bims-hafaim 2023-10-22 papers

Issue of 2023–10–22
seven papers selected by
Kyle McCommis, Saint Louis University

J Cardiovasc Transl Res. 2023 Oct 16.

Advances in Metabolic Remodeling and Intervention Strategies in Heart Failure.

Simin Meng, Yi Yu, Shuo Yu, Shiyu Zhu, Mengjia Shi, Meixiang Xiang, Hong Ma.

The heart is the most energy-demanding organ throughout the whole body. Perturbations or failure in energy metabolism contributes to heart failure (HF), which represents the advanced stage of various heart diseases. The poor prognosis and huge economic burden associated with HF underscore the high unmet need to explore novel therapies targeting metabolic modulators beyond conventional approaches focused on neurohormonal and hemodynamic regulators. Emerging evidence suggests that alterations in metabolic substrate reliance, metabolic pathways, metabolic by-products, and energy production collectively regulate the occurrence and progression of HF. In this review, we provide an overview of cardiac metabolic remodeling, encompassing the utilization of free fatty acids, glucose metabolism, ketone bodies, and branched-chain amino acids both in the physiological condition and heart failure. Most importantly, the latest advances in pharmacological interventions are discussed as a promising therapeutic approach to restore cardiac function, drawing insights from recent basic research, preclinical and clinical studies.

Keywords: Heart failure; Metabolic remodeling; Mitochondria; Oxidative phosphorylation; Pharmacological therapy

DOI: https://doi.org/10.1007/s12265-023-10443-0

Exp Physiol. 2023 Oct 16.

Effect of exercise on improving myocardial mitochondrial function in decreasing diabetic cardiomyopathy.

Feng Zhang, Jian Jian Lin, Hao Nan Tian, Jun Wang.

NEW FINDINGS: What is the topic of this review? The mechanism of exercise decrease diabetic cardiomyopathy by improving the mitochondrial homeostasis of the myocardium, and new insights for the treatment of diabetic cardiomyopathy with exercise. What advances does it highlight? Mitochondrial dysfunction induced by a high-glucose environment is one of the main causes of diabetic cardiomyopathy. The mitochondrial mechanism is mainly mitochondrial metabolic substrate disorder, mitochondrial dynamics change, mitochondrial Ca2+ regulation imbalance, and so on. Exercise can improve the function of myocardial mitochondria in multiple ways, so as to achieve the effect of decreasing diabetic cardiomyopathy.
ABSTRACT: Diabetic cardiomyopathy (DCM) is a significant cause of heart failure in patients with diabetes, and its pathogenesis is closely related to myocardial mitochondrial injury and functional disability. Studies have shown that the development of diabetic cardiomyopathy is related to disorders in mitochondrial metabolic substrates, changes in mitochondrial dynamics, an imbalance in mitochondrial Ca2+ regulation, defects in the regulation of microRNAs, and mitochondrial oxidative stress. Physical activity may play a role in resistance to the development of diabetic cardiomyopathy by improving myocardial mitochondrial biogenesis, the level of autophagy and dynamic changes in fusion and division; enhancing the ability to cope with oxidative stress; and optimising the metabolic substrates of the myocardium. This paper puts forward a new idea for further understanding the specific mitochondrial mechanism of the occurrence and development of diabetic cardiomyopathy and clarifying the role of exercise-mediated myocardial mitochondrial changes in the prevention and treatment of diabetic cardiomyopathy. This is expected to provide a new theoretical basis for exercise to reduce diabetic cardiomyopathy symptoms.

Keywords: DCM; diabetic cardiomyopathies; exercise; myocardial mitochondria

DOI: https://doi.org/10.1113/EP091309

Cardiovasc Res. 2023 Oct 16. pii: cvad154. [Epub ahead of print]

Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators.

Jirko Kühnisch, Simon Theisen, Josephine Dartsch, Raphaela Fritsche-Guenther, Marieluise Kirchner, Benedikt Obermayer, Anna Bauer, Anne-Karin Kahlert, Michael Rothe, Dieter Beule, Arnd Heuser, Philipp Mertins, Jennifer A Kirwan, Nikolaus Berndt, Calum A MacRae, Norbert Hubner, Sabine Klaassen.

