bims-hafaim 2023-06-11 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023‒06‒11
nine papers selected by
Kyle McCommis
Saint Louis University

Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Polypharmacy Status.
Transcriptome data analysis of primary cardiomyopathies reveals perturbations in arachidonic acid metabolism.
Pristimerin protects against pathological cardiac hypertrophy through improvement of PPARα pathway.
Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction: an overview of 36 systematic reviews.
Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue.
Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy.
A Patient-Level Pooled Analysis of Two Empagliflozin Trials on Left Ventricular Remodeling.
Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study.
Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers.

JACC Heart Fail. 2023 May 21. pii: S2213-1779(23)00250-0. [Epub ahead of print]

Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Polypharmacy Status.

Alexander Peikert, Parag Goyal, Muthiah Vaduganathan, Brian L Claggett, Ian J Kulac, Zi Michael Miao, Orly Vardeny, Mikhail N Kosiborod, Akshay S Desai, Pardeep S Jhund, Carolyn S P Lam, Silvio E Inzucchi, Felipe A Martinez, Rudolf A de Boer, Adrian F Hernandez, Sanjiv J Shah, Magnus Petersson, Anna Maria Langkilde, John J V McMurray, Scott D Solomon.

  BACKGROUND: Patients with heart failure (HF) have a high burden of multimorbidity, often necessitating numerous medications. There may be clinical concern about introducing another medication, especially among individuals with polypharmacy.OBJECTIVES: This study examined the efficacy and safety of addition of dapagliflozin according to the number of concomitant medications in HF with mildly reduced or preserved ejection fraction.
METHODS: In this post hoc analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, 6,263 participants with symptomatic HF with left ventricular ejection fraction >40% were randomized to dapagliflozin or placebo. Baseline medication use (including vitamins and supplements) was collected. Efficacy and safety outcomes were assessed by medication use categories ("nonpolypharmacy": <5 medications; "polypharmacy": 5 to 9 medications; and "hyperpolypharmacy": ≥10 medications) and continuously. The primary outcome was worsening HF or cardiovascular death.
RESULTS: Overall, 3,795 (60.6%) patients met polypharmacy and 1,886 (30.1%) met hyperpolypharmacy criteria. Higher numbers of medications were strongly associated with higher comorbidity burden and increased rates of the primary outcome. Compared with placebo, dapagliflozin similarly reduced the risk of the primary outcome irrespective of polypharmacy status (nonpolypharmacy HR: 0.88 [95% CI: 0.58-1.34]; polypharmacy HR: 0.88 [95% CI: 0.75-1.03]; hyperpolypharmacy HR: 0.73 [95% CI: 0.60-0.88]; Pinteraction = 0.30). Similarly, benefits with dapagliflozin were consistent across the spectrum of total medication use (Pinteraction = 0.06). Although adverse events increased with higher number of medications, they were not more frequent with dapagliflozin, regardless of polypharmacy status.
CONCLUSIONS: In the DELIVER trial, dapagliflozin safely reduced worsening HF or cardiovascular death across a broad range of baseline medication use, including among individuals with polypharmacy (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Keywords:  SGLT2 inhibitors; heart failure with mildly reduced ejection fraction; heart failure with preserved ejection fraction; polypharmacy

DOI:  https://doi.org/10.1016/j.jchf.2023.05.014
Front Cardiovasc Med. 2023 ;10 1110119

Transcriptome data analysis of primary cardiomyopathies reveals perturbations in arachidonic acid metabolism.

Pankaj Kumar Chauhan, Ramanathan Sowdhamini.

  Introduction: Cardiomyopathies are complex heart diseases with significant prevalence around the world. Among these, primary forms are the major contributors to heart failure and sudden cardiac death. As a high-energy demanding engine, the heart utilizes fatty acids, glucose, amino acid, lactate and ketone bodies for energy to meet its requirement. However, continuous myocardial stress and cardiomyopathies drive towards metabolic impairment that advances heart failure (HF) pathogenesis. So far, metabolic profile correlation across different cardiomyopathies remains poorly understood.Methods: In this study, we systematically explore metabolic differences amongst primary cardiomyopathies. By assessing the metabolic gene expression of all primary cardiomyopathies, we highlight the significantly shared and distinct metabolic pathways that may represent specialized adaptations to unique cellular demands. We utilized publicly available RNA-seq datasets to profile global changes in the above diseases (|log2FC| ≥ 0.28 and BH adjusted p-val 0.1) and performed gene set analysis (GSA) using the PAGE statistics on KEGG pathways.
Results: Our analysis demonstrates that genes in arachidonic acid metabolism (AA) are significantly perturbed across cardiomyopathies. In particular, the arachidonic acid metabolism gene PLA2G2A interacts with fibroblast marker genes and can potentially influence fibrosis during cardiomyopathy.
Conclusion: The profound significance of AA metabolism within the cardiovascular system renders it a key player in modulating the phenotypes of cardiomyopathies.

Keywords:  GSA; arachidonic acid; cardiomyopathies; heart failure; metabolism; transcriptome

DOI:  https://doi.org/10.3389/fcvm.2023.1110119
Toxicol Appl Pharmacol. 2023 Jun 01. pii: S0041-008X(23)00211-9. [Epub ahead of print] 116572

Pristimerin protects against pathological cardiac hypertrophy through improvement of PPARα pathway.

Ye Lu, Zhaoxiang Zeng, Xianhao Bao, Mingwei Wu, Zaiping Jing, Jiaxuan Feng.

  Pristimerin (PM), serving as a biological component mainly obtained from Celastraceae and Hippocrateaceae families, has been extensively explored for its numerous pharmacological activities, especially anti-cancer activity. However, the function of PM on pathological cardiac hypertrophy is poorly understood. This work was intended to investigate the effects of PM on pressure-overload induced myocardial hypertrophy and its potential pathways. Mouse model of pathological cardiac hypertrophy was generated by transverse aortic constriction (TAC) or minipump administration of the β-adrenergic agonist ISO for 4 weeks, and PM (0.5 mg/Kg/d, i.p.) was treated for 2 weeks. PPARα-/- mice received TAC surgery were used for mechanism exploration. Moreover, neonatal rat cardiomyocytes (NRCMs) were utilized to explore the effect of PM following Angiotensin II (Ang II, 1.0 μM) administration. We found that PM attenuated pressure-overload induced cardiac dysfunction, myocardial hypertrophy and fibrosis in mice. Likewise, PM incubation dramatically reversed Ang II-mediated cardiomyocytes hypertrophy in NRCMs. RNA-Sequence showed that PM selectively contributed to improvement of PPARα/PGC1 signaling, while silencing PPARα abrogated the beneficial effects of PM on Ang II-treated NRCMs. Importantly, PM ameliorated Ang II-induced mitochondrial dysfunction and decrease in metabolic genes, whereas knockdown of PPARα eliminated these alterations in NRCMs. Similarly, PM presented limited protective effects on pressure-overload induced systolic dysfunction and myocardial hypertrophy in PPARα deficient mice. Overall, this study revealed that PM exerted protective activity against pathological cardiac hypertrophy through improvement of PPARα/PGC1 pathway.

Keywords:  Cardiac hypertrophy; Mitochondria; PPARα; Pristimerin

DOI:  https://doi.org/10.1016/j.taap.2023.116572
Heart Fail Rev. 2023 Jun 07.

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction: an overview of 36 systematic reviews.

Paschalis Karakasis, Konstantinos Pamporis, Panagiotis Stachteas, Dimitrios Patoulias, Konstantinos I Bougioukas, Nikolaos Fragakis.

  The recently published randomized trials (RCTs) evaluating the effect of Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) led researchers to perform a plethora of systematic reviews (SRs), often providing contradictory conclusions. This overview of reviews was aimed at summarizing the evidence of these SRs, quantifying the overlap, re-analyzing the evidence in case new studies that were identified, and mapping knowledge gaps. Literature search was conducted through Medline, Scopus, and Cochrane until March 22, 2023. Overall, 36 SRs synthesizing results from 18 RCTs were identified. A substantial overlap was identified among the SRs synthesizing large heart failure or cardiovascular outcome trials (CVOTs). Regarding the composite outcome of cardiovascular (CV) mortality or hospitalization for heart failure (HHF), all authors reported a significant favorable effect. A beneficial effect was also noted for CV and all-cause mortality, albeit not significant. Our meta-analysis demonstrated a significant improvement in health-related quality-of-life (HRQoL) as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS, MD = 1.97, p < 0.001), Total Symptom Score (KCCQ-TSS, MD = 2.29, p < 0.001), Clinical Summary Score (KCCQ-CSS, MD = 1.59, p < 0.001), and the 6-min walking distance (MD = 10.78 m, p = 0.032). Regarding safety, SGLT2i were associated with a significantly lower risk of serious adverse events compared to placebo (RR = 0.94, p = 0.002). The use of SGLT2i in HFpEF is both efficient and safe. Further research is required to clarify the impact of SGTL2i on different subphenotypes of HFpEF and the cardiorespiratory capacity of these patients.

Keywords:  Heart failure; Hospitalization; Preserved ejection fraction; Quality of life; Sodium-glucose cotransporter-2 inhibitors

DOI:  https://doi.org/10.1007/s10741-023-10324-3
bioRxiv. 2023 May 25. pii: 2023.05.24.542198. [Epub ahead of print]

Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue.

Junwei Du, Leland C Sudlow, Kiana Shahverdi, Haiying Zhou, Megan Michie, Thomas H Schindler, Joshua D Mitchell, Shamim Mollah, Mikhail Y Berezin.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart's energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2 . Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage.Significance Statement: This study uncovers the detrimental impact of chronic oxaliplatin treatment on heart metabolism in mice, linking high accumulative dosages to cardiotoxicity and heart damage. By identifying significant changes in gene expression related to energy metabolic pathways, the findings pave the way for the development of diagnostic methods to detect oxaliplatin-induced cardiotoxicity at an early stage. Furthermore, these insights may inform the creation of therapies that compensate for the energy deficit in the heart, ultimately preventing heart damage and improving patient outcomes in cancer treatment.

