bims-hafaim Biomed News
on Heart Failure Metabolism
Issue of 2021‒03‒28
eleven papers selected by
Kyle McCommis
Saint Louis University

  1. Sci Rep. 2021 Mar 24. 11(1): 6722
      Prognosis of severe heart failure remains poor. Urgent new therapies are required. Some heart failure patients do not respond to established multidisciplinary treatment and are classified as "non-responders". The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Mitofusin-1 (Mfn1), a mitochondrial fusion protein, is significantly reduced in non-responding patients. This study aimed to elucidate the role of Mfn1 in the failing heart. Twenty-two idiopathic dilated cardiomyopathy (IDCM) patients who underwent endomyocardial biopsy of intraventricular septum were included. Of the 22 patients, 8 were non-responders (left ventricular (LV) ejection fraction (LVEF) of < 10% improvement at late phase follow-up). Electron microscopy (EM), quantitative PCR, and immunofluorescence studies were performed to explore the biological processes and molecules involved in failure to respond. Studies in cardiac specific Mfn1 knockout mice (c-Mfn1 KO), and in vitro studies with neonatal rat ventricular myocytes (NRVMs) were also conducted. A significant reduction in mitochondrial size in cardiomyocytes, and Mfn1, was observed in non-responders. A LV pressure overload with thoracic aortic constriction (TAC) c-Mfn1 KO mouse model was generated. Systolic function was reduced in c-Mfn1 KO mice, while mitochondria alteration in TAC c-Mfn1 KO mice increased. In vitro studies in NRVMs indicated negative regulation of Mfn1 by the β-AR/cAMP/PKA/miR-140-5p pathway resulting in significant reduction in mitochondrial respiration of NRVMs. The level of miR140-5p was increased in cardiac tissues of non-responders. Mfn1 is a biomarker of heart failure in non-responders. Therapies targeting mitochondrial dynamics and homeostasis are next generation therapy for non-responding heart failure patients.
  2. J Lipid Res. 2021 Mar 20. pii: S0022-2275(21)00051-1. [Epub ahead of print] 100069
      Long-chain fatty acid oxidation is frequently impaired in primary and systemic metabolic diseases affecting the heart, thus therapeutically increasing reliance on normally minor energetic substrates, such as ketones and medium chain fatty acids, could benefit cardiac health. However, the molecular fundamentals of this therapy are not fully known. Here, we explored the ability of octanoate, an eight-carbon medium-chain fatty acid known as an unregulated mitochondrial energetic substrate, to ameliorate cardiac hypertrophy in long-chain fatty acid oxidation deficient hearts due to carnitine palmitoyltransferase 2 deletion (Cpt2M-/-). CPT2 converts acylcarnitines to acyl-CoAs in the mitochondrial matrix for oxidative bioenergetic metabolism. In Cpt2M-/- mice, high octanoate-ketogenic diet failed to alleviate myocardial hypertrophy, dysfunction, and acylcarnitine accumulation suggesting that this alternative substrate is not sufficiently compensatory for energy provision. Aligning this outcome, we identified a major metabolic distinction between muscles and liver, wherein heart and skeletal muscle mitochondria were unable to oxidize free octanoate but liver was able to oxidize free octanoate. Liver mitochondria, but not heart or muscle, highly expressed medium-chain acyl-CoA synthetases, potentially enabling octanoate activation for oxidation and circumventing acylcarnitine-shuttling. Conversely, octanoylcarnitine was oxidized by liver, skeletal muscle, and heart, with rates in heart 4-fold greater than liver and, in muscles, was not dependent upon CPT2. Together, these data suggest that dietary octanoate cannot rescue CPT2-deficient cardiac disease. These data also suggest the existence of tissue-specific mechanisms for octanoate oxidative metabolism, with liver being independent of free carnitine availability while cardiac and skeletal muscles depend on carnitine but not on CPT2.