AIMS: Mutation of the PRDM16 gene causes human dilated and non-compaction cardiomyopathy. The PRDM16 protein is a transcriptional regulator that affects cardiac development via Tbx5 and Hand1, thus regulating myocardial structure. The biallelic inactivation of Prdm16 induces severe cardiac dysfunction with post-natal lethality and hypertrophy in mice. The early pathological events that occur upon Prdm16 inactivation have not been explored.
METHODS AND RESULTS: This study performed in-depth pathophysiological and molecular analyses of male and female Prdm16csp1/wt mice that carry systemic, monoallelic Prdm16 gene inactivation. We systematically assessed early molecular changes through transcriptomics, proteomics, and metabolomics. Kinetic modelling of cardiac metabolism was performed in silico with CARDIOKIN. Prdm16csp1/wt mice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice. Prdm16csp1/wt cardiac tissue of both sexes showed reductions in metabolites associated with amino acid as well as glycerol metabolism, glycolysis, and the tricarboxylic acid cycle. Prdm16csp1/wt cardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively. An accumulation of triacylglycerides exclusively in male Prdm16csp1/wt hearts suggests a sex-specific metabolic adaptation. Metabolic modelling using CARDIOKIN identified a reduction in fatty acid utilization in males as well as lower glucose utilization in female Prdm16csp1/wt cardiac tissue. On the level of transcripts and protein expression, Prdm16csp1/wt hearts demonstrate an up-regulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre-B-cell leukaemia transcription factor interacting protein 1 (Pbxip1). The strongest concordant transcriptional up-regulation was detected for Prdm16 itself, probably through an autoregulatory mechanism.
CONCLUSIONS: Monoallelic, global Prdm16 mutation diminishes cardiac performance in Prdm16csp1/wt mice. Metabolic alterations and transcriptional dysregulation in Prdm16csp1/wt affect cardiac tissue. Female Prdm16csp1/wt mice develop a more pronounced phenotype, indicating sexual dimorphism at this early pathological window. This study suggests that metabolic dysregulation is an early event in the PRDM16 associated cardiac pathology.

Keywords: Cardiomyopathy; Metabolism; Mutation; Prdm16

DOI: https://doi.org/10.1093/cvr/cvad154

Mo Med. 2023 Sep-Oct;120(5):120(5): 354-358

Metabolic Drivers and Rescuers of Heart Failure.

Rachel C Weiss, Thiago N Menezes, Kyle S McCommis.

Cardiac hypertrophy and heart failure involve a number of metabolic alterations. Human genetic mutations and murine genetic deficiency models of metabolic enzymes or transporters largely suggest that these alterations in metabolism are maladaptive and contribute to the cardiac remodeling and dysfunction. Here, we discuss insights into metabolic alterations identified in cardiac hypertrophy and failure, as well as dietary and pharmacologic therapies that counteract these metabolic alterations and have been shown to significantly improve heart failure.

Cureus. 2023 Sep;15(9): e45290

How Does It Work? Unraveling the Mysteries by Which Empagliflozin Helps Diabetic and Non-diabetic Patients With Heart Failure.

Vernicia K Hernandez, Brad T Parks Melville, Khadijah Siwaju.

In patients with heart failure, empagliflozin offers significant cardiovascular benefits. However, its exact mode of action is unknown. Understanding the way by which empagliflozin works in heart failure may uncover additional therapeutic targets or identify other classes of drugs that may be useful to clinicians and patients. This literature review aims to unravel the mysteries by which empagliflozin reduces cardiovascular death, cardiovascular events, and heart failure hospitalization in diabetic and non-diabetic patients. Three researchers conducted the data collection. We incorporated research that used human models, animal models, patients with diabetes, and patients without diabetes. Pathology, pathophysiology, metabolism, physiology, empagliflozin, heart failure, and cardiovascular were the search terms used to probe the mesh database on PubMed. This study showed that the mechanisms by which empagliflozin could lead to positive clinical outcomes in heart failure (HF) are as follows: down-regulation of the mammalian target of rapamycin complex 1 signaling (mTORC), decreasing sarcoplasmic reticulum calcium loss, increasing cytosolic calcium loss, inducing electrolyte-free osmotic diuresis, improving fuel efficiency, and protecting the endothelial glycocalyx. These findings were inconsistent, with no generally accepted hypotheses within the scientific community. Hence we conclude that further research is required to determine the function of Empagliflozin in heart failure and the degree to which the aforementioned mechanisms of action contribute to cardiac protection.

