bims-hafaim 2022-07-31 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–07–31
nine papers selected by
Kyle McCommis, Saint Louis University

Effects of Dapagliflozin According to the Heart Failure Collaboratory Medical Therapy Score: Insights From DAPA-HF.
GDH promotes isoprenaline-induced cardiac hypertrophy by activating mTOR signaling via elevation of α-ketoglutarate level.
Endosomal v-ATPase as a Sensor Determining Myocardial Substrate Preference.
Short-Chain Fatty Acids in the Metabolism of Heart Failure - Rethinking the Fat Stigma.
TRPV1 Protects Against Pressure Overload-Induced Cardiac Hypertrophy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes.
Opposing effects of genetic variation in MTCH2 for obesity versus heart failure.
Reversible Thiol Oxidation Increases Mitochondrial Electron Transport Complex Enzyme Activity but Not Respiration in Cardiomyocytes from Patients with End-Stage Heart Failure.
Understanding How Heart Metabolic Derangement Shows Differential Stage Specificity for Heart Failure with Preserved and Reduced Ejection Fraction.
Dapagliflozin Protects Methamphetamine-Induced Cardiomyopathy by Alleviating Mitochondrial Damage and Reducing Cardiac Function Decline in a Mouse Model.

JACC Heart Fail. 2022 Aug;pii: S2213-1779(22)00246-3. [Epub ahead of print]10(8): 543-555

Effects of Dapagliflozin According to the Heart Failure Collaboratory Medical Therapy Score: Insights From DAPA-HF.

Jawad H Butt, Pooja Dewan, Ersilia M DeFilippis, Tor Biering-Sørensen, Kieran F Docherty, Pardeep S Jhund, Mikhail N Kosiborod, Felipe A Martinez, Olof Bengtsson, Niklas Dyrby Johansen, Anna Maria Langkilde, Mikaela Sjöstrand, Muthiah Vaduganathan, Scott D Solomon, Marc S Sabatine, Lars Køber, Mona Fiuzat, John J V McMurray.

   BACKGROUND: The Heart Failure Collaboratory (HFC) has developed a score integrating classes and doses of guideline-directed medical therapies prescribed for patients with heart failure (HF) and reduced ejection fraction. One potential use of this score is to test whether new treatments demonstrate incremental benefits, even in patients receiving comprehensive guideline-directed medical therapy.
OBJECTIVES: The authors investigated the efficacy of dapagliflozin according to a modified HFC score in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.
METHODS: In DAPA-HF, 4,744 patients with HF and reduced ejection fraction were randomized to dapagliflozin or placebo. The modified HFC score accounted for race and electrocardiogram rhythm and rate, with a maximum possible score of 100%. The primary outcome was the composite of worsening HF or cardiovascular death.
RESULTS: The median modified HFC score was 50% (IQR: 27.5%-62.5%; range 0%-100%). Compared with the lowest tertile, the highest tertile of the treatment score was associated with a lower risk of worsening HF or cardiovascular death (tertile 1, reference; tertile 2, HR: 0.97 [95% CI: 0.82-1.14]; tertile 3, HR: 0.83 [95% CI: 0.70-0.99]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of treatment score (the HRs for dapagliflozin vs placebo from tertile 1 to 3 were: 0.76 [95% CI: 0.61-0.94], 0.76 [95% CI: 0.60-0.97], and 0.71 [95% CI: 0.55-0.90]), respectively; Pinteraction = 0.89). Consistent benefits were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TTS).
CONCLUSIONS: Dapagliflozin, compared with placebo, improved all outcomes examined, regardless of the modified HFC score. This score can be easily calculated in clinical trials and used to evaluate the incremental effects of new treatments. (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:  Heart Failure Collaboratory (HFC); clinical trial; dapagliflozin; heart failure

DOI:  https://doi.org/10.1016/j.jchf.2022.03.009
Naunyn Schmiedebergs Arch Pharmacol. 2022 Jul 29.

