bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2021‒08‒22
seven papers selected by
Kyle McCommis
Saint Louis University

  1. Front Cardiovasc Med. 2021 ;8 723996
      Perturbations in myocardial energy substrate metabolism are key contributors to the pathogenesis of heart diseases. However, the underlying causes of these metabolic alterations remain poorly understood. Recently, post-translational acetylation-mediated modification of metabolic enzymes has emerged as one of the important regulatory mechanisms for these metabolic changes. Nevertheless, despite the growing reports of a large number of acetylated cardiac mitochondrial proteins involved in energy metabolism, the functional consequences of these acetylation changes and how they correlate to metabolic alterations and myocardial dysfunction are not clearly defined. This review summarizes the evidence for a role of cardiac mitochondrial protein acetylation in altering the function of major metabolic enzymes and myocardial energy metabolism in various cardiovascular disease conditions.
    Keywords:  fatty acid oxidation; glucose oxidation; lysine acetylation; mitochondria; sirtuins; succinylation
  2. Front Cardiovasc Med. 2021 ;8 683522
      Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification. Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks. Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation. Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.
    Keywords:  heart failure; maladaptive cardiac hypertrophy; mice; pressure-overload; thyroid hormones
  3. Physiol Rep. 2021 Aug;9(16): e14961
      Obesity, type 2 diabetes, and heart disease are linked to an unhealthy diet. Sarco(endo)plasmic reticulum calcium (Ca2+ ) ATPase 2a (SERCA2a) controls cardiac function by transporting Ca2+ in cardiomyocytes. SERCA2a is altered by diet and acetylation, independently; however, it is unknown if diet alters cardiac SERCA2a acetylation. Sirtuin (SIRT) 3 is an enzyme that might preserve health under conditions of macronutrient excess by modulating metabolism via regulating deacetylation of target proteins. Our objectives were to determine if muscle-specific SIRT3 overexpression attenuates the pathological effects of high fat-high sucrose (HFHS) feeding and if HFHS feeding alters cardiac SERCA2a acetylation. We also determined if SIRT3 alters cardiac SERCA2a acetylation and regulates cardiac SERCA2a activity. C57BL/6J wild-type (WT) mice and MCK-mSIRT3-M1-Flag transgenic (SIRT3TG ) mice, overexpressing SIRT3 in cardiac and skeletal muscle, were fed a standard-diet or a HFHS-diet for 4 months. SIRT3TG and WT mice developed obesity, glucose intolerance, cardiac dysfunction, and pathological cardiac remodeling after 4 months of HFHS feeding, indicating muscle-specific SIRT3 overexpression does not attenuate the pathological effects of HFHS-feeding. Overall cardiac lysine acetylation was increased by 63% in HFHS-fed mice (p = 0.022), though HFHS feeding did not alter cardiac SERCA2a acetylation. Cardiac SERCA2a acetylation was not altered by SIRT3 overexpression, whereas SERCA2a Vmax was 21% higher in SIRT3TG (p = 0.039) than WT mice. This suggests that SIRT3 overexpression enhanced cardiac SERCA2a activity without direct SERCA2a deacetylation. Muscle-specific SIRT3 overexpression may not prevent the complications associated with an unhealthy diet in mice, but it appears to enhance SERCA2a activity in the mouse heart.
