Thick Filament Proteins and Performance in Human Heart Failure

Palmer, Bradley M.

doi:10.1007/s10741-005-5249-1

Cited by 50 publications

(43 citation statements)

References 107 publications

(237 reference statements)

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“…33 We have also observed a low level of MyBP-C and troponin I phosphorylation in both failing heart 17,31 and myectomy muscle samples. 34 An increase in ALC-1 content in ventricular myosin from less than 5% in donor heart to 2-27% in hypertrophic and failing heart muscle has been reported, 27,35 comparable with our finding of 11% in donor and 20% in myectomy muscle. We did not examine the amount of a and bMHC isoforms present, however an investigation by Noguchi et al 36 showed that the in vitro motility sliding speed was not different in failing and donor heart myosin despite a variation of the proportion of aMHC from 0 to 13%.…”

Section: Myosin From Myectomy Muscle Is Functionally Abnormalsupporting

confidence: 90%

“…As the combination of increased expression of ALC-1 and decreased phosphorylation of MLC-2, troponin I, and MyBP-C is commonly observed in failing heart muscle, 17,33,35 it appears that the contractile proteins in myectomy muscle are modified in a similar manner to failing heart. This is compatible with our observations that in both myocytes and in vitro motility assays contractility is similarly dysfunctional in myectomy and failing heart samples ( Figures 1 and 3).…”

Section: Myosin From Myectomy Muscle Is Functionally Abnormalmentioning

confidence: 99%

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The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy

Jacques

Briceno

McKenna

et al. 2008

Journal of Molecular and Cellular Cardiology

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Aim The aim of the study was to compare the functional and structural properties of the motor protein, myosin, and isolated myocyte contractility in heart muscle excised from hypertrophic cardiomyopathy patients by surgical myectomy with explanted failing heart and non-failing donor heart muscle. Methods Myosin was isolated and studied using an in vitro motility assay. The distribution of myosin light chain-1 isoforms was measured by two-dimensional electrophoresis. Myosin light chain-2 phosphorylation was measured by sodium dodecyl sulphate-polyacrylamide gel electrophoresis using Pro-Q Diamond phosphoprotein stain. Results The fraction of actin filaments moving when powered by myectomy myosin was 21% less than with donor myosin (P ¼ 0.006), whereas the sliding speed was not different (0.310 + 0.034 for myectomy myosin vs. 0.305 + 0.019 mm/s for donor myosin in six paired experiments). Failing heart myosin showed 18% reduced motility. One myectomy myosin sample produced a consistently higher sliding speed than donor heart myosin and was identified with a disease-causing heavy chain mutation (V606M). In myectomy myosin, the level of atrial light chain-1 relative to ventricular light chain-1 was 20 + 5% compared with 11 + 5% in donor heart myosin and the level of myosin light chain-2 phosphorylation was decreased by 30-45%. Isolated cardiomyocytes showed reduced contraction amplitude (1.61 + 0.25 vs. 3.58 + 0.40%) and reduced relaxation rates compared with donor myocytes (TT 50% ¼ 0.32 + 0.09 vs. 0.17 + 0.02 s). Conclusion Contractility in myectomy samples resembles the hypocontractile phenotype found in endstage failing heart muscle irrespective of the primary stimulus, and this phenotype is not a direct effect of the hypertrophy-inducing mutation. The presence of a myosin heavy chain mutation causing hypertrophic cardiomyopathy can be predicted from a simple functional assay.

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Section: Myosin From Myectomy Muscle Is Functionally Abnormalsupporting

confidence: 90%

Section: Myosin From Myectomy Muscle Is Functionally Abnormalmentioning

confidence: 99%

The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy

Jacques

Briceno

McKenna

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…After birth, the α-type myosin heavy chain (α-MHC), which has a higher ATPase activity and shortening velocity, is predominant in the ventricles while β-MHC is suppressed (49). However, several stimuli are able to modify this transcriptional pattern, with β-MHC gene expression often being induced together with other genes of the fetal program during cellular remodeling.…”

Section: Molecular Substrate For Contractile Dysfunctionmentioning

confidence: 99%

“…However, several stimuli are able to modify this transcriptional pattern, with β-MHC gene expression often being induced together with other genes of the fetal program during cellular remodeling. As a result, myocytes exhibit slower shortening velocity and impaired relaxation, which could contribute, at least in part, to contractile dysfunction (49). During relaxation, most of the cytosolic Ca 2+ is rapidly taken up by SR vesicles, and a smaller amount is secreted through the sarcolemma membrane by a membrane anchored ATPase.…”

