Insulin Resistance In Heart Failure Research Articles

Prognostic Implications of Insulin Resistance in Heart Failure in Japan.

Diabetes mellitus (DM) is a major risk and prognostic factor for heart failure (HF). Insulin resistance (IR) is an important component of DM, but the relationship between IR and HF prognosis has not yet been established across a wide variety of HF populations. We retrospectively evaluated the relationship between IR and clinical outcomes of HF patients at our hospital between 2017 and 2021. IR was defined as a homeostatic model assessment of IR (HOMA-IR) index ≥ 2.5, calculated from fasting blood glucose and insulin concentrations. The primary outcome was a composite of all-cause death and hospitalisation for HF (HHF). Among 682 patients included in the analyses, 337 (49.4%) had IR. The median age was 70 [interquartile range (IQR): 59-77] years old, and 66% of the patients were men. Among the patients, 41% had a left ventricular ejection fraction below 40%, and 32% had DM. The median follow-up period was 16.5 [IQR: 4.4-37.3] months. IR was independently associated with the primary outcome (HR: 1.91, 95% CI: 1.39-2.62, p < 0.0001), death (hazard ratio [HR]: 1.86, 95% confidence interval [CI]: 1.28-2.83, p < 0.01), and HHF (HR: 1.91, 95% CI: 1.28-2.83, p < 0.01). HOMA-IR is an independent prognostic factor of HF in a wide variety of HF populations.

Contribution of skeletal muscle-specific microRNA-133b to insulin resistance in heart failure.

Insulin resistance (IR) is one of the hallmarks of heart failure (HF). Abnormalities in skeletal muscle (SM) metabolism have been identified in patients with HF. However, the underlying mechanisms of IR development in SM in HF are poorly understood. Herein, we hypothesize that HF upregulates miR-133b in SM and in turn alters glucose metabolism and the propensity toward IR. Mitochondria isolated from SM of mice with HF induced by transverse aortic constriction (TAC) showed lower respiration and downregulation of muscle-specific components of the tricarboxylic acid (TCA) cycle, AMP deaminase 1 (AMPD1), and fumarate compared with those from control animals. RNA-Seq and subsequent qPCR validation confirmed upregulation of SM-specific microRNA (miRNA), miR-133b, in TAC versus sham animals. miR-133b overexpression alone resulted in significantly lower mitochondrial respiration, cellular glucose uptake, and glycolysis along with lower ATP production and cellular energy reserve compared with the scramble (Scr) in C2C12 cells. miR-133b binds to the 3'-untranslated region (UTR) of KLF15, the transcription factor for the insulin-sensitive glucose transporter, GLUT4. Overexpression of miR-133b lowers GLUT4 and lowers pAkt in presence of insulin in C2C12 cells. Finally, lowering miR-133b in primary skeletal myocytes isolated from TAC mice using antagomir-133b reversed the changes in KLF15, GLUT4, and AMPD1 compared with the scramble-transfected myocytes. Taken together, these data demonstrate a role for SM miR-133b in altered glucose metabolism in HF and suggest the therapeutic potential in HF to improve glucose uptake and glycolysis by restoring GLUT4 abundance. The data uncover a novel mechanism for IR and ultimately SM metabolic abnormalities in patients with HF.NEW & NOTEWORTHY Heart failure is associated with systemic insulin resistance and abnormalities in glucose metabolism but the underlying mechanisms are poorly understood. In the skeletal muscle, the major peripheral site of glucose utilization, we observe an increase in miR-133b in heart failure mice, which reduces the insulin-sensitive glucose transporter (GLUT4), glucose uptake, and metabolism in C2C12 and in myocytes. The antagomir for miR-133b restores GLUT4 protein and markers of metabolism in skeletal myocytes from heart failure mice demonstrating that miR-133b is an exciting target for systemic insulin resistance in heart failure and an important player in the cross talk between the heart and the periphery in the heart failure syndrome.

Metformin in Pulmonary Hypertension in Left Heart Disease.

Metformin is ubiquitously used in the management of Type II Diabetes Mellitus (DMII). Over the years, our growing knowledge of its therapeutic potential has broadened its use to the treatment of infertility in polycystic ovarian syndrome, gestational diabetes, and even obesity. Recently, it has been suggested as a novel therapy in cardiovascular disease (CVD). Given that CVD is the leading cause of death in patients with DMII, with ~ 75% dying from a cardiovascular event, the intersection of DMII and CVD provides a unique therapeutic target. In particular, pulmonary hypertension (PH) related to CVD (Group II PH) may be an optimal target for metformin therapy. The objective of this review article is to provide an overview of the pathophysiology of PH related to left heart disease (PH-LHD), outline the proposed pathophysiologic mechanism of insulin resistance in heart failure and PH-LHD, and evaluate the role metformin may have in heart failure and PH-LHD.

