bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2022‒12‒11
six papers selected by
Kyle McCommis
Saint Louis University
  1. Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved.
  2. dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.
  3. Multi-omics analyses identify molecular signatures with prognostic values in different heart failure aetiologies.
  4. Empagliflozin, irrespective of blood pressure, improves outcomes in heart failure with preserved ejection fraction: the EMPEROR-Preserved trial.
  5. Efficacy of SGLT2 Inhibitors in Patients With Diabetes and Nonobstructive Hypertrophic Cardiomyopathy.
  6. Mitochondrial mutations in protein coding genes of respiratory chain including complexes IV, V, and mt-tRNA genes are associated risk factors for congenital heart disease.
  1. Nat Med. 2022 Dec 05.
    Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved.
    Stefan D Anker, Javed Butler, Muhammad Shariq Usman, Gerasimos Filippatos, João Pedro Ferreira, Edimar Bocchi, Michael Böhm, Hans Pieter Brunner-La Rocca, Dong-Ju Choi, Vijay Chopra, Eduardo Chuquiure, Nadia Giannetti, Juan Esteban Gomez-Mesa, Stefan Janssens, James L Januzzi, José R González-Juanatey, Bela Merkely, Stephen J Nicholls, Sergio V Perrone, Ileana L Piña, Piotr Ponikowski, Michele Senni, David Sim, Jindrich Spinar, Iain Squire, Stefano Taddei, Hiroyuki Tsutsui, Subodh Verma, Dragos Vinereanu, Jian Zhang, Tomoko Iwata, Janet M Schnee, Martina Brueckmann, Stuart J Pocock, Faiez Zannad.
      The EMPEROR-Preserved trial showed that the sodium-glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF)  > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41-49%). In patients with LVEF  ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71-0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66-1.04, P = 0.11). For patients with an LVEF of 41-49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57-0.88, P = 0.002) for the primary outcome (Pinteraction = 0.27), and 0.57 (95%CI: 0.42-0.79, P < 0.001) for total HHF (Pinteraction = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.
    DOI:  https://doi.org/10.1038/s41591-022-02041-5
  2. J Mol Cell Cardiol. 2022 Dec 02. pii: S0022-2828(22)00570-3. [Epub ahead of print]
    dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.
    Ketaki N Mhatre, Jason D Murray, Galina Flint, Timothy S McMillen, Gerhard Weber, Majid Shakeri, An-Yue Tu, Sonette Steczina, Robert Weiss, David J Marcinek, Charles E Murry, Daniel Raftery, Rong Tian, Farid Moussavi-Harami, Michael Regnier.
      Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.
    Keywords:  Cardiac DRX; Cardiomyocyte metabolism; Contraction; Mitochondrial remodeling; Myosin activator; dATP
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.11.010
  3. J Mol Cell Cardiol. 2022 Dec 06. pii: S0022-2828(22)00571-5. [Epub ahead of print]
    Multi-omics analyses identify molecular signatures with prognostic values in different heart failure aetiologies.
    Joseph Pierre Aboumsallem, Canxia Shi, Sanne De Wit, George Markousis-Mavrogenis, Valentina Bracun, Tim R Eijgenraam, Martijn F Hoes, Wouter C Meijers, Elles M Screever, Marloes E Schouten, Adriaan A Voors, Herman H W Silljé, Rudolf A De Boer.
      BACKGROUND: Heart failure (HF) is the leading cause of morbidity and mortality worldwide, and there is an urgent need for more global studies and data mining approaches to uncover its underlying mechanisms. Multiple omics techniques provide a more holistic molecular perspective to study pathophysiological events involved in the development of HF.METHODS: In this study, we used a label-free whole myocardium multi-omics characterization from three commonly used mouse HF models: transverse aortic constriction (TAC), myocardial infarction (MI), and homozygous Phospholamban-R14del (PLN-R14Δ/Δ). Genes, proteins, and metabolites were analysed for differential expression between each group and a corresponding control group. The core transcriptome and proteome datasets were used for enrichment analysis. For genes that were upregulated at both the RNA and protein levels in all models, clinical validation was performed by means of plasma level determination in patients with HF from the BIOSTAT-CHF cohort.
