bims-hafaim 2023-05-28 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023–05–28
seven papers selected by
Kyle McCommis, Saint Louis University

Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges.
The metabolic state of the heart regulates mitochondrial supercomplex abundance in mice.
Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER.
Integrated Control of Fatty Acid Metabolism in Heart Failure.
Dapagliflozin and diuretic utilization in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.
Distinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity Cardiomyopathy.
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.

Nat Rev Cardiol. 2023 May 26.

Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges.

Julia Ritterhoff, Rong Tian.

Cardiac metabolism is vital for heart function. Given that cardiac contraction requires a continuous supply of ATP in large quantities, the role of fuel metabolism in the heart has been mostly considered from the perspective of energy production. However, the consequence of metabolic remodelling in the failing heart is not limited to a compromised energy supply. The rewired metabolic network generates metabolites that can directly regulate signalling cascades, protein function, gene transcription and epigenetic modifications, thereby affecting the overall stress response of the heart. In addition, metabolic changes in both cardiomyocytes and non-cardiomyocytes contribute to the development of cardiac pathologies. In this Review, we first summarize how energy metabolism is altered in cardiac hypertrophy and heart failure of different aetiologies, followed by a discussion of emerging concepts in cardiac metabolic remodelling, that is, the non-energy-generating function of metabolism. We highlight challenges and open questions in these areas and finish with a brief perspective on how mechanistic research can be translated into therapies for heart failure.

DOI: https://doi.org/10.1038/s41569-023-00887-x
Redox Biol. 2023 May 15. pii: S2213-2317(23)00141-6. [Epub ahead of print]63 102740

The metabolic state of the heart regulates mitochondrial supercomplex abundance in mice.

Yuting Zheng, Andrew A Gibb, Hongkai Xu, Siqi Liu, Bradford G Hill.

  Mitochondrial supercomplexes are observed in mammalian tissues with high energy demand and may influence metabolism and redox signaling. Nevertheless, the mechanisms that regulate supercomplex abundance remain unclear. In this study, we examined the composition of supercomplexes derived from murine cardiac mitochondria and determined how their abundance changes with substrate provision or by genetically induced changes to the cardiac glucose-fatty acid cycle. Protein complexes from digitonin-solubilized cardiac mitochondria were resolved by blue-native polyacrylamide gel electrophoresis and were identified by mass spectrometry and immunoblotting to contain constituents of Complexes I, III, IV, and V as well as accessory proteins involved in supercomplex assembly and stability, cristae architecture, carbohydrate and fat oxidation, and oxidant detoxification. Respiratory analysis of high molecular mass supercomplexes confirmed the presence of intact respirasomes, capable of transferring electrons from NADH to O2. Provision of respiratory substrates to isolated mitochondria augmented supercomplex abundance, with fatty acyl substrate (octanoylcarnitine) promoting higher supercomplex abundance than carbohydrate-derived substrate (pyruvate). Mitochondria isolated from transgenic hearts that express kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (GlycoLo), which decreases glucose utilization and increases reliance on fatty acid oxidation for energy, had higher mitochondrial supercomplex abundance and activity compared with mitochondria from wild-type or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-expressing hearts (GlycoHi), the latter of which encourages reliance on glucose catabolism for energy. These findings indicate that high energetic reliance on fatty acid catabolism bolsters levels of mitochondrial supercomplexes, supporting the idea that the energetic state of the heart is regulatory factor in supercomplex assembly or stability.

Keywords:  Glycolysis; Heart; Metabolism; Mitochondria; Respirasome; Supercomplex

DOI:  https://doi.org/10.1016/j.redox.2023.102740
Eur Heart J. 2023 May 23. pii: ehad276. [Epub ahead of print]

Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER.

Jawad H Butt, Toru Kondo, Mingming Yang, Pardeep S Jhund, Kieran F Docherty, Muthiah Vaduganathan, Brian L Claggett, Adrian F Hernandez, Carolyn S P Lam, Silvio E Inzucchi, Felipe A Martinez, Rudolf A de Boer, Mikhail N Kosiborod, Akshay S Desai, Lars Køber, Piotr Ponikowski, Marc S Sabatine, Sanjiv J Shah, Natalia Zaozerska, Ulrica Wilderäng, Olof Bengtsson, Scott D Solomon, John J V McMurray.

   AIMS: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation.
METHODS AND RESULTS: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD.
CONCLUSION: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

Keywords:  Amputation; Clinical trial; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Peripheral artery disease

DOI:  https://doi.org/10.1093/eurheartj/ehad276
Metabolites. 2023 Apr 29. pii: 615. [Epub ahead of print]13(5):

Integrated Control of Fatty Acid Metabolism in Heart Failure.

Xiaoting Li, Xukun Bi.

