A mechanistic analysis of the force-frequency relation in non-failing and progressively failing human myocardium

Alpert, Norman R.; Leavitt, Bruce J.; Ittleman, Frank P.; Hasenfuß, Gerd; Pieske, Burkert; Mulieri, Louis A.

doi:10.1007/978-3-642-47070-7_2

Cited by 8 publications

(12 citation statements)

References 21 publications

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“…In excitable myocardial strips from patients with hemodynamic overload due to chronic mitral regurgitation and non-ischemic dilated cardiomyopathy economy is markedly increased, well out of proportion to that explainable by changes in myosin isoform content [61,68]. A similar finding was reported in chronic tachycardia heart failure in dogs [70].…”

Section: Functional Consequences Of Sarcomeric Protein Modification Imentioning

confidence: 78%

“…Profound depression of rate-dependent contractile reserve or even a negative force Treppe in association with lowering of the optimal stimulation frequency have been reported in end-stage, failing hearts [57], and may constitute a significant source of disability in these patients. Less severe depression of the FFR has been reported in patients with mitral regurgitation [59], pressure overload hypertrophy [60] and diabetic cardiomyopathy [61]. More recently, the possible contribution of the myofilament to the normal FFR has been recognized based on the results of sinusoidal analysis experiments performed in skinned myocardial strips [49,56].…”

Section: Functional Consequences Of Sarcomeric Protein Modification Imentioning

confidence: 98%

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Functional Consequences of Sarcomeric Protein Abnormalities in Failing Myocardium

LeWinter

2005

Heart Fail Rev

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Sarcomeric protein abnormalities have been recognized for many years in heart failure due to dilated cardiomyopathy (DCM). In contrast, virtually nothing is known about myofilament abnormalities in heart failure occurring in association with diastolic dysfunction. With the exception of sarcomeric protein mutations that cause DCM, the most important mechanism of myofilament dysfunction in DCM is probably altered post-translational modification, in particular the phosphorylation state of troponins I and T and possibly myosin light chain. Other modifications, including oxidation and glycation, may also play a role. Myosin heavy chain isoform switching occurs in human heart failure, but its functional significance is uncertain. Myofilament abnormalities contribute significantly to myocardial dysfunction in DCM, although their relative importance compared with abnormal calcium handling is debated. One consistent functional abnormality in DCM is increased myofilament calcium sensitivity of tension generation, which contributes to slowed or incomplete relaxation. More recently, decreases in the optimal frequency of myofilament work and power generation have been recognized. These changes may contribute to depression of the force-frequency relation in DCM. Altered mechanoenergetics constitute one of the most important manifestations of myofilament dysfunction in heart failure. DCM and hemodynamic overload are associated with more economical and efficient energy utilization by the contractile machinery, which may be protective of the myocardium. This change is strongly associated with depressed myofibrillar ATPase activity. We speculate that the effectiveness of mechanical therapies such as resynchronization may at least in part be related to improved mechanical function without loss of this mechanoenergetic advantage.

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Section: Functional Consequences Of Sarcomeric Protein Modification Imentioning

confidence: 78%

Section: Functional Consequences Of Sarcomeric Protein Modification Imentioning

confidence: 98%

Functional Consequences of Sarcomeric Protein Abnormalities in Failing Myocardium

LeWinter

2005

Heart Fail Rev

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“…As shown in animal models [26,[33][34][35][36], an elevation in α-MHC content in human myocardium would likely enhance those measures of mechanical and enzymatic performance which have consistently been found diminished in human cardiopathologies [26,[33][34][35][36]. However, it must be emphasized that modifications in gene expression as accompany ventricular remodeling and heart failure may in some cases be compensatory as opposed to causative of the disease state [5,21,38,40,41,43].…”

Section: Findings In Human Heart Failurementioning

confidence: 89%

“…Although not yet demonstrated, the differences in myofibrillar mechanical performance between failing and non-failing myocardium may then be independent of enzymatic function determined solely by the myosin molecule [21][22][23].…”

Section: Findings In Human Heart Failurementioning

confidence: 92%

“…Reductions in myofibrillar Mg.ATPase activity per protein content associated with heart failure have most often pointed to fundamental changes in actomyosin crossbridge kinetics, and therefore in myosin enzymatic function within the myofilament lattice, as a significant contributor to the progression and condition of human heart failure [2,3,[17][18][19][20][21][22]. It should be noted, however, that myosin isolated from failing and non-failing human ventricles hydrolyzes Ca.ATP in the absence of actin at similar rates [18,22,23].…”

Section: Findings In Human Heart Failurementioning

confidence: 95%

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Thick Filament Proteins and Performance in Human Heart Failure

Palmer

2005

Heart Fail Rev

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Modifications in thick filament protein content and performance are thought to underlie contraction-relaxation dysfunction in human heart failure. It has been found that myofibrillar Mg.ATPase is reduced in failing myocardium, which may be due in part to the reduction in alpha-myosin heavy chain (MHC) isoform content from approximately 5-10% in normal myocardium to <2% in failing myocardium. The physiological importance of this seemingly small amount of alpha-MHC appears substantiated by the development of cardiopathologies in humans with mutated alpha-MHC at normal abundance. Therefore, the replacement of alpha-MHC by beta-MHC (possessing slower actomyosin enzymatic kinetics) may underlie to a significant degree the reduced myocardial shortening velocity and reduced relaxation function in human heart failure. The atrial isoform of myosin essential light chain (ELC) may replace up to 25% of the ventricular isoform in failing ventricles and in so doing promotes myocardial shortening velocity. An elevated accumulation of the higher performing atrial-ELC, unlike the reduced content of the higher performing alpha-MHC, is therefore considered a compensatory response in heart failure. Phosphorylation of the myofilament proteins myosin regulatory light chain and troponin-I are both reduced in heart failure and collectively result in an elevated myofilament sensitivity to calcium activation, which inhibits relaxation function. These and other modifications in thick filament proteins, as discussed in this review, directly affect mechanical power output and relaxation function of the myocardium and thereby may be considered to cause or in some cases to compensate for the otherwise ineffective myocardial performance in heart failure.

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Assessment of myocardial ventricular function in donor hearts: Is isovolumic acceleration measured by tissue Doppler the Holy Grail?

Cheung

Redington

2004

The Journal of Heart and Lung Transplantation

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A mechanistic analysis of the force-frequency relation in non-failing and progressively failing human myocardium

Cited by 8 publications

References 21 publications

Functional Consequences of Sarcomeric Protein Abnormalities in Failing Myocardium

Functional Consequences of Sarcomeric Protein Abnormalities in Failing Myocardium

Thick Filament Proteins and Performance in Human Heart Failure

Assessment of myocardial ventricular function in donor hearts: Is isovolumic acceleration measured by tissue Doppler the Holy Grail?

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