bims-hafaim Biomed News
on Heart Failure Metabolism
Issue of 2021‒02‒21
23 papers selected by
Kyle McCommis
Saint Louis University

  1. Circulation. 2021 Feb 17.
      Background: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension and diabetes. O-GlcNAcylation is a post-translational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. The total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Failing myocardium is marked by increased O-GlcNAcylation, but it is unknown if excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure. Methods: We developed two new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAcylation independent of pathological stress. Results: We found that OGT transgenic hearts showed increased O-GlcNAcylation, and developed severe dilated cardiomyopathy, ventricular arrhythmias and premature death. In contrast, OGA transgenic hearts had lower O-GlcNAcylation but identical cardiac function to wild type littermate controls. Additionally, OGA transgenic hearts were resistant to pathological stress induced by pressure overload with attenuated myocardial O-GlcNAcylation levels after stress and decreased pathological hypertrophy compared to wild type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc mediated cardiac pathology. Conclusions: Our data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, due to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is beneficial against pressure overload induced pathologic remodeling and heart failure. These findings suggest attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.
    Keywords:  Dilated cardiomyopathy; O-GlcNAcylation; mitochondrial energetics; mouse model
  2. Circulation. 2021 Feb 19.
      Background: The failing heart is energy-starved with impaired oxidation of long chain fatty acids (LCFA) at the level of reduced carnitine palmitoyltransferase 1 (CPT1) activity at the outer mitochondrial membrane. Recent work shows elevated ketone oxidation in failing hearts as an alternate carbon source for oxidative ATP generation. We hypothesized that another short chain carbon source, short chain fatty acids (SCFA) that bypass CPT1, could similarly support energy production in failing hearts. Methods: Cardiac hypertrophy and dysfunction was induced in rats by transverse-aortic constriction (TAC). 14 weeks after TAC or sham-operation, isolated hearts were perfused with either the four carbon, 13C-labeled ketone (D3-hydroxybutyrate) or the four carbon, 13C -labeled SCFA, butyrate in the presence of glucose and the LCFA, palmitate. Oxidation of ketone and SCFA was compared by in vitro 13C NMR spectroscopy, as was the capacity for short chain carbon sources to compensate for impaired LCFA oxidation in the hypertrophic heart. Adaptive changes in enzyme expression and content for the distinct pathways of ketone and SCFA oxidation were examined in both failing rat and human hearts. Results: TAC produced pathological hypertrophy and increased the fractional contributions of ketone to acetyl CoA production in the tricarboxylic acid cycle (0.60±0.02 sham ketone vs 0.70±0.02 TAC ketone, p<0.05). However, butyrate oxidation in failing hearts was 15% greater (0.803±0.02 TAC SCFA) than ketone oxidation. SCFA was also more readily oxidized than ketone in sham hearts by 15% (0.693±0.02 sham SCFA). Despite greater SFCA oxidation, TAC did not change short chain acyl CoA dehydrogenase content. However, failing hearts of humans and the rat model both contain significant increases in acyl CoA synthetase medium chain 3 enzyme gene expression and protein content. The increased oxidation of SCFA and ketones occurred at the expense of LCFA oxidation, with LCFA contributing less to acetyl CoA production in failing hearts perfused with SCFA (0.19±0.012 TAC SCFA vs. 0.3163±0.036 TAC ketone). Conclusions: SCFA are more readily oxidized than ketones in failing hearts, despite both bypassing reduced CPT1 activity, and represents an unexplored carbon source for energy production in failing hearts.
    Keywords:  ketones; short chain fatty acids
  3. Front Pharmacol. 2020 ;11 569132
      Heart failure is a systemic syndrome caused by multiple pathological factors. Current treatments do not have satisfactory outcomes. Several basic studies have revealed the protective effect of trimetazidine on the heart, not only by metabolism modulation but also by relieving myocardial apoptosis, fibrosis, autophagy, and inflammation. Clinical studies have consistently indicated that trimetazidine acts as an adjunct to conventional treatments and improves the symptoms of heart failure. This review summarizes the basic pathological changes in the myocardium, with an emphasis on the alteration of cardiac metabolism in the development of heart failure. The clinical application of trimetazidine in heart failure and the mechanism of its protective effects on the myocardium are carefully discussed, as well as its main adverse effects. The intention of this review is to highlight this treatment as an effective alternative against heart failure and provide additional perspectives for future studies.
