Myosin isoenzymes in normal and hypertrophied human ventricular myocardium

We tested the hypothesis that hypertrophy of the human heart is associated with the redistribution of ventricular isomyosins. Human cardiac myosin was isolated from autopsy samples of left ventricular free wall of patients with cardiac hypertrophy and of fetal, young, and adult subjects without heart disease. The following parameters were studied: electrophoretic migration in denaturing and non-denaturing conditions; immunological cross-reactivities with three different types of antibodies; and early phosphate burst size and steady state ATPase activities stimulated by K+-EDTA, Ca++, Mg++, and actin. The antibodies were chosen for their ability to recognize selectively the rat V1 and V3 cardiac isomyosins. The first type was a monoclonal antibody, CCM-52, prepared against embryonic chick cardiac myosin, the second was an anti-beef atrial myosin, and the third was an anti-rat V1 myosin. CCM-52 reacted with a greater affinity with rat V3 than with rat V1, and was a probe of mammalian V3. Anti-beef atrial myosin and anti-rat V1 myosin both recognized specifically beef atrial and rat V1 myosins, and were thus considered as probes of mammalian V1. Under non-denaturing conditions, human myosins migrated as rat V3 isomyosin; under denaturing conditions, no difference was observed in any of the electrophoretic parameters between all samples tested, except for the fetal hearts which contained a fetal type of light chain. The immunological studies indicated that human myosins were composed mostly of a V3 type (HV3), but contained also some V1 isomyosin. A technique was developed to quantify the amount of human VI isomyosin which was found to range from almost 0 to 15% of total myosin, and to vary from one heart to the other, regardless of the origin of the heart. Enzymatic studies showed no significant difference between normal, hypertrophied, and fetal hearts in any of the activities tested. However, there was a significant correlation between Ca++-stimulated ATPase activities and HV1 amount (at 0.05 M KCl, n = 18, r2 equal 0.49, P less than 0.01; at 0.5 M KCl, n = 18, r 2 = 0.5, P less than 0.01). These data demonstrate the heterogeneity of human ventricular myosin, which appears to be composed, as in other mammalian species, of V1 and V3 isoforms of different ATPase activities (V1 greater than V3). However it seems that V1 to V3 shifts do not appear to be of physiological significance in the adaptation of human heart to chronic mechanical overloads.     

Isoproterenol sensitivity of isolated cardiac myocytes from rats with monocrotaline-induced right-sided hypertrophy and heart failure

Rats treated with the alkaloid monocrotaline developed right ventricular hypertrophy with a left:right ventricle weight ratio of 1.35 +/- 0.10 (mean +/- s.e.m., n = 25) compared with 3.83 +/- 0.40 (n = 14) in diet-matched controls (P less than 0.001). Urine volume and sodium content were reduced and body water increased consistent with heart failure. In 10 out of 26 treated rats pleural, pericardial or peritoneal effusions were present. Urine norepinephrine content was significantly raised (P less than 0.02) but epinephrine was unchanged. Plasma norepinephrine levels were raised though not significantly. Myocytes isolated from the right ventricle had a reduced myosin Ca2+-activated ATPase (P less than 0.05) activity and a shift towards slower V2 and V3 myosin isoforms. There was no decrease in maximum contraction amplitude with calcium or isoproterenol in either left or right ventricular cells of treated rats. Right ventricular cells from treated rats showed a reduced rate of contraction in maximum isoproterenol (P less than 0.05) and a significant rightward shift in PD2 (P less than 0.05) representing a two-fold increase in EC50 for isoproterenol compared with right ventricular cells from control animals. There was no shift in EC50 for isoproterenol in left ventricle cells. In parallel experiments, myocytes isolated from both ventricles of rats treated with isoproterenol for one week showed a rightward shift of more than 50-fold in the isoproterenol concentration-response curve and a depressed response to maximum isoproterenol. In the rat monocrotaline model of right-sided cardiac hypertrophy and failure, changes in sensitivity to beta-adrenoceptor agonists are slight, and present only in the right ventricle. The lack of change in the left ventricle seems to suggest that this functional desensitisation is not a consequence of raised circulating catecholamines.     

