Ultrastructural stereological analysis of acute myocardial hypertrophy of hypertensive etiology

The myocardium of Wistar rats was studied by electron microscopy after ligation of the renal artery resulting in a stable elevation of blood pressure. The ultrastructural data on the development of heart hypertrophy were described within 5 to 35 days after operation using the morphometric and stereological methods and correlation analysis. The hypertrophied cardiomyocytes showed a reduction in the ratio of the total volume density of the mitochondria, sarcoplasmic reticulum and T system to the volume density of myofibrils. It was discovered that hypertrophy of cardiomyocytes is marked by an increase in the sarcoplasmic reticulum rather than in myofibrils and other cell compartments, whereas the relative volume of mitochondria decreases.     

Ultrastructural stereological analysis of the absolute parameters of the cardiomyocytes in myocardial hypertrophy

Arterial hypertension was produced in male Wistar rats by abdominal aorta ligation. By the 35th day of experiment the animals had developed myocardial hypertrophy. The subcellular organization of cardiomyocytes was studied by electron microscopy and stereology (computation of relative and absolute parameters). In myocardial hypertrophy, the absolute volume of myofibrils, sarcoplasmic reticulum and T system in the left ventricle of the heart was increased, whereas the absolute volume of the mitochondria remained unchanged. The general surface area of all organelles was noticeably increased. The myofibrils and sarcoplasmic reticulum experienced greater changes, which may reflect the features of compensatory processes under the experimental conditions described.     

Coronary vasodilator reserve, capillarity, and mitochondria in trained hypertensive rats

To test the hypothesis that exercise training can reverse the decrements in coronary reserve, capillary density, and mitochondrial volume density evident during established hypertension, we trained spontaneously hypertensive (SHR) and normotensive (WKY) rats on a treadmill over a 3-mo period. At 7 mo of age we used microspheres to evaluate myocardial perfusion in conscious rats. Exercise training did not alter hypertension or left ventricular hypertrophy but did increase maximal O2 consumption in both SHR and WKY. A decrement in left and right ventricular coronary reserve in SHR, compared with WKY, was indicated by 1) a smaller increment in myocardial perfusion during maximal vasodilation with dipyridamole and 2) a higher minimal coronary vascular resistance per unit mass. Exercise training had no significant effect on any index of myocardial perfusion in SHR or WKY. A 12% decrement in capillary numerical density in the endomyocardium of SHR was not reversed by exercise training. We estimated the volume densities of mitochondria, myofibrils, and sarcoplasm using electron microscopy and point-counting stereology on perfusion-fixed hearts. None of the parameters in either SHR or WKY was changed by exercise training. It is concluded that exercise training does not reverse the decrements in coronary reserve and capillary numerical density associated with hypertension in adult rats. Moreover the previously observed enhancement of mitochondrial volume density due to exercise in young hypertensive rats was not observed in adult SHR.     

Myocardial lysosomes in pressure-overload hypertrophy

Summary Combined electron microscopic and cytochemical studies were used to investigate the effects of chronic-pressure overload hypertrophy on myocardial lysosomes, mitochondria, and myofibrils in the left ventricle of the cat. Myocardial hypertrophy was induced by an 84% banding constriction of the ascending aorta. After one month of aortic constriction the experimental animals demonstrated a 51% increase in left ventricular mass. No qualitative ultrastructural differences were noted between the myocardial tissues of the hypertrophy and normal group. However, the cytochemical reaction product to acid phosphatase appeared more frequently in the myocardium of the hypertrophy group compared to that of the normal group. By use of quantitative morphometry the percentage of mitochondria, myofibrils and lysosomes per myocardial cell was determined in both hypertrophy and normal groups of animals. Despite significant increases in the left ventricular mass of hypertrophy animals, a normal balance of mitochondria and myofibrils was maintained within the myocardium. Further analysis indicated an enhanced lysosomal population in the hypertrophy group compared to the normal group.This research was supported by a grant from the California Affiliate of the American Heart Association     

Evaluation of the effectiveness of the long-term use of obzidan in experimental myocardial infarct

