bims-hafaim 2022-04-03 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–04–03
nine papers selected by
Kyle McCommis, Saint Louis University

Enhanced NCLX-dependent mitochondrial Ca2+ efflux attenuates pathological remodeling in heart failure.
Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy.
Ketone Body β-Hydroxybutyrate Prevents Myocardial Oxidative Stress in Septic Cardiomyopathy.
Sericin-mediated improvement of dysmorphic cardiac mitochondria from hypercholesterolaemia is associated with maintaining mitochondrial dynamics, energy production, and mitochondrial structure.
Insulin treatment in patients with diabetes mellitus and heart failure in the era of new antidiabetic medications.
The first experience with sodium-glucose cotransporter 2 inhibitor for the treatment of systemic right ventricular failure.
Myocardial Fatigue: a Mechano-energetic Concept in Heart Failure.
Exercise training differently improve cardiac function and regulate myocardial mitophagy in ischemic and pressure-overloaded heart failure mice.
Diabetes Mellitus, Race, and Effects of Omega-3 Fatty Acids on Incidence of Heart Failure Hospitalization.

J Mol Cell Cardiol. 2022 Mar 28. pii: S0022-2828(22)00037-2. [Epub ahead of print]167 52-66

Enhanced NCLX-dependent mitochondrial Ca2+ efflux attenuates pathological remodeling in heart failure.

Joanne F Garbincius, Timothy S Luongo, Pooja Jadiya, Alycia N Hildebrand, Devin W Kolmetzky, Adam S Mangold, Rajika Roy, Jessica Ibetti, Mary Nwokedi, Walter J Koch, John W Elrod.

  Mitochondrial calcium (mCa2+) uptake couples changes in cardiomyocyte energetic demand to mitochondrial ATP production. However, excessive mCa2+ uptake triggers permeability transition and necrosis. Despite these established roles during acute stress, the involvement of mCa2+ signaling in cardiac adaptations to chronic stress remains poorly defined. Changes in NCLX expression are reported in heart failure (HF) patients and models of cardiac hypertrophy. Therefore, we hypothesized that altered mCa2+ homeostasis contributes to the hypertrophic remodeling of the myocardium that occurs upon a sustained increase in cardiac workload. The impact of mCa2+ flux on cardiac function and remodeling was examined by subjecting mice with cardiomyocyte-specific overexpression (OE) of the mitochondrial Na+/Ca2+ exchanger (NCLX), the primary mediator of mCa2+ efflux, to several well-established models of hypertrophic and non-ischemic HF. Cardiomyocyte NCLX-OE preserved contractile function, prevented hypertrophy and fibrosis, and attenuated maladaptive gene programs in mice subjected to chronic pressure overload. Hypertrophy was attenuated in NCLX-OE mice, prior to any decline in cardiac contractility. NCLX-OE similarly attenuated deleterious cardiac remodeling in mice subjected to chronic neurohormonal stimulation. However, cardiomyocyte NCLX-OE unexpectedly reduced overall survival in mice subjected to severe neurohormonal stress with angiotensin II + phenylephrine. Adenoviral NCLX expression limited mCa2+ accumulation, oxidative metabolism, and de novo protein synthesis during hypertrophic stimulation of cardiomyocytes in vitro. Our findings provide genetic evidence for the contribution of mCa2+ to early pathological remodeling in non-ischemic heart disease, but also highlight a deleterious consequence of increasing mCa2+ efflux when the heart is subjected to extreme, sustained neurohormonal stress.

Keywords:  Calcium; Mitochondria; NCLX; anabolism; heart failure; hypertrophy

DOI:  https://doi.org/10.1016/j.yjmcc.2022.03.001
Nat Commun. 2022 Apr 01. 13(1): 1757

Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy.