The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats

To examine the influence of the sex hormones on mechanical properties and biochemistry of the adult heart, we studied left ventricular function and cardiac contractile proteins in hearts from 20-week-old male and female rats that had been gonadectomized at 18 days of age, compared with hearts from sham-operated animals. Testosterone and estradiol were not detectable in serum from male and female gonadectomized rats, respectively. The male rats had lower body and heart weights than male sham operated rats, whereas these values were higher in female gonadectomized than in female sham-operated rats. Left ventricular function was studied in a working heart apparatus at similar heart rate and at controlled levels of aortic diastolic pressure and left atrial pressure. At moderate left atrial pressure, end-diastolic pressure and volume per gram dry left ventricle were the same in all groups, but at high left atrial pressure, end-diastolic pressure, and volume per gram dry left ventricle were lower in male and female gonadectomized than in the respective sham-operated rats. Further increases in left atrial pressure were associated with mechanical alternans in male and female gonadectomized rats. Significantly (P less than 0.05) lower values for cardiac output, peak systolic pressure, ejection fraction, and myocardial oxygen consumption occurred in male gonadectomized compared with sham-operated rats at moderate and high left atrial pressure at higher levels of aortic diastolic pressure. Decreases in these values for female gonadectomized compared with sham-operated rats occurred only at high left atrial pressure. A significant downward shift in the mean force-velocity relationship was observed in all gonadectomized rats at both moderate and high left atrial pressure. In a follow-up study, when end-diastolic pressure was kept the same at both moderate and high left atrial pressure in female sham-operated and gonadectomized rats by reducing heart rate, decreases in contractile function in gonadectomized rats were observed at all preloads. Ca++-myosin ATPase activity was significantly reduced by 34% in male and by 19% in female gonadectomized rats when compared to respective sham-operated control hearts. These alterations in myosin ATPase activity were associated with a reduction in the V1 myosin isoenzyme and an increase in the V3 isoenzyme. Thus, left ventricular filling and left ventricular function were impaired in hearts of gonadectomized rats. Alterations in function were associated with depressed cardiac myosin ATPase activity in male and female gonadectomized rats.(ABSTRACT TRUNCATED AT 400 WORDS)     

Myosin isoenzymes of vascular smooth and cardiac muscle in the spontaneously hypertensive and normotensive male and female rat: a comparative study

Cardiac hypertrophy in hypertensive subjects, its biochemical markers, and functional consequences are of great clinical importance but still unclear. We observed a shift of the ventricular isomyosin of adult spontaneously hypertensive (H) rats of both sexes to the V3 form and a decreased myofibrillar ATPase activity in the H animals when compared to normotensive (N) controls. Compared to the male H rats, age-matched female H animals revealed a lower blood pressure, the same or even an elevated magnitude of cardiac hypertrophy, a different ventricular isomyosin pattern, and a higher myofibrillar ATPase activity. In female H rats the V1 and V3 isomyosins were equally distributed (35% V1 and 35% V3), but in male H animals the V3 was predominant (24% V1 and 45% V3). The Ca2+-regulated Mg2+-dependent myofibrillar ATPase of the rat ventricle correlated positively with the amount of V1 when measured at pCa 5 (maximum activation). At submaximum Ca2+-concentrations (pCa 6.9-5.9) the myofibrillar ATPase activities were not changed with the proportion of V1. The cooperativity of the Ca2+-activation of the myofibrillar ATPase increased with increasing amount of V1 (Hill-coefficient 3.7 with 100% V1) and decreased with increased proportion of V3 (Hill-coefficient 1.3 at 45% V3). Two myosin isoenzymes were detected in the aorta of rats, a slow migrating (S2) and a fast migrating (S1) form having both a higher mobility than the ventricular isomyosins. Only one band was observed in the portal vein, which revealed the same mobility as S2. Hypertension did not change the appearance of these vascular smooth muscle isomyosins neither in male nor in female animals.     