The authors performed a comprehensive study of the recovery processes in the myocardium after occlusion of the coronary artery in 126 white rats under the effect of a long-term treatment with propranolol (0.5 mg/kg). The drug reduced the size of necrosis by 2.6 times, significantly decreased the S-T segment rise on the ECG (up to 0.86 +/- 0.09 mV versus 1.85 +/- 0.15 mV, in untreated animals with myocardial infarction, P less than 0.001). The treated animals manifested the improvement of the morphologic status of the perinecrotic area and the myocardium of the posterior wall of the left ventricle. Cardiomyocytes preserved to a considerable degree the ultrastructure of the mitochondria, demonstrating an increase in DK and protein biosynthesis (up to 296.1%, P less than 0.001). At the same time the long-term treatment with propranolol led to an appreciable activation of intracellular reparative regeneration, acceleration of the renewal of organelles, thereby promoting a decrease in the hypertrophy of cardiomyocytes (by 22.1%, P less than 0.001) as compared with control. It is concluded that propranolol administered in a dose of 0.05 mg/kg favours rapid recovery of the functional structures of the myocardium.     

Myotrophin: purification of a novel peptide from spontaneously hypertensive rat heart that influences myocardial growth

Mechanisms involved in the development or the regression of myocardial hypertrophy cannot be fully explained as responses to blood pressure control alone. We had hypothesized that the development of hypertrophy is initiated by a signal (mechanical or humoral) to the myocardium, which in turn produces a soluble factor that triggers protein synthesis and initiates myocardial growth. Using the stimulation of protein synthesis in isolated cardiac myocytes obtained from normal rat hearts as an assay system, we have identified a soluble factor from the hypertrophied myocardium of spontaneously hypertensive rats. This factor, which has been purified to apparent homogeneity, is a protein of 12 kDa. The sequence of three internally liberated peptides containing 7-24 residues was determined. Based on the determined amino acid sequences of these peptides, this factor (designated myotrophin) appears to be a novel protein that shows no homology with any previously described growth factors. Myotrophin is present in human, dog, and rat hypertrophied hearts (28-35% stimulation of protein synthesis over control) and in small amounts in normal hearts (5-6% stimulation). Myotrophin causes two dose-dependent effects in neonatal cardiac myocytes: an increase in the surface area of the myocyte and the appearance of organized myofibrils, which become apparent within 48 h. Myotrophin may play an important role in the pathogenesis of cardiac hypertrophy as well as in the normal development of cardiac myocytes.     

The features of mitochondria of cardiomyocytes from rats with chronic heart failure

Electron-microscopy study of rat myocardium 2 weeks after a heart attack revealed significant alterations in the ultrastructure of cardiomyocytes than for the control. The location of myofibrils was less regular than for normal cells. The population of interfibrillar mitochondria decreased. Mitochondrial cristae were located less densely and formed cellated structures. Swollen mitochondria were observed in the periinfarction and intact areas, indicating the development of ischemia in the myocardium as a whole. Six months after the occlusion of coronary vessels alterations in the location of myofibrils and mitochondria were mainly observed in the peri-infarction area. Mitochondria also formed cellated structures. A 30% decrease in the density of the arrangement of the inner membranes of mitochondria on an area unit was found in the periinfarction zone. The ratio between the relative volumes of mitochondria and myofibrils in the cardiomyocytes of the peri-infarction area was increased by 20%. The area of mitochondria in the intact zone of the left ventricle was 30% greater than for the control. A study of isolated living cardiomyocytes revealed that the mitochondrial- membrane potential in the rats subjected to myocardial infarction half a year ago previously was significantly lower than for the mitochondrial-membrane potential in the control rats. Thus, cardiomyocytes that were similar to healthy cardiomyocytes in their morphology exhibited lower total mitochondrial-membrane potential, indicating their decreased energy state.     

Cardiac hypertrophy in rats after supravalvular aortic constriction. I. Size and number of cardiomyocytes, endothelial and interstitial cells

