Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure

Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.

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Small-hairpin RNA and pharmacological targeting of neutral sphingomyelinase prevent diaphragm weakness in rats with heart failure and reduced ejection fraction

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00516.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. L679-L690 ◽

Cited By ~ 2

Author(s):

Philip D. Coblentz ◽

Bumsoo Ahn ◽

Linda F. Hayward ◽

Jeung-Ki Yoo ◽

Demetra D. Christou ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Knockout Mice ◽

Pharmacological Intervention ◽

Hairpin Rna ◽

Reduced Ejection Fraction ◽

Neutral Sphingomyelinase ◽

Mitochondrial Ros ◽

Virus Serotype ◽

Diaphragm Weakness

Heart failure with reduced ejection fraction (HFREF) increases neutral sphingomyelinase (NSMase) activity and mitochondrial reactive oxygen species (ROS) emission and causes diaphragm weakness. We tested whether a systemic pharmacological NSMase inhibitor or short-hairpin RNA (shRNA) targeting NSMase isoform 3 (NSMase3) would prevent diaphragm abnormalities induced by HFREF caused by myocardial infarction. In the pharmacological intervention, we used intraperitoneal injection of GW4869 or vehicle. In the genetic intervention, we injected adeno-associated virus serotype 9 (AAV9) containing shRNA targeting NSMase3 or a scrambled sequence directly into the diaphragm. We also studied acid sphingomyelinase-knockout mice. GW4869 prevented the increase in diaphragm ceramide content, weakness, and tachypnea caused by HFREF. For example, maximal specific forces (in N/cm2) were vehicle [sham 31 ± 2 and HFREF 26 ± 2 ( P < 0.05)] and GW4869 (sham 31 ± 2 and HFREF 31 ± 1). Respiratory rates were (in breaths/min) vehicle [sham 61 ± 3 and HFREF 84 ± 11 ( P < 0.05)] and GW4869 (sham 66 ± 2 and HFREF 72 ± 2). AAV9-NSMase3 shRNA prevented heightening of diaphragm mitochondrial ROS and weakness [in N/cm2, AAV9-scrambled shRNA: sham 31 ± 2 and HFREF 27 ± 2 ( P < 0.05); AAV9-NSMase3 shRNA: sham 30 ± 1 and HFREF 30 ± 1] but displayed tachypnea. Both wild-type and ASMase-knockout mice with HFREF displayed diaphragm weakness. Our study suggests that activation of NSMase3 causes diaphragm weakness in HFREF, presumably through accumulation of ceramide and elevation in mitochondrial ROS. Our data also reveal a novel inhibitory effect of GW4869 on tachypnea in HFREF likely mediated by changes in neural control of breathing.

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Glucagon-Like Peptide 1 Receptor Agonists and Heart Failure

Circulation ◽

10.1161/circulationaha.120.045888 ◽

2020 ◽

Vol 142 (12) ◽

pp. 1205-1218 ◽

Cited By ~ 1

Author(s):

Muhammad Shahzeb Khan ◽

Gregg C. Fonarow ◽

Darren K. McGuire ◽

Adrian F. Hernandez ◽

Muthiah Vaduganathan ◽

...

Keyword(s):

Heart Failure ◽

Cardiovascular Disease ◽

Ejection Fraction ◽

Atherosclerotic Cardiovascular Disease ◽

Reduced Ejection Fraction ◽

Receptor Agonists ◽

Sodium Glucose Cotransporter ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

With worsening epidemiological trends for both the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) worldwide, it is critical to implement optimal prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly. Several guidelines and consensus statements have recommended glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter type 2 inhibitors as add-ons to lifestyle interventions with or without metformin in those at high atherosclerotic cardiovascular disease risk. However, these recommendations are either silent about HF or fail to differentiate between the prevention of HF in those at risk versus the treatment of individuals with manifest HF. Furthermore, these documents do not differentiate among those with different HF phenotypes. This distinction, even though important, may not be critical for sodium-glucose cotransporter type 2 inhibitors in view of the consistent data for benefit for both atherosclerotic cardiovascular disease– and HF-related outcomes that have emerged from the regulatory-mandated cardiovascular outcome trials for all sodium-glucose cotransporter type 2 inhibitors and the recent DAPA-HF trial (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction)demonstrating the benefit of dapagliflozin on HF-related outcomes in patients with HF with reduced ejection fraction with or without T2DM. However, the distinction may be crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents. Indeed, in several of the new statements, glucagon-like peptide-1 receptor agonists are suggested treatment not only for patients with T2DM and atherosclerotic cardiovascular disease, but also in those with manifest HF, despite a lack of evidence for the latter recommendation. Although glucagon-like peptide-1 receptor agonists may be appropriate to use in patients at risk for HF, mechanistic insights and observations from randomized trials suggest no clear benefit on HF-related outcomes and even uncertainty regarding the safety in those with HF with reduced ejection fraction. Conversely, theoretical rationales suggest that these agents may benefit patients with HF with preserved ejection fraction. Considering that millions of patients with T2DM have HF, these concerns have public health implications that necessitate the thoughtful use of these therapies. Achieving this aim will require dedicated trials with these drugs in both patients who have HF with reduced ejection fraction and HF with preserved ejection fraction with T2DM to assess their efficacy, safety, and risk-benefit profile.

