Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

Velden, Jolanda van der; Tocchetti, Carlo G.; Varricchi, Gilda; Bianco, Anna Monica; Sequeira, Vasco; Hilfiker‐Kleiner, Denise; Hamdani, Nazha; Leite‐Moreira, Adelino F.; Mayr, Manuel; Falcão-Pires, Inês; Thum, Thomas; Dawson, Dana; Balligand, Jean‐Luc; Heymans, Stéphane

doi:10.1093/cvr/cvy147

Cited by 78 publications

(63 citation statements)

References 95 publications

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“…There is good evidence that HCM patients exhibit elevated metabolic activity and increased myocardial stiffness ( 6 , 24 , 45 – 47 ). We propose that the decrease in myocardial stiffness observed in AID-TAT treated cTnI-G203S mice, evidenced by reduced FS ( Table 1 ), may be associated with restored cytoskeletal organization ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization and validation of a preventative therapy for hypertrophic cardiomyopathy in a murine model of the disease

Viola

Shah

Johnstone

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Currently there is an unmet need for treatments that can prevent hypertrophic cardiomyopathy (HCM). Using a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-G203S) is associated with increased mitochondrial metabolic activity, consistent with the human condition. These alterations precede development of the cardiomyopathy. Here we examine the efficacy of in vivo treatment of cTnI-G203S mice with a peptide derived against the α-interaction domain of the cardiac L-type calcium channel (AID-TAT) on restoring mitochondrial metabolic activity, and preventing HCM. cTnI-G203S or age-matched wt mice were treated with active or inactive AID-TAT. Following treatment, targeted metabolomics was utilized to evaluate myocardial substrate metabolism. Cardiac myocyte mitochondrial metabolic activity was assessed as alterations in mitochondrial membrane potential and flavoprotein oxidation. Cardiac morphology and function were examined using echocardiography. Cardiac uptake was assessed using an in vivo multispectral imaging system. We identified alterations in six biochemical intermediates in cTnI-G203S hearts consistent with increased anaplerosis. We also reveal that AID-TAT treatment of precardiomyopathic cTnI-G203S mice, but not mice with established cardiomyopathy, restored cardiac myocyte mitochondrial membrane potential and flavoprotein oxidation, and prevented myocardial hypertrophy. Importantly, AID-TAT was rapidly targeted to the heart, and not retained by the liver or kidneys. Overall, we identify biomarkers of HCM resulting from the cTnI mutation Gly203Ser, and present a safe, preventative therapy for associated cardiomyopathy. Utilizing AID-TAT to modulate cardiac metabolic activity may be beneficial in preventing HCM in “at risk” patients with identified Gly203Ser gene mutations.

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Section: Discussionmentioning

confidence: 99%

Characterization and validation of a preventative therapy for hypertrophic cardiomyopathy in a murine model of the disease

Viola

Shah

Johnstone

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…While classic models of HF are characterized by reduced ejection fraction, HCM is a paradigm of diastolic dysfunction with normal or even super-normal myocardial contractility. Consequently, any a priori assumption that the conclusions of prior studies on HF might be extended to HCM would have been arbitrary [4]. This is why we embarked on the present investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Mutation can be demonstrated in approximately 60% of HCM patients and are considered causative [2,3]. A common cellular phenotype induced by HCM sarcomere mutations is an inefficient sarcomere contraction, which is attributed to diverse changes in sarcomere properties including increased myofilament Ca 2+ sensitivity and triphosphatase (ATPase) activity suggesting increased adenosine triphosphate (ATP) utilization [4]. This is consistent with in vivo studies using 31 P-magnetic resonance (MR) spectroscopy that have demonstrated impaired cardiac energetics under resting conditions and during exercise in patients with HCM [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Energetics and Ca2+-Activated ATPase in Obstructive Hypertrophic Cardiomyopathy

Lombardi

Lazzeroni

Pisano

et al. 2020

JCM

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Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered mitochondria were described in biopsies, but little is known about possible perturbations of mitochondrial function and adenosine triphosphate (ATP) production/consumption. The aim of this study was to investigate possible abnormalities in mitochondrial enzymes generating/scavenging reactive oxygen species, and changes in the Ca2+-activated ATPases in myocardial tissue from patients with obstructive HCM undergoing surgical myectomy compared to unused donor hearts (CTRL). Methods and Results: Both the amount and activity of mitochondrial Complex I (nicotinamide adenine dinucleotide -reduced form, NADH, dehydrogenase) were upregulated in HCM vs. CTRL, whilst the activity of Complex V (ATP synthase) was not reduced and ATP levels were significantly higher in HCM vs. CTRL. Antioxidant Mn-activated superoxide dismutase (SOD2) and (m)-aconitase activities were increased in HCM vs. CTRL. The Cu/Zn-activated superoxide dismutase (SOD1) amount and mtDNA copy number were unaltered in HCM. Total Ca2+-activated ATPase activity and absolute amount were not different HCM vs. CTRL, but the ratio between ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting type 2 (ATP2A2) and type 1 (ATP2A1), ATP2A2/ATP2A1, was increased in HCM in favor of the slow isoform (ATP2A2). Conclusion: HCM is characterized by mitochondrial Complex I hyperactivity and preserved Ca2+-activated ATPase activity with a partial switch towards slow ATP2A2. This data may give insight into the abnormal cellular energetics observed in HCM cardiomyopathy but other studies would need to be performed to confirm the observations described here.

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“…Accordingly, DCM caused by TTN gene variants has been linked with mitochondrial dysfunction and metabolic perturbations as cause of disease progression [ 19 ]. Overall, these studies indicate that timely disease stage-specific treatment of metabolic perturbations may slow down disease progression in cardiomyopathy patients [ 20 ]. An observational cohort to determine the predictive value of metabolic biomarkers (BIO FOr CARe: identification of biomarkers for development and progression of HCM in carriers of the Dutch MYBPC3 founder carriers) and a clinical trial using metabolic drug therapy aimed to improve energetics of the heart at preclinical stage in HCM gene variant carriers are currently being performed by several DOSIS principal investigators (ENERGY trial) [ 21 ].…”

Section: Altered Metabolism As Key Driver Of Disease In Cardiomyopathmentioning

confidence: 99%

Strength of patient cohorts and biobanks for cardiomyopathy research

et al. 2020

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In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.

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Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

Cited by 78 publications

References 95 publications

Characterization and validation of a preventative therapy for hypertrophic cardiomyopathy in a murine model of the disease

Characterization and validation of a preventative therapy for hypertrophic cardiomyopathy in a murine model of the disease

Mitochondrial Energetics and Ca2+-Activated ATPase in Obstructive Hypertrophic Cardiomyopathy

Strength of patient cohorts and biobanks for cardiomyopathy research

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