bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2022‒01‒02
eight papers selected by
Kyle McCommis
Saint Louis University

  1. JACC Heart Fail. 2022 Jan;pii: S2213-1779(21)00423-6. [Epub ahead of print]10(1): 52-64
      OBJECTIVES: This study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure).BACKGROUND: Black patients may respond differently to certain treatments for HFrEF than White patients.
    METHODS: Patients with New York Heart Association functional class II to IV with an ejection fraction of ≤40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for DAPA-HF. Because >99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.
    RESULTS: Of the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients.
    CONCLUSIONS: Dapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).
    Keywords:  dapagliflozin; heart failure; hospitalization; mortality; sodium glucose cotransporter 2 (SGLT2) inhibitor
  2. Front Cardiovasc Med. 2021 ;8 789267
      Ischemic heart disease refers to myocardial degeneration, necrosis, and fibrosis caused by coronary artery disease. It can lead to severe left ventricular dysfunction (LVEF ≤ 35-40%) and is a major cause of heart failure (HF). In each contraction, myocardium is subjected to a variety of mechanical forces, such as stretch, afterload, and shear stress, and these mechanical stresses are clinically associated with myocardial remodeling and, eventually, cardiac outcomes. Mitochondria produce 90% of ATP in the heart and participate in metabolic pathways that regulate the balance of glucose and fatty acid oxidative phosphorylation. However, altered energetics and metabolic reprogramming are proved to aggravate HF development and progression by disturbing substrate utilization. This review briefly summarizes the current insights into the adaptations of cardiomyocytes to mechanical stimuli and underlying mechanisms in ischemic heart disease, with focusing on mitochondrial metabolism. We also discuss how mechanical circulatory support (MCS) alters myocardial energy metabolism and affects the detrimental metabolic adaptations of the dysfunctional myocardium.
    Keywords:  heart failure; ischemic heart disease; left ventricular assist device; mechanical unloading; mitochondrial metabolism; veno-arterial ECMO
  3. Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01653-3. [Epub ahead of print]37(13): 110157
      Lipid storage in fat tissue is important for energy homeostasis and cellular functions. Through RNAi screening in Drosophila fat body, we found that knockdown of a Drosophila NAD kinase (NADK), which phosphorylates NAD to synthesize NADP de novo, causes lipid storage defects. NADK sustains lipogenesis by maintaining the pool of NADPH. Promoting NADPH production rescues the lipid storage defect in the fat body of NADK RNAi animals. Furthermore, NADK and fatty acid synthase 1 (FASN1) regulate mitochondrial mass and function by altering the levels of acetyl-CoA and fatty acids. Reducing the level of acetyl-CoA or increasing the synthesis of cardiolipin (CL), a mitochondrion-specific phospholipid, partially rescues the mitochondrial defects of NADK RNAi. Therefore, NADK- and FASN1-mediated fatty acid synthesis coordinates lipid storage and mitochondrial function.
    Keywords:  Drosophila; FASN; NADK; lipogenesis; mitochondrial metabolism
  4. Curr Vasc Pharmacol. 2021 Dec 27.
      Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have changed the clinical landscape of diabetes mellitus (DM) therapy through their favourable effects on cardiovascular outcomes. Notably, the use of SGLT2i has been linked to cardiovascular benefits regardless of DM status, while their pleiotropic actions remain to be fully elucidated. What we do know is that SGLT2i exert beneficial effects even at the level of the myocardial cell, and that these are linked to an improvement in the energy substrate, resulting in less inflammation and fibrosis. SGLT2i ameliorate myocardial extracellular matrix remodeling, cardiomyocyte stiffness and concentric hypertrophy, achieving beneficial remodeling of the left ventricle with significant implications for the pathogenesis and outcome of heart failure. Most studies show a significant improvement in markers of diastolic dysfunction along with a reduction in left ventricular hypertrophy. In addition to these effects there is electrophysiological remodeling, which explains initial data suggesting that SGLT2i have an antiarrhythmic action against both atrial and ventricular arrhythmias. However, future studies need to clarify not only the exact mechanisms of this beneficial functional, structural, and electrophysiological cardiac remodeling, but also its magnitude, and to determine whether this is a class or a drug effect.
