Effects of growth hormone following chronic angiotensin-converting enzyme inhibition in chronic heart failure: their relation to infarct size.

Growth hormone (GH) has been attracted as a possible adjunctive treatment for severe heart failure. However, its treatment effects have been still controversial. To assess severity of basal cardiac disease states in which GH might be effective, we analyzed the relation of treatment effects of GH following chronic angiotensin-converting enzyme (ACE) inhibition on cardiac function and structures to infarct size in rat model of chronic heart failure after myocardial infarction. One day after coronary occlusion, rats were randomized to either an ACE inhibitor, temocapril (T) (80 mg/L in drinking water) or placebo for 12 weeks. The animals received concomitant recombinant human (rh) GH (2 mg/kg/day, SC) (T + GH) or vehicle during the final 2 weeks. Compared with the T group, the T + GH group with large MI had smaller increments of left ventricular (LV) dP/dt(max) (0 vs 17%) and cardiac output (9 vs 49%), less improvement of LV relaxation (tau) (-3 vs 29%) and systemic vascular resistance (8 vs 29%), and a greater increase in LV end-diastolic pressure (123 vs -5%) than did the T+GH group with moderate MI. In the T + GH group when compared with the T group, these functional alterations were associated with a 12% reduction in the LV capillary density and a 21% increase in hydroxyproline contents in rats with large MI, whereas a 12% increase in the density and similar collagen contents were found in rats with moderate MI. Thus, prominent beneficial cardiovascular effects of the additive short-term, high-dose GH to chronic high-dose ACE inhibition were obtained in rats with moderate MI, whereas little additional benefit or even detrimental effects of GH were found in rats with large MI. The present study may provide an insight into the therapeutic strategy of GH given late after MI in the presence of chronic ACE inhibition in congestive heart failure.

Subacute tuberculous pericarditis with fibroelastic constriction diagnosed upon pericardiectomy.

A patient with subacute pericarditis showed no evidence suggesting tuberculosis until pericardiectomy was performed because of hemodynamic deterioration. The excised pericardium had a rubbery fibroelastic consistency; histologically, there were granulomatous changes characteristic of tuberculosis. Although tuberculous pericarditis is a difficult diagnosis, this case illustrates the diagnostic and therapeutic importance of early pericardiectomy before myocardial inflammatory infiltration occurs together with end-stage pericardial fibrosis and calcification.

Effects of growth hormone on cardiac dysfunction and gene expression in genetic murine dilated cardiomyopathy.

Beneficial cardiac effects of growth hormone (GH) have been shown in heart failure in several settings, but studies are lacking on this and other forms of treatment in the cardiomyopathic (CM) mouse heart. In mice with dilated cardiomyopathy due to disruption of the muscle LIM protein (MLP) gene [MLP null mice (MLP-/-)], natural history was first assessed by an initial echocardiogram at 8 weeks and a later follow-up study (n = 31). In most mice, left ventricular (LV) dilation increased and/or function decreased by 5 months, and 3 of 12 mice followed for 9 months died. At the end of follow-up, 22 MLP-/- mice (average age 10.2 months) had both LV dilation and reduced LV function and were selected for studies of GH effects on cardiac function and gene expression; mice were randomized to vehicle (controls) or recombinant human (rh) GH and restudied after 2 weeks. In the GH-treated group compared to the control group, LV % fractional shortening and LV wall thickness (echocardiography) were increased, the LV dP/dtmax (catheter-tip micromanometry) was enhanced, and LV relaxation (tau) improved; however, the LV weight was not significantly increased. The LV expression of many genes was altered in MLP-/- mice, and several were influenced by GH. Thus, short-term RhGH treatment improved LV function in a setting of chronic cardiac deterioration and significantly reduced elevated LV mRNA expression of some (ANP, BNP) but not other members of the embryonic gene program. The MLP null cardiomyopathic mouse can be useful for exploring altered signaling and therapeutic interventions in heart failure.

Progressive cardiac dysfunction and fibrosis in the cardiomyopathic hamster and effects of growth hormone and angiotensin-converting enzyme inhibition.

