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Relation of hemoglobin A(1C) to left ventricular relaxation in patients with type 1 diabetes mellitus and without overt heart disease
Abstract
Previous studies using Doppler and M-mode echocardiography have demonstrated that abnormalities of left ventricular (LV) diastolic relaxation are sensitive markers of early myocardial dysfunction. Tissue Doppler echocardiography and color M-mode propagation velocity (Vp) are novel noninvasive techniques that provide an estimate of LV relaxation 1–3 and are less dependent on preload. 4,5 Furthermore, mitral infl ow early fi lling (E) can be used in conjunction with tissue Doppler echocardiography early diastolic velocity (EM) and Vp to estimate LV fi lling pressures. 3,4 The present study examines whether subclinical diastolic dysfunction is found in asymptomatic type 1 diabetic patients, and evaluates the relation between diastolic dysfunction and glycemic control using novel echocardiographic techniques. The study group included 25 type 1 diabetic patients who were compared with 26 age- and gendermatched normal volunteers. Exclusion criteria were any history of hypertension, myocardial infarction, unstable angina pectoris, or congestive heart failure. Subjects were also excluded if they had any evidence of global or regional LV dysfunction, valvular stenosis, or regurgitation, or abnormal end-diastolic or endsystolic dimensions on transthoracic echocardiography. All participants had normal electrocardiograms. The study protocol was approved by an institutional review board, and all participants provided informed consent. Participants were examined in the supine position by 2-dimensional– guided transthoracic standard pulsed, color Doppler, and tissue Doppler echocardiography using an Acuson Sequoia (Mountain View, California) echocardiographic machine equipped with tissue Doppler echocardiographic technology. Recordings were acquired with a 1.7 to 3.5 harmonic Doppler transducer. Recordings of myocardial wall velocities, transmitral Doppler fl ow, and 2-dimensional images were obtained from the apical acoustic window. M-mode and 2-dimensional echocardiographic images of the left ventricle were obtained for evaluation of ventricular septal and posterior wall
... In this study asymptomatic Left ventricular diastolic dysfunction is common in patients with diabetes and that its severity is correlated with glycemic control. These results correlate well with the published data (17). ...
... In this study there is negative correlation of HbA1c level with E wave and E/A and positive correlation with A wave, IVRT, and DT (p=0.0001). These results correlate well with results in a study conducted by Mehdi et al. (17). Among the diabetes mellitus group HbA1c level had negative correlation with Em (-0.43, p=0.003) and E/A ratio (p=0.01), ...
... IVRT (p=0.0001) and DT (p=0.03) (17). ...
... This is in contrast with a smaller study that also used TDI to investigate the effects of T1DM on LV diastolic function. 23 In that study, Em was lower in the T1DM group than in the NC group. 23 Differences in TDI methods, patient populations, screening procedures, and numbers of patients may explain some of the differences between the results of our TDI-derived measures and those of the previous study. ...
... 23 In that study, Em was lower in the T1DM group than in the NC group. 23 Differences in TDI methods, patient populations, screening procedures, and numbers of patients may explain some of the differences between the results of our TDI-derived measures and those of the previous study. 23 To our knowledge, these are the only studies to use TDI to investigate the load-independent effects of T1DM on LV diastolic function. ...
... 23 Differences in TDI methods, patient populations, screening procedures, and numbers of patients may explain some of the differences between the results of our TDI-derived measures and those of the previous study. 23 To our knowledge, these are the only studies to use TDI to investigate the load-independent effects of T1DM on LV diastolic function. Interestingly, in that study and in the Cardiovascular Health Study, atrial function defined by PWD-derived measures of A-wave velocity was altered in the T1DM patients, which is concordant with our findings. ...
... Our MRI scans showed that filling of the left ventricle was reduced in adolescents with diabetes independent of sex, age, and fitness level. This study was not designed to investigate detailed diastolic function and systolic function, such as ventricular relaxation and filling patterns; however, previous echocardiography assessments in adults and youth with diabetes found altered filling patterns, impaired left ventricular relaxation, and higher filling pressures at rest (10,21,22), all of which may alter resting EDV. We therefore speculate that the abnormal filling pattern previously observed in adolescents with diabetes at rest is maintained or perhaps worsened during exercise, reducing filling volumes (and consequently, stroke volume) during exercise (10,22). ...
... Ejection fractions were similar between groups in both conditions, which may reflect a sympathetically mediated increase in contractility at rest to compensate for a decreased EDV. Increased resting sympathetic outflow has been reported in patients with diabetes (25) and has been associated with elevated heart rate (26) and altered left ventricular relaxation (21). The adolescents with type 1 diabetes in this study had elevated heart rate while upright, and although it was not the aim of the current study, we and others have previously reported impaired left ventricular relaxation in adolescents with diabetes (10,22). ...
... In agreement with previous studies using Doppler echocardiography (10,21), we observed no changes in left ventricular mass. Whalley et al. (22) showed that a group of girls with type 1 diabetes had similar left ventricular mass (indexed for body FFM) compared with healthy girls. ...
OBJECTIVE
To determine whether adolescents with type 1 diabetes have left ventricular functional changes at rest and during acute exercise and whether these changes are affected by metabolic control and diabetes duration.
RESEARCH DESIGN AND METHODS
The study evaluated 53 adolescents with type 1 diabetes and 22 control adolescents. Baseline data included peak exercise capacity and body composition by dual-energy X-ray absorptiometry. Left ventricular functional parameters were obtained at rest and during acute exercise using magnetic resonance imaging.
RESULTS
Compared with nondiabetic control subjects, adolescents with type 1 diabetes had lower exercise capacity (44.7 ± 09 vs. 48.5 ± 1.4 mL/kg fat-free mass [FFM]/min; P < 0.05). Stroke volume was reduced in the diabetes group at rest (1.86 ± 0.04 vs. 2.05 ± 0.07 mL/kg FFM; P = 0.02) and during acute exercise (1.89 ± 0.04 vs. 2.17 ± 0.06 mL/kg FFM; P = 0.01). Diabetic adolescents also had reduced end-diastolic volume at rest (2.94 ± 0.06 vs. 3.26 ± 0.09 mL/kg FFM; P = 0.01) and during acute exercise (2.78 ± 0.05 vs. 3.09 ± 0.08 mL/kg FFM; P = 0.01). End-systolic volume was lower in the diabetic group at rest (1.08 ± 0.03 vs. 1.21 ± 0.04 mL/kg FFM; P = 0.01) but not during acute exercise. Exercise capacity and resting and exercise stroke volumes were correlated with glycemic control but not with diabetes duration.
CONCLUSIONS
Adolescents with type 1 diabetes have reduced exercise capacity and display alterations in cardiac function compared with nondiabetic control subjects, associated with reduced stroke volume during exercise.
... 9 Among the diabetes mellitus group, HbA1c had a negative correlation with Em (p=0.031). 13 In Group 3 Left ventricular diastolic dysfunction was found in 80% patients comparing to 45% of patients in Group-2 and 25% of patients in the Group-1 with statistical significant differences (p<0.05). Diastolic function of the left ventricle in patients with diabetes is dependent on HbA1c level. ...
... These results correlate well with the published data. 13 In this study there is negative correlation of HbA1c level with E wave, E/A, and Em and positive correlation with A wave, IVRT, DT and LA size (p=0.0001). These results correlate well with results in a study conducted by Mehdi et al. 13 Among the diabetes mellitus group HbA1c level had negative correlation with Em (-0.43, p=0.003) and E/A ratio (p=0.01), ...
... 13 In this study there is negative correlation of HbA1c level with E wave, E/A, and Em and positive correlation with A wave, IVRT, DT and LA size (p=0.0001). These results correlate well with results in a study conducted by Mehdi et al. 13 Among the diabetes mellitus group HbA1c level had negative correlation with Em (-0.43, p=0.003) and E/A ratio (p=0.01), positive correlation with A wave (p=0.005), ...
Diabetes is associated with Left ventricular diastolic and systolic dysfunction known as diabetic cardiomyopathy. Echocardiography is helpful for the detection of diastolic dysfunction and Echocardiographic screening for asymptomatic diabetic cardiomyopathy should be performed in all asymptomatic diabetic subjects. Identification of diabetic cardiomyopathy should result in the initiation of therapies to prevent the progression of diabetic cardiomyopathy. The objectives of this Descriptive case series was to determine the effect of glycaemic status on left ventricular diastolic function in normotesive type 2 diabetic patients.
This study was performed at Cardiology department, PGMI Lady Reading Hospital, Peshawar from March 2007 to September 2007. Sixty normotesive type 2 diabetic patients were enrolled, 20 well control, 20 moderately control and 20 poorly control (Group-3). Main outcome measures was Left ventricular diastolic function determined by Echocardiography.
Out of 60 patients there were 32 (53.3%) males and 28 (46.7%) females. Mean E/A ratio in Group 1 was 1.38 +/- 0.29, in Group 2 was 1.16 +/- 0.39 and in Group 3 was 0.60 +/- 0.15 (p < 0.05). IVRT in Group-1 was 91 +/- 7.87 mSec, in Group-2 was 100 +/- 7.83 mSec and in Group-3 was 109 +/- 6.45 mSec (p < 0.05). DT in Group 1 was 207.2 +/- 12.6 mSec, in Group 2 was 218 +/- 11.3 mSec and in Group 3 was 229.7 +/- 9.52 mSec (p < 0.05). Mean Em at mitral annulus in Group-1 was 0.14 +/- 0.04 m/Sec, in Group-2 was 0.11 +/- 0.04 m/Sec and in Group-3 was 0.10 +/- 0.03 m/Sec (p = 0.002). Left ventricular diastolic dysfunction was documented in 4 (25%) patients in Group-1, 9 (45%) patients in Group-2 and 16 (80%) patients in Group-3 (p < 0.05). There was Strong correlation between HbA1c level and diastolic indexes (p < 0.05).
Diastolic dysfunction is more frequent in poorly controlled diabetic patients and its severity is correlated with glycaemic control.
... Studies to evaluate the use of TDI in detection of cardiac dysfunction in children with T1DM are few and conflicting [8][9][10][11][12]. Whereas study about the correlation between HbA1c levels and MPI is still rarely done. ...
... p=0.047). A previous study by Shishehbor et al. [12] reported a strong positive correlation between E/e' ratio and HbA1c levels in 25 adult patients with T1DM (r=0.68 and p<0.05). On the contrary, different research by Gul et al. [26] showed no significant correlation between HbA1c levels and E/e' ratio (p>0.05). ...
Background: Diabetic cardiomyopathy is one of the macrovascular complications in type 1 diabetes mellitus (T1DM). Left ventricular dysfunction primarily reflects diastolic dysfunction which is early sign of diabetic cardiomyopathy. Improved glycemic control can delay the onset and progression of this complication. An important indicator of long-term glycemic control is glycosylated hemoglobin (HbA1c). Objective: The aim of this study is to evaluate the correlation between HbA1c levels with left ventricular diastolic function in children with T1DM. Methods: This study was an observational study with cross-sectional design in children aged 1 month-18 years with T1DM, at Prof Dr. I.G.N.G. Ngoerah Hospital, Denpasar from November 2019–September 2021, using consecutive sampling. Glycosylated hemoglobin (HbA1c) was meassured by blood samping and LV function was assessed by using tissue Doppler imaging (TDI). Statistical analysis was done by Pearson and Spearman correlation test. A p-values of <0.05 was considered statistically significant. Results: A total of 36 subjects were recruited in this study. There was a low positive correlation between HbA1c levels with E/e’ ratio (r=0.284, p=0.047), and MPI (r=0.358, p=0.020). After adjusting body mass index and duration of T1DM as confounding variables, we found a low positive correlation between HbA1c levels and E/e’ ratio (r=0.325, p=0.030), MPI (r = 0.390, p=0.020). Conclusion: HbA1C has a positive correlation with left ventricular diastolic function in children with T1DM.
