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PubMed1987

Effect of age on the development of cardiac hypertrophy produced by aortic constriction in the rat.

To test the hypothesis that the capacity to develop left ventricular (LV) hypertrophy might diminish with advancing age, we examined the hypertrophic response to ascending aortic constriction in 3 groups of adult Fischer 344 rats (9 months, 18 months, and 22 months of age). Aortic constriction was created so that aortic cross-sectional areas would be the same for the 3 groups of rats. Four weeks after imposition of aortic constriction, there was no significant difference in peak LV pressure, peak-to-peak and mean systolic pressure gradients between left ventricle and aorta, cardiac output, LV minute work, or cross-sectional area of the aortic constrictions in the 3 groups. In 9-month-old aortic-constricted rats, LV dry wt (LVDW)/body wt, LVDW/tibial length, and myocyte width increased by 23% (p less than 0.01), 14% (p less than 0.01), and 27% (p less than 0.01), respectively, compared with sham-operated rats. In contrast, in 18-month-old and 22-month-old aortic-constricted rats, LVDW/body wt and LVDW/tibial length were unchanged compared with sham-operated controls, and increases in myocyte width were only modest 4 weeks following constriction. RNA concentration in the myocardium 5 days after constriction increased by 21% (p less than 0.001) in 9-month-old rats but showed no significant rise in 18-month-old rats. These results suggest that advancing age is associated with a diminished capacity to develop myocardial hypertrophy in response to acute pressure overload and that a reduced ability to synthesize protein may be one of the major contributing factors to a diminished capacity for hypertrophy in advanced age.

Aging↗
PubMed1995

The molecular genetics of cardiovascular disease.

The following consideration of this past year's published studies uses the cited reports as important examples of the ongoing characterization of the molecular basis of cardiac disease and the process of cardiac development. Mutations in cardiac troponin T and alpha-tropomyosin have been identified in familial hypertrophic cardiomyopathy, as have new beta-myosin heavy chain gene mutations. The general relation between beta-myosin heavy chain gene mutations that produce a charge change versus conservative amino acid replacements and sudden death remains unresolved. New fibrillin 1 gene mutations have been identified in patients with Marfan syndrome, the neonatal form of Marfan syndrome, and ectopia lentis. The same mutation is rarely found in more than one family. The association of supravalvar aortic stenosis and elastin gene mutations was further strengthened. The complexity of the relation between dystrophin mutations and the cell-specific loss of dystrophin expression can result in patients having cardiomyopathy and no myopathy. X-chromosome inactivation was shown to be the basis of cardiomyopathy in women with a single mutated dystrophin allele. New candidate genes that control cardiac morphogenesis and myocyte differentiation were proposed. New evidence to support 22q11 microdeletions as a common basis of nonsyndromic conotruncal malformations was published. These studies represent an important beginning. Although mutant genes have been recognized in affected individuals with various syndromes and congenital cardiac abnormalities, our understanding of how a genotype yields a given phenotype remains to be established.

Adult↗
PubMed1995

Recent insights into the regulation of cardiac Ca2+ flux during perinatal development and in cardiac failure.

Systolic and diastolic cardiac function improve during the transition from fetus to newborn to adult. This perinatal maturation is temporally correlated with and at least partially dependent on subcellular changes in the expression of several gene products that regulate cytosolic Ca2+ concentration. Expression of the Na(+)-Ca2+ exchanger of the sarcolemma is highest in the fetus, whereas expression of the sarcoplasmic reticulum Ca2+ pump and the voltage-dependent Ca2+ channel of the sarcolemma increase in conjunction with the perinatal maturation of cardiac function. Whereas cardiac relaxation in the normal mature heart depends primarily on the sarcoplasmic reticulum Ca2+ pump, relaxation in the fetal heart appears to be more dependent on transsarcolemmal Ca2+ flux. Like the fetal heart during prolonged relaxation, the failing human heart exhibits impaired relaxation and abnormal Ca2+ flux regulation. Although altered expression of several gene products has been demonstrated in the failing heart, the responsible factor(s) remains unknown.

Adult↗
PubMed1976

Antihypertensive effect and side-effects of bendroflumethiazide and propranolol.