Right versus left ventricular stimulation: influence on induction of ventricular tachyarrhythmias in dogs

The contribution of left (versus right) ventricular stimulation to the induction of ventricular tachyarrhythmias was studied in 37 dogs with chronic experimental myocardial infarction, and 17 dogs with normal hearts. Programmed stimulation of the endocardium at both ventricular apices employed an aggressive protocol of up to 7 extrastimuli. The right ventricle was the most successful site for induction of ventricular tachycardia after myocardial infarction (74% of dogs with ventricular tachycardia). Ten of 11 animals with slow ventricular tachycardia (greater than or equal to 140 msec) were inducible from the right ventricle. In contrast, left ventricular stimulation was required to induce rapid ventricular tachycardia (cycle length less than 140 msec) in 5 of 10 dogs (P less than 0.05). No animal required more than five extrastimuli from any site for induction of ventricular tachycardia. In the normal heart, ventricular fibrillation was induced most often from the right ventricle (77% of dogs) when compared with the left ventricle (47%, P less than 0.05). Ventricular tachycardia was never induced in normal animals. These results show that the right ventricular apex is the most successful site for induction of "slow" ventricular tachycardia in this canine model when using five extrastimuli. Rapid ventricular tachycardia is frequently induced from the infarcted left ventricle, but this arrhythmia may not be clinically significant. The normal right ventricle is significantly more susceptible to ventricular fibrillation than is the left ventricle, but this does not interfere with induction of ventricular tachycardia in the infarcted heart.     

Cardiac contractile proteins in hypertrophied and failing guinea pig heart.

OBJECTIVE: The aim was to study changes in contractile proteins which accompany marked hypertrophy and heart failure in mammalian hearts initially containing predominantly V3 isomyosin. METHODS: Left ventricular myosin and myofibrillar ATPase activity and right ventricular actomyosin ATPase activity were measured in normal guinea pig hearts, in hearts which were hypertrophied as a result of progressive left ventricular systolic overload following ascending aortic banding, and in hypertrophied hearts from animals which showed signs of overt congestive heart failure. Male guinea pigs weighing 225-275 g at the time of aortic banding were used for the studies. RESULTS: Left ventricular myosin and myofibrillar ATPase activity and right ventricular actomyosin ATPase activity were correlated with body weight, left and right ventricular weight, and left ventricular peak systolic pressure during aortic occlusion. Left ventricular myosin ATPase activity and right ventricular actomyosin ATPase activity were markedly depressed in hypertrophied ventricles compared to control ventricles. Cardiac myofibrillar ATPase activity was lower in hypertrophied failing hearts than in control hearts over a wide range of calcium concentrations. In control animals and in those without heart failure, there was a nearly identical inverse relationship between left ventricular mass up to 1600 mg and myosin ATPase activity. Hypertrophied failing hearts were larger but showed little further reduction in cardiac myosin ATPase activity. Representative gel scans of non-dissociating pyrophosphate gels of left ventricular myosin from an 8 d postoperative aortic constricted animal and from its age and weight matched control showed predominantly V3 isomyosin with small amounts of V1 isoenzyme. However, preparations taken from guinea pigs 16 d after aortic constriction showed only the V3 isoform, whereas the V1 isoform was still apparent in control. Hypertrophied failing left ventricles developed less pressure per unit mass during brief aortic occlusion than non-failing left ventricles with comparable myosin ATPase activities. CONCLUSIONS: These observations raise important questions as to the distribution of myosin isoforms in the normal adult guinea pig, and the possibility that myosin ATPase activity might be altered by post-translational modification. Although cardiac myosin ATPase activity correlates with left ventricular performance, it cannot fully explain the depressed performance of failing hearts in this model. Additional immunological studies of cardiac contractile proteins are required as well as studies designed to explore the implications of altered myosin ATPase activity for both contractile function and overall cellular homeostasis.     