    Keywords:  basic research; clinical research; ischemic heart failure; non-ischemic heart failure; trimetazidine
  4. Front Cell Dev Biol. 2021 ;9 629932
      Pressure overload-induced hypertrophic remodeling is a critical pathological process leading to heart failure (HF). Suppressor of cytokine signaling-3 (SOCS3) has been demonstrated to protect against cardiac hypertrophy and dysfunction, but its mechanisms are largely unknown. Using primary cardiomyocytes and cardiac-specific SOCS3 knockout (SOCS3cko) or overexpression mice, we demonstrated that modulation of SOCS3 level influenced cardiomyocyte hypertrophy, apoptosis and cardiac dysfunction induced by hypertrophic stimuli. We found that glucose regulatory protein 78 (GRP78) was a direct target of SOCS3, and that overexpression of SOCS3 inhibited cardiomyocyte hypertrophy and apoptosis through promoting proteasomal degradation of GRP78, thereby inhibiting activation of endoplasmic reticulum (ER) stress and mitophagy in the heart. Thus, our results uncover SOCS3-GRP78-mediated ER stress as a novel mechanism in the transition from cardiac hypertrophy to HF induced by sustained pressure overload, and suggest that modulating this pathway may provide a new therapeutic approach for hypertrophic heart diseases.
    Keywords:  cardiac hypertrophy; endoplasmic reticulum stress; glucose regulatory protein 78; heart failure; socs3
  5. Front Cardiovasc Med. 2021 ;8 645986
    Keywords:  cardiovascular diseases; mitochondrial ROS; mitochondrial dynamics; mitochondrial dysfunction; mitophagy
  6. Circulation. 2021 Feb 16. 143(7): 699-712
      BACKGROUND: The heart undergoes physiological hypertrophy during pregnancy in healthy individuals. Metabolic syndrome (MetS) is now prevalent in women of child-bearing age and might add risks of adverse cardiovascular events during pregnancy. The present study asks if cardiac remodeling during pregnancy in obese individuals with MetS is abnormal and whether this predisposes them to a higher risk for cardiovascular disorders.METHODS: The idea that MetS induces pathological cardiac remodeling during pregnancy was studied in a long-term (15 weeks) Western diet-feeding animal model that recapitulated features of human MetS. Pregnant female mice with Western diet (45% kcal fat)-induced MetS were compared with pregnant and nonpregnant females fed a control diet (10% kcal fat).
    RESULTS: Pregnant mice fed a Western diet had increased heart mass and exhibited key features of pathological hypertrophy, including fibrosis and upregulation of fetal genes associated with pathological hypertrophy. Hearts from pregnant animals with WD-induced MetS had a distinct gene expression profile that could underlie their pathological remodeling. Concurrently, pregnant female mice with MetS showed more severe cardiac hypertrophy and exacerbated cardiac dysfunction when challenged with angiotensin II/phenylephrine infusion after delivery.
    CONCLUSIONS: These results suggest that preexisting MetS could disrupt physiological hypertrophy during pregnancy to produce pathological cardiac remodeling that could predispose the heart to chronic disorders.
    Keywords:  cardiac; cardiac remodeling; fibrosis; hypertrophy; metabolic syndrome; pregnancy
  7. Antioxid Redox Signal. 2021 Feb 16.
      Significance: Mitochondria-derived reactive oxygen species (mtROS) are by-products of normal physiology that may disrupt cellular redox homeostasis on a regular basis. Nonetheless, failure to resolve sustained mitochondrial stress to mitigate high levels of mtROS might contribute to the etiology of numerous pathological conditions, such as obesity, insulin resistance, and cardiovascular disease (CVD). Recent Advances: Notably, recent studies have demonstrated that moderate mitochondrial stress might result in the induction of different stress response pathways that ultimately improve the organism's ability to deal with subsequent stress, a process termed mitohormesis. mtROS have been shown to play a key role in regulating this adaptation. Critical Issue: mtROS regulate the convergence of different signaling pathways that, when disturbed, might impair cardiometabolic health. Conversely, mtROS seem to be required to mediate activation of prosurvival pathways, contributing to improved cardiometabolic fitness. In the present review, we will primarily focus on the role of mtROS in the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway and examine the role of endoplasmic reticulum (ER) stress in coordinating the convergence of ER stress and oxidative stress signaling through activation of Nrf2 and activating transcription factor 4 (ATF4). Future Directions: The mechanisms underlying cardiometabolic protection in response to mitochondrial stress have only started to be investigated. Integrated understanding of how mtROS and ER stress cooperatively promote activation of prosurvival pathways might shed mechanistic insight into the role of mitohormesis in mediating cardiometabolic protection and might inform future therapeutic avenues for the treatment of metabolic diseases contributing to CVD.
