bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2023–01–01
seven papers selected by
Kyle McCommis, Saint Louis University
  1. Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy.
  2. Effectiveness and safety of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 inhibitors for patients with heart failure with reduced ejection fraction: a meta-analysis.
  3. Sodium-glucose co-transporter 2 inhibitors in heart failure with mildly reduced or preserved ejection fraction: an updated systematic review and meta-analysis.
  4. Effects of the Sodium-Glucose Cotransporter Inhibitors on Cardiovascular Death and All-Cause Mortality: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Clinical Trials.
  5. Effects of glucagon-like peptide-1 receptor agonists on patients with heart failure: a meta-analysis of randomized controlled trials.
  6. Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia.
  7. Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure.
  1. Cell Death Dis. 2022 Dec 26. 13(12): 1073
    Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy.
    Jingyu Ni, Hao Zhang, Xiaodan Wang, Zhihao Liu, Tong Nie, Lan Li, Jing Su, Yan Zhu, Chuanrui Ma, Yuting Huang, Jingyuan Mao, Xiumei Gao, Guanwei Fan.
      The failing heart is characterized by an increase in glucose uptake and glycolytic rates that is not accompanied by a concomitant increase in glucose oxidation. Lower coupling of glucose oxidation to glycolysis possibly owes to unchanged or reduced pyruvate oxidation in mitochondria. Therefore, increasing pyruvate oxidation may lead to new therapies for heart disease. Dihydrolipoamide dehydrogenase (DLD) is a component of the pyruvate dehydrogenase complex (PDH). DLD mutations or defects are closely associated with metabolic diseases. However, few studies explore the effects of DLD mutants or acylation status on PDH activity and pyruvate metabolism. P300 is protein 2-hydroxyisobutyryltransferases in cells, and P300-dependent lysine 2-hydroxyisobutyrylation of glycolytic enzymes affects glucose metabolism. However, there are no relevant reports on the effect of 2-hydroxyisobutyrylation on the energy metabolism of heart failure, and it is worth further in-depth study. In this study, we showed that 2-hydroxyisobutyrylation is an essential protein translational modification (PTM) that regulates the activity of pyruvate dehydrogenase complex (PDHc). In a mouse model of transverse aortic constriction (TAC)-induced cardiac hypertrophy, the 2-hydroxyisobutylation of DLD was significantly increased, related to the decrease in PDH activity. In addition, our data provide clear evidence that DLD is a direct substrate of P300. As one of the main active ingredients of ginseng, ginsenoside Rg3 (Rg3) can reduce the 2-hydroxyisobutylation levels of DLD and restore the PDH activity by inhibiting the acyltransferase activity of P300, thereby producing beneficial effects whenever the heart is injured. Therefore, this study suggests a novel strategy for reversing myocardial hypertrophy.
    DOI:  https://doi.org/10.1038/s41419-022-05516-y
  2. J Cardiovasc Med (Hagerstown). 2023 Feb 01. 24(2): 123-131
    Effectiveness and safety of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 inhibitors for patients with heart failure with reduced ejection fraction: a meta-analysis.
    Yun Huang, Chongbo Fang, YuYu Zhang, Lili Ma, Hua Zhou, Honghua Ye.
      The current review aimed to study the effectiveness and safety of angiotensin receptor-neprilysin inhibitor (ARNI) combined with sodium-glucose cotransporter-2 (SGLT2) inhibitors versus ARNI or SGLT2 inhibitors monotherapy in patients with heart failure with reduced ejection fraction (HFrEF). Studies containing patients with HFrEF who used ARNI combined with SGLT2 inhibitors versus ARNI or SGLT2 inhibitors alone were retrieved from the Medline, Embase, and Cochrane Library databases. From the selected studies, the pooled risk ratios with 95% confidence intervals of dichotomous outcomes were assessed by a random or fixed effects model in our meta-analysis. Compared with ARNI monotherapy, the reduction in ARNI combined with SGLT2 inhibitors in a composite of the first hospitalization for heart failure or cardiovascular death was 32%, hospitalization for heart failure was 35% and cardiovascular death was 35%; also all-cause death was 30%, worsening renal function was 35%, respectively, for patients with HFrEF. In addition, compared with SGLT2 inhibitors monotherapy, the reduction in ARNI combined with SGLT2 inhibitors in cardiovascular death was 36% and all-cause death was 28%, respectively, for patients with HFrEF. Although the estimated treatment effect is a 55% increase in volume depletion, overall, ARNI combined with SGLT2 inhibitors might be effective and safe for patients with HFrEF, and volume depletion should be given more attention.
    DOI:  https://doi.org/10.2459/JCM.0000000000001426
  3. Eur J Med Res. 2022 Dec 29. 27(1): 314
    Sodium-glucose co-transporter 2 inhibitors in heart failure with mildly reduced or preserved ejection fraction: an updated systematic review and meta-analysis.