    Keywords:  carnitine palmitoyltransferase; carnitine-shuttle; fatty acid oxidation; medium-chain fatty acids; mitochondria
  3. Cardiovasc Res. 2021 Mar 22. pii: cvab112. [Epub ahead of print]
      AIMS: Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure.METHODS AND RESULTS: RT-qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5-/-). Before manifesting cardiac dysfunction, Atg5-/- mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5-/- cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5-/- cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload.
    CONCLUSION: Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.
    Keywords:  autophagy; beta-adrenergic signalling; calcium; cardiomyocytes; mitochondria
  4. Cardiovasc Res. 2021 Mar 22. pii: cvab111. [Epub ahead of print]
      AIMS: Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor for endogenous medium/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress.METHODS AND RESULTS: In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodeling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-days post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signaling and oxylipin synthesis as well as reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signaling-deficient Ffar4 R270H polymorphism correlated with eccentric remodeling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC.
    CONCLUSIONS: Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.
    Keywords:  (cPLA2α); 18-hydroxyeicosapentaenoic acid (18-HEPE); Free fatty acid receptor 4 (Ffar4); GPR120; cytoplasmic phospholipase A2α; eicosapentaenoic acid (EPA); heart failure
  5. Oxid Med Cell Longev. 2021 ;2021 5545261
      Mitochondrial dysfunction has been suggested to be the key factor in the development and progression of cardiac hypertrophy. The onset of mitochondrial dysfunction and the mechanisms underlying the development of cardiac hypertrophy (CH) are incompletely understood. The present study is based on the use of multiple bioinformatics analyses for the organization and analysis of scRNA-seq and microarray datasets from a transverse aortic constriction (TAC) model to examine the potential role of mitochondrial dysfunction in the pathophysiology of CH. The results showed that NADH:ubiquinone oxidoreductase core subunit S1- (Ndufs1-) dependent mitochondrial dysfunction plays a key role in pressure overload-induced CH. Furthermore, in vivo animal studies using a TAC mouse model of CH showed that Ndufs1 expression was significantly downregulated in hypertrophic heart tissue compared to that in normal controls. In an in vitro model of angiotensin II- (Ang II-) induced cardiomyocyte hypertrophy, Ang II treatment significantly downregulated the expression of Ndufs1 in cardiomyocytes. In vitro mechanistic studies showed that Ndufs1 knockdown induced CH; decreased the mitochondrial DNA content, mitochondrial membrane potential (MMP), and mitochondrial mass; and increased the production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes. On the other hand, Ang II treatment upregulated the expression levels of atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain beta; decreased the mitochondrial DNA content, MMP, and mitochondrial mass; and increased mitochondrial ROS production in cardiomyocytes. The Ang II-mediated effects were significantly attenuated by overexpression of Ndufs1 in rat cardiomyocytes. In conclusion, our results demonstrate downregulation of Ndufs1 in hypertrophic heart tissue, and the results of mechanistic studies suggest that Ndufs1 deficiency may cause mitochondrial dysfunction in cardiomyocytes, which may be associated with the development and progression of CH.
  6. Am J Physiol Cell Physiol. 2021 Mar 24.
      The nuclear genome-encoded mitochondrial DNA (mtDNA) transcription factor A (TFAM) is indispensable for mitochondrial energy production in the developing and postnatal heart; a similar role for TFAM is inferred in adult heart. Here, we provide evidence that challenges this long-standing paradigm. Unexpectedly, conditionalTfam ablation in vivo in adult mouse cardiomyocytes resulted in a prolonged period of functional resilience characterized by preserved mtDNA content, mitochondrial function, and cardiac function, despite mitochondrial structural alterations and decreased transcript abundance. Remarkably, TFAM protein levels did not directly dictate mtDNA content in the adult heart, and mitochondrial translation was preserved with acute TFAM inactivation, suggesting maintenance of respiratory chain assembly/function. Long-term Tfam inactivation, however, downregulated the core mtDNA transcription and replication machinery, leading to mitochondrial dysfunction and cardiomyopathy. Collectively, in contrast to the developing heart, these data reveal a striking resilience of the differentiated adult heart to acute insults to mtDNA regulation.
