Adaptation of the heart of the experimental animal to physical loading (morphometric characteristics)

Physical loadings produce in experimental animals various adaptive rearrangements in the cardiac muscle parts. Peculiar changes in the parts of the hyperfunctioning myocardium essentially depends on the character of physical strains. Static physical loadings produce an increase of the cardiac mass with a predominant hypertrophy of the right ventricle and dilatation of its cavity in most rats. Under swimming--in half of the observations the cardiac hypetrophy occurs mainly at the expense of analogous structural rearrangement in the left ventricle.     

Functional, morphologic and histochemical changes in the myocardium and their role in the development of cor pulmonale following pulmonary resection]

Functional, morphological and histochemical alterations were studied in 32 dogs within the period of 5 days--18 months after resection of 32-80% of the pulmonary tissue. According to the presence of hypertrophy of the heart right ventricle wall, morphological changes of the myocardium and disorders in the functional features of the cardiovascular activity all the animals were divided into 4 groups: 1--control animals; 2--experimental animals without hypertrophy of the right ventricle wall; 3--experimental animals with hypertrophy of the right ventricle wall in the stage of compensation; 4--experimental animals with hypertrophy of the right ventricle wall in the stage of decompensation. In the myocardium of the second group animals a decrease of aerobic processes and an increase of anaerobic ones were found to take place. The aerobic processes increased and the anaerobic processes decreased in the myocardium of dogs having hypertrophy of the right ventricle wall in the stage compensation. In the muscle of the decompensated pulmonary heart there occurred a pronounced decrease of aerobic and anaerobic processes, a disturbance of the protein and fat metabolism. All this resulted in a decreased contractive function of the myocardium with distrubed hemodynamics. The investigations have shown the interrelationships of morphological, histochemical and ECG alterations in the dynamics of the pulmonary heart development after resection of lungs.     

高原低氧适应动物新疆灰旱獭右心室重构的组织学改变

目的探讨新疆灰旱獭高原低氧适应性改变致右心室重构组织学改变。方法应用免疫组化技术检测新疆灰旱獭右心室缝隙连接蛋白43(CX43)蛋白表达,同时应用HE染色和Masson染色观察心室肌结构和纤维化程度变化。结果心肌细胞肥大,胶原纤维增多,右心室肥厚指数、体重指数明显增高。CX43蛋白表达减少和(或)分布的改变。结论高原低氧致新疆灰旱獭右心室结构重构,可作为研究高原低氧适应性机制的理想动物模型。     

State of the capillary network of rat myocardium in the presence of hypertrophy and physical loading

Morphofunctional state of the capillary network in various myocardial parts was studied in white rats under normal conditions, myocardial hypertrophy of different degree and under physical loading. It was demonstrated that density, metabolic surface and capacity of the capillary bed is larger in the right ventricle than in the left one. The capillary blood supply in hypertrophied myocardium, increasing simultaneously with hypertrophy, at the state of rest corresponds to its increasing mass. On the contrary, under maximal physical loading functioning of the capillary part in the myocardium becomes unadequate that is evident from a decreasing activity of the test animals.     

Structural changes in the rat myocardium in the process of adaptation to high-altitude hypoxia]

Changes in the weight of diverse parts of the heart, in cross-sectional area of myocytes and vascularization of the myocardium were studied in rat experiments under altitude hypoxia (3200 m above the sea level) during adaptation of the animals to hypoxia. Morphologically, the compensatory and adaptive reactions of the rat to hypoxia were shown by its increases weight at the expense of hypertrophy of the right ventricular myocardium. Vascularization of the myocardium augmented synchronously to its growing hypertrophy.     

Expression of neural cell adhesion molecule immunoreactivity in hypertrophic myocardium

Myocardial neural cell adhesion molecule (N-CAM) is temporally regulated, being expressed during cardiac morphogenesis and innervation and suppressed in the adult heart. We have investigated the plasticity of N-CAM expression in hypertrophic muscle using the rat model of chronic hypoxia to selectively induce right ventricular hypertrophy over a 14 day time course. Sarcolemmal and intercalated disc N-CAM immunostaining was more extensive in the ventricular myocardium of hypoxic rats compared to normoxic controls. Quantitative assessment of the immunoreactivity in tissue extracts demonstrated a selective increase in the amount of N-CAM immunoreactivity in the hypertrophic myocardium of the right ventricle of rats exposed to hypoxia and this was associated with an increase of the 125 kDa isoform. We conclude that myocardial hypertrophy may be a factor influencing N-CAM expression in the heart and adhesion molecules may have a role in cardiac remodelling.     