BACKGROUND: Growth hormone (GH) improves cardiac function in the rat with myocardial infarction, but its effects in a model of primary dilated cardiomyopathy have not been reported. GH effects were examined at early (4 months) and late (10 months) phases of disease in the cardiomyopathic (CM) hamster, and the combination of GH with chronic ACE inhibition was assessed in late-phase heart failure. METHODS AND RESULTS: CM hamsters (CHF 147 line) at 4 months showed severe systolic left ventricular (LV) dysfunction with normal LV filling pressure, and at 10 months there was more severe systolic as well as diastolic dysfunction with increasing myocardial fibrosis. Recombinant human GH alone for 3 weeks at age 4 months increased LV wall thickness and reduced systolic wall stress without altering diastolic wall stress, whereas at 10 months, wall stress and fractional shortening did not improve. The LV dP/dt(max) was enhanced at both ages by GH, which at 4 months reflected increased contractility, but at 10 months was most likely caused by elevation of the LV filling pressure. The increasing degree of fibrosis correlated inversely with LV function but was unaffected by GH. In other CM hamsters, high-dose ACE inhibition alone (quinapril), started at 8 months and continued for 11 weeks, improved LV function and inhibited unfavorable remodeling, but the addition of GH for 3 weeks at age 10 months produced increased wall thickness with little additional functional benefit and increased the LV filling pressure and diastolic wall stress. CONCLUSIONS: GH treatment alone improved LV dysfunction at 4 months of age in CM hamsters by increasing contractility and reducing wall stress but had few beneficial effects at 10 months in severe LV failure. After chronic ACE inhibition, addition of GH at 10 months had no additional beneficial effects and further increased LV diastolic pressure. These differing effects of GH may relate to the progressive increase of LV fibrosis in the CM hamster.

Effects of growth hormone and IGF-I on cardiac hypertrophy and gene expression in mice.

Cardiac hypertrophic and contractile responses were studied in mice administered growth hormone (GH) and insulin-like growth factor (IGF-I) (8 mg . kg-1 . day-1), alone or in combination (IGF-I/GH), for 2 wk. Also, changes in expression of selected left ventricular (LV) genes in response to IGF-I/GH were compared with those in other forms of cardiac hypertrophy. GH or IGF-I alone at three to four times the usual dose in rats failed to produce increases in heart and LV weights and hemodynamic effects; however, IGF-I/GH was synergistic, increasing body weight and LV weights by 39 and 35%, respectively. A measure of myocardial contractility (maximal first derivative of LV pressure, catheter-tip micromanometry) was increased by 34% in the IGF/GH group, related in part to a force-frequency effect, since the heart rate increased by 21%. Other mice were treated surgically to produce pressure overload (transverse aortic constriction) or volume overload (arteriovenous fistula) for 2 wk; LV weights were then matched to those in the IGF-I/GH group, and mRNA levels of selected markers were assessed. In contrast to the increased mRNA levels of atrial natriuretic factor, alpha-skeletal actin, and collagen III generally observed in overloaded hearts, changes in IGF-I/GH-treated mice were not significant. Thus high-dose IGF-I/GH produce cardiac hypertrophy and a positive inotropic effect without causing significant changes in expression of fetal and other selected myocardial genes, suggesting that this hypertrophy may be of a more physiological type than that due to mechanical overload.

Celiprolol, a beta-adrenoceptor antagonist with vasodilator effect, improves hemodynamic response to catecholamine, spontaneous locomotor activity, and survival in cardiomyopathic hamsters with advanced heart failure.

To assess the effects of celiprolol, which is a selective beta1-antagonist with vasodilating properties, on chronic heart failure in the cardiomyopathic hamster UM-X7.1 (CMH), we studied survival in treated CMH (celiprolol, 100 mg/kg/day) and untreated CMH. We also measured the hamsters' locomotor activity (by using an Automex system), in vivo left ventricular (LV) pressure with or without dobutamine infusion, and the myocardial beta-adrenergic-receptor density (Bmax), all at the age of approximately 210 days. Survival was significantly improved in the treated group compared with untreated group by 33.4% at the age of 210 days, and the median probabilities of survival were age 252 days in the treated group and 203 days in the untreated group (p < 0.01). The locomotor activity count was significantly higher in the treated group (14,945+/-6,895) than in the untreated group (8,264+/-2,945 counts/day; p < 0.05). The response of LV peak +/-dP/dt to dobutamine was significantly improved in the treated group by 22.9 and 34.8%, respectively, at 18 microg/kg/min. Bmax was also higher in the treated group than in the untreated group (80.1+/-15.1 vs. 65.2+/-10.6 fmol/mg; p < 0.05). This study suggests that long-term treatment with celiprolol could improve both survival and the hemodynamic responses to dobutamine, associated with the upregulation of beta-receptors, and increased locomotor activity.

Effects of growth hormone and insulin-like growth factor I in experimental heart failure.

These studies suggest that IGF-I and GH have generally favourable effects on the failing heart. They further demonstrate the ability of the severely depressed and failing heart to respond to the trophic and inotropic effects of GH. There is, however, a need for a better understanding of the mechanism of the contractility effect, the character of the hypertrophy observed (whether it is a more favourable type than that secondary to mechanical overload) and the vascular actions, both trophic and vasodilatory. In addition, the degree to which high-dose ACE inhibition or angiotensin II receptor blockade may inhibit some of these effects requires further study. Finally, it is clear that additional experimental studies and clinical trials are needed to investigate the long-term effects of GH on morbidity and mortality in heart failure, as well as the possible side-effects and other actions, such as the potential of GH to enhance skeletal muscle size and strength.

Animal models of heart failure recent developments and perspectives.