Comparison of contractile state and myosin isozymes of rat right and left ventricular myocardium

We compared myocardial mechanics and myosin isozymes of right and left ventricular papillary muscles from adult (6 to 8 month old) male rats. Analysis of force velocity relations indicate that right ventricular papillary muscles contract more rapidly than left at light loads (2.68 +/- 0.13 vs 2.18 +/- 0.07 muscle lengths/s measured 75 ms following stimulation, at 0.5 g/mm2; P less than 0.01). Right ventricular papillary muscles had significantly more of the alpha heavy chain containing V1 myosin isozyme and less of the V3 containing beta heavy chain myosin isozyme than left ventricular preparations (P less than 0.05). Papillary muscle and ventricular free wall myosin isozyme distribution were not significantly different within their respective chambers. The presence of a relatively larger proportion of the alpha heavy chain containing myosin isozyme (V1) in right ventricle papillary muscles relative to left correlated with the more rapid velocities of shortening seen in right ventricular papillary muscles (r = 0.60; P less than 0.01).     

Isolated ventricular myocytes from failing and non-failing human heart; the relation of age and clinical status of patients to isoproterenol response.

Single cardiac myocytes were isolated from the ventricles of failing and non-failing human hearts. The contraction amplitude, time-to-peak shortening and time to 50% and 90% relaxation were measured in cells stimulated at 0.2 Hz at 32 degrees C. The effects of increasing extracellular calcium and isoproterenol were investigated using cumulative concentration/response curves. Maximum contraction amplitude in high calcium or velocities of contraction or relaxation were not impaired in cells from failing hearts. Beta-adrenoceptor function in a single cell was assessed by the maximum contraction amplitude in the presence of isoproterenol relative to that with high calcium in the same cell (isoproterenol/calcium ratio). A decrease in the isoproterenol/calcium ratio correlated positively with an increase in the isoproterenol EC50 (concentration for half-maximal effect) for a cell (P less than 0.02, n = 39). The isoproterenol/calcium ratio in left ventricular myocytes decreased with increasing severity of disease, correlating with failure as defined by New York Heart Association class (P less than 0.001, n = 26 patients), left ventricular ejection fraction (P less than 0.001, n = 24), left ventricular end diastolic pressure (P less than 0.05, n = 21) and amount of diuretics prescribed (P less than 0.001, n = 26). In right ventricular myocytes, only increasing NYHA class correlated with decreasing isoproterenol/calcium ratios. There was a correlation of the isoproterenol/calcium ratio between right and left ventricular cells from patients with ischemic heart disease (P less than 0.05), n = 11). Beta-adrenoceptor subsensitivity occurred in mitral valve disease, ischemic heart disease, congenital abnormalities and congestive cardiomyopathy, but not in the right ventricle of patients with myocarditis. The isoproterenol/calcium ratio correlated negatively with the age of the patient (P less than 0.001, n = 26, left ventricle). Multiple regression indicated that the maximum contraction amplitudes in either high isoproterenol or high calcium declined significantly with age only, but that both age and severity of disease contributed to the decrease in isoproterenol/calcium ratio. Time-to-peak tension in isoproterenol, as well as relaxation times in high calcium also decreased with the age of the patient. Analysis of variance showed that between-patient variation was significantly greater than between-cell for most of the parameters measured. Beta-adrenoceptor desensitisation may be detected in individual myocytes from failing hearts, and this relates more to the severity of disease and the age of the patient rather than the etiology of heart failure. A decline in absolute contractility of muscle cells with age was detected.     

