bims-hafaim 2024-06-02 papers

Issue of 2024–06–02
five papers selected by
Kyle McCommis, Saint Louis University

Front Biosci (Landmark Ed). 2024 May 22. 29(5): 200

Alterations of Myocardial Mitochondrial Morphology and Function in a Canine Model of Premature Ventricular Contractions-Induced Cardiomyopathy.

Tao Liu, Manqi Yang, Bo Cui, Hao Ju, Jinchun Wu, Zongli Ren, Sheng Cao, Min Yan, Fan Zhang, Zheyu Liu, Shuijing He, Jiajun Zhang, Roddy Hiram, Feng Xiong, Mian Cheng, Gang Wu.

AIMS: Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we investigated the effects of PVCs with different coupling intervals (CIs) on myocardial mitochondrial remodelling in a canine model of PVCCM.
METHODS AND RESULTS: Twenty-one beagles underwent pacemaker implantation and were randomised into the sham (n = 7), short-coupled PVCs (SCP, n = 7), and long-coupled PVCs (LCP, n = 7) groups. Right ventricular (RV) apical bigeminy was produced for 12-week to induce PVCCM in the SCP (CI, 250 ms) and LCP (CI, 350 ms) groups. Echocardiography was performed at baseline and biweekly thereafter to evaluate cardiac function. Masson's trichrome staining measured ventricular interstitial fibrosis. The ultrastructural morphology of the myocardial mitochondria was analysed using transmission electron microscopy. Mitochondrial Ca2+ concentration, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, membrane potential, and electron transport chain (ETC) complex activity were measured to assess myocardial mitochondrial function. Twelve-week-PVCs led to left ventricular (LV) enlargement with systolic dysfunction, disrupted mitochondrial morphology, increased mitochondrial Ca2+ concentration and ROS levels, decreased mitochondrial ATP content and membrane potential, and impaired ETC complex activity in both the SCP and LCP groups (all p < 0.01 vs the sham group). Ventricular fibrosis was observed only in canines with LCP. Worse cardiac function and more pronounced abnormalities in mitochondrial morphology and function were observed in the LCP group than to the SCP group (all p < 0.05).
CONCLUSION: We demonstrated myocardial mitochondrial abnormalities in dogs with PVCCM, characterised by abnormal mitochondrial morphology, mitochondrial Ca2+ overload, oxidative stress, and impaired mitochondrial energy metabolism. Compared to SCP, long-term LCP exposure resulted in more severe mitochondrial remodelling and cardiac dysfunction in dogs.

Keywords: cardiomyopathy; coupling interval; mitochondria; myocardial fibrosis; premature ventricular contractions

DOI: https://doi.org/10.31083/j.fbl2905200

Cell Stress Chaperones. 2024 May 29. pii: S1355-8145(24)00076-2. [Epub ahead of print]

Mechanisms involved in the regulation of mitochondrial quality control by PGAM5 in heart failure.

Yanli Wang, Tiantian Ren, Cuizhi Li, Qiaomin Wu, Jinfeng Liu, Xuanke Guan, Xing Chang, Zhiming Liu, Ruxiu Liu.

Heart failure refers to a group of clinical syndromes in which various heart diseases lead to the inability of cardiac output to meet the metabolic needs of the body's tissues. Cardiac metabolism requires enormous amounts of energy; thus, impaired myocardial energy metabolism is considered a key factor in the occurrence and development of heart failure. Mitochondria serve as the primary energy source for cardiomyocytes, and their regular functionality underpins healthy cardiac function. The mitochondrial quality control system is a crucial mechanism for regulating the functionality of cardiomyocytes, and any abnormality in this system can potentially impact the morphology and structure of mitochondria, as well as the energy metabolism of cardiomyocytes. PGAM5, a multifunctional protein, plays a key role in the regulation of mitochondrial quality control through multiple pathways. Therefore, abnormal PGAM5 function is closely related to mitochondrial damage. This article reviews the mechanism of PGAM5's involvement in the regulation of the mitochondrial quality control system in the occurrence and development of heart failure, thereby providing a theoretical basis for future in-depth research.