... Moreover, Valle et al., reported a total of 39 patients out of 76 (51%) were diagnosed with LV diastolic dysfunction (16). This was also consistent with Shishehbor MH, et al., who found a higher prevalence of asymptomatic diastolic dysfunction in type 1 diabetes mellitus, even in the absence of hypertension and cardiac disease (17). ...
... Fourthly, the cellular mechanisms that underlie diabetic diastolic dysfunction are probably due to hyperglycaemia, which generates reactive oxygen species causing mitochondrial dysfunction, and hyperinsulinaemia which promotes myocyte hypertrophy (23) and (24). In the present study, Patients with LVDD had higher HbA1c than those without LVDD, similar results was found by Shishehbor et al., who reported that The severity of the diastolic dysfunction correlates independently with elevated glycosylated haemoglobin (17). The study found a higher levels of BNP assay among patients with LVDD more than patients without LVDD. ...
Background: Several studies have revealed that BNP levels may reflect diastolic dysfunction.But, few studies demonstrated the role of BNP in early detection of diastolic dysfunction in diabetic patients. Hence there is a need, for recognizing those with asymptomatic left ventricular diastolic dysfunction, and at a risk of developing clinical HF. Purpose: the study is aimed at evaluating the role of BNP in the early identification of diastolic dysfunction. Methods: 60 patients with type 2 DM were included in the study of those attending medical and diabetic polyclinic in the state of Kuwait through a period of 6 months in 2012. Results: The mean age of the patients was 53.87 ± 7.98 years. They were 23 (38.3%) males and 37 (61.7%) females. A total of 20 patients (33.3%) out of 60 patients were diagnosed with LVDD. The patients with LVDD had a higher BNP levels (P=0. 000**) in comparison to the patient without LVDD. Receiver operating characteristic curve (ROC) was generated for identifying the sensitivity and specificity of the BNP and the area under the curve was 1.000 at a cutoff value >92 pg/ml was 100% specificity and 100% sensitive for detecting the presence or absence of LVDD by echocardiography with 100% PPV and 100% NPV. Conclusion: The BNP assay could be used as a marker of early LV diastolic dysfunction in diabetic patients for early prevention and management of overt heart failure.
... The combination of assessing mitral annulus motion with tissue Doppler during early diastole (é) and early passive mitral inflow velocity (E) provides an acceptable estimate of LV filling pressure, with E/é b 8 being associated with normal filling pressure, whereas values N12-15 are associated with elevated filling pressures. Moreover, studies have demonstrated a reduction of é in type 2 DM and an independent correlation between increased E/é and glycosylated hemoglobin (HbA1 c ), mortality, and the risk of development of overt HF [4,5,[9][10][11][12]. Therefore, the E/é ratio may be used to detect and follow the progression of LV DD in patients with DM. ...
... The subgroup division was based on FPG, in most cases only a single measurement. The addition of an OGTT and/or HbA1 c measurements would have been preferable, as IGT and DM defined by OGTT are more common among women than men [22], and HbA1 c provides an estimate of the average glucose levels, and perhaps sustained myocardial affection, over an [8][9][10][11][12] week period [29]. The oversampling of subjects with either IFG or DM also prevented us from using FPG as a continuous variable. ...
To examine whether increasing fasting plasma glucose (FPG) levels were associated with worsening left ventricular (LV) diastolic function, independently of LV mass index (LVMI) in elderly, otherwise healthy subjects.
We tested cross-sectional associations between echocardiographically determined averaged E/é ratio/diastolic function, LVMI, cardiovascular risk factors, and FPG categorized as normal (NFG), impaired (IFG), and new-onset diabetes mellitus (DM), in 483 men and 208 women aged 56-79years without overt cardiovascular disease, who received no cardiovascular, anti-diabetic, or lipid-lowering drugs and had a preserved LV ejection fraction >50%. Median E/é was significantly higher among subjects with diabetes than those without (8 vs. 7; p=0.03), as was the prevalence of grade 2 or 3 diastolic dysfunction (25% vs. 16%; p=0.02). E/é and diastolic function were significantly associated with LVMI (p≤0.002), but not FPG category, on multivariable analysis. However, interaction analyses revealed that increasing LVMI was primarily associated with worsening diastolic function (higher E/é) in subjects with FPG>6mmol/L (β=0.005 for IFG and DM vs. 0.001 for NFG; p=0.02), whereas increasing systolic blood pressure was primarily associated with worsening diastolic function (higher E/é) in subjects with FPG≤6.9mmol/L (β=0.005 for NFG and 0.003 for IFG vs. -0.001 for DM; p=0.001).
Diastolic dysfunction was significantly more prevalent among patients with DM than those without. The importance of LVMI increased, but the importance of systolic blood pressure decreased with higher FPG category.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
... Although diabetes is a well recognized risk factor for the acceleration of ischaemic heart disease and hypertension, the relationship between diabetes and cardiac disease independent of these diseases is less well understood. Diabetic patients without significant coronary artery disease may develop features of abnormal LV relaxation with normal systolic function [198][199][200][201]. The severity of the diastolic dysfunction correlates independently with the derangement in glycaemic control as manifested by elevated glycosylated haemoglobin [199][200][201]. ...
... Diabetic patients without significant coronary artery disease may develop features of abnormal LV relaxation with normal systolic function [198][199][200][201]. The severity of the diastolic dysfunction correlates independently with the derangement in glycaemic control as manifested by elevated glycosylated haemoglobin [199][200][201]. A nationwide case control study showed that diabetes was independently associated with idiopathic cardiomyopathy [202]. ...
Epidemiological and clinical studies suggest that HF with a preserved ejection fraction will become the more common form of HF which clinicians will encounter. The spectrum of diastolic disease extends from the asymptomatic phase to fulminant cardiac failure. These patients are commonly encountered in operating rooms and critical care units. A clearer understanding of the underlying pathophysiology and clinical implications of HF with a preserved ejection fraction is fundamental to directing further research and to evaluate interventions. This review highlights the impact of diastolic dysfunction and HF with a preserved ejection fraction during the perioperative period and during critical illness.
... This was in agreement with Gul et al. [27] who found insignificant correlation between echocardiographic parameters and HbA1c%. In contrary, Shishehbor et al. [29], Adel et al. [28], and Kim [3] found inverse correlation between HbA1c% and diastolic function. Also Grandi et al. [30] concluded that, in patients with type 1 diabetes, a close relation was found between glycemic control and LV diastolic function, which improves when glycemic control improves. ...
... This was in agreement with Gul et al. [27] who found insignificant correlation between echocardiographic parameters and HbA1c%. In contrary, Shishehbor et al. [29], Adel et al. [28], and Kim [3] found inverse correlation between HbA1c% and diastolic function. Also Grandi et al. [30] concluded that, in patients with type 1 diabetes, a close relation was found between glycemic control and LV diastolic function, which improves when glycemic control improves. ...
Diabetes and cardiac affection
... Using STZ-induced diabetes rat models (Malhotra et al., 1981), Malhotra et al. (1981) showed the efficacy of intensive glycemic control in mitigating the structural and molecular changes in cardiomyopathy. Abnormal diastolic functioning correlated with glycemic control in T1DM subjects (Shishehbor et al., 2003). When T1DM subjects were intensively treated thrice or four times with insulin daily, the reduction of inflammatory markers was not reassuring (Schaumberg et al., 2005). ...
Diabetic cardiomyopathy (DMCM) is the leading cause of mortality and morbidity among diabetic patients. DMCM is characterized by an increase in oxidative stress with systemic inflammation that leads to cardiac fibrosis, ultimately causing diastolic and systolic dysfunction. Even though DMCM pathophysiology is well studied, the approach to limit this condition is not met with success. This highlights the need for more knowledge of underlying mechanisms and innovative therapies. In this regard, emerging evidence suggests a potential role of non-coding RNAs (ncRNAs), including micro-RNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) as novel diagnostics, mechanisms, and therapeutics in the context of DMCM. However, our understanding of ncRNAs’ role in diabetic heart disease is still in its infancy. This review provides a comprehensive update on pre-clinical and clinical studies that might develop therapeutic strategies to limit/prevent DMCM.
... In addition, type 2 diabetes is usually associated with altered LV diastolic function (18, 45,48,49). The negative impact of LVDD on submaximal exercise responses (8) and maximal exercise capacity (21) has been reported. ...
The aim of this study was to examine the impact of well-controlled uncomplicated type 2 diabetes (T2D) on exercise performance. Six obese sedentary men with T2D and 7 control participants without diabetes matched for age, sex and body mass index were recruited. Anthropometric characteristics, blood samples, resting cardiac and pulmonary functions and maximal oxygen uptake (VO 2 max) and ventilatory threshold were measured on a first visit. On the four subsequent visits, participants performed step transitions (6 min) of moderate-intensity exercise on an upright cycle ergometer from unloaded pedaling to 80 % of ventilatory threshold. VO 2 (τVO 2 ) and HR (τHR) kinetics were characterized with a mono-exponential model. VO 2 max (27.8±4.0 vs. 27.5±5.3 ml kg ⁻¹ min ⁻¹ ; p=0.95), τVO 2 (43±6 vs. 43±10 s; p=0.73) and τHR (42±17 vs. 43±13 s; p=0.94) were similar between diabetics and controls respectively. The remaining variables were also similar between groups. These results suggest that well-controlled T2D is not associated with a reduction in VO 2 max or slower τVO 2 and τHR.
... Tissue Doppler E/E′, which is the ratio of transmitral flow to mitral annular velocity, is a marker of assessment of increased LVEDP and it has been correlated with glycated hemoglobin (HbA1C) levels and hence glycemic control in patients with diastolic dysfunction. 44 In a study by Boyer et al including patients with DM, 46% were diagnosed with diastolic dysfunction by Doppler echocardiography and the percentage increased to 74% after addition of TDI. 45 Left atrial volume index is also independently associated with the degree of diastolic dysfunction. 46 In another study by Bonito et al, 47 half of the patients with normal diastolic function by standard Doppler echocardiography had abnormal TDI velocities, suggesting diastolic dysfunction. ...
Diabetes causes cardiomyopathy and increases the risk of heart failure independent of hypertension and coronary heart disease. This condition called "Diabetic Cardiomyopathy" (DCM) is becoming a well- known clinical entity. Recently, there has been substantial research exploring its molecular mechanisms, structural and functional changes, and possible development of therapeutic approaches for the prevention and treatment of DCM. This review summarizes the recent advancements to better understand fundamental molecular abnormalities that promote this cardiomyopathy and novel therapies for future research. Additionally, different diagnostic modalities, up to date screening tests to guide clinicians with early diagnosis and available current treatment options has been outlined.
... (42) Thus, TDI has an obvious complementary role in the assessment of DD and this role should be applied clinically, and in addition to its diagnostic use it can give us a prognostic guide depending on LV filling indices. (43)(44)(45)(46)(47)(48) Definitions and grading: (49,50) * E-wave [early left ventricle (LV) filling -reflects the period of active LV relaxation. * A-wave (late LV filling) -reflects LV-LA pressure gradient in diastole , influenced by LV relaxation. ...
Background: Left ventricular diastolic dysfunction (DD) is considered the first stage of diabetic cardiomyopathy; it occurs in absence of coronary artery disease, hypertension or valvular heart disease &can precede the systolic dysfunction in these patients. Objectives of the study: The purpose of this study is to assess the diastolic function in diabetic patients of both types 1&2 using conventional, Doppler echocardiograghy and tissue Doppler imaging, and to reveal the impact of age, gender & duration of diabetes on prevalence and grading of DD. Patients and methods: This is an observational case control analytic study in which 100 persons were enrolled, 50 of them were diabetic patients, and the other 50 were age, sex matched healthy control subjects. In both groups` groups`systolic and diastolic functions were assessed by conventional, Doppler and tissue Doppler echocardiography. Results: Among the 50 patients, 27 (54%) of them were females and 23 (46%) were males, 27 (54%) of them were type1 diabetes and 23(46%) were type2 diabetes. Control group consisted of 50 subjects including 24(48%) females and 26(52%) males. Patient's age ranges from 15 to 70 years with mean age (39±16.09), control subject's age ranges from 15 to 72 years with mean age (37.64±14.53). There was significant relationship between aging and prevalence of DD (P value=0.02).Gender not related to prevalence of diastolic dysfunction. There was significant decrease in E/A ratio between both groups (P value=0.0007), while E/É ratio between both groups was not significant. DD also was higher in type2 diabetes compared with type1 (P value<0.001).Diabetic duration has no impact on prevalence of DD. Conclusion: Diabetic patients have significant DD detected on both conventional and tissue Doppler echocardiography. Diastolic function is affected with increasing age, but not with gender. The diabetic cardiac changes as well as the echocardiographic parameters seem not to be affected with diabetic duration.
... Previous studies analyzed endothelial function, arterial stiffness, CIMT, autonomic neuropathy and left ventricular (LV) function in T1D-associated hyperglycemia with preclinical atherosclerosis [3][4][5][6]. After an 18-year follow-up period, the Oslo study confirmed correlation between HbA1c and the degree of atherosclerosis examined by intravascular ultrasound. ...
Individuals with type 1 diabetes have an increased risk of premature atherosclerosis. The aim of this study was to evaluate the possible predictive significance of elevated plasma total homocysteine (tHcy), lower serum 25-hydroxy vitamin D (25(OH)D) concentrations and increased carotid intima-media thickness (CIMT) for the development of coronary atherosclerosis in patients with type 1 diabetes mellitus (T1D) and no previous history of ischemic heart disease. The study included 73 patients previously diagnosed with T1D. The patients were divided into groups with and without non-obstructive moderate coronary artery stenosis. Coronary artery stenosis was examined using coronary multidetector computed tomographic angiography (MDCTA); CIMT was measured by B-mode ultrasound. The patients with moderate stenosis had significantly higher HbA1c (p
... Doppler imaging studies have been used to provide load-independent assessments of cardiac relaxation. These studies not only have confirmed evidence of diastolic dysfunction in asymptomatic patients with diabetes but also have demonstrated a direct relationship between the extent of diastolic dysfunction and glycemic control [28] . Although diastolic dysfunction is the hallmark of diabetic cardiomyopathy, concomitant subtle systolic dysfunction is present even at earlier stages of the disease [23] . ...
... Нагромадження колагену в міокарді при ЦД частково зумовлене сповільненням його деградації внаслідок глікозилювання залишків лізину на колагені [321]. Патологія серця при ЦД може просто відображати збільшений інтерстиціальний фіброз у міокарді, тому що нагромадження колагену відбувається головним чином внаслідок збільшення кількості колагену III типу [453]. Дослідження біопсійного матеріалу виявило гіпертрофію кардіоміоцитів і внутрішньотканинний фіброз міокарда навіть при помірному ЦД [417], що підтверджено і при патанатомічному дослідженні (рис. ...
... Hyperglycemia is associated with subclinical CVD measured by tests of endothelial function, arterial stiffness, cIMT, autonomic neuropathy and left ventricular function in patients with T1DM [1,[28][29][30][31][32][33][34][35][36]. The severity of atherosclerosis by intravascular ultrasound correlates with an increase in HbA1c. ...
Background:
Cardiovascular disease (CVD) as a result of macrovascular changes is the leading cause of mortality in patients with type 1 diabetes (T1DM). While CVD complications are seen predominantly in adulthood, the atherosclerotic process begins in childhood and is accelerated in patients with T1DM. This review focuses on the epidemiology of traditional CVD risk factors in adolescents with T1DM, its association with markers of CVD and an overview of studies looking into each individual risk factor.
Conclusion:
The risk factors that are reviewed here are hypertension, dyslipidemia, smoking, obesity, lack of exercise, hyperglycemia and diabetic nephropathy. We highlight the importance of early identification, and interventions, which include optimizing glycemic control, pharmacotherapy, regular physical activity and dietary changes.
... Since metformin has been associated with a small reduction in maximal aerobic capacity (Braun et al. 2008), it is worth mentioning that exclusion of the two diabetics using metformin from our analyses (data not shown) did not influence our findings. In addition, type 2 diabetes is usually associated with altered LV diastolic function (Shishehbor et al. 2003;Boyer et al. 2004;Baldi et al. 2006;Erdogan et al. 2011). The negative impact of LVDD on submaximal exercise responses (Regensteiner et al. 2009) and maximal exercise capacity (Poirier et al. 2000) has been reported. ...
The aim of this study was to examine the impact of well-controlled uncomplicated type 2 diabetes (T2D) on exercise performance. Ten obese sedentary men with T2D and nine control participants without diabetes matched for age, sex, and body mass index were recruited. Anthropometric characteristics, blood samples, resting cardiac, and pulmonary functions and maximal oxygen uptake (VO2max) and ventilatory threshold were measured on a first visit. On the four subsequent visits, participants (diabetics: n = 6; controls: n = 7) performed step transitions (6 min) of moderate-intensity exercise on an upright cycle ergometer from unloaded pedaling to 80% of ventilatory threshold. VO2 (τVO2) and HR (τHR) kinetics were characterized with a mono-exponential model. VO2max (27.0 ± 3.4 vs. 26.7 ± 5.0 mL kg−1 min−1; P = 0.85), τVO2 (43 ± 6 vs. 43 ± 10 sec; P = 0.73), and τHR (42 ± 17 vs. 43 ± 13 sec; P = 0.94) were similar between diabetics and controls respectively. The remaining variables were also similar between groups, with the exception of lower maximal systolic blood pressure in diabetics (P = 0.047). These results suggest that well-controlled T2D is not associated with a reduction in VO2max or slower τVO2 and τHR.
... For several years, most studies in type 2 diabetes were focused mainly on LV structural and functional abnormalities (Fang et al., 2003;Galderisi, 2006;Jarnert et al., 2008;Poulsen et al., 2010;Shishehbor et al., 2003). In recent years, however, there has been a growing scientific interest in exploring the functional and structural changes of the LA as well as the prognostic impact of LA enlargement on CVD outcomes in this patient population (Kadappu et al., 2012;Poulsen et al., 2013;Tadic & Cuspidi, 2015). ...
... Glycemia is associated with preclinical atherosclerosis in studies that include tests of endothelial function, arterial stiffness, cIMT, autonomic neuropathy, and left ventricular (LV) function in T1DM. 16,39,[126][127][128][129][130][131][132] The extent of atherosclerosis by intravascular ultrasound also correlated with HbA 1c over 18 years of follow-up in the Oslo Study; a 1% increase in mean HbA 1c was associated with a 6.4% increase in coronary vessel stenosis. 78 Intensive DM therapy has been shown to prevent the increase in resting heart rate characteristic of patients with T1DM, 133 and autonomic function was significantly better in patients with intensive DM management. ...
Despite the known higher risk of cardiovascular disease (CVD) in individuals with type 1 diabetes mellitus (T1DM), the pathophysiology underlying the relationship between cardiovascular events, CVD risk factors, and T1DM is not well understood. Management approaches to CVD reduction have been extrapolated in large part from experience in type 2 diabetes mellitus (T2DM), despite the longer duration of disease in T1DM than in T2DM and the important differences in the underlying pathophysiology. Furthermore, the phenotype of T1DM is changing. As a result of the findings of the Diabetes Control and Complications Trial (DCCT), which compared intensive glycemic control with usual care, and its follow-up observational study, Epidemiology of Diabetes Interventions and Complications (EDIC), intensive management of diabetes mellitus (DM) has become the standard of care and has led to increasing longevity. However, our understanding of CVD in T1DM comes in large part from the previous era of less intensive glycemic control. More intensive glycemic control is associated with significant risk of weight gain, which may be magnified by the obesity epidemic. There is growing interest in better understanding the adverse effects of glycemia, the prevalence and type of lipid abnormalities in T1DM, the prognostic role of albuminuria and renal insufficiency, and the role of blood pressure (BP) in CVD. Obesity-associated metabolic abnormalities such as the proinflammatory state likely modify CVD risk in T1DM; however, the effect may be different from what is seen in T2DM. These concepts, and how they may affect management, have not been fully explored.
The present review will focus on the importance of CVD in patients with T1DM. We will summarize recent observations of potential differences in the pathophysiology of T1DM compared with T2DM, particularly with regard to atherosclerosis. We will explore the implications of these concepts for treatment of CVD risk factors in patients with …
... Diastolic dysfunction (DD) is the most frequent echocardiographic finding in asymptomatic T1DM patients with normal LVEF. DD in T1DM have mainly been examined by standard echocardiography parameters like E/A, and also by tissue Doppler imaging like E/e' [11][12][13][14][15][16]. Routine diastolic parameter E/A cannot distinguish pseudonormal and normal patterns of transmitral inflow because of its preload dependence. ...
Objectives
To clarify the time-course changes in left ventricular myocardial deformation using velocity vector imaging and to provide insights into our understanding of the cardiac pathophysiology in diabetes mellitus.
Methods
Thirty New Zealand white rabbits were randomly divided into either the control group (n = 10) or the diabetes mellitus (DM) group (induced with STZ, n = 20). For the myocardial deformation studies, echocardiography and syngo-vector velocity imaging (VVI) were performed at baseline and after 2, 4, 8, and 12 weeks in all of the rabbits. The left ventricular (LV) global longitudinal and circumferential strain and strain rate were measured. For histomorphological study of the heart structure, 2 of the STZ-induced rabbits were killed at 2, 4, 8, and 12 weeks. Routine hematoxylin and eosin staining was performed.
Results
At 2 weeks, the global longitudinal strain (GLS), systolic strain rate (GLSRs), and diastolic strain rate (GLSRd) were significantly lower in the DM group compared with the control group (-18.16% versus -24.00%, -1.86 s-1 versus -2.49 s-1, 1.93 s-1 versus 2.42 s-1, respectively, P < 0.05), while, compared with the control group, the global circumferential strain (GCS), systolic strain rate (GCSRs), and diastolic strain rate (GCSRd) in the DM group were significantly decreased (-12.77% versus -23.31%, -1.31 s-1 versus -2.20 s-1, 1.41 s-1 versus 2.15 s-1, respectively, P < 0.05) at 8 weeks. With the progression of untreated diabetes, the histoanatomical alterations intensified gradually beginning at 2 weeks.
Conclusions
The progressive impairments in LV myocardial deformation and structure occurred early in diabetic rabbits with normal LV ejection fraction (EF), FS, and E/A. VVI could be used to evaluate subtle cardiac dysfunction in the early phase of DM.
... Poor glycemic control has been observed to be a risk factor for development of poor systolic and diastolic function [6,7,[32][33][34]. The effect of hyperglycemia on the heart is believed to influence heart metabolism via the production of advanced glycosylation end products, oxidative stress, and protein kinase C activation [33]. ...
