Figure 1- - available via license: Creative Commons Attribution-NonCommercial 3.0 Unported
Content may be subject to copyright.
ACE inhibitors prevent cardiac dilation and beta-blockers reverse it. Coh JN et al JACC 2000; 35: 569-82.
Source publication
In heart failure syndrome, myocardial dysfunction causes an increase in neurohormonal
activity, which is an adaptive and compensatory mechanism in response to the
reduction in cardiac output. Neurohormonal activity is initially stimulated in an
attempt to maintain compensation; however, when it remains increased, it contributes
to the intensificati...
Context in source publication
Context 1
... adrenergic activity appears to have a greater role in ventricular remodeling. Studies have demonstrated that beta-blockers promoted a more intense reversal of cardiac dilation than ACE inhibitors (Figure 1). ACE inhibitors prevent ventricular dilation and promote small increases in ejection ...
Similar publications
Obesity and hypertension independently promote pathological left ventricular remodelling (LVR) and left ventricular hypertrophy (LVH), but to what extent they do so when they do not coexist is unclear. We used data from the Cardiovision Brno 2030 study to assess—for the first time in a region where no investigations have been previously carried out...
Intramyocardial dissecting hematoma is an under-recognized complication after acute myocardial
infarction. Transthoracic echocardiography allows diagnosing intramyocardial hematoma at the bedside,
documenting its evolution and assessing the effects on left ventricular remodeling. Cardiac magnetic
resonance imaging provides complimentary information...
Background: The Holter electrocardiogram (ECG) provides a long signal that represents the heart’s responses to both autonomic regulation and various phenomena, including heart tissue remodeling. Loss of information is a common result when using global statistical metrics. Method: Breaking the signal into short data segments (e.g., windows) provides...
An effective approach for determining the clinical classification of heart failure (HF) patients is to estimate cardiac hemodynamics during exercise. This approach is further strengthened when measurements including cardiac power are used to describe cardiac hemodynamics. We hypothesize cardiac power quantifies the hemodynamic and pressure generati...
Exosomes are vesicles with a size range of 50 to 200 nm and released by different cells, which are essential for the exchange of information between cells. They have attracted a lot of interest from medical researchers. Exosomal non-coding RNAs play an important part in pathological cardiac remodelings, such as cardiomyocyte hypertrophy, cardiomyoc...
Citations
... [8][9][10] Patients without hypertrophy regression after HF therapies have a poor quality of life and increased mortality compared to those who have reverse remodeling. 11,12 Experimental studies in infarction-induced cardiac remodeling and HF also showed consistent results, [13][14][15] further supporting the benefits from hypertrophy inhibition in MI-induced HF. Therefore, targeting at hypertrophy regression may be a potential therapeutic strategy for ventricular remodeling and HF. ...
... At present, only less than 50% of patients underwent hypertrophy regression after HF treatments. 11,12 During the past few decades, underlying intracellular mechanisms of infarction-induced cardiac hypertrophy have provided several potential therapeutic targets, including protein-coding and non-coding genes. Sodium/ hydrogen exchange (NHE) is a common downstream mediator to Ang II and ET-1 in the cardiac cell, and the inhibition of NHE could significantly reduce cardiac hypertrophy and HF at 1-week and 12week post-MI. ...
Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction (MI) heart failure (HF). Here, we report a novel small molecule HHQ16, an optimized derivative of astragaloside IV , which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy. The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2 -affiliated transcript lnc9456 in the heart. While minimally expressed in normal mouse heart, lnc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation (LADL) and in cardiomyocytes subjected to hypertrophic stimulation. The critical role of lnc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro. A physical interaction between lnc9456 and G3BP2 increased NF-κB nuclear translocation, triggering hypertrophy-related cascades. HHQ16 physically bound to lnc9456 with a high-affinity and induced its degradation. Cardiomyocyte-specific lnc9456 overexpression induced, but knockout prevented LADL-induced, cardiac hypertrophy and dysfunction. HHQ16 reversed the effect of lnc9456 overexpression while lost its protective role when lnc9456 was deleted, further confirming lnc9456 as the bona fide target of HHQ16. We further identified the human ortholog of lnc9456 , also an Egr2 -affiliated transcript, lnc4012 . Similarly, lnc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy. HHQ16 also specifically bound to lnc4012 and caused its degradation and antagonized its hypertrophic effects. Targeted degradation of pathological increased lnc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.
