Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy

Crilley, Jenifer; Boehm, Ernest; Blair, Edward; Rajagopalan, B.; Blamire, Andrew M.; Styles, Peter; McKenna, William J.; Östman‐Smith, Ingegerd; Clarke, Kieran; Watkins, Hugh

doi:10.1016/s0735-1097(02)03009-7

Cited by 362 publications

(295 citation statements)

References 34 publications

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“…Investigators compared the cardiac phosphocreatine (PCr) to ATP ratio in 31 patients harbouring mutations in the genes for either β-myosin heavy chain, cardiac troponin T, or myosin-binding protein C, and in 24 control individuals. The PCr/ATP ratio was reduced in the patients with HCM by 30% relative to controls, and the reduction was of a similar magnitude in all three disease-gene groups, and not related to the degree or presence of hypertrophy 13,17 . ATP is produced in the mitochondria, but is used elsewhere, mainly by sarcomeric proteins and ion transporters.…”

Section: Energy Depletion Hcm and Diastolementioning

confidence: 76%

“…Additionally, overall resting myocardial blood flow (assessed using PET and 13 N-labelled ammonia) did not differ between patients with HCM and controls (although the vasodilator 'reserve', assessed using dipyridamole, was blunted) 62 . Accordingly, Crilley et al showed that the myocardial perfusion reserve index in these patients did not correlate with energy impairment 13 . Carriers of the HCM-associated MYBPC3 mutation have reduced myocardial efficiency in the absence of hypertrophy and microvascular dysfunction 63 .…”

Section: [H3] Energy Inefficiency or Ischaemia?mentioning

confidence: 95%

“…In <10-15 s, the total amount of ATP present within a myocyte is consumed by myocardial work and requires constant replenishment 17 . High energy needs make the myocardium sensitive to genetic and acquired perturbations in energy supply, and to inefficiency in its utilization, which result in the HCM phenotype in some patients 12,13 . The rationale for inefficient energy utilization as a cause of the HCM phenotype rests on several lines of evidence.…”

Section: Energy Depletion Hcm and Diastolementioning

confidence: 99%

“…In this Perspectives article, we focus primarily on the energy depletion hypothesis, but we also summarize the evidence for Ca 2+ sensitization, and discuss how the two theories overlap. Increasing evidence indicates that energy depletion has an important role in the development of hypertrophy and in the wider pathophysiology of HCM [9][10][11][12][13][14][15] . We summarize this evidence, and then discuss the phenotypic manifestations of energy depletion in three realms of cardiac function: diastolic dysfunction, dynamic systolic dysfunction (especially against imposed afterload), and arrhythmogenesis.…”

mentioning

confidence: 99%

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Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

2016

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Evidence indicates that anatomical and physiological phenotypes of hypertrophic cardiomyopathy (HCM) stem from genetically mediated, inefficient cardiomyocyte energy utilization, and subsequent cellular energy depletion. However, HCM often presents clinically with normal left ventricular (LV) systolic function or hyperkinesia. If energy inefficiency is a feature of HCM, why is it not manifest as resting LV systolic dysfunction? In this Perspectives article, we focus on an idiosyncratic form of reversible systolic dysfunction provoked by LV obstruction that we have previously termed the 'lobster claw abnormality' — a mid-systolic drop in LV Doppler ejection velocities. In obstructive HCM, this drop explains the mid-systolic closure of the aortic valve, the bifid aortic pressure trace, and why patients cannot increase stroke volume with exercise. This phenomenon is characteristic of a broader phenomenon in HCM that we have termed dynamic systolic dysfunction. It underlies the development of apical aneurysms, and rare occurrence of cardiogenic shock after obstruction. We posit that dynamic systolic dysfunction is a manifestation of inefficient cardiomyocyte energy utilization. Systolic dysfunction is clinically inapparent at rest; however, it becomes overt through the mechanism of afterload mismatch when LV outflow obstruction is imposed. Energetic insufficiency is also present in nonobstructive HCM. This paradigm might suggest novel therapies. Other pathways that might be central to HCM, such as myofilament Ca2+ hypersensitivity, and enhanced late Na+ current, are discussed

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Section: Energy Depletion Hcm and Diastolementioning

confidence: 76%

Section: [H3] Energy Inefficiency or Ischaemia?mentioning

confidence: 95%

Section: Energy Depletion Hcm and Diastolementioning

confidence: 99%

mentioning

confidence: 99%

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Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