The influence of disease duration and glycemic control on cardiac function in type 1 diabetes mellitus (T1DM) patients remains controversial. There is little data on young patients in the Sub-Saharan continent. The aim of this study was to determine the effect of disease duration and glycemic control on the cardiac function of children and adolescents with diabetes using echocardiography. In this cross sectional study, 26 T1DM subjects and 33 matched controls had conventional echocardiography done. The relationship between their cardiac parameters, disease duration and glycated hemoglobin (HbA1c) level was assessed with correlation and regression analysis. Five (19.2 %) subjects had evidence of abnormal fractional shortening. There was no significant difference in systolic function between the diabetics and controls. The isovolumic relaxation time and Deceleration time were significantly prolonged in the diabetics (P = 0.034, P = 0.001 respectively). There was a significant correlation between disease duration and end diastolic diameter (EDD) (P = 0.000) and Left ventricular mass (P = 0.000). Disease duration was also an independent predictor of EDD (P = 0.007), even after adjusting for age, body mass index and mean arterial pressure. There were no significant correlations between HbA1c and measures of cardiac structure or function. The right ventricular diastolic function was poorer in the T1DM subjects compared to the controls. Thus, the disease duration independently predicts left ventricular enlargement in this population of Sub-Saharan youths (who have relatively poor glycemic control).
... 3,4 None of these studies, however, have excluded coronary artery disease by angiography. 1,2,4 LV dysfunction in the absence of hypertension, coronary artery and valvular heart disease has been defined as diabetic cardiomyopathy. 5 However, there are still uncertainties about the diagnosis of diabetic cardiomyopathy and how it develops. ...
Our aims were to study left ventricular (LV) function and myocardial blood flow reserve (MBFR) in long-term type 1 diabetes and associations with advanced glycation end products (AGEs). A total of 20 type 1 diabetes patients from the Oslo Study without significant stenosis on coronary angiography were compared with 26 controls. LV systolic and diastolic functions were assessed by two-dimensional strain and the ratio between pulsed Doppler transmitral early (E) velocity and tissue Doppler velocity (E'), respectively. MBFR was evaluated by contrast echocardiography. The AGE methylglyoxal-derived hydroimidazolone was analysed in serum. Glyoxal hydroimidazolone in skin collagen was determined by liquid chromatography-mass spectrometry. Strain was significantly reduced (-19.5% ± 1.9% vs -21.4% ± 3.5%, p < 0.05), and E/E' increased in the diabetes patients compared to controls, 7.3 ± 2 versus 6.0 ± 1.5, p < 0.05. Significant lower MBFR was present in the diabetes patients, 3.4 (2.1, 5.3) versus 5.9 (3.9, 9.6), p < 0.01. Both AGEs correlated significantly with E/E'. The impaired LV function with correlation to AGEs in concert with reduced MBFR in diabetics without coronary artery disease may indicate possible mechanisms for diabetic cardiomyopathy.
... They also were not able to show any correlation between metabolic control and ventricular function, a finding which is similar to our results. Diastolic and systolic functions were reported to be correlated with metabolic control in studies performed on adults (37,38). ...
Objective
Adiponectin and high-sensitivity C-reactive protein (hsCRP) can be used as early biochemical markers of cardiovascular diseases (CVDs). Radiologically, non-invasive flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (CIMT) measurements may be used as indicators in the early diagnosis of CVDs. To compare the biochemical markers of atherosclerosis with radiological markers of CVDs (CIMT, FMD, ventricular systolic and diastolic functions) and to assess the relationship of these parameters with metabolic control in diabetic children and adolescents. Methods: A total of 55 patients with type 1 diabetes mellitus (T1DM) of at least 5-year duration and 30 healthy subjects were included in the study. Serum adiponectin, hsCRP, hemoglobin A1c (HbA1c), and lipid levels were evaluated in the patients and in the controls. CIMT, FMD, ventricular systolic and diastolic functions were assessed by echocardiography.Results: Mean age of the patients with diabetes was 17.6 years; mean diabetes duration was 10.4 years. Mean serum hsCRP was elevated in children with diabetes (0.21±0.31 vs. 0.10±0.16 μg/mL, p=0.00), while no significant difference from the controls was found in adiponectin levels. Mean CIMT was significantly higher in diabetic children compared to the control group (0.53±0.11 vs. 0.34±0.46 mm, p=0.00). Mean FMD of the diabetic children was significantly lower than that of the controls (6.86±2.85% vs. 12.13±1.99%, p=0.00). Diabetes duration was positively correlated with CIMT and negatively correlated with FMD. Right ventricular (RV) and left ventricular (LV) myocardial performance index (MPI) were higher in the patient group (p=0.00). Conclusions: Our data suggest that in addition to standard echocardiography, tissue Doppler echocardiography, FMD, and CIMT can be used as early-stage radiological markers and hsCRP as an early-stage biochemical marker of atherosclerosis in the routine follow-up of T1DM patients.
... Prior studies have shown a correlation between HbA 1c and diastolic function in older individuals with type 1 diabetes, suggesting that glycemic control may be an important determinant of diastolic function (11). ...
SUMMARY Left ventricular diastolic dysfunction is a main feature of diabetic heart disease. The aim of this prospective study was to evaluate the relation of hemoglobin A 1c and diastolic function in type 1 diabetes mellitus. We examined echocardiographic studies of 25 patients with type 1 diabetes without clinical evidence of heart disease and 25 healthy age- and sex-matched normal individuals. In patients with type 1 diabetes, there was a diastolic dysfunction with lower transmitral E/A (1.28±0.3 vs. 1.6±0.3; p=0.01), more prolonged isovolumic relaxation time (99±11 vs. 71±8, p=0.003) in comparison with normal subjects. Furthermore, HbA 1c correlated with diastolic indices. These results demonstrate that asymptomatic diastolic dysfunction is common in patients with type 1 diabetes mellitus and that its severity correlates with glycemic control.
... Peripheral brachial BP was used to calculate AD, rather than central arterial BP, but this calculation has been used before in other studies (52)(53)(54). Diastolic dysfunction was not assessed, although this impairment has been found in T1DM individuals (55,56). We were also unable to recruit our own age-and sex-matched normal subjects but have compared our T1DM results to those of normal subjects in the literature. ...
Intensive diabetes therapy reduces the prevalence of coronary calcification and progression of atherosclerosis, and the risk of cardiovascular disease events in the DCCT/EDIC study. The effects of intensive therapy on measures of cardiac function and structure and their association with glycemia have not been explored in type 1 diabetes (T1DM). We assess whether intensive treatment compared to conventional treatment during the DCCT led to differences in these parameters during EDIC. After 6.5 years of intensive versus conventional therapy in the DCCT, and 15 years additional follow-up in EDIC, left ventricular indices were measured by cardiac magnetic resonance (CMR) imaging in 1017 of the 1371 members of the DCCT cohort. There were no differences between the DCCT intensive versus conventional treatment in end diastolic volume, end systolic volume, stroke volume, cardiac output, left ventricular mass, ejection fraction, LV mass/EDV, nor aortic distensibility. Mean DCCT/EDIC HbA1c over time was associated with EDV, SV, CO, LVmass, LVmass/EDV, and AD. These associations persisted after adjustment for CVD risk factors. Cardiac function and remodeling in T1DM assessed by CMR in the EDIC cohort was associated with prior glycemic exposure, but there was no effect of intensive versus conventional treatment during the DCCT on cardiac parameters.
... PLB protein and mRNA levels were significantly increased in diabetic rats [104]. Depressed SERCA-2a activity will cause inefficient sequestration of Ca 2? in the sarcoplasmatic reticulum (SR), resulting in Ca 2? overload in the cytosol and impaired relaxation, which would correlate with clinical findings of diastolic dysfunction [187]. Indeed, over-expression of SERCA-2a improves calcium handling [211] and protects against cardiomyopathy in diabetic rodents [204]. ...
Diabetes mellitus is an important and prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs in diabetic patients independent of a recognized cause such as coronary artery disease or hypertension. The disease course consists of a hidden subclinical period, during which cellular structural insults and abnormalities lead initially to diastolic dysfunction, later to systolic dysfunction, and eventually to heart failure. Left ventricular hypertrophy, metabolic abnormalities, extracellular matrix changes, small vessel disease, cardiac autonomic neuropathy, insulin resistance, oxidative stress, and apoptosis are the most important contributors to diabetic cardiomyopathy onset and progression. Hyperglycemia is a major etiological factor in the development of diabetic cardiomyopathy. It increases the levels of free fatty acids and growth factors and causes abnormalities in substrate supply and utilization, calcium homeostasis, and lipid metabolism. Furthermore, it promotes excessive production and release of reactive oxygen species, which induces oxidative stress leading to abnormal gene expression, faulty signal transduction, and cardiomyocytes apoptosis. Stimulation of connective tissue growth factor, fibrosis, and the formation of advanced glycation end-products increase the stiffness of the diabetic hearts. Despite all the current information on diabetic cardiomyopathy, translational research is still scarce due to limited human myocardial tissue and most of our knowledge is extrapolated from animals. This paper aims to elucidate some of the molecular and cellular pathophysiologic mechanisms, structural changes, and therapeutic strategies that may help struggle against diabetic cardiomyopathy.
... 37 A significant positive relationship between LA volume, E/eЈ ratio, and glycemic control has been previously reported in T2DM patients. 38 Second, they had a lower aЈ velocity, which reflects LA systolic performance and is inversely correlated with LV filling pressure. 39 Third, the IVRT/T E-eЈ ratio, which provides incremental information to the E/eЈ ratio on LV filling pressure in subjects with normal ejection fraction and E/eЈ ratio between 8 and 15, 21,25 was lower in patients with abnormal MTWA than in those with normal MTWA, thus further supporting a raised LVEDP among these patients. ...
Abnormal microvolt T-wave alternans (MTWA), a marker of ventricular arrhythmic risk, is a highly prevalent condition in patients with type 2 diabetes mellitus (T2DM) and is correlated with glycemic control. However, there is uncertainty as to whether central or peripheral hemodynamic factors are associated with abnormal MTWA in T2DM individuals.
We studied 50 consecutive, well-controlled T2DM outpatients without a history of ischemic heart disease and with normal systolic function. All patients underwent a complete echocardiographic Doppler evaluation with spectral tissue Doppler analysis. MTWA analysis was performed noninvasively during submaximal exercise. Effective arterial elastance, arterial compliance, and heart rate variability were also measured. Compared with patients with MTWA negativity (n = 38), those with MTWA abnormality (n = 12, 24%) had significantly lower e' (7.6 ± 1.3 versus 9.1 ± 1.7 cm/s; P < 0.01), a' (10.2 ± 1.6 versus 12.7 ± 1.9 cm/s; P < 0.001) and s' velocities (8.7 ± 1.1 versus 10.2 ± 1.5 cm/s; P = 0.001) and higher indexed left ventricular mass (121.3 ± 16.4 versus 107.5 ± 16.5 g/m2; P = 0.016), indexed left atrial volume (33.5 ± 11.9 versus 23.6 ± 5.6 mL/m2; P < 0.001), and E/e' ratio (8.8 ± 1.4 versus 6.5 ± 1.3; P < 0.001). Multivariable logistic regression analysis revealed that higher E/e' ratio was the only independent correlate of abnormal MTWA (adjusted odds ratio, 3.52; 95% confidence interval, 1.19 to 10.6; P = 0.02) after controlling for glycemic control and other potential confounders.