GDH promotes isoprenaline-induced cardiac hypertrophy by activating mTOR signaling via elevation of α-ketoglutarate level.

Zhi-Rong Lin, Zhen-Zhen Li, Yan-Jun Cao, Wen-Jing Yu, Jian-Tao Ye, Pei-Qing Liu.

  Numerous studies reveal that metabolism dysfunction contributes to the development of pathological cardiac hypertrophy. While the abnormal lipid and glucose utilization in cardiomyocytes responding to hypertrophic stimuli have been extensively studied, the alteration and implication of glutaminolysis are rarely discussed. In the present work, we provide the first evidence that glutamate dehydrogenase (GDH), an enzyme that catalyzes conversion of glutamate into ɑ-ketoglutarate (AKG), participates in isoprenaline (ISO)-induced cardiac hypertrophy through activating mammalian target of rapamycin (mTOR) signaling. The expression and activity of GDH were enhanced in cultured cardiomyocytes and rat hearts following ISO treatment. Overexpression of GDH, but not its enzymatically inactive mutant, provoked cardiac hypertrophy. In contrast, GDH knockdown could relieve ISO-triggered hypertrophic responses. The intracellular AKG level was elevated by ISO or GDH overexpression, which led to increased phosphorylation of mTOR and downstream effector ribosomal protein S6 kinase (S6K). Exogenous supplement of AKG also resulted in mTOR activation and cardiomyocyte hypertrophy. However, incubation with rapamycin, an mTOR inhibitor, attenuated hypertrophic responses in cardiomyocytes. Furthermore, GDH silencing protected rats from ISO-induced cardiac hypertrophy. These findings give a further insight into the role of GDH in cardiac hypertrophy and suggest it as a potential target for hypertrophy-related cardiomyopathy.

Keywords:  Cardiac hypertrophy; Glutamate dehydrogenase; Isoprenaline; mTOR signaling; ɑ-ketoglutarate

DOI:  https://doi.org/10.1007/s00210-022-02252-0
Metabolites. 2022 Jun 22. pii: 579. [Epub ahead of print]12(7):

Endosomal v-ATPase as a Sensor Determining Myocardial Substrate Preference.

Shujin Wang, Yinying Han, Miranda Nabben, Dietbert Neumann, Joost J F P Luiken, Jan F C Glatz.

  The heart is a metabolically flexible omnivore that can utilize a variety of substrates for energy provision. To fulfill cardiac energy requirements, the healthy adult heart mainly uses long-chain fatty acids and glucose in a balanced manner, but when exposed to physiological or pathological stimuli, it can switch its substrate preference to alternative substrates such as amino acids (AAs) and ketone bodies. Using the failing heart as an example, upon stress, the fatty acid/glucose substrate balance is upset, resulting in an over-reliance on either fatty acids or glucose. A chronic fuel shift towards a single type of substrate is linked with cardiac dysfunction. Re-balancing myocardial substrate preference is suggested as an effective strategy to rescue the failing heart. In the last decade, we revealed that vacuolar-type H+-ATPase (v-ATPase) functions as a key regulator of myocardial substrate preference and, therefore, as a novel potential treatment approach for the failing heart. Fatty acids, glucose, and AAs selectively influence the assembly state of v-ATPase resulting in modulation of its proton-pumping activity. In this review, we summarize these novel insights on v-ATPase as an integrator of nutritional information. We also describe its exploitation as a therapeutic target with focus on supplementation of AA as a nutraceutical approach to fight lipid-induced insulin resistance and contractile dysfunction of the heart.

Keywords:  CD36; GLUT4; amino acids; endosomal acidification; glucose; heart; lipid; vacuolar-type H+-ATPase

DOI:  https://doi.org/10.3390/metabo12070579
Front Cardiovasc Med. 2022 ;9 915102

Short-Chain Fatty Acids in the Metabolism of Heart Failure - Rethinking the Fat Stigma.