The ascending aorta of 22 adult male Sprague-Dawley rats was constricted with a silver ring, and 25 animals were subjected to a sham-operation. The hearts, including the main arteries, were fixed by retrograde perfusion 3, 7, 14, 21 and 35 days after the operation. The cross-sectional area of the aorta was reduced by the constriction to an average of 20% of the values found after sham-operation. Twenty-one days after the constriction the weight of the left ventricular myocardium including the septum was increased 1.7-fold compared with controls. No further increase in weight was observed 35 days after the operation. The relative volumes of the tissue components remained largely constant in the subepicardial myocardium. In the subendocardial myocardium, however, the volume fraction of interstitial and, to a lesser extent, of endothelial tissue was significantly increased. Twenty-one days after constriction the estimated total volumes of the different myocardial components per left ventricle were increased 1.7-fold for heart muscle parenchyma, 1.8-fold for endothelial tissue, 2.9-fold for interstitial tissue, and 1.3-fold for capillary lumina compared with controls. At 35 days, only the interstitial tissue showed a further increase to 4.8-fold of control values. The mean cardiomyocyte volume was increased after aortic constriction in proportion to the increase in left ventricular weight, i.e. 1.7-fold over controls at 21 days. After 35 days its value was 29,500 +/- 790 micron 3 in rats subjected to aortic constriction compared with 16,800 +/- 640 micron 3 in controls. At this time the estimated number of cardiomyocytes per left ventricle showed no significant differences between experimental animals (2.9 X 10(7)) and controls (3.1 X 10(7)). Endothelial and interstitial cells were not only increased in average single cell volume (1.3-fold and 2.0-fold, respectively), but also in number per left ventricle (1.4-fold and 2.7-fold, respectively). Two-dimensional parameters indicated that during hypertrophy the capillary supply lagged behind the overall mass increase but achieved control levels on termination of hypertrophic growth at 35 days. These results show that even in pronounced hypertrophy the increase in mass of the myocardial parenchyma in the rat is due exclusively to an enlargement of cardiomyocytes (hypertrophy), whereas in endothelial and interstitial tissues enlargement of cells as well as increase in cell number (hyperplasia) also plays a role.     

Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs

Mild hypothermia reduces myocardial infarct size in small animals; however, the extent of myocardial protection in large animals with greater thermal mass remains unknown. We evaluated the effects of mild endovascular cooling on myocardial temperature, infarct size, and cardiac output in 60- to 80-kg isoflurane-anesthetized pigs. We occluded the left anterior descending coronary artery for 60 min, followed by reperfusion for 3 h. An endovascular heat-exchange catheter was used to either lower core body temperature to 34 degrees C (n = 11) or maintain temperature at 38 degrees C (n = 11). Additional studies assessed myocardial viability and microvascular perfusion with (99m)Tc-sestamibi autoradiography. Endovascular cooling reduced infarct size compared with normothermia (9 +/- 6% vs. 45 +/- 8% of the area at risk; P < 0.001), whereas the area at risk was comparable (19 +/- 3% vs. 20 +/- 7%; P = 0.65). Salvaged myocardium showed normal sestamibi uptake, confirming intact microvascular flow and myocyte viability. Cardiac output was maintained in hypothermic hearts because of an increase in stroke volume, despite a decrease in heart rate. Mild endovascular cooling to 34 degrees C lowers myocardial temperature sufficiently in human-sized hearts to cause a substantial cardioprotective effect, preserve microvascular flow, and maintain cardiac output.     

Role of myofibrillogenesis regulator-1 in myocardial hypertrophy

Myofibrillogenesis regulator-1 (MR-1) is a novel homologous gene, identified from a human skeletal muscle cDNA library, that interacts with contractile proteins and exists in human myocardial myofibrils. The present study investigated MR-1 protein expression in hypertrophied myocardium and MR-1 involvement in cardiac hypertrophy. Cardiac hypertrophy was induced by abdominal aortic stenosis (AAS) in Sprague-Dawley rats. Left ventricular (LV) hypertrophy was assessed by the ratio of LV wet weight to whole heart weight (LV/HW) or LV weight to body weight (LV/BW). Rat MR-1 (rMR-1) expression in the myocardium was detected by immunohistochemical and Western blotting analysis. Hypertrophy was induced by ANG II incubation in cultured neonatal rat cardiomyocytes. The effect of rMR-1 RNA interference on ANG II-induced hypertrophy was studied by transfection of cardiomyocytes with an RNA interference plasmid, pSi-1, which targets rMR-1. Hypertrophy in cardiomyocytes was assessed by [3H]Leu incorporation and myocyte size. rMR-1 protein expression in cardiomyocytes was detected by Western blotting. We found that AAS resulted in a significant increase in LV/HW and LV/BW: 89% and 86%, respectively (P < 0.01). Immunohistochemistry and Western blot analysis demonstrated upregulated rMR-1 protein expression in hypertrophic myocardium. ANG II induced a 24% increase in [3H]Leu incorporation and a 65.8% increase in cell size compared with control cardiomyocytes (P < 0.01), which was prevented by treatment with losartan, an angiotensin (AT1) receptor inhibitor, or transfection with pSi-1. rMR-1 expression increased in ANG II-induced hypertrophied cardiomyocytes, and pSi-1 transfection abolished the upregulation. These findings suggest that MR-1 is associated with cardiac hypertrophy in rats in vivo and in vitro.     