    Keywords:  diabetes; remodeling; sodium–glucose cotransporter-2 inhibitors
  5. Cardiovasc Res. 2021 Dec 31. pii: cvab367. [Epub ahead of print]
      AIMS: Obesity, diabetes and metabolic syndromes are risk factors of atrial fibrillation (AF). We tested the hypothesis that metabolic disorders have a direct impact on the atria favoring the formation of the substrate of AF.METHODS & RESULTS: Untargeted metabolomic and lipidomic analysis was used to investigate the consequences of a prolonged high fat diet (HFD) on mouse atria. Atrial properties were characterized by measuring mitochondria respiration in saponin-permeabilized trabeculae, by recording action potential with glass microelectrodes in trabeculae and ionic currents in myocytes using the perforated configuration of patch clamp technique and by several immuno-histological and biochemical approaches. After 16 weeks of HFD, obesogenic mice showed a vulnerability to AF. The atrial myocardium acquired an adipogenic and inflammatory phenotypes. Metabolomic and lipidomic analysis revealed a profound transformation of atrial energy metabolism with a predominance of long-chain lipid accumulation and beta-oxidation activation in the obese mice. Mitochondria respiration showed an increased use of palmitoyl-CoA as energy substrate. Action potentials were short duration and sensitive to the K-ATP-dependent channel inhibitor, whereas K-ATP current was enhanced in isolated atrial myocytes of obese mouse.
    CONCLUSION: HFD transforms energy metabolism, causes fat accumulation, and induces electrical remodeling of the atrial myocardium of mice that become vulnerable to AF.
    TRANSLATIONAL PERSPECTIVE: Understanding the link between metabolic diseases and atrial fibrillation is of major importance. One hypothesis claims that, in addition to shared co-morbidities, metabolic disorders favor the substrate of atrial fibrillation. Here we show that after prolonged high fat diet, the atrial myocardium becomes adipogenic, inflamed and vulnerable to atrial fibrillation. This tissue remodeling appears to result from an unbalance between uptake and oxidation of fatty acid resulting in long-chain lipid storage, activation of metabolic-sensitive potassium channels and action potential shortening. Therefore, diet appears to be an important link between metabolic disorders and atrial fibrillation.
  6. Am J Physiol Cell Physiol. 2021 12 29.
      Selective autophagy of the mitochondria, known as mitophagy, is a major mitochondrial quality control pathway in the heart that is involved in removing unwanted or dysfunctional mitochondria from the cell. Baseline mitophagy is critical for maintaining the fitness of the mitochondrial population by continuous turnover of aged and less functional mitochondria. Mitophagy is also critical in adapting to stress associated with mitochondrial damage or dysfunction. The removal of damaged mitochondria prevents ROS-mediated damaged to proteins and DNA and suppresses activation of inflammation and cell death. Impairments in mitophagy are associated with the pathogenesis of many diseases, including cancers, inflammatory diseases, neurodegeneration, and cardiovascular disease. Mitophagy is a highly regulated and complex process that requires the coordination of labeling dysfunctional mitochondria for degradation while simultaneously promoting de novo autophagosome biogenesis adjacent to the cargo. In this review, we provide an update on our current understanding of these steps in mitophagy induction and discuss the physiological and pathophysiological consequences of altered mitophagy in the heart.