    Keywords:  heart; mitochondria; mtDNA
  7. Eur J Pharmacol. 2021 Mar 22. pii: S0014-2999(21)00166-7. [Epub ahead of print] 174013
      RATIONALE: Higenamine (HG), is one of the main active components in many widely used Chinese herbs, and a common ingredient of health products in Europe and North America. Several groups, including our own, have previously shown the beneficial effects of HG against cardiomyocyte death during acute ischemic damage. However, the effect of HG on chronic cardiac remodeling, such as cardiac fibrosis, remains unknown.OBJECTIVE: Herein, we aim to investigate the role of HG in cardiac fibrosis in vivo as well as its cellular and molecular mechanisms.
    METHODS AND RESULTS: Chronic pressure overload with transverse aortic constriction (TAC) significantly increased cardiac hypertrophy, fibrosis, and cardiac dysfunction in mice, which were significantly attenuated by HG. Consistently, cardiac fibrosis induced by the chronic infusion of isoproterenol (ISO), was also significantly reduced by HG. Interestingly, our results showed that HG had no effect on adult mouse CM hypertrophy in vitro. However, HG suppressed the activation of cardiac fibroblasts (CFs) in vitro. Furthermore, TGF-β-induced expression of ACTA2, a marker of fibroblast activation, was significantly suppressed by HG. Concomitantly, HG inhibited TGF-β-induced phosphorylation of Smad2/3 in CFs. HG also reduced the expression of extracellular matrix molecules such as collagen I and collagen III. To our surprise, the inhibitory effect of HG on CFs activation was independent of the activation of the beta2 adrenergic receptor (β2-AR) that is known to mediate the effect of HG on antagonizing CMs apoptosis.
    CONCLUSION: Our findings suggest that HG ameliorates pathological cardiac fibrosis and dysfunction at least partially by suppressing TGF-β/Smad signaling and CFs activation.
    Keywords:  Cardiac fibrosis · Cardiac fibroblast · Higenamine · TGF-β/Smad
  8. ESC Heart Fail. 2021 Mar 21.
      AIMS: This study aimed to determine the effects of sodium-glucose cotransporter-2 inhibitor (SGLT2i) in heart failure with reduced ejection fraction (HFrEF), compare the effect of SGLT2i with angiotensin receptor neprilysin inhibitor (ARNI), and find whether combination of SGLT2i and ARNI is better than monotherapy.METHODS AND RESULTS: Embase, Medline, and Cochrane Central Registry of Controlled Trials were searched for randomized controlled trials evaluating SGLT2i or ARNI in HFrEF. And a total of six trials were included. SGLT2i was found to significantly reduce the risk of cardiovascular death or hospitalization for heart failure by 27% [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.67-0.80], hospitalization for heart failure by 31% (HR 0.69, 95% CI 0.62-0.77), cardiovascular death by 16% (HR 0.84, 95% CI 0.74-0.95), and all-cause death by 16% (HR 0.84, 95% CI 0.75-0.94) in HFrEF only with a statistically higher risk of genital infection (risk ratio (RR) 2.78, 95% CI 1.46-5.29). The reduction in cardiovascular death or hospitalization for heart failure was of similar magnitude in patients with or without diabetes mellitus (HR 0.71, 95% CI 0.64-0.80 vs. HR 0.75, 95% CI 0.65-0.87) using SGLT2i. Indirect treatment comparison showed that SGLT2i and ARNI had similar effects on primary outcome (HR 0.93, 95% CI 0.82-1.06). And combination of SGLT2i and ARNI achieved a better prognosis performance (HR 0.68, 95% CI 0.53-0.89) compared with ARNI monotherapy.
    CONCLUSIONS: SGLT2i could safely reduce cardiovascular death or hospitalization for heart failure in HFrEF regardless of diabetes mellitus status. SGLT2i and ARNI demonstrate similar effects, while combination of SGLT2i and ARNI results in a better cardiovascular protective effect.