Mingming Zhao, Haoran Wei, Chenze Li, Rui Zhan, Changjie Liu, Jianing Gao, Yaodong Yi, Xiao Cui, Wenxin Shan, Liang Ji, Bing Pan, Si Cheng, Moshi Song, Haipeng Sun, Huidi Jiang, Jun Cai, Minerva T Garcia-Barrio, Y Eugene Chen, Xiangbao Meng, Erdan Dong, Dao Wen Wang, Lemin Zheng.

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.

DOI: https://doi.org/10.1038/s41467-022-29060-7
Oxid Med Cell Longev. 2022 ;2022 2513837

Ketone Body β-Hydroxybutyrate Prevents Myocardial Oxidative Stress in Septic Cardiomyopathy.

Liwei Ji, Qinqin He, Yinghai Liu, Yan Deng, Maodi Xie, Kaiteng Luo, Xintian Cai, Yunxia Zuo, Wei Wu, Qian Li, Ronghua Zhou, Tao Li.

Septic cardiomyopathy is a life-threatening complication of severe sepsis and septic shock. Oxidative stress and mitochondrial dysfunction have been identified as significant abnormalities in septic cardiomyopathy. However, specific treatments are rare. This study aims to investigate the impact of β-hydroxybutyrate (β-OHB) on septic cardiomyopathy and explore the underlying mechanism(s). We found that pretreatment of D-β-hydroxybutyrate-(R)-1,3 butanediol monoester (ketone ester, 3 mg/g body weight, once daily) by gavage for three days elevated the levels of ketone bodies, especially that of β-hydroxybutyrate (β-OHB) in the circulation and mouse hearts, which exerted a protective effect against lipopolysaccharide (LPS, 20 mg/kg)-induced septic cardiomyopathy in mice. In addition, an LPS-stimulated macrophage-conditioned medium (MCM) was used to mimic the pathological process of septic cardiomyopathy. Mechanistically, β-OHB alleviated myocardial oxidative stress and improved mitochondrial respiratory function through the antioxidant FoxO3a/MT2 pathway activated via histone deacetylase (HDAC) inhibition, which ultimately enhanced heart performance in septic cardiomyopathy. Our results, therefore, suggested an unappreciated critical role of β-OHB in septic heart protection as well as highlighted the potential of β-OHB as a simple remedy for the septic cardiomyopathy population.

DOI: https://doi.org/10.1155/2022/2513837
Pharm Biol. 2022 Dec;60(1): 708-721

Sericin-mediated improvement of dysmorphic cardiac mitochondria from hypercholesterolaemia is associated with maintaining mitochondrial dynamics, energy production, and mitochondrial structure.

Kitiya Rujimongkon, Sumate Ampawong, Duangnate Isarangkul, Onrapak Reamtong, Pornanong Aramwit.

   CONTEXT: Sericin is a component protein in the silkworm cocoon [Bombyx mori Linnaeus (Bombycidae)] that improves dysmorphic cardiac mitochondria under hypercholesterolemic conditions. This is the first study to explore cardiac mitochondrial proteins associated with sericin treatment.
OBJECTIVE: To investigate the mechanism of action of sericin in cardiac mitochondria under hypercholesterolaemia.
MATERIALS AND METHODS: Hypercholesterolaemia was induced in Wistar rats by feeding them 6% cholesterol-containing chow for 6 weeks. The hypercholesterolemic rats were separated into 2 groups (n = 6 for each): the sericin-treated (1,000 mg/kg daily) and nontreated groups. The treatment conditions were maintained for 4 weeks prior to cardiac mitochondria isolation. The mitochondrial structure was evaluated by immunolabeling electron microscopy, and differential mitochondrial protein expression was determined and quantitated by two-dimensional gel electrophoresis coupled with mass spectrometry.
RESULTS: A 32.22 ± 2.9% increase in the percent striated area of cardiac muscle was observed in sericin-treated hypercholesterolemic rats compared to the nontreatment group (4.18 ± 1.11%). Alterations in mitochondrial proteins, including upregulation of optic atrophy 1 (OPA1) and reduction of NADH-ubiquinone oxidoreductase 75 kDa subunit (NDUFS1) expression, are correlated with a reduction in mitochondrial apoptosis under sericin treatment. Differential proteomic observation also revealed that sericin may improve mitochondrial energy production by upregulating acetyl-CoA acetyltransferase (ACAT1) and NADH dehydrogenase 1α subcomplex subunit 10 (NDUFA10) expression.
DISCUSSION AND CONCLUSIONS: Sericin treatment could improve the dysmorphic mitochondrial structure, metabolism, and energy production of cardiac mitochondria under hypercholesterolaemia. These results suggest that sericin may be an alternative treatment molecule that is related to cardiac mitochondrial abnormalities.