Exercise training increases the Ca(2+) sensitivity of tension in rat cardiac myocytes.

The heart is known to respond to a program of chronic exercise in ways that enhance cardiac function. However, the cellular mechanisms involved in training-induced improvements in the contractile function of the myocardium are not known. In this study we tested the hypothesis that increased contractility of the myocardium associated with exercise training is due, in part, to increases in the Ca(2+) sensitivity of steady-state tension. Female Sprague-Dawley rats were randomly divided into sedentary control (C) and exercise-trained (T) groups. The T rats underwent 11 wk of progressive treadmill exercise (1 h/day, 5 days/wk, 26 m/min, 20% grade). Evidence of training effect included a 5.9% increase in heart mass, increases in heart weight-to-body weight ratio, and a 60% increase in skeletal muscle citrate synthase activity in T rats compared with C rats. After the training program, cardiac myocytes were isolated from T and C hearts. Myocytes were chemically skinned (i.e., the sarcolemma was removed) and attached to a force transducer, and steady-state tension was determined in solutions of various Ca(2+) concentrations ([Ca(2+)]). Myocytes isolated from the hearts of T rats showed a significantly (P < 0.01) increased sensitivity of tension to [Ca(2+)]. The [Ca(2+)] giving 50% of maximal tension (pCa(50)) was 5.90 +/- 0.033 and 5.82 +/- 0.023 (SD) in T and C myocytes, respectively (n = 70 myocytes/group). This result suggests that exercise training affects the myofibrillar proteins, such that Ca(2+) sensitivity is increased, and that this may be the mechanism that underlies, at least in part, the effect of training to increase myocardial contractility.     

Regular exercise is associated with a protective metabolic phenotype in the rat heart

Adaptation of myocardial energy substrate utilization may contribute to the cardioprotective effects of regular exercise, a possibility supported by evidence showing that pharmacological metabolic modulation is beneficial to ischemic hearts during reperfusion. Thus we tested the hypothesis that the beneficial effect of regular physical exercise on recovery from ischemia-reperfusion is associated with a protective metabolic phenotype. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured in isolated working hearts from sedentary control (C) and treadmill-trained (T: 10 wk, 4 days/wk) female Sprague-Dawley rats submitted to 20 min ischemia and 40 min reperfusion. Training resulted in myocardial hypertrophy (1.65 +/- 0.05 vs. 1.30 +/- 0.03 g heart wet wt, P < 0.001) and improved recovery of function after ischemia by nearly 50% (P < 0.05). Glycolysis was 25-30% lower in T hearts before and after ischemia (P < 0.05), whereas rates of glucose oxidation were 45% higher before ischemia (P < 0.01). As a result, the fraction of glucose oxidized before and after ischemia was, respectively, twofold and 25% greater in T hearts (P < 0.05). Palmitate oxidation was 50-65% greater in T than in C before and after ischemia (P < 0.05), whereas lactate oxidation did not differ between groups. Alteration in content of selected enzymes and proteins, as assessed by immunoblot analysis, could not account for the reduction in glycolysis or increase in glucose and palmitate oxidation observed. Combined with the studies on the beneficial effect of pharmacological modulation of energy metabolism, the present results provide support for a role of metabolic adaptations in protecting the trained heart against ischemia-reperfusion injury.     