The antihypertensive effect and side-effects during 12 months' treatment with bendroflumethiazide and propranolol have been compared in two randomly selected, equally large groups (n= 53) of previously untreated male hypertensives. Systolic BP above 170 or diastolic BP above 105 mmHg on two occasions were defined as hypertension. The same BP reduction was achieved in both groups. During the 12 months' treatment one subject on bendroflumethiazide developed diabetes mellitus and one on propranolol developed cardiac decompensation. None developed gout. Contrary to what had been presumed, glucose tolerance improved during 12 months' treatment with both agents, while there were no changes in fasting blood sugar, insulin or triglyceride concentrations. No changes were found in serum potassium or total body potassium during 12 months' bendroflumethiazide treatment, while serum potassium increased during treatment with propranolol. Uric acid increased slightly during treatment with both agents. Prolongation of the follow-up to 24 months did not change any of the findings regarding metabolic changes during treatment. The frequency of subjective side-effects decreased to the same extent during treatment with both drugs. It is concluded that bendroflumethiazide and propranolol are equally useful as antihypertensive agents and that the risk of impariment of glucose metabolism and potassium balance seems to be very slight during treatment with bendroflumethiazide in mild hypertension.

Bendroflumethiazide↗
PubMedDate not supplied

Effects of cardiomyoplasty on cardiac growth in rats.

BACKGROUND AND AIM OF THE STUDY: Cardiomyoplasty (CMP) has been proposed as a treatment for pediatric patients, but restriction of cardiac growth by the muscle wrap is a potential source of concern. This possibility was investigated in an immature animal model. METHODS: Six-week-old rats (body weight 203.8 +/- 5.4 g, mean +/- SEM) underwent either left thoracotomy with CMP (group I, n = 7), or thoracotomy without CMP (group II, n = 8). A third group (group III, n = 7) served as untreated controls. Final measurements were made 20 weeks later after body weights had reached a plateau. RESULTS: Preoperative body weights were not significantly different between the groups. At elective sacrifice, the body weights of animals that underwent surgery did not differ significantly (group I, 558.0 +/- 21.5 g and group II, 617.3 +/- 20.3 g), but were significantly less than those of control animals (727.6 +/- 13.3 g, p < 0.001 and p < 0.01, respectively). Cardiac ventricular weights in the CMP group were significantly less than those of control animals (group I, 1.21 +/- 0.06 g; group III 1.45 +/- 0.04 g; p < 0.01), but were not statistically different from those of the sham thoracotomy group (group II, 1.36 +/- 0.05 g). Mean left ventricular end-diastolic volumes were similar in all groups (group I, 0.67 +/- 0.07 mL; group II, 0.66 +/- 0.07 mL; and group III, 0.69 +/- 0.10 mL; p = ns). CONCLUSIONS: A major surgical procedure impairs growth in juvenile rats. no evidence emerged from this study for additional restriction of cardiac development due to cardiac wrapping. However, studies that include stimulated muscle wraps are needed before CMP should be considered for the pediatric age group.

Animals↗
PubMed2005

Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute beta-adrenergic stimulation.

Signaling pathways underlying transition of cardiomyocyte growth from hyperplasia in fetal/newborn to hypertrophy in postnatal/adult hearts are not well understood. We have shown that beta-adrenergic receptor (beta-AR)-mediated regulation of neonatal cardiomyocyte proliferation involves p70 ribosomal protein S6 kinase (p70S6K). Here we examined the ontogeny of phosphoinositide 3-kinase (PI3K)/p70S6K signaling pathway in rat hearts and investigated the influence of beta-AR on this pathway during development. Cardiac PI3K and p70S6K1 activities were high in the embryonic day 20 fetus, decreased gradually postnatally, and were low in the adult. In contrast, p70S6K2 was barely detectable. Phosphorylation of p70S6K1, Akt, and phosphoinositide-dependent protein kinase 1 were markedly increased in late gestation and early postnatal life but not in adult hearts. Phosphatase and tensin homolog on chromosome 10 (PTEN), a negative regulator of PI3K, was highly expressed in adult hearts but only at low levels and mostly in the phosphorylated (inactivated) form in the fetus. Beta-AR stimulation resulted in increased cardiac p70S6K1 activity only in animals > or = 2 wk old, whereas Akt level was increased in all developmental stages tested. These increases were accompanied by increased Bcl-2 associated death promoter (Ser136) phosphorylation without changes in PTEN level. Thus there is globally high input of cardiac PI3K signaling during the fetal-neonatal transition period. Inactivation of PTEN may in part contribute to the high activity of PI3K signaling, which coincides with the period of high cardiomyocyte proliferation. Beta-AR stimulation activates cardiac p70S6K1 and Akt in postnatal animals and may activate cardiac survival signals. These data provide further evidence for the importance of beta-AR and PI3K signaling in the regulation of cardiac growth during development.