    Keywords:  Angiotensin receptor neprilysin inhibitor; Heart failure with reduced ejection fraction; Meta-analysis; Sodium-glucose cotransporter-2 inhibitor
  9. Vnitr Lek. 2021 ;67(1): 43-47
      Type 2 diabetes mellitus (T2DM) is common in patients with chronic heart failure and is associated with high morbidity and mortality. Significant advances have recently occured in the treatment of diabetes mellitus type 2 (T2DM) and cardiovascular diseases. Several new glucose lowering drugs have shown either neutral or positive cardiovascular effect especially on hospitalisations, but also on mortality. Some of these drugs have safety characteristics with strong practical implication in heart failure, for example sodium-glucose co-transporters type 2 inhibitors (SGLT-2). Position paper of the European Society of Cardiology/Heart Failure Association was published in October 2019 and in June 2020. The results of EMPEROR reduced study were presented on European congress in september 2020. In this phase III, placebo-controlled trial, 3730 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less were randomly assigned to receive either empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Over a median of 16 months, the primary outcome (cardiovascular mortality and hospitalisation for heart failure) occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P.
    Keywords:  SGLT2 inhibitors; empagliflozin; heart failure.
  10. PLoS One. 2021 ;16(3): e0248554
      Mitochondrial dynamics is a possible modulator of myocardial ischemia/reperfusion injuries (IRI). We previously reported that mice partially deficient in the fusion protein OPA1 exhibited higher IRI. Therefore, we investigated whether deficiency in the fission protein DRP1 encoded by Dnm1l gene would affect IRI in Dnm1l+/- mouse. After baseline characterization of the Dnm1l+/- mice heart, using echocardiography, electron microscopy, and oxygraphy, 3-month-old Dnm1l+/- and wild type (WT) mice were exposed to myocardial ischemia/reperfusion (I/R). The ischemic area-at-risk (AAR) and area of necrosis (AN) were delimited, and the infarct size was expressed by AN/AAR. Proteins involved in mitochondrial dynamics and autophagy were analyzed before and after I/R. Mitochondrial permeability transition pore (mPTP) opening sensitivity was assessed after I/R. Heart weight and left ventricular function were not significantly different in 3-, 6- and 12-month-old Dnm1l+/- mice than in WT. The cardiac DRP1 protein expression levels were 60% lower, whereas mitochondrial area and lipid degradation were significantly higher in Dnm1l+/- mice than in WT, though mitochondrial respiratory parameters and mPTP opening did not significantly differ. Following I/R, the infarct size was significantly smaller in Dnm1l+/- mice than in WT (34.6±3.1% vs. 44.5±3.3%, respectively; p<0.05) and the autophagic markers, LC3 II and P62 were significantly increased compared to baseline condition in Dnm1l+/- mice only. Altogether, data indicates that increasing fusion by means of Dnm1l deficiency was associated with protection against IRI, without alteration in cardiac or mitochondrial functions at basal conditions. This protection mechanism due to DRP1 haploinsufficiency increases the expression of autophagic markers.
  11. Sci Rep. 2021 Mar 22. 11(1): 6498
      In patients with cardiovascular disorders, blood total ketone body (TKB) levels increase with worsening heart failure and are consumed as an alternative fuel to fatty acid and glucose. We investigated factors contributing to the increase in the blood TKB levels in patients with cardiovascular disorders. The study population consisted of 1030 consecutive patients who underwent cardiac catheterization. Covariance structure analyses were performed to clarify the direct contribution of hemodynamic parameters, including the left ventricular end-diastolic pressure (LVEDP), left ventricular end-systolic volume index (LVESVI), left ventricular end-diastolic volume index (LVEDVI), and B-type natriuretic peptide (BNP) levels, to TKB by excluding other confounding factors. These analyses showed that the TKB levels were significantly associated with the BNP level (P = 0.003) but not the LVEDP, LVESVI, or LVEDVI levels. This was clearly demonstrated on a two-dimensional contour line by Bayesian structure equation modeling. The TKB level was positively correlated with the BNP level, but not LVEDP, LVESVI or LVEDVI. These findings suggested that elevated blood TKB levels were more strongly stimulated by the increase in BNP than by hemodynamic deterioration. BNP might induce the elevation of TKB levels for use as an important alternative fuel in the failing heart.