Cardiomyocyte Stiffness in Diastolic Heart Failure (original) (raw)
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Circulation, 2015
Background— The purpose of this study was to determine whether patients with heart failure and a preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness and the extent to which discovered changes depend on changes in extracellular matrix fibrillar collagen and cardiomyocyte titin. Methods and Results— Seventy patients undergoing coronary artery bypass grafting underwent an echocardiogram, plasma biomarker determination, and intraoperative left ventricular epicardial anterior wall biopsy. Patients were divided into 3 groups: referent control (n=17, no hypertension or diabetes mellitus), hypertension (HTN) without (–) HFpEF (n=31), and HTN with (+) HFpEF (n=22). One or more of the following studies were performed on the biopsies: passive stiffness measurements to determine total, collagen-dependent and titin-dependent stiffness (differential extraction assay), collagen assays (biochemistry or histology), or titin isoform and phosphorylation assays. In comp...
Sensing and Responding of Cardiomyocytes to Changes of Tissue Stiffness in the Diseased Heart
Frontiers in Cell and Developmental Biology
Cardiomyocytes are permanently exposed to mechanical stimulation due to cardiac contractility. Passive myocardial stiffness is a crucial factor, which defines the physiological ventricular compliance and volume of diastolic filling with blood. Heart diseases often present with increased myocardial stiffness, for instance when fibrotic changes modify the composition of the cardiac extracellular matrix (ECM). Consequently, the ventricle loses its compliance, and the diastolic blood volume is reduced. Recent advances in the field of cardiac mechanobiology revealed that disease-related environmental stiffness changes cause severe alterations in cardiomyocyte cellular behavior and function. Here, we review the molecular mechanotransduction pathways that enable cardiomyocytes to sense stiffness changes and translate those into an altered gene expression. We will also summarize current knowledge about when myocardial stiffness increases in the diseased heart. Sophisticated in vitro studies...
Circulation Journal, 2014
Background: Ventricular dilation is known as a pivotal predictor in recent-onset cardiomyopathy (ROCM), but its pathophysiology is not fully understood. In the present study we investigated whether single-cell stiffness of right and left ventricular-derived fibroblasts has an effect on cardiac phenotype in patients with ROCM. Methods and Results: Patients with endomyocardial biopsy-proven ROCM were included (n=10). Primary cardiac fibroblasts (CFBs) were cultured from left and right ventricular endomyocardial biopsies and their single-cell stiffness was analyzed by quantification of Young's modulus using colloidal probe atomic force microscopy. Cardiac fibrosis was analyzed by Masson's trichrome staining. CFBs from the left ventricle showed significantly decreased stiffness when compared with CFBs from the right ventricle, indexed by decreased stiffness (Young's modulus 3,374±389 vs. 4,837±690 Pa; P<0.05). Young's modulus of CFBs derived from the left ventricle correlated negatively with the left ventricular end-diastolic dimension derived from 2-dimensional echocardiography (R 2 =0.77; P<0.01). Neither left nor right ventricular fibrosis correlated with the respective ventricular dimensions. Conclusions: Our data suggest that a decrease in single-cell stiffness of left ventricular fibroblasts could trigger left ventricular dilation in patients with ROCM. This implies a new potential mechanism for the ventricular dilation with this disease.
Myocardial Structure and Function Differ in Systolic and Diastolic Heart Failure
Circulation, 2006
Background— To support the clinical distinction between systolic heart failure (SHF) and diastolic heart failure (DHF), left ventricular (LV) myocardial structure and function were compared in LV endomyocardial biopsy samples of patients with systolic and diastolic heart failure. Methods and Results— Patients hospitalized for worsening heart failure were classified as having SHF (n=22; LV ejection fraction (EF) 34±2%) or DHF (n=22; LVEF 62±2%). No patient had coronary artery disease or biopsy evidence of infiltrative or inflammatory myocardial disease. More DHF patients had a history of arterial hypertension and were obese. Biopsy samples were analyzed with histomorphometry and electron microscopy. Single cardiomyocytes were isolated from the samples, stretched to a sarcomere length of 2.2 μm to measure passive force (F passive ), and activated with calcium-containing solutions to measure total force. Cardiomyocyte diameter was higher in DHF (20.3±0.6 versus 15.1±0.4 μm, P <0.001...
Circulation, 2007
Background-The pathophysiology of diastolic heart failure (DHF) is poorly understood. One potential explanation is an active fibrotic process that produces increased ventricular stiffness, which compromises filling. The present study investigates collagen metabolism in hypertensive patients in different phases of diastolic function with and without proven DHF. Methods and Results-We studied 86 hypertensive patients divided into groups according to the presence of DHF (32 with, 54 without) and phase of diastolic function (20 with normal function, 38 with impaired relaxation, 10 with pseudonormalization, and 16 with restrictive-like filling). Serum carboxy-terminal, amino-terminal, and carboxyterminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, matrix metalloproteinases (MMPs; total MMP-1, active MMP-2, and MMP-9), and tissue inhibitor of MMPs levels were assayed by radioimmunoassay and ELISA. Doppler-echocardiographic assessment of diastolic filling was made with measurements of E/A ratio, E-wave deceleration time, and isovolumic relaxation time. Serum carboxy-terminal telopeptide of procollagen type I, carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 levels (PϽ0.001 for all, controlled for age and gender) were greater in patients with DHF than in those without. When we controlled for age and gender, levels of serum carboxy-terminal telopeptide of procollagen type I, tissue inhibitor of MMP-1, amino-terminal propeptide of procollagen type III (all PϽ0.001), carboxy-terminal telopeptide of procollagen type I(Pϭ0.008), and MMP-2 (Pϭ0.03) were greater in more severe phases of diastolic dysfunction. Within phases of diastolic dysfunction, serum carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 were elevated in those with DHF compared with those without DHF (all PϽ0.001). Conclusions-These data demonstrate serological evidence of an active fibrotic process in DHF, which is more marked in more severe diastolic dysfunction. This observation may help explain the pathophysiology of DHF and may suggest new avenues for diagnostic and therapeutic intervention. (Circulation. 2007;115:888-895.)