Adrenergic beta-Agonists↗
PubMed2006

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo.

Combinatorial interactions between cis elements and trans-acting factors are required for regulation of cardiac gene expression during normal cardiac development and pathological cardiac hypertrophy. Sp factors bind GC boxes and are implicated in recruitment and assembly of the basal transcriptional complex. In this study, we show that the cardiac troponin T (cTnT) promoter contains a GC box that is necessary for basal and cAMP-mediated activity of cTnT promoter constructs transfected in embryonic cardiomyocytes. Cardiac nuclear proteins bind the cTnT GC box in a sequence-specific fashion and consist of Sp1, Sp2, and Sp3 protein factors. By chromatin immunoprecipitation, Sp1 binds the cTnT promoter "in vivo." Cotransfected Sp1 trans-activates the cTnT promoter in cardiomyocytes in culture. Sp3 represses Sp1-mediated transcriptional activation of the cTnT gene in embryonic cardiomyocytes. Sp3 repression of Sp1-mediated cTnT promoter activation is dose dependent, inferring a mechanism of competitive binding/inhibition. To evaluate the role of Sp factors in cardiac gene expression in vivo, we have established a clinically relevant animal model of pathological cardiac hypertrophy where the fetal cardiac program is activated. In this animal model, cardiac hypertrophy results from increased left-right shunting, volume loading of the left ventricle, and pressure loading of the right ventricle. Sp1 expression is increased in all four hypertrophied cardiac chambers, whereas Sp3 expression is diminished. This observation is consistent with the in vitro activating function of Sp1 and inhibitory effects of Sp3 on activity of cTnT promoter constructs. Sp factor levels are modulated during the hypertrophic cardiac program in vivo.

Animals↗
PubMed2001

Complete heart block and sudden death in mice overexpressing calreticulin.

The expression of calreticulin, a Ca(2+)-binding chaperone of the endoplasmic reticulum, is elevated in the embryonic heart, and because of impaired cardiac development, knockout of the Calreticulin gene is lethal during embryogenesis. The elevated expression is downregulated after birth. Here we have investigated the physiological consequences of continued high expression of calreticulin in the postnatal heart, by producing transgenic mice that overexpress the protein in the heart. These transgenic animals exhibit decreased systolic function and inward I(Ca,L), low levels of connexin43 and connexin40, sinus bradycardia, and prolonged atrioventricular (AV) node conduction followed by complete heart block and sudden death. We conclude that postnatal downregulation of calreticulin is essential in the development of the cardiac conductive system, in particular in the sinus and AV nodes, when an inward Ca(2+) current is required for activation. This work identifies a novel pathway of events, leading to complete heart block and sudden cardiac death, which involves high expression of calreticulin in the heart.

Animals↗
PubMed2002

Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression.

To investigate the role of insulin signaling on postnatal cardiac development, physiology, and cardiac metabolism, we generated mice with a cardiomyocyte-selective insulin receptor knockout (CIRKO) using cre/loxP recombination. Hearts of CIRKO mice were reduced in size by 20-30% due to reduced cardiomyocyte size and had persistent expression of the fetal beta-myosin heavy chain isoform. In CIRKO hearts, glucose transporter 1 (GLUT1) expression was reduced by about 50%, but there was a twofold increase in GLUT4 expression as well as increased rates of cardiac glucose uptake in vivo and increased glycolysis in isolated working hearts. Fatty acid oxidation rates were diminished as a result of reduced expression of enzymes that catalyze mitochondrial beta-oxidation. Although basal rates of glucose oxidation were reduced, insulin unexpectedly stimulated glucose oxidation and glycogenolysis in CIRKO hearts. Cardiac performance in vivo and in isolated hearts was mildly impaired. Thus, insulin signaling plays an important developmental role in regulating postnatal cardiac size, myosin isoform expression, and the switching of cardiac substrate utilization from glucose to fatty acids. Insulin may also modulate cardiac myocyte metabolism through paracrine mechanisms by activating insulin receptors in other cell types within the heart.