    Keywords:  ER stress; ROS; cardiometabolic health; mitochondria; mitohormesis
  8. Cureus. 2021 Jan 13. 13(1): e12673
      Patients with end-stage heart failure may require hospitalization for the treatment of respiratory distress. Morphine may be used to relieve symptoms. However, use of morphine is problematic because heart failure is often associated with renal dysfunction. In this case report, intravenous fentanyl infusion reduced dyspnea in a patient with end-stage heart failure who was on dialysis induction to treat renal failure. The patient was able to eat and sleep after administration of an intravenous fentanyl solution and experienced no apparent respiratory depression as a side effect of fentanyl. There have been few reports of dyspnea relief with fentanyl infusion. Because of its adjustable duration of effect, intravenous fentanyl may be a more effective and useful option than rapid or extended-release agents in cases such as this one.
    Keywords:  dyspnea; end-stage heart failure; fentanyl; palliative care
  9. J Cardiol. 2021 Feb 13. pii: S0914-5087(21)00039-3. [Epub ahead of print]
    Keywords:  Heart failure; Heart rate; Hemodynamics
  10. ESC Heart Fail. 2020 Dec;7(6): 3392-3400
      AIMS: Intravenous ferric carboxymaltose (FCM) has been shown to improve functional capacity and quality of life in iron deficient heart failure patients. However, FCM's effect on hospitalizations and mortality remains unclear as previous randomized controlled trials (RCTs) and their meta-analyses have been underpowered to detect significant differences. We sought to conduct an updated meta-analysis using recently published RCT data.METHODS AND RESULTS: Online databases were searched from inception until November 2020 for RCTs evaluating the effects of FCM on clinical outcomes in iron-deficient heart failure patients. Outcomes of interest included heart failure hospitalizations, all-cause mortality, and cardiovascular mortality. Meta-analysis was performed using a fixed-effect model and estimates were reported as odds ratios (ORs), hazard ratios, or rate ratios (RRs) along with corresponding 95% confidence intervals (CIs). A total of 1947 patients (n = 1062 in the FCM group; n = 885 in the placebo group) were included. FCM, compared with placebo, significantly reduced the risk of the composite endpoint of time to first heart failure hospitalization or cardiovascular death (hazard ratio = 0.76; 95% CI = 0.63-0.90; I2 = 55%). FCM also significantly reduced the risk of recurrent heart failure hospitalizations (RR = 0.68; 95% CI = 0.54-0.85; I2 = 71%) and recurrent cardiovascular hospitalizations (RR = 0.71; 95% CI = 0.59-0.86; I2 = 56%). However, FCM had no significant effect on the risk of all-cause (OR = 0.97; 95% CI = 0.73-1.28; I2 = 0%) or cardiovascular mortality (OR = 0.93; 95% CI = 0.69-1.27; I2 = 0%).
    CONCLUSIONS: Ferric carboxymaltose reduces heart failure hospitalizations and cardiovascular hospitalizations with no beneficial effect on all-cause and cardiovascular mortality in iron-deficient heart failure patients. These findings reinforce the role of FCM as a therapeutic option in heart failure patients.
    Keywords:  Heart failure; Iron deficiency; Iron therapy; Meta‐analysis
  11. Eur J Heart Fail. 2021 Feb 16.
      AIMS: We examined the efficacy and safety of dapagliflozin, compared with placebo, according to aetiology in patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).METHODS AND RESULTS: Aetiology was investigator-reported and categorized as ischaemic or non-ischaemic. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. A total of 4,744 patients were randomised in DAPA-HF, of whom 2,674 (56.4%) patients had an ischaemic aetiology. Participants with an ischaemic aetiology had a higher risk of cardiovascular mortality (hazard ratio [HR] 1.35 [95%CI 1.13-1.63]), but lower risk of HF hospitalisation (0.83 [0.70-0.98]) than non-ischaemic patients. Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in both patients with ischaemic and non-ischaemic aetiology (HR 0.77 [95%CI 0.65-0.92] and 0.71 [0.58-0.87], respectively, P for interaction=0.55). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Dapagliflozin, as compared with placebo, increased the proportion of patients with an improvement of KCCQ-TSS of ≥5 points (P for interaction=0.32) and decreased the proportion with a deterioration in KCCQ-TSS of ≥5 points (P for interaction=0.76), irrespective of aetiology. Study drug discontinuation and serious adverse events were similar according to treatment groups, irrespective of aetiology.
    CONCLUSIONS: Dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, similarly in patients with ischaemic and non-ischaemic aetiology. In addition, dapagliflozin was safe and well-tolerated, irrespective of aetiology.
