Diabetic cardiomyopathy - A comprehensive updated review

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Abstract

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.

Introduction

There is a well-established relationship between diabetes mellitus (DM) and cardiovascular (CV) disease (CVD). Several studies have demonstrated the epidemiological link between heart failure (HF) and DM. Clearly, DM can increase the risk of HF, even independently of the traditional risk for HF, including hypertension (HTN), coronary heart disease (CHD) and valvular heart disease (VHD). Longstanding DM results in structural and functional changes that lead to development and progression of HF, independent of myocardial ischemic or microvascular atherosclerotic disease process. This disease process was first described in 1972 by Rubler et al on histopathologic evaluation during postmortem examination of DM patients with HF who did not have CHD, HTN or VHD.1 It was found to be a unique pathological subset that seemed to act independent of the traditional risk factors resulting from direct effects of abnormal myocardial metabolism. This unique form of CVD was termed as diabetic cardiomyopathy (DCM). Later, in the Framingham Heart Study, patient with DM were found to have significantly increased risk of HF independent of the factors that cause accelerated atherogenesis and CHD.2 Since then many studies have demonstrated the structural and functional changes in the myocardium of patients with DM that are not related to other traditional CVD risk factors.

Section snippets

Structural changes in DCM

There are several structural changes in myocardium of patients with DM that lead to left ventricular (LV) dysfunction. DM causes increased absolute and relative increases in LV wall thickness and LV mass (LVM) independent of obesity, HTN and other factors that could also increase LVM and LV hypertrophy (LVH).3 Initially there is a subclinical period of these structural and functional abnormalities that result from LVH, fibrosis and impaired myocardial relaxation. Therefore, most of these DM

Pathophysiology of DCM

The pathophysiology of DCM is multifactorial and involves complex metabolic pathways involving alteration in fatty acid metabolism, chronic hyperglycemia- induced changes in circulating hormones and cytokines. These pathways have been summarized in Table 3. The molecular abnormalities induced by the DM milieu are different from those elicited by HTN or ischemia.

Cardiac biomarkers

A wide spectrum of cardiovascular biomarkers has been described in patients with DM. Some of these biomarkers include brain natriuretic peptide (BNP), cardiac troponins and MMPs. Alterations in the levels of these biomarkers can suggest myocardial structural and functional dysfunction. Elevated levels of BNP have been found to show positive correlation with LV dysfunction. In asymptomatic patients BNP can be useful to screen DM patients for the presence of subclinical LV dysfunction.36

Cardiac

Epidemiology

There is consistent epidemiological evidence that DM is common in patients with HF.65 In fact, the most common CV complication in patients with DM is HF. In the major HF trials, DM patients often represent most of study subjects. Cardiomyopathy does not occur only in DM patients, but rather in pre-DM patients with metabolic syndrome who have elevated inflammatory markers and microalbuminuria associated with incident HF. Patients with DM and HF have increased mortality compared to non-DM

Screening for DCM

The majority of patients with DCM have asymptomatic LV dysfunction in the initial stages. Many of these patients with LV dysfunction remain undiagnosed and untreated at Stage A of HF. Identification of these patients at early stages can help identify patients at high risk for further progression of disease. This necessitates the development of screening tests to identify those patients who are at increased risk.

The role of BNP has been studied for screening asymptomatic DM patients. BNP is a

Role of antioxidants

Hyperglycemia induced oxidative stress is a major risk factor in development of myocardial dysfunction in DCM as explained above. Multiple studies have evaluated the role of antioxidants, including vitamin E, Metallothionein, synthetic glutathione peroxidase and multiple other antioxidant approaches.84 The efficacy of these agents has been studied in animal models with DM. These agents have shown to have cardio protective effects in animal models, suggesting the usefulness of vitamin E

Angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARBs)

ACEI and ARBs significantly reduce the risk of developing myocardial fibrosis and LV stiffness. The beneficial role of ACEI/ARBs in DCM results from their role in reverting the development of abnormal extracellular matrix deposition and fibroblast activity by decreasing the synthesis of collagen and increasing activity of MMP.97 They also modulate the response of cardiac myocytes to sympathetic system and RAAS and downgrade the development of LVH and cardiac remodeling. In multiple

Incretin-based therapies (IBT)

IBT include Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of DM. These agents exert their CV effects both indirectly through their actions on myocardial metabolism and direct functional effects on cardiac myocytes and coronary vasculature.107 The metabolic effects result from an increase in insulin levels and a decrease in glucagon levels with concomitant decrease in levels of circulating free fatty acids. This enhances the

Conclusions

DCM is more common than it is recognized clinically. It is an important cause of HF worldwide and constitutes a significant burden of health care cost across the nation. The pathophysiology of DCM is complex and despite significant advances, many areas are still not well understood and are target for future studies. Taken together, there are underlying pathological changes resulting from multiple abnormal biochemical pathways ranging from abnormal calcium signaling, deranged glucose/fatty acids

Disclosures/Conflict of interest

The authors report no financial relationships or conflicts of interest regarding the content herein.

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