... It has been postulated that progressive LV enlargement alters ventricular geometry and annular dilatation causing increased severity of MR [26]. Several medicines (i.e., sacubitril/valsartan, carvedilol, losartan) have been reported to possess reverse remodeling effects [27], with long-standing treatment, resulting in less LV remodeling and subsequently less mitral annular dilatation. Pimobendan has been shown to reduce severity of MR for both short-term and long-term treatment [3,28]. ...
Background:
Pimobendan has been proven to delay the onset of congestive heart failure (CHF) in dogs with mitral regurgitation (MR); however, molecular underlying mechanisms have not been fully elucidated. This study aimed to investigate (1) the effects of pimobendan on cardiac function, cardiac mitochondrial quality and morphology, and cardiac ultrastructure in a rat model of chronic MR and (2) the direct effect of pimobendan on intracellular reactive oxygen species (ROS) production in cardiac cells. MR was surgically induced in 20 Sprague-Dawley rats, and sham procedures were performed on 10 rats. Eight weeks post-surgery, the MR rats were randomly divided into two groups: the MR group and the MR + pimobendan group. Pimobendan (0.15 mg/kg) was administered twice a day via oral gavage for 4 weeks, whereas the sham and MR groups received equivalent volumes of drinking water. Echocardiography was performed at baseline (8 weeks post-surgery) and at the end of the study (4 weeks after treatment). At the end of the study protocol, all rats were euthanized, and their hearts were immediately collected, weighed, and used for transmission electron microscopy and mitochondrial quality assessments. To evaluate the role of pimobendan on intracellular ROS production, preventive or scavenging properties were tested with H2O2-induced ROS generation in rat cardiac myoblasts (H9c2).
Results:
Pimobendan preserved cardiac functions and structure in MR rats. In addition, pimobendan significantly improved mitochondrial quality by attenuating ROS production and depolarization (P < 0.05). The cardiac ultrastructure and mitochondrial morphology were significantly preserved in the MR + pimobendan group. In addition, pimobendan appeared to play as a ROS scavenger, but not as a ROS preventer, in H2O2-induced ROS production in H9c2 cells.
Conclusions:
Pimobendan demonstrated cardioprotective effects on cardiac function and ultrastructure by preserving mitochondrial quality and acted as an ROS scavenger in a rat model of MR.
... A reduced LA reservoir strain, the most studied LA functional parameter, proved to be an independent predictor of reduced exercise tolerance and poor prognosis in these patients [6,12]. Developing specific treatment strategies aimed at improving LA function could have a positive impact on the course of the disease and on the symptoms of the patients [26]. In this pilot study, we investigated the effects produced by a supervised concurrent exercise program, lasting 12 weeks, on LA and LV function parameters in HFmrEF patients. ...
Left atrial dysfunction is associated with exercise intolerance and poor prognosis in heart failure (HF). The effects of exercise training on atrial function in patients with HF with mid-range ejection fraction (HFmrEF) are unknown. The purpose of the present study was to assess the effects of a supervised concurrent training (SCT) program, lasting 12 weeks, on left atrial function of patients with HFmrEF. The study included 70 stable patients, who were randomly assigned into two groups: SCT with (three sessions/week) or a control (CON) group directed to follow contemporary exercise preventive guidelines at home. Before starting the training program and at 12 weeks, all patients performed an ergometric test, a 6 min walk test, and echocardiography. Between-group comparisons were made by analysis of variance (ANOVA). At 12 weeks, the duration of the ergometric test and distance walked at 6 min walk test presented a significant greater increase in SCT compared to the control (between-group p 0.0001 and p 0.004 respectively). Peak atrial longitudinal strain and conduit strain presented an increase of 29% and 34%, respectively, in the SCT, and were unchanged in CON (between-group p 0.008 and p 0.001, respectively). Peak atrial contraction strain increased by 21% in SCT, with no changes in CON (between-group p 0.002). Left ventricular global longitudinal strain increased significantly in SCT compared to control (between-groups p 0.03). In conclusions, SCT improved left atrial and left ventricular function in HFmrEF. Further studies are needed in order to verify whether these favourable effects of SCT on LA function are sustained and whether they will translate into clinical benefits for patients with HFmrEF.
... Elevated blood pressure is a significant risk factor for heart failure (51). Heart failure is associated with abnormalities in the left ventricular structure and function (52). In humans, heart failure has been characterized by chamber dilation, reduced cardiac muscle contractility, and lessened cardiac output (53,54). ...