In this pilot study, we found that early diastolic dysfunction, as measured by tissue Doppler imaging, is independently associated with MTWA abnormality in T2DM individuals with normal systolic function. Further larger studies are needed to examine the reproducibility of these results.
... Few studies have been examined DD using TDI in type 1 diabetic patients. [19][20][21][22] Nevertheless, exact effect of diabetes-related factors (glycemic control, duration of diabetes, occurrence of complication) on diastolic function is still controversial and has been poorly settled. 20, 23 We sought to compare diastolic parameters of both PW Doppler and relatively novel TDI in patients having type 1 DM and healthy controls to evaluate the impact of possible diabetes on left ventricular dysfunction. ...
We sought to compare diastolic parameters in patients having type 1 diabetes mellitus (DM) and healthy controls using both pulse-wave (PW) Doppler and relatively novel tissue-Doppler imaging (TDI) to evaluate the possible effect of diabetes on left ventricular dysfunction.
One hundred and thirty-two patients were evaluated (81 type 1 diabetic patients and 51 healthy volunteers). The detailed M-mode, two-dimensional, colour Doppler; PW Doppler; and TDI analyses were performed on resting subjects in a regular setting. Posterior wall thickness, left atrial indexed diameter, and A velocity were significantly higher in the diabetics when compared with control group (P = 0.019, <0.001, 0.033, respectively). Rest of the M-mode and PW Doppler parameters of diabetics were comparable with those of control subjects (P > 0.05 for all). However, both septal E' and lateral E' velocities were significantly lower in diabetics than in the control subjects on TDI echocardiographic examination (P < 0.001 and 0.011, respectively). In addition, E'/septal E' and E/lateral E' ratios were significantly higher in the diabetic group (P < 0.001 and 0.008, respectively).
TDI is a more accurate and powerful method than PW or M-mode in determination of early cardiac involvement related to type 1 DM even in the subclinical phase as well as hereditary cardiomyopathies.
Prevention of heart failure is an urgent public health need with national and global implications. Despite recent advances in the therapy of cardiovascular disorders, heart failure remains a challenging disease with a high prevalence and a dismal long-term prognosis. It is evident that the heart failure burden will not be eliminated by an improvement in the survival of patients who are already affected with the disease; instead, a drastic reduction in the incidence of heart failure is required to prevent an increase in the heart failure burden. It is therefore important that we develop a strategy of prevention of heart failure that applies to the large number of “at-risk” individuals. Such a strategy would complement our current approaches that are aimed at intensive management of patients with manifest heart failure. There are established risk factors and structural prerequisites for the development of heart failure and therapeutic interventions performed even before the appearance of left ventricular dysfunction or symptoms can prevent the development of heart failure. The burden of heart failure risk factors and the effect of their prevention and treatment on incident heart failure are examined in this chapter.
Heart failure is common in the diabetic population, but while diabetic cardiomyopathy can cause heart failure, it is underestimated. Hyperglycemia, dyslipidemia and inflammation in diabetes are thought to play key roles in the pathogenesis of diabetic cardiomyopathy. Echocardiography has been the optimal noninvasive imaging test to evaluate the presence of cardiac dysfunction and it can provide clues to detect diabetic cardiomyopathy. This review discusses the echocardiographic findings of diabetic cardiomyopathy.
According to estimates, around 5% of the world population has hazel eyes. And there are about as many people with diabetes mellitus (DM). Red hair occurs naturally in up to 2% of the human population. And about as many people are estimated to have atrial fibrillation (AF). If a hazel eyed person with red hair does not surprise us, should a diabetic patient with AF? Accumulating epidemiologic data suggest, however, that the DM-AF association may be more than a simple coincidence. But, how strong is this evidence? Experimental studies bring evidence for a DM-induced atrial proarrhythmic remodelling. But how relevant are these data for the clinical setting? In this review, we aim to provide a critical analysis of the existing clinical and experimental, epidemiologic, and mechanistic data that bridge DM and AF, we emphasize a number of questions that remain to be answered, and we identify hotspots for future research. The therapeutic implications of the DM-AF coexistence are also discussed, with a focus on rhythm control and on conventional and DM-specific upstream therapies for AF management.
Background: Diabetes mellitus is one of the most common diseases. Left ventricular diastolic dysfunction may represent the early stage of diabetic cardiomyopathy thus reinforcing the importance of the early examination of diastolic function in individuals with diabetes.Methods: This is a hospital based cross-sectional study done at a tertiary care hospital catering mainly to rural population. Patients having type 2 diabetes mellitus were scrutinized for doppler echocardiography and HbA1c levels. As per the previous studies and considering the prevalence of asymptomatic diastolic dysfunction in diabetics, the sample size was calculated. Statistical analysis was done by using descriptive and inferential statistics using chi square test.Results: In the present study 45 patients had HbA1C between 6.5- 8.0, out of which 9 had type I diastolic dysfunction, 1 had type II diastolic dysfunction and 35 had no diastolic dysfunction. 16 patients had HbA1C between 8.1- 9.5, out of which 7 had type I diastolic dysfunction, 8 had type II diastolic dysfunction and 1 had no diastolic dysfunction. 14 patients had HbA1C more than 9.5, out of which 4 had type I diastolic dysfunction, 5 had type II diastolic dysfunction, 4 had type III diastolic dysfunction and 1 patient did not had any diastolic dysfunction. The Chi-Square value is 55.51 and p value is 0.000 (Significant).Conclusions: Diastolic dysfunction correlates with the levels of glycosylated hemoglobin, duration of diabetes mellitus, presence of microvascular complications like diabetic retinopathy, neuropathy and nephropathy.
Background: Debut and/or progression of type 1 diabetes mellitus often occurs during adoles- cence, a stage characterized by the desire for independence and sometimes risky behaviors. The aim of the study was to compare glycemic control and epidemiology in adolescents and adults with type 1-Diabetes. Methods: We per- formed an observational cross-sectional study with 99 type 1 diabetics, assessing variables of medical history, laboratory results (glycemic control, urinary albumin excretion, lipid profile) and chronic micro and macrovascular complica- tions. Adolescents were defined as subjects aged 18 years or less and adults, subjects over 18. We performed a comparative analysis of the varia- bles between the adolescent group (n=34) and adult group (n=65) of the study. Results: The average age of the subjects was 25.0 ± 9.9 years, with an average duration of diabetes of 12.8 ± 8.6 years. There were statistically significant differences between adolescents and adults with type 1 diabetes in the following variables: age at diagnosis (P=0.005), baseline age (P=0.002), body mass index (P<0.001), presence of dyslipidemia (P<0.001), diabetic retinopathy (P=0.018) and diabetic nephropathy (P=0.001), insulin requirements (P=0.041), use of ACE inhibitors (P=0.001) and statins (P<0.001), HbA1c levels (P=0.009) and triglycerides (P=0.038). The average glycemic control was significantly worse in the adolescent group (HbA1c = 9.35 ± 2.26%) compared with adults (HbA1c = 8.23 ± 1.81%), however, this did not translate into increased prevalence of chronic complications at the time when analysis was made. Conclusions: Adolescence can exert a significant and deleterious effect on the metabol- ic control of type 1 diabetes mellitus compared with the adult stage of life.
Diabetic cardiomyopathy (DCM) was first recognized more than four decades ago and occurred independent of cardiovascular diseases or hypertension in both type 1 and type 2 diabetic patients. The exact mechanisms underlying this disease remain incompletely understood. Several pathophysiological bases responsible for DCM have been proposed, including the presence of hyperglycemia, nonenzymatic glycosylation of large molecules (e.g., proteins), energy metabolic disturbance, mitochondrial damage and dysfunction, impaired calcium handling, reactive oxygen species formation, inflammation, cardiac cell death, and cardiac hypertrophy and fibrosis, leading to impairment of cardiac contractile functions. Increasing evidence also indicates the phenomenon called “metabolic memory” for diabetes-induced cardiovascular complications, for which epigenetic modulation seemed to play an important role, suggesting that the aforementioned pathogenic bases may be regulated by epigenetic modification. Therefore, this review aims at briefly summarizing the current understanding of the pathophysiological bases for DCM. Although how epigenetic mechanisms play a role remains incompletely understood now, extensive clinical and experimental studies have implicated its importance in regulating the cardiac responses to diabetes, which are believed to shed insight into understanding of the pathophysiological and epigenetic mechanisms for the development of DCM and its possible prevention and/or therapy. © 2017 American Physiological Society. Compr Physiol 7:693-711, 2017.
Background:
Several studies have pointed out the existence of cardiac dysfunction in patients with type 1 diabetes mellitus (DM) even in the absence of ischemic, valvular, or hypertensive heart disease. The present study evaluated cardiac dysfunction and the relationship between severity of disease and degree of cardiac dysfunction in children with type 1 DM.
Methods:
In this prospective study, 31 patients with type 1 DM and 33 sex- and age-matched healthy children were evaluated with conventional echocardiography and tissue Doppler echocardiography (TDE). A correlation between cardiac functions and glycated hemoglobin (HbA1C) was examined.
Results:
TDE results indicated that mitral valve early diastolic annular peak flow rate (E'), mitral valve systolic flow rate (S'), ratio of mitral valve early diastolic peak flow rate to mitral valve early diastolic annular peak flow rate (E/E'), and left ventricular (LV) myocardial performance index (MPI) were higher, and LV ejection time (ET) was shorter in patients with type 1 DM (p<0.05). In addition, tricuspid valve E' and right ventricular (RV) MPI were higher, while RV ET and tricuspid E/E' were lower in patients with type 1 DM compared to healthy children (p<0.05).
Conclusions:
Although conventional echocardiography revealed no difference between patients with type 1 DM and healthy children, TDE showed dysfunctions of both ventricles. This state is closely related to degree of blood glucose level control. These findings signify diagnostic value of TDE in the early detection of cardiac effects among patients with type 1 DM.
Diabetic cardiomyopathy increases the risk of heart failure and death. At present, there are no effective approaches to preventing its development in the clinic. Here we report that reduction of cardiac GTP cyclohydrolase 1 (GCH1) degradation by genetic and pharmacological approaches protects the heart against diabetic cardiomyopathy. Diabetic cardiomyopathy was induced in C57BL/6 wild-type mice and transgenic mice with cardiomyocyte-specific overexpression of GCH1 with streptozotocin, and control animals were given citrate buffer. We found that diabetes-induced degradation of cardiac GCH1 proteins contributed to adverse cardiac remodeling and dysfunction in C57BL/6 mice, concomitant with decreases in tetrahydrobiopterin, dimeric and phosphorylated neuronal nitric oxide synthase, sarcoplasmic reticulum Ca(2+) handling proteins, intracellular [Ca(2+)]i, and sarcoplasmic reticulum Ca(2+) content and increases in phosphorylated p-38 mitogen-activated protein kinase and superoxide production. Interestingly, GCH-1 overexpression abrogated these detrimental effects of diabetes. Furthermore, we found that MG 132, an inhibitor for 26S proteasome, preserved cardiac GCH1 proteins and ameliorated cardiac remodeling and dysfunction during diabetes. This study deepens our understanding of impaired cardiac function in diabetes, identifies GCH1 as a modulator of cardiac remodeling and function, and reveals a new therapeutic target for diabetic cardiomyopathy.