老年人器质性心脏病室性早搏的心电图特点

目的 探讨老年人器质性心脏病室性早搏的特点。方法 对照分析了132例老年人器质性心脏病组引起的室性早搏及94例老年非心脏病组（对照组）室性早搏的心电图特点。结果 老年心脏病组室性早搏起源于左室98例，起源于右室34例；对照组起源于左室20例，起源于右室74例。老年人心脏病组室性早搏QRS波振幅〈20mV者占67．4％，时限〉0．12s者占77．3％，有切迹或呈错折波占87．1％。与对照组比较有显著差异（P〈0．05）。结论 老年人心脏病室性早搏多起源于左室，QRS波振幅〈20mV，时限〉0．12s，形态有切迹或错折波。     

Effects of intraventricular growth hormone-releasing factor on growth hormone release: further evidence for ultrashort loop feedback

We examined the effects of cerebroventricular injection of synthetic human GH-releasing factor [hGRF-(1-44)] on regulation of GH release in conscious male rats. These results were compared with the direct effects of hGRF on hormone released from dispersed anterior pituitary cells. Administration of two higher doses of hGRF (200 and 2000 ng) into the third ventricle (3V) produced a dose-related increase in plasma GH levels (P less than 0.001). Injection of hGRF into the 3V at two lower doses actually reduced GH release. Infusion of 20 ng (5 pmol) hGRF reduced plasma GH from 5-60 min (P less than 0.005), with a maximum suppression of 66%. The 2-ng (0.5-pmol) dose decreased GH secretion by 45% (P less than 0.05). hGRF stimulated a significant and dose-dependent release of GH from dispersed pituitary cells at concentrations of 10(-10) and 10(-9) M (P less than 0.025). The specificity of GRF for GH control, whether stimulatory or inhibitory, was seen by the failure of GRF to modify PRL, TSH, or LH release. Our results indicate that injection of larger doses of GRF into the 3V produce GH release, but at lower doses, 3V GRF may exert an action centrally to inhibit GH release. We propose that hypothalamic GRF may decrease its own neurosecretion by negative ultrashort loop feedback.     

Echocardiographic and Doppler evaluation of left ventricular hypertrophy and diastolic function in black and white hypertensive patients

Echocardiography including Doppler examination has been used to assess left ventricular hypertrophy and diastolic function in 24 patients: 12 black Negro patients and 12 white patients who were matched with respect to age, heart rate and systolic and diastolic blood pressure. Significant left ventricular hypertrophy was present with normal systolic function but impaired diastolic function with a decrease in peak E velocity, an increase in peak A velocity and reversal of the E/A ratio. In the combined groups LV mass and LVPW correlated with systolic blood pressure (P less than 0.05). In the blacks systolic and diastolic blood pressure correlated with LV mass and LVPW thickness (P less than 0.05). Septal thickness correlated only with systolic blood pressure (P less than 0.01). In contrast the indices of diastolic function did not correlate with blood pressure or with left ventricular hypertrophy. No morphological differences in the left ventricle have been shown between the two groups but both had significant left ventricular hypertrophy. Whilst diastolic function is abnormal, this appeared to be independent of either blood pressure or degree of left ventricular hypertrophy. A neurohumeral mechanism has not been discounted.     

Effect of hypertonic mannitol and intraaortic counterpulsation on regional myocardial blood flow and ventricular performance in dogs during myocardial ischemia.