The leading cause of death in patients with non-alcoholic fatty liver disease (NAFLD) is cardiovascular disease (CVD). However, the mechanisms are unknown. Mice deficient in hepatocyte PPARα (PparaHepKO) exhibit hepatic steatosis on a regular diet, making them prone to manifesting NAFLD. We hypothesized that the PparaHepKO mice might be predisposed to poorer cardiovascular phenotypes due to increased liver fat content. We use PparaHepKO and littermate control mice fed a regular chow diet to avoid complications with a high-fat diet, such as insulin resistance and increased adiposity. After 30 weeks on a standard diet, male PparaHepKO mice exhibited elevated hepatic fat content compared to littermates as measured by Echo MRI (11.95 ± 1.4 vs. 3.74 ± 1.4%, p<0.05), hepatic triglycerides (1.4 ± 0.10 vs. 0.3 ± 0.01mM, p<0.05), and Oil Red O staining, despite no changes in body weight, fasting blood glucose, and insulin. The PparaHepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, p<0.05), impaired diastolic function, cardiac remodeling, and enhanced vascular stiffness. To determine mechanisms controlling the increase in stiffness in the aorta, we used state-of-the-art PamGene technology to measure kinase activity. Our data suggest that the loss of hepatic PPARα induces alterations in the aortas that reduce the kinase activity of tropomyosin receptor kinases (TRKs) and p70S6K kinase, which might contribute to the pathogenesis of NAFLD-induced CVD. These data indicate that hepatic PPARα protects the cardiovascular system through some as-of-yet undefined mechanism.
... Elevated blood pressure is a significant risk factor for heart failure (51). Heart failure is associated with abnormalities in the left ventricular structure and function (52). In humans, heart failure has been characterized by chamber dilation, reduced cardiac muscle contractility, and lessened cardiac output (53,54). ...
Non-alcoholic fatty liver disease (NAFLD) often clusters with obesity, diabetes, and hyperlipidemia. For unknown reasons, the leading cause of death in patients with NAFLD is cardiovascular disease (CVD). Most preclinical models of NAFLD are induced by high-fat diet feeding that induces obesity and glucose intolerance, each provoking CVD independent of changes in hepatic fat. To determine the role of NAFLD in the promotion of CVD, independent of changes in body weight and insulin sensitivity, we utilized our hepatocyte-specific PPARα knockout ( Ppara HepKO ) and littermate control ( Ppara fl / fl ) mice. After 30 weeks on a standard diet, male Ppara HepKO mice exhibited elevated hepatic fat content compared to littermates as measured by Echo MRI (11.95 ± 1.4 vs. 3.74 ± 1.4%, p<0.05), hepatic triglycerides (1.4 ± 0.10 vs. 0.3 ± 0.01mM, p<0.05), and Oil Red O staining, despite body weight, fasting blood glucose, and insulin levels being the same as controls. The Ppara HepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, p<0.05), impaired diastolic function, and adverse cardiac remodeling consisting of dilated cardiomyopathy. The mice with the loss of hepatic PPARα displayed alterations in vascular stiffness, including increased pulsatility index, resistive index, and intima-media thickness in the abdominal aorta and carotid artery, which was corroborated with reduced kinase signaling in the aortas of the Ppara HepKO mice. Our findings indicate that hepatic PPARα is vital in protecting the cardiovascular system via a liver-specific mechanism. Also, the Ppara HepKO mice are possibly a novel model for studying NAFLD-induced CVD.
This work was supported by National Institute of Health R01DK126884, and the National Heart, Lung and Blood Institute P01 HL05197-11 (D.E.S) and the National Institute of General Medical Sciences P20GM104357-02.
This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
... LV reverse remodeling is a common goal of neurohormonal antagonists and is associated with improved prognosis [12]. Besides being proved for older drug classes such as ACEi or BB, the ability to induce reverse remodeling is also well described for ARNI; indeed, multiple studies revealed that SV is associated with improved LVEF, reduced atrial and ventricular volumes, lower natriuretic peptide values and improved diastolic function [13][14][15]. ...