Cardiac Insulin Resistance in Heart Failure: The Role of Mitochondrial Dynamics.

Heart failure (HF) frequently coexists with conditions associated with glucose insufficiency, such as insulin resistance and type 2 diabetes mellitus (T2DM), and patients with T2DM have a significantly high incidence of HF. These two closely related diseases cannot be separated on the basis of their treatment. Some antidiabetic drugs failed to improve cardiac outcomes in T2DM patients, despite lowering glucose levels sufficiently. This may be, at least in part, due to a lack of understanding of cardiac insulin resistance. Basic investigations have revealed the significant contribution of cardiac insulin resistance to the pathogenesis and progression of HF; however, there is no clinical evidence of the definition or treatment of cardiac insulin resistance. Mitochondrial dynamics play an important role in cardiac insulin resistance and HF because they maintain cellular homeostasis through energy production, cell survival, and cell proliferation. The innovation of diagnostic tools and/or treatment targeting mitochondrial dynamics is assumed to improve not only the insulin sensitivity of the myocardium and cardiac metabolism, but also the cardiac contraction function. In this review, we summarized the current knowledge on the correlation between cardiac insulin resistance and progression of HF, and discussed the role of mitochondrial dynamics on the pathogenesis of cardiac insulin resistance and HF. We further discuss the possibility of mitochondria-targeted intervention to improve cardiac metabolism and HF.

Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure

BackgroundBranched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure.MethodFor human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day).ResultEchocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups.ConclusionWe conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.

Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

Insulin resistance in heart failure: differences between patients with reduced and preserved left ventricular ejection fraction.

Insulin resistance (IR) is a characteristic feature of heart failure (HF) pathophysiology that affects symptoms and mortality. Differences in the pathophysiological profile of IR in HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not characterized in detail. The aim of this study was to evaluate features of IR in HFpEF vs. HFrEF. We included 18 patients with HFrEF (EF 30 ± 11%, body mass index (BMI) 26.5 ± 3.3 kg/m(2)), 22 HFpEF patients (EF 63 ± 7%, BMI 28.6 ± 4.8 kg/m(2)), and 20 healthy controls of similar age, all without diabetes mellitus. Patients were in stable ambulatory condition and on stable medical regimens for HF. IR was assessed at fasting steady state by the homeostasis model assessment (HOMA) index and within the physiological range of insulin-glucose interactions by the short insulin sensitivity test (SIST). Fasting-state IR was observed in HFpEF and in HFrEF in comparison with controls (HOMA 1.9, interquartile range (IQR) 1.5-3.6 vs. HOMA 3.1, IQR 1.4-3.7 vs. controls 1.2, IQR 1.8-0.9, respectively; analysis of variance P < 0.001), but no statistical difference was observed between HFpEF and HFrEF. The dynamic test over the physiological range of insulin-glucose interactions revealed a more severe IR in HFrEF as compared with HFpEF. Thus, glucose levels remained the highest in HFrEF (76 (64-89) mg/dL) at the end of the SIST compared with HFpEF and controls (68 (58-79) and 56 (44-66) mg/dL, respectively, P < 0.001). IR is present in non-diabetic patients with HFpEF and HFrEF. However, distinct differences in the insulin sensitivity characteristics in HFpEF and HFrEF become apparent by more advanced testing. Patients with HFrEF showed more severe IR.

Admission Glycaemia and Acute Insulin Resistance in Heart Failure Complicating Acute Coronary Syndrome

Few data are so far available on the relation between increased glucose values and insulin resistance and mortality at short-term in patients with acute heart failure (AHF). The present investigation, performed in 409 consecutive patients with AHF complicating acute coronary syndrome (ACS), was aimed at assessing the prognostic role of admission glycaemia and acute insulin resistance (as indicated by the Homeostatic Model Assessment - HOMA index) for death during Intensive Cardiac Care (ICCU) stay. Admission glucose tertiles were considered. In our series, diabetic patients accounted for the 33%. Patients in the third glucose tertiles exhibited the lowest LVEF (both on admission and at discharge), a higher use of mechanical ventilation, intra-aortic balloon pump and inotropic drugs and the highest in-ICCU mortality rate. In the overall population, hyperglycaemic patients (both diabetic and non diabetic) were 227 (227/409, 55.5%). Admission glycaemia was an independent predictor of in-ICCU mortality, together with admission LVEF and eGFR, while acute insulin resistance (as indicated by HOMA-index) was not associated with early death. The presence of admission hyperglycaemia in non-diabetic patients was independently associated with in-ICCU death while hyperglycaemia in diabetic patients was not. According to our results, hyperglycaemia is a common finding in patients with ACS complicated by AHF and it is an independent predictor of early death. Non-diabetic patients with hyperglycaemia are the subgroup with the highest risk of early death.

