bims-hafaim 2024-02-18 papers

Issue of 2024–02–18
seven papers selected by
Kyle McCommis, Saint Louis University

JACC Basic Transl Sci. 2024 Jan;9(1): 1-15

Functional Impact of Alternative Metabolic Substrates in Failing Human Cardiomyocytes.

Alexia Vite, Timothy R Matsuura, Kenneth C Bedi, Emily L Flam, Zoltan Arany, Daniel P Kelly, Kenneth B Margulies.

Recent studies suggest that metabolic dysregulation in patients with heart failure might contribute to myocardial contractile dysfunction. To understand the correlation between function and energy metabolism, we studied the impact of different fuel substrates on human nonfailing or failing cardiomyocytes. Consistent with the concept of metabolic flexibility, nonfailing myocytes exhibited excellent contractility in all fuels provided. However, impaired contractility was observed in failing myocytes when carbohydrates alone were used but was improved when additional substrates were added. This study demonstrates the functional significance of fuel utilization shifts in failing human cardiomyocytes.

Keywords: carbohydrates, contractility; free fatty acids; heart failure; metabolic flexibility; metabolic fuel utilization; tissue metabolites

DOI: https://doi.org/10.1016/j.jacbts.2023.07.009

Circulation. 2024 Feb 16.

FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.

Bowen Li, Fangfang Liu, Xihui Chen, Tangdong Chen, Juan Zhang, Yifeng Liu, Yan Yao, Weihong Hu, Mengjie Zhang, Bo Wang, Liwen Liu, Kun Chen, Yuanming Wu.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common heritable myocardiopathy. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the myocardiopathy phenotype.
METHODS: FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2-knockdown zebrafish, and Fars2-knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification.
RESULTS: We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2-deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2-knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNAPhe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis.
CONCLUSIONS: Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.

Keywords: autophagy; cardiomyopathies; heart failure; ligases; mitochondria; mitochondrial dynamics

DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.064489

Intern Emerg Med. 2024 Feb 14.

Sodium-glucose cotransporter-2 inhibitors in heart failure patients across the range of body mass index: a systematic review and meta-analysis of randomized controlled trials.

Anastasia Adamou, David Dimitris Chlorogiannis, Ioannis G Kyriakoulis, Iliana Stamatiou, Despoina Koukousaki, Ioannis Kardoutsos, Dimitrios Sagris, Wolfram Doehner, George Ntaios.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in patients with heart failure, with or without diabetes. We sought to assess whether there is an interaction of these effects with body mass index (BMI). A systematic review of the MEDLINE and Scopus databases (last search: November 15th, 2022) was performed according to the PRISMA statement. Studies eligible for this review were randomized control trials (RCTs) with patients with chronic heart failure with either preserved or reduced ejection fraction randomly assigned to SGLT2 inhibitors or placebo. Data were extracted independently by two reviewers. BMI was classified according to the WHO classification into under/normal weight (BMI: < 25 kg/m2), overweight (BMI: 25-29.9 kg/m2), obesity class I (BMI: 30-34.9 kg/m2), and obesity classes II/III (BMI: ≥ 35 kg/m2). All analyses were performed using RevMan 5.4. Among 1461 studies identified in the literature search, 3 were eligible and included in the meta-analysis. Among 14,737 patients (32.2% were women), 7,367 were randomized to an SGLT2 inhibitor (dapagliflozin or empagliflozin) and 7,370 to placebo. There were significantly fewer hospitalizations for HF (OR: 0.70, 95%CI: 0.64-0.76), cardiovascular deaths (OR:0.86, 95%CI: 0.77-0.97) and all-cause deaths (OR:0.90, 95%CI: 0.82-0.98) in the SGLT2 inhibitors group compared to the placebo group, without any interaction with BMI group (test for subgroup differences: x2 = 1.79, p = 0.62; x2 = 0.27, p = 0.97; x2 = 0.39, p = 0.94, respectively). There is no interaction between the efficacy of SGLT2 inhibitors and BMI in patients with HF with either preserved or reduced ejection fraction. SGLT2 inhibitors are associated with improved outcomes regardless of the BMI.Trial registration: PROSPERO ID: CRD42022383643.

Keywords: BMI; Ejection fraction; HF; SGLT2

DOI: https://doi.org/10.1007/s11739-024-03532-8

JACC Basic Transl Sci. 2024 Jan;9(1): 16-17

Fueling the Failing Heart: The Key May Be Ketones.

Adam J Chicco.

Keywords: beta-hydroxybutyrate; branch chain amino acids; citrate synthase activity; failing heart; free fatty acids; glucose/lactate/pyruvate; heart failure; nonfailing heart; sarcomere length

DOI: https://doi.org/10.1016/j.jacbts.2023.09.012

Curr Pharm Biotechnol. 2024 Feb 13.

The Role of NAD+ in Myocardial Ischemia-induced Heart Failure in Sprague-Dawley Rats and Beagles.

Zuowei Pei, Chenguang Yang, Ying Guo, Min Dong, Fang Wang.

INTRODUCTION: Nicotinamide adenine dinucleotide (NAD+) participates in various processes that are dysregulated in cardiovascular diseases. Supplementation with NAD+ may be cardioprotective. However, whether the protective effect exerted by NAD+ in heart failure (HF) is more effective before acute myocardial infarction (MI) or after remains unclear. The left anterior descending arteries of male Sprague Dawley rats and beagles that developed HF following MI were ligated for 1 week, following which the animals were treated for 4 weeks with low, medium, and high doses of NAD+ and LCZ696.
METHOD: Cardiac function, hemodynamics, and biomarkers were evaluated during the treatment period. Heart weight, myocardial fibrosis, and MI rate were measured eventually.
RESULT: Compared with the HF groups, groups treated with LCZ696 and different doses of NAD+ showed increased ejection fractions, fractional shortening, cardiac output, and stroke volume and decreased end-systolic volume, end-systolic dimension, creatine kinase, and lactic dehydrogenase. LV blood pressure was lower in the HF group than in the control group, but this decrease was significantly greater in the medium and high NAD+ dose groups.
CONCLUSION: The ratios of heart weight indexes, fibrotic areas, and MI rates in the CZ696 and medium and high NAD+ dose groups were lower than those in the HF group. Medium and high-dose NAD+ showed superior positive effects on myocardial hypertrophy, cardiac function, and myocardial fibrosis and reduced the MI rate.