Introduction
Heart failure with reduced ejection fraction (HFrEF) patients are prone to developing ventricular arrhythmias. In the PARADIGM-HF trial, sacubitril-valsartan (SV) showed a reduction in the composite endpoint of death and HF hospitalization in HFrEF patients; subgroup analysis of this trial revealed a reduction in both sudden death and deaths from worsening HF. The mechanism by which SV may affect the incidence of ventricular arrhythmias is currently under debate, and the literature provides conflicting results. The aim of our study was to evaluate the potential antiarrhythmic effect of this drug in patients with HFrEF carrying an implantable cardiac defibrillator (ICD) or a cardiac resynchronization therapy with a defibrillator (CRT-D).
Methods
This was a single-center, observational and retrospective study. Inclusion criteria were implantation of an ICD or CRT-D device between 2009 and 2019, age ≥18 years, left ventricle ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) functional class ≥II, and treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker for at least 12 months, followed by replacement with SV. Exclusion criteria were NYHA class IV, frequent alterations in chronic medication for HFrEF, and implantation of an ICD or CRT-D after the introduction of SV. The primary outcome was the occurrence of ventricular arrhythmias in the form of appropriate device shocks, ventricular fibrillation, or ventricular tachycardia. The comparisons were performed between two periods of time (12 months before and 12 months after SV) in the same group of patients.
Results
Fifty-four patients met the inclusion criteria. The mean age was 69.5 ± 1.65 years, and 74.1% of patients were male. The number of patients experiencing appropriate shocks was significantly lower after SV initiation (2% vs. 18%; p=0.016). The percentage of VT (13 vs. 20%; p=0.549) and VF episodes (4% vs. 13% for VF; p=0.289) were also lower, but these differences were not statistically significant. There were no significant differences in the value of NT-proBNP (1128 vs. 775 pg/mL; p=0.858), LVEF (28.4 vs. 29.6%; p=0.315), and left ventricular end-diastolic diameter (65.0 vs. 66.0 mm; p=0.5492).
Conclusion
SV seems to reduce the risk of arrhythmic events requiring appropriate shock therapy.
... Reverse cardiac remodeling including reduction of LV volumes is a major pathway for clinical benefits of both pharmacological and device related HF therapy [23] Several studies including the Empire HF trial have demonstrated reductions in LV and LA volumes [21,24,25] in a SGLT2 inhibitor treated patient population. The effect on LVEF has been more conflicting with Empagliflozin in Non-diabetic Heart Failure Patients With Reduced Ejection Fraction (EMPA-TROPOISM) suggesting improvement in LVEF after 6 months treatment with empagliflozin [24], whereas Empire HF and Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF) failed to find significant changes in LVEF after 12 and 36 weeks treatment with an SGLT2 inhibitor, respectively [21,25]. ...
... These factors include hypertension duration, type of hypertrophy (concentric versus eccentric), age, BMI, sex, physical activity, genetic background, disease aetiology and concurrent medications. The result is that <50% of patients receiving heart failure therapies currently undergo hypertrophy regression, and those without hypertrophy regression have poor quality of life and increased mortality compared with patients who have reverse remodelling 271,272 . However, if regression of cardiac hypertrophy were considered a primary end point in the treatment of heart disease, as many studies suggest it should be, data-informed choice of therapy is possible thanks to the wealth of clinical literature. ...
Left ventricular hypertrophy is a leading risk factor for cardiovascular morbidity and mortality. Although reverse ventricular remodelling was long thought to be irreversible, evidence from the past three decades indicates that this process is possible with many existing heart disease therapies. The regression of pathological hypertrophy is associated with improved cardiac function, quality of life and long-term health outcomes. However, less than 50% of patients respond favourably to most therapies, and the reversibility of remodelling is influenced by many factors, including age, sex, BMI and disease aetiology. Cardiac hypertrophy also occurs in physiological settings, including pregnancy and exercise, although in these cases, hypertrophy is associated with normal or improved ventricular function and is completely reversible postpartum or with cessation of training. Studies over the past decade have identified the molecular features of hypertrophy regression in health and disease settings, which include modulation of protein synthesis, microRNAs, metabolism and protein degradation pathways. In this Review, we summarize the evidence for hypertrophy regression in patients with current first-line pharmacological and surgical interventions. We further discuss the molecular features of reverse remodelling identified in cell and animal models, highlighting remaining knowledge gaps and the essential questions for future investigation towards the goal of designing specific therapies to promote regression of pathological hypertrophy.