Heart failure is a complex syndrome characterized by inability of the heart to supply sufficient cardiac output to meet the metabolic needs of the body. Over the past few decades, a number of animal models of heart failure have been developed to study questions that cannot be readily studied in the clinical setting. Because the syndrome of heart failure in humans has many underlying causes, ranging from primary myocardial disease (often of unknown etiology) to myocardial failure consequent to ventricular overload with secondary cardiac hypertrophy (as in hypertension, valvular heart disease, or myocardial infarction), no single animal model can successfully mimic the pathophysiology of these clinical settings. Regardless of the original cardiac abnormality, however, the end-stage heart failure syndrome generally presents a picture of cardiac dilation and circulatory congestion associated with maladaptive neurohumoral responses affecting the heart and peripheral circulation, which provide prime targets for new treatment strategies. An ideal animal model of heart failure should mimic the clinical setting as closely as possible, be accessible and reproducible, relatively stable under chronic conditions, and sufficiently economical to permit experiments in a large number of animals. In this review, we discuss the advantages and disadvantages of naturally occurring models of heart failure and models in which heart failure is induced in normal animals, focusing in particular on models that are useful for exploring disease mechanisms and interventions to prevent or treat heart failure. Much is being learned from large animals such as the dog and pig, although small animal models (rat and hamster) have many favorable features, and as genetic methods and miniaturized physiologic techniques mature, the mouse is beginning to provide gene-based models of cardiac failure aimed at better understanding of molecular mechanisms. (Trends Cardiovasc Med 1997;7:161-167). © 1997, Elsevier Science Inc.

Influence of aortic impedance on the development of pressure-overload left ventricular hypertrophy in rats.

BACKGROUND: Aortic input impedance, which represents LV afterload, is considered to be a major determinant for the development of pressure-overload left ventricular (LV) hypertrophy. METHODS AND RESULTS: To test whether the sustained change in aortic input impedance might affect the mode of development of LV hypertrophy, coarctation of either the ascending aorta (G1, n = 13) or suprarenal abdominal aorta (G2, n = 12) was performed over 4 weeks in 6-weeks-old Wistar rats. Although peak LV pressure and total systemic resistance were increased similarly in G1 and G2, time to peak LV pressure was decreased by 24% (P < .01) in G1 compared with G2. The aortic input impedance spectra revealed that the early systolic loading in G1 was characterized by an increase in characteristic impedance, whereas the late systolic loading in G2 was by an augmented arterial wave reflection. G1 showed a smaller increase (P < .01) in either the ratio of LV weight (mg) to body weight (g) or LV wall thickness than G2 after aortic banding. Myocyte diameter was also smaller (P < .05) in G1 (14.3 +/- 0.7 mm) than in G2 (16.1 +/- 1.2 mm). The ex vivo passive pressure-volume relation had a rightward shift in G1 compared with G2, suggesting less concentric LV hypertrophy in G1. CONCLUSIONS: The sustained early systolic loading due to the increase in characteristic impedance was accompanied by less concentric, reduced hypertrophy, whereas the sustained late systolic loading due to the augmented arterial wave reflection was accompanied by concentric, adequate hypertrophy.

Left atrial conduit function for left ventricular filling dynamics in patient with myocardial infarction.

This study observed the left function in determining filling dynamics of the left ventricle in patients with myocardial infarction. The study consisted of eight control subjects and ten patients with myocardial infarction. The left ventricular filling volume is considered to be composed of the left atrial passive emptying, active emptying, and conduit volumes. The change of left ventricular filling volume was correlated with that of conduit volume (r = .87, P less than .01). However, the change of left ventricular filling volume did not have any correlation to those of left atrial passive emptying and active emptying volumes. These results suggested that the left atrial conduit function was important in determining filling dynamics of the left ventricle.

[Left ventricular isovolumic relaxation time estimated by the aortic root echocardiogram].

Dual echocardiogram was recorded simultaneously with phonocardiogram (PCG) to analyze the isovolumic relaxation time (IRT) of the left ventricle (LV) in 85 patients with various heart diseases and in 23 normal subjects. The measurements used were time intervals from the onset of the aortic component of the second heart sound (IIA) to the onset of the posterior deflection of the posterior aortic wall in the aortic root echocardiogram (X) (IIA-X interval), and to the onset of the most rapid opening motion of the anterior mitral leaflet (D') (IIA-D' interval) during early diastole. 1. The IIA-X interval was directly proportional to the IIA-D' interval in the entire study population. 2. The IIA-X interval was prolonged with advancing age in normal subjects. 3. The IIA-X interval was significantly increased in patients with hypertensive heart disease, old myocardial infarction, hypertrophic cardiomyopathy, and dilated cardiomyopathy, but significantly decreased in patients with mitral stenosis. Thus, the IIA-X interval, which was measured easily and noninvasively from the aortic root echocardiogram is a reliable indicator of the isovolumic relaxation time of the left ventricle, as well as of the IIA-D' interval.