Constantin L Palm, Kirsten T Nijholt, Barbara M Bakker, B Daan Westenbrink.

  Heart failure (HF) remains a disease with immense global health burden. During the development of HF, the myocardium and therefore cardiac metabolism undergoes specific changes, with decreased long-chain fatty acid oxidation and increased anaerobic glycolysis, diminishing the overall energy yield. Based on the dogma that the failing heart is oxygen-deprived and on the fact that carbohydrates are more oxygen-efficient than FA, metabolic HF drugs have so far aimed to stimulate glucose oxidation or inhibit FA oxidation. Unfortunately, these treatments have failed to provide meaningful clinical benefits. We believe it is time to rethink the concept that fat is harmful to the failing heart. In this review we discuss accumulating evidence that short-chain fatty acids (SCFAs) may be an effective fuel for the failing heart. In contrast to long-chain fatty acids, SCFAs are readily taken up and oxidized by the heart and could serve as a nutraceutical treatment strategy. In addition, we discuss how SCFAs activate pathways that increase long chain fatty acid oxidation, which could help increase the overall energy availability. Another potential beneficial effect we discuss lies within the anti-inflammatory effect of SCFAs, which has shown to inhibit cardiac fibrosis - a key pathological process in the development of HF.

Keywords:  cardiac fibrosis (CF); fatty acid oxidation (FAO); heart failure; metabolic reprogramming; short-chain fatty acid (SCFA)

DOI:  https://doi.org/10.3389/fcvm.2022.915102
J Cardiovasc Pharmacol. 2022 Jun 27.

TRPV1 Protects Against Pressure Overload-Induced Cardiac Hypertrophy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes.

Yuxiang Wang, Xiuchuan Li, Xiaoli Xu, Xuemei Qu, Yongjian Yang.

ABSTRACT: Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel that mediates the relationship between mitochondrial function and pathological myocardial hypertrophy. However, its underlying mechanisms remain unclear. This study aimed to investigate whether TRPV1 activation improves the morphology and function of intracellular mitochondria to protect cardiomyocytes after pressure overload-induced myocardial hypertrophy. The myocardial hypertrophy model was established by performing transverse aortic constriction (TAC) surgery in C57BL/6J male mice. The data revealed that TRPV1 activation significantly reduced myocardial hypertrophy, promoted ejection fraction (EF) % and fractional shortening (FS) %, and decreased the left ventricular internal diameter in end-diastole (LVIDd) and left ventricular internal diameter in end-systole (LVIDs) after TAC. Moreover, in vitro experiments revealed that TRPV1 reduces cardiomyocyte area and improves mitochondrial function by promoting mitochondria-associated endoplasmic reticulum membranes (MAMs) formation in a phenylephrine (PE)-treated cardiomyocyte hypertrophy model. TRPV1 up-regulates the phosphorylation levels of AMP-activated protein kinase (AMPK) and expression of mitofusin2 (MFN2). TRPV1 function is blocked by single-stranded RNA interfering with silent interfering MFN2. And activation of TRPV1 reduced mitochondrial reactive oxygen species (ROS) caused by PE, while disruption of MAMs by siMFN2 abolished TRPV1-mediated mitochondrial protection. Our findings suggest that TRPV1 effectively protects against pressure overload-induced cardiac hypertrophy by promoting MAM formation and conserved mitochondrial function via the AMPK/MFN2 pathway in cardiomyocytes.

DOI: https://doi.org/10.1097/FJC.0000000000001301
Hum Mol Genet. 2022 Jul 29. pii: ddac176. [Epub ahead of print]

Opposing effects of genetic variation in MTCH2 for obesity versus heart failure.

Julie A Fischer, Tanner O Monroe, Lorenzo L Pesce, Konrad T Sawicki, Mattia Quattrocelli, Rosemary Bauer, Samuel D Kearns, Matthew J Wolf, Megan J Puckelwartz, Elizabeth M McNally.

