The prevalence of type 2 diabetes is rising at an alarming rate in China due to aging of the population, increased frequency of obesity, and suboptimal nutritional habits.1 Although many diabetic patients now survive severe coronary lesions or myocardial infarction as a result of dramatic advances in the management of ischemic heart disease in general and acute myocardial infarction specifically,2,3 they are subsequently succumbing to the consequences of myocardial damage, with an increased incidence of congestive heart failure (CHF).4 Since patients with both diabetes and CHF had a 1.5-2.0-fold higher risk of mortality, compared wtih those with CHF alone,5 the association between diabetes and CHF features an intriguing and alarming issue in clinical cardiology.5-7
In this issue of Chinese Medical Journal, Shi et al8 have shown that the prevalence of CHF with diabetes increased from 16.9% in the late 1990s to 29.1% within recent years, and grew from 18.5% in patients aged <60 years to 26.6% for those 60-80 years or older. Patients with CHF and diabetes are often manifested by a cluster of abnormal biochemical and hemodynamic changes, and have poor clinical outcomes. Glucose-lowering treatment and use of β-blockers could favorably improve the prognosis of these patients. Epidemiological studies revealed that patients with type 2 diabetes were 2 to 5 times more prone to develop CHF than age-matched controls.6,7 The reported range of patients with CHF who have concomitant diabetes in randomized clinical trials (approximately 15%—35%) certainly underestimates real figures because diabetic patients are often excluded from heart failure trials, especially when they have renal insufficiency.6 In fact, the prevalence of diabetes ranged 26%-44% in previous registry studies for patients hospitalized with heart failure,9 and clinically subtle and unrecognized asymptomatic diastolic left ventricular dysfunction occurs even more frequently in diabetic patients by echo-Doppler assessment.10
Both CHF and diabetes are believed to share pathophysiological processes, including neurohormonal activation, endothelial dysfunction, and increased oxidative stress.11 Diabetes acts synergistically with other risk factors, accelerating coronary atherosclerosis and increasing risk of myocardial infarction and ischemic heart failure. It may also affect cardiac structure and myocardial fibrosis as well as coronary micro-circulation independent of other established risk factors for CHF.12,13 Likewise, heart failure per se predisposes patients to development of diabetes. Besides the fact that heart failure itself is linked to the development of insulin-resistance and new-onset diabetes,11 risk factors for CHF, including hypertension, hyperlipidemia, premature atherosclerosis, and left ventricular hypertrophy, occur with increased frequency in the diabetic population and may directly contribute to the development of CHF.7,9,11
One potential risk factor associated with adverse outcomes in patients with diabetes and CHF is poor glycemic control. Shi et al8 observed that an elevated serum glycosylated hemoglobin (HbA1c) level ≥7% was associated with enlarged left ventricular volume, decreased ejection fraction and reduced survival. After adjustment for confounding factors, HbA1c level ≥7% remains an independent risk factor for adverse outcomes in CHF patients with diabetes. In a large cohort study including 5815 patients with baseline HbA1c measurements, Aguilar et al14 have shown that the association between mortality and HbA1c in diabetic patients with CHF appears U-shaped, with the lowest risk of death in those patients with modest glucose control (7.1% < HbA1c ≤7.8%). Although each 1% increase in HbA1c was associated with a 12% increased risk of hospitalization for CHF or death,5,11,15 unawareness of spontaneous or iatrogenic hypoglycemia may worsen clinical outcomes, and thus should be avoided in cardiac patients.14
The interaction between advanced glycation end products (AGEs) and its receptor (RAGE), and the subsequent signaling have been implicated in diabetic complications.16 AGEs, acting as pro-inflammatory triggers, are associated with endothelial dysfunction and coronary artery disease, and have also been implicated in cardiac dysfunction and CHF.17 The endogenous secretory RAGE (esRAGE), generated through alternative splicing of cRAGE, is proteolytically cleaved from the cell surface by matrix metalloproteinases, and then shed into the bloodstream. Both variant isoforms are thought to act as decoy receptors for AGEs and several inflammatory cytokines. Several studies have suggested that decreased esRAGE and/or increased cRAGE levels may be used as biomarkers of hyperactive ligand-RAGE pathway in diabetes, atherosclerosis and other inflammatory diseases, even in CHF.18
High mobility group box-1 (HMGB1) has been demonstrated to be a ligand for RAGE, cRAGE and esRAGE,17 and its signaling via RAGE activates inflammatory pathways and intensifies cellular oxidative stress, which results in profound production of inflammatory cytokines and elevated expression of adhesion molecules.19 Increased serum levels of HMGB1 and cRAGE, and decreased esRAGE levels induce oxidative stress and trigger inflammatory pathways, and are associated with aggravation of cardiac remodeling in diabetic patients. These changes became more evident in those died of cardiac sudden death or refractory heart failure.
