P1665Identifying metabolic treatment strategies for heart failure - A meta-analytic approach

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T D Nguyen ◽  
C Schenkl ◽  
P Schlattmann ◽  
E Heyne ◽  
T Doenst ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Publication Bias ◽  
Treatment Strategies ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Beneficial Result ◽  
Study Characteristics ◽  
Metabolic Treatment

Abstract Background Current expert consensus suggests modulation of cardiac glucose oxidation (GO) or fatty acid oxidation (FAO) as a therapeutic approach for heart failure (HF). However, inconsistency exists and there is no systematic evidence supporting this concept. Objective We conducted a systematic review of preclinical studies to assess the role of metabolic treatment in HF. We aimed to identify, via meta-analytic techniques, specific metabolic strategies that potentially improve cardiac function. Methods We searched PubMed, Web of Science and reference lists of identified primary studies from inception to 31 December 2018. We included all interventional studies that assessed changes in cardiac function together with those in cardiac GO and/or FAO in established animal models of HF. Two investigators extracted study characteristics and data independently. We encompassed all available measures of cardiac function in the analysis instead of selecting one single outcome. Effect sizes were calculated as Hedges' g. We used I2 to estimate heterogeneity, metaregression to explore sources of heterogeneity and contour-enhanced funnel plot to assess publication bias. Results Our search returned 64 reports that fulfilled the inclusion criteria (n=1532 animals). The overall effect of treatments associated with metabolic changes was 0.78±0.16 g, p<0.001. There was a high heterogeneity (I2 = 86.7%) and no signs of publication bias. Metaregression revealed that treatments associated with an increase in GO (1.09±0.13 g, p<0.001) markedly enhance cardiac function. In contrast, those associated with decreased GO may worsen outcome. Although most experts suggest inhibiting FAO to improve cardiac function in HF, we found a beneficial result with a large total effect size for approaches that boost FAO (1.69±0.65 g, p<0.01). Conclusions Our data highlight the role of cardiac metabolism in treating HF. Specifically, increasing GO or FAO may considerably improve cardiac function. Furthermore, the findings challenge the common notion that inhibiting cardiac FAO is protective.

scholarly journals The Role of Metabolism in Heart Failure and Regeneration

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiyoung Bae ◽  
Wyatt G. Paltzer ◽  
Ahmed I. Mahmoud
Keyword(s):  
Heart Failure ◽  
Cell Fate ◽  
Therapeutic Potential ◽  
Systolic Heart Failure ◽  
Cardiac Metabolism ◽  
Mitochondrial Metabolism ◽  
Acid Oxidation ◽  
Adult Heart ◽  
Mammalian Heart

Heart failure is the leading cause of death worldwide. The inability of the adult mammalian heart to regenerate following injury results in the development of systolic heart failure. Thus, identifying novel approaches toward regenerating the adult heart has enormous therapeutic potential for adult heart failure. Mitochondrial metabolism is an essential homeostatic process for maintaining growth and survival. The emerging role of mitochondrial metabolism in controlling cell fate and function is beginning to be appreciated. Recent evidence suggests that metabolism controls biological processes including cell proliferation and differentiation, which has profound implications during development and regeneration. The regenerative potential of the mammalian heart is lost by the first week of postnatal development when cardiomyocytes exit the cell cycle and become terminally differentiated. This inability to regenerate following injury is correlated with the metabolic shift from glycolysis to fatty acid oxidation that occurs during heart maturation in the postnatal heart. Thus, understanding the mechanisms that regulate cardiac metabolism is key to unlocking metabolic interventions during development, disease, and regeneration. In this review, we will focus on the emerging role of metabolism in cardiac development and regeneration and discuss the potential of targeting metabolism for treatment of heart failure.

Caloric restriction limits fatty acid oxidation and improves cardiac function in heart failure associated with obesity

2018 ◽  
Vol 124 ◽  
pp. 99
Author(s):  
Qutuba G. Karwi ◽  
Liyan Zhang ◽  
Abhishek Gupta ◽  
Arata Fukushima ◽  
Vaibhav Patel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Function ◽  
Caloric Restriction ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation

scholarly journals Metabolic Therapy in Heart Failure

2015 ◽  
Vol 1 (2) ◽  
pp. 112 ◽  
Author(s):  
Yury Lopatin ◽  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Patients With Heart Failure ◽  
Cardiac Energy Metabolism ◽  
Conventional Medical Therapy ◽  
Cardiac Energy ◽  
Metabolic Impairments

Metabolic impairments play an important role in the development and progression of heart failure. The use of metabolic modulators, the number of which is steadily increasing, may be particularly effective in the treatment of heart failure. Recent evidence suggests that modulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation represents a promising approach to the treatment of patients with heart failure. This review focuses on the role of metabolic modulators, in particular trimetazidine, as a potential additional medication to conventional medical therapy in heart failure.

