive and transmit signals.
The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction.
Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (sigma), and resultant changes in cell strain (epsilon) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the sigma on the agarose gel at a constant rate to define the cardiocyte sigma-versus-epsilon relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte sigma-versus-epsilon relationship during an increase and then a decrease in sigma. In both protocols, myofilament activation was minimized by a reduction in [Ca2+]i. Myofilament activation effects were assessed in protocol C by defining cardiocyte sigma versus epsilon during an increase in sigma with physiological [Ca2+]i. In protocol A, the cardiocyte sigma-versus-epsilon relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the sigma-versus-epsilon relation in hypertrophied cardiocytes was shifted to the left compared with normal cells.
Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction.
Diastolic dysfunction is an important cause of congestive heart failure; however, the basic mechanisms causing diastolic congestive heart failure are not fully understood, especially the role of the cardiac muscle cell, or cardiocyte, in this process. Before the role of the cardiocyte in this pathophysiology can be defined, methods for measuring cardiocyte constitutive properties must be developed and validated. Thus this study was designed to evaluate a new method to characterize cardiocyte constitutive properties, the gel stretch method. Cardiocytes were isolated enzymatically from normal feline hearts and embedded in a 2% agarose gel containing HEPES-Krebs buffer and laminin. This gel was cast in a shape that allowed it to be placed in a stretching device. The ends of the gel were held between a movable roller and fixed plates that acted as mandibles. Distance between the right and left mandibles was increased using a stepper motor system. The force applied to the gel was measured by a force transducer. The resultant cardiocyte strain was determined by imaging the cells with a microscope, capturing the images with a CCD camera, and measuring cardiocyte and sarcomere length changes. Cardiocyte stress was characterized with a finite-element method. These measurements of cardiocyte stress and strain were used to determine cardiocyte stiffness. Two variables affecting cardiocyte stiffness were measured, the passive elastic spring and viscous damping. The passive spring was assessed by increasing the force on the gel at 1 g/min, modeling the resultant stress vs. strain relationship as an exponential [sigma = A/k(ekepsilon - 1)]. In normal cardiocytes, A = 23.0 kN/m2 and k = 16. Viscous damping was assessed by examining the loop area between the stress vs. strain relationship during 1 g/min increases and decreases in force. Normal cardiocytes had a finite loop area = 1.39 kN/m2, indicating the presence of viscous damping. Thus the gel stretch method provided accurate measurements of cardiocyte constitutive properties. These measurements have allowed the first quantitative assessment of passive elastic spring properties and viscous damping in normal mammalian cardiocytes.
The aim of the study was to test the hypothesis that angiotensin II (Ang II) blockade would improve exercise tolerance in patients with diastolic dysfunction and a marked increase in systolic blood pressure (SBP) during exercise.
Diastolic dysfunction may be exacerbated during exercise, especially if there is a marked increase in SBP. Angiotensin II may contribute to the hypertensive response to exercise and impair diastolic performance.
We performed a randomized, double-blind, placebo-controlled, crossover study of two weeks of losartan (50 mg q.d.) on exercise tolerance and quality of life. The subjects were 20 patients, mean age 64 +/- 10 years with normal left ventricular systolic function (EF >50%), no ischemia on stress echocardiogram, mitral flow velocity E/A <1, normal resting SBP (<150 mm Hg), and a hypertensive response to exercise (SBP >200 mm Hg). Exercise echocardiograms (Modified Bruce Protocol) and the Minnesota Living With Heart Failure questionnaire were administered at baseline, and after each two-week treatment period, separated by a two-week washout period.
Resting blood pressure (BP) was unaltered by placebo or losartan. During control, patients were able to exercise for 11.3 +/- 2.5 (mean +/- SD) min, with a peak exercise SBP of 226 +/- 24 mm Hg. After two weeks of losartan, baseline BP was unaltered, but peak SBP during exercise decreased to 193 +/- 27 mm Hg (p < 0.05 vs. baseline and placebo), and exercise time increased to 12.3 +/- 2.6 min (p < 0.05 vs. baseline and placebo). With placebo, there was no improvement in exercise duration (11.0 +/- 2.0 min) or peak exercise SBP (217 +/- 26 mm Hg). Quality of life improved with losartan (18 +/- 22, p < 0.05) compared to placebo (22 +/- 26).
In patients with Doppler evidence of diastolic dysfunction at rest and a hypertensive response to exercise, Ang II receptor blockade blunts the hypertensive response to exercise, increases exercise tolerance and improves quality of life.
