Impaired Insulin Sensitivity as an Independent Risk Factor for Mortality in Patients With Stable Chronic Heart Failure

Doehner, Wolfram; Rauchhaus, Mathias; Ponikowski, Piotr; Godsland, Ian F.; Haehling, Stephan von; Okonko, Darlington O.; Leyva, Francisco; Proudler, Anthony J.; Coats, Andrew J.S.; Anker, Stefan D.

doi:10.1016/j.jacc.2005.02.093

Cited by 253 publications

(188 citation statements)

References 33 publications

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“…5) because of increased adrenergic tone and the release of natriuretic peptides and inflammatory molecules (73). Furthermore, there is evidence that myocardial insulin resistance is an independent risk factor for mortality in stable patients with chronic heart failure (74). Also, myocardial insulin resistance is associated with a mismatch between insulin-mediated glucose uptake and myocardial blood flow, possibly as a result of remodeling (75).…”

Section: Future Studiesmentioning

confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

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The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trialdmodest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid leveldmay be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.First among cardiovascular (CV) end point trials of glucose-lowering agents (1), the EMPA-REG OUTCOME trialdusing 10 or 25 mg/day sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin against placebo in 7,020 patients with type 2 diabetes (T2D) who were at increased CV riskdreported a 14% reduction in major CV events and marked relative risk reductions in CV mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) over a median time period of 2.6 years (2). Of note, all the pathologic categories of CV death (ischemic, pump failure, arrhythmic, embolic) contributed to the overall reduction in CV death in a patient cohort well treated with the use of renin-angiotensin-aldosterone inhibitors, statins, and acetylsalicylic acid. Furthermore, separation of the cumulative incidence functions between pooled-dose groups and placebo was already evident months after randomization. This unusual time course and the discrepancy between the relative risk reduction of the primary end point (nonfatal myocardial infarction, stroke, and CV mortality) and CV mortality itself suggests that active treatment affected case fatality rates more than event rates. In other words, empagliflozin treatment appeared mostly to rescue patients from impending cardiac decompensation. This interpretation is supported by the recent post hoc analyses of heart failure, documenting a large benefit in first and recurrent heart failure hospitalization across virtually every patient subgroup (3). Despite the fact that the diagnosis of heart failure was based on investigator reporting, th...

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Section: Future Studiesmentioning

confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

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“…It is also worth mentioning that a general reduction in substrate oxidation rates and mitochondrial function has been demonstrated for failing hearts, suggesting that preceding or coexisting insulin resistance may, under certain conditions, contribute to the oxidative defects observed in heart failure (Hoppel et al, 1982;Ide et al, 2001;Ventura-Clapier et al, 2004;Neubauer, 2007). Indeed, epidemiological studies suggest that insulin resistance is an independent risk factor for heart failure (Swan et al, 1997;Doehner et al, 2005). Thus, CIRKO mice represent a useful model to dissect the mechanisms by which impaired insulin signaling may compromise mitochondrial function in diabetic hearts, independently of hyperglycemia and hyperlipidemia, which may even have relevance for the pathology of cardiac diseases beyond diabetic cardiomyopathy.…”

Section: Genetically Engineered Mice To Evaluate Potential Mechanismsmentioning

confidence: 99%

Rodent models of diabetic cardiomyopathy

Bugger

Abel

2009

Disease Models &Amp; Mechanisms

244

198

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Diabetic cardiomyopathy increases the risk of heart failure in individuals with diabetes, independently of co-existing coronary artery disease and hypertension. The underlying mechanisms for this cardiac complication are incompletely understood. Research on rodent models of type 1 and type 2 diabetes, and the use of genetic engineering techniques in mice, have greatly advanced our understanding of the molecular mechanisms responsible for human diabetic cardiomyopathy. The adaptation of experimental techniques for the investigation of cardiac physiology in mice now allows comprehensive characterization of these models. The focus of the present review will be to discuss selected rodent models that have proven to be useful in studying the underlying mechanisms of human diabetic cardiomyopathy, and to provide an overview of the characteristics of these models for the growing number of investigators who seek to understand the pathology of diabetes-related heart disease.

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“…Dysregulation of muscle-mediated glucose removal from the circulation is central to insulin resistance and type II diabetes (Defronzo et al, 1985). Although heart muscle is not a major site of glucose disposal, recent clinical studies have revealed that reduced insulin sensitivity is a risk factor for mortality in individuals with coronary heart failure (Swan et al, 1997;Doehner et al, 2005). In addition, it has been shown that measurements of insulinstimulated glucose disposal are prognostic markers of coronary heart failure (Paolisso et al, 1999;Doehner et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Although heart muscle is not a major site of glucose disposal, recent clinical studies have revealed that reduced insulin sensitivity is a risk factor for mortality in individuals with coronary heart failure (Swan et al, 1997;Doehner et al, 2005). In addition, it has been shown that measurements of insulinstimulated glucose disposal are prognostic markers of coronary heart failure (Paolisso et al, 1999;Doehner et al, 2005). Heart muscle glucose transport shares many similarities to that occurring in skeletal muscle and is known to be associated with the translocation of the GLUT4 glucose transporter isoform from intracellular reservoir compartments to the limiting membranes of the sarcolemma and the transverse-tubule system of the cardiomyocytes (Fischer et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

A common trafficking route for GLUT4 in cardiomyocytes in response to insulin, contraction and energy-status signalling

Fazakerley

Lawrence

Lizunov

et al. 2009

Journal of Cell Science

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A new mouse model has been developed to study the localisation and trafficking of the glucose transporter GLUT4 in muscle. The mouse line has specific expression of a GFP and HA-epitope-tagged version of GLUT4 under the control of a muscle-specific promoter. The exofacial HA-tag has enabled fluorescent labelling of only the GLUT4 exposed at the external surface. A distinction between sarcolemma labelling and transverse-tubule labelling has also been possible because the former compartment is much more accessible to intact anti-HA antibody. By contrast, the Fab fragment of the anti-HA antibody could readily detect GLUT4 at the surface of both the sarcolemma and transverse tubules. Here, we have used this mouse model to examine the route taken by cardiomyocyte GLUT4 as it moves to the limiting external membrane surface of sarcolemma and transverse-tubules in response to insulin, contraction or activators of energy-status signalling, including hypoxia. HA-GLUT4-GFP is largely excluded from the sarcolemma and transverse-tubule membrane of cardiomyocytes under basal conditions, but is similarly trafficked to these membrane surfaces after stimulation with insulin, contraction or hypoxia. Internalisation of sarcolemma GLUT4 has been investigated by pulse-labelling surface GLUT4 with intact anti-HA antibody. At early stages of internalisation, HA-tagged GLUT4 colocalises with clathrin at puncta at the sarcolemma, indicating that in cells returning to a basal state, GLUT4 is removed from external membranes by a clathrin-mediated route. We also observed colocalisation of GLUT4 with clathrin under basal conditions. At later stages of internalisation and at steady state, anti-HA antibody labeled-GLUT4 originating from the sarcolemma was predominantly detected in a peri-nuclear compartment, indistinguishable among the specific initial stimuli. These results taken together imply a common pathway for internalisation of GLUT4, independent of the initial stimulus.

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Impaired Insulin Sensitivity as an Independent Risk Factor for Mortality in Patients With Stable Chronic Heart Failure

Cited by 253 publications

References 33 publications

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

Rodent models of diabetic cardiomyopathy

A common trafficking route for GLUT4 in cardiomyocytes in response to insulin, contraction and energy-status signalling

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