    Yintang Wang, Tong Gao, Chang Meng, Siyuan Li, Lei Bi, Yu Geng, Ping Zhang.
       OBJECTIVES: Heart failure with mildly reduced ejection fraction (HFmrEF)  or  heart failure with preserved ejection fraction (HFpEF)  are associated with significant morbidity and mortality, as well as growing health and economic burden. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are very promising for the outcome improvement of patients with HFpEF or HFmrEF. The meta-analysis was performed to investigate the effects of SGLT2 inhibitors in HFpEF or  HFmrEF, by pooling data from all clinically randomized controlled trials (RCTs) available to increase power to testify.
    METHODS: Studies were searched in electronic databases from inception to November, 2022. We performed a meta-analysis to estimate the effect of SGLT2 inhibitors on clinical endpoints in patients with HFpEF or HFmrEF, using trial-level data with consistent endpoint definitions. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Hazard ratio (HR) was pooled with 95% confidence interval (CI) for dichotomous data. This study was registered with INPLASY 2022110095.
    RESULTS: Six studies involving 15,989 participants were included into the final analysis. Pooled analyses revealed that SGLT2 inhibitors significantly reduced the composite of HF hospitalization or cardiovascular death [HR: 0.79 (0.72-0.85); I2 = 0%; P < 0.00001] and HF hospitalizations [HR: 0.74 (0.67-0.82); I2 = 0%; P < 0.00001]. This finding was seen in both HFmrEF trials [HR: 0.76 (0.67-0.87); I2 = 49%; P < 0.0001] and HFpEF subgroup studies [HR: 0.70 (0.53-0.93); I2 = 0%; P = 0.01]. The incidence of any serious adverse events [OR: 0.89 (0.83-0.96); I2 = 0%; P = 0.002] was significantly lower in the SGLT2 inhibitor arm. No significant differences were observed between the two groups with regard to cardiovascular death and all-cause death.
    CONCLUSIONS: This meta-analysis of patients with heart failure of left ventricular ejection fraction (LVEF) > 40% showed that SGLT2 inhibitors significantly reduce the risk of  the composite of cardiovascular death and hospitalization for heart failure, but not cardiovascular death and all-cause death. Nevertheless, given that SGLT2 inhibitors may reduce the risk of hospitalization for heart failure, they should be considered the fundamental treatment for all patients with HFpEF or  HFmrEF.
    Keywords:  Heart failure (HF); Heart failure with mildly reduced ejection fraction (HFmrEF); Heart failure with preserved ejection fraction (HFpEF); Outcomes; Sodium-glucose co-transporter (SGLT2) inhibitors
    DOI:  https://doi.org/10.1186/s40001-022-00945-z
  4. Am J Cardiovasc Drugs. 2022 Dec 27.
    Effects of the Sodium-Glucose Cotransporter Inhibitors on Cardiovascular Death and All-Cause Mortality: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Clinical Trials.
    Nathaniel Eraikhuemen, Simon Leung, Shalonda Barnes Warren, Dovena Lazaridis, Carla Hawkins Smith, Margaretta L Kearson, Valerie Marcellus.
       BACKGROUND: Patients with diabetes mellitus are at an increased risk of cardiovascular morbidity and all-cause mortality. Heart failure and type 2 diabetes often occur concomitantly, and each disease independently increases the risk for the other.
    OBJECTIVE: Emerging data have revealed that some sodium-glucose cotransporter inhibitors (SGLTi) improve cardiovascular and renal outcomes, particularly in patients with type 2 diabetes. The magnitude of this effect in patients without any underlying condition remains unclear. As a result, we conducted a meta-analysis of the mortality outcomes of available SGLTi in patients with or without cardiovascular diseases, type 2 diabetes, cardiovascular risk factors, and heart failure.
    METHODS: We performed a systematic review and meta-analysis of randomized, placebo-controlled major cardiovascular outcome trials of SGLTi in patients regardless of their cardiovascular disease or risk status. PubMed, Cochrane, Google Scholar, MEDLINE, and EMBASE were searched for the relevant studies. Three reviewers extracted study data and three reviewers summarized the strength of the evidence. Efficacy outcomes included all-cause mortality, major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of all-cause mortality, cardiovascular death, or hospitalization for heart failure. Odds ratios with 95% confidence intervals were pooled across trials to calculate the overall effect size.
    RESULTS: A total of 5043 all-cause mortality events were observed in the study groups. In 42,050 patients who received SGLTi, 2581 events were reported, and 2462 events were reported in 35,491 patients who received placebo (odds ratio = 0.86, 95% confidence interval 0.80-0.93, p = 0.0003). The use of SGLTi significantly reduced cardiovascular mortality compared with control across the patients' population (odds ratio = 0.86, 95% confidence interval 0.79-0.93, p = 0.0001). There was a consistent pattern of mortality beneficial estimates for all patients with different co-morbid conditions in the SGLTi-treated arm compared with the placebo-treated group. The presence or absence of significant cardiovascular disease risk factors (including a family history of premature coronary artery disease, baseline estimated glomerular filtration rate, dyslipidemia, hypertension, smoking, history of cardiovascular disease, and older age) did not affect the estimated mortality benefits.