Morphofunctional changes in the myocardium after extensive bilateral resection of the lungs

In the experiment, performed on 89 dogs, after 67-75% resection of the lungs, functional morphology of the myocardium has been studied by means of histological, electron microscopical and morphometrical methods. Bilateral extensive resections of the lungs are accompanied with hypertrophy of the cardiac muscle, that is revealed at all the levels of its structural organization. Simultaneously, the hypertrophy develops against the background of dystrophic and destructive changes of the myocardium, their depth and extensiveness correlate with duration of the postoperative observations. If an extrapulmonary anastomosis is formed between the inferior lobular pulmonary artery and the corresponding vein before the resection of 67-75% of the lungs, it eliminates the acute overloading of the right ventricle, makes better conditions for development of compensatory-adaptive processes in the myocardium, prevents advancement of the cardio-pulmonary deficiency during the postoperative period.     

Variations in morphologic alterations in the hearts of white rats during adaptation to different types of physical loads

While adapting to physical loadings various in their character, most of rats develop a moderate hypertrophy in the right cardiac ventricle without any noticeable changes in the organ's mass. ECG dynamics is positive. Myocardial hypertrophy, at the expense of increasing mass of the left ventricle, is most regularly observed in animals subjected to forced endurance training (daily swimming); less regularly--if the loading is applied with intervals (swimming every other day) and is practically absent in rats performing work with force application. Pathological ECG changes occur more often on the background of myocardial hypertrophy and are brought about by dystrophic disorders in muscular fibres, their focal micronecrosis, by edema of the interstitial and perivascular tissue.     

Induction of hypertrophy in vitro by mechanical loading in adult rabbit myocardium

To study myocardial hypertrophy under in vitro conditions, we developed an experimental system and protocol in which mechanical conditions of isolated multicellular myocardium can be controlled while function can be continuously assessed. This in vitro culture system now allows us to investigate how mechanical overload impacts on cardiac hypertrophy in the absence of systemic factors. In this system, small right ventricular rabbit trabeculae were subjected to different modes of mechanical load, while being electrically stimulated to contract at 1 Hz at 37 degrees C. Muscles subjected to prolonged isometric contractions at high, but physiological, pre- and afterload showed a rapid induction of cardiac hypertrophy; overall muscle diameter increased by 4.3 +/- 1.4 and 17.9 +/- 4.0% after 24 and 48 h, respectively. This finding was confirmed at the cellular level; individual myocyte width significantly increased after 24 and 48 h. In muscles subjected to a low preload, or in the absence of afterload, this hypertrophic response was absent. Functionally, after 24 h of isometric contractions at high load, active developed tension had gradually increased to 168 +/- 22% of starting values. Proteomic analysis of this cultured myocardium demonstrated reproducible changes in the protein expression pattern and included an upregulation of myofilament proteins, myosin light chain isoforms, alpha-b crystalline, and breast cancer 1 protein, and a downregulation of myoglobin. We conclude that multicellular myocardium can be stressed to undergo rapid hypertrophy in vitro, and changes in function and protein expression can be investigated during the transition from healthy myocardium to early hypertrophy.     

Control of myocardial tissue components and cardiocyte organelles in pressure-overload hypertrophy of the cat right ventricle