    RESULTS: Cell death and tissue repair-related pathways were upregulated in all preclinical models. Fatty acid oxidation, ATP metabolism, and Energy derivation processes were downregulated in all investigated HF aetiologies. Putrescine, a metabolite known for its role in cell survival and apoptosis, demonstrated a 4.9-fold (p < 0.02) increase in PLN-R14Δ/Δ, 2.7-fold (p < 0.005) increase in TAC mice, and 2.2-fold (p < 0.02) increase in MI mice. Four Biomarkers were associated with all-cause mortality (PRELP: Hazard ratio (95% confidence interval) 1.79(1.35, 2.39), p < 0.001; CKAP4: 1.38(1.21, 1.57), p < 0.001; S100A11: 1.37(1.13, 1.65), p = 0.001; Annexin A1 (ANXA1): 1.16(1.04, 1.29) p = 0.01), and three biomarkers were associated with HF-Related Rehospitalization, (PRELP: 1.88(1.4, 2.53), p < 0.001; CSTB: 1.15(1.05, 1.27), p = 0.003; CKAP4: 1.18(1.02, 1.35), P = 0.023).
    CONCLUSIONS: Cell death and tissue repair pathways were significantly upregulated, and ATP and energy derivation processes were significantly downregulated in all models. Common pathways and biomarkers with potential clinical and prognostic associations merit further investigation to develop optimal management and therapeutic strategies for all HF aetiologies.
    Keywords:  ATP; Autophagy; Cell death; Heart failure; Metabolomics; Multi-omics; Polyamine; Proteomics; Tissue repair; Transcriptomics
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.12.001
  4. Eur Heart J. 2022 Dec 07. pii: ehac693. [Epub ahead of print]
    Empagliflozin, irrespective of blood pressure, improves outcomes in heart failure with preserved ejection fraction: the EMPEROR-Preserved trial.
    Michael Böhm, Stefan Anker, Felix Mahfoud, Lucas Lauder, Gerasimos Filippatos, João Pedro Ferreira, Stuart J Pocock, Martina Brueckmann, Ilias Saloustros, Elke Schüler, Christoph Wanner, Faiez Zannad, Milton Packer, Javed Butler.
      AIMS: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and preserved ejection fraction. This study aims to evaluate if systolic blood pressure (SBP) moderates these effects.METHODS AND RESULTS: The association of SBP and the treatment effects of empagliflozin in EMPEROR-Preserved (empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction) was evaluated. Randomized patients (n = 5988) were grouped according to SBP at baseline (<110 mmHg, n = 455; 110-130 mmHg, n = 2415; > 130 mmHg, n = 3118). The effect of empagliflozin on blood pressure, cardiovascular death or HF hospitalization (primary outcome), total HF hospitalizations, and rate of decline in estimated glomerular filtration rate was studied. Over a median of 26.2 months, the placebo-corrected decline was small and not significantly different across baseline SBP. On placebo, the risk of cardiovascular death or hospitalization for HF was 8.58 at >130 mmHg, 8.26 at 110-130 mmHg, and 11.59 events per 100 patient-years at <110 mmHg (P = 0.12 vs. > 130 mmHg, P = 0.08 vs. 110-130 mmHg). There was no evidence for baseline SBP moderating the effect of empagliflozin on risk of HF events (primary endpoint interaction P = 0.69, recurrent HF hospitalizations interaction P = 0.55). When comparing empagliflozin with placebo, SBP did not meaningfully associate with adverse events such as hypotension, volume depletion, and acute renal failure.
    CONCLUSION: In EMPEROR-Preserved, empagliflozin was effective and safe without SBP meaningfully moderating empagliflozin's treatment effects. This analysis of EMPEROR-Preserved shows that empagliflozin can be used safely and effectively without blood pressure being a meaningful moderator of the drug benefit.
    CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique identifier: NCT03057951.
    Keywords:  Cardiovascular outcomes; Empagliflozin; Heart failure; Kidney outcomes; Preserved ejection fraction; Systolic blood pressure
    DOI:  https://doi.org/10.1093/eurheartj/ehac693
  5. Am J Cardiol. 2022 Dec 03. pii: S0002-9149(22)01178-X. [Epub ahead of print]188 80-86
    Efficacy of SGLT2 Inhibitors in Patients With Diabetes and Nonobstructive Hypertrophic Cardiomyopathy.
    Muthiah Subramanian, Vucha Sravani, Sanga Pavan Krishna, Swapnakala Bijjam, Chandramukhi Sunehra, Sachin Yalagudri, Daljeet Kaur Saggu, Calambur Narasimhan.