    CONCLUSIONS: Sodium-glucose cotransporter inhibitors significantly reduced major adverse cardiovascular events, including hospitalization and all-cause mortality in patients with or without established atherosclerotic cardiovascular disease. We observed a beneficial trend in patients with heart failure with preserved ejection fraction, and no benefits in patients with stroke or myocardial infarction.
    DOI:  https://doi.org/10.1007/s40256-022-00561-6
  5. J Cardiovasc Med (Hagerstown). 2023 Feb 01. 24(2): 132-137
    Effects of glucagon-like peptide-1 receptor agonists on patients with heart failure: a meta-analysis of randomized controlled trials.
    Shota Obata, Yoshihisa Miyamoto, Leandro Slipczuk, Hisato Takagi, Toshiki Kuno.
       AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events (MACE) and heart failure in patients with type 2 diabetes mellitus (T2DM). However, these outcomes are not similarly demonstrated in those with prior heart failure in subgroup analyses of several randomized controlled trials (RCTs). We evaluated the effect of GLP-1RAs on MACE and heart failure admissions for T2DM patients with a previous history of heart failure.
    METHODS: We searched PubMed and EMBASE through March 2022 to identify RCTs examining the effects of GLP-1RAs compared with placebo on MACE and heart failure admission in T2DM patients with a history of heart failure. MACE were mainly defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. We performed a meta-analysis with a random-effects model.
    RESULTS: Our analysis included subgroup analyses of 7 RCTs enrolling a total of 8,965 patients with T2DM and heart failure. Pooled analysis demonstrated a significantly decreased MACE (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99; P = 0.039; I2 = 18.1%) in the GLP-1RAs group. In contrast, the rate of heart failure admission was not significantly different between the two groups (hazard ratio, 1.03; 95% confidence interval, 0.91-1.16; P = 0.67; I2 = 0.0%).
    CONCLUSION: GLP-1RAs significantly reduced MACE in T2DM patients with prior heart failure compared with the placebo group but did not affect the risk of heart failure admission.
    DOI:  https://doi.org/10.2459/JCM.0000000000001430
  6. J Am Heart Assoc. 2022 Dec 30. e028623
    Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia.
    Sharif A Sabe, Cynthia M Xu, Mohamed Sabra, Dwight Douglas Harris, Akshay Malhotra, Ahmed Aboulgheit, Madigan Stanley, M Ruhul Abid, Frank W Sellke.
      Background Sodium-glucose cotransporter-2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium-glucose cotransporter-2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate-activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate-activated protein kinase, and antioxidant signaling may contribute to these effects.
    Keywords:  canagliflozin; chronic myocardial ischemia; coronary disease; coronary microcirculation; sodium glucose cotransporter 2 inhibitor
    DOI:  https://doi.org/10.1161/JAHA.122.028623
  7. J Pers Med. 2022 Nov 01. pii: 1805. [Epub ahead of print]12(11):
    Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure.
    Midori Yukino-Iwashita, Yuji Nagatomo, Akane Kawai, Akira Taruoka, Yusuke Yumita, Kazuki Kagami, Risako Yasuda, Takumi Toya, Yukinori Ikegami, Nobuyuki Masaki, Yasuo Ido, Takeshi Adachi.
      Heart failure (HF) is a syndrome with global clinical and socioeconomic burden worldwide owing to its poor prognosis. Accumulating evidence has implicated the possible contribution of gut microbiota-derived metabolites, short-chain fatty acids (SCFAs), on the pathology of a variety of diseases. The changes of SCFA concentration were reported to be observed in various cardiovascular diseases including HF in experimental animals and humans. HF causes hypoperfusion and/or congestion in the gut, which may lead to lowered production of SCFAs, possibly through the pathological changes of the gut microenvironment including microbiota composition. Recent studies suggest that SCFAs may play a significant role in the pathology of HF, possibly through an agonistic effect on G-protein-coupled receptors, histone deacetylases (HDACs) inhibition, restoration of mitochondrial function, amelioration of cardiac inflammatory response, its utilization as an energy source, and remote effect attributable to a protective effect on the other organs. Collectively, in the pathology of HF, SCFAs might play a significant role as a key mediator in the gut-heart axis. However, these possible mechanisms have not been entirely clarified and need further investigation.
    Keywords:  G-protein-coupled receptors; acetate; butyrate; heart failure; histone deacetylases; propionate; short-chain fatty acid
    DOI:  https://doi.org/10.3390/jpm12111805
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