Previous studies have demonstrated that there is a disproportionate increase in connective tissue in right ventricular myocardium subjected to pressure-overload hypertrophy associated with depressed cardiac contractility. While the myocardium is primarily responsive to load, the aim of the present study was to determine whether catecholamines also modulate the response of myocardial tissue components and cardiocyte organelles in pressure-overload-induced cardiac hypertrophy. Four experimental groups of cats were examined: a sham-operated control group, a group which had their pulmonary arteries banded in order to induce a pressure overload, a group which had been subjected to the same pressure overload, but in addition had beta-adrenoceptor blockade produced prior to and during the pressure overloading, and a group which had been subjected to the same pressure overload, but in addition had alpha-adrenoceptor blockade produced prior to and maintained during the pressure overloading. As in our previous study, there was a significant and equivalent degree of right ventricular hypertrophy in all experimental groups with pressure overload when assessed either as the ratio of right ventricular weight to body weight or as cardiocyte cross-sectional area. At the light microscopic level, the disproportionate increase in the volume density of myocardial connective tissue seen in banded animals was completely prevented by either alpha- or beta-adrenoceptor blockade. At the electron microscopic level, there was a reduction in the mitochondrial and myofibrillar volume fractions following beta-adrenoceptor blockade. The results of this study provide evidence for a modulatory role of catecholamines in the control of myocardial connective-tissue proliferation in pressure-overload-induced cardiac hypertrophy. There is also evidence to support the role of the adrenergic nervous system in regulating cardiocyte subcellular organelles, independent of the regulation of cardiocyte size.     

Pressure overload and neurohumoral activation differentially affect the myocardial proteome

Treatment with monocrotaline causes pulmonary hypertension in rats. This results in severe pressure overload-induced hypertrophy of the right ventricles, whilst the normally loaded left ventricles do not hypertrophy. Both ventricles are affected by enhanced neuroendocrine stimulation in this model. We analyzed in this model load-induced and catecholamine-induced changes of right and left ventricular proteome by two-dimensional gel electrophoresis, tryptic in-gel digest, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. All analyzed animals showed right ventricular hypertrophy without signs of heart failure. Changes of 27 proteins in the right and 21 proteins in the left ventricular myocardium were found. Given the hemodynamic features of this animal model, proteome changes restricted to the right ventricle are caused by pressure overload. We describe for the first time a potentially novel pathway (BRAP2/BRCA1) that is involved in myocardial hypertrophy. Furthermore, we demonstrate that increased afterload-induced hypertrophy leads to striking changes in the energy metabolism with down-regulation of pyruvate dehydrogenase (subunit beta E1), isocitrate dehydrogenase, succinyl coenzyme A ligase, NADH dehydrogenase, ubiquinol-cytochrome C reductase, and propionyl coenzyme A carboxylase. These changes go in parallel with alterations of the thin filament proteome (troponin T, tropomyosin), probably associated with Ca(2+) sensitization of the myofilaments. In contrast, neurohumoral stimulation of the left ventricle increases the abundance of proteins relevant for energy metabolism. This study represents the first in-depth analysis of global proteome alterations in a controlled animal model of pressure overload-induced myocardial hypertrophy.     

Myocardial reaction of the right ventricle to lung resection

Right-sided pulmonectomy (resection of 63-65% of the lung parenchyma) in white noninbred rats resulted in development of chronic cor pulmonale, that develops according to the stages: I--from the time of the operation up to the 10th-15th days after the operation--the stage of acute disturbances and mobilization forces of the organism; II--from the 11th-15th up to the 90th day is the stage of a relative steady compensatory hypertrophy of the cardiac right ventricle; III--after the 90th day--the stage of decompensation. The hypertrophy of the right ventricle myocardium transfers into its dilatation. Amount of cardiomyocytes and their nuclei in 1 mg of the right ventricle tissue progressively decreases, quantity of multinuclear cardiomyocytes increases, ploidy of the nuclei changes: number of tetraploid nuclei decreases, octaploid nuclei appear. Lethality among the animals is 56%.     

Characteristic features of EchoCG parameters in men and women with different geometric configurations

An echocardiographic study of 190 subjects in the second period of adult age (108 women and 82 men) has been conducted. The absolute and relative sizes of the left ventricle (LV), left atrium (LA), right ventricle (RV), myocardium mass, and LV mass index were determined. Morphological changes in the heart detected by echocardiography (EchoCG) depended on the geometric configuration of the LV. The size of the RV was significantly increased in women with hypertrophy of the myocardium of the LV. All the EchoCG parameters with the exception of relative wall thickness (RWT) were gender-dependent. The gender-dependent differences in LV remodeling included higher values of LV mass index in men, different dynamics of the LV mass index (LVMI) in subjects with different geometric configurations of the LV, and more pronounced elevation of the index in women with eccentric hypertrophy of the LV (LV EG), in particular. The functional capacity of the heart was lower in men than in women.     