Keywords:  Silkworm; cocoon; heart; mitochondrial proteome; proteomics

DOI:  https://doi.org/10.1080/13880209.2022.2055088
BMJ Open Diabetes Res Care. 2022 Mar;pii: e002708. [Epub ahead of print]10(2):

Insulin treatment in patients with diabetes mellitus and heart failure in the era of new antidiabetic medications.

Lidia Staszewsky, Marta Baviera, Mauro Tettamanti, Pierluca Colacioppo, Fabio Robusto, Antonio D'Ettorre, Vito Lepore, Ida Fortino, Lucia Bisceglia, Ettore Attolini, Elisabetta Anna Graps, Gianluca Caldo, Maria Carla Roncaglioni, Silvio Garattini, Roberto Latini.

   BACKGROUND: Coexistent heart failure (HF) and diabetes mellitus (DM) are associated with marked morbidity and mortality. Optimizing treatment strategies can reduce the number and severity of events. Insulin is frequently used in these patients, but its benefit/risk ratio is still not clear, particularly since new antidiabetic drugs that reduce major adverse cardiac events (MACEs) and renal failure have recently come into use. Our aim is to compare the clinical effects of insulin in a real-world setting of first-time users, with sodium-glucose cotransporter-2 inhibitor (SGLT-2i), glucagon-like peptide-1 receptor agonist (GLP-1RA) and the other antihyperglycemic agents (other-AHAs).
METHODS: We used the administrative databases of two Italian regions, during the years 2010-2018. Outcomes in whole and propensity-matched cohorts were examined using Cox models. A meta-analysis was also conducted combining the data from both regions.
RESULTS: We identified 34 376 individuals ≥50 years old with DM and HF; 42.0% were aged >80 years and 46.7% were women. SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin and particularly death from any cause (SGLT-2i, hazard ratio (95% CI) 0.29 (0.23 to 0.36); GLP-1RA, 0.482 (0.51 to 0.42)) and first hospitalization for HF (0.57 (0.40 to 0.81) and 0.67 (0.59 to 0.76)).
CONCLUSIONS: In patients with DM and HF, SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin, and particularly any cause of death and first hospitalization for HF. These groups of medications had high safety profiles compared with other-AHAs and particularly with insulin. The inadequate optimization of HF and DM cotreatment in the insulin cohort is noteworthy.

Keywords:  Diabetes Mellitus, Type 2; Heart Failure; Insulin; Treatment Outcome

DOI:  https://doi.org/10.1136/bmjdrc-2021-002708
ESC Heart Fail. 2022 Mar 30.

The first experience with sodium-glucose cotransporter 2 inhibitor for the treatment of systemic right ventricular failure.

Anastasia D Egorova, Marieke Nederend, Laurens F Tops, Hubert W Vliegen, Monique R M Jongbloed, Philippine Kiès.

  In congenitally corrected transposition of the great arteries, the morphological right ventricle supports the systemic circulation. This chronic exposure to pressure overload ultimately leads to systemic right ventricular (sRV) dysfunction and heart failure. Pharmacological options for the treatment of sRV failure are poorly defined and no solid recommendations are made in the most recent guidelines. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a new class of antihyperglycaemic drugs that have been demonstrated to significantly reduce the risk of worsening heart failure and death from cardiovascular causes in patients with chronic heart failure with reduced left ventricular ejection fraction, yet no data are available in sRV patients. We report on the treatment and clinical follow-up of a patient with advanced heart failure and poor sRV function in the context of congenitally corrected transposition of the great arteries, who did not tolerate sacubitril/valsartan and had a high burden of heart-failure-related hospitalizations. Treatment with dapagliflozin was well tolerated and resulted in (small) subjective and objective functional and echocardiographic improvement and a reduction in heart-failure-related hospitalizations.