      The objective of this study was to evaluate the effects of sodium glucose co-transporter 2 inhibitors (SGLT2i) on functional capacity and diastolic function in patients with diabetes with nonobstructive hypertrophic cardiomyopathy (nHCM) and preserved left ventricular (LV) function. From January 2019 to October 2020, a prospective open-label study was performed on patients with type 2 diabetes mellitus and nHCM with New York Heart Association class II-III symptoms. Patients with a LV ejection fraction <50% were excluded. Patients were recruited from January 2019 to November 2019 to the SGLT2i arm and from November 2019 to October 2020 to the control arm. The primary composite end point was defined as achieving an improvement of at least 1.5 in E/e' and a reduction of ≥1 New York Heart Association functional class after 6 months of therapy. At baseline, there were no significant differences between the SGLT2i (n = 24) and control arms (n = 24). More patients in the SGLT2i arm achieved the primary end point than the patients in the control arm (70.8% vs 4.2%, p <0.001). After 6 months of therapy, patients in the SGLT2i arm showed a significant improvement in all diastolic function parameters (E/e' 16.3 ± 1.9 vs 13.3 ± 1.6, p <0.001; E/A 2.8 ± 0.1 vs 2.4 ± 0.1, p <0.001; left atrial volume 45.6 ± 5.2 vs 40.8 ± 4.9 ml/m2, p = 0.003). There was also an improvement in the 6-minute walk distance (295.1 ± 31.5 vs 343.0 ± 31.1 m, p <0.001) and N-terminal pro-B-type natriuretic peptide (481.4 ± 52.6 vs 440.9 ± 43.9 pg/ml, p <0.001) in patients who received SGLT2i. There was no significant change in the LV mass in the SGLT2i or control arm (-0.1 ± 0.3 vs 0.1 ± 0.5 g/m2, p = 0.319) after 6 months of therapy. A patient in the SGLT2i arm discontinued therapy because of a urinary tract infection. In conclusion, the use of SGLT2i improved diastolic function and functional capacity in patients with diabetes with nHCM and a preserved LV function.
    DOI:  https://doi.org/10.1016/j.amjcard.2022.10.054
  6. EXCLI J. 2022 ;21 1306-1330
    Mitochondrial mutations in protein coding genes of respiratory chain including complexes IV, V, and mt-tRNA genes are associated risk factors for congenital heart disease.
    Mohammad Mehdi Heidari, Mehri Khatami, Akram Kamalipour, Mustafa Kalantari, Mahsa Movahed, Mohammad Hayet Emmamy, Mehdi Hadadzadeh, José Bragança, Mohsen Namnabat, Bahareh Mazrouei.
      Most studies aiming at unraveling the molecular events associated with cardiac congenital heart disease (CHD) have focused on the effect of mutations occurring in the nuclear genome. In recent years, a significant role has been attributed to mitochondria for correct heart development and maturation of cardiomyocytes. Moreover, numerous heart defects have been associated with nucleotide variations occurring in the mitochondrial genome, affecting mitochondrial functions and cardiac energy metabolism, including genes encoding for subunits of respiratory chain complexes. Therefore, mutations in the mitochondrial genome may be a major cause of heart disease, including CHD, and their identification and characterization can shed light on pathological mechanisms occurring during heart development. Here, we have analyzed mitochondrial genetic variants in previously reported mutational genome hotspots and the flanking regions of mt-ND1, mt-ND2, mt-COXI, mt-COXII, mt-ATPase8, mt-ATPase6, mt-COXIII, and mt-tRNAs (Ile, Gln, Met, Trp, Ala, Asn, Cys, Tyr, Ser, Asp, and Lys) encoding genes by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) in 200 patients with CHD, undergoing cardiac surgery. A total of 23 mitochondrial variations (5 missense mutations, 8 synonymous variations, and 10 nucleotide changes in tRNA encoding genes) were identified and included 16 novel variants. Additionally, we showed that intracellular ATP was significantly reduced (P=0.002) in CHD patients compared with healthy controls, suggesting that the mutations have an impact on mitochondrial energy production. Functional and structural alterations caused by the mitochondrial nucleotide variations in the gene products were studied in-silico and predicted to convey a predisposing risk factor for CHD. Further studies are necessary to better understand the mechanisms by which the alterations identified in the present study contribute to the development of CHD in patients.
    Keywords:  congenital heart disease; in-silico analysis; mitochondrial genome; mt-tRNA; mutation
    DOI:  https://doi.org/10.17179/excli2022-5298
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