(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice.

We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg(-1)·day(-1), n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.

Cardiogenic diabetes

It has been well established since the Framingham studies that diabetes mellitus is a risk factor for heart failure. Several recent reports suggested that the reverse is also true, and heart failure may also predispose to diabetes. We reviewed the literature and summarized the evidence of a higher incidence of new-onset diabetes in heart failure. Because a high rate of insulin resistance in heart failure is a known phenomenon, a higher incidence of diabetes in heart failure is intuitive. Although the facts confirming such connection is surprisingly scarce, we felt it was important to collect, analyze, and summarize the evidence.

Cardiac insulin resistance in heart failure may be mediated through PTP1B activation in rats and humans

Cardiac insulin resistance in heart failure may be mediated through PTP1B activation in rats and humans

Effects of metformin on insulin resistance in heart failure. Which came first: the chicken or the egg?

Effects of metformin on insulin resistance in heart failure. Which came first: the chicken or the egg?

Ventricular Assist Device Implantation Corrects Myocardial Lipotoxicity, Reverses Insulin Resistance, and Normalizes Cardiac Metabolism in Patients With Advanced Heart Failure

Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose use for ATP generation. We hypothesized that cardiac accumulation of toxic lipid intermediates inhibits insulin signaling in advanced heart failure and that mechanical unloading of the failing myocardium corrects impaired cardiac metabolism. We analyzed the myocardium and serum of 61 patients with heart failure (body mass index, 26.5±5.1 kg/m(2); age, 51±12 years) obtained during left ventricular assist device implantation and at explantation (mean duration, 185±156 days) and from 9 control subjects. Systemic insulin resistance in heart failure was accompanied by decreased myocardial triglyceride and overall fatty acid content but increased toxic lipid intermediates, diacylglycerol, and ceramide. Increased membrane localization of protein kinase C isoforms, inhibitors of insulin signaling, and decreased activity of insulin signaling molecules Akt and Foxo were detectable in heart failure compared with control subjects. Left ventricular assist device implantation improved whole-body insulin resistance (homeostatic model of analysis-insulin resistance, 4.5±0.6-3.2±0.5; P<0.05) and decreased myocardial levels of diacylglycerol and ceramide, whereas triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/phosphatidylinositol-3 kinase/Akt signaling cascade after left ventricular assist device implantation was confirmed by increased phosphorylation of Akt and Foxo, which was accompanied by decreased membrane localization of protein kinase C isoforms after left ventricular assist device implantation. Mechanical unloading after left ventricular assist device implantation corrects systemic and local metabolic derangements in advanced heart failure, leading to reduced myocardial levels of toxic lipid intermediates and improved cardiac insulin signaling.

P53-Induced Adipose Tissue Inflammation Is Critically Involved in the Development of Insulin Resistance in Heart Failure

Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance.

Oxidative stress and heart failure

Oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense, has been shown to play an important role in the pathophysiology of cardiac remodeling and heart failure (HF). It induces subtle changes in intracellular pathways, redox signaling, at lower levels, but causes cellular dysfunction and damage at higher levels. ROS are derived from several intracellular sources, including mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. The production of ROS is increased within the mitochondria from failing hearts, whereas normal antioxidant enzyme activities are preserved. Chronic increases in ROS production in the mitochondria lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further ROS generation, and cellular injury. ROS directly impair contractile function by modifying proteins central to excitation-contraction coupling. Moreover, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors and mediate apoptosis. They also stimulate cardiac fibroblast proliferation and activate the matrix metalloproteinases, leading to the extracellular matrix remodeling. These cellular events are involved in the development and progression of maladaptive myocardial remodeling and failure. Oxidative stress is also involved in the skeletal muscle dysfunction, which may be associated with exercise intolerance and insulin resistance in HF. Therefore, oxidative stress is involved in the pathophysiology of HF in the heart as well as in the skeletal muscle. A better understanding of these mechanisms may enable the development of novel and effective therapeutic strategies against HF.