Keywords:  Adult congenital heart diseaseChronic heart failureSodium-glucose cotransporter inhibitor; Congenital heart disease; Heart failure; Systemic right ventricle

DOI:  https://doi.org/10.1002/ehf2.13871
Curr Cardiol Rep. 2022 Mar 30.

Myocardial Fatigue: a Mechano-energetic Concept in Heart Failure.

Patrick Tran, Helen Maddock, Prithwish Banerjee.

   PURPOSE OF REVIEW: This review combines existing mechano-energetic principles to provide a refreshing perspective in heart failure (HF) and examine if the phenomenon of myocardial fatigue can be rigorously tested in vitro with current technological advances as a bridge between pre-clinical science and clinical practice.
RECENT FINDINGS: As a testament to the changing paradigm of HF pathophysiology, there has been a shift of focus from structural to functional causes, as reflected in its modern universal definition and redefined classification. Bolstered by recent landmark trials of sodium-glucose cotransport-2 inhibitors across the HF spectrum, there is a rekindled interest to revisit the basic physiological tenets of energetic efficiency, metabolic flexibility, and mechanical load on myocardial performance. Indeed, these principles are well established in the study of skeletal muscle fatigue. Since both striated muscles share similar sarcomeric building blocks, is it possible that myocardial fatigue can occur in the face of sustained adverse supra-physiological load as a functional cause of HF? Myocardial fatigue is a mechano-energetic concept that offers a novel functional mechanism in HF. It is supported by current studies on exercise-induced cardiac fatigue and reverse translational science such as from recent landmark trials on sodium glucose co-transporter 2 inhibitors in HF. We propose a novel framework of myocardial fatigue, injury, and damage that aligns with the contemporary notion of HF as a continuous spectrum, helps determine the chance and trajectory of myocardial recovery, and aims to unify the plethora of cellular and molecular mechanisms in HF.

Keywords:  Cardiac energetic; Cardiomyocytes; Heart failure; Mechanical load; Metabolism; Myocardial fatigue

DOI:  https://doi.org/10.1007/s11886-022-01689-2
Exp Physiol. 2022 Apr 02.

Exercise training differently improve cardiac function and regulate myocardial mitophagy in ischemic and pressure-overloaded heart failure mice.

Chen Guo, Meng-Jie Chen, Jin-Rui Zhao, Rui-Yun Wu, Yue Zhang, Qiang-Qiang Li, Hong Zhao, Jia-Hao Dou, Shou-Fang Song, Jin Wei.

