Abstract-Although diabetes is recognized as a potent and prevalent risk factor for ischemic heart disease, less is known as to whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Left ventricular systolic and diastolic dysfunction, left ventricular hypertrophy, and alterations in the coronary microcirculation have all been observed, although not consistently, in diabetic cardiomyopathy and are not fully explained by the cellular effects of hyperglycemia alone. The recent recognition that diabetes involves more than abnormal glucose homeostasis provides important new opportunities to examine and understand the impact of complex metabolic disturbances on cardiac structure and function. (Circ Res. 2006;98:596-605.)Key Words: insulin resistance Ⅲ diabetic cardiomyopathy Ⅲ diastolic function Ⅲ cardiac hypertrophy T he conventional wisdom holds that diabetes causes myocardial contractile dysfunction through accelerated atherosclerosis and hypertension. Much less appreciated and more controversial is the notion that diabetes mellitus affects cardiac structure and function, independent of blood pressure or coronary artery disease. Diabetic cardiomyopathy is a clinical condition, diagnosed when ventricular dysfunction develops in patients with diabetes in the absence of coronary atherosclerosis and hypertension. [1][2][3][4] Despite the potential importance of this disease entity, the complex and multifactorial nature of the cellular and molecular perturbations that predispose to altered myocardial structure and function remain incompletely understood.The epidemiological link between diabetes mellitus and the development of heart failure, independent of atherosclerotic cardiovascular disease, has been evident for the better part of three decades. The increased risk of heart failure persists in the diabetic patients after considering age, blood pressure, weight, cholesterol, as well as history of coronary artery disease. 5,6 Notably, there is a significant association between diabetes and diastolic dysfunction leading to congestive heart failure in the absence of impaired systolic function. 7,8 More recently, patients with unexplained idiopathic dilated cardiomyopathy were found to be 75% more likely to have diabetes than age matched controls. 9 The association between diabetes and cardiomyopathy was strongest among individuals with microvascular complications of diabetes that parallels the duration and the severity of hyperglycemia. However, it has been difficult to ascertain from these epidemiological correlations the causal relationship between the commonly observed metabolic abnormalities and the specific cardiac phenotype. In this review, we provide an update of our current understanding of the complexities of diabetic cardiomyopathy with a special emphasis on the relationship between the Cellular Mechanisms Predisposing to Diabetic CardiomyopathyThe 3 characteristic metabolic disturbances evident in diabetic states are hyperlipidemia (usually in the form of increased trigly...

Recent evidence suggests that glucagon-like peptide-1 (GLP-1) enhances recovery of left ventricular (LV) function after transient coronary artery occlusion. However, it is uncertain whether GLP-1 has direct effects on normal or ischemic myocardium and whether the mechanism involves increased myocardial glucose uptake. LV function and myocardial glucose uptake and lactate production were measured under basal conditions and after 30 min of low-flow ischemia and 30 min of reperfusion in the presence and absence of GLP-1-(7-36) amide. The response was compared with standard buffer alone or buffer containing insulin (100 U/ml). GLP-1 decreased the left ventricular developed pressure (baseline: 100 Ϯ 2 mm Hg; GLP-1: 75 Ϯ 3 mm Hg, p Ͻ 0.05) and LV dP/dt (baseline: 4876 Ϯ 65 mm Hg/s; GLP-1: 4353 Ϯ 76 mm Hg/s, p Ͻ 0.05) in normal hearts. GLP-1 increased myocardial glucose uptake (baseline: 33 Ϯ 3 mol/min/g; GLP-1: 81 Ϯ 7 mol/min/g, p Ͻ 0.05) by increasing nitric oxide production and glucose transporter (GLUT)-1 translocation. GLP-1 enhanced recovery after 30 min of low-flow ischemia with significant improvements in LV end-diastolic pressure (control: 13 Ϯ 4 mm Hg; GLP-1: 3 Ϯ 2 mm Hg, p Ͻ 0.05) and LV developed pressure (control: 66 Ϯ 6 mm Hg; GLP-1: 98 Ϯ 5 mm Hg, p Ͻ 0.05). GLP-1 increased LV function, myocardial glucose uptake, and GLUT-1 and GLUT-4 translocation during reperfusion to an extent similar to that with insulin. GLP-1 has direct effects on the normal heart, reducing contractility, but increasing myocardial glucose uptake through a non-Akt-1-dependent mechanism, distinct from the actions of insulin. However, GLP-1 increased myocardial glucose uptake and enhanced recovery of cardiac function after low-flow ischemia in a fashion similar to that of insulin.

