Mechanism of Pressure-Overload Right Ventricular Hypertrophy in Infant Rabbits (original) (raw)
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Circulation. Heart failure, 2009
Progressive left ventricular (LV) dysfunction can be a major late complication in patients with chronic right ventricular pressure overload (eg, tetralogy of Fallot). Therefore, we examined LV function (serial echocardiography and ex vivo Langendorff) and histology in a model of infant pressure-load right ventricular hypertrophy (RVH). Ten-day-old rabbits (n=6 per time point, total n=48) that underwent pulmonary artery banding were euthanized at 2 to 8 weeks after pulmonary artery banding, and comparisons were made with age-matched sham controls. LV performance (myocardial performance index) decreased during the progression of RVH, although the LV ejection fraction was maintained. In addition, RVH caused significant septal displacement, reduced septal contractility, and decreased LV end-systolic and end-diastolic dimensions, resulting in LV diastolic dysfunction with the appearance of preserved ejection fraction. Significant septal and LV free-wall apoptosis (myocyte-specific TUNEL ...
The Journal of Thoracic and Cardiovascular Surgery, 2009
Background-Abnormal hemodynamic loading often accompanies congenital heart disease, both before and after surgical repair. Adaptive and maladaptive myocardial responses to increased load are numerous. This study examined the hypothesis that myocyte loss occurs during compensatory hypertrophic growth in the developing infant myocardium subjected to progressive pressure overload.
Journal of Anatomy, 2008
Myocardial hyperplasia is generally considered to occur only during fetal development. However, recent evidence suggests that this type of response may also be triggered by cardiac overload after birth. In congenital heart disease, loading conditions are frequently abnormal, thereby affecting ventricular function. We hypothesized that chronic right ventricular pressure overload imposed on neonatal hearts initiates a hyperplastic response in the right ventricular myocardium. To test this, young lambs (aged 2-3 weeks) underwent adjustable pulmonary artery banding to obtain peak right ventricular pressures equal to left ventricular pressures for 8 weeks. Transmural cardiac tissue samples from the right and left ventricles of five banded and five age-matched control animals were studied. We found that chronic right ventricular pressure overload resulted in a twofold increase in right-to-left ventricle wall thickness ratio. Morphometric right ventricular myocardial tissue analysis revealed no changes in tissue composition between the two groups; nor were right ventricular myocyte dimensions, relative number of binucleated myocytes, or myocardial DNA concentration significantly different from control values. In chronic pressure overloaded right ventricular myocardium, significantly ( P < 0.01) more myocyte nuclei were positive for the proliferation marker proliferating cellular nuclear antigen than in control right ventricular myocardium. Chronic right ventricular pressure overload applied in neonatal sheep hearts results in a significant increase in right ventricular free wall thickness which is primarily the result of a hyperplastic myocardial response.
AJP: Heart and Circulatory Physiology, 2013
Right ventricular (RV) and left ventricular (LV) myocardium differ in their pathophysiological response to pressure-overload hypertrophy. In this report we use microarray and proteomic analyses to identify pathways modulated by LV-aortic banding (AOB) and RV-pulmonary artery banding (PAB) in the immature heart. Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta [LV-AOB; n = 6]. RV-PAB was achieved by banding the pulmonary artery ( n = 6). Controls ( n = 6 each) were sham-manipulated. After 4 (LV-AOB) and 6 (RV-PAB) wk recovery, the hearts were removed and matched RNA and proteins samples were isolated for microarray and proteomic analysis. Microarray and proteomic data demonstrate that in LV-AOB there is increased transcript expression levels for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium, and protein kinase-A signaling and increased protein expression levels of proteins for cellular macromolecular complex ...
Initial Mechanisms of the Development of Hypertonic Heart
Bulletin of Experimental Biology and Medicine, 2004
In rabbits, arterial hypertension was simulated according to Goldblatt. One, 2, 4, and 6 weeks after surgery, the hearts of control and experimental animals were extirpated for morphological examination. In semithin sections of the left and right ventricles, morphometry was performed using an Avtandilov grid. Ultrathin sections of these organs were examined under an electron microscope. It was found that the initial signs of myocardial hypertrophy appeared soon after hypertension modeling, and more early in the right ventricle. Activation of apoptosis was noted in cardiomyocytes of both ventricles, and its intensity correlated with the degree of myocardial hypertrophy. It is hypothesized that apoptosis limits the development of hypertrophy in the myocardium.
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.)
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
It is generally thought that adult mammalian cardiomyocytes compensate for an increased workload by hypertrophy, whereas fetal myocardium grows by cellular proliferation. We analyzed the response of late-fetal rat hearts upon an increased workload imposed by premature constriction of the ductus arteriosus with indomethacin. Initially the fetal heart responds by proliferative growth, as both wet weight and labeling index (bromodeoxyuridine incorporation) of the ventricles increased, whereas neither a change in the fibroblast fraction, ploidy and nucleation in the ventricles is observed. However, this hyperplastic growth is abrogated by a subsequent burst in apoptosis and followed by a hypertrophic response as based on a decrease in DNA and increase in both RNA and protein concentration. This hypertrophic growth was accompanied by a 1.4-fold increase in the volume of the cardiomyocytes. Changes in the molecular phenotype characteristic of pressure-overload hypertrophic growth accompany the process. Thus, the levels of expression of β-myosin heavy chain and atrial natriuretic factor mRNA increased, of sarcoplasmic/endoplasmic reticulum ATPase (SERCA2) mRNA decreased, and of α-myosin heavy chain, phospholamban, and calsequestrin mRNA did not change. In situ hybridization showed that the pattern of mRNA expression changed first in the right ventricular wall and subsequently in the left ventricular free wall as well. It is concluded that pressure-overload imposed on the late-fetal heart induces limited proliferative growth complemented by extensive hypertrophic growth.
In Vivo Assessment of Left Ventricular Hypertrophy in Rats: Necropsy Validation
Biotechnology & Biotechnological Equipment, 2006
Development of left ventricular hypertrophy (LVH) is a compensatory response to hemodynamic overload and echocardiography is a noninvasive, sensitive method to study the process of myocardial remodeling and functional changes. In this study we assessed in vivo the time-course of the left ventricular structural and functional changes after aortic banding and validated them by necropsy. Wistar rats were subjected to abdominal aorta banding (AAB) or sham operation. A control group of age-and sex-matched, were maintained and sacrificed in parallel with operated animals. Echocardiographic assessment was performed before and at days 10, 15, 20, 25, 35 and 45 post-operation. Some rats were euthanized at each time point to obtain body and organ weights. Echo left ventricular wall thickness (LVWT) increased progressively on the 10 th and the 15 th day, then there was a reduction on the 20 th day, followed by a second marked increase on the 25 th day and after 35 th day it presented a plateau. On the 45 th day LVWT in AAB rats increased to 35% compared with SH. The percentage of left ventricular fractional shortening was similar in different groups at each time point. These parameters remained stable in control groups. Echocardiographic parameters and actual whole heart mass were well coincided. Echo LVWT correlated well with actual whole heart mass (r=0.724, P < 0.001). We developed an easier model of significant LVH in rats, not requiring thoracotomy. The progression of myocardial hypertrophy is a time-dependent, stage developing process. The model is suitable to study the mechanisms governing the development of left ventricular hypertrophy for therapeutic benefit.