  Genetic variation in genes regulating metabolism may be advantageous in some settings but not others. The non-failing adult heart relies heavily on fatty acids as a fuel substrate and source of ATP. In contrast, the failing heart favors glucose as a fuel source. A bootstrap analysis for genes with deviant allele frequencies in cardiomyopathy cases versus controls identified the MTCH2 gene as having unusual variation. MTCH2 encodes an outer mitochondrial membrane protein, and prior genome-wide studies associated MTCH2 variants with body mass index, consistent with its role in metabolism. We identified the referent allele of rs1064608 (p.Pro290) as being overrepresented in cardiomyopathy cases compared to controls, and linkage disequilibrium analysis associated this variant with the MTCH2 cis eQTL rs10838738 and lower MTCH2 expression. To evaluate MTCH2, we knocked down Mtch in Drosophila heart tubes which produced a dilated and poorly functioning heart tube, reduced adiposity and shortened life span. Cardiac Mtch mutants generated more lactate at baseline, and they displayed impaired oxygen consumption in the presence of glucose but not palmitate. Treatment of cardiac Mtch mutants with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, reduced lactate and rescued lifespan. Deletion of MTCH2 in human cells similarly impaired oxygen consumption in the presence of glucose but not fatty acids. These data support a model in which MTCH2 reduction may be favorable when fatty acids are the major fuel source, favoring lean body mass. However, in settings like heart failure, where the heart shifts toward using more glucose, reduction of MTCH2 is maladaptive.

Keywords:  MTCH2; glucose; heart failure; lactate; metabolism; mitochondria; obesity; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1093/hmg/ddac176
Cells. 2022 Jul 25. pii: 2292. [Epub ahead of print]11(15):

Reversible Thiol Oxidation Increases Mitochondrial Electron Transport Complex Enzyme Activity but Not Respiration in Cardiomyocytes from Patients with End-Stage Heart Failure.

Ravi A Kumar, Trace Thome, Omar M Sharaf, Terence E Ryan, George J Arnaoutakis, Eric I Jeng, Leonardo F Ferreira.

  Cardiomyocyte dysfunction in patients with end-stage heart failure with reduced ejection fraction (HFrEF) stems from mitochondrial dysfunction, which contributes to an energetic crisis. Mitochondrial dysfunction reportedly relates to increased markers of oxidative stress, but the impact of reversible thiol oxidation on myocardial mitochondrial function in patients with HFrEF has not been investigated. In the present study, we assessed mitochondrial function in ventricular biopsies from patients with end-stage HFrEF in the presence and absence of the thiol-reducing agent dithiothreitol (DTT). Isolated mitochondria exposed to DTT had increased enzyme activity of complexes I (p = 0.009) and III (p = 0.018) of the electron transport system, while complexes II (p = 0.630) and IV (p = 0.926) showed no changes. However, increased enzyme activity did not carry over to measurements of mitochondrial respiration in permeabilized bundles. Oxidative phosphorylation conductance (p = 0.439), maximal respiration (p = 0.312), and ADP sensitivity (p = 0.514) were unchanged by 5 mM DTT treatment. These results indicate that mitochondrial function can be modulated through reversible thiol oxidation, but other components of mitochondrial energy transfer are rate limiting in end-stage HFrEF. Optimal therapies to normalize cardiac mitochondrial respiration in patients with end-stage HFrEF may benefit from interventions to reverse thiol oxidation, which limits complex I and III activities.

Keywords:  HFrEF; bioenergetics; cardiac; heart failure; mitochondria; redox

DOI:  https://doi.org/10.3390/cells11152292
Biomolecules. 2022 Jul 11. pii: 969. [Epub ahead of print]12(7):

Understanding How Heart Metabolic Derangement Shows Differential Stage Specificity for Heart Failure with Preserved and Reduced Ejection Fraction.

