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Heart failure and diabetes mellitus


Pathophysiological mechanisms of heart failure in diabetes

Insulin signaling and heart failure

This review covers normal insulin signaling in the myocardium and vasculature, the pathophysiological changes in these processes that occur in heart failure and conditions associated with insulin resistance, as well as and the therapeutic approaches that aiming to address them. 

Summary points
  • Epidemiological data point to a link between elevated blood glucose, insulin resistance and diabetes mellitus, on the one hand, and heart failure, on the other.
  • Binding of insulin to its receptor leads to the activation of several intracellular signaling pathways, including phosphatidylinositol-3-kinase (PI3K)/Akt and mitogen-activated protein MAP kinase pathways.
  • Insulin stimulates a wide variety of processes, such as glycogen and protein synthesis, glucose and fatty acid metabolism, glucose uptake, mitochondrial fusion, gene expression, cell growth, apoptosis, autophagy and vasodilation.
  • Insulin-resistant patients have impaired: glucose uptake in muscle and adipose tissues, suppression of glucose production in the liver and suppression of lipolysis. Conversely, triglyceride synthesis and secretion of very low-density lipoproteins is increased. Low-grade inflammation is commonly observed.
  • Insulin resistance can affect the heart in a number of ways, including through increased fatty acid utilization, accumulation of bioactive lipids, mitochondrial dysfunction, decreased cardiac efficiency, oxidative stress, inflammation, increased apoptosis and altered calcium metabolism.
  • Evidence suggests that left ventricular dysfunction and remodeling can be caused by hyperactivation of PI3K/Act pathway and G-protein receptor kinase-2, repression of myocardial autophagy and FOXO-mediated activation of autophagic and atrophic pathways, myosin isoform switching and lipotoxicity.
  • In some patients with diabetes, worsening of heart failure has been observed after certain glucose-lowering treatments, including thiazolidinediones, dipeptidyl peptidase 4 inhibitors and possibly insulin.
  • Further research is required to devise better strategies to normalize the metabolic milieu characterizing heart failure.

Riehle C, Abel ED. Circ Res 2016; 118: 1151–1169. doi: 10.1161/CIRCRESAHA.116.306206

Insulin resistance: An additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes

This review discusses the pathophysiology of cardiovascular disease in patients with diabetes, in particular the roles played by oxidative stress, inflammation, abnormal glucose uptake and endothelial dysfunction in the development of cardiovascular disease.

Summary points
  • A number of pathological processes commonly observed in patients with diabetes contribute to the development of cardiovascular complications, including oxidative stress, inflammation, hypertension, endothelial dysfunction, obesity, dyslipidemia, hypoglycemia and autonomic neuropathy.
  • Accumulation of excess fat activates an inflammatory cascade that affects several stages of insulin signaling, eventually leading to insulin resistance.
  • Hyperglycemia can lead to oxidative stress by causing activation of the polyol pathway, formation of advanced glycation end products, increasing free fatty acid and leptin levels and stimulating production of reactive oxygen species in mitochondria.
  • Insulin resistance is associated with hypertension, dyslipidemia, hypercoagulability and atherosclerosis.
  • Insulin resistance causes impaired endothelial function by reducing bioavailability of nitric oxide.

Patel TP et al. Heart Fail Rev 2016; 21: 11–23. doi: 10.1007/s10741-015-9515-6

Cardiac structure and function across the glycemic spectrum in elderly men and women free of prevalent heart disease: The Atherosclerosis Risk In the Community study

This large, prospective study provides evidence for the relationship between dysglycemia and alterations in cardiac structure and function characteristic of heart failure.

Summary points
  • Previous studies indicate that patients with diabetes have increased left ventricular wall thickness and mass and impaired diastolic function.
  • The aim of this study was to examine the relationship between dysglycemia and cardiac structure and function measured by transthoracic echocardiography.
  • Patient population consisted of 4419 elderly individuals with no prevalent coronary heart disease or heart failure.
  • Blood glucose levels were normal in 39% of patients, while 31% had pre-diabetes and 30% had diabetes.
  • Higher blood glucose levels were found to be associated with increased left ventricular mass, worse diastolic function and slightly worse left ventricular systolic function (p≤0.01 for all comparisons).
  • Multivariate analysis revealed that for every 1% increase in the level of glycated hemoglobin left ventricular mass was increased by 3.0g, E/E′ by 0.5 and global longitudinal strain by 0.3%.
  • Hyperglycemic states may contribute to subtle subclinical impairments in cardiac structure and function.

Skali H et al. Circ Heart Fail 2015; 8: 448–454. doi: 10.1161/CIRCHEARTFAILURE.114.001990

Cardiometabolic syndrome and increased risk of heart failure

This review covers the pathophysiological mechanisms underlying diastolic dysfunction and heart failure in patients with cardiometabolic syndrome, proposes a solution to attendant diagnostic problems and outlines treatment options. 

