Diabetic Cardiomyopathy: Mediators and Mechanisms

Scope of the Problem

Heart disease is the greatest noninfectious health hazard ever to confront the human race. Rampant for some years in the developed world, this epidemic is spreading rapidly around the globe. As one prominent example, it is estimated that 5 million Americans have heart failure (HF), a syndrome with a 5-year mortality of approximately 50%. Indeed, HF has remained the leading cause of death in industrialized nations for several years. Accordingly, HF, the end result of disease-related remodeling of the myocardium, is responsible for a huge societal burden of morbidity, mortality, and cost.

Numerous events contribute to the rise in HF, but the increasing prevalence of diabetes is a significant contributor. For one, cardiovascular disease, including HF, is the leading cause of morbidity and mortality in patients with diabetes (see also Chapter 23 ). Although the underlying causes of diabetes-associated heart disease are multifactorial, the importance of ventricular dysfunction independent of coronary artery disease (CAD) or hypertension, a condition termed diabetic cardiomyopathy, has been emphasized. The diabetes and cardiovascular communities embraced the concept of diabetic cardiomyopathy as a distinct entity in the early 1970s when autopsy specimens from diabetic patients with nephropathy revealed a myopathic process in the absence of epicardial CAD. Over the years, substantial evidence has accumulated that a specific, discrete diabetic cardiomyopathy, distinct from ischemic injury, does indeed exist. The exact prevalence, nature, and cause of cardiac dysfunction directly attributable to diabetes per se have given rise to considerable debate, inasmuch as the disease is associated with numerous comorbidities, including hypertension, coronary atherosclerosis, and microvascular dysfunction.

Constant and unremitting metabolic stress on the heart leads over time to progressive deterioration of myocardial structure and function. This suggests that therapeutic interventions early in the disease, targeting specific metabolic and structural derangements, may be required. This is especially relevant because rigid control of hyperglycemia, however central to treatment, has not fulfilled hopes of meaningful morbidity and mortality benefit. Recent and ongoing research into mechanisms of metabolic control, insulin resistance, and diabetes-associated derangements portend novel therapies designed to benefit the rapidly expanding cohort of patients with diabetes, a benefit with tremendous societal impact. Current therapies are insufficient to arrest the progression of HF. Developing new therapies will require greater understanding of molecular events underlying pathologic cardiac remodeling. Substantial work will be required to elucidate the role(s) of specific molecular mechanisms in the pathogenesis of diabetes-induced remodeling. It is our hope that insights gleaned from such studies will lead to identification of therapeutic targets with clinical relevance.

Epidemiological Evidence

The incidence and prevalence of diabetes mellitus (DM) are both rising rapidly (see also Chapter 1 ). DM affects 350 million people around the world, and the World Health Organization (WHO) has projected that diabetes-related deaths will double between 2005 and 2030 ( www.who.int/diabetes/en/ ). Within this burgeoning health care problem of worldwide proportions, obesity-related type 2 diabetes mellitus (T2DM) accounts for more than 90% of all diagnosed diabetes in adults. Furthermore, more than 60% of patients who present with symptomatic chronic heart disease have abnormal glucose homeostasis (see also Chapter 23 ). Patients with DM and established cardiovascular disease have an unfavorable prognosis. In fact, diabetes and insulin resistance are powerful predictors of cardiovascular morbidity and mortality, and each is an independent risk factor for death in patients with established HF.

The term diabetic cardiomyopathy, although admittedly vague, refers to the multifactorial manifestations of diabetes-related left ventricular (LV) failure characterized by both systolic and diastolic function ( Box 24-1 ). The Framingham Heart Study showed that men with diabetes are twice as likely to develop HF as their nondiabetic counterparts, and women with diabetes have a fivefold increase in the rate of HF. The clinical spectrum of HF ranges from asymptomatic to overt symptoms at rest. Diabetes complicated by hypertension represents a particularly high-risk group for the development of HF. Diastolic dysfunction is common (> 50% prevalence in some studies) and can sometimes be linked to diabetes in the absence of concomitant hypertension.

Box 24-1

Data from Boudina S, Abel ED: Diabetic cardiomyopathy revisited, Circulation 115:3213-3223, 2007.

Diabetic Cardiomyopathy: Hallmark Features

Structural and Morphologic

• Near-normal end-diastolic volume

• Elevated left ventricular mass relative to chamber volume

• Elevated wall thickness to chamber radius

• Myocardial hypertrophy

• Myocardial fibrosis

• Intramyocyte lipid accumulation

Functional

• Abnormal left ventricular diastolic function (observed in 75% of asymptomatic diabetic patients)

• Compromised left ventricular systolic function

• Reduced ventricular elasticity

• Clinical heart failure

Echocardiographic studies confirm that diastolic abnormalities occur in young diabetic patients who have no known diabetic complications. One study reported that patients with diabetes manifest early findings of systolic dysfunction preceding echocardiographically detectable changes in LV ejection fraction. Patients with diabetes who are also hypertensive have increased LV mass when compared with their nondiabetic counterparts, and LV function may in fact be hyperdynamic.