Myocardial insulin resistance induced by high fat feeding in heart failure is associated with preserved contractile function

Previous studies have reported that high fat feeding in mild to moderate heart failure (HF) results in the preservation of contractile function. Recent evidence has suggested that preventing the switch from fatty acid to glucose metabolism in HF may ameliorate dysfunction, and insulin resistance is one potential mechanism for regulating substrate utilization. This study was designed to determine whether peripheral and myocardial insulin resistance exists with HF and/or a high-fat diet and whether myocardial insulin signaling was altered accordingly. Rats underwent coronary artery ligation (HF) or sham surgery and were randomized to normal chow (NC; 14% kcal from fat) or a high-fat diet (SAT; 60% kcal from fat) for 8 wk. HF + SAT animals showed preserved systolic (+dP/dt and stroke work) and diastolic (-dP/dt and time constant of relaxation) function compared with HF + NC animals. Glucose tolerance tests revealed peripheral insulin resistance in sham + SAT, HF + NC, and HF + SAT animals compared with sham + NC animals. PET imaging confirmed myocardial insulin resistance only in HF + SAT animals, with an uptake ratio of 2.3 ± 0.3 versus 4.6 ± 0.7, 4.3 ± 0.4, and 4.2 ± 0.6 in sham + NC, sham + SAT, and HF + NC animals, respectively; the myocardial glucose utilization rate was similarly decreased in HF + SAT animals only. Western blot analysis of insulin signaling protein expression was indicative of cardiac insulin resistance in HF + SAT animals. Specifically, alterations in Akt and glycogen synthase kinase-3β protein expression in HF + SAT animals compared with HF + NC animals may be involved in mediating myocardial insulin resistance. In conclusion, HF animals fed a high-saturated fat exhibited preserved myocardial contractile function, peripheral and myocardial insulin resistance, decreased myocardial glucose utilization rates, and alterations in cardiac insulin signaling. These results suggest that myocardial insulin resistance may serve a cardioprotective function with high fat feeding in mild to moderate HF.

Aldosterone status associated with insulin resistance in patients with heart failure—data from the ALOFT study

Background:Aldosterone has a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone “escapes” from inhibition by drugs that interrupt the renin-angiotensin axis; such patients...

Role of insulin resistance in heart failure and high fat diet

Both heart failure (HF) and high saturated fat diets (SAT) are associated with the development of insulin resistance. Whether insulin resistance exists in a model that involves both HF+SAT has not been studied. Previous studies reported that HF+SAT rats have improved left ventricular contractile and mitochondrial function compared to HF animals fed normal chow (NC). We hypothesize that myocardial insulin resistance exists in HF+SAT rats and that it serves a cardioprotective role. Male Wistar rats underwent coronary ligation or sham surgery and were fed NC (10% kcal fat) or SAT (60% kcal saturated fat) for 8 weeks. Five weeks post ligation, a glucose tolerance test (GTT) was performed to determine peripheral insulin resistance via plasma glucose and insulin concentrations. Echocardiography was done at 7 weeks post ligation to assess cardiac function. Tissue was harvested 8 weeks post ligation to assess the insulin signaling pathway via targets such as AKT, mTOR, GSK3β, eIF‐2, and AMPK by protein and RNA analysis. Preliminary results indicate that HF+NC and Sham+SAT have abnormal GTTs compared to Sham+NC. However, HF+SAT animals do not have impaired GTT. Ongoing studies will assess whether differences in GTT result from alterations in insulin signaling and whether these alterations in HF+SAT serve in a cardioprotective function in heart failure. (Grant # NHLBI HL‐081857 &amp; AHA 0535361N)

Insulin Resistance in Heart Failure: Prevalence and Relation to Disease Severity

Insulin Resistance in Heart Failure: Prevalence and Relation to Disease Severity

Metabolic Mechanisms in Heart Failure

Although neurohumoral antagonism has successfully reduced heart failure morbidity and mortality, the residual disability and death rate remains unacceptably high. Though abnormalities of myocardial metabolism are associated with heart failure, recent data suggest that heart failure may itself promote metabolic changes such as insulin resistance, in part through neurohumoral activation. A detrimental self-perpetuating cycle (heart failure --> altered metabolism --> heart failure) that promotes the progression of heart failure may thus be postulated. Accordingly, we review the cellular mechanisms and pathophysiology of altered metabolism and insulin resistance in heart failure. It is hypothesized that the ensuing detrimental myocardial energetic perturbations result from neurohumoral activation, increased adverse free fatty acid metabolism, decreased protective glucose metabolism, and in some cases insulin resistance. The result is depletion of myocardial ATP, phosphocreatine, and creatine kinase with decreased efficiency of mechanical work. On the basis of the mechanisms outlined, appropriate therapies to mitigate aberrant metabolism include intense neurohumoral antagonism, limitation of diuretics, correction of hypokalemia, exercise, and diet. We also discuss more novel mechanistic-based therapies to ameliorate metabolism and insulin resistance in heart failure. For example, metabolic modulators may optimize myocardial substrate utilization to improve cardiac function and exercise performance beyond standard care. The ultimate success of metabolic-based therapy will be manifest by its capacity further to lessen the residual mortality in heart failure.