Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion

Ashrafian, Houman; Redwood, Charles; Blair, Edward; Watkins, Hugh

doi:10.1016/s0168-9525(03)00081-7

Cited by 294 publications

(249 citation statements)

References 39 publications

Supporting

Mentioning

223

Contrasting

Unclassified

Order By: Relevance

“…Those mutations may weaken the myosin-LA affinity, reduce stiffness and unitary force generation of the single myosin molecule, slow down actin filament sliding velocity, and depress cardiac performance. The resulting cardiac hypocontractility could then activate hypertrophic pathways leading to the FHC phenotype [35].…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanism regulating myosin and cardiac functions by ELC

Lossie

Köhncke

Mahmoodzadeh

et al. 2014

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

The essential myosin light chain (ELC) is involved in modulation of force generation of myosin motors and cardiac contraction, while its mechanism of action remains elusive. We hypothesized that ELC could modulate myosin stiffness which subsequently determines its force production and cardiac contraction. We therefore generated heterologous transgenic mouse (TgM) strains with cardiomyocyte-specific expression of ELC with human ventricular ELC (hVLC-1; TgM hVLC-1 ) or E56G-mutated hVLC-1 (hVLC-1 E56G ; TgM E56G ). hVLC-1 or hVLC-1 E56G expression in TgM was around 39% and 41%, respectively of total VLC-1. Laser trap and in vitro motility assays showed that stiffness and actin sliding velocity of myosin with hVLC-1 prepared from TgM hVLC-1 (1.67pN/nm and 2.3µm/s, respectively) were significantly higher than myosin with hVLC-1 E56G prepared from TgM E56G (1.25pN/nm and 1.7µm/s, respectively) or myosin with mouse VLC-1 (mVLC-1) prepared from C57/BL6 (1.41 pN/nm and 1.5±0.03 µm/s , respectively). Maximal left ventricular pressure development of isolated perfused hearts in vitro prepared from TgM hVLC-1 (80.0mmHg) were significantly higher than hearts from TgM E56G (66.2mmHg) or C57/BL6 (59.3±3.9 mmHg). These findings show that ELCs decreased myosin stiffness, in vitro motility, and thereby cardiac functions in the order hVLC-1 > hVLC-1 E56G ≈ mVLC-1. They also suggest a molecular pathomechanism of cardiomyopathies caused by hVLC-1 mutations.

show abstract

Section: Resultsmentioning

confidence: 99%

Molecular mechanism regulating myosin and cardiac functions by ELC

Lossie

Köhncke

Mahmoodzadeh

et al. 2014

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…This suggests that the LV experiences cellular energy stress in end-stage HF. The energy imbalance resulting from impaired energy production may worsen by increased energy demand due to inefficient sarcomeric ATP utilization, perhaps further undermining ventricle function [30].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine heart failure

Zhong

DiSilvestre

et al. 2006

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Alterations of cardiac gene expression are central to ventricular dysfunction in human heart failure (HF). The canine tachycardia pacing-induced HF model is known to reproduce the main hemodynamic, echocardiographic and electrophysiological changes observed in human HF. In this study, we use this HF model to compare gene expression profiles in the left and right ventricles (LV, RV) of normal and end-stage failing canine hearts and compare the transcription profiles to those in human and murine models of HF. In end-stage HF, the LV exhibits down regulation of genes involved in energy production, cardiac contraction, and modulation of excitation-contraction coupling as compared with normal LV. The majority of transcriptomic changes between normal and end-stage canine HF were shared by the RV and LV. Genes down regulated only in the LV included those involved in aerobic energy production pathways, regulation of actin filament length, and enzymelinked receptor protein signaling pathways. In normal canine hearts, genes encoding specific components of the contractile apparatus exhibit LV-RV asymmetric expression patterns; in failing hearts, cardiac fetal transcription factors MEF2 and MITF and the stress-responsive transcription factor ATF4 showed interventricular differences in expression. The comparison among the canine tachypacing, mouse transgenic, and human HF reveals that human disease involves down regulation of genes in a broad range of biological processes while experimentally induced HF is associated with down regulation of energy pathways, and that human ischemic HF and canine HF share a similar over representation of transcriptional pathways in the up regulated genes. This study provides insights into the molecular pathways leading to end-stage tachycardia-induced HF, and into global transcriptomic differences between the animal HF models and human HF.

show abstract

“…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%

“…Moreover, two groups have shown impaired myocardial energetics with MR spectroscopy in patients with Friedreich ataxia associated with hypertrophic heart disease 29,30 . Fourth, energy depletion is hypothesized to allow an increase in cytosolic Ca 2+ that might mediate an upregulation of transcriptional processes that result in hypertrophy 12 . MR spectroscopy has shown that the observed levels of energetic depletion in HCM could compromise sarco/endoplasmic reticulum calcium ATPase (SERCA), that transports Ca 2+ from the cytosol into the sarcoplasmic reticulum, because of the very high obligate energy requirements of this ion transporter 8 .…”

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%

See 1 more Smart Citation

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

2016

View full text Add to dashboard Cite

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

show abstract

Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion

Cited by 294 publications

References 39 publications

Molecular mechanism regulating myosin and cardiac functions by ELC

Molecular mechanism regulating myosin and cardiac functions by ELC

Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine heart failure

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Contact Info

Product

Resources

About