Pathophysiology and Molecular Mechanisms

A number of molecular mechanisms have been proposed to contribute to the pathogenesis of diabetic cardiomyopathy. However, evidence for a direct, causal link between insulin resistance, a hallmark of type 2 diabetes, and ventricular dysfunction has not been established. The natural history of diabetic cardiomyopathy has been broadly divided into two phases ( Table 24-1 ). Although the first phase represents short-term, physiologic adaptation to the metabolic alterations of diabetes, the second phase involves degenerative changes that the myocardium is unable to repair and that ultimately culminate in irreversible pathologic remodeling.

The hormone insulin is central to the control of intermediary metabolism, orchestrating substrate usage for storage or oxidation in all cells. As a result, insulin has profound effects on both carbohydrate and lipid metabolism throughout the body, as well as significant influences on protein metabolism. Consequently, derangements in insulin signaling have widespread and devastating effects in numerous tissues, including the cardiovascular system. Insulin is the main hormone for regulation of blood glucose, and, in general, normoglycemia is maintained by precisely tuned insulin secretion. It is important to note that the normal pancreatic beta cell can adapt to changes in requirements for circulating insulin; when the downstream actions of insulin are hampered (e.g., in insulin resistance), the pancreas compensates by upregulating beta cell function (hyperinsulinemia). Relative insulin resistance occurs when the biologic actions of insulin are inadequate for both glucose disposal in peripheral tissues and suppression of hepatic glucose production.

T2DM is typified by hyperglycemia, hyperinsulinemia, and obesity, and insulin resistance is a cardinal feature. The disease itself arises from a variety of causes, including dysregulated glucose sensing or insulin secretion (maturity-onset diabetes of the young), autoimmune-mediated beta cell destruction (type 1 diabetes mellitus [T1DM]), or insufficient compensatory insulin secretion in the setting of peripheral insulin resistance or T2DM, which accounts for 90% of diabetes. These events, acting through a variety of mediators such as altered intracellular calcium, increased reactive oxygen species (ROS), ceramides, hexosamines, and advanced glycation end products (AGEs), contribute to the pathogenesis of the disorder. In addition, the interplay between dysregulated function of endothelial cells and fibroblasts contributes, highlighting the multifactorial etiology of diabetic cardiomyopathy. Recent studies have highlighted that transcriptional and metabolic derangements within the cardiomyocyte itself are important elements in the pathogenesis of the disorder, as well.

The concept of diabetic cardiomyopathy is based on the notion that the disease, DM, itself is a key factor eliciting changes at the molecular and cellular levels of the myocyte, culminating in structural and functional abnormalities in the heart. In other words, the diabetic milieu is toxic to the myocyte, above and beyond contributions from ischemia (CAD) or pressure stress (hypertension). Whereas the cause of diabetic cardiomyopathy is multifactorial and incompletely characterized, progress has been made in recent years to define underlying mechanisms ( Fig. 24-1 ). As a result, several novel molecular targets with potential therapeutic relevance have been proposed ( Fig. 24-2 ).

Cardiomyocytes are capable of metabolizing a spectrum of substrates. The myocardium as a “metabolic omnivore” normally relies on metabolism of fatty acids (FAs) and glucose, and to a lesser extent lactate and ketone bodies, to produce adenosine triphosphate (ATP). These substrates, however, are unable to enter the cardiomyocyte by simple diffusion and must be taken up by facilitated transport. FA uptake is mediated by FAT (fatty acid translocase; also known as cluster of differentiation 36 [CD36]), and glucose intake is accomplished by both GLUT-1 and GLUT-4 (glucose transporter types 1 and 4). In response to availability of nutrients or increased cardiac work, plasma insulin concentrations rise. This, in turn, provokes translocation of both GLUT-4 and FAT to the myocyte sarcolemma. To date, several studies have implicated signaling pathways that regulate GLUT-4 translocation with those involved in transport of FAT to the sarcolemma. ^, However, during the development of insulin resistance and T2DM, FAT becomes preferentially sarcolemma-localized, whereas GLUT-4 remains internalized. This reciprocal positioning of GLUT-4 and FAT is central to aberrant substrate uptake in the diabetic heart, where FA metabolism is chronically increased at the expense of glucose. ^, Moreover, dyslipidemia triggered by insulin resistance provokes increases in systemic free FAs, which in turn promote uptake and usage of fat in cardiomyocytes. In addition, the interplay of preferential substrate usage is affected by a variety of other mediators, as previously reviewed.