Patients with diabetes have an increased risk for development of cardiomyopathy, even in the absence of well known risk factors like coronary artery disease and hypertension. Diabetic cardiomyopathy was first recognized approximately four decades ago. To date, several pathophysiological mechanisms thought to be responsible for this new entity have also been recognized. In the presence of hyperglycemia, non-enzymatic glycosylation of several proteins, reactive oxygen species formation, and fibrosis lead to impairment of cardiac contractile functions. Impaired calcium handling, increased fatty acid oxidation, and increased neurohormonal activation also contribute to this process. Demonstration of left ventricular hypertrophy, early diastolic and late systolic dysfunction by sensitive techniques, help us to diagnose diabetic cardiomyopathy. Traditional treatment of heart failure is beneficial in diabetic cardiomyopathy, but specific strategies for prevention or treatment of cardiac dysfunction in diabetic patients has not been clarified yet. In this review we will discuss clinical and experimental studies focused on pathophysiology of diabetic cardiomyopathy, and summarize diagnostic and therapeutic approaches developed towards this entity.
Diabetic cardiomyopathy is recognized as a distinct disease entity characterized by left ventricular dysfunction in absence of hypertension or coronary artery disease, and independent of glucose control. Early detection may be particularly important for preventing cardiovascular morbidity and mortality, but prospective evidence for this approach is lacking. The pathophysiology of diabetic cardiomyopathy does not remain completely understood. Besides several animal models, contemporary imaging techniques have helped not only to define this clinical entity, but to also understand pathophysiologic mechanisms. This review aims to highlight the current understanding of the disease process and to discuss current imaging methods and their limitations.
Heart failure is a well-recognized clinical problem in patients with diabetes. The Framingham Heart Study demonstrated that
patients with diabetes have an increased incidence of heart failure, which contributes significantly to their high cardiovascular
morbidity and mortality (1,2). The age-adjusted risk of developing heart failure was 2.4 times higher in diabetic than in nondiabetic men. In women, the
impact of diabetes was even more striking, with the risk of heart failure being 5.1 times greater in the presence of diabetes.
The incidence of heart failure in older patients was substantial: 22–27 per 1000 patient years over 18 years. Although Framingham
and many other studies did not distinguish between patients with type 1 and type 2 diabetes, the majority of their patients
had type 2 diabetes. However, in the era before treatment with combined oral hypoglycemic agents, many patients with type
2 diabetes were treated with insulin and such patients had a four- to fivefold increased risk of heart failure compared to
nondiabetic patients.
Since diabetic cardiomyopathy was first reported four decades ago, substantial information on its pathogenesis and clinical features has accumulated. In the heart, diabetes enhances fatty acid metabolism, suppresses glucose oxidation, and modifies intracellular signaling, leading to impairments in multiple steps of excitation-contraction coupling, inefficient energy production, and increased susceptibility to ischemia/reperfusion injury. Loss of normal microvessels and remodeling of the extracellular matrix are also involved in contractile dysfunction of diabetic hearts. Use of sensitive echocardiographic techniques (tissue Doppler imaging and strain rate imaging) and magnetic resonance spectroscopy enables detection of diabetic cardiomyopathy at an early stage, and a combination of the modalities allows differentiation of this type of cardiomyopathy from other organic heart diseases. Circumstantial evidence to date indicates that diabetic cardiomyopathy is a common but frequently unrecognized pathological process in asymptomatic diabetic patients. However, a strategy for prevention or treatment of diabetic cardiomyopathy to improve its prognosis has not yet been established. Here, we review both basic and clinical studies on diabetic cardiomyopathy and summarize problems remaining to be solved for improving management of this type of cardiomyopathy.
The mechanisms responsible for the increased risk of heart failure (HF) post-myocardial infarction (MI) may differ between patients with versus without diabetes. We hypothesized that after high-risk MI, patients with diabetes would demonstrate patterns of remodeling that are suggestive of reduced ventricular compliance and that are associated with an increased risk of death or HF.
We performed quantitative echocardiographic analysis in 153 patients with diabetes and 451 patients without diabetes enrolled in the VALIANT Echo study. Diabetes was associated with a higher risk of death or HF in age-adjusted models (hazard ratio 1.44, 95% CI 1.04-2.00, P = .028). Diabetic patients were similar to nondiabetic patients with respect to left ventricular (LV) volume and ejection fraction but had higher LV mass index (104.1 ± 27.5 vs 97.1 ± 28.6 g/m(2), P = .009), relative wall thickness (0.41 ± 0.08 vs 0.38 ± 0.07, P < .0001), and left atrial volume index (LAVi) (26.2 ± 8.1 vs 24.0 ± 8.2 mL/m(2), P = .008)-all parameters that were significantly related to the risk of death or HF hospitalization. Changes in LV volume and ejection fraction from baseline to 20 months were not different, although diabetic patients demonstrated greater increase in LAVi (4.4 ± 7.7 vs 2.2 ± 6.7 mL/m(2), P = .01).
After high-risk MI, diabetic patients were at higher risk of death or HF and demonstrated greater baseline LV mass index, relative wall thickness, and LAVi as well as greater left atrial enlargement at 20-month follow-up. These findings suggest greater baseline concentric remodeling and long-term elevation in LV diastolic pressure post-MI among diabetic patients, which may partially mediate this risk.
We assessed the relationship between diabetes and cardiac structure and function following myocardial infarction (MI) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular (LV) size.
The ASPIRE trial enrolled 820 patients 2-8 weeks after MI with ejection fraction ≤ 45% and randomized them to the direct renin inhibitor aliskiren (n= 423) or placebo (n = 397) added to standard medical therapy. Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies. Compared with non-diabetic patients, diabetic patients (n = 214) were at higher risk for a composite of cardiovascular (CV) death, heart failure hospitalization, recurrent MI, stroke, or aborted sudden death (14 vs. 7%; adjusted hazard ratio 1.63, 95% confidence interval 1.01-2.64, P= 0.045), despite similar left ventricular ejection fraction (37.9 ± 5.3 vs. 37.6 ± 5.2%, P= 0.48) and end-systolic volume (ESV) (84 ± 25 vs. 82 ± 28 mL, P= 0.46). Diabetic patients demonstrated greater concentric remodelling (relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07, P= 0.0002) and evidence of higher LV filling pressure (E/E' 11.1 ± 5.3 vs. 9.1 ± 4.3, P= 0.0011). At 36 weeks, diabetic patients experienced similar per cent reduction in ESV overall (-4.9 ± 17.9 vs. -5.5 ± 16.9, P= 0.67) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren (interaction P = 0.08).
Compared with non-diabetic patients, diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function. Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure, suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients.
This study assessed the impact of tissue Doppler derived myocardial early diastolic relaxation velocity (E(m)) on the other parameters of diastolic function (preload dependent transmitral early diastolic velocity [E], tissue Doppler derived myocardial late diastolic velocity [A(m)], preload dependent transmitral late diastolic velocity [A]) and evaluated the correlation of these parameters with selected clinical variables in type 2 diabetic patients. Using tissue Doppler echocardiography, 82 type 2 diabetic patients were evaluated, divided into two equal groups of E(m) < 7.5 cm/s or > or = 7.5 cm/s. Patients with E(m) < 7.5 cm/s had significantly lower E/A and E(m)/A(m), and higher E/E(m) values. Multilinear regression showed a negative correlation between E(m) and glycated haemoglobin (Hb(A1c)) and duration of diabetes, a negative correlation of E(m)/A(m) with age, duration of diabetes and Hb(A1c), and a positive correlation of E/E(m) with age, duration of diabetes and use of diuretics. The E/A ratio only correlated negatively with age. It is concluded that E(m) is a reliable parameter of diastolic function, and that the tissue Doppler parameters of diastolic function are associated with diabetes compensation and diabetes duration.
Diabetic individuals have a significantly increased likelihood of developing cardiovascular disease. Whilst part of this association is explained by the presence of concomitant risk factors, large epidemiological studies have consistently reported diabetes as a strong risk factor for the development of heart failure after adjusting for such covariates. This has resulted in the notion that there is a distinct cardiomyopathy specific to diabetes, termed 'diabetic cardiomyopathy'. The natural history is characterized by a latent subclinical period, during which there is evidence of diastolic dysfunction and left ventricular hypertrophy, before overt clinical deterioration and systolic failure ensue. These clinical findings have been supported by a growing body of experimental data which support the notion that diabetes inflicts a direct insult to the myocardium, with cellular, structural and functional changes manifest as the diabetic myocardial phenotype. Several of these mechanisms appear to work in unison, forming complicated reciprocal pathways of disease. Reactive oxygen species and alterations in intracellular calcium homeostasis appear to play significant roles in many of these mechanisms. Determining the hierarchy of this cascade of disease will allow identification of the pathological trigger most responsible for disease. Translational research in this field is currently hindered by a lack of clinical studies and intervention trials specifically in patients with diabetic cardiomyopathy. Future clinical and experimental studies of accurate models of diabetic cardiomyopathy should help to define the true aetiology and lead to the development of specific pharmacotherapies for this condition, ultimately reducing the increased cardiovascular morbidity and mortality in diabetic patients.
The aim of this study was to evaluate atrial electromechanical coupling obtained by tissue Doppler imaging (TDI), left and right ventricular diastolic functions, and left atrial (LA) mechanical functions in patients with type 1 diabetes mellitus (DM-1).
A total of 43 patients with DM-1 (age 19.6 +/- 6.8 years) and 42 age- and gender-matched controls (age 19.5 +/- 6.4 years) were included. Atrial electromechanical coupling was measured with TDI and corrected for heart rate. P-wave dispersion (Pd) was calculated from the 12-lead electrocardiograms. Systolic and diastolic functions in both ventricles were assessed using conventional echocardiography and TDI. Myocardial performance index was calculated with TDI. LA maximal, minimal, and pre-systolic volumes were measured according to the biplane area-length method. LA mechanical function parameters were calculated.
Intra- and interatrial electromechanical delays and Pd were significantly higher in patients with DM-1 compared with controls (P = .02, P < .0001, and P = 0.005, respectively). A-wave velocity and isovolumic relaxation time were higher and E/A ratio was lower in patients with DM-1 (P = .03, P = .03, and P = .003, respectively). According to TDI, systolic velocities and myocardial performance index values of both ventricles were comparable. Diastolic filling velocities of the left ventricle, including E(m) global, A(m) global, E(m)/A(m) ratio, and right ventricular A(m), were different between groups (P = .03, P = .02, P < .001, and P = .02, respectively). LA passive emptying fraction was decreased, and LA active emptying volume and LA active emptying fraction were increased in patients with DM-1 (P = .02, P = .001, and P < .0001, respectively). Interatrial electromechanical delay was positively correlated with the presence of DM-1, age, LA active emptying fraction, and Pd (P < .001, P = .007, P < .001, and P = .002, respectively), and was negatively correlated with E(m)/A(m) ratio and LA passive emptying fraction (P < .001 and P = .001, respectively). In multivariate analyses, age and DM-1 were independent predictors of interatrial electromechanical delay (P = .001 and P < .001, respectively).
This study shows that intra- and interatrial electromechanical delays are prolonged diastolic functions of both ventricles and that LA mechanical functions are impaired in patients with DM-1. Age and the presence of DM-1 were independent factors of the interatrial electromechanical delay.
Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazolidinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy.