Activation of sympathetic nervous system and rennin-angiotensin-aldosterone system plays an important pathophysiological role in diabetes and CHF through a multiplicity of adverse effects on the heart, blood vessel, and kidney.11 Compelling clinical evidence has demonstrated that the standard of care for all patients with CHF caused by left ventricular systolic dysfunction, regardless of severity or etiology, should include pharmacotherapy with angiotensin-converting enzyme (ACE) inhibitors and β-blockers unless contraindicated. 20 Patients with CHF and diabetes experienced significant benefits from treatment with ACE inhibitors similar to those of their non-diabetic counterparts,21 and the use of aldosterone blockade lowers mortality beyond that achieved with standard therapy in CHF.22 The United Kingdom Prospective Diabetes Study (UKPDS) indicated that β-blockade prevented CHF in patients with diabetes when tight blood pressure control was sustained,23 and reduced mortality in patients with diabetes and symptoms of severe heart failure. Noticeably, β-blockers remain underutilized in diabetic patients with CHF because of perceived negative metabolic effects. Because β-blockers could blunt adrenaline release inducing hypoglycemia and lipid abnormality, and decrease insulin sensitivity, dose regimen must be adjusted individually, especially for CHF patients with diabetes.23,24
In general, glucose-lowering treatment favorably affects left ventricular function and outcomes of patients with CHF and diabetes. Metformin, alone or in combination, was associated with lower morbidity and mortality compared with sulfonylurea monotherapy in patients with CHF and diabetes.25 It should be noted that although thiazolidinediones are likely to be of cardiovascular benefit in CHF patients with diabetes in terms of improvement of blood pressure control, endothelial function and anti-atherosclerotic effects, these agents may have the potential to cause weight gain or edema as a result of fluid retention and fat accumulation, which could accelerate or aggravate CHF.13,26
Since coronary artery disease is the main consequence of diabetes and the first cause of CHF, it seems logical to optimize anti-ischemic therapy in diabetic patients with heart failure.20-23 Statins are increasingly used in the treatment of type 2 diabetes as they could afford a significant benefit on outcome.27 A retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) suggests an improved prognosis of revascularized diabetic patients with symptomatic heart failure compared with other diabetic patients.28 Ortolani et al29 observed that percutaneous coronary intervention of de novo lesions with drug-eluting stent implantation resulted in lower rates of cardiac death, non-fatal myocardial infarction, and target vessel revascularization, but left ventricular ejection fraction <35% remained an independent predictor for adverse clinical outcome. The results of 10-year follow-up of the Bypass Angioplasty Revascularization Investigation (BARI) trial30 and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study26 confirm the long-term superiority of coronary artery bypass grafting versus percutaneous coronary intervention or medical treatment in diabetic patients with extensive coronary disease and substantial myocardial ischemia.
In summary, diabetes and CHF are prevalent because of a common neurohormonal link between the two pathological conditions. Patients with diabetes and CHF are characterized by more significant biochemical and hemodynamic abnormalities, and have higher risk of morbidity and mortality than those with diabetes or CHF alone. Medical therapies with ACE inhibitors, β-blockers, and glucose-lowering agents are mandatory on an individual decision-making basis for these patients. Further studies are needed to investigate the prognostic significance of AGEs and abnormal myocardial insulin signaling in the diabetic failing heart,17,31 and optimal coronary revascularization strategy for patients with diabetes and CHF.32
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