Keywords: NAD+; cardiac function; heart failure; myocardial fibrosis; myocardial infarction rate.

DOI: https://doi.org/10.2174/0113892010275059240103054554

Am J Physiol Heart Circ Physiol. 2024 Feb 16.

Cardiac reverse remodelling in a mouse model with many phenotypical features of heart failure with preserved ejection fraction: effects of modifying lifestyle.

Mohamed Lamine Aidara, Elisabeth Walsh-Wilkinson, Sara-Ève Thibodeau, Emylie-Ann Labbé, Audrey Morin-Grandmont, Genevieve Gagnon, Dominique K Boudreau, Marie Arsenault, Yohan Bossé, Jacques Couet.

Multiple factors cause heart failure with preserved ejection fraction (HFpEF) and involve various systems. HFpEF prevalence is rapidly rising, and its prognosis remains poor after the first hospitalization. Adopting a more active lifestyle has been shown to provide beneficial clinical outcomes for HFpEF patients. Using a two-hit HFpEF murine model, we studied cardiac reverse remodelling (RR) after stopping the causing stress and introducing voluntary exercise (VE). We checked in 2-month-old male and female C57Bl6/J mice the heart's response to angiotensin II (AngII; 1.5 mg/kg/day for 28 days) fed or not with a high-fat diet (HFD). Then, AngII and/or the HFD were stopped, and VE was started for an additional four weeks. AngII and AngII+HFD (metabolic-hypertensive stress or MHS) caused cardiac hypertrophy (CH) and myocardial fibrosis, left ventricular (LV) concentric remodelling, atrial enlargement, and reduced exercise capacity. HFD alone induced CH and LV concentric remodelling in female mice only. CH and LV concentric remodelling were reversed four weeks after stopping AngII, starting VE, and a low-fat diet. Left atrial enlargement and exercise capacity were improved but differed from controls. We performed bulk LV RNA sequencing and observed that MHS upregulated 58% of the differentially expressed genes (DEGs) compared to controls. In the RR group, compared to MHS animals, 60% of the DEGs were downregulated. In an HFpEF mouse model, we show that correcting hypertension, diet, and introducing exercise can lead to extensive cardiac reverse remodelling.

Keywords: heart failure; mouse; myocardial recovery; reverse remodeling; sex differences

DOI: https://doi.org/10.1152/ajpheart.00462.2023

Curr Cardiol Rep. 2024 Feb 10.

Lysophosphatidic Acid-Mediated Inflammation at the Heart of Heart Failure.

Rajesh Chaudhary, Tahra Suhan, Mahmud W Tarhuni, Ahmed Abdel-Latif.

PURPOSE OF REVIEW: The primary aim of this review is to provide an in-depth examination of the role bioactive lipids-namely lysophosphatidic acid (LPA) and ceramides-play in inflammation-mediated cardiac remodeling during heart failure. With the global prevalence of heart failure on the rise, it is critical to understand the underlying molecular mechanisms contributing to its pathogenesis. Traditional studies have emphasized factors such as oxidative stress and neurohormonal activation, but emerging research has shed light on bioactive lipids as central mediators in heart failure pathology. By elucidating these intricacies, this review aims to: Bridge the gap between basic research and clinical practice by highlighting clinically relevant pathways contributing to the pathogenesis and prognosis of heart failure. Provide a foundation for the development of targeted therapies that could mitigate the effects of LPA and ceramides on heart failure. Serve as a comprehensive resource for clinicians and researchers interested in the molecular biology of heart failure, aiding in better diagnostic and therapeutic decisions.
RECENT FINDINGS: Recent findings have shed light on the central role of bioactive lipids, specifically lysophosphatidic acid (LPA) and ceramides, in heart failure pathology. Traditional studies have emphasized factors such as hypoxia-mediated cardiomyocyte loss and neurohormonal activation in the development of heart failure. Emerging research has elucidated the intricacies of bioactive lipid-mediated inflammation in cardiac remodeling and the development of heart failure. Studies have shown that LPA and ceramides contribute to the pathogenesis of heart failure by promoting inflammation, fibrosis, and apoptosis in cardiac cells. Additionally, recent studies have identified potential targeted therapies that could mitigate the effects of bioactive lipids on heart failure, including LPA receptor antagonists and ceramide synthase inhibitors. These recent findings provide a promising avenue for the development of targeted therapies that could improve the diagnosis and treatment of heart failure. In this review, we highlight the pivotal role of inflammation induced by bioactive lipid signaling and its influence on the pathogenesis of heart failure. By critically assessing the existing literature, we provide a comprehensive resource for clinicians and researchers interested in the molecular mechanisms of heart failure. Our review aims to bridge the gap between basic research and clinical practice by providing actionable insights and a foundation for the development of targeted therapies that could mitigate the effects of bioactive lipids on heart failure. We hope that this review will aid in better diagnostic and therapeutic decisions, further advancing our collective understanding and management of heart failure.

Keywords: Bioactive lipids; Ceramide; Heart failure; Immune cells; Inflammation; Lysophosphatidic acid

DOI: https://doi.org/10.1007/s11886-024-02023-8