   NEW FINDINGS: What is the central question of this study? The cardioprotective effects of different aerobic exercises on chronic heart failure with different etiologies and whether mitophagy is involved remain elusive. What is the main finding and its importance? Moderate-intensity continuous training may be the "optimum" modality for improving cardiac structure and function in ischemic heart failure, while both moderate-intensity continuous training and high-intensity interval training were suitable for pressure-overloaded heart failure. Various mitophagy pathways especially PRKN-dependent pathways participated in the protective effects of exercise on heart failure.
ABSTRACT: The cardioprotective effects of different aerobic exercises on chronic heart failure with different etiologies and whether mitophagy is involved remain elusive. In the current research, left anterior descending ligation and transverse aortic constriction surgeries were used to establish mice models of heart failure, followed by 8 weeks of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT). The results showed that MICT significantly improved ejection fraction (P < 0.05) and fractional shortening (P < 0.05), mitigated left ventricular end-systolic dimension (P < 0.01), brain natriuretic peptide (P < 0.0001), and fibrosis (P < 0.0001), while HIIT only decreased brain natriuretic peptide (P < 0.0001) and fibrosis (P < 0.0001) for ischemic heart failure. Both MICT and HIIT significantly increased ejection fraction (P < 0.0001) and fractional shortening (MICT: P < 0.001, HIIT: P < 0.0001), reduced left ventricular end-diastolic and end-systolic dimension, brain natriuretic peptide (P < 0.0001), and fibrosis (MICT: P < 0.01, HIIT: P < 0.0001), even HIIT was better in reducing brain natriuretic peptide on pressure-overloaded heart failure. Myocardial autophagy and mitophagy were compromised in heart failure, exercises improved myocardial autophagic flux and mitophagy inconsistently in heart failure with different etiologies. Significant correlations were found between multiple mitophagy pathways and cardioprotection of exercises. Collectively, MICT may be the "optimum" modality for ischemic heart failure, both MICT and HIIT (especially HIIT) were suitable for pressure-overloaded heart failure. Exercises differently improved myocardial autophagy/mitophagy and multiple mitophagy-related pathways were closely implicated in cardioprotection of exercises for chronic heart failure. This article is protected by copyright. All rights reserved.

Keywords:  cardiac function; exercise capacity; exercise rehabilitation; heart failure; mitophagy

DOI:  https://doi.org/10.1113/EP090374
JACC Heart Fail. 2022 Apr;pii: S2213-1779(22)00054-3. [Epub ahead of print]10(4): 227-234

Diabetes Mellitus, Race, and Effects of Omega-3 Fatty Acids on Incidence of Heart Failure Hospitalization.

Luc Djoussé, Nancy R Cook, Eunjung Kim, Joseph Walter, Omar T Al-Ramady, Heike Luttmann-Gibson, Christine M Albert, Samia Mora, Julie E Buring, J Michael Gaziano, JoAnn E Manson.

   OBJECTIVES: The primary aim was to evaluate whether prevalent type 2 diabetes (T2D) modifies the effects of omega-3 supplementation on heart failure (HF) hospitalization. The secondary aim was to examine if race modifies the effects of omega-3 supplements on HF risk.
BACKGROUND: It is unclear whether race and T2D modify the effects of omega-3 supplementation on the incidence of HF.
METHODS: In this ancillary study of the parent VITAL (Vitamin D and Omega-3 Trial)-a completed randomized trial testing the efficacy of vitamin D and omega-3 fatty acids on cardiovascular diseases and cancer, we assessed the role of T2D and race on the effects of omega-3 supplements on the incidence of HF hospitalization (adjudicated by a review of medical records and supplemented with a query of Centers for Medicare and Medicaid Services data).
RESULTS: When omega-3 supplements were compared with placebo, the HR for first HF hospitalization was 0.69 (95% CI: 0.50-0.95) in participants with prevalent T2D and 1.09 (95% CI: 0.88-1.34) in those without T2D (P for interaction = 0.019). Furthermore, prevalent T2D modified the effects of omega-3 fatty acids on the incidence of recurrent HF hospitalization (HR: 0.53; 95% CI: 0.41-0.69 in participants with prevalent T2D vs HR: 1.07; 95% CI: 0.89-1.28 in those without T2D; P interaction <0.0001). In our secondary analysis, omega-3 supplementation reduced recurrent HF hospitalization only in Black participants (P interaction race × omega-3 = 0.0497).
CONCLUSIONS: Our data show beneficial effects of omega-3 fatty acid supplements on incidence of HF hospitalization in participants with T2D but not in those without T2D, and such benefit appeared to be stronger in Black participants with T2D. (Intervention With Vitamin D and Omega-3 Supplements and Incident Heart Failure; NCT02271230; Vitamin D and Omega-3 Trial [VITAL]; NCT01169259 [parent study]).

Keywords:  heart failure; marine omega-3 fatty acids; race; type 2 diabetes

DOI:  https://doi.org/10.1016/j.jchf.2021.12.006