In experimental diabetes, diastolic dysfunction of the left ventricle has been associated with collagen-linked glycation. To determine whether less severe hyperglycemia may have similar effects, we gave alloxan to mongrel dogs (group 2) to induce impaired glucose tolerance (IGT) for comparison with normal subjects (group 1). After 6 months, hemodynamic studies were performed in the anesthetized animals. Basal heart rate, aortic pressure, and ejection fraction were comparable in the two groups, but calculated chamber stiffness was increased in group 2, associated with a reduced end diastolic volume and increased pressure. During infusion of dextran, the volume and pressure responses were similarly abnormal in group 2. In the myocardium, the collagen concentration rose with an increased interstitial distribution histologically. To assess glycation, collagen was extracted, digested with collagenase, and measured for fluorescence. Advanced glycation end products were increased in group 2 to 10.6 +/- 1.6 vs. 6.9 +/- 0.7 fluorescent units (FU)/mg collagen in group 1 (P < 0.01). To assess whether this could be pharmacologically prevented, we administered enalapril to inhibit ACE during the 6 months of glucose intolerance to group 3. This resulted in normal glycation and significant reduction in chamber stiffness increment. We gave group 4 animals aminoguanidine daily for 6 months, which prevented abnormal collagen glycation and chamber stiffness. Thus, in animals with IGT, collagen-linked glycosylation appeared to be a major factor affecting diastolic function and was shown to be amenable to pharmacological intervention.
In people with diabetes, glycation of apolipoproteins correlates with other indices of recent glycemic control, including HbA1. For several reasons, increased glycation of apolipoproteins may play a role in the accelerated development of atherosclerosis in diabetic patients. Recognition of glycated LDL by the classical LDL receptor is impaired, whereas its uptake by human monocyte-macrophages is enhanced. These alterations may contribute to hyperlipidemia and accelerated foam-cell formation, respectively. Glycation of LDL also enhances its capacity to stimulate platelet aggregation. The uptake of VLDL from diabetic patients by human monocyte-macrophages is enhanced. This enhancement may be due, at least in part, to increased glycation of its lipoproteins. Glycation of HDL impairs its recognition by cells and reduces its effectiveness in reverse cholesterol transport. Glycation of apolipoproteins may also generate free radicals, increasing oxidative damage to the apolipoproteins themselves, the lipids in the particle core, and any neighboring macromolecules. This effect may be most significant in extravasated lipoproteins. In these, increased glycation promotes covalent binding to vascular structural proteins, and oxidative reactions may cause direct damage to the vessel wall. Glycoxidation, or browning, of sequestered lipoproteins may further enhance their atherogenicity. Finally, glycated or glycoxidized lipoproteins may be immunogenic, and lipoprotein-immune complexes are potent stimulators of foam-cell formation.
Objectives:
This study assessed the clinical utility of mitral annulus velocity in the evaluation of left ventricular diastolic function.
Background:
Mitral inflow velocity recorded by Doppler echocardiography has been widely used to evaluate left ventricular diastolic function but is affected by other factors. The mitral annulus velocity profile during diastole may provide additional information about left ventricular diastolic function.
Methods:
Mitral annulus velocity during diastole was measured by Doppler tissue imaging (DTI) 1) in 59 normal volunteers (group 1); 2) in 20 patients with a relaxation abnormality as assessed by Doppler mitral inflow variables (group 2) at baseline and after saline loading; 3) in 11 patients (group 3) with normal diastolic function before and after intravenous nitroglycerin infusion; and 4) in 38 consecutive patients (group 4) undergoing cardiac catheterization in whom mitral inflow velocity and tau as well as mitral annulus velocity were measured simultaneously.
Results:
In group 1, mean +/- SD peak early and late diastolic mitral annulus velocity was 10.0 +/- 1.3 and 9.5 +/- 1.5 cm/s, respectively. In group 2, mitral inflow velocity profile changed toward the pseudonormalization pattern with saline loading (deceleration time 311 +/- 84 ms before to 216 +/- 40 ms after intervention, p < 0.001), whereas peak early diastolic mitral annulus velocity did not change significantly (5.3 +/- 1.2 cm/s to 5.7 +/- 1.4 cm/s, p = NS). In group 3, despite a significant change in mitral inflow velocity profile after nitroglycerin, peak early diastolic mitral annulus velocity did not change significantly (9.5 +/- 2.2 cm/s to 9.2 +/- 1.7 cm/s, p = NS). In group 4, peak early diastolic mitral annulus velocity (r = -0.56, p < 0.01) and the early/late ratio (r = -0.46, p < 0.01) correlated with tau. When the combination of normal mitral inflow variables with prolonged tau (> or = 50 ms) was classified as pseudonormalization, peak early diastolic mitral annulus velocity < 8.5 cm/s and the early/late ratio < 1 could identify the pseudonormalization with a sensitivity of 88% and specificity of 67%.
Conclusions:
Mitral annulus velocity determined by DTI is a relatively preload-independent variable in evaluating diastolic function.
Glucose irreversibly modifies long-lived macromolecules by forming AGEs as a function of glucose concentration and time. AGEs cause qualitative and quantitative changes in extracellular matrix components such as type IV collagen, laminin, and vitronectin. These AGE-induced changes can affect cell adhesion, growth, and matrix accumulation. AGE-modified proteins also alter cell function by interacting with specific receptors on macrophages and endothelial cells, inducing changes that promote matrix overproduction, focal thrombosis, and vasoconstriction. DNA and nuclear proteins also may be targets for AGE damage. The persistence of accumulated AGEs during periods of normal glucose homeostasis may explain the phenomenon of hyperglycemic memory. Pharmacological inhibition of in vivo AGE formation by aminoguanidine prevents or ameliorates diabetic retinopathy, nephropathy, and neuropathy in animal models. These data suggest that aminoguanidine and other AGE inhibitors have a potential therapeutic role in the treatment of diabetic patients.
To determine the accuracy of echocardiographic left ventricular (LV) dimension and mass measurements for detection and quantification of LV hypertrophy, results of blindly read antemortem echocardiograms were compared with LV mass measurements made at necropsy in 55 patients. LV mass was calculated using M-mode LV measurements by Penn and American Society of Echocardiography (ASE) conventions and cube function and volume correction formulas in 52 patients. Penn-cube LV mass correlated closely with necropsy LV mass (r = 0.92, p less than 0.001) and overestimated it by only 6%; sensitivity in 18 patients with LV hypertrophy (necropsy LV mass more than 215 g) was 100% (18 of 18 patients) and specificity was 86% (29 of 34 patients). ASE-cube LV mass correlated similarly to necropsy LV mass (r = 0.90, p less than 0.001), but systematically overestimated it (by a mean of 25%); the overestimation could be corrected by the equation: LV mass = 0.80 (ASE-cube LV mass) + 0.6 g. Use of ASE measurements in the volume correction formula systematically underestimated necropsy LV mass (by a mean of 30%). In a subset of 9 patients, 3 of whom had technically inadequate M-mode echocardiograms, 2-dimensional echocardiographic (echo) LV mass by 2 methods was also significantly related to necropsy LV mass (r = 0.68, p less than 0.05 and r = 0.82, p less than 0.01). Among other indexes of LV anatomy, only measurement of myocardial cross-sectional area was acceptably accurate for quantitation of LV mass (r = 0.80, p less than 0.001) or diagnosis of LV hypertrophy (sensitivity = 72%, specificity = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)
IN this seminar we review recent studies suggesting that the central pathologic features of diabetic complications are caused by the hyperglycemia-accelerated formation of nonenzymatic advanced glycosylation end products in tissue. We will emphasize new research findings with important clinical implications, since older information is available in previously published reviews.1 , 2 Other biochemical mechanisms by which hyperglycemia may contribute to the development of diabetic complications are not discussed here, since they are comprehensively reviewed elsewhere.3 4 5 6 7 8 Differences between Early and Advanced Glycosylation Products The central pathophysiologic features of diabetic vascular complications are an abnormal leakage of proteins from the circulation and a progressive . . .
Nonenzymatically glycosylated proteins gradually form fluorescent cross-linked protein adducts--a process termed "browning." The rate of this reaction increases with the glucose concentration. Assaying for the presence of browning products in long-lived proteins should therefore provide information on long-term metabolic control. We measured collagen-linked fluorescence typical for nonenzymatic browning in skin-biopsy specimens from 41 subjects with longstanding Type I diabetes and from 25 controls. Fluorescence correlated with age and (weakly) with the duration of diabetes. Mean age-adjusted fluorescence values were twice as high in diabetic subjects as in control subjects (P less than 0.0001) and increased with the severity of retinopathy, nephropathy, and arterial and joint stiffness. The correlation was significant for retinopathy (r = 0.42; P less than 0.01), arterial stiffness (r = 0.41; P less than 0.01), joint stiffness (r = 0.34; P less than 0.05), and the sum of all complications (r = 0.47; P less than 0.01). Fluorescence also correlated with systolic (r = 0.42; P less than 0.01) and diastolic (r = 0.36; P less than 0.05) blood pressures. If one can assume that the fluorescence results from a browning product of glucose, our data suggest that there is an overall correlation between the severity of diabetic complications and cumulative glycemia over many years.
In discussions of vascular complications of diabetes the fact that capillary basement membranes are, in general, thickened (CBMT) in poorly controlled diabetics is no longer at issue. However, three important questions concerning the pathophysiologic significance of CBMT remain unanswered: (1) How and why do capillary basement membranes thicken in diabetes? (2) What is the functional significance of capillary basement membrane changes in diabetes? (3) What is the nature of the relationship of CBMT to other forms of diabetic vascular disease; in particular, is CBMT observed in tissues amenable to needle biopsy, i.e., skeletal muscle, useful in identifying individuals at high risk for developing clinically significant retinopathy, nephropathy, or atherosclerotic vascular disease?
In this survey, we will consider the nature of capillary basement membrane changes in diabetes and subsequently address the above questions.
We explored the relation between the thickness of the quadriceps-muscle capillary basement membrane and the glycemia level in 102 young patients with Type I diabetes (median age, 17 years; range, 12 to 29). Membrane thickness was measured in serial biopsy specimens obtained after two consecutive 2 1/2-year observation periods, and glycemia was assessed in terms of glycosylated hemoglobin and fasting blood glucose levels determined at eight-week intervals. An association between membrane thickness and glycemia level was apparent in both cross-sectional and longitudinal analysis. Cross-sectional analysis of data on 39 postpubertal patients (growth less than 1.0 cm during the five years) showed a positive association of membrane thickness to glycosylated hemoglobin (r = 0.53, P = 0.0002) and blood glucose values (r = 0.37, P = 0.01) averaged over the antecedent 2 1/2-year period. By contrast, in 32 pubertal patients (growth greater than 7.5 cm) there was a significant negative association of membrane thickness to both glycosylated hemoglobin (r = -0.40, P = 0.01) and blood glucose (r = -0.42, P = 0.009). In longitudinal analysis, there was no correlation between changes in membrane thickness and average glycemia levels during the two follow-up periods in 32 pubertal patients (for glycosylated hemoglobin, r = 0.11; P = 0.25), but in the postpubertal group (n = 20) there was a significant positive covariation (r = 0.57, P = 0.0004). The data indicate that in postpubertal diabetic patients, the thickness of the muscle capillary basement membrane is positively related to the level of glycemia, but this relation does not obtain in the pubertal state.
To validate the use of pulsed Doppler tissue imaging that measures myocardial wall velocities and to define the characteristics of these velocities in normal subjects, we obtained and compared the anteroseptal and posterior wall velocities in 24 volunteers with pulsed Doppler tissue imaging and digitized M-mode echocardiography. We also studied the relation between velocity components and hemodynamic events timed by standard Doppler flows. There was an excellent correlation between Doppler and M-mode-derived velocities (r = 0.95, p < 0.001), with higher reproducibility for Doppler (r = 0.99) than for M-mode (r = 0.95, p < 0.001). Biphasic velocities that were uniformly present during isovolumic contraction and relaxation were attributed to geometric changes due to asynchronous contraction and ventricular interdependence. We conclude that wall velocities obtained by pulsed Doppler tissue imaging are accurate and reproducible. This method may prove useful for studying the contractile and elastic properties of the myocardium.
