Energetic drain driving hypertrophic cardiomyopathy

Sequeira, Vasco; Bertero, Edoardo; Maack, Christoph

doi:10.1002/1873-3468.13496

Cited by 41 publications

(40 citation statements)

References 97 publications

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“…1,2 This complex disease can be broadly defined by patho logically enhanced cardiac actin-myosin interac tions, with core pathophysiological features that include hyper contractility, diastolic abnormalities, and dynamic left ventricular outflow tract (LVOT) obstruction. [2][3][4] Patients with obstructive hypertrophic cardiomyopathy are often symptomatic and can have atrial fibrillation, heart failure, and malignant ventricular arrhythmias. 2,5 Current treat ment for obstructive hypertrophic cardio myopathy focuses on symptomatic relief with β blockers, nondihydro pyridine calcium channel blockers, and diso pyramide.…”

Section: Introductionmentioning

confidence: 99%

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial

Olivotto¹,

Oręziak²,

et al. 2020

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Background Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. Methods In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1•5 mL/kg per min or greater increase in peak oxygen consumption (pVO 2) and at least one NYHA class reduction or a 3•0 mL/kg per min or greater pVO 2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO 2 , NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.

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Section: Introductionmentioning

confidence: 99%

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial

Olivotto¹,

Oręziak²,

et al. 2020

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“…The acute effect of butyrate perfusion was not due to an improvement in contractile efficiency as the cost of contraction (amount of ATP synthesized per unit of work performed) was not different between the groups (Figure F), suggesting that butyrate did not decrease the demand for ATP. Importantly, butyrate perfusion improved ∣ΔG ~ATP ∣ to >52 kJ/mol, thereby potentially fully satisfying SERCA ΔG ~ATP requirements as well as the ΔG ~ATP requirements of other ATP‐dependent contractile and cellular processes such as Na/K ATPase (∣ΔG ~ATP ∣~ 48 kJ/mol) and myosin ATPase (∣ΔG ~ATP ∣~ 47 kJ/mol) …”

Section: Discussionmentioning

confidence: 97%

Increasing mitochondrial ATP synthesis with butyrate normalizes ADP and contractile function in metabolic heart disease

Panagia

Baka

et al. 2020

NMR in Biomedicine

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Metabolic heart disease (MHD), which is strongly associated with heart failure with preserved ejection fraction, is characterized by reduced mitochondrial energy production and contractile performance. In this study, we tested the hypothesis that an acute increase in ATP synthesis, via short chain fatty acid (butyrate) perfusion, restores contractile function in MHD. Isolated hearts of mice with MHD due to consumption of a high fat high sucrose (HFHS) diet or on a control diet (CD) for 4 months were studied using 31 P NMR spectroscopy to measure high energy phosphates and ATP synthesis rates during increased work demand. At baseline, HFHS hearts had increased ADP and decreased free energy of ATP hydrolysis (ΔG~A TP ), although contractile function was similar between the two groups. At high work demand, the ATP synthesis rate in HFHS hearts was reduced by over 50%. Unlike CD hearts, HFHS hearts did not increase contractile function at high work demand, indicating a lack of contractile reserve. However, acutely supplementing HFHS hearts with 4mM butyrate normalized ATP synthesis, ADP, ΔG~A TP and contractile reserve. Thus, acute reversal of depressed mitochondrial ATP production improves contractile dysfunction in MHD. These findings suggest that energy starvation may be a reversible cause of myocardial dysfunction in MHD, and opens new therapeutic opportunities. K E Y W O R D SATP synthesis, contractile function, heart failure, metabolic syndrome, metabolism, mitochondria, nuclear magnetic resonance spectroscopy 1 | INTRODUCTION While energetic deficits are well described in the failing heart, the temporal and causal relationship between a chronic energetic deficit and contractile dysfunction is debated. 1-3 Moreover, little information is available on whether energetic defects are reversible, or if they contribute to decreased cardiac performance in chronic myocardial disease. 1,4,5 Thus, the hemodynamic consequences of myocardial energetic abnormalities Abbreviations: BCA, bromocrotonic acid; CD, control diet; CEST, chemical exchange saturation transfer; Cr, creatine; DevP, left ventricular-developed pressure; HFHS, high fat high sucrose;HFpEF, heart failure with preserved ejection fraction; KH, Krebs-Henseleit; LCFA, long chain fatty acid; LVEDP, left ventricular end diastolic pressure; LVH, left ventricular hypertrophy; LVSP, left ventricular systolic pressure; MHD, metabolic heart disease; PCr, phosphocreatine; Pi, inorganic phosphate; ROS, reactive oxygen species; RPP, rate pressure product; SCFA, short chain fatty acid; SERCA, sarcoplasmic reticulum calcium ATPase; ΔG~ATP, free energy of ATP hydrolysis.

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“…These compensatory and deteriorate changes in cardiomyocyte are associated with re-expression of foetal genes, which are mainly related to sarcomere contraction, ion signal regulation and activity, and mitochondrial function. [5][6][7] Increased myofilament Ca 2+ sensitivity has been identified in animal model and patients with pathological hypertrophy, leading changes of intracellular Ca 2+ homoeostasis and causing Ca 2+ -triggered arrhythmias, which could increase force development and adenosine triphosphate (ATP) consumption. 8,9 Mitochondrial disorganization and dysfunction in cardiac hypertrophy could cause energy supply and demands imbalance.…”

Section: Introductionmentioning

confidence: 99%