Studies were performed to determine if intervention with hypertonic mannitol and intraaortic balloon counterpulsation increases regional myocardial blood flow during acute myocardial ischemia. Anesthetized dogs on right heart bypass were studied. Heart rate was kept constant by atrial pacing. Myocardial ischemia was provided by ligating the proximal left anterior descending coronary artery for 12 minute periods. Infusion of hypertonic mannitol begun immediately after ligation increased coronary blood flow to the ischemic area by 36 +/- 9.0% (standard error) (P less than 0.01) and to the nonischemic left ventricle by 21 +/- 8.8% (P less than 0.05) as compared with flow in the same regions during the control coronary ligation. Intraaortic balloon counterpulsation begun immediately after ligation increased regional coronary flow to the ischemic region by 20 +/- 8.4% (P less than 0.05) but did not significantly alter flow to the nonischemic left ventricle as compared with levels during the control ligation. Combined intraaortic counterpulsation and hypertonic mannitol increased coronary flow to the ischemic region by 46 +/- 13% (P less than 0.02) and to the nonischemic left ventricle by 59 +/- 22% (P less than 0.05) as compared with flow during occlusion of the left anterior descending artery with mannitol alone. The data demonstrate that both hypertonic mannitol and intraaortic counterpulsation increase left ventricular ischemic regional flow and that combined hypertonic mannitol and intraaortic balloon counterpulsation provide a greater increase in regional coronary blood flow to both the ischemic and nonischemic regions of the left ventricle than mannitol alone.     

Pathophysiologic assessment of hypertensive heart disease with echocardiography

Assessment of the pathophysiologic changes associated with systemic hypertension has been limited by difficulty in justifying invasive studies of the left ventricle. Echocardiography, because it is notinvasive, offers an attractive method of assessing cardiac dimensions and function in hypertensive heart disease. Fourteen age-matched normotensive subjects and 31 patients with hypertension (but without clinical evidence of coronary artery disease) were studied before receiving any antihypertensive therapy. The patients with hypertension were classified into three groups on the basis of previously established electrocardiographic and chest X-ray criteria: group I, normal electrocardiogram and chest roentgenogram (13 patients); group II, left atrial abnormality by electrocardiogram and a normal chest roentgenogram (8 patients); and group III, left ventricular hypertrophy by electrocardiogram or chest roentgenogram, or both (10 patients). Mean arterial pressure increased significantly from group I to group II and from group II to group III (P is less than 0.01), and this increase was associated with a similar progressive increase in left ventricular mass assessed with echocardiogram (P is less than 0.01). A significant increase was also found in both posterior wall and septal thickness in groups II (P is less than 0.05) and III (P is less than 0.01). In association with this increased mass a significant decrease in ejection fraction and fractional fiber shortening was demonstrated in groups II (P is less than 0.05) and III (P is less than 0.01) although cardiac index was reduced only in group III (P is less than 0.05). Thus, increased ventricular mass can be identified with echocardiography at an early stage of hypertensive heart disease when only left atrial abnormality is identifiable with electrocardiographic criteria and decreased left ventricular performance occurs with increasing arterial pressure and left ventricular hypertrophy.     

心脏功能的定量化分析

目的：利用左心室压力容积环（Ｐ－Ｖ环）对心功能进行定量化分析。方法：本文提出了Ｐ－Ｖ环左侧的面积为心室收缩末势能的概念。心室总能量为收缩末势能，搏出功（ｓｔｒｏｋｅｗｏｒｋ）与充盈功之和，其能量效率为搏出功与总能量之比。利用心室造影资料绘制了２９例正常人和１１５例冠心病患者按ＮＹＨＡ分级的各种心功能心室Ｐ－Ｖ环，并分析了心室能量指标。结果：正常心室有最适搏出功，总能量和收缩末势能最低而能量效率最高。随着心功能减退，总能量和收缩末势能增大而搏出功保持稳定，能量效率下降。结论：利用Ｐ－Ｖ环对心室能量分析可对心功能及储备能力进行定量化评估。     

Short-term hemodynamic effects of diatrizoate and ioxaglate contrast media in left ventriculography