The development of congestive heart failure (CHF) is associated with left ventricle (LV) dilation and myocardial remodeling. The matrix metalloproteinases (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. Whether increased MMP activity directly contributes to the LV remodeling with CHF remains unknown. Accordingly, this study examined the effects of chronic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (n=12); (2) CHF/MMPi, rapid pacing and concomitant MMPi (PD166793, 20 mg/kg per day [n=10]), and (3) control (n=11). With pacing CHF, LV fractional shortening was reduced (19+/-1 versus 45+/-1%), and end-diastolic dimension increased (5.67+/-0.11 versus 3.55+/-0.05 cm), compared with baseline values (P<0.05). In the CHF/MMPi group, LV endocardial shortening increased (25+/-2%) and the end-diastolic dimension was reduced (4.92+/-0.17 cm) compared with CHF-only values (P<0.05). LV midwall shortening was reduced to a comparable degree in the CHF-only and CHF/MMPi groups. LV peak wall stress increased 3-fold with pacing CHF compared with controls and was significantly reduced in the CHF/MMPi group. LV myocardial stiffness was unchanged with CHF but was increased in the CHF/MMPi group. LV myocyte length was increased with pacing CHF compared with controls (180+/-3 versus 125+/-4 microm, P<0.05) and was reduced in the CHF/MMPi group (169+/-4 microm, P<0.05). Basal-state myocyte shortening velocity was reduced with pacing CHF compared with controls (33+/-2 versus 66+/-1 microm/s, P<0.05) and was unchanged in the CHF/MMPi group (31+/-2 microm/s). Using an ex vivo assay system, myocardial MMP activity was increased with pacing CHF and was reduced with chronic MMPi. In summary, concomitant MMPi with developing CHF limited LV dilation and reduced wall stress. These results suggest that increased myocardial MMP activity contributes to LV myocardial remodeling in developing CHF.
Extension of the I-band segment of titin gives rise to part of the diastolic force of cardiac muscle. Previous studies of human cardiac titin transcripts suggested a series of differential splicing events in the I-band segment of titin leading to the so-called N2A and N2B isoform transcripts. Here we investigated titin expression at the protein level in a wide range of mammalian species. Results indicate that the myocardium coexpresses 2 distinct titin isoforms: a smaller isoform containing the N2B element only (N2B titin) and a larger isoform with both the N2B and N2A elements (N2BA titin). The expression ratio of large N2BA to small N2B titin isoforms was found to vary greatly in different species; eg, in the left ventricle the ratio is approximately 0.05 in mouse and approximately 1.5 in pig. Differences in the expression ratio were also found between atria and ventricles and between different layers of the ventricular wall. Immunofluorescence experiments with isoform-specific antibodies suggest that coexpression of these isoforms takes place at the single-myocyte level. The diastolic properties of single cardiac myocytes isolated from various species expressing high levels of the small (rat and mouse) or large (pig) titin isoform were studied. On average, pig myocytes are significantly less stiff than mouse and rat myocytes. Gel analysis indicates that this result cannot be explained by varying amounts of titin in mouse and pig myocardium. Rather, low stiffness of pig myocytes can be explained by its high expression level of the large isoform: the longer extensible region of this isoform results in a lower fractional extension for a given sarcomere length and hence a lower force. Implications of our findings to cardiac function are discussed.
Left ventricular (LV) pressure (PO) or volume (VO) overload is accompanied by myocardial remodeling, but mechanisms that contribute to this progressive remodeling process remain unclear. The matrix metalloproteinases (MMPs) contribute to tissue remodeling in a number of disease states. This study tested the hypothesis that increased MMP expression and activity occur after the induction of an LV overload, which is accompanied by a loss of endogenous MMP inhibitory control. LV MMP zymographic activity and species abundance were measured in dogs under the following conditions: acute PO induced by ascending aortic balloon inflation (6 h, n = 9), prolonged PO by aortic banding (10 days, n = 5), acute VO through mitral regurgitation secondary to chordal rupture (6 h, n = 6), prolonged VO due to mitral regurgitation (14 days, n = 7), and sham controls (n = 11). MMP zymographic activity in the 92-kDa region, indicative of MMP-9 activity, increased over threefold in acute PO and VO and fell to control levels in prolonged PO and VO. The MMP-9 activity-to-abundance ratio increased by over fourfold with acute VO and twofold in acute PO, suggesting a loss of inhibitory control. Endogenous MMP inhibitor content was unchanged with either PO or VO. Interstitial collagenase (MMP-1) content decreased by 50% with acute VO but not with acute PO. Stromelysin (MMP-3) levels increased by 40% with acute VO and increased by 80% with prolonged PO. Although changes in LV myocardial MMP activity and inhibitory control occurred in both acute and prolonged PO and VO states, these changes were not identical. These results suggest that the type of overload stimulus may selectively influence myocardial MMP activity and expression, which in turn would affect the overall LV myocardial remodeling process in LV overload.
