Passive Stiffness of Myocardium From Congenital Heart Disease and Implications for Diastole (original) (raw)
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Constitutive Properties of Adult Mammalian Cardiac Muscle Cells
2010
Background-The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction. Methods and Results-Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (), and resultant changes in cell strain (⑀) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the on the agarose gel at a constant rate to define the cardiocyte -versus-⑀ relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte -versus-⑀ relationship during an increase and then a decrease in . In both protocols, myofilament activation was minimized by a reduction in [Ca 2ϩ ] i . Myofilament activation effects were assessed in protocol C by defining cardiocyte versus ⑀ during an increase in with physiological [Ca 2ϩ ] i . In protocol A, the cardiocyte -versus-⑀ relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the -versus-⑀ relation in hypertrophied cardiocytes was shifted to the left compared with normal cells. Conclusions-Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction. (Circulation. 1998;98:567-579.)
Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium
Circulation Research, 1988
Cardiac muscle is tethered within a fibrillar collagen matrix that serves to maximize force generation. In the human pressure-overloaded, hypertrophied left ventricle, collagen concentration is known to be increased; however, the structural and biochemical remodeling of collagen and its relation to cell necrosis and myocardial mechanics is less clear. Accordingly, this study was undertaken in a nonhuman primate model of left ventricular hypertrophy caused by gradual onset experimental hypertension. The amount of collagen, its light microscopic features, and proportions of collagen types I, III, and V were determined together with diastolic and systolic mechanics of the intact ventricle during the evolutionary, early, and late phases of established left ventricular hypertrophy (4, 35, and 88 weeks, respectively). In comparison to controls, we found 1) increased collagen at 4 weeks, as well as a greater proportion of type III, in the absence of myocyte necrosis; 2) collagen septae were thick and dense at 35 weeks, while the proportion of types I and i n had converted to control; 3) necrosis was evident at 88 weeks, and the structural remodeling and proportion of collagen types I and III reflected the extent of scar formation; and 4) unlike diastolic myocardial stiffness, which was unchanged at 4,35, or 88 weeks, the systolic stress-strain relation of the myocardium was altered in either a beneficial or detrimental manner in accordance with structural remodeling of collagen and scar formation. Thus, early in left ventricular hypertrophy, reactive fibrosis and collagen remodeling occur in the absence of necrosis while, later on, reparative fibrosis is present. In this study, the remodeled collagen matrix appeared responsible for variations in force generation observed during various phases of left ventricular hypertrophy. (Circulation Research 1988;62:757-765) I n the adult heart, left ventricular hypertrophy (LVH) is primarily the result of myocyte growth. 12 However, the volume of the interstitial compartment is also increased. 1 Using either the hydroxyproline assay or morphometric analysis, it has been shown that the concentration of collagen is increased in man 3 " 6 and rat 1-714 with LVH secondary to a chronic pressure overload. At present, it is uncertain whether such enhanced collagen formation results from greater de novo synthesis, 15 " 20 myocyte necrosis, 21 or both. Moreover, the structural and biochemical features of the remodeled collagen matrix in LVH are largely unknown. Nevertheless, because collagen represents a relatively nonelastic element, particularly type I collagen, we 622 " 24 and others 4-3-*" 14 have suggested that it may account for abnormalities in myocardial mechanics that appear with LVH.
Journal of Molecular and Cellular Cardiology, 2010
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, increased ventricular stiffness and impaired diastolic filling. We investigated to what extent myocardial functional defects can be explained by alterations in the passive and active properties of human cardiac myofibrils. Skinned ventricular myocytes were prepared from patients with obstructive HCM (two patients with MYBPC3 mutations, one with a MYH7 mutation, and three with no mutation in either gene) and from four donors. Passive stiffness, viscous properties, and titin isoform expression were similar in HCM myocytes and donor myocytes. Maximal Ca 2+-activated force was much lower in HCM myocytes (14 ± 1 kN/m 2) than in donor myocytes (23 ± 3 kN/m 2 ; P < 0.01), though crossbridge kinetics (k tr) during maximal Ca 2+ activation were 10% faster in HCM myocytes. Myofibrillar Ca 2+ sensitivity in HCM myocytes (pCa 50 = 6.40 ± 0.05) was higher than for donor myocytes (pCa 50 = 6.09 ± 0.02; P < 0.001) and was associated with reduced phosphorylation of troponin-I (ser-23/24) and MyBP-C (ser-282) in HCM myocytes. These characteristics were common to all six HCM patients and may therefore represent a secondary consequence of the known and unknown underlying genetic variants. Some HCM patients did however exhibit an altered relationship between force and cross-bridge kinetics at submaximal Ca 2+ concentrations, which may reflect the primary mutation. We conclude that the passive viscoelastic properties of the myocytes are unlikely to account for the increased stiffness of the HCM ventricle. However, the low maximum Ca 2+-activated force and high Ca 2+ sensitivity of the myofilaments are likely to contribute substantially to any systolic and diastolic dysfunction, respectively, in hearts of HCM patients. Research Highlights ► The passive stiffness of skinned HCM cardiac myocytes was similar to that of normal (donor) myocytes. ► Maximum Ca-activated force production was reduced by 40% in HCM vs donor © 2010 Elsevier Ltd.