Ultrastructural morphometry of the myocardium of Thunnus alalunga

The common ventricle in the heart of the Thunnus alalunga was studied. The ventricular myocardium consists of an outer compact layer and a thick inner spongy layer. The compact layer has slightly larger cells (4-6 microns diameter) than the spongy layer (2.5-5 microns diameter). Ultrastructurally the myocardium displays normal arrangements of myofibrils and mitochondria. The sarcoplasmic reticulum is poorly developed. The intercalated discs are simple with the fascia adherens being the most frequent junctional type observed; occasionally a desmosome was seen. Nexus type junctions are present but are unassociated with the intercalated discs. There are no t-tubules evident but the plasmalemma exhibits numerous caveolae which rarely form couplings with the sarcoplasmic reticulum. A morphometric analysis of the volume percent of mitochondria and myofibrils showed that the myocardial cells in the spongy layer of the heart have a significantly greater volume percentage of mitochondria than the compact layer. No significant differences were found between myocardial regions when the volume percentages of myofibrils were compared. The physiological studies revealed that the albacore tuna has heart rates (120 bpm) and ventricular blood pressures (100 mmHg) that are among the highest reported for fish.     

STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium

The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 +/- 58 vs. 1,028 +/- 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/dt(max); 4,648 +/- 309 vs. 2,737 +/- 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum -dP/dt (-dP/dt(min); -2,239 +/- 205 vs. -1,215 +/- 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/dt(max) (4,648 +/- 309 vs. 3,241 +/- 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and -dP/dt(min) (-2,239 +/- 205 vs. -1,323 +/- 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.     

Isozymes of creatine kinase in mammalian cell culures

Previous studies on the energy metabolism of rat myocardial cells in culture supported the hypothesis that the creatine-phosphocreatine–creatine kinase system plays an important role in the intracellular transport of energy from the mitochondria to the myofibrils and in the regulation of energy production coupled to energy utilization in this model system. Effective functional compartmentation of ATP could result from the binding of creatine kinase to cellular organelles (e.g., myofibrils and mitochondria) such that high energy charge at the myofibrils is maintained by the reverse creatine kinase reaction, while phosphocreatine is synthesized mainly at the mitochondria in the forward creatine kinase reaction. It was, therefore, essential to demonstrate the presence of mitochondrial creatine kinase in the cultured myocardial cells to support this hypothesis, particularly since the mitochondrial creatine kinase was reportedly absent in fetal hearts. Using electrophoresis on cellulose acetate strips, the mitochondrial creatine kinase isozyme, as well as MM, MB, and BB isozymes, have now been demonstrated in myocardial cultures derived from neonatal rats. The mitochondrial creatine kinase increased with age in culture and with age of animal from which the culture is derived. Furthermore, the addition of creatine to culture media stimulates its synthesis. The mitochondrial creatine kinase isozyme was not detected in nonmuscle cells in culture derived from the neonatal rat hearts, nor in L6 muscle cell line. Phosphocreatine was present in all cells, but the regulation of energy metabolism and energy shuttle by creatine-phosphocreatine–creatine kinase could be operative only in the cells where the mitochondrial creatine kinase is present. This regulatory mechanism provides for an efficient system concomitant with the continuous energy demand of the myocardium; it is not ubiquitous and its development in myocardial cells seems to be triggered postnatally.     

慢性心力衰竭大鼠心肌毛细血管密度及血管内皮生长因子变化

目的观察慢性心力衰竭大鼠心肌毛细血管密度及血管内皮生长因子(VEGF)变化,探究冠脉微循环障碍的病理特点及病因机制.方法实验组(n=15)皮下注射异丙肾上腺素,对照组(n=10)皮下注射生理盐水,间隔24h,连续2次.12周后测定血液动力学;计算左心室重量/体重;HE染色、Masson染色分别观察左心室病理改变、胶原变化;西非单叶豆素组织化学染色结合图像分析确定心内膜下心肌毛细血管密度、心肌细胞密度、毛细血管密度与心肌细胞密度的比值(毛细血管/心肌细胞);观察心内膜下心肌VEGF免疫组织化学变化.结果同对照组比较,实验组左心室收缩、舒张功能下降(P<0.05);左心室重量/体重升高(P<0.001);心内膜下心肌散在坏死,胶原沉积;心内膜下心肌毛细血管密度、心肌细胞密度、毛细血管/心肌细胞下降(P<0.05);VEGF合成增加(P<0.001).结论慢性心力衰竭大鼠心内膜下心肌毛细血管分布稀疏;该区域毛细血管代偿性生成减少与心肌VEGF表达无关.     