European heart journal, 2015
The aim of the present study was to clarify the significance of myocardial ultrastructural changes in patients with dilated cardiomyopathy (DCM). Endomyocardial biopsy of the left ventricle was performed in 250 consecutive DCM patients (54.9 ± 13.9 years, 79% men), presenting initially as decompensated heart failure (HF). Myofilament changes of cardiomyocytes were evaluated by electron microscopy and compared with clinical and morphometric data. Mortality and HF recurrence were evaluated during the follow-up period. During the follow-up period (4.9 ± 3.9 years), 24 patients (10%) died and 67 (27%) were readmitted because of HF recurrence, including those who had died because of HF. Myofilament changes, classified as either focal derangement of myofilaments (sarcomere damage) or diffuse myofilament lysis (disappearance of most sarcomeres in cardiomyocytes), were identified in 164 patients (66%). Multivariate analysis identified a family history of DCM [hazard ratio (HR) 4.763; 95% co...
Changes in in vivo myocardial tissue properties due to heart failure
2013
A clinical image data driven mechanics analysis was used to quantify changes in tissue-specific passive and contractile material properties for groups of normal and HF patients. We have developed an automated mechanics modelling framework to firstly construct left ventricular (LV) mechanics models based on shape information derived from non-invasive dynamic magnetic resonance images, then to characterise passive tissue stiffness and maximum contractile stress by matching the simulated LV mechanics with data from the dynamic cardiac images. Preliminary statistical analysis revealed that patients with hypertrophy or non-ischemic heart failure exhibited increased passive myocardial stiffness compared to the normals. Elevated maximum contractile stress was also observed for hypertrophic patients. Tissue-specific parameter estimation analysis of this kind can potentially be applied in the clinical setting to provide a more specific disease measure to assist with stratification of HF patients.
Heart, 2000
Aim-To investigate in vivo the intermediate cytoskeletal filaments desmin and vimentin in myocardial tissues from patients with dilated cardiomyopathy, and to determine whether alterations in these proteins are associated with impaired contractility. Methods-Endomyocardial biopsies were performed in 12 patients with dilated cardiomyopathy and in 12 controls (six women with breast cancer before anthracycline chemotherapy and six male donors for heart transplantation). Biopsy specimens were analysed by light microscopy and immunochemistry (desmin, vimentin). Myocyte contractile protein function was evaluated by the actin-myosin in vitro motility assay. Left ventricular ejection fraction was assessed by echocardiography and radionuclide ventriculography. Results-Patients with dilated cardiomyopathy had a greater cardiomyocyte diameter than controls (p < 0.01). The increase in cell size was associated with a reduction in contractile function, as assessed by actin-myosin motility (r = −0.643; p < 0.01). Quantitative immunochemistry showed increased desmin and vimentin contents (p < 0.01), and the desmin distribution was disturbed in cardiomyopathy. There was a linear relation between desmin distribution and actin-myosin sliding in vitro (r = 0.853; p < 0.01) and an inverse correlation between desmin content and ejection fraction (r = −0.773; p < 0.02). Negative correlations were also found between myocardial vimentin content and the actin-myosin sliding rate (r = −0.74; p < 0.02) and left ventricular ejection fraction (r = −0.68; p < 0.01). Conclusions-Compared with normal individuals, the myocardial tissue of patients with dilated cardiomyopathy shows alterations of cytoskeletal intermediate filament distribution and content associated with reduced myocyte contraction. (Heart 2000;84:659-667)
The role of the cytoskeleton in heart failure
Cardiovascular Research, 2000
The cytoskeleton of cardiac myocytes consists of actin, the intermediate filament desmin and of aand b-tubulin that form the microtubules by polymerization. Vinculin, talin, dystrophin and spectrin represent a separate group of membrane-associated proteins. In numerous experimental studies, the role of cytoskeletal alterations especially of microtubules and desmin, in cardiac hypertrophy and failure (CHF) has been described. Microtubules were found to be accumulated thereby posing an increased load on myocytes which impedes sarcomere motion and promotes cardiac dysfunction. Other groups were unable to confirm microtubular densification. The possibility exists that these changes are species, load and chamber dependent. Recently, damage of the dystrophin molecule and MLP (muscle LIM protein) were identified as possible causes of CHF. Our own studies in human hearts with chronic CHF due to dilated cardiomyopathy (DCM) showed that a morphological basis of reduced contractile function exists: the cytoskeletal and membraneassociated proteins are disorganized and increased in amount confirming experimental reports. In contrast, the contractile myofilaments and the proteins of the sarcomeric skeleton including titin, a-actinin, and myomesin are significantly decreased. These changes can be assumed to occur in stages and are here presented as a testable hypothesis: (1) The early and reversible stage as present in animal experiments is characterized by accumulation of cytoskeletal proteins to counteract an increased strain without loss of contractile material.