bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024–03–17
six papers selected by
Kyle McCommis, Saint Louis University
  1. Dapagliflozin in patients with heart failure and previous myocardial infarction: A participant-level pooled analysis of DAPA-HF and DELIVER.
  2. Mitochondrial Dysfunction in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Opportunities.
  3. Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review).
  4. DPP-4 inhibitor sitagliptin treatment results in altered myocardial metabolic proteome and oxidative phosphorylation in a swine model of chronic myocardial ischemia.
  5. Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy.
  6. Phytoformulation with hydroxycitric acid and capsaicin protects against high-fat-diet-induced obesity cardiomyopathy by reducing cardiac lipid deposition and ameliorating inflammation and apoptosis in the heart.
  1. Eur J Heart Fail. 2024 Mar 15.
    Dapagliflozin in patients with heart failure and previous myocardial infarction: A participant-level pooled analysis of DAPA-HF and DELIVER.
    Alexander Peikert, Muthiah Vaduganathan, Brian L Claggett, Ian J Kulac, Alberto Foà, Akshay S Desai, Pardeep S Jhund, Jaclyn Carberry, Carolyn S P Lam, Mikhail N Kosiborod, Silvio E Inzucchi, Felipe A Martinez, Rudolf A de Boer, Adrian F Hernandez, Sanjiv J Shah, Lars Køber, Piotr Ponikowski, Marc S Sabatine, Magnus Petersson, Anna Maria Langkilde, John J V McMurray, Scott D Solomon.
       AIMS: Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium-glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood.
    METHODS AND RESULTS: The DAPA-HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant-level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate-adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02-1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72-0.96) and without previous MI (HR 0.76, 95% CI 0.68-0.85; pinteraction  = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI.
    CONCLUSION: History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI.
    Keywords:  Heart failure with mildly reduced ejection fraction; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Myocardial infarction; SGLT2 inhibitors
    DOI:  https://doi.org/10.1002/ejhf.3184
  2. Int J Mol Sci. 2024 Feb 25. pii: 2667. [Epub ahead of print]25(5):
    Mitochondrial Dysfunction in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Opportunities.
    Giovanna Gallo, Speranza Rubattu, Massimo Volpe.
      Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from mitochondrial fatty acid oxidation to glycolytic pathways. This adaptive process of cardiomyocytes does not represent an effective strategy to increase the energy supply and to restore the energy homeostasis in heart failure, thus contributing to a vicious circle and to disease progression. The increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, damage of proteins and lipids, leakage of mitochondrial DNA, and inflammatory responses, finally stimulating different signaling pathways which lead to cardiac remodeling and failure. Furthermore, the parallel neurohormonal dysregulation with angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, which occurs in heart failure, stimulates ventricular cardiomyocyte hypertrophy and aggravates the cellular damage. In this review, we will discuss the pathophysiological mechanisms related to mitochondrial dysfunction, which are mainly dependent on increased oxidative stress and perturbation of the dynamics of membrane potential and are associated with heart failure development and progression. We will also provide an overview of the potential implication of mitochondria as an attractive therapeutic target in the management and recovery process in heart failure.
    Keywords:  cardiac disease; cardiac rehabilitation; cellular recovery; electron transport chain; heart failure; inflammation; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3390/ijms25052667
  3. Mol Med Rep. 2024 May;pii: 73. [Epub ahead of print]29(5):
    Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review).
    Bixian Chen, Jing Guo, Hongmei Ye, Xinyu Wang, Yufei Feng.
      Cardiovascular diseases are caused by pathological cardiac remodeling, which involves fibrosis, inflammation and cell dysfunction. This includes autophagy, apoptosis, oxidative stress, mitochondrial dysfunction, changes in energy metabolism, angiogenesis and dysregulation of signaling pathways. These changes in heart structure and/or function ultimately result in heart failure. In an effort to prevent this, multiple cardiovascular outcome trials have demonstrated the cardiac benefits of sodium‑glucose cotransporter type 2 inhibitors (SGLT2is), hypoglycemic drugs initially designed to treat type 2 diabetes mellitus. SGLT2is include empagliflozin and dapagliflozin, which are listed as guideline drugs in the 2021 European Guidelines for Heart Failure and the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guidelines for Heart Failure Management. In recent years, multiple studies using animal models have explored the mechanisms by which SGLT2is prevent cardiac remodeling. This article reviews the role of SGLT2is in cardiac remodeling induced by different etiologies to provide a guideline for further evaluation of the mechanisms underlying the inhibition of pathological cardiac remodeling by SGLT2is, as well as the development of novel drug targets.