Short-term effects in left ventricular performance induced by two contrast media (low osmolar ioxaglate and high osmolar diatrizoate) were evaluated in 24 and 26 patients, respectively. In both groups a diagnosis of valvular heart disease with or without left ventricular disease had been made by noninvasive methods. Changes of hemodynamic data were evaluated in intervals of 20 sec for one min after left ventricular cineangiography. Heart rate increased following injection of both contrast media but was greater with diatrizoate for 20-60 sec (P less than 0.01). A difference in left ventricular systolic pressure was found during 0-60 sec (P less than 0.01), with a decrease in peak left ventricular systolic pressure using diatrizoate (P less than 0.01). In 16 patients without valvular insufficiency, the positive inotropic effect as shown by maximum positive left ventricular pressure slope was more pronounced for diatrizoate during the period of 40-60 sec (P less than 0.05). A decrease in left ventricle relaxation as shown by an increase in the time constant of pressure decay was found for both contrast media. There was no significant difference in relaxation time constant between the two contrast media. During the period of 20-40 sec, the increase in left ventricular end-diastolic pressure was more pronounced for ioxaglate (P less than 0.01) with no untoward consequences in our population of patients.     

The effect of growth hormone on rat myocardial collagen.

Growth hormone (GH) can increase cardiac performance, but conditions with GH excess, such as acromegaly, are associated with hypertrophy and fibrosis of the heart. The aim of this study was to examine the effect of GH administration on rat myocardial collagen.Female rats were injected with GH (5 mg/kg/day) for 80 days. The weight of the right ventricle (RV) and the left ventricle (LV) was increased in the GH-treated group compared with the control group (P< 0.001). No differences in the ratio of heart weight/body weight or ventricle weight/body weight were found. The total amount of RV and LV collagen was increased in the GH-treated group (P< 0.001), but the collagen concentration was decreased (P< 0.001). Histomorphometry showed that the area fraction of collagen relative to myocytes remained unchanged. The composition of ventricular collagen in the GH-injected group did not differ from that of the control group concerning the relative amounts of collagen types I and III and pyridinoline, a mature collagen cross-link.We conclude that GH induced a substantial, but proportionate growth of the myocardium without formation of fibrosis. GH actually decreased the collagen concentration, and did not change the composition of myocardial collagen.     

The aging of the heart: weight and structural changes in the left ventricle with age]

Structural alterations of the cardiovascular system with aging are difficult to differentiate from superimposed pathologic processes. To determine whether aging "per se" affects the dimension of the heart, the weight of the heart, and the left ventricle and their rations to body weight, left ventricle wall thickness, the number of myocyte nuclei in the ventricle and the myocyte cell volume per nucleus were measured in 67 autopsies of subjects, 45 males and 22 females, who died from causes independent of cardiovascular diseases, from 17 to 90 years old. With aging, total heart weight increased slightly, while left ventricular and interventricular septum weights after dissection of the subepicardial fat decreased significantly (r = 0.44; p less than 0.001). Although left ventricular wall thickness remained constant with time, left ventricular weight to body weight ratio decreased progressively. At the structural level the number of myocyte nuclei within the left ventricle decreased (r = 0.45; p less than 0.001), whereas myocyte cell volume per nucleus increased (r = 0.30; p greater than 0.05) with age. Thus, the aging process of the heart is associated with a reduction in volume of the myocardial mass resulting from myocyte cell loss and reactive hypertrophy of the spared myocytes.     

Myocardial changes in pressure overload-induced left ventricular hypertrophy. A study on tissue composition, polyploidization and multinucleation.