    Keywords:  SERCA; acetylation; calcium handling; diabetes; obesity; sirtuins
  4. Am J Physiol Heart Circ Physiol. 2021 Aug 20.
      Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular Ca2+ handling and impaired mitochondrial function accompanied with reduced mito-[Ca2+]. Pharmacological or genetic facilitation of mito-Ca2+ uptake was shown to restore Ca2+ transient amplitude in DCM and HF, improving contractility. However, recent reports suggest that pharmacological enhancement of mito-Ca2+ uptake can exacerbate ryanodine receptor-mediated spontaneous sarcoplasmic reticulum (SR) Ca2+ release in ventricular myocytes (VMs) from diseased animals, increasing propensity to stress-induced ventricular tachyarrhythmia. To test whether chronic recovery of mito-[Ca2+] restores systolic Ca2+ release without adverse effects in diastole, we overexpressed mitochondrial Ca2+ uniporter (MCU) in VMs from male rat hearts with hypertrophy induced by thoracic aortic banding (TAB). Measurement of mito-[Ca2+] using genetic probe mtRCamp1h revealed that mito-[Ca2+] in TAB VMs paced at 2 Hz under β-adrenergic stimulation is lower compared to Shams. Adenoviral 2.5-fold MCU overexpression in TAB VMs fully restored mito-[Ca2+]. However, it failed to improve cytosolic Ca2+ handling and reduce pro-arrhythmic spontaneous Ca2+ waves. Furthermore, mitochondrial-targeted genetic probes MLS-HyPer7 and OMM-HyPer revealed a significant increase in emission of reactive oxygen species (ROS) in TAB VMs with 2.5-fold MCU overexpression. Conversely, 1.5-fold MCU overexpression in TABs, that led to partial restoration of mito-[Ca2+], reduced mito-ROS and spontaneous Ca2+ waves. Our findings emphasize the key role of elevated mito-ROS in disease-related pro-arrhythmic Ca2+ mishandling. These data establish non-linear mito-[Ca2+]/mito-ROS relationship, whereby partial restoration of mito-[Ca2+] in diseased VMs is protective, while further enhancement of MCU-mediated Ca2+-uptake exacerbates damaging mito-ROS emission.
    Keywords:  calcium-dependent ventricular arrhythmia; mitochondrial calcium uniporter; mitochondrial calcium uptake; mitochondrial reactive oxygen species; ryanodine receptor
  5. Sheng Li Xue Bao. 2021 Aug 25. 73(4): 584-596
      Heart failure (HF), a clinical syndrome with high morbidity and mortality, is becoming a growing public health problem. Dilated cardiomyopathy (DCM) is one of the major causes of HF, yet the molecular mechanisms underlying DCM-mediated HF are not completely understood. Previous studies have shown that dysregulation of arachidonic acid (AA) metabolism could contribute to the development of HF. To explore the roles of microRNAs (miRNAs) in regulating AA metabolism in HF, we used two public datasets to analyze the expression changes of miRNAs in the patients of DCM-mediated HF. A total of 101 and 88 miRNAs with significant abundance alterations in the two dataset were obtained, respectively. Around 1/3 of these miRNAs were predicted to target AA metabolic pathway genes. We also investigated the distribution of known single nucleotide polymorphisms (SNPs) within the sequences of miRNAs dysregulated in DCM-mediated HF patients, and identified miRNAs harboring high number of SNPs in either the seed regions or the entire sequences. These information could provide clues for further functional studies of miRNAs in the pathogeny of DCM-mediated HF.
  6. Circ Rep. 2021 Aug 10. 3(8): 440-448
      Background: The efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in elderly patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. Methods and Results: In a multicenter, controlled trial, the CANONICAL study, we enrolled 82 HFpEF (left ventricular ejection fraction [LVEF] ≥50%) patients with type 2 diabetes (T2D) aged ≥65 years, with plasma B-type natriuretic peptide (BNP) ≥100 pg/mL or plasma N-terminal pro BNP (NT-proBNP) ≥400 pg/mL or history of HF. Patients were randomly assigned to 2 groups and were administered either the SGLT2 inhibitor canagliflozin (100 mg/day) for 24 weeks or standard therapy. The primary endpoints were changes in body weight (BW) and BNP concentrations. Mean (±SD) patient age, body mass index, and LVEF were 75.7±6.5 years, 25.0±3.6 kg/m2 and 61.5±7.6%, respectively. At 24 weeks, BW was significantly lower in the canagliflozin than standard therapy group. The extent of BNP reductions at 4 weeks was significantly greater in the canagliflozin than standard therapy group (P<0.05), but at 24 weeks there was no significant difference between the 2 groups. Conclusions: In this study, canagliflozin treatment reduced BW, but did not significantly reduce plasma BNP concentrations compared with standard therapy after 24 weeks treatment in T2D patients with HFpEF. Further large-scale randomized studies are needed to conclude the beneficial effects of canagliflozin in T2D patients with HFpEF.
    Keywords:  B-type natriuretic peptide; Elderly; Heart failure with preserved ejection fraction; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes