Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications.

The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.

Determinants of exercise capacity in patients with type 2 diabetes.

OBJECTIVE: Type 2 diabetes is associated with reduced exercise capacity, but the cause of this association is unclear. We sought the associations of impaired exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS: Subclinical left ventricular (LV) dysfunction was sought from myocardial strain rate and the basal segmental diastolic velocity (Em) of each wall in 170 patients with type 2 diabetes (aged 56 +/- 10 years, 91 men), good quality echocardiographic images, and negative exercise echocardiograms. The same measurements were made in 56 control subjects (aged 53 +/- 10 years, 29 men). Exercise capacity was calculated in metabolic equivalents, and heart rate recovery (HRR) was measured as the heart rate difference between peak and 1 min after exercise. In subjects with type 2 diabetes, exercise capacity was correlated with clinical, therapeutic, biochemical, and echocardiographic variables, and significant independent associations were sought using a multiple linear regression model. RESULTS: Exercise capacity, strain rate, Em, and HRR were significantly reduced in type 2 diabetes. Exercise capacity was associated with age (r = -0.37, P < 0.001), male sex (r = 0.26, P = 0.001), BMI (r = -0.19, P = 0.012), HbA(1c) (A1C; r = -0.22, P = 0.009), Em (r = 0.43, P < 0.001), HRR (r = 0.42, P < 0.001), diabetes duration (r = -0.18, P = 0.021), and hypertension history (r = -0.28, P < 0.001). Age (P < 0.001), male sex (P = 0.007), BMI (P = 0.001), Em (P = 0.032), HRR (P = 0.013), and A1C (P = 0.0007) were independent predictors of exercise capacity. CONCLUSIONS: Reduced exercise capacity in patients with type 2 diabetes is associated with diabetes control, subclinical LV dysfunction, and impaired HRR.

Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine.

OBJECTIVES: We sought to use quantitative markers of the regional left ventricular (LV) response to stress to infer whether diabetic cardiomyopathy is associated with ischemia. BACKGROUND: Diabetic cardiomyopathy has been identified in clinical and experimental studies, but its cause remains unclear. METHODS: We studied 41 diabetic patients with normal resting LV function and a normal dobutamine echo and 41 control subjects with a low probability of coronary disease. Peak myocardial systolic velocity (Sm) and early diastolic velocity (Em) in each segment were averaged, and mean Sm and Em were compared between diabetic patients and controls and among different stages of dobutamine stress. RESULTS: Both Sm and Em progressively increased from rest to peak dobutamine stress. In the diabetic group, Sm was significantly lower than in control subjects at baseline (4.2 +/- 0.9 cm/s vs. 4.7 +/- 0.9 cm/s, p = 0.012). However, Sm at a low dose (6.0 +/- 1.3), before peak (8.4 +/- 1.8), and at peak stress (8.9 +/- 1.8) in diabetic patients was not significantly different from that of controls (6.3 +/- 1.4, 8.9 +/- 1.6, and 9.6 +/- 2.1 cm/s, respectively). The Em (cm/s) in the diabetic group (rest: 4.2 +/- 1.2; low dose: 5.0 +/- 1.4; pre-peak: 5.3 +/- 1.1; peak: 5.9 +/- 1.5) was significantly lower than that of controls (rest: 5.8 +/- 1.5; low dose: 6.6 +/- 1.5; pre-peak: 6.9 +/- 1.3; peak: 7.3 +/- 1.7; all p < 0.001). However, the absolute and relative increases in Sm or Em from rest to peak stress were similar in diabetic and control groups. CONCLUSIONS: Subtle LV dysfunction is present in diabetic patients without overt cardiac disease. The normal response to stress suggests that ischemia due to small-vessel disease may not be important in early diabetic heart muscle disease.

Echocardiographic detection of early diabetic myocardial disease.

OBJECTIVES: We sought to determine whether disturbances of myocardial contractility and reflectivity could be detected in diabetic patients without overt heart disease and whether these changes were independent and incremental to left ventricular hypertrophy (LVH). BACKGROUND: Left ventricular (LV) dysfunction is associated with diabetes mellitus, but LVH is common in this population and the relationship between diabetic LV dysfunction and LVH is unclear. METHODS: We studied 186 patients with normal ejection fraction and no evidence of CAD: 48 with diabetes mellitus only (DM group), 45 with LVH only (LVH group), 45 with both diabetes and LVH (DH group), and 48 normal controls. Peak strain and strain rate of six walls in apical four-chamber, long-axis, and two-chamber views were evaluated and averaged for each patient. Calibrated integrated backscatter (IB) was assessed by comparison of the septal or posterior wall with pericardial IB intensity. RESULTS: All patient groups (DM, DH, LVH) showed reduced systolic function compared with controls, evidenced by lower peak strain (p < 0.001) and strain rate (p = 0.005). Calibrated IB, signifying myocardial reflectivity, was greater in each patient group than in controls (p < 0.05). Peak strain and strain rate were significantly lower in the DH group than in those in the DM alone (p < 0.03) or LVH alone (p = 0.01) groups. CONCLUSIONS: Diabetic patients without overt heart disease demonstrate evidence of systolic dysfunction and increased myocardial reflectivity. Although these changes are similar to those caused by LVH, they are independent and incremental to the effects of LVH.

Screening for heart disease in diabetic subjects.

BACKGROUND: The prevalence of left ventricular hypertrophy (LVH), coronary artery disease, and subclinical cardiomyopathy in diabetic patients without known cardiac disease is unclear. We sought the frequency of these findings to determine whether plasma brain natriuretic peptide (BNP) could be used as an alternative screening tool to identify subclinical LV dysfunction. METHODS: Asymptomatic patients with diabetes mellitus without known cardiac disease (n = 101) underwent clinical evaluation, measurement of BNP, exercise stress testing, and detailed echocardiographic assessment. After exclusion of overt dysfunction or ischemia, subclinical myocardial function was sought on the basis of myocardial systolic (Sm) and diastolic velocity (Em). Association was sought between subclinical dysfunction and clinical, biochemical, exercise, and echocardiographic variables. RESULTS; Of 101 patients, 22 had LVH and 16 had ischemia evidenced by exercise-induced wall motion abnormalities. Only 4 patients had abnormal BNP levels; BNP was significantly increased in patients with LVH. After exclusion of LVH and coronary artery disease, subclinical cardiomyopathy was identified in 24 of 66 patients. Subclinical disease could not be predicted by BNP. CONCLUSIONS: Even after exclusion of asymptomatic ischemia and hypertrophy, subclinical systolic and diastolic dysfunction occurs in a significant number of patients with type 2 diabetes. However, screening approaches, including BNP, do not appear to be sufficiently sensitive to identify subclinical dysfunction, which requires sophisticated echocardiographic analysis.

Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus.

OBJECTIVE: New imaging techniques have permitted the detection of subclinical LV dysfunction (LVD) in up to half of patients with type 2 diabetes mellitus (DM) with a normal EF. However, the connection between early LVD and prognosis is unclear. This study aimed to define the long-term outcome of LVD associated with type 2 DM. METHODS: In this prospective cohort study, 230 asymptomatic patients with type 2 DM underwent measurement of global longitudinal 2D strain (GLS) for detection of LVD and were followed for up to 10 years. All subjects had normal EF (≥50%) and no evidence of coronary artery disease at recruitment. Outcome data were obtained through centralised state-wide death and hospital admission registries. The primary endpoint was all-cause mortality and hospitalisation. RESULTS: On study entry, almost half (45%) of the cohort had evidence of LVD as detected by GLS. Over a median follow-up of 7.4±2.6 years (range 0.6-9.7 years), 68 patients (30%) met the primary endpoint (LVD: 37%; normal LV function: 24%). GLS was independently associated with the primary endpoint (HR=1.10; p=0.04), as was systolic blood pressure (HR=1.02; p<0.001) and levels of glycosylated haemoglobin (HR=1.28; p=0.011). Patients with LVD had significantly worse outcome than those without (χ(2)=4.73; p=0.030). CONCLUSIONS: Subclinical LVD is common in asymptomatic patients with type 2 DM, is readily detectable by GLS imaging and is independently associated with adverse outcome. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12612001178831).

Vascular dysfunction and heart failure: epiphenomenon or etiologic agent?

Endothelial function plays a key role in the local regulation of vascular tone. Alterations in endothelial function may result in impaired release of endothelium-derived relaxing factors or increased release of endothelium-derived contracting factors. Heart failure may impair endothelial function by means of reduced synthesis and release of nitric oxide (NO) or by increased degradation of NO and increased production of endothelin-1. Endothelial dysfunction may worsen heart function by means of peripheral effects, causing increased afterload and central effects such as myocardial ischemia and inducible nitric oxide synthase (iNOS)-induced detrimental effects. Evidence from clinical studies has suggested that there is a correlation between decreased endothelial function and increasing severity of congestive heart failure (CHF). Treatments that improve heart function may also improve endothelial dysfunction. The relationship between endothelial dysfunction and heart failure may be masked by the stage of endothelial dysfunction, the location of vessels being tested, and the state of endothelial-dependent vasodilatation response.

Association of severe coronary stenosis with subclinical left ventricular dysfunction in the absence of infarction.

BACKGROUND: Regional left ventricular (LV) dysfunction may occur in patients with coronary artery disease (CAD) in the absence of infarction, but the causes of this phenomenon are unclear. We sought to identify whether changes in regional LV function were related to stenosis severity, using sensitive new ultrasound markers of function. METHODS: We studied 67 individuals with no history of infarction and with normal LV systolic function: 49 patients with CAD and 18 control subjects without CAD. All patients underwent color Doppler tissue imaging, integrated backscatter (IB), anatomic M-mode echocardiography, and strain rate imaging to detect changes in structure and function. Peak early and late diastolic myocardial velocity, cyclic variation of IB, wall thickness, and percent wall thickening were measured in each basal and mid segment. Strain rate and peak systolic strain were calculated in each wall. CAD was defined as >or=50% diameter stenosis. Normokinetic segments (n = 354) subtended by CAD were divided according to stenosis severity into 3 groups: group 1 (subtended by 50%-69% stenosis); group 2 (subtended by 70%-98% stenosis); and group 3 (subtended by >or=99% stenosis). Each parameter in each group was compared with that in 216 segments from control subjects. RESULTS: Segments subtended by significant CAD showed lower peak early and late diastolic myocardial velocity compared with control segments. Group 3 showed significantly lower myocardial velocities than group 2 for both peak early (4.8 +/- 1.8 vs 6.0 +/- 2.0 cm/s, P <.05) and late (4.5 +/- 2.1 vs 5.6 +/- 2.1 cm/s, P <.05) diastolic myocardial velocity. Group 3 also showed a significantly lower cyclic variation IB than did control segments (6.7 +/- 2.3 vs 7.9 +/- 2.6 dB, P <.05), but there was no difference in calibrated IB, wall thickness, strain parameters, or percent wall thickening. These differences were not attributable to the distribution of segments for patients with severe CAD, nor were they explained on the basis of collaterals. CONCLUSION: Although the absolute values show overlap between groups, the results of this study indicate that subtle changes of regional LV function may occur in the absence of infarction, in association with severe coronary stenoses.

Is quantitative interpretation likely to increase sensitivity of dobutamine stress echocardiography? A study of false-negative results.

BACKGROUND: False-negative interpretations of dobutamine stress echocardiography (DSE) may be associated with reduced wall stress. Using measurements of contraction, we sought whether these segments were actually ischemic but unrecognized or showed normal contraction. METHODS: We studied 48 patients (29 men; mean age 60 +/- 10 years) with normal regional function on the basis of standard qualitative interpretation of DSE. At coronary angiography within 6 months of DSE, 32 were identified as having true-negative and 16 as having false-negative results of DSE. Three apical views were used to measure regional function with color Doppler tissue, integrated backscatter, and strain rate imaging. Cyclic variation of integrated backscatter was measured in 16 segments, and strain rate and peak systolic strain was calculated in 6 walls at rest and peak stress. RESULTS: Segments with false-negative results of DSE were divided into 2 groups with and without low wall stress according to previously published cut-off values. Age, sex, left ventricular mass, left ventricular geometric pattern, and peak workload were not significantly different between patients with true- and false-negative results of DSE. Importantly, no significant differences in cyclic variation and strain parameters at rest and peak stress were found among segments with true- and false-negative results of DSE with and without low wall stress. Stenosis severity had no influence on cyclic variation and strain parameters at peak stress. CONCLUSIONS: False-negative results of DSE reflect lack of ischemia rather than underinterpretation of regional left ventricular function. Quantitative markers are unlikely to increase the sensitivity of DSE.

