Cardiovascular disease is responsible for approximately 60% to 80% of deaths among diabetic patients.^1,2 Most of these deaths have been attributed to impaired myocardial contraction due to accelerated atherosclerosis and hypertension.³ The Framingham data showed a 2.4-fold greater incidence of congestive heart failure in men with diabetes and a 5.1-fold greater incidence in women with diabetes independent of coronary artery disease (CAD).⁴ In addition, patients with diabetes have an increased risk of mortality after acute myocardial infarction (MI) compared with their nondiabetic counterparts.^1,5,6 This suggests that the myocardium of diabetic patients may be more susceptible to hypertensive and ischemia-mediated damage.⁵

Diabetic cardiomyopathy is a clinical condition characterized by altered myocardial function in the absence of CAD, hypertension, and valvular or congenital heart disease.^1-3,7 These patients exhibit changes in cardiac structure that may be attributed to the direct effect of diabetes mellitus. Echocardiographic studies on large databases of diabetic heart failure patients have shown an association with left ventricular hypertrophy, increased heart mass, and mildly reduced systolic function.^8,9 Pathologic changes include myocyte hypertrophy, perivascular fibrosis, and increased deposition of matrix collagen, cell membrane lipids, and cellular triglycerides.^7,10

Rubler and colleagues first identified diabetic heart failure patients without CAD or hypertension.¹¹ Over the subsequent 30 years, epidemiologic, clinical, and experimental data have shown a link between idiopathic cardiomyopathy and diabetes. Although the causal relationship between the metabolic abnormalities in diabetes and cellular consequences that lead to altered cardiac structure and function are not fully understood, there are several proposed mechanisms.

Mechanisms
• Hyperglycemia. Hyperglycemia induces multiple biochemical effects that lead to glucose oxidation and generation of reactive oxygen species, which causes DNA damage. The divergence away from the normal glycolytic pathway of glucose leads to the formation of alternate mediators that include advanced glycation end products (AGEs) and activation of protein kinase C.^1,3,12 Advanced glycation end products deactivate nitric oxide and impair coronary vasodilation, as well as lead to myocardial inflammation, endothelial dysfunction, and collagen deposition with fibrosis.^1,3,5,10,12 The process of advanced glycation has also been related to alterations in Ca⁺ movement. Decreased function of sarcoplasmic/endoplasmic reticulum Ca⁺ ATPase 2a leads to impaired cardiac relaxation and increased ventricular stiffness.^1,3,5,7,12 These alterations may contribute to the left ventricular diastolic dysfunction noted in some studies.⁷ Activation of the protein kinase C transduction pathway in animal models has demonstrated many of the findings seen in diabetic cardiomyopathy, including reduction in tissue blood flow, enhanced extracellular matrix deposition, capillary basement thickening, and increased vascular permeability.^1,3,7 These together provide mechanisms whereby hyperglycemia may contribute to decreased systolic and diastolic function.

• Fatty acids. The heart initially adapts to hyperglycemia and hyperlipidemia via reliance on free fatty acid as fuel, but increased intracellular free fatty acid levels have been associated with contractile dysfunction by altering cellular metabolism, function, and gene expression.^1,3,7,12 One proposed mechanism involves peroxisome proliferator-activated receptor-alpha (PPAR-α). Continued exposure to elevated levels of free fatty acid with decreased expression on PPAR-α accelerates lipid accumulation.^10,12 This phenomenon of lipotoxicity results in increased ceramide levels, which can then induce reactive oxygen species and apoptosis with subsequent contractile dysfunction.¹² Increased free fatty acids in diabetic patients may lead to vascular endothelial damage through pathways involving free fatty acid-induced reactive oxygen species production via activation of protein kinase C.

