Changes in Myocardial Microstructure and Mechanics With Progressive Left Ventricular Pressure Overload (original) (raw)
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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.
Regression of pressure overload-induced left ventricular hypertrophy in mice
AJP: Heart and Circulatory Physiology, 2005
As a prelude to investigating the mechanism of regression of pressure overload-induced left ventricular (LV) hypertrophy (LVH), we studied the time course for the development and subsequent regression of LVH as well as accompanying alterations in cardiac function, histology, and gene expression. Mice were subjected to aortic banding for 4 or 8 wk to establish LVH, and regression was initiated by release of aortic banding for 6 wk. Progressive increase in LV mass and gradual chamber dilatation and dysfunction occurred after aortic banding. LVH was also associated with myocyte enlargement, interstitial fibrosis, and enhanced expression of atrial natriuretic peptide, collagen I, collagen III, and matrix metalloproteinase-2 but suppressed expression of α-myosin heavy chain and sarcoplasmic reticulum Ca2+-ATPase. Aortic debanding completely or partially reversed LVH, chamber dilatation and dysfunction, myocyte size, interstitial fibrosis, and gene expression pattern, each with a distinct...
Temporal alterations in cardiac fibroblast function following induction of pressure overload
Cell and Tissue Research, 2010
Increases in cardiovascular load (pressure overload) are known to elicit ventricular remodeling including cardiomyocyte hypertrophy and interstitial fibrosis. While numerous studies have focused on the mechanisms of myocyte hypertrophy, comparatively little is known regarding the response of the interstitial fibroblasts to increased cardiovascular load. Fibroblasts are the most numerous cell type in the mammalian myocardium and have long been recognized as producing the majority of the myocardial extracellular matrix. It is only now becoming appreciated that other aspects of fibroblast behavior are important to overall cardiac function. The present studies were performed to examine the temporal alterations in fibroblast activity in response to increased cardiovascular load. Rat myocardial fibroblasts were isolated at specific time-points (3, 7, 14, and 28 days) after induction of pressure overload by abdominal aortic constriction. Bioassays were performed to measure specific parameters of fibroblast function including remodeling and
European Heart Journal, 2011
Aortic stenosis induces pressure overload and myocardial remodelling with concentric hypertrophy and alterations in extracellular matrix (ECM). Aortic valve replacement leads to reverse remodelling, a process of which knowledge is scarce. The aims of the present study were to examine alterations in myocardial gene expression and subsequently identify molecular alterations important for the early phase of reverse remodelling. After 4 weeks of ascending aortic banding, mice were subjected to a debanding operation (DB) and followed for 3, 7, or 14 days. Cardiac function was assessed by echocardiography/tissue Doppler ultrasonography. Myocardial gene expression was examined using Affymetrix microarray and the topGO software and verified by real-time polymerase chain reaction. Quantitative measurements of collagen subtypes were performed. Aortic banding increased left ventricular mass by 60%, with normalization to sham level 14 days after DB. Extracellular matrix genes were the most regulated after DB. Three days after DB, collagen I was transiently increased, whereas collagens III and VIII increased later at 7 days. The ECM genes were the most altered during reverse remodelling. There was a change in isoform constitution as collagen type I increased transiently at 3 days followed by a later increase in types III and VIII at 7 days after DB. This might be important for the biomechanical properties of the heart and recovery of cardiac function.
Mechanical Stimuli for Left Ventricular Growth During Pressure Overload
Experimental Mechanics, 2020
Background: The mechanical stimulus (i.e. stress or stretch) for growth occurring in the pressure-overloaded left ventricle (LV) is not exactly known. Objective: To address this issue, we investigate the correlation between local ventricular growth (indexed by local wall thickness) and the local acute changes in mechanical stimuli after aortic banding. Methods: LV geometric data were extracted from 3D echo measurements at baseline and 2 weeks in the aortic banding swine model (n = 4). We developed and calibrated animal-specific finite element (FE) model of LV mechanics against pressure and volume waveforms measured at baseline. After the simulation of the acute effects of pressure-overload, the local changes of maximum, mean and minimum myocardial stretches and stresses in three orthogonal material directions (i.e., fiber, sheet and sheet-normal) over a cardiac cycle were quantified. Correlation between mechanical quantities and the corresponding measured local changes in wall thickness was quantified using the Pearson correlation number (PCN) and Spearman rank correlation number (SCN). Results: At 2 weeks after banding, the average septum thickness decreased from 10.6 ± 2.92mm to 9.49 ± 2.02mm, whereas the LV free-wall thickness increased from 8.69 ± 1.64mm to 9.4 ± 1.22mm. The FE results show strong correlation of growth with the changes in maximum fiber stress (PCN = 0.5471, SCN = 0.5111) and changes in the mean sheet-normal stress (PCN= 0.5266, SCN = 0.5256). Myocardial stretches, however, do not have good correlation with growth. Conclusion: These results suggest that fiber stress is the mechanical stimuli for LV growth in pressure-overload.