Role of diastolic dyssynchrony in the delayed relaxation pattern of left ventricular filling.

We investigated the extent to which diastolic dyssynchrony contributes to the delayed relaxation pattern of left ventricular filling and limitation in exercise capacity. In 100 patients with diabetes, preserved left ventricular systolic function, normal filling pressure, and no coronary disease, we measured magnitude of early diastolic tissue lengthening (tissue velocity and strain rate) and diastolic dyssynchrony (SD in QRS to peak early diastolic tissue velocity interval across 4 basal myocardial segments). From transmitral flow patients were divided into those with normal filling (50 patients) and delayed relaxation (50 patients). Myocardial lengthening was reduced and SD in interval from QRS onset to peak early diastolic tissue velocity across all segments was higher in patients with delayed relaxation compared with control patients. Myocardial lengthening was the only predictor of delayed relaxation and correlation with exercise capacity was better for lengthening indices than SD in interval from QRS onset to peak early diastolic tissue velocity across all segments. Therefore, in this group a reduced rate of myocardial lengthening plays a more important role in delayed relaxation than diastolic dyssynchrony.

Relationship between longitudinal and radial contractility in subclinical diabetic heart disease.

Subclinical left ventricular (LV) dysfunction may be identified by reduced longitudinal contraction. We sought to define the effects of subclinical LV dysfunction on radial contractility in 53 patients with diabetes mellitus with no LV hypertrophy, normal ejection fraction and no ischaemia as assessed by dobutamine echocardiography, in comparison with age-matched controls. Radial peak myocardial systolic velocity (Sm) and early diastolic velocity (Em), strain and strain rate were measured in the mid-posterior and mid-anteroseptal walls in parasternal views and each variable was averaged for individual patients (radial contractility). These variables were also measured in the mid-posterior and mid-anteroseptal walls in the apical long-axis view and each variable was averaged for individual patients (longitudinal contractility). Mean radial Sm, strain and strain rate were significantly increased in diabetic patients (2.9 +/- 0.6 cm/s, 28 +/- 5% and 1.8 +/- 0.4 s(-1) respectively) compared with controls (2.4 +/- 0.7 cm/s, 23 +/- 4% and 1.6 +/- 0.3 s(-1) respectively; all P<0.001), but there was no difference in Em (3.3 +/- 1.2 compared with 3.1 +/- 1.1 cm/s, P=not significant). In contrast, longitudinal Sm, Em, strain and strain rate were significantly lower in diabetic patients (3.6 +/- 1.1 cm/s, 4.3 +/- 1.6 cm/s, 21 +/- 4% and 1.6 +/- 0.3 s(-1) respectively) than in controls (4.3 +/- 1.0 cm/s, 5.7 +/- 2.3 cm/s, 26 +/- 4% and 1.9 +/- 0.3 s(-1) respectively; all P< or =0.001). Thus radial contractility appears to compensate for reduced longitudinal contractility in subclinical LV dysfunction occurring in the absence of ischaemia or LV hypertrophy.

A practical guide to exercise training for heart failure patients.

BACKGROUND: Exercise training has been shown to improve exercise capacity in patients with heart failure. We sought to examine the optimal strategy of exercise training for patients with heart failure. METHODS: Review of the published data on the characteristics of the training program, with comparison of physiologic markers of exercise capacity in heart failure patients and healthy individuals and comparison of the change in these characteristics after an exercise training program. RESULTS: Many factors, including the duration, supervision, and venue of exercise training; the volume of working muscle; the delivery mode (eg, continuous vs. intermittent exercise), training intensity; and the concurrent effects of medical treatments may influence the results of exercise training in heart failure. Starting in an individually prescribed and safely monitored hospital-based program, followed by progression to an ongoing and progressive home program of exercise appears to be the best solution to the barriers of anxiety, adherence, and "ease of access" encountered by the heart failure patient. CONCLUSIONS: Various exercise training programs have been shown to improve exercise capacity and symptom status in heart failure, but these improvements may only be preserved with an ongoing maintenance program.