A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.
In cardiomyocytes, generation of restoring forces (RFs) responsible for elastic recoil involves deformation of the sarcomeric protein titin in conjunction with shortening below slack length. At the left ventricular (LV) level, recoil and filling by suction require contraction to an end-systolic volume (ESV) below equilibrium volume (Veq) as well as large-scale deformations, for example, torsion or twist. Little is known about RFs and suction in the failing ventricle. We undertook a comparison of determinants of suction in open-chest dogs previously subjected to 2 weeks of pacing tachycardia (PT) and controls. To assess the ability of the LV to contract below Veq, we used a servomotor to clamp left atrial pressure and produce nonfilling diastoles, allowing measurement of fully relaxed pressure at varying volumes. We quantified twist with sonomicrometry. We also assessed transmural ratios of N2B to N2BA titin isoforms and total titin to myosin heavy chain (MHC) protein. In PT, the LV did not contract below Veq, even with marked reduction of volume (end-diastolic pressure [EDP], 1 to 2 mm Hg), whereas in controls ESV was less than Veq when EDP was less than approximately 5 mm Hg. In PT, both systolic twist and diastolic untwisting rate were reduced, and there was exaggerated transmural variation in titin isoform and titin-to-MHC ratios, consistent with the more extensible N2BA being present in larger amounts in the subendocardium. Thus, in PT, determinants of suction at the level of the LV are markedly impaired. The altered transmural titin isoform gradient is consistent with a decrease in RFs and may contribute to these findings.
In arterial hypertension, left ventricular hypertrophy (LVH) includes myocyte hypertrophy and fibrosis, which leads to LV diastolic dysfunction and, finally, heart failure. In spontaneously hypertensive rats, myocardial fibrosis was regressed and LV diastolic function was improved by treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether this holds true for patients with hypertensive heart disease was addressed in this prospective, randomized, double-blind trial.
A total of 35 patients with primary hypertension, LVH, and LV diastolic dysfunction were treated with either lisinopril (n=18) or hydrochlorothiazide (HCTZ; n=17). At baseline and after 6 months, LV catheterization with endomyocardial biopsy, Doppler echocardiography with measurements of LV peak flow velocities during early filling and atrial contraction and isovolumic relaxation time, and 24-hour blood pressure monitoring were performed. Myocardial fibrosis was measured by LV collagen volume fraction and myocardial hydroxyproline concentration. With lisinopril, collagen volume fraction decreased from 6.9+/-0.6% to 6. 3+/-0.6% (P:<0.05 versus HCTZ) and myocardial hydroxyproline concentration from 9.9+/-0.3 to 8.3+/-0.4 microg/mg of LV dry weight (P:<0.00001 versus HCTZ); this was associated with an increase in the early filling and atrial contraction LV peak flow velocity ratio from 0.72+/-0.04 to 0.91+/-0.06 (P:<0.05 versus HCTZ) and a decrease in isovolumic relaxation time from 123+/-9 to 81+/-5 ms (P:<0.00002 versus HCTZ). Normalized blood pressure did not significantly change in either group. No LVH regression occurred in lisinopril-treated patients, whereas with HCTZ, myocyte diameter was reduced from 22. 1+/-0.6 to 20.7+/-0.7 microm (P:<0.01 versus lisinopril).
In patients with hypertensive heart disease, angiotensin-converting enzyme inhibition with lisinopril can regress myocardial fibrosis, irrespective of LVH regression, and it is accompanied by improved LV diastolic function.
The most frequent hospital diagnosis-related group is congestive heart failure (CHF). CHF increases dramatically with age, making it an important problem in our aging population. CHF is caused by a primary abnormality in diastolic function (diastolic heart failure [DHF]) in 50% of patients with CHF who are > 70 years of age. Mortality rates in patients with DHF are comparable to those of patients with systolic heart failure, approaching 50% over 5 years. Successful therapy of DHF requires making a correct diagnosis, identifying the underlying cause, and applying specific and individualized treatment.