    Keywords:  SGLT2 inhibitors; cardiac fibroblasts; cardiac remodeling; molecular mechanisms; myocardial hypertrophy
    DOI:  https://doi.org/10.3892/mmr.2024.13197
  4. Physiol Rep. 2024 Mar;12(5): e15976
    DPP-4 inhibitor sitagliptin treatment results in altered myocardial metabolic proteome and oxidative phosphorylation in a swine model of chronic myocardial ischemia.
    Dwight D Harris, Sharif A Sabe, Mark Broadwin, Krishna Bellam, Cynthia M Xu, Janelle W Li, M Ruhul Abid, Frank W Sellke.
      Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies.
    Keywords:  DPP-4 inhibitor; chronic myocardial ischemia; oxidative phosphorylation; proteomics; sitagliptin
    DOI:  https://doi.org/10.14814/phy2.15976
  5. J Mol Cell Cardiol. 2024 Mar 13. pii: S0022-2828(24)00034-8. [Epub ahead of print]189 83-89
    Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy.
    Kimberley M Mellor, Upasna Varma, Parisa Koutsifeli, Lorna J Daniels, Victoria L Benson, Marco Annandale, Xun Li, Yohanes Nursalim, Johannes V Janssens, Kate L Weeks, Kim L Powell, Terence J O'Brien, Rajesh Katare, Rebecca H Ritchie, James R Bell, Roberta A Gottlieb, Lea M D Delbridge.
      Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis - glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease.
    Keywords:  Autophagy; Cardiac glycogen; Cardiac metabolism; Diabetic heart disease; Glycophagy
    DOI:  https://doi.org/10.1016/j.yjmcc.2024.02.009
  6. J Tradit Complement Med. 2024 Mar;14(2): 162-172
    Phytoformulation with hydroxycitric acid and capsaicin protects against high-fat-diet-induced obesity cardiomyopathy by reducing cardiac lipid deposition and ameliorating inflammation and apoptosis in the heart.
    V V Sathibabu Uddandrao, P Chandrasekaran, G Saravanan, Parim Brahmanaidu, S Sengottuvelu, P Ponmurugan, S Vadivukkarasi, Umesh Kumar.
       Background and aim: Phytoformulation therapy is a pioneering strategy for the treatment of metabolic disorders and related diseases. The aim of the present study was to investigate the protective effect of a phytoformulation consisting of hydroxycitric acid and capsaicin against obesity-related cardiomyopathy.
    Experimental procedure: Sprague-Dawley rats were fed HFD for 21 weeks, and phytoformulation (100 mg/kg body weight) was administered orally for 45 days starting at week 16.
    Results and conclusion: We found that HFD supplementation resulted in significant hyperglycemia and caused an increase in cardiac lipid deposition, inflammation and apoptosis in the heart. Phytoformulation therapy not only significantly decreased blood levels of glucose, cholesterol, triglycerides, free fatty acids, and inflammatory cytokines in obese rats, but also protected cardiac tissue, as shown by histological analysis. Conversely, phytoformulation therapy decreased mRNA levels for sterol regulatory element-binding factor 1, fatty acid synthase, acetyl-CoA carboxylase, and fatty acid binding protein 1 genes involved in fatty acid synthesis and absorption in obese rats. It increased the levels of lysosomal acid lipase, hormone-sensitive lipase, and lipoprotein lipase genes involved in fatty acid degradation in the heart. In addition, the phytoformulation improved cardiac inflammation and apoptosis by downregulating the genes nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), tumour necrosis factor α, interleukin-6, toll-like receptor-4 (TLR-4), BCL2-associated X and caspase-3. In conclusion, our results show that the phytoformulation improved insulin sensitivity and attenuated myocardial lipid accumulation, inflammation, and apoptosis in the heart of HFD-induced obese rats by regulating fatty acid metabolism genes and downregulating NF-kB/TLR-4/caspase-3.
    Keywords:  Cardiovascular disorders; Functional foods; Metabolic disorders; Natural medicine; Nutraceuticals
    DOI:  https://doi.org/10.1016/j.jtcme.2023.08.004
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