... Numerous drugs have been developed to relieve the symptoms of and prevent heart failure progression [67]. While some partly prevented cardiac growth and remodeling in heart failure [68], a few studies focused on the effects of current drugs on cardiac remodeling in familial cardiomyopathies. Hence, we employed the HCM/DCM signaling model to explore the outcomes of available heart failure medications and two new categories of drugs (myosin inhibitors and activators) on cardiomyocyte morphology explained by changes in cardiomyocyte mass and eccentricity (Table 1). ...
Familial cardiomyopathy is a precursor of heart failure and sudden cardiac death. Over the past several decades, researchers have discovered numerous gene mutations primarily in sarcomeric and cytoskeletal proteins causing two different disease phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathies. However, molecular mechanisms linking genotype to phenotype remain unclear. Here, we employ a systems approach by integrating experimental findings from preclinical studies (e.g., murine data) into a cohesive signaling network to scrutinize genotype to phenotype mechanisms. We developed an HCM/DCM signaling network model utilizing a logic-based differential equations approach and evaluated model performance in predicting experimental data from four contexts (HCM, DCM, pressure overload, and volume overload). The model has an overall prediction accuracy of 83.8%, with higher accuracy in the HCM context (90%) than DCM (75%). Global sensitivity analysis identifies key signaling reactions, with calcium-mediated myofilament force development and calcium-calmodulin kinase signaling ranking the highest. A structural revision analysis indicates potential missing interactions that primarily control calcium regulatory proteins, increasing model prediction accuracy. Combination pharmacotherapy analysis suggests that downregulation of signaling components such as calcium, titin and its associated proteins, growth factor receptors, ERK1/2, and PI3K-AKT could inhibit myocyte growth in HCM. In experiments with patient-specific iPSC-derived cardiomyocytes (MLP-W4R;MYH7-R723C iPSC-CMs), combined inhibition of ERK1/2 and PI3K-AKT rescued the HCM phenotype, as predicted by the model. In DCM, PI3K-AKT-NFAT downregulation combined with upregulation of Ras/ERK1/2 or titin or Gq protein could ameliorate cardiomyocyte morphology. The model results suggest that HCM mutations that increase active force through elevated calcium sensitivity could increase ERK activity and decrease eccentricity through parallel growth factors, Gq-mediated, and titin pathways. Moreover, the model simulated the influence of existing medications on cardiac growth in HCM and DCM contexts. This HCM/DCM signaling model demonstrates utility in investigating genotype to phenotype mechanisms in familial cardiomyopathy.
... Now, in the era of primary PCI with the possibility of attaining immediate revascularization of the infarct-related artery, it has been increasingly noticed that reverse remodeling stands as an important bright-side counterpart among the LV geometric changes post-STEMI [19]. Previous studies tackled the concept of reverse remodeling in the course of HF management with either pharmacological (namely, ACEIs and/ or B-blockers) [20,21], or non-pharmacological measures (namely, cardiac resynchronization therapy) [18]. ...
Acute ST-segment elevation myocardial infarction (STEMI) is associated with left ventricular (LV) structural and functional consequences. We aimed to elucidate LV geometric changes following STEMI using three-dimensional (3D) echocardiography (3DE) and to assess their functional implications using two-dimensional (2D) speckle tracking echocardiography (STE). The study included 71 patients with STEMI who underwent baseline and 6-month follow-up 2D- and 3DE. Measured parameters included LV dimensions, biplane volumes, wall motion assessment, 2D LV global longitudinal strain (GLS), and 3D LV volumes, sphericity index and systolic dyssynchrony index. According to 3DE, LV geometric changes were classified as, adverse remodeling, reverse remodeling, and minimal LV volumetric changes. The occurrence of in-hospital and follow-up major adverse cardiovascular events (MACE) was assessed among the study population. The incidence of developing adverse remodeling was 25.4% while that of reverse remodeling was 36.6%. Adverse remodeling patients had significantly higher in-hospital MACE. Reverse remodeling was associated with significantly improved GLS, that was less evident in those with minimal LV geometric changes, and non-significant improvement for adverse remodeling group. LV baseline 2D GLS significantly correlated with follow-up 3D volumes among both reverse and adverse remodeling groups. Female gender and higher absolute GLS change upon follow-up were significantly associated with reverse remodeling. ROC-derived cutoff for adverse remodeling reallocated a substantial number of patients from the minimal change group to the adverse remodeling. Following acute STEMI, two-dimensional GLS was associated with and potentially predictive of changes in LV volumes as detected by three-dimensional echocardiography.