Extracellular matrix provides a structural, chemical, and mechanical substrate that is essential in cardiac development, growth, and responses to pathophysiological signals. Transmembrane receptors termed integrins provide a dynamic interaction of environmental cues and intracellular events. Integrins orchestrate multiple functions in the intact organism including organogenesis, regulation of gene expression, cell proliferation, differentiation, migration, and death. They are expressed in all cellular components of the cardiovascular system, including the vasculature, blood, cardiac myocytes and nonmuscle cardiac cells. The focus of this review will be on the role of integrins in the myocardium. We will provide background on integrin structure and function, discuss how the expression of integrins is critical to the form and function of the developing and postnatal myocardium, and review the known data on integrins as signaling molecules in the heart. Finally, we will offer insights to the future research directions into this important family of extracellular matrix receptors in the myocardium.
beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.
Modulation by NO of systolic myocardial function received widespread attention but most studies focused on potential negative inotropic properties of NO. The very original observations on the effects of NO on myocardial contraction already provided evidence that NO modified myocardial contractile performance mainly through a relaxation-hastening effect (i.e. earlier onset of relaxation) and through an increase in myocardial distensibility. The present review discusses the relaxation hastening and distensibility-increasing effects of NO in experimental preparations, in the normal human heart, in left ventricular hypertrophy of aortic stenosis, in the human allograft and in dilated nonischemic cardiomyopathy. This 'diastolic flip side' of the myocardial effects of NO appears to be beneficial especially for patients who are dependent on the LV Frank-Starling response to maintain cardiac output.
Tachycardia accompanying exercise shortens the duration of diastole, reducing the time available for the left ventricular (LV) filling. Thus, the LV must fill more rapidly for the stroke volume to increase (or even be maintained) during exercise. Normally, this is accomplished without requiring an excessive increase in left atrial (LA) pressure by an acceleration of LV relaxation and a fall in LV early diastolic pressure during exercise. This response is lost following the development of heart failure due to systolic dysfunction, both in experimental animals and in patients. In fact, in such situations, LV relaxation slows and LV early diastolic pressure increases due to exercise. Thus, any diastolic dysfunction present at rest in CHF during systolic dysfunction is exacerbated during exercise. Similarly, patients with primary diastolic dysfunction heart failure with preserved systolic function may not be able to augment LV filling rates without an abnormal increase in LA pressure. Thus, diastolic dysfunction may contribute to exercise intolerance, both in systolic dysfunction and primary diastolic dysfunction. Acute studies suggest that treatment with angiotensin II receptor blockers or verapamil may improve exercise tolerance in some patients with primary diastolic dysfunction.
The Frank-Starling mechanism, by which load directly regulates muscle length and thus performance is the means by which the mechanics and energetics of cardiac muscle are regulated on a beat-to-beat basis. When this short-term compensation for increased load is insufficient, the long-term compensation of cardiac hypertrophy ensues. The simplest and most direct mechanism for load regulation of cardiac mass would obtain if an analog of the short-term Frank-Starling mechanism of functional regulation operated in the long-term time domain of mass regulation; that is, if heart muscle were able to directly transduce increased load into growth. It is now clear that load does indeed serve as a direct regulator of cardiac mass in the adult. Cardiac hypertrophy, at the levels of intact animal, isolated tissue, and cultured cells, is a direct response of the adult mammalian cardiocyte to increased load, modified by but without the requisite involvement of factors external to the cell. The extent to which such hypertrophy is compensatory is critically dependent on the type of hemodynamic overload that serves as the hypertrophic stimulus. Thus, cardiac hypertrophy is not intrinsically maladaptive; rather, it is the nature of the inducing load rather than hypertrophy itself that is responsible for the frequent deterioration of initially compensatory hypertrophy into the congestive heart failure state. As one example reviewed here of this load specificity of maladaptation, increased microtubule network density is a persistent feature of severely pressure overloaded, hypertrophied and failing myocardium which imposes a viscous load on active myofilaments during contraction.
The cytoskeleton and related proteins in the human failure heart Paulus WJ Beneficial effects of nitric oxide on cardiac diastolic function: "the flip side of the coin
- S Kostin
- S Hein
- E Arnon
Kostin S, Hein S, Arnon E, et al. The cytoskeleton and related proteins in the human failure heart. Heart Failure Rev. 2000;5:271–280. 9. Paulus WJ. Beneficial effects of nitric oxide on cardiac diastolic function: "the flip side of the coin." Heart Failure Rev. 2000;5:337–344.