Cardiovascular Research, 2003
Objective: To assess whether the variable impact of quantitative changes in myocardial collagen on left ventricular (LV) diastolic myocardial stiffness (myocardial k) and remodelling (increased volume intercept of diastolic pressure-volume relations) in LV hypertrophy (LVH) is associated with alterations in myocardial collagen cross-linking. Methods: We evaluated myocardial collagen content (hydroxyproline concentrations [HPRO]) and the degree of myocardial collagen cross-linking (solubility to cyanogen bromide digestion) in 14-15-and 21-22-month-old spontaneously hypertensive rats (SHRs), and in aortic-banded rats with pressure overload hypertrophy (POH). Results: In rats with POH and in SHRs irrespective of age, increases in myocardial [HPRO] were noted. However, hypertensive rats differed in the material and geometric properties of the myocardium, and in qualitative aspects of fibrosis. In 14-15-month-old SHRs myocardial k (determined from diastolic stress-strain relations) and insoluble (cross-linked) [HPRO] were increased, but no LV remodelling or increases in myocardial soluble (non-cross-linked) [HPRO] were noted. In rats with POH, LV remodelling and increases in soluble myocardial [HPRO] occurred, but no increase in k or insoluble myocardial [HPRO] were observed. In 21-22-month-old SHRs, increases in k, soluble and insoluble myocardial [HPRO], as well as LV remodelling occurred. Conclusions: Collagen cross-linking may determine the diverse relation that exists between increases in myocardial collagen concentrations and either myocardial stiffness or chamber remodelling in hypertension. These findings support the notion that fibrosis contributes to myocardial stiffness as well as LV dilatation in LVH, albeit an effect that is modulated by collagen quality.
Circulation, 2003
Background-The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF. Methods and Results-Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] Ͼ50%, nϭ12; group 2: EF 30% to 50%, nϭ12; group 3: EF Ͻ30%, nϭ10) undergoing aortic valve replacement. Control patients were patients with mitral valve stenosis but normal LV (nϭ6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35 (splicing factor) content. ACE and TGF- 1 were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5‰ in control and group 1, 1.05 in group 2, and 6.05‰ in group 3. Death by oncosis was 0‰ in control, 3‰ in group 1, and increased to 5‰ (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02‰ in group 1 and 0.01‰ in group 2. Cardiomyocyte mitosis was never observed. Conclusions-These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction. (Circulation. 2003;107:984-991.)
Subcellular Remodeling and Heart Dysfunction in Cardiac Hypertrophy due to Pressure Overloada
Annals of the New York Academy of Sciences, 1999
Rats were treated with etomoxir, an inhibitor of palmitoyltransferase-1, to examine the role of a shift in myocardial metabolism in cardiac hypertrophy. Pressure overload was induced by abdominal aorta banding for 8 weeks. Sham-operated animals served as control. Left ventricular dysfunction, as reflected by decreased LVDP, +dP/dt, −dP/dt, and elevated LVEDP in the pressure overloaded animals, was improved by treatment with etomoxir. Cardiac hypertrophy in pressure-overload rats decreased the sarcoplasmic reticular (SR) Ca 2+ uptake and Ca 2+ release as well as myofibrillar Ca 2+-stimulated ATPase and myosin Ca 2+-ATPase activities; these changes were attenuated by treatment with etomoxir. Steady-state mRNA levels for =and >-myosin heavy chains, SR Ca 2+-pump, and protein content of SR Ca 2+-pump were reduced in hypertrophied hearts; these alterations were prevented by etomoxir treatment. The results indicate that modification of changes in myocardial metabolism by etomoxir may prevent remodeling of myofibrils and SR membrane and thereby improve cardiac function in hypertrophied heart.