Reduced Contraction and Altered Frequency Response of Isolated Ventricular Myocytes From Patients With Heart Failure

Davies, C. S. L.; Davia, Kerry; Bennett, J. G.; Pepper, John; Poole‐Wilson, P.A.; Harding, Siân E.

doi:10.1161/01.cir.92.9.2540

Cited by 190 publications

(102 citation statements)

References 32 publications

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“…4H), indicating that cyclic stretch reduces stress generation even if sarcomeres are highly aligned. Our results are similar to measurements made from myocytes isolated from failing and nonfailing human hearts, in which, at physiological frequencies, percent shortening in failing myocytes was approximately half that in nonfailing myocytes (13,14). These data suggest that it is possible to recapitulate failing myocardium on a 2D chip that is amenable to comparison with animal and clinical studies.…”

Section: Resultssupporting

confidence: 85%

“…Functionally, myocytes isolated from failing hearts show defective excitationcontraction coupling (10), including reduced calcium uptake into the sarcoplasmic reticulum (11). Contractile function is also reduced, as shown by decreased cardiac output in dogs subjected to chronic rapid pacing (12) and decreased tension in left ventricular strips isolated from failing human myocardium (13,14). Thus, dilated and failing hearts are characterized by multiscale maladaptive remodeling, best studied in an experimental system capable of replicating and quantifying a broad range of these effects.…”

mentioning

confidence: 99%

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Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

McCain

Sheehy

Grosberg

et al. 2013

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

139

124

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The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structurefunction relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased α-to β-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart. organs on chips | mechanotransduction | muscular thin films | microarray | contraction

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Section: Resultssupporting

confidence: 85%

mentioning

confidence: 99%

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

McCain

Sheehy

Grosberg

et al. 2013

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

139

124

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show abstract

“…A key contributor to the dysfunction may be depressed myocardial contractility [20,21]. Studies that have examined the function of cardiac myocytes (CM) isolated from failing hearts suggest that a defect in CM contractility may contribute to the overall cardiac dysfunction [22]. The responsible agents or mechanisms, however, remain incompletely characterized.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 modulates contractility in adult cardiac myocytes

Pyo¹,

Sui²,

Dhume³

et al. 2006

Journal of Molecular and Cellular Cardiology

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The inflammatory response is critical to the development and progression of heart failure. Chemokines and their receptors are a distinct class of inflammatory modulators that may play a role in mediating myocardial dysfunction in heart failure. Levels of the chemokine CXCL12, also known as stromal cell-derived factor (SDF), and its receptor, CXCR4, are elevated in patients with heart failure, and we undertook this study to determine whether this chemokine system can directly affect cardiac function in the absence of leukocytes. Murine papillary muscles and adult rat cardiac myocytes treated with CXCL12, the only identified ligand of CXCR4, demonstrate blunted inotropic responses to physiologic concentrations of calcium. The negative inotropic effects on cardiac myocytes are accompanied by a proportional diminution of calcium transients. The effects are abrogated by AMD3100, a specific CXCR4 inhibitor. Overexpression of the receptor through adenoviral infection with a CXCR4 construct accentuates the negative inotropic effects of CXCL12 on cardiac myocytes during calcium stimulation. CXCR4 activation also attenuates beta-adrenergicmediated increases in calcium mobilization and fractional shortening in cardiac myocytes. In electrophysiologic studies, CXCL12 decreases forskolin-and isoproterenol-induced voltage-gated L-type calcium channel activation. These studies demonstrate that activation of CXCR4 results in a direct negative inotropic modulation of cardiac myocyte function. The specific mechanism of action involves alterations of calcium channel activity on the membrane. The presence of functional CXCR4 on cardiac myocytes introduces a new target for treating cardiac dysfunction.

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“…This finding indicates that myocyte loss and abnormalities of the matrix are not solely responsible for the LV dysfunction associated with hypertension. Clinically, it is well recognized that LV dysfunction becomes apparent at higher stimulation rates (28,29). Several investigators have assessed the cardiomyocyte functions in hypertrophied hearts (22) and their evaluations, including the force-frequency relation, are controversial.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte Functions Couple with Left Ventricular Geometric Patterns in Hypertension.

2000

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Previous studies have suggested the prognostic significance of left ventricular (LV) geometric patterns in essential hypertension.However, the relation between cardiomyocyte functional changes and LV geometric patterns has not been clarified. This study was designed to assess the morphological and functional changes in isolated myocytes derived from different LV geometric patterns in hypertension. After 2-3 weeks of a high-salt (8%) diet from the age of 6 weeks, 20 Dahl salt-sensitive (DS) rats were classified into the following three groups on the basis of an echocardiographically determined LV mass index and the relative wall thickness:concentric hypertrophy (11), eccentric hypertrophy (4), and concentric remodeling

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Reduced Contraction and Altered Frequency Response of Isolated Ventricular Myocytes From Patients With Heart Failure

Cited by 190 publications

References 32 publications

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

CXCR4 modulates contractility in adult cardiac myocytes

Cardiomyocyte Functions Couple with Left Ventricular Geometric Patterns in Hypertension.

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