2016

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“…Whether impaired energetics in HCM is the consequence, or the cause, of LVH remains unclear. Nonetheless, impaired energy metabolism in HCM exists even in the absence of hypertrophy, suggesting that compromised energetics precede hypertrophy and may play a causal role in the development of the HCM phenotype [28]. Concordantly, HCM cardiomyocytes exhibit sarcomeric mutations resulting in inefficient ATP utilization, with subsequent increased cost of force generation and excess demand on myocytes [29].…”

Section: Myocardial Efficiencymentioning

confidence: 99%

Determinants of myocardial energetics and efficiency in symptomatic hypertrophic cardiomyopathy

Timmer

Germans

Götte

et al. 2010

Eur J Nucl Med Mol Imaging

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Purpose Next to hypertrophy, hypertrophic cardiomyopathy (HCM) is characterized by alterations in myocardial energetics. A small number of studies have shown that myocardial external efficiency (MEE), defined by external work (EW) in relation to myocardial oxidative metabolism (MVO 2 ), is reduced. The present study was conducted to identify determinants of MEE in patients with HCM by use of dynamic positron emission tomography (PET) and cardiovascular magnetic resonance imaging (CMR). Methods Twenty patients with HCM (12 men, mean age: 55.2 ± 13.9 years) and 11 healthy controls (7 men, mean age: 48.1 ± 10 years) were studied with [ 11 C]acetate PET to assess MVO 2 . CMR was performed to determine left ventricular (LV) volumes and mass (LVM). Univariate and multivariate analyses were employed to determine independent predictors of myocardial efficiency.Results Between study groups, MVO 2 (controls: 0.12 ± 0.04 ml·min −1 ·g −1 , HCM: 0.13 ± 0.05 ml·min −1 ·g −1 , p = 0.64) and EW (controls: 9,139 ± 2,484 mmHg·ml, HCM: 9,368 ± 2,907 mmHg·ml, p = 0.83) were comparable, whereas LVM was significantly higher (controls: 99 ± 21 g, HCM: 200 ± 76 g, p < 0.001) and MEE was decreased in HCM patients (controls: 35 ± 8%, HCM: 21 ± 10%, p < 0.001). MEE was related to stroke volume (SV), LV outflow tract gradient, NH 2 -terminal pro-brain natriuretic peptide (NT-proBNP) and serum free fatty acid levels (all p < 0.05). Multivariate analysis revealed that SV (ß = 0.74, p < 0.001) and LVM (ß = −0.43, p = 0.013) were independently related to MEE. Conclusion HCM is characterized by unaltered MVO 2 , impaired EW generation per gram of myocardial tissue and subsequent deteriorated myocardial efficiency. Mechanical external efficiency could independently be predicted by SV and LVM.

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How Hypertrophic Cardiomyopathy Became a Contemporary Treatable Genetic Disease With Low Mortality

et al. 2016

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Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease encumbered throughout much of its almost 60-year history by a large measure of misunderstanding and the perception of a grim outcome without effective treatment options. However, it is now apparent that the majority of patients affected with HCM can achieve normal or near-normal life expectancy without disability, and usually do not require major treatment interventions. Nevertheless, for those patients with HCM who are at risk for (or experience) disease-related complications, a constellation of comprehensive nonpharmacologic management strategies have evolved over the last 15 years, altering the natural history and disease course for many, including implantable defibrillators, heart transplant, external defibrillation/therapeutic hypothermia, advances in surgical myectomy, and alcohol ablation. In particular, expanded contemporary risk stratification strategies have led to a more reliable selection of patients likely to achieve primary prevention of sudden death with implantable defibrillators. Most recently, large cohort studies using current management strategies and therapeutic measures have shown that it is now possible to achieve significantly improved survival with a low HCM-related mortality of 0.5% per year across all ages, and including children and young adults characteristically with the most aggressive disease course. These clinical management initiatives, instituted by the practicing cardiology community, have succeeded in preserving life and restoring an active lifestyle for thousands of patients with HCM, while providing many with a measure of reassurance and a reasonable expectation for an extended (if not normal) life span.

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Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy

Cited by 362 publications

References 34 publications

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Determinants of myocardial energetics and efficiency in symptomatic hypertrophic cardiomyopathy

How Hypertrophic Cardiomyopathy Became a Contemporary Treatable Genetic Disease With Low Mortality

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