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Therapeutic implications of statins in heart failure with reduced ejection fraction and heart failure with preserved ejection fraction: a review of current literature

F1000Research ◽

10.12688/f1000research.28254.1 ◽

2021 ◽

Vol 10 ◽

pp. 16

Author(s):

Chol Techorueangwiwat ◽

Chanavuth Kanitsoraphan ◽

Panupong Hansrivijit

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cohort Studies ◽

Clinical Outcomes ◽

Lipid Lowering ◽

Current Evidence ◽

Controlled Trials ◽

Preserved Ejection Fraction ◽

Reduced Ejection Fraction ◽

Meta Analyses

Statins are one of the standard treatments to prevent cardiovascular events such as coronary artery disease and heart failure (HF). However, data on the use of statins to improve clinical outcomes in patients with established HF remains controversial. We summarized available clinical studies which investigated the effects of statins on clinical outcomes in patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Statins possess many pleiotropic effects in addition to lipid-lowering properties that positively affect the pathophysiology of HF. In HFrEF, data from two large randomized placebo-controlled trials did not show benefits of statins on mortality of patients with HFrEF. However, more recent prospective cohort studies and meta-analyses have shown decreased risk of mortality as well as cardiovascular hospitalization with statins treatment. In HFpEF, most prospective and retrospective cohort studies as well as meta analyses have consistently reported positive effects of statins, including reducing mortality and improving other clinical outcomes. Current evidence also suggests better outcomes with lipophilic statins in patients with HF. In summary, statins might be effective in improving survival and other clinical outcomes in patients with HF, especially for patients with HFpEF. Lipophilic statins might also be more beneficial for HF patients. Based on current evidence, statins did not cause harm and should be continued in HF patients who are already taking the medication. Further randomized controlled trials are needed to clarify the benefits of statins in HF patients.

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Towards quadruple therapy for heart failure with reduced ejection fraction: DAPA-HF secondary analysis data

Russian Journal of Cardiology ◽

10.15829/1560-4071-2020-3870 ◽

2020 ◽

Vol 25 (5) ◽

pp. 3870

Author(s):

Zh. D. Kobalava ◽

V. V. Medovchshikov ◽

N. B. Yeshniyazov

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Sglt2 Inhibitor ◽

Secondary Analysis ◽

Analysis Data ◽

Adverse Outcomes ◽

Reduced Ejection Fraction ◽

Sodium Glucose Cotransporter ◽

Patients With Heart Failure ◽

First Time

Patients with heart failure with reduced ejection fraction (HFrEF), despite optimal evidence-based treatment, have a high residual risk of adverse outcomes. The favorable results of studies on cardiovascular safety and the effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D), including outcomes associated with heart failure, were the reason for studying the effectiveness in patients with HFrEF regardless of the T2D status. For the first time in the DAPA-HF study, the SGLT2 inhibitor dapagliflozin in patients with HFrEF showed a positive effect on hard endpoints. Data of the secondary analysis confirmed the effectiveness of dapagliflozin regardless of the T2D status, therapy, age, and quality of life. The results of DAPA-HF have become a serious statement for changing the standards of the guideline-recommended therapy of HFrEF.

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Suppression of Tumourigenicity 2 in Heart Failure With Preserved Ejection Fraction

Cardiac Failure Review ◽

10.15420/cfr.2019.10 ◽

2020 ◽

Vol 6 ◽

Author(s):

Veronika Zach ◽

Felix Lucas Bähr ◽

Frank Edelmann

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Incidence Rates ◽

Current Evidence ◽

Ageing Population ◽

Preserved Ejection Fraction ◽

Reduced Ejection Fraction ◽

Novel Biomarkers ◽

Underlying Mechanisms ◽

Receptor Family

Heart failure (HF), with steadily increasing incidence rates and mortality in an ageing population, represents a major challenge. Evidence suggests that more than half of all patients with a diagnosis of HF suffer from HF with preserved ejection fraction (HFpEF). Emerging novel biomarkers to improve and potentially guide the treatment of HFpEF are the subject of discussion. One of these biomarkers is suppression of tumourigenicity 2 (ST2), a member of the interleukin (IL)-1 receptor family, binding to IL-33. Its two main isoforms – soluble ST2 (sST2) and transmembrane ST2 (ST2L) – show opposite effects in cardiovascular diseases. While the ST2L/IL-33 interaction is considered as being cardioprotective, sST2 antagonises this beneficial effect by competing for binding to IL-33. Recent studies show that elevated levels of sST2 are associated with increased mortality in HF with reduced ejection fraction. Nevertheless, the significance of sST2 in HFpEF remains uncertain. This article aims to give an overview of the current evidence on sST2 in HFpEF with an emphasis on prognostic value, clinical association and interaction with HF treatment. The authors conclude that sST2 is a promising biomarker in HFpEF. However, further research is needed to fully understand underlying mechanisms and ultimately assess its full value.