    Keywords:  Parkin; autophagy; heart; mitochondria; mitophagy
  7. Oxid Med Cell Longev. 2021 ;2021 6779559
      Ample clinical case reports suggest a high incidence of cardiomyopathy in diabetes mellitus (DM). Recent evidence supports an essential role of trehalose (TLS) in cardiomyocyte survival signaling. Our previous study found that prokineticin2 (PK2) was involved in the process of diabetic cardiomyopathy (DCM). The present study examined the protective effects and mechanisms of TLS on DM-induced cardiomyocyte injury in mice and H9c2 cardiomyocytes. C57BL/6J mice were intraperitoneally injected with 50 mg·kg-1·d-1 streptozotocin for five consecutive days to establish an experimental diabetic model and then administered TLS (1 mg·g-1·d-1, i.p.) for two days every 4 weeks and given 2% TLS in drinking water for 24 weeks. Echocardiography, myocardial structure, apoptosis, pyroptosis, autophagy, and the PK2/PKR pathway were assessed. Cardiomyocytes exposed to high glucose (HG) were treated with TLS in the absence or presence of the PK2 antagonist PKRA7, and proteins involved in apoptosis, autophagy, and pyroptosis and the PK2/PKR pathways were evaluated using Western blot analysis. Diabetic mice demonstrated metabolic disorder, abnormal myocardial zymograms, and aberrant myocardial systolic and diastolic function, which were accompanied by pronounced apoptosis, pyroptosis, and dampened autophagy. TLS treatment relieved these effects. PK2 and receptor expressions were downregulated in diabetic mice, and TLS nullified this effect. PKRA7 eliminated the impact of TLS on cardiomyocytes. This evidence suggests that TLS rescues DM-induced myocardial function, pyroptosis, and apoptosis, likely via the PK2/PKR pathway.
  8. Cardiovasc Res. 2021 Dec 25. pii: cvab368. [Epub ahead of print]
      AIMS: Whether high body mass index (BMI) causally influences development and prognosis of heart failure has implications for clinical practice. We tested the hypotheses that high BMI causally influences heart failure incidence and mortality.METHODS AND RESULTS: Using observational and Mendelian randomization causal, genetic analyses, we studied 106,121 individuals from the Copenhagen General Population Study, 18,407 from the Copenhagen City Heart Study, and 977,323 from publicly available databases. In observational analyses in the Copenhagen studies with 10 years of median follow-up, multivariable adjusted hazard ratios per 1 kg/m2 increment of BMI were 1.06 (95% confidence interval: 1.05-1.07; p < 0.001; n = 124,528; events = 6,589) for heart failure incidence, 1.04 (1.03-1.06; p < 0.001; n = 124,528; events = 1,237) for heart failure mortality, and 1.01 (1.00-1.01; p < 0.001; n = 124,528; events = 24,144) for all-cause mortality. In genetic analyses in the Copenhagen studies, the age and sex adjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.19 (1.05-1.36; p = 0.008; n = 118,200; events = 6,541) for heart failure incidence, 1.27 (0.82-1.98; p = 0.28; n = 118,200; events = 889) for heart failure mortality, and 1.11 (1.02-1.22; p = 0.022; n = 118,200; events = 16,814) for all-cause mortality. Finally, combining genetic data from the Copenhagen studies, the Genetic Investigation of ANthropometric Traits (GIANT), the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES), and the UK Biobank, the unadjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.39 (1.27-1.52; p < 0.001; n = 1,095,523; events = 53,850) for heart failure incidence, 1.18 (1.00-1.38; p = 0.05; n = 576,853; events = 2,373) for heart failure mortality, and 1.02 (1.00-1.04; p = 0.03; n = 576,853; events = 44,734) for all-cause mortality.
    CONCLUSION: High BMI causally increases the risk of both heart failure incidence and mortality.
    TRANSLATIONAL PERSPECTIVE: Obesity should be recognised as a causal factor for development of heart failure, heart failure mortality, and all-cause mortality in treatment guidelines. Further research into the effect of weight loss surgery/medication to lower the risk of heart failure or mortality after a diagnosis of heart failure is needed.
    Keywords:  Heart failure; body mass index; cardiovascular disease; obesity; obesity paradox; overweight