• Autonomic dysfunction and gene expression. Animal diabetic cardiomyopathy models have demonstrated biochemical and cellular abnormalities similar to those resulting from volume overload.⁵ Hyperglycemia has been shown to activate the same intracellular signaling pathways (protein kinase C and mitogenic activated protein kinase) as those activated due to wall stretch.⁵ This impaired myocardial function will eventually lead to activation of the neurohormonal systems, including the renin-angiotensin-aldoste-rone (RAA) system, despite little change in myocardial loading.^1,3,5,12 In addition, activation of the RAA system leads to a re-expression of genes used mostly during fetal life and can result in alterations in contractile proteins β and α myosin heavy chain, referred to as the fetal gene program.^1,5,12 In animal models, these changes lead to contractile dysfunction, resulting in cardiac hypertrophy and atrophy.¹ It appears that diabetes induces patterns of gene expression similar to those of heart failure, which eventually worsen myocardial function. Based on this proposed scenario, diabetic cardiomyopathy would seem to follow the same path of remodeling recognized in heart failure of other etiologies.  

Risk factors, screening, and diagnosis of heart failure in diabetic patients
The American College of Cardiology/American Heart Association guidelines for the management of heart failure incorporated diabetes as a risk factor in 2001.¹³ In addition, the Joint National Commission VI noted that diabetic patients should be considered to be at high risk for heart failure, even when blood pressure is normal.¹⁴ Many heart failure patients may not exhibit the signs and symptoms of myocardial dysfunction; therefore, the diagnosis of heart failure in diabetic patients may require additional studies.

It has been suggested that diastolic dysfunction may be the earliest clinical manifestation of cardiac disease in diabetes. An increased prevalence of diastolic dysfunction in diabetic patients with normal blood pressure has been noted.^7,10,15,16 Echocardiography would allow detection of myocardial abnormalities before the onset of symptoms. Conventional echocardiography may be limited, at times, by not accounting for pseudonormal filling patterns and, therefore, diastolic dysfunction may be underestimated. Newer modalities in echocardiography, such as tissue Doppler imaging, allow assessment of myocardial tissue velocities, providing useful tools for defining subtle changes in systolic and diastolic dysfunction.^1,15

Prevention and treatment
There are several well-established interventions that have been shown to improve mortality in heart failure patients. Both angiotensin-converting enzyme inhibition and beta-blockade have been shown to block RAA; to prevent and, in the case of betablockers, to reverse cardiac remodeling; to improve left ventricular function; and to reduce the risk of death. In diabetic patients, tight glycemic control is also paramount.

• Glycemic control. Iribarren and colleagues found that poor glycemic control may be associated with an increased risk of heart failure among diabetic patients because of either progression of atherosclerosis or diabetic cardiomyopathy, or both.¹⁷ Glycemic control may decrease free fatty acid oxidation and improve glucose utilization, and evidence exists that tight glycemic control may improve mortality in diabetic patients after acute MI.¹⁶ The proposed mechanism involves a shift in substrate utilization from free fatty acid to glucose, which may improve myocardial contractility and lower oxygen consumption.⁵ Better glycemic control also decreases formation of AGEs, endothelial dysfunction, and triglyceride loading, and may improve intracellular Ca⁺ levels.^5,17

• Glitazones. Glitazones act by increasing insulin sensitivity in skeletal muscles by binding PPAR-δ and PPAR-α. This subsequently leads to decreased triglyceride and low-density lipoprotein cholesterol levels, while increasing high-density lipoprotein cholesterol levels. It is proposed that glitazones, in addition to insulin-sensitizing skeletal muscle, improve glucose metabolism and decrease free fatty acid utilization. Glitazones have been shown to reduce myocardial triglyceride and ceramide levels and to reverse apoptosis in animal models.⁵ The effect of this may be to protect the myocardium from ischemic injury and improve recovery of function following ischemic insult. Caution should be taken when using glitazones in advanced heart failure patients because of possible fluid retention. Clinical trials designed to evaluate the use of glitazones in diabetic heart failure patients are currently under way.

Conclusion
Since the discovery of diabetic cardiomyopathy more than 30 years ago, there have been multiple attempts to elucidate a clear pathogenesis of this disease process. Clinical, epidemiologic, and experimental data suggest that the process is multifactorial.

Although a large body of evidence exists suggesting that diabetic patients are prone to significant alterations at the cellular level causing structural and functional abnormalities, there is controversy regarding the most relevant cellular mechanism responsible for the changes.

References
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