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RyR2 and Calcium Release in Heart Failure

Frontiers in Physiology ◽

10.3389/fphys.2021.734210 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jean-Pierre Benitah ◽

Romain Perrier ◽

Jean-Jacques Mercadier ◽

Laetitia Pereira ◽

Ana M. Gómez

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Calcium Release ◽

Contractile Function ◽

Sinus Node ◽

Release Channel ◽

Reduced Ejection Fraction ◽

Fk506 Binding Protein ◽

Failing Heart ◽

Calmodulin Kinase

Heart Failure (HF) is defined as the inability of the heart to efficiently pump out enough blood to maintain the body's needs, first at exercise and then also at rest. Alterations in Ca2+ handling contributes to the diminished contraction and relaxation of the failing heart. While most Ca2+ handling protein expression and/or function has been shown to be altered in many models of experimental HF, in this review, we focus in the sarcoplasmic reticulum (SR) Ca2+ release channel, the type 2 ryanodine receptor (RyR2). Various modifications of this channel inducing alterations in its function have been reported. The first was the fact that RyR2 is less responsive to activation by Ca2+ entry through the L-Type calcium channel, which is the functional result of an ultrastructural remodeling of the ventricular cardiomyocyte, with fewer and disorganized transverse (T) tubules. HF is associated with an elevated sympathetic tone and in an oxidant environment. In this line, enhanced RyR2 phosphorylation and oxidation have been shown in human and experimental HF. After several controversies, it is now generally accepted that phosphorylation of RyR2 at the Calmodulin Kinase II site (S2814) is involved in both the depressed contractile function and the enhanced arrhythmic susceptibility of the failing heart. Diminished expression of the FK506 binding protein, FKBP12.6, may also contribute. While these alterations have been mostly studied in the left ventricle of HF with reduced ejection fraction, recent studies are looking at HF with preserved ejection fraction. Moreover, alterations in the RyR2 in HF may also contribute to supraventricular defects associated with HF such as sinus node dysfunction and atrial fibrillation.

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Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.636152 ◽

2021 ◽

Vol 8 ◽

Author(s):

Qingchun Zeng ◽

Qing Zhou ◽

Weitao Liu ◽

Yutong Wang ◽

Xingbo Xu ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Large Scale ◽

Heart Diseases ◽

Cardiovascular Death ◽

Serum Glucose ◽

Clinical Syndrome ◽

Sglt2 Inhibitors ◽

Reduced Ejection Fraction ◽

Beneficial Effects

Heart failure (HF) is a common complication or late-stage manifestation of various heart diseases. Numerous risk factors and underlying causes may contribute to the occurrence and progression of HF. The pathophysiological mechanisms of HF are very complicated. Despite accumulating advances in treatment for HF during recent decades, it remains an intractable clinical syndrome with poor outcomes, significantly reducing the quality of life and expectancy of patients, and imposing a heavy economic burden on society and families. Although initially classified as antidiabetic agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated reduced the prevalence of hospitalization for HF, cardiovascular death, and all-cause death in several large-scale randomized controlled clinical trials. These beneficial effects of SGLT-2 inhibitors can be attributed to multiple hemodynamic, inflammatory and metabolic mechanisms, not only reducing the serum glucose level. SGLT2 inhibitors have been used increasingly in treatment for patients with HF with reduced ejection fraction due to their surprising performance in improving the prognosis. In addition, their roles and mechanisms in patients with HF with preserved ejection fraction or acute HF have also attracted attention. In this review article, we discuss the possible mechanisms and applications of SGLT2 inhibitors in HF.

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Optimizing Guideline-directed Medical Therapies for Heart Failure with Reduced Ejection Fraction During Hospitalization

US Cardiology Review ◽

10.15420/usc.2020.29 ◽

2021 ◽

Vol 15 ◽

Author(s):

Neal M Dixit ◽

Shivani Shah ◽

Boback Ziaeian ◽

Gregg C Fonarow ◽

Jeffrey J Hsu

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Outpatient Setting ◽

Evidence Based ◽

Mineralocorticoid Receptor Antagonists ◽

Reduced Ejection Fraction ◽

Sodium Glucose Cotransporter ◽

Neprilysin Inhibitor ◽

Patients With Heart Failure ◽

Annual Direct Cost

Heart failure remains a huge societal concern despite medical advancement, with an annual direct cost of over $30 billion. While guideline-directed medical therapy (GDMT) is proven to reduce morbidity and mortality, many eligible patients with heart failure with reduced ejection fraction (HFrEF) are not receiving one or more of the recommended medications, often due to suboptimal initiation and titration in the outpatient setting. Hospitalization serves as a key point to initiate and titrate GDMT. Four evidence-based therapies have clinical benefit within 30 days of initiation and form a crucial foundation for HFrEF therapy: renin-angiotensin-aldosterone system inhibitors with or without a neprilysin inhibitor, β-blockers, mineralocorticoid-receptor-antagonists, and sodium-glucose cotransporter-2 inhibitors. The authors present a practical guide for the implementation of these four pillars of GDMT during a hospitalization for acute heart failure.

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