JACC: Basic to Translational Science, 2020
A large animal model of progressive pressure overload (PO) was created that evolved into phenotypic features of HFpEF. The progression from PO to the HFpEF pathophysiology was accompanied by specific shifts in the collagen matrix microstructure over and above collagen content (i.e., fibrosis). Using early changes in regional myocardial stiffness measurements by speckle tracking methodology predicted the extent and magnitude of the HFpEF phenotype at later timepoints.
Effects of collagen microstructure on the mechanics of the left ventricle
Biophysical Journal, 1988
The microstructure of the collagen sheath or weave surrounding a myocyte and the collagen struts interconnecting neighboring myocytes is incorporated into a fluid-fiber-collagen continuum description of the myocardium. The sheaths contribute to anisotropic elasticity, whereas the struts contribute to an isotropic component. Elastic moduli of the composite myocyte-sheath complex and the strut matrix are estimated from existing passive biaxial loading data from sheets of canine myocardium. The contribution of the sheath to the elasticity of the myocyte-sheath complex is critically dependent on the helical pitch angle. Calculations for a cylindrical model of the left ventricle using both a fluid-fiber and fluid-fiber-collagen stress tensor show that the collagen strut matrix tends to limit muscle fiber lengthening; increase myocardial tissue pressure during systole, with endocardial tissue pressure exceeding left ventricular pressure; decrease tissue pressure during diastole, and thus facilitate myocardial blood flow; and aid filling during ventricular relaxation by providing a suction effect that relies on a release of stored elastic energy from the previous contraction. Calculations show that this energy is stored mostly in the collagen struts.
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...
American Journal of Physiology-heart and Circulatory Physiology, 2007
Much attention has been focused on the passive mechanical properties of the myocardium, which determines left ventricular (LV) diastolic mechanics, but the significance of the visceral pericardium (VP) has not been extensively studied. A unique en face three-dimensional volumetric view of the porcine VP was obtained using two-photon excitation fluorescence to detect elastin and backscattered second harmonic generation to detect collagen, in addition to standard light microscopy with histological staining. Below a layer of mesothelial cells, collagen and elastin fibers, extending several millimeters, form several distinct layers. The configuration of the collagen and elastin layers as well as the location of the VP at the epicardium providing a geometric advantage led to the hypothesis that VP mechanical properties play a role in the residual stress and passive stiffness of the heart. The removal of the VP by blunt dissection from porcine LV slices changed the opening angle from 53.3 ± 10.3 to 27.3 ± 5.7° (means ± SD, P < 0.05, n = 4). In four porcine hearts where the VP was surgically disrupted, a significant decrease in opening angle was found (35.5 ± 4.0°) as well as a rightward shift in the ex vivo pressure-volume relationship before and after disruption and a decrease in LV passive stiffness at lower LV volumes (P < 0.05). These data demonstrate the significant and previously unreported role that the VP plays in the residual stress and passive stiffness of the heart. Alterations in this layer may occur in various disease states that effect diastolic function. Keywords collagen; diastolic function; myocardial elasticity; residual stress; water permeability; elastin; 2photon microscopy; porcine heart; optical properties Diastolic mechanics of the left ventricle (LV) are a result of dynamic interactions of filling pressure (39), mitral valve mechanics (17), and LV wall properties (4). The mechanical properties of the LV wall, resulting from a variety of cellular and extracellular elements, determine active relaxation and passive stiffness of the LV during diastole (7,41). The passive mechanical elements of the entire myocardium have been extensively studied . Another mechanical element that is separate from the LV wall is the encasing parietal pericardium (PP). The PP influences right ventricle (RV) and LV interactions and limits the ventricular volume as well as influences the overall the pressure-volume relationship of the heart, in vivo . Despite the fact that the visceral pericardium (VP) shares many physical aspects of the PP (18), including a closed structure that completely encompasses the
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.
Changes in Titin and Collagen Underlie Diastolic Stiffness Diversity of Cardiac Muscle
Journal of Molecular and Cellular Cardiology, 2000
Small (N2B) and large (N2BA) cardiac titin isoforms are differentially expressed in a species-specific and heart locationspecific manner. To understand how differential expression of titin isoforms may influence passive stiffness of cardiac muscle we investigated the mechanical properties of mouse left ventricular (MLV) wall muscle (expressing predominantly the small titin isoform), bovine left atrial (BLA) wall muscle (predominantly the large isoform), and bovine left ventricular (BLV) wall muscle (expressing small and large isoforms at similar levels). Results indicate that the overall passive muscle stiffness of the muscle types varies nearly tenfold , with stiffness increasing in the following order: BLA, BLV and MLV. To investigate the basis of the variation in the overall muscle stiffness, the contributions of titin and collagen to muscle stiffness were determined. Results showed that increased muscle stiffness results from increases in both titin-and collagen-based passive stiffness, indicating that titin and collagen change in a coordinated fashion. The expression level of the small titin isoform correlates with titin's contribution to overall muscle stiffness, suggesting that differential expression of titin isoforms is an effective means to modulate the filling behavior of the heart.