bims-hafaim 2024-09-01 papers

Issue of 2024–09–01
nine papers selected by
Kyle McCommis, Saint Louis University

Nat Cardiovasc Res. 2024 Aug;3(8): 907-914

Myocardial ultrastructure of human heart failure with preserved ejection fraction.

Mariam Meddeb, Navid Koleini, Aleksandra Binek, Mohammad Keykhaei, Reyhane Darehgazani, Seoyoung Kwon, Celia Aboaf, Kenneth B Margulies, Ken C Bedi, Mohamed Lehar, Kavita Sharma, Virginia S Hahn, Jennifer E Van Eyk, Cinthia I Drachenberg, David A Kass.

Over half of patients with heart failure have a preserved ejection fraction (>50%, called HFpEF), a syndrome with substantial morbidity/mortality and few effective therapies1. Its dominant comorbidity is now obesity, which worsens disease and prognosis1-3. Myocardial data from patients with morbid obesity and HFpEF show depressed myocyte calcium-stimulated tension4 and disrupted gene expression of mitochondrial and lipid metabolic pathways5,6, abnormalities shared by human HF with a reduced EF but less so in HFpEF without severe obesity. The impact of severe obesity on human HFpEF myocardial ultrastructure remains unexplored. Here we assessed the myocardial ultrastructure in septal biopsies from patients with HFpEF using transmission electron microscopy. We observed sarcomere disruption and sarcolysis, mitochondrial swelling with cristae separation and dissolution and lipid droplet accumulation that was more prominent in the most obese patients with HFpEF and not dependent on comorbid diabetes. Myocardial proteomics revealed associated reduction in fatty acid uptake, processing and oxidation and mitochondrial respiration proteins, particularly in very obese patients with HFpEF.

DOI: https://doi.org/10.1038/s44161-024-00516-x

Nat Cardiovasc Res. 2023 May;2(5): 425-437

Ketones and the cardiovascular system.

Gary D Lopaschuk, Jason R B Dyck.

Ketone bodies, the main one being β-hydroxybutyrate, have emerged as important regulators of the cardiovascular system. In healthy individuals, as well as in individuals with heart failure or post-myocardial infarction, ketones provide a supplemental energy source for both the heart and the vasculature. In the failing heart, this additional energy may contribute to improved cardiac performance, whereas increasing ketone oxidation in vascular smooth muscle and endothelial cells enhances cell proliferation and prevents blood vessel rarefication. Ketones also have important actions in signaling pathways, posttranslational modification pathways and gene transcription; many of which modify cell proliferation, inflammation, oxidative stress, endothelial function and cardiac remodeling. Attempts to therapeutically increase ketone delivery to the cardiovascular system are numerous and have shown mixed results in terms of effectiveness. Here we review the bioenergetic and signaling effects of ketones on the cardiovascular system, and we discuss how ketones can potentially be used to treat cardiovascular diseases.

DOI: https://doi.org/10.1038/s44161-023-00259-1

Lancet. 2024 Aug 24. pii: S0140-6736(24)01498-3. [Epub ahead of print]404(10454): 773-786

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial.

SELECT Trial Investigators

BACKGROUND: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure.
METHODS: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597.
FINDINGS: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype.
INTERPRETATION: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group.
FUNDING: Novo Nordisk.

DOI: https://doi.org/10.1016/S0140-6736(24)01498-3

Nat Cardiovasc Res. 2023 Jun;2(6): 504-516

Metabolite signaling in the heart.

Emily Flam, Zolt Arany.

The heart is the most metabolically active organ in the body, sustaining a continuous and high flux of nutrient catabolism via oxidative phosphorylation. The nature and relative contribution of these fuels have been studied extensively for decades. By contrast, less attention has been placed on how intermediate metabolites generated from this catabolism affect intracellular signaling. Numerous metabolites, including intermediates of glycolysis and the tricarboxylic acid (TCA) cycle, nucleotides, amino acids, fatty acids and ketones, are increasingly appreciated to affect signaling in the heart, via various mechanisms ranging from protein-metabolite interactions to modifying epigenetic marks. We review here the current state of knowledge of intermediate metabolite signaling in the heart.

DOI: https://doi.org/10.1038/s44161-023-00270-6

J Physiol. 2024 Aug 27.

HFrEF and HFpEF: are mitochondria at the heart of the matter?

Amanda Groenewald, Liam Zhang, Amelia S Power.

Keywords: calcium dynamics; heart failure; mitochondria

DOI: https://doi.org/10.1113/JP287344