慢性低氧对大鼠左右心室的功能及TRPC亚家族表达的影响

目的：探讨慢性低氧3周对大鼠左右心室的影响以及规范性瞬时感受器电位亚家族（TRPC）在慢性低氧诱导的右心室心肌肥厚中的表达。方法：将SD雄性大鼠48只随机分为对照组（CON组）和慢性低氧肺动脉高压模型组（CH组）（n=24）,CH组将大鼠置于连续的慢性低氧（10％±0．2％）环境饲养三周以诱导大鼠发生心肌肥厚。通过左、右心室插管法测定右心室内压（RVSP）、左心室内压（LVSP）、心率（HR）、平均体循环动脉压（mSAP）、左、右心室内压力最大上升速率（＋dp／dtmax）、最大下降速率（-dp／dkmax）、右心肥大指数（RVMI）、左心肥大指数（LVMI）;HE染色观察左、右心室心肌组织切片;通过SYBR Green荧光定量PCR法检测CON组、CH组大鼠的肥厚侧心室心肌组织编码TRPC 1／3／4／5／6／7的rnRNA表达;结合real-time RT-PCR结果对mRNA表达有显著变化的TRPC亚型通过免疫印迹法检测相应蛋白的表达。结果：与CON组相比：CH组的RVSP、RVMI、右心室±dp／dtmax显著增高（P〈0．01）,LVSP、左心室±dp／dmax无显著变化,LVMI显著降低（P〈0．01）;CH组右心室心肌细胞显著增粗（P〈0．01）,细胞内肌原纤维数量增多,心肌纤维排列紊乱,细胞核深染,形状不整;左心室心肌纤维无明显改变;CH组编码TRPCI的mRNA和蛋白显著增高（P〈0．05）,而编码其余TRPC亚型的mRNA无显著变化。结论：慢性低氧3周可特异性诱导sD大鼠产生右心室心肌肥厚,上调了编码右心室心肌细胞TRPCI通道蛋白的mRNA和蛋白的表达,TRPCI可能参与了心肌肥厚的发生发展。     

Rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium

Ubiquitin-mediated protein degradation is necessary for both increased ventricular mass and survival signaling for compensated hypertrophy in pressure-overloaded (PO) myocardium. Another molecular keystone involved in the hypertrophic growth process is the mammalian target of rapamycin (mTOR), which forms two distinct functional complexes: mTORC1 that activates p70S6 kinase-1 to enhance protein synthesis and mTORC2 that activates Akt to promote cell survival. Independent studies in animal models show that rapamycin treatment that alters mTOR complexes also reduces hypertrophic growth and increases lifespan by an unknown mechanism. We tested whether the ubiquitin-mediated regulation of growth and survival in hypertrophic myocardium is linked to the mTOR pathway. For in vivo studies, right ventricle PO in rats was conducted by pulmonary artery banding; the normally loaded left ventricle served as an internal control. Rapamycin (0.75 mg/kg per day) or vehicle alone was administered intraperitoneally for 3 days or 2 wk. Immunoblot and immunofluorescence imaging showed that the level of ubiquitylated proteins in cardiomyocytes that increased following 48 h of PO was enhanced by rapamycin. Rapamycin pretreatment also significantly increased PO-induced Akt phosphorylation at S473, a finding confirmed in cardiomyocytes in vitro to be downstream of mTORC2. Analysis of prosurvival signaling in vivo showed that rapamycin increased PO-induced degradation of phosphorylated inhibitor of κB, enhanced expression of cellular inhibitor of apoptosis protein 1, and decreased active caspase-3. Long-term rapamycin treatment in 2-wk PO myocardium blunted hypertrophy, improved contractile function, and reduced caspase-3 and calpain activation. These data indicate potential cardioprotective benefits of rapamycin in PO hypertrophy.     