Section: Molecular Substrate For Contractile Dysfunctionmentioning

confidence: 99%

Remodeling in the ischemic heart: the stepwise progression for heart

Mill¹,

Stefanon

Santos

et al. 2011

Braz J Med Biol Res

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Coronary artery disease is the leading cause of death in the developed world and in developing countries. Acute mortality from acute myocardial infarction (MI) has decreased in the last decades. However, the incidence of heart failure (HF) in patients with healed infarcted areas is increasing. Therefore, HF prevention is a major challenge to the health system in order to reduce healthcare costs and to provide a better quality of life. Animal models of ischemia and infarction have been essential in providing precise information regarding cardiac remodeling. Several of these changes are maladaptive, and they progressively lead to ventricular dilatation and predispose to the development of arrhythmias, HF and death. These events depend on cell death due to necrosis and apoptosis and on activation of the inflammatory response soon after MI. Systemic and local neurohumoral activation has also been associated with maladaptive cardiac remodeling, predisposing to HF. In this review, we provide a timely description of the cardiovascular alterations that occur after MI at the cellular, neurohumoral and electrical level and discuss the repercussions of these alterations on electrical, mechanical and structural dysfunction of the heart. We also identify several areas where insufficient knowledge limits the adoption of better strategies to prevent HF development in chronically infarcted individuals.

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“…Although the human heart primarily possesses ␤-MHC, this finding is germane to the human heart, because nonfailing human hearts are believed to contain between 5% and 10% ␣-MHC compared with 0% to 2% present in failing heart. 10 Moreover, demonstrating that ER activation blunts ␣-to ␤-MHC switching in response to hypertension could potentially explain the greater hypertrophic reserve observed in female rodent hearts in response to pressure overload. The conversion of ␣-to…”

mentioning

confidence: 99%

Estrogen Receptor Activation—Good, Aldosterone Receptor Blockade—Beneficial, Communication Between Receptors…Priceless

Barbato

2007

Hypertension

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Steroid receptors are essentially transcription factors. When estrogens activate estrogen receptors (ERs) and aldosterone activates the mineralocorticoid receptor (MR) these steroid-receptor complexes enter the nucleus. On entry, these complexes bind to their respective response elements leading to the regulation of gene expression. This transcriptional regulation of key genes in target tissues yields relevant reproductive and endocrine functions. Because ER and MR are expressed in cardiac myocytes, fibroblasts, and vascular cells, genes essential to cardiovascular function and cardiovascular pathophysiology are regulated by aldosterone and estrogens. 1,2 The consensus from research on cardiovascular tissue focusing on estrogens is that ER activation is beneficial. Specifically, ER activation has been suggested to attenuate mitogen-activated protein kinase growth signaling in response to pressure overload, increase endothelial NO synthesis, reduce vascular cell proliferation, and decrease endothelin expression. 1 In addition, blunted hypertrophic responses in female mice lacking the ryanodine receptor-associated protein and guanylyl cyclase-A receptor suggest that estrogens may attenuate calcineurin/nuclear factor-activated T-cell signaling and or mediate downstream signaling in the atrial natriuretic peptide-guanylyl cyclase cascade. 3,4 Whereas ER activation with specific and nonspecific estrogen agonists produce molecular responses favoring cardiovascular protection, the contrary has been demonstrated with studies examining MR activation. 2 The deleterious nature of excessive MR activation was evidenced by the Randomized Aldactone Evaluation Study. 2 The Randomized Aldactone Evaluation Study demonstrated improved outcomes in patients with heart failure being treated with the MR antagonist spironolactone. The rationale for the use of spironolactone in heart failure was based on the ability of aldosterone, via the genomic pathway, to initiate cardiac fibrosis and inflammation in animal models. 2 Although the Randomized Aldactone Evaluation Study improved our understanding of the pathophysiology of heart failure and its therapeutic strategies, studies demonstrating myocardial aldosterone synthesis and the absence of fibrosis in normal rat hearts containing elevated myocardial aldosterone concentrations raised questions regarding direct actions of aldosterone in the heart. 5 Particularly, in the continuum between health and disease, it was unclear how an essential steroid vital to normal cardiovascular function and pressurevolume regulation could become so deleterious. This notion prompted speculation that the myocardium was protected from the physiological effects of aldosterone and that loss of this protection gives way to the pathological aldosterone-MR-mediated actions. To this end, the work by Arias-Loza et al, 6 appearing in this issue of Hypertension, presents data that may provide an initial explanation of how ER activation may protect the cardiovascular system from the deleterious actions of excessive MR...

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Thick Filament Proteins and Performance in Human Heart Failure

Cited by 50 publications

References 107 publications

The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy

The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy

Remodeling in the ischemic heart: the stepwise progression for heart

Estrogen Receptor Activation—Good, Aldosterone Receptor Blockade—Beneficial, Communication Between Receptors…Priceless

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