A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload

2018 ◽  
Vol 115 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Andrea Grund ◽  
Malgorzata Szaroszyk ◽  
Janina K Döppner ◽  
Mona Malek Mohammadi ◽  
Badder Kattih ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Binding Protein ◽  
Treatment Strategies ◽  
Pressure Overload ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

scholarly journals Metabolic inflammation in heart failure with preserved ejection fraction

2020 ◽  
Author(s):  
Gabriele G Schiattarella ◽  
Daniele Rodolico ◽  
Joseph A Hill
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Metabolism ◽  
Biological Processes ◽  
Preserved Ejection Fraction ◽  
Metabolic Inflammation ◽  
Treatment And Prevention ◽  
Metabolic Comorbidities ◽  
Inflammatory Burden

Abstract One in 10 persons in the world aged 40 years and older will develop the syndrome of HFpEF (heart failure with preserved ejection fraction), the most common form of chronic cardiovascular disease for which no effective therapies are currently available. Metabolic disturbance and inflammatory burden contribute importantly to HFpEF pathogenesis. The interplay within these two biological processes is complex; indeed, it is now becoming clear that the notion of metabolic inflammation—metainflammation—must be considered central to HFpEF pathophysiology. Inflammation and metabolism interact over the course of syndrome progression, and likely impact HFpEF treatment and prevention. Here, we discuss evidence in support of a causal, mechanistic role of metainflammation in shaping HFpEF, proposing a framework in which metabolic comorbidities profoundly impact cardiac metabolism and inflammatory pathways in the syndrome.

scholarly journals Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy

2018 ◽  
Vol 115 (20) ◽  
pp. E4661-E4669 ◽  
Author(s):  
Xudong Liao ◽  
Yuyan Shen ◽  
Rongli Zhang ◽  
Keiki Sugi ◽  
Neelakantan T. Vasudevan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Late Phase ◽  
Myeloid Cells ◽  
Pressure Overload ◽  
Genetic Mutations ◽  
Nonischemic Cardiomyopathy ◽  
Resident Macrophage ◽  
Temporal And Spatial

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart’s adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.

New insights into the pathological role of TNF-α in early cardiac dysfunction and subsequent heart failure after infarction in rats

2004 ◽  
Vol 287 (1) ◽  
pp. H340-H350 ◽  
Author(s):  
C. Berthonneche ◽  
T. Sulpice ◽  
F. Boucher ◽  
L. Gouraud ◽  
J. de Leiris ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Pressure ◽  
Subsequent Development ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Direct Role ◽  
Volume Curve ◽  
Tnf Α

A marked increase in plasma TNF-α has been described in patients with chronic heart failure (CHF). Nevertheless, little is known about the direct role of this cytokine early after myocardial infarction (MI) and its possible effects on the subsequent development of CHF. Wistar rats were subjected to permanent in vivo coronary artery ligation. At 5, 7, and 9 days after MI, cardiac function, passive compliance of the left ventricle (LV), and cardiac geometry were evaluated. The same model was used to perform pharmacological studies 7 days and 10 wk after MI in rats treated with monomeric recombinant human soluble TNF-α receptor type II (sTNF-RII, 40 μg/kg iv) or a placebo on day 3. Maximal alterations of cardiac function and geometry occurred 7 days after MI, which correlated chronologically with a peak of cardiac and serum TNF-α, as shown by immunohistochemistry and ELISA, respectively. sTNF-RII improved LV end-diastolic pressure under basal conditions and after volume overload 7 days and 10 wk after MI. Moreover, a significant leftward shift of the pressure-volume curve in the sTNF-RII-treated group 7 days after MI indicated a preservation of LV volume. Infarct expansion index was also significantly improved by sTNF-RII 7 days after MI ( P < 0.01). Nevertheless, 10 wk after MI, geometric indexes and passive pressure-volume curves were not significantly improved by the treatment. In conclusion, TNF-α plays a major role in cardiac alterations 7 days after MI in rats and contributes to hemodynamic derangement, but not to cardiac remodeling, in subsequent CHF.

scholarly journals Modulation of Cardiac Metabolism in Heart Failure

2019 ◽  
Vol 17 ◽  
Author(s):  
Giuseppe Rosano ◽  
Andrew Coats
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Skeletal Muscles ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Patients With Heart Failure ◽  
Free Fatty Acid Oxidation ◽  
Capacity Modulation

Heart failure is associated with altered cardiac metabolism, in part, due to maladaptive mechanisms, in part secondary to comorbidities such as diabetes and ischaemic heart disease. The metabolic derangements taking place in heart failure are not limited to the cardiac myocytes, but extend to skeletal muscles and the vasculature causing changes that contribute to the worsening of exercise capacity. Modulation of cardiac metabolism with partial inhibition of free fatty acid oxidation has been shown to be beneficial in patients with heart failure. At the present, the bulk of evidence for this class of drugs comes from Trimetazidine. Newer compounds partially inhibiting free fatty acid oxidation or facilitating the electron transport on the mitochondrial cristae are in early phase of their clinical development.

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