Response of the rat cardiovascular system to a moderate altitude in connection with endurance training

The authors investigated whether an altitude of 1,350 m would affect the rat cardiovascular system in the same way as genuine altitude hypoxia and the way it would take effect when combined with endurance training in the form of swimming It was found that 8 weeks spent at this altitude led to an increase in absolute and relative heart weight, to right ventricular hypertrophy, and to increased resistance of the myocardium to acute anoxia. Physical training at a moderate altitude resulted in an increase in the relative weight of the musculature of both the right and the left ventricle and of the septum. Unlike low altitude training, however, growth of the two compartments of the heart was proportional. The resistance of the myocardium of trained animals against anoxia was the same, irrespective of whether they trained at a low or a high altitude. The results show that even a moderate altitude is not a matter of indifference for the rat organism, but that it leads to characteristic manifestations of altitude hypoxia in the cardiovascular system.     

Elevated expression of activated Na+/H+ exchanger protein induces hypertrophy in isolated rat neonatal ventricular cardiomyocytes

The plasma membrane protein the Na(+)/H(+) exchanger isoform1 (NHE1) has been implicated in various cardiac pathologies including ischemia/reperfusion damage to the myocardium and cardiac hypertrophy. Levels of NHE1 protein and activity are elevated in cardiac disease; however, the mechanism by which these factors contribute to the accompanying hypertrophy in the myocardium is still not clear. To investigate the mechanism of NHE1-induced hypertrophy in the myocardium we constructed two adenoviral vectors expressing either wild type NHE1 protein or a constitutively active NHE1 protein. Infection of neonatal rat ventricular cardiomyocytes (NRVM) resulted in elevated expression of both wild type NHE1 or constitutively active NHE1. Only expression of activated NHE1 protein resulted in an increase in cell size and in an increase in protein synthesis in isolated cardiomyocyte cells. The results demonstrate that expression of activated NHE1 promotes cardiac hypertrophy in isolated cardiac cells and that simple elevation of levels of wild type NHE1 protein does not have a significant hypertrophic effect in NRVM. The results suggest that regulation of NHE1 activity is a critical direct effector of the hypertrophic effect induced in the myocardium by the NHE1 protein.     

Right ventricular upregulation of the Ca(2+) binding protein S100A1 in chronic pulmonary hypertension

The Ca(2+) binding protein S100A1 increases the Ca(2+) release from the sarcoplasmatic reticulum by interacting with the ryanodine receptor. In order to understand whether this effect might be operative in the early course of hypertrophy, when myocardium is able to meet increased workload, we investigated the expression of S100A1 in a model of moderate right ventricular hypertrophy. The pulmonary arteries of nine pigs were embolised three times with Sephadex G-50. After 70 days, all pigs showed a moderate pulmonary hypertension. Right ventricular tissue of embolised animals showed a significant increase of connective tissue and enlargement of myocyte diameters. In controls, we found a differential expression of S100A1 with significantly lower S100A1 protein levels in right ventricular compared to left ventricular tissue. In pulmonary hypertension, S100A1 expression increased significantly in hypertrophied right ventricles while it was unchanged in left ventricular tissue. No change was observed in the expression of SERCA2a and phospholamban. Our data show, for the first time, that moderate pressure overload results in an upregulation of S100A1. This may reflect an adaptive response of myocardial Ca(2+) homeostasis to a higher workload.     

Enzyme activities in red and white muscles of guinea-pigs and rabbits indigenous to high altitude.

The activities of several enzymes functioning in different areas of fuel catabolism were measured under standardized conditions, using crude homogenates of sartorius and ventricular muscle from outbred guinea-pigs and rabbits indigenous to high or low altitude. The activities of sartorius and myocardium were found to reflect the metabolic patterns known to be associated with white and red muscle. Both species had right ventricular hypertrophy at high altitude. The enzyme activities in the high altitude guinea-pig were not significantly different from those in the sea level animals. In the high altitude rabbit, compared with the low altitude rabbit, the activities of glyceraldehyde-3-phosphate deydrogenase and phosphofructokinase were greater in both the sartorius and myocardium. In addition, mitochondrial glycerol-3-phosphate dehydrogenase activity was greater in the sartorius at high altitude, while aspartate aminotransferase and beta-hydroxyacylcoenzyme A dehydrogenase activities were greater in the myocardium at high altitude. Succinate dehydrogenase activity was comparable at the two altitudes for both tissues. There was a greater proportion of skeletal muscle type lactate dehydrogenase in the high altitude rabbit myocardium but no difference was found with the guinea-pig.