An ultrastructural stereological analysis of the myocardium in homoiothermal animals during cooling]

By methods of electron microscopy and stereology the ultrastructural cardiomyocyte reorganization of rats exposed to influence of low temperatures (exposure during 16 days at -7 degrees C) was studied. It was shown, that with this regime of cooling the disturbance of intracellular regeneration in cardiomyocytes occurred and the complex of morphological changes typical for the syndrome of regenerative-plastic deficiency was developed. The most essential changes were seen in myofibrils and mitochondria. According to the stereologic data a change in spatial reorganization of cardiomyocytes was connected largely with these organelles. With the increase in cooling duration an increase in the volume density of myofibrils and a decrease in this parameter for mitochondria were marked. As a result of these changes the mitochondria/myofibrils volume ratio was essentially decreased. As a whole, ultrastructural reorganization of cardiomyocytes under the influence of low temperatures on rats was characterized by a decrease in the ratio of the organelle volume to myofibrillar volume. The same quantitative reorganization was revealed in atrophied cardiomyocytes under the conditions of the decreased inflow of plastic substances to cells.     

Effect of chronic stress on the ultrastructure of the myocardium and hypothalamus of "emotional" and "nonemotional" rats

The influence of chronic stress on the ultrastructure of the myocardium and hypothalamus was studied in experiments on male rats with different levels of emotional-behavioral reactivity. "Emotional" rats manifested a pronounced increase in glycogen granules in myocytes and intercellular space, appearance of the areas of overcontraction of myofibrils, conglomerates of aggregated platelets in myocardial capillaries, and red cell egress from myocardial and hypothalamic capillaries. Alterations in the ultrastructure of the myocardium and hypothalamus in "nonemotional" rats were less marked and consisted in the appearance of the areas of overcontraction of myofibrils, enlargement of sarcoplasmic reticulum caverns, and in an increase in the lipid content in cardiomyocytes. The ultrastructural changes in the myocardium and hypothalamus of "emotional" and "nonemotional" rats indicate different reactivity of the animals and are likely to be accounted for by different levels of activation of their adrenergic systems.     

Formation of transversely oriented myofibrils in myocardiocytes in the presence of heart enlargement]

Myocardial hypertrophy was induced in rats and mice by training in the pressure chamber (high altitude hypoxia) or ligation of the apex of the heart. Transversely oriented myofibrils developed in the subsarcolemma area of some cardiomyocytes of the ventricles in a fortnight; the Z bands of the newly-formed myofibrils were connected with the T tubules as in the normal myofibrils. It is supposed that this phenomenon was due to the appearance under the sarcolemma of transversely directed mechanical forrces as a result of enlargement of the cell volume.     

T4-induced cardiac hypertrophy and the perfused and total microvasculature of the heart

The purpose of the present investigation was to determine the effects of thyroxine (T4), which induces myocardial hypertrophy, on the number per square millimetre and volume per cubic millimetre of both the total and perfused portions of the arteriolar and capillary beds of the heart. Studies were conducted in the subendocardial and subepicardial regions of the left ventricle of anesthetized open-chest rabbits. Fluorescein isothiocyanate-dextran (i.v.) or radioactive microspheres (intra-atrial) were injected to label the perfused microvessels or to determine coronary flow in three groups of rabbits: controls, and rabbits given 0.5 mg/kg T4 for 3 days and for 16 days. Fluorescent photography was used to identify the perfused microvessels. An alkaline phosphatase stain was employed to locate the total microvascular bed. There were 2369 +/- 638 (SD) capillaries/mm2 and 4 +/- 3 arterioles/mm2 in control hearts. These decreased significantly to 1380 +/- 199/mm2 and 1 +/- 1/mm2, respectively, after 16 days of T4. In controls, 60 +/- 5% of the capillaries and 59 +/- 21% of the arterioles were perfused. This increased significantly to 90 +/- 5 and 86 +/- 18%, respectively, by 16 days of T4 treatment. Similar changes, although smaller, were observed after 3 days of T4. Coronary blood flow increased to 1.7 times control after 3 days and 2.9 times after 16 days of T4. No significant subepicardial versus subendocardial differences were observed in any condition or measurement. Thus, the physiological response to the increased work and increase in anatomic minimum diffusion distance is to increase flow and the proportion of the capillary bed perfused to at least maintain physiological diffusion distances.