Keywords: PGAM5; heart failure; mitochondrial autophagy; mitochondrial biogenesis; mitochondrial fission and fusion; mitochondrial quality control

DOI: https://doi.org/10.1016/j.cstres.2024.05.004

J Am Coll Cardiol. 2024 May 13. pii: S0735-1097(24)07020-7. [Epub ahead of print]

Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program.

STEP-HFpEF Trial Committees and Investigators

BACKGROUND: The glucagon-like peptide-1 receptor agonist, semaglutide, improved health status and reduced body weight in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain.
OBJECTIVES: This study sought to determine if semaglutide 2.4 mg reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP.
METHODS: This was a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes]) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NT-proBNP at 52 weeks and change in the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight by baseline NT-proBNP.
RESULTS: In total, 1,145 patients were randomized. Semaglutide compared with placebo reduced NT-proBNP at 52 weeks (estimated treatment ratio: 0.82; 95% CI: 0.74-0.91; P = 0.0002). Improvements in health status were more pronounced in those with higher vs lower baseline NT-proBNP (estimated difference: tertile 1: 4.5 points, 95% CI: 0.8-8.2; tertile 2: 6.2 points, 95% CI: 2.4-10.0; tertile 3: 11.9 points, 95% CI: 8.1-15.7; P interaction = 0.02; baseline NT-proBNP as a continuous variable: P interaction = 0.004). Reductions in body weight were consistent across baseline NT-proBNP levels (P interaction = 0.21).
CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide reduced NT-proBNP. Participants with higher baseline NT-proBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NT-proBNP.

Keywords: N-terminal pro–B-type natriuretic peptide; heart failure with preserved ejection fraction; obesity; semaglutide

DOI: https://doi.org/10.1016/j.jacc.2024.04.022

FASEB J. 2024 Jun 15. 38(11): e23709

UCP1-dependent brown adipose activation accelerates cardiac metabolic remodeling and reduces initial hypertrophic and fibrotic responses to pathological stress.

Azariyas A Challa, Pablo Vidal, Santosh K Maurya, Chandan K Maurya, Lisa A Baer, Yang Wang, Natasha Maria James, Parth J Pardeshi, Matthew Fasano, Andrew N Carley, Kristin I Stanford, E Douglas Lewandowski.

Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of β-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-β1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.

Keywords: UCP1; brown adipose tissue; cardiac metabolic remodeling; pathological hypertrophy; pressure overload

DOI: https://doi.org/10.1096/fj.202400922R

Clin Res Cardiol. 2024 May 28.

Increased epicardial adipose tissue is associated with left atrial mechanical dysfunction in patients with heart failure with mildly reduced and preserved ejection fraction.

M Lobeek, T M Gorter, B D Westenbrink, D J Van Veldhuisen, M Rienstra.

INTRODUCTION: Heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF) is often accompanied by atrial dysfunction. It has been suggested that specific ectopic fat depots, such as epicardial adipose tissue (EAT), may directly influence the myocardial cells and, therefore, be involved in the pathophysiology of atrial mechanical dysfunction. In this study, we aimed to investigate the association between EAT and left atrial (LA) mechanical dysfunction.
METHODS AND RESULTS: In total, 82 patients with symptomatic HF and left ventricular ejection fraction > 40% were prospectively enrolled. All patients underwent CMR while in sinus rhythm. LA mechanical dysfunction was defined as the presence of LA end-systolic volume index > 52 mL/m2 and LA reservoir strain < 23%. EAT volume was indexed for body surface area. Mean age was 69 ± 10 years, 42 (51%) were women and mean body mass index (BMI) was 29 ± 6 kg/m2. Mean LVEF was 55 ± 9% and 34 (41%) patients had LA mechanical dysfunction. In patients with LA mechanical dysfunction, the EAT volume was significantly higher than in patients without LA mechanical dysfunction (90 vs 105 mL/m2, p = 0.02) while BMI was similar. In multivariable logistic regression analyses, increased EAT remained significantly associated with LA mechanical dysfunction (OR 1.31, 95% CI 1.03-1.66, p = 0.03).
CONCLUSION: Increased EAT was associated with LA mechanical dysfunction in patients with HFmrEF and HFpEF. Further research is needed to elucidate the exact mechanisms that underlie this association.

Keywords: Atrial mechanical dysfunction; CMR; Epicardial adipose tissue; HFmrEF; HFpEF

DOI: https://doi.org/10.1007/s00392-024-02466-7