DOI: https://doi.org/10.1101/2023.05.24.542198
Elife. 2023 Jun 05. pii: e82619. [Epub ahead of print]12

Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy.

Karthickeyan Chella Krishnan, Elie-Julien El Hachem, Mark P Keller, Sanjeet G Patel, Luke Carroll, Alexis Diaz Vegas, Isabela Gerdes Gyuricza, Christine Light, Yang Cao, Calvin Pan, Karolina Elżbieta Kaczor-Urbanowicz, Varun Shravah, Diana Anum, Matteo Pellegrini, Chi Fung Lee, Marcus M Seldin, Nadia A Rosenthal, Gary A Churchill, Alan D Attie, Benjamin Parker, David E James, Aldons J Lusis.

  Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

Keywords:  computational biology; genetic, association studies; genetics; genomics; heart failure; hypertrophy; metabolic syndrome; mitochondria; mouse; proteomics; systems biology

DOI:  https://doi.org/10.7554/eLife.82619
J Card Fail. 2023 Jun 05. pii: S1071-9164(23)00195-1. [Epub ahead of print]

A Patient-Level Pooled Analysis of Two Empagliflozin Trials on Left Ventricular Remodeling.

EMPA-HEART investigators



Keywords:  SGLT2 inhibitor; empagliflozin; remodeling; ventricular myocardium

DOI:  https://doi.org/10.1016/j.cardfail.2023.05.017
J Inherit Metab Dis. 2023 Jun 05.

Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study.

Jerry Vockley, Barbara K Burton, Gerard Berry, Nicola Longo, John Phillips, Amarilis Sanchez-Valle, Kimberly A Chapman, Pranoot Tanpaiboon, Stephanie Grunewald, Elaine Murphy, Xiaoxiao Lu, Syeda Rahman, Kathryn Ray, Bridget Reineking, Laura Pisani, Antonio Nino Ramirez.

  Long-chain fatty acid oxidation disorders (LC-FAODs) result in life-threatening energy metabolism deficiencies/energy source depletion. Triheptanoin is an odd-carbon, medium chain triglyceride (that is an anaplerotic substrate of calories and fatty acids) for treating pediatric and adult patients with LC-FAODs. Study CL202 (NCT02214160), an open-label extension study of study CL201 (NCT01886378), evaluated the long-term safety/efficacy of triheptanoin in patients with LC-FAODs (N = 94), including cohorts who were triheptanoin naïve (n = 33) or had received triheptanoin in study CL201 (n = 24) or in investigator-sponsored trials/expanded access programs (IST/EAPs; n = 37). Primary endpoint was the annualized rate of LC-FAOD major clinical events (MCEs; rhabdomyolysis, hypoglycemia, cardiomyopathy). Mean±standard deviation (SD) triheptanoin treatment durations were 27.4±19.9, 46.9±13.6, and 49.6±21.4 months for the triheptanoin-naïve, CL201 rollover, and IST/EAP cohorts, respectively. In the triheptanoin-naïve cohort, median (interquartile range [IQR]) MCE rate significantly decreased from 2.00 (0.67-3.33) events/patient/year pre-triheptanoin to 0.28 (0.00-1.43) events/patient/year with triheptanoin (p = 0.0343), a reduction of 86%. In the CL201 rollover cohort, mean±SD MCE rate significantly decreased from 1.76±1.64 events/patient/year pre-triheptanoin to 1.00±1.00 events/patient/year with triheptanoin (p = 0.0347), a reduction of 43%. In the IST/EAP cohort, mean±SD MCE rate was 1.40±2.37 (median [IQR] 0.57 [0.00-1.67]) events/patient/year with triheptanoin. Safety data were consistent with previous observations. Treatment-related treatment-emergent adverse events (TEAEs) occurred in 68.1% of patients and were mostly mild/moderate in severity. Five patients had 7 serious treatment-related TEAEs; all resolved. Our results confirm the long-term efficacy of triheptanoin for patients with LC-FAOD. This article is protected by copyright. All rights reserved.

Keywords:  cardiomyopathy; hypoglycemia; long-chain fatty acid oxidation disorders; rhabdomyolysis; triheptanoin (Dojolvi®)

DOI:  https://doi.org/10.1002/jimd.12640
J Cardiovasc Transl Res. 2023 Jun 06.

Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers.

Mark Jansen, A F Schmidt, J J M Jans, I Christiaans, S N van der Crabben, Y M Hoedemaekers, D Dooijes, J D H Jongbloed, L G Boven, R H Lekanne Deprez, A A M Wilde, J van der Velden, R A de Boer, J P van Tintelen, F W Asselbergs, A F Baas.

  Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value.

Keywords:  Acylcarnitine; Biomarker; Hypertrophic Cardiomyopathy; MYBPC3; Metabolism

DOI:  https://doi.org/10.1007/s12265-023-10398-2