Summary points
  • A two-step model of the pathogenesis of heart failure in individuals with metabolic syndrome is proposed. During the first, reversible step, risk factors (obesity, insulin resistance, type 2 diabetes, dyslipoproteinemia and hypertension) cause insufficient energy supply. During the second step, remodeling causes myocardial stiffness and impairment of late diastolic function.
  • Diastolic dysfunction is initially precipitated by metabolic alterations associated with insulin resistance, such as altered substrate use, decreased ATP generation, dysregulation of perfusion and impaired calcium handling in the myocardium. After that the remodeling process is promoted by inflammatory and cytokine abnormalities, lipo- and glucotoxicity, oxidative stress and upregulation of the renin-angiotensin-aldosterone and sympathetic nervous systems.
  • The following definition of diastolic dysfunction was proposed: diastolic dysfunction is the deficit between the E’ and an age-related normal value from healthy individuals E’norm.
  • Non-pharmacological therapies for cardiometabolic syndrome include various dietary approaches, exercise training and bariatric surgery, while pharmacological therapies include orlistat, sibutramine and rimonabant, of which only orlistat is currently available.
  • Non-pharmacological therapies for diastolic dysfunction and heart failure include various dietary approaches, exercise training and bariatric surgery, while pharmacological therapies include metformin, glitazones, glucagon-like peptide-1 analogues, dipeptidyl peptidase 4 inhibitors and sodium-dependent glucose cotransporter 2 inhibitors.

Von Bibra H, Paulus W, St John Sutton M. Curr Heart Fail Rep 2016; 13: 219–229. doi: 10.1007/s11897-016-0298-4

Diastolic dysfunction in the diabetic continuum: Association with insulin resistance, metabolic syndrome, and type 2 diabetes

This study provides evidence for the association between ventricular diastolic dysfunction and insulin resistance, metabolic syndrome and diabetes.

Summary points
  • Obesity is associated with diastolic dysfunction, while insulin resistance has been suggested as one of the underlying pathophysiological mechanisms.
  • This study aimed to evaluate the relationship between left ventricular diastolic dysfunction and insulin resistance, metabolic syndrome and diabetes.
  • The patient population consisted of 1063 individuals ≥45 years old (38% male) selected from a cohort representative of the adult population of Porto, Portugal.
  • Assessments included echocardiography for diastolic function and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score.
  • Metabolic syndrome was diagnosed in 41.8% of patients, and diabetes in 11.9%.
  • Overall, 23.7% of patients had left ventricular diastolic dysfunction: 14.5% in the mild and 9.2% in the moderate or severe form.
  • Lateral E’ velocity and E/E’ ratio were found to correlate with HOMA-IR score(ρ=−0.20, p<0.0001, and ρ=0.20, p<0.0001, respectively).
  • Across HOMA-IR quartiles, a progressive worsening in E’ velocity (p<0.001 for trend) and E/E’ ratio (p<0.001 for trend) were observed.
  • HOMA-IR score was 0.95 (P25-75: 0.56-1.69) in patients with normal diastolic function, 1.30 (P25-75: 0.70-2.03) in patients with grade I diastolic dysfunction and 1.59 (P25-75: 0.83-2.41) in patients with moderate/severe diastolic dysfunction.
  • Diastolic dysfunction was diagnosed in 16.3% of patients without metabolic syndrome, 32.6% of patients with metabolic syndrome and no diabetes, and 36.6% of patients with metabolic syndrome and diabetes (p for trend <0.001).
  • HOMA-IR score and metabolic syndrome were found to be independently associated with left ventricular diastolic dysfunction.
  • Decrease in diastolic function precedes the onset of diabetes.

Fontes-Carvalho R et al. Cardiovasc Diabetol 2015; 14: 4. doi: 10.1186/s12933-014-0168-x

Can the onset of heart failure be delayed by treating diabetic cardiomyopathy?

This review covers the pathogenesis of diabetic cardiomyopathy, particularly the role of coronary artery disease. The authors propose a novel definition of DC and describe an individualized approach to the management of coronary artery disease in patients with diabetes.

Summary points
  • Diabetic cardiomyopathy is defined as functional and structural abnormalities of myocardium in diabetics, without concomitant coronary artery disease.
  • In patients with diabetes, impaired coronary circulation leads to chronic myocardial ischemia, which, in turn, causes fibrosis characteristic of diabetic cardiomyopathy.
  • The non-ischemic mechanisms of diabetic cardiomyopathy include oxidative stress, increased susceptibility to ischemia/reperfusion injury, altered intracellular Ca2+ turnover, with reduced Ca2+ sensitivity of contractile proteins, the accumulation of advanced glycation end-products and cardiac autonomic neuropathy.
  • Recent advances in the understanding of the etiology of diabetic cardiomyopathy include recognition of the role of resistin, high concentrations of RNA-binding motif protein 9 (RBM9), elevated fructose levels and impairment in the ubiquitin-proteasome system.
  • The authors propose a new definition of diabetic cardiomyopathy: diabetic cardiomyopathy is “…a result of a long-lasting process, affecting the myocardium, that sets up, at a very early stage of metabolic changes (mainly associated with insulin resistance or resistin overexpression), even before diabetes is diagnosed, and soon after its beginning is accelerated by progressive myocardial ischemia.”
  • In diabetic patients with coronary artery disease, the best current approach to prevent diabetic cardiomyopathy from developing to heart failure is surgical revascularization.

Marcinkiewicz A, Ostrowski S, Drzewoski J. Diabetol Metab Syndr 2017; 9: 21. doi: 10.1186/s13098-017-0219-z

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