Morphological changes in human myocardium associated with pressure overload-induced left ventricular hypertrophy were studied in 22 normal and 21 hypertrophic hearts obtained at autopsy. Samples were obtained from the left lateral ventricular wall, half way between the apex and the base. Myocyte dimensions, polyploidization, multinucleation and relative volume fractions were studied. Regression analysis in relation to indexed heart weight yielded statistically significant correlation coefficients for myocyte volume: r = 0.69 (P less than 0.001), for degree of polyploidization: r = 0.77 (P less than 0.001), for number of nuclei per myocyte: r = 0.47 (P less than 0.01) and for volume fraction of myocytes: r = 0.32 (P less than 0.05). Approximate numbers of myocytes and connective tissue cells per left ventricle were calculated. Correlation coefficients related to indexed heart weight were r = 0.34 (P less than 0.05) for the number of myocytes and r = 0.76 (P less than 0.001) for the number of connective tissue cells. Based on regression analysis in relation to indexed heart weight, we calculated that a doubling of indexed heart weight was associated with an increase in mean myocyte volume by 65%, degree of polyploidization by 24%, multinucleation by 7%, number of myocytes by 20% and number of connective tissue cells by 141%. The volume percentage of myocytes decreased by 6% in favour of the connective tissue fraction. These changes in myocardial composition indicate that the term 'hypertrophy' inadequately describes the actual myocardial changes in response to pressure overload.     

Assessment of left atrial function in patients with hypertensive heart disease

Left atrial function in patients with hypertensive heart disease was compared with that in control subjects. In patients with hypertensive heart disease, the time constant of left ventricular relaxation was significantly greater than that in controls (54 +/- 18 vs 31 +/- 16 msec; p less than 0.01). The ratio of left ventricular filling volume before atrial contraction (left atrial reservoir volume/left atrial emptying volume before atrial contraction, and conduit volume/flow volume from the pulmonary vein into the left ventricle) to left ventricular stroke volume was significantly smaller than that in controls (65 +/- 13 vs 76 +/- 7%; p less than 0.05). In patients with hypertensive heart disease, the ratio of reservoir volume to stroke volume was not significantly different from that in controls, while the ratio of conduit volume to stroke volume was significantly smaller than that in controls (43 +/- 13 vs 57 +/- 9%; p less than 0.05). The latter ratio was inversely correlated with the time constant of left ventricular relaxation (r = -0.05, p less than 0.05). In patients with hypertensive heart disease, the ratio of left ventricular filling volume during atrial contraction to stroke volume was significantly larger than that in controls (35 +/- 13 vs 24 +/- 7%; p less than 0.05). The ratio of left ventricular filling volume during atrial contraction to stroke volume had a significant inverse correlation with the ratio of conduit volume to stroke volume (r = -0.84, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in Ca2+ cycling proteins and G alpha q signaling after left ventricular assist device support in failing human hearts

OBJECTIVE: Left ventricular assist device support mechanically unloads the failing ventricle with resultant improvement in cardiac geometry and function in patients with end-stage heart failure. Activation of the G alpha q signaling pathway, including protein kinase C, appears to be involved in the progression of heart failure. Similarly down-regulation of Ca2+ cycling proteins may contribute to contractile depression in this clinical syndrome. Thus we examined whether protein kinase C activation and decreased Ca2+ cycling protein levels could be reversed by left ventricular assist device support. METHODS: Left ventricular myocardial specimens were obtained from seven patients during placement of left ventricular assist device and heart transplantation. We examined changes in protein levels of G alpha q, phospholipase C beta 1, regulators of G protein signaling (RGS), sarcoplasmic reticulum Ca2+ ATPase, phospholamban and translocation of protein kinase C isoforms (alpha, beta 1, and beta 2). RESULTS: The paired pre- and post-left ventricular assist device samples revealed that RGS2, a selective inhibitor of G alpha q, was decreased (P < 0.01), while the status of G alpha q, phospholipase C beta 1, RGS3 and RGS4 were unchanged after left ventricular assist device implantation. Translocation of protein kinase C isoforms remained unchanged. Left ventricular assist device support increased sarcoplasmic reticulum Ca2+ ATPase protein level (P < 0.01), while phospholamban abundance was unchanged. CONCLUSIONS: We conclude that altered protein expression and stoichiometry of the major cardiomyocyte Ca2+ cycling proteins rather than reduced phospholipase C beta 1 activation may contribute to improved mechanical function produced by left ventricular assist device support in human heart failure.