Federico Ferro, Renza Spelat, Camilla Valente, Paolo Contessotto.

  Heart failure (HF) is a clinical condition defined by structural and functional abnormalities in the heart that gradually result in reduced cardiac output (HFrEF) and/or increased cardiac pressures at rest and under stress (HFpEF). The presence of asymptomatic individuals hampers HF identification, resulting in delays in recognizing patients until heart dysfunction is manifested, thus increasing the chance of poor prognosis. Given the recent advances in metabolomics, in this review we dissect the main alterations occurring in the metabolic pathways behind the decrease in cardiac function caused by HF. Indeed, relevant preclinical and clinical research has been conducted on the metabolite connections and differences between HFpEF and HFrEF. Despite these promising results, it is crucial to note that, in addition to identifying single markers and reliable threshold levels within the healthy population, the introduction of composite panels would strongly help in the identification of those individuals with an increased HF risk. That said, additional research in the field is required to overcome the current drawbacks and shed light on the pathophysiological changes that lead to HF. Finally, greater collaborative data sharing, as well as standardization of procedures and approaches, would enhance this research field to fulfil its potential.

Keywords:  biomarkers; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; metabolomics; microbiota

DOI:  https://doi.org/10.3390/biom12070969
Front Pharmacol. 2022 ;13 925276

Dapagliflozin Protects Methamphetamine-Induced Cardiomyopathy by Alleviating Mitochondrial Damage and Reducing Cardiac Function Decline in a Mouse Model.

Shanqing He, Yajun Yao, Nan Yang, Youcheng Wang, Dishiwen Liu, Zhen Cao, Huiyu Chen, Yuntao Fu, Mei Yang, Songjun Wang, Guangjie He, Qingyan Zhao.

  Background: Methamphetamine (METH)-induced cardiovascular toxicity has been attributed to its destructive effect on mitochondrial function at least to some extent. Previous studies highlighted the benefits of dapagliflozin (DAPA) on the cardiovascular system, but the response of METH-induced cardiomyopathy to DAPA is never addressed before. The present study aimed to investigate the potential ability of DAPA in preventing METH-induced cardiomyopathy. Materials and Methods: C57BL/6 mice were randomly divided into control group (n = 24), METH group (n = 24), and METH + DAPA group (n = 24). The METH-induced cardiomyopathy group received intraperitoneal METH injections at gradually increasing doses thrice weekly for 14 weeks. Mice in the METH + DAPA group were simultaneously treated with DAPA 1 mg/kg/day by intragastric administration. Echocardiography was performed to assess cardiac function. Reactive oxygen species (ROS), JC-1, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were performed to evaluate oxidative stress, mitochondrial damage, and apoptosis, respectively. Mitochondrial and apoptosis-related protein expression was measured by western blotting. Results: Mice exposed to METH exhibited reduced cardiac function (left ventricular ejection fraction [LVEF]: 56.51 ± 6.49 vs. 73.62 ± 1.42, p < 0.01), fibrotic remodeling, and mitochondrial dysfunction, leading to apoptosis (apoptotic cells%: 7.4 ± 1.3 vs. 1.3 ± 0.5, p < 0.01). DAPA significantly reduced mitochondrial dynamics and function, ROS, apoptosis (apoptotic cells%: 2.4 ± 0.8 vs. 7.4 ± 1.3, p < 0.01), cardiac function decline (LVEF: 70.99 ± 4.936 vs. 56.51 ± 6.49, p < 0.01), and fibrotic remodeling. These results indicated that DAPA could be considered as an effective therapeutic agent in the protection against METH-associated cardiomyopathy. Conclusion: DAPA protects against METH-induced cardiomyopathy in mice by decreasing mitochondrial damage and apoptosis.

Keywords:  apoptosis; cardiomyopathy; dapagliflozin; methamphetamine; mitochondrial

DOI:  https://doi.org/10.3389/fphar.2022.925276