  Disrupted fatty acid metabolism is one of the most important metabolic features in heart failure. The heart obtains energy from fatty acids via oxidation. However, heart failure results in markedly decreased fatty acid oxidation and is accompanied by the accumulation of excess lipid moieties that lead to cardiac lipotoxicity. Herein, we summarized and discussed the current understanding of the integrated regulation of fatty acid metabolism (including fatty acid uptake, lipogenesis, lipolysis, and fatty acid oxidation) in the pathogenesis of heart failure. The functions of many enzymes and regulatory factors in fatty acid homeostasis were characterized. We reviewed their contributions to the development of heart failure and highlighted potential targets that may serve as promising new therapeutic strategies.

Keywords:  cardiac lipotoxicity; fatty acid homeostasis; heart failure

DOI:  https://doi.org/10.3390/metabo13050615
Eur Heart J. 2023 May 23. pii: ehad283. [Epub ahead of print]

Dapagliflozin and diuretic utilization in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.

Safia Chatur, Muthiah Vaduganathan, Brian Claggett, Orly Vardeny, Akshay S Desai, Pardeep S Jhund, Rudolf A de Boer, Carolyn S P Lam, Mikhail N Kosiborod, Sanjiv J Shah, Felipe Martinez, Silvio E Inzucchi, Adrian F Hernandez, Tariq Haddad, Sumeet S Mitter, Zi Michael Miao, Magnus Petersson, Anna Maria Langkilde, John J V McMurray, Scott D Solomon.

   AIMS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated.
METHODS AND RESULTS: In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001).
CONCLUSION: In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.

Keywords:  SGLT2i; diuretics; heart failure with mildly reduced ejection fraction; heart failure with preserved ejection fraction

DOI:  https://doi.org/10.1093/eurheartj/ehad283
Circ Res. 2023 May 26.

Distinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity Cardiomyopathy.

Mingming Tong, Risa Mukai, Satvik Mareedu, Peiyong Zhai, Shin-Ichi Oka, Chun-Yang Huang, Chiao-Po Hsu, Fawad A K Yousufzai, Luke Fritzky, Wataru Mizushima, Gopal J Babu, Junichi Sadoshima.

   RATIONALE: Obesity induces cardiomyopathy characterized by hypertrophy and diastolic dysfunction. Whereas mitophagy mediated through an Atg7-dependent mechanism serves as an essential mechanism to maintain mitochondrial quality during the initial development of obesity cardiomyopathy, Rab9-dependent alternative mitophagy takes over the role during the chronic phase. Although it has been postulated that DRP1 (dynamin-related protein 1)-mediated mitochondrial fission and consequent separation of the damaged portions of mitochondria are essential for mitophagy, the involvement of DRP1 in mitophagy remains controversial.
OBJECTIVE: We investigated whether endogenous DRP1 is essential in mediating the 2 forms of mitophagy during high-fat diet (HFD)-induced obesity cardiomyopathy and, if so, what the underlying mechanisms are.
METHODS AND RESULTS: Mice were fed either a normal diet or an HFD (60 kcal %fat). Mitophagy, evaluated with Mito-Keima, was increased after 3 weeks of HFD consumption. The induction of mitophagy by HFD consumption was completely abolished in tamoxifen-inducible cardiac-specific Drp1knockout (Drp1 MCM) mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. The increase in LC3-dependent general autophagy and colocalization between LC3 and mitochondrial proteins was abolished in Drp1 MCM mice. Activation of alternative mitophagy was also completely abolished in Drp1 MCM mice during the chronic phase of HFD consumption. DRP1 was phosphorylated at Ser616, localized at the mitochondria-associated membranes, and associated with Rab9 and Fis1 only during the chronic, but not acute, phase of HFD consumption.
CONCLUSIONS: DRP1 is an essential factor in mitochondrial quality control during obesity cardiomyopathy that controls multiple forms of mitophagy. Although DRP1 regulates conventional mitophagy through a mitochondria-associated membrane-independent mechanism during the acute phase, it acts as a component of the mitophagy machinery at the mitochondria-associated membranes in alternative mitophagy during the chronic phase of HFD consumption.

Keywords:  diet, high-fat; mice, knockout; mitochondria; mitophagy; obesity cardiomyopathy

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.322512
Int J Mol Sci. 2023 May 11. pii: 8632. [Epub ahead of print]24(10):

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.

Federica Conte, Juda-El Sam, Dirk J Lefeber, Robert Passier.

  Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.

Keywords:  arrhythmogenic disorders; cardiomyopathies; congenital disorders of glycosylation; congenital heart disease; disorders of pentose phosphate pathway; disorders of sugar transporters; glycogen storage disorders; heart failure; inborn errors of metabolism; lysosomal storage disorders

DOI:  https://doi.org/10.3390/ijms24108632