This study sought to determine the applicability of the combined information obtained from transmitral Doppler flow and color M-mode Doppler flow propagation velocities for estimating pulmonary capillary wedge pressure.
Although Doppler-derived measurements of left ventricular (LV) filling have been applied to determine left atrial pressure, their accuracy has been limited by the variable effect of ventricular relaxation in these indexes. Recently, flow propagation velocity measured by color M-mode Doppler echocardiography has been suggested as an index of ventricular relaxation.
We studied 45 patients admitted to the intensive care unit who underwent invasive hemodynamic monitoring. We measured peak early (E) and late (A) transmitral Doppler velocities, E/A ratio and flow propagation velocity (vp) and compared them by linear regression with pulmonary capillary wedge pressure (pw).
We found a modest positive correlation between pw and E (r = 0.62, p < 0.001) and the E/A ratio (r = 0.52, p < 0.001) and a negative correlation between pw and vp (r = -0.34, p = 0.02). By stepwise linear regression, only E and vp were statistically significant predictors of pw. However, the E/vp ratio provided the best estimate of pw (r = 0.80, p < 0.001; pw = 5.27 x [E/vp] + 4.6, SEE 3.1 mm Hg).
The ratio of component velocity (E) over the color M-mode propagation velocity during early LV filling, by correcting for the effect of LV relaxation, provides a better estimate of pw than standard measurements of transmitral Doppler flow.
This investigation was designed 1) to assess whether the early diastolic velocity of the mitral annulus (Ea) obtained with Doppler tissue imaging (DTI) behaves as a preload-independent index of left ventricular (LV) relaxation; and 2) to evaluate the relation of the mitral E/Ea ratio to LV filling pressures.
Recent observations suggest that Ea is an index of LV relaxation that is less influenced by LV filling pressures.
One hundred twenty-five study subjects were classified into three groups according to mitral E/A ratio, LV ejection fraction (LVEF) and clinical symptoms: 34 asymptomatic subjects with a normal LVEF and an E/A ratio > or =1; 40 with a normal LVEF, an E/A ratio <1 and no heart failure symptoms (impaired relaxation [IR]); and 51 with heart failure symptoms and an E/A ratio >1 (pseudonormal [PN]). Ea was derived from the lateral border of the annulus. A subset of 60 patients had invasive measurement of pulmonary capillary wedge pressure (PCWP) simultaneous with Doppler echocardiographic DTI.
Ea was reduced in the IR and PN groups compared with the group of normal subjects: 5.8 +/- 1.5 and 5.2 +/- 1.4 vs. 12 +/- 2.8 cm/s, respectively (p < 0.001). Mean PCWP (20 +/- 8 mm Hg) related weakly to mitral E (r = 0.68) but not to Ea. The E/Ea ratio related well to PCWP (r = 0.87; PCWP = 1.24 [E/Ea] + 1.9), with a difference between Doppler and catheter measurements of 0.1 +/- 3.8 mm Hg.
Ea behaves as a preload-independent index of LV relaxation. Mitral E velocity, corrected for the influence of relaxation (i.e., the E/Ea ratio), relates well to mean PCWP and may be used to estimate LV filling pressures.
Doppler echocardiography is one of the most useful clinical tools for the assessment of left ventricular (LV) diastolic function. Doppler indices of LV filling and pulmonary venous (PV) flow are used not only for diagnostic purposes but also for establishing prognosis and evaluating the effect of therapeutic interventions. The utility of these indices is limited, however, by the confounding effects of different physiologic variables such as LV relaxation, compliance and filling pressure. Since alterations in these variables result in changes in Doppler indices of opposite direction, it is often difficult to determine the status of a given variable when a specific Doppler filling pattern is observed. Recently, color M-mode and tissue Doppler have provided useful insights in the study of diastolic function. These new Doppler applications have been shown to provide an accurate estimate of LV relaxation and appear to be relatively insensitive to the effects of preload compensation. This review will focus on the complementary role of color M-mode and tissue Doppler echocardiography and traditional Doppler indices of LV filling and PV flow in the assessment of diastolic function.
Patients with type 2 diabetes often have impaired exercise capacity compared with nondiabetic subjects. Left ventricular (LV) diastolic dysfunction has been shown to limit exercise performance in nondiabetic subjects. Men with well-controlled type 2 diabetes were divided into 2 groups: normal LV diastolic function (group 1, n = 9) or LV diastolic dysfunction (group 2, n = 10) based on standard echocardiographic criteria using pulmonary veins and transmitral flow recordings. They were matched for age and had no evidence of systemic hypertension, macroalbuminuria, coronary artery disease, congestive heart failure, clinical diabetic complications, and thyroid disease. Good metabolic control was demonstrated by glycated hemoglobin levels of 6.7+/-1.6% and 6.6+/-2.5% (means +/- SD) in patients with LV diastolic dysfunction and in controls, respectively. Each subject performed a symptom-limited modified Bruce protocol treadmill exercise test. Maximal treadmill performance was higher in subjects with normal diastolic function compared with subjects with LV diastolic dysfunction when expressed in time (803+/-29 vs. 662+/-44 seconds, respectively, p<0.02) or in METs (11.4+/-1.2 vs. 9.5+/-1.9 METs, respectively, p<0.02). Moreover, there was a correlation between E/A ratio and exercise duration (r = 0.64, p = 0.004) or E/A ratio and METs (r = 0.658, p = 0.003). There were no significant differences in maximal heart rate, maximal systolic and diastolic blood pressure, or maximal rate-pressure product attained during the exercise test. In conclusion, this study demonstrated that LV diastolic dysfunction influences maximal treadmill performance and could explain lower maximal performance observed in patients with type 2 diabetes.
Noninvasive assessment of diastolic filling by Doppler echocardiography provides important information about left ventricular (LV) status in selected subsets of patients. This study was designed to assess whether mitral annular velocities as assessed by tissue Doppler imaging are associated with invasive measures of diastolic LV performance and whether additional information is gained over traditional Doppler variables.
One hundred consecutive patients referred for cardiac catheterization underwent simultaneous Doppler interrogation. Invasive measurements of LV pressures were obtained with micromanometer-tipped catheters, and the mean LV diastolic pressure (M-LVDP) was used as a surrogate for mean left atrial pressure. Doppler signals from the mitral inflow, pulmonary venous inflow, and TDI of the mitral annulus were obtained. Isolated parameters of transmitral flow correlated with M-LVDP only when ejection fraction <50%. The ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/E') showed a better correlation with M-LVDP than did other Doppler variables for all levels of systolic function. E/E' <8 accurately predicted normal M-LVDP, and E/E' >15 identified increased M-LVDP. Wide variability was present in those with E/E' of 8 to 15. A subset of those patients with E/E' 8 to 15 could be further defined by use of other Doppler data.
The combination of tissue Doppler imaging of the mitral annulus and mitral inflow velocity curves provides better estimates of LV filling pressures than other methods (pulmonary vein, preload reduction). However, accurate prediction of filling pressures for an individual patient requires a stepwise approach incorporating all available data.
To evaluate the prevalence of left ventricular (LV) diastolic dysfunction in patients with type 2 diabetes mellitus free of cardiovascular disease, we studied 86 normotensive men and women (mean age 46 +/- 6 years) with Doppler echocardiography. All subjects were asymptomatic for ischemic heart disease or heart failure. The traditional transmitral filling patterns were used to characterize diastolic physiology. The Valsalva maneuver was used to differentiate normal from pseudonormal LV filling pattern. All patients had a normal electrocardiogram at rest and a negative result on exercise echocardiography for inducible wall motion abnormalities. Global LV systolic function was normal (mean LV ejection fraction 58%, range 53% to 76%). Diastolic dysfunction was found in 41 subjects (47%) of which 26 (30%) had impaired relaxation and 15 (17%) had a pseudonormal filling pattern. The mean LV mass index was 101 g/m2 (range 86 to 122). All patients with a normal-filling physiology had gender-adjusted normal LV mass index (mean 93 +/- 11 g/m2), whereas 62% of those with either abnormal relaxation (mean 103 +/- 12 g/m2, p <0.001) or a pseudonormal pattern (mean 110 +/- 12 g/m2, p <0.001) had increased LV mass index. No subject in this cohort had restrictive diastolic physiology. In conclusion, diastolic dysfunction in type 2 diabetes mellitus patients is often found despite adequate metabolic control and freedom from clinically detectable heart disease. The Valsalva maneuver can unmask an additional 17% of patients with subclinical abnormal LV filling pattern, who otherwise would be classified as having a normal diastolic physiology. Increased LV mass index is closely associated with abnormal LV filling characteristics.
Because a pseudonormal pattern of ventricular filling has never been considered in studies that reported a prevalence of left ventricular diastolic dysfunction (LVDD) between 20 and 40%, our aim was to more completely evaluate the prevalence of LVDD in subjects with diabetes.
We studied 46 men with type 2 diabetes who were aged 38-67 years; without evidence of diabetic complications, hypertension, coronary artery disease, congestive heart failure, or thyroid or overt renal disease; and with a maximal treadmill exercise test showing no ischemia. LVDD was evaluated by Doppler echocardiography, which included the use of the Valsalva maneuver and pulmonary venous recordings to unmask a pseudonormal pattern of left ventricular filling.
LVDD was found in 28 subjects (60%), of whom 13 (28%) had a pseudonormal pattern of ventricular filling and 15 (32%) had impaired relaxation. Systolic function was normal in all subjects, and there was no correlation between LVDD and indexes of metabolic control.
LVDD is much more common than previously reported in subjects with well-controlled type 2 diabetes who are free of clinically detectable heart disease. The high prevalence of this phenomenon in this high-risk population suggests that screening for LVDD in type 2 diabetes should include procedures such as the Valsalva maneuver and pulmonary venous recordings to unmask a pseudonormal pattern of ventricular filling.
We sought to determine the effect of diabetes mellitus (DM) on left ventricular (LV) filling pattern in normotensive (NT) and hypertensive (HTN) individuals.
Diastolic abnormalities have been extensively described in HTN but are less well characterized in DM, which frequently coexists with HTN.
We analyzed the transmitral inflow velocity profile at the mitral annulus in four groups from the Strong Heart Study: NT-non-DM (n = 730), HTN-non-DM (n = 394), NT-DM (n = 616) and HTN-DM (n = 671). The DM subjects were further divided into those with normal filling pattern (n = 107) and those with abnormal relaxation (AbnREL) (n = 447).
The peak E velocity was lowest in HTN-DM, intermediate in NT-DM and HT-non-DM and highest in the NT-non-DM group (p < 0.001), with a reverse trend seen for peak A velocity (p < 0.001). In multivariate analysis, E/A ratio was lowest in HTN-DM and highest in NT-non-DM, with no difference between NT-DM and HTN-non DM (p < 0.001). Likewise, mean atrial filling fraction and deceleration time were highest in HTN-DM, followed by HTN-non-DM or NT-DM and lowest in NT-non-DM (both p < 0.05). Among DM subjects, those with AbnREL had higher fasting glucose (p = 0.03) and hemoglobin A1C (p = 0.04).
Diabetes mellitus, especially with worse glycemic control, is independently associated with abnormal LV relaxation. The severity of abnormal LV relaxation is similar to the well-known impaired relaxation associated with HTN. The combination of DM and HTN has more severe abnormal LV relaxation than groups with either condition alone. In addition, AbnREL in DM is associated with worse glycemic control.
Retinopathy, and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy