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To determine how collagen is remodeled in the heart during the development of cardiac hypertrophy, the collagen concentration and the proportions of types I, III, and V collagen were analyzed in the hearts of 10-, 20-, 32-, and 40-week-old spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. The collagen concentration was calculated after the hydroxyproline content was measured and the proportions of types I, III, and V collagen were determined by non-interrupted SDS-polyacrylamide gel electrophoresis (SDS-PAGE). There was no significant difference between the collagen concentrations in 10-week-old SHR and WKY. At 20 weeks, the collagen concentration in the hearts of the SHR had decreased significantly (p < 0.01) when compared to that in the WKY, at 40 weeks, this concentration in SHR had increased significantly (p < 0.05) when compared to that in the WKY. Type V collagen in WKY increased with age and type I collagen in the 20- and 40-week-old WKY decreased significantly (p < 0.05) when compared to that in the 10-week-old WKY. However, the proportion of type I collagen in the 20-week-old WKY did not differ from that of the 40-week-old WKY. There was no significant difference between the proportions of the various types of collagen in 10-week-old SHR and those in age- and sex-matched WKY. However, the proportion of type V collagen in the 20- and 40-week-old SHR was significantly (p < 0.01) higher than that in age- and sex-matched WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

In previous studies, magnetic resonance imaging (MRI) using contrast agents was found to be useful in distinguishing reperfused infarcts from nonreperfused infarcts. However, there have been only a few detailed studies using consecutive MR images for the assessment of myocardial reperfusion during an acute myocardial infarction and also no studies have been performed using a percutaneous transluminal coronary occlusion model (closed chest model). We induced acute myocardial infarction in dogs by occluding and then reperfusing the coronary artery with a balloon catheter. ECG-gated MR images were taken using the spin-echo technique before and after Gd-DTPA injection during both coronary artery occlusion and after reperfusion. We defined the intensity ratio (IR) as the signal intensity at the ischemic area divided by that at the nonischemic area on MR images and compared each image by the IR. Without Gd-DTPA, there was no difference between infarcted and normally perfused myocardium. Infarcted myocardium had a low signal intensity (IR = 0.68 +/- 0.14) soon after Gd-DTPA injection. This difference diminished with time. After reperfusion the infarcted myocardium had a high signal intensity (IR:1.76 +/- 0.34). We conclude that Gd-DTPA- enhanced MRI can distinguish reperfused from nonreperfused infarcts soon after Gd-DTPA administration.

The ultrastructural characteristics of collagen and the localization of collagen types were studied in formalin-fixed autopsied human hearts from patients who died in an advanced stage of dilated cardiomyopathy (DCM). The three-dimensional architecture of collagen fibers was studied by scanning electron microscopy by using the cell-maceration method. The localization of collagen type I-VI was demonstrated immunohistochemically using monoclonal antibodies specific to each collagen following the treatment of specimens with trypsin. In the hearts obtained from control subjects without heart disease, there were no significant differences in the ultrastructure and localization of collagens between the fresh and the formalin-fixed hearts. Therefore, formalin-fixation did not affect the ultrastructure of collagen or the immunoreactivity. In DCM, a dense endomysial weave network consisting of fine fibrils was associated predominantly with collagen type I and III, associated moderately with type VI collagen, but less associated with type IV collagen. Perimysial collagen bundles and collagen strands increased both in number and thickness. The outstanding finding was the presence of giant coiled perimysial fibers measuring about 20-30 microns in diameter. The prominent increase in perimysial fibrosis was closely associated with the accumulation of both type I and type III collagen, and associated moderately with type VI collagen. Interestingly, type V collagen increased in the intracellular matrix of the myocardium in DCM. Type II collagen was not present in either normal or diseased hearts. These structural and immunohistochemical characteristics of collagen may provide insights important to assessing the pathogenesis of the cardiac lesion of DCM.

Whether cardiac hypertrophy is a compensatory response or a cause of decompensation has been an interesting and important controversy in cardiology. The purpose of this study is to assess qualitative and quantitative changes in biological factors involved in the evolution and the development of right ventricular hypertrophy (RVH) and right ventricular failure in response to pressure overload in rats with pulmonary hypertension induced by monocrotaline injection, and to clarify the process from compensation to deterioration in cardiac hypertrophy biochemically and morphologically. Significant RVH was produced in rats at 2 weeks after single subcutaneous injection of monocrotaline, and signs of right ventricular failure became obvious at 4 weeks as RVH became more severe. In the right ventricle of these rats, we found that: 1) myosin isoenzymes shifted from V1 to V3 both at 2 and 4 weeks; 2) total collagen content increased, and type III and type V collagens increased with a relative decrease in type I collagen at both 2 and 4 weeks; 3) intracellular Ca2+ transient recorded from isolated myocytes showed a lower peak and slower descent slope compared to those of control rats; 4) ultrastructural changes observed by scanning electron microscopy at 1 and 2 weeks disappeared gradually as heart failure developed, and degeneration or destruction of mitochondria or sarcoplasmic reticulum became remarkable at 3 and 4 weeks. These findings suggest that cardiac hypertrophy might be an ominous sign of cardiac failure rather than a benign adaptive process, at least in this model.

We investigated biochemical and structural changes in collagen in ventricles in right ventricular hypertrophy (RVH) induced by monocrotaline injection in Sprague-Dawley rats. Rats injected with monocrotaline showed significant RVH after 2 weeks compared with the vehicle-treated rats (controls). After 4 weeks, the monocrotaline-treated rats showed severe RVH with heart failure. After 2 weeks, the proportion of type III collagen in the right ventricles (RV) of the monocrotaline-treated rats increased significantly compared with controls, with a concomitant decrease in type I collagen. After 4 weeks, there was a significant increase in the proportion of type III and type V collagens in the RV. In the left ventricles (LV), the proportion of collagen types was similar in the monocrotaline-treated and control rats at 2 and 4 weeks. There was no significant difference in collagen concentration (% collagen in dry defatted tissue) between the monocrotaline-treated rats and controls at either 2 or 4 weeks in the LV and RV. Scanning electron microscopy revealed that the collagen fibrillar sheaths around the myocytes in the endomysium of the RV had thickened and formed a dense network in the monocrotaline-treated rats. In the perimysium, tendon-like collagen fibers increased and became thicker than those in the RV of controls. Giant coiled perimysial fibers were also observed in the monocrotaline-treated RV. These structural changes were more pronounced after 4 weeks of monocrotaline-treatment: Loss of myocytes was evident and was accompanied by replacement fibrosis, where dense collagen fibers aggregated parallel to the long axes of the myocytes. Our results show that biochemical and structural remodeling of collagen occurred in the RV but not in the LV during the development of RVH and heart failure, providing important clues to the pathogenesis and pathophysiology of RVH and cardiac failure in response to pressure overload.

To investigate the changes in beta-adrenergic receptors in the right and left ventricles during the development of cardiac hypertrophy, right ventricular hypertrophy (RVH) was induced in rats by a single injection of monocrotaline (M) (60 mg/kg). The rats demonstrated RVH at 2 weeks and severe RVH with congestive heart failure at 4 weeks after the injection. Changes in the beta-adrenergic receptors in the membrane fractions of both ventricles were examined in the M-treated vs. control rats using 125I-iodocyanopindolol (ICYP). Plasma and tissue catecholamines were measured. Plasma levels of norepinephrine (NE) and epinephrine (EP) showed no change at 2 weeks after the injection. However, at 4 weeks there was a significant increase in NE (p less than 0.01), but not in EP. There was no significant change in NE or EP in either ventricle at 2 weeks vs. the controls. However, at 4 weeks there was a significant increase in both NE and EP in the right ventricle (RV) (p less than 0.05). NE in the left ventricle (LV) tended to increase, but not a significant extent (p less than 0.1). With the development of RVH at 2 weeks, the maximum number of binding sites (Bmax) in both the RV and LV showed a significant decrease (p less than 0.01). There was a 21% decrease of Bmax in the RV and 15% in the LV at 2 weeks vs. the controls. At 4 weeks, the changes in Bmax were more prominent, with a 57% decrease in the RV and 22% in the LV.(ABSTRACT TRUNCATED AT 250 WORDS)