    Keywords:  Heart failure; aetiology; dapagliflozin; randomised trial
  12. Int J Cardiol. 2021 Feb 12. pii: S0167-5273(21)00288-6. [Epub ahead of print]
      BACKGROUND: Few studies investigated the combination of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and angiotensin receptor-neprilysin inhibitors (ARNIs) in patients with heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus (T2DM).METHODS: During 2016 to 2018, patients with HFrEF and T2DM were identified from Chang Gung Research Database; a database deriving from the original electronic medical records of 7 hospitals in Taiwan. They were classified into four subgroups according to the medications received as follows: 1) SGLT2i and ARNI; 2) SGLT2i and no ARNI; 3) ARNI and no SGLT2i; and 4) no SGLT2i and no ARNI. We examined clinical and safety (hyperkalemia and acute renal dysfunction) outcomes over 1-year of follow-up.
    RESULTS: A total of 2312 patients were eligible for analysis, including 169, 285, 338, and 1520 in subgroups 1, 2, 3 and 4, respectively. There were large differences in baseline characteristics and treatments among subgroups. Subgroup 1 had the lowest rates of HF hospitalizations, all-cause death, and the composite of both, and subgroup 4 had the highest event rates. A similar pattern was observed for the safety outcomes. These differences were attenuated after adjusting for differences in baseline variables and therapy.
    CONCLUSIONS: Treatment with a combination of SGLT2i and ARNI was well tolerated in diabetic patients with HFrEF and was associated with lower risk of heart failure hospitalization.
    Keywords:  Angiotensin receptor-neprilysin inhibitors; Heart failure with reduced ejection fraction; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes mellitus
  13. JACC Cardiovasc Interv. 2021 Feb 22. pii: S1936-8798(20)32371-2. [Epub ahead of print]14(4): 398-400
    Keywords:  diabetes; glucose control; hemoglobin A(1c); percutaneous coronary intervention
  14. JAMA Cardiol. 2021 Feb 17.
      Importance: Dapagliflozin has been shown to reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF and reduced ejection fraction (HFrEF). However, clinical inertia often underlies deferred initiation of effective therapies.Objective: To examine timing of onset of clinical benefit with dapagliflozin and magnitude as a function of proximity to prior HF hospitalization.
    Design, Setting, and Participants: This is a secondary analysis of a completed multinational trial. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial was a double-blind, placebo-controlled randomized clinical trial of dapagliflozin in patients with chronic HFrEF (n = 4744). From February 2017 to August 2018, the study enrolled patients in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less; the median (range) follow-up time was 18.2 (0-27.8) months. Hazard ratios (HRs) were calculated for the primary efficacy outcome with dapagliflozin vs placebo by time following randomization. Efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment.
    Exposures: None.
    Main Outcomes and Measures: Composite of cardiovascular death or worsening HF.
    Results: A total of 4744 patients were included (1109 women [23.4%]; mean [SD] age, 66.3 [10.9] years). The reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94]; P = .03). A total of 2251 patients (47.4%) had been previously hospitalized for HF, and 1301 (27.4%) had been hospitalized within 12 months prior to enrollment. Among patients treated with placebo, there was a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjusted P = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively. Across these subgroups, dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84 [95% CI, 0.69-1.01]), 27% (HR, 0.73 [95% CI, 0.54-0.99]), and 36% (HR, 0.64 [95% CI, 0.51-0.80]), respectively (P = .07 for trend). Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, -1.9% to 6.1%), 4.1% (95% CI, -3.6% to 11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend).
    Conclusions and Relevance: In this study, treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin.
    Trial Registration: Identifier NCT03036124.
  15. PET Clin. 2021 Feb 12. pii: S1556-8598(20)30105-X. [Epub ahead of print]
      This article provides a review of the latest radiotracers for planar/single-photon emission computed tomography (SPECT) and positron emission tomography (PET)/computed tomography (CT) imaging of cardiac amyloidosis, detailing their affinity, specificity, and sensitivity for cardiac amyloidosis. There are several tracers available that have differing affinities for transthyretin (ATTR) and immunoglobulin light chain (AL), and new developments in technology have allowed for disease burden quantification. Bone scintigraphy is an excellent option for visualizing ATTR cardiac amyloidosis. Negative testing does not exclude the possibility of AL cardiac amyloidosis and absolute quantitation of amyloid burden is limited.
    Keywords:  Cardiac amyloidosis; Molecular imaging; PET; SPECT
  16. Eur J Heart Fail. 2021 Feb;23 Suppl 1 3-13