Keywords: cardiovascular effect; diabetic patient; empagliflozin; heart failure knowledge; sodium-glucose cotransporter-2 (sglt2) inhibitors

DOI: https://doi.org/10.7759/cureus.45290

Circ Cardiovasc Imaging. 2023 Oct;16(10): e014863

Role of Cardiac Energetics in Aortic Stenosis Disease Progression: Identifying the High-risk Metabolic Phenotype.

Shveta Monga, Ladislav Valkovič, Saul G Myerson, Stefan Neubauer, Masliza Mahmod, Oliver J Rider.

BACKGROUND: Severe aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and cardiac metabolic alterations with evidence of steatosis and impaired myocardial energetics. Despite this common phenotype, there is an unexplained and wide individual heterogeneity in the degree of hypertrophy and progression to myocardial fibrosis and heart failure. We sought to determine whether the cardiac metabolic state may underpin this variability.
METHODS: We recruited 74 asymptomatic participants with AS and 13 healthy volunteers. Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to adenosine triphosphate ratio. Myocardial lipid content was determined using proton spectroscopy. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging.
RESULTS: Phosphocreatine/adenosine triphosphate was reduced early and significantly across the LV wall thickness quartiles (Q2, 1.50 [1.21-1.71] versus Q1, 1.64 [1.53-1.94]) with a progressive decline with increasing disease severity (Q4, 1.48 [1.18-1.70]; P=0.02). Myocardial triglyceride content levels were overall higher in all the quartiles with a significant increase seen across the AV pressure gradient quartiles (Q2, 1.36 [0.86-1.98] versus Q1, 1.03 [0.81-1.56]; P=0.034). While all AS groups had evidence of subclinical LV dysfunction with impaired strain parameters, impaired systolic longitudinal strain was related to the degree of energetic impairment (r=0.219; P=0.03). Phosphocreatine/adenosine triphosphate was not only an independent predictor of LV wall thickness (r=-0.20; P=0.04) but also strongly associated with myocardial fibrosis (r=-0.24; P=0.03), suggesting that metabolic changes play a role in disease progression. The metabolic and functional parameters showed comparable results when graded by clinical severity of AS.
CONCLUSIONS: A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied AS hearts, and these metabolic changes precede irreversible LV remodeling and subclinical dysfunction. As such, cardiac metabolism may play an important and potentially causal role in disease progression.

Keywords: aortic valve stenosis; magnetic resonance imaging; metabolism

DOI: https://doi.org/10.1161/CIRCIMAGING.122.014863

Curr Diabetes Rev. 2023 Oct 12.

An Overview of Diabetic Cardiomyopathy.

Abdul Quaiyoom, Ranjeet Kumar.

Diabetic cardiomyopathy (DCM) is a myocardial disorder that is characterised by structural and functional abnormalities of the heart muscle in the absence of hypertension, valvular heart disease, congenital heart defects, or coronary artery disease (CAD). After witnessing a particular form of cardiomyopathy in diabetic individuals, Rubler et al. came up with the moniker diabetic cardiomyopathy in 1972. Four stages of DCM are documented, and the American College of Cardiology/American Heart Association Stage and New York Heart Association Class for HF have some overlap. Diabetes is linked to several distinct forms of heart failure. Around 40% of people with heart failure with preserved ejection fraction (HFpEF) have diabetes, which is thought to be closely associated with the pathophysiology of HFpEF. Diabetes and HF are uniquely associated in a bidirectional manner. When compared to the general population without diabetes, those with diabetes have a risk of heart failure that is up to four times higher. A biomarker is a trait that is reliably measured and assessed as a predictor of healthy biological activities, pathological processes, or pharmacologic responses to a clinical treatment. Several biomarker values have been discovered to be greater in patients with diabetes than in control subjects among those who have recently developed heart failure. Myocardial fibrosis and hypertrophy are the primary characteristics of DCM, and structural alterations in the diabetic myocardium are often examined by non-invasive, reliable, and reproducible procedures. An invasive method called endomyocardial biopsy (EMB) is most often used to diagnose many cardiac illnesses.

Keywords: Complications; Diabetic Cardiomyopathy; Diagnosis; Heart Failure; Pathophysiology

DOI: https://doi.org/10.2174/0115733998255538231001122639