Background-Glucagon-like peptide-1 (GLP-1) treatment leads to short-term improvements in myocardial function in ischemic and nonischemic cardiomyopathy. It is unknown whether GLP-1 improves survival when administered over a longer time period. Spontaneously hypertensive, heart failure-prone (SHHF) rats progress to advanced heart failure and death over a 15-month period. The authors sought to determine whether a continuous infusion of GLP-1 would reduce mortality in this model. Methods and Results-At 9 months of age, 50 SHHF rats were randomized to receive a 3-month, continuous infusion of either GLP-1 or saline. Metabolic parameters were measured and cardiac ultrasounds performed at study initiation and completion of treatment. Surviving rats were euthanized at 12 months. Hearts were perfused in an isolated, isovolumic heart preparation, and Tunel staining of myocardial samples was performed. Baseline metabolic and cardiac functional parameters were comparable. GLP-1-treated SHHF rats had greater survival (72% versus 44%, Pϭ0.008) at 12 months of age. In addition, GLP-1 treatment led to higher plasma insulin, lower plasma triglycerides, and preserved left ventricular (LV) function. GLP-1-treated rats demonstrated decreased myocyte apoptosis by Tunel staining as well as reduced caspase-3 activation. No increase in p-BAD expression was seen. In isolated hearts, the LV systolic pressure and LV-developed pressure were greater in the GLP-1 group. Myocardial glucose uptake was also increased in GLP-1-treated SHHF rats. Conclusions-Chronic GLP-1 treatment prolongs survival in obese SHHF rats. This is associated with preserved LV function and LV mass index, increased myocardial glucose uptake, and reduced myocyte apoptosis. (Circ Heart Fail. 2008;1:153-160.)

Background: Women comprise approximately one-third of the advanced heart failure population but may receive fewer advanced heart failure therapies including left ventricular assist devices (LVADs). During the early pulsatile-flow device era, women had higher post-LVAD mortality and increased complications. However, knowledge about these differences in the continuous-flow device era is limited. Therefore, we sought to explore temporal trends in LVAD utilization and post-LVAD mortality by sex. Methods and Results: Patients with LVAD implantation from 2004 to 2016 were identified using the Nationwide Inpatient Sample. Trends in LVAD utilization and post-LVAD inpatient mortality were compared by sex and device era. Although LVADs are being increasingly utilized for patients with advanced systolic heart failure, women continue to represent a smaller proportion of LVAD recipients—25.8% in 2004 to 21.9% in 2016 ( P for trend, 0.91). Women had increased inpatient mortality after LVAD implantation compared with men in the pulsatile-flow era (46.9% versus 31.1%, P <0.0001) but not in the continuous-flow era (13.3% versus 12.1%, P =0.27; P for interaction=0.0002). Inpatient mortality decreased for both sexes over time after LVAD, with a sharp fall in 2008 to 2009. Female sex was independently associated with increased post-LVAD inpatient mortality beyond adjustment for demographics and risk factors during the pulsatile-flow era (odds ratio, 2.13; 95% CI, 1.45–3.10; P <0.0001) but not during the continuous-flow era (1.18; 0.93–1.48; P =0.16). Conclusions: Although utilization of LVAD therapy increased over time for both sexes, LVAD implantation remains stably lower in women, which may suggest a potential underutilization of this potentially life-saving therapy. Prospective studies are needed to confirm these findings.