This study aimed to evaluate the change in external work and its control mechanism in the concentric hypertrophied heart induced by systemic hypertension. The calculated stroke work, myocardial contractility, afterload, and preload were examined in the baseline period (Control Stage, CS) and in the eighth week after the induction of perinephritic hypertension (Hypertensive Stage, HS) in unanesthetized dogs. These variables were examined with echocardiograms and high-fidelity left ventricular (LV) and ascending aortic pressures. Mean aortic pressure was significantly (p less than 0.05) elevated from 95 +/- 10 to 134 +/- 27 mmHg in HS. The ratio of end-diastolic wall thickness to radius significantly (p less than 0.05) increased in the HS. The calculated stroke work of the LV chamber was significantly (p less than 0.05) increased from 7022 +/- 1203 to 8860 +/- 1548 X 10(3) erg in HS while the stroke work normalized for wall thickness by calculating the wall stress was not altered (3069 +/- 1086 v.s. 2989 +/- 866 erg; CS v.s. HS) with no significant change in heart rate in HS. In the HS, the end-systolic wall stress (afterload) and the slope of end-systolic wall stress-dimension relationship (myocardial contractility) were unchanged while the end-diastolic wall stress (preload) slightly reduced. These results suggest that, in the concentric hypertrophied left ventricle induced by systemic hypertension, the LV myocardial external work is normal, whereas the LV chamber external work increases.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study is to clarify the pharmacological effects of E-1020 a new cAMP-specific phosphodiesterase (PDE) inhibitor, on cAMP or cytosolic free calcium (Ca) of cultured vascular smooth muscle cells (VSMC). VSMC were separated from the thoracic aorta of 2- to 3-month-old Wistar Kyoto rats (WKY). cAMP was measured by using the 125I-cAMP radioimmunoassay kit. The cytosolic free Ca of VSMC was measured by using the fluorescence Ca indicator, Fura-2/acetoxymethyl ester (Fura-2/AM). As a result, E-1020 increased the cAMP of VSMC in a dose-dependent manner, and about two fold increase in cAMP was observed by 10(-4) M E-1020. E-1020 decreased the cytosolic free concentration of Ca in a dose-dependent manner, and a significant decrease in cytosolic free Ca was observed by greater than 10(-6) M E-1020. These effects of E-1020 on cAMP and cytosolic free Ca were enhanced in the presence of low concentration (10(-8) M) of DL-noradrenaline. That is, a more prominent decrease in cytosolic free Ca than that of E-1020 alone was observed. Our results show that E-1020 decreases cytosolic free Ca of VSMC in parallel with increase in cAMP, and thereby suggest a potential vasodilating activity in vivo.

Intracellular membranous ultrastructural changes in the noninfarcted myocardium of the left ventricle were studied by examining experimental myocardial infarction in rats with a field emission scanning electron microscope. The left coronary artery was ligated at its origin for 7 days. The resulting infarcts comprised approximately 40% of the total area of the left ventricles. In a light microscopic study, the transverse diameter of myocytes had increased to 17.1 +/- 2.9 microns in the noninfarcted myocardium, compared to 14.1 +/- 3.1 microns in the myocardium of sham-operated rats (p less than 0.01). For the scanning electron microscopic study, the specimens were processed according to the Osmium-DMSO-Osmium method. Marked morphological changes of intracellular membranous structures were found in the noninfarcted myocardium, especially in the lacelike network of sarcoplasmic reticulum which occasionally formed large flattened cisternae, and in the marked proliferation of surface caveolae. It is speculated that these early ultrastructural changes in the noninfarcted myocardium reflect an adaptation of microorganellae in the failing hearts of the rats.

Eight patients with clinically stable chronic respiratory failure, hypoxemia (PaO2 less than or equal to 60 mmHg) and pulmonary hypertension (mean pulmonary arterial pressure greater than or equal to 20 mmHg) were allocated to long-term domiciliary oxygen therapy, and were followed for three months. Oxygen was supplied for from 15 to 18 hours daily from an oxygen concentrator at a flow rate sufficient to raise the PaO2 to 60 to 80 mmHg. We examined the effects of this therapy on right ventricular performance both at rest and during exercise in these patients. Hemodynamic data were obtained by right heart catheterization. Right ventricular ejection fractions (RVEF) were ascertained using first-pass quantitative radionuclide 81mKr angiocardiography. Thirty minutes of oxygen inhalation at rest had no significant effect on cardiac function, both before therapy (T0) and after 3 months of therapy (T1). The mean pulmonary arterial pressure and the pulmonary vascular resistance during exercise were not significantly different between T0 and T1. On the other hand, at T0, the RVEF tended to decrease from 51.6 +/- 4.9% (during oxygen inhalation at rest) to 48.7 +/- 7.9% (during exercise), whereas at T1 it significantly (p less than 0.05) increased from 48.8 +/- 6.8% (during oxygen inhalation at rest) to 54.2 +/- 8.2% (during exercise). Thus, while 3 months of long-term domiciliary oxygen therapy did not reduce the right ventricular afterload either at rest or during exercise, it was found to improve the right ventricular systolic performance during exercise. This suggested that long-term oxygen therapy could be useful in improving the quality of daily life of patients with chronic respiratory failure.

To study myocardial contractility in hypertensive hearts with normal wall motion, we examined left ventricular end-systolic wall stress-dimension relationships (ESWDR) during a baseline period (CS: control stage) and in the eighth week after induction of systemic hypertension by Page's method (HS: hypertensive stage) in unanesthetized dogs. The mean aortic blood pressure increased from 94 +/- 11 to 142 +/- 26 mmHg (p less than 0.01). The end-diastolic left ventricular posterior wall thickness increased significantly during the HS (9.4 +/- 1.3 vs 7.3 +/- 1.3 mm; HS vs CS), and its dimension was significantly (p less than 0.05) smaller than it was during the CS (37.0 +/- 4.2 vs 39.9 +/- 4.6 mm; HS vs CS). There were no significant differences between the 2 stages in left ventricular fractional shortening (31.9 +/- 5.0 vs 32.6 +/- 2.8; HS vs CS), in end-systolic meridional left ventricular wall stress (75.3 +/- 10.8 vs 68.3 +/- 15.6 10(3) dynes/cm2; HS vs CS), or in the ESWDR slopes (98.6 +/- 17.7 vs 94.0 +/- 19.7; HS vs CS). The ESWDR dimension intercepts significantly decreased from 2.0 +/- 0.3 to 1.8 +/- 0.3 cm during the HS; that is, the relationship shifted to the left with no significant change in the slope. At autopsy, the ratio of left ventricular weight to body weight of the hypertensive dogs was significantly (p less than 0.01) greater than that of sham-operated control dogs (6.0 +/- 0.9 vs 4.3 +/- 0.5 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

In order to determine whether isovolumic relaxation period (IRP) reflects left ventricular relaxation under different afterload conditions, 17 anesthetized, open chest dogs were studied, and the left ventricular pressure decay time constant (T) was calculated. In 12 dogs, angiotensin II and nitroprusside were administered, with the heart rate constant at 90 beats/min. Multiple linear regression analysis showed that the aortic dicrotic notch pressure (AoDNP) and T were major determinants of IRP, while left ventricular end-diastolic pressure was a minor determinant. Multiple linear regression analysis, correlating T with IRP and AoDNP, did not further improve the correlation coefficient compared with that between T and IRP. We concluded that correction of the IRP by AoDNP is not necessary to predict T from additional multiple linear regression. The effects of ascending aortic constriction or angiotensin II on IRP were examined in five dogs, after pretreatment with propranolol. Aortic constriction caused a significant decrease in IRP and T, while angiotensin II produced a significant increase in IRP and T. IRP was affected by the change of afterload. However, the IRP and T values were always altered in the same direction. These results demonstrate that IRP is substituted for T and it reflects left ventricular relaxation even in different afterload conditions. We conclude that IRP is a simple parameter easily used to evaluate left ventricular relaxation in clinical situations.

To elucidate the metabolic properties of the heart of spontaneously hypertensive rats (SHR), we examined the uptakes of 3H-uridine (3H) and 14C-leucine (14C) into single cultured heart cells, as well as the total protein content and cell size of heart cells in the presence and absence of stimulation, and compared the findings with those obtained with Wistar Kyoto rat (WKY) cells. As a result, (1) Spontaneous uptakes of 3H and 14C into WKY heart cells increased rapidly from day 2 to days 5-6, and then decreased gradually. In contrast, in SHR heart cells a constant increase in the uptakes of 3H and 14C was observed until the 10th day. The uptakes of both 3H and 14C into 10-day-old SHR heart cells were significantly higher than those into WKY heart cells (p less than 0.05). (2) The total protein content of SHR heart cells cultured for 4 or 5 days was significantly less than that of WKY heart cells, but there was no significant difference between cells cultured for more than 6 days. As for cell size, no significant difference was observed regardless of how long the cells were cultured. However, the increment in SHR heart cell total protein and cell size during cultivation appeared to be higher than they were in WKY heart cells. (3) Stimulation of heart cells with 10(-8) - 10(-5) M L(-)-isoproterenol (ISO) for 1 hour increased the uptake of 3H into heart cells from both kinds of rats, with no significant difference between the two.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent extensive studies suggested that some humoral factors may contribute to the development and/or reversal of cardiac hypertrophy in hypertension. The purpose of this study is to examine whether there exists humoral factor(s) for cardiac hypertrophy in experimental perinephritic hypertension in dogs. Hypertension was induced by the method of Page with some modifications. Humoral factors were studied using a microassay system that was independent of pressure overload, hemodynamic effects, and other factors. L(-)-isoproterenol (ISO) and angiotensin II (AngII) increased the uptake of 3H-uridine into 10-day-old cultured heart cells. The maximal response to ISO or AngII was obtained by 10(-5) M ISO or 10(-10) M AngII, and the percent increments in the uptake of 3H-uridine was 38.4 +/- 20.4%, and 45.1 +/- 22.5%, respectively. Moreover, ISO, DL-noradrenaline, and AngII stimulated protein synthesis of 7-day-old or 14-day-old cultured heart cells in this order (9.5 +/- 1.5, 7.3 +/- 1.2, 2.0 +/- 0.5 micrograms/6 x 10(5) by 7-day-old heart cells; 23.8 +/- 8.3, 19.0 +/- 9.4, 4.4 +/- 1.1 micrograms/6 x 10(5) by 14-day-old heart cells). Heart and kidney extracts were obtained from experimental perinephritic hypertensive dogs and sham-operated dogs. The heart extract obtained from hypertrophied left ventricle (LV) of the experimental hypertensive dogs, but not of the sham-operated dogs, increased the uptake of 3H-uridine into 10-day-old heart cells. The mean percent increment in uptake of 3H-uridine induced by the hypertrophied LV heart extract at a final concentration of 5 x 10(-3)% V/V (1-3 micrograms) in different experiments was about 15%. High performance liquid chromatography (HPLC) demonstrated that the LV heart extract obtained from the perinephritic hypertensive dogs contained at least 16 molecules. Among them, one with a molecular weight of approximately 11,200 daltons stimulated uptake of both 3H-uridine and 14C-leucine into cultured heart cells. These results demonstrated that heart extract obtained from hypertrophied LV of perinephritic hypertensive dogs contained at least one factor which may induce and/or modulate myocardial hypertrophy in this model for hypertension.

To ascertain whether or not left ventricular geometry changes during preload reduction and afterload increment, the shortening characteristics of small segments in the left ventricular free wall were examined using 4 pairs of ultrasonic crystals in 10 dogs. Three pairs of ultrasonic crystals were circumferentially implanted in the basal, the midventricular and the apical portion of the left ventricle. Another pair of crystals were longitudinally placed in the midventricle. In the control state, the shortening at the apex was largest of all segments. During preload reduction, the end-diastolic length decreased significantly in each segment. The percent shortening decreased significantly at the apical and the longitudinal segment, but it remained unchanged at the midventricular and the basal segment. During afterload increment, the end-diastolic length increased significantly, but the percent shortening remained unchanged in each segment. We concluded that left ventricular geometry was altered during preload reduction and that the apical part is more responsive to preload change than the other portion.