Animals↗
PubMed1991

Development of cardiac failure by coronary small vessel disease in hypertensive heart disease?

In essential hypertension, ventricular function is determined primarily by the degree of hypertrophy (myocardial factor) and by organic complications in the coronary artery (coronary factor). Ventricular function is inversely correlated with ventricular size and systolic wall stress, inasmuch as ventricular function diminishes when these two variables increase. Even the young hypertensive heart of normal size with no angiographic abnormalities appears to be prone to ischemia, because the coronary reserve is seriously limited even in the absence of coronary stenosis. Unlike ventricular distensibility, myocardial compliance may be normal, even in the presence of pronounced myocardial hypertrophy. As myocardial compliance decreases, systolic wall stress increases and ventricular function is reduced. The hypertensive heart, the most common form of an irregular hypertrophy of the ventricular wall, is found in 14% of such cases. Analysis of the degree of hypertrophy shows that the hypertrophy can be inappropriately high (high mass-to-volume ratio, reduced wall stress), appropriate, or inappropriately low (normal mass-to-volume ratio, increased wall stress). One of the profound mechanisms influencing both myocardial and coronary function in hypertensive heart disease is the pressure-dependent development of smooth vascular hypertrophy (media) or coronary resistance vessels. Consequently, the oxygen supply to the myocardium is impaired and secondary lesions occur such as fibrosis, increased myocardial and perivascular collagen content and scars within the heart muscle. Diastolic dysfunction develops, as well as an increase in myocardial stiffness, thus promoting the transition from the concentric (compensated) to the eccentric or dilated (decompensated) state, with the consequence of the occurrence of cardiac failure. On the basis of both functional and morphological criteria, evidence is presented in this report that coronary small vessel disease is one of the underlying mechanism for the development of cardiac failure in hypertensive heart disease.

Cardiomegaly↗
PubMed2004

Embryonic conduction tissue: a spatial correlation with adult arrhythmogenic areas.

INTRODUCTION: The occurrence of arrhythmias in adult patients may arise preferentially in anatomic regions derived from the specialized cardiac conduction system. To examine this hypothesis, we performed a detailed analysis of the developing cardiac conduction system using the recently described CCS-lacZ transgenic mouse strain. METHODS AND RESULTS: Transgenic embryos (E9.5-15.5) were stained for beta-galactosidase activity and co-stained with the myocardial marker HHF35. Results were reconstructed three dimensionally. CCS-lacZ expression was observed in the sinoatrial node, left and right venous valves, septum spurium, right and left atrioventricular ring, His bundle, bundle branches, and right ventricular moderator band. Furthermore, lacZ-positive cells could be demonstrated for the first time in the left atrium, in the posterior wall surrounding the pulmonary venous orifice. and, in later stages, surrounding the pulmonary venous wall. These cells were continuous with the left venous valve in the right atrium. LacZ-positive tissue also could be identified in Bachmann's bundle, running retro-aortically between the right atrium and left atrium. CONCLUSION: Known arrhythmogenic areas including Bachmann's bundle, the pulmonary veins, and sinus venosus derived internodal structures, demonstrate lacZ expression. These data support the hypothesis that areas derived from the developing cardiac conduction system may contribute to the arrhythmogenic substrate in adult hearts.

Animals↗
PubMed1996

Use of vital capacity for cardiac failure risk estimation in persons with coronary disease and left ventricular hypertrophy.

Cardiac failure is a common lethal outcome of coronary heart disease and left ventricular hypertrophy. The efficacy of forced vital capacity (FVC), measured biennially, in predicting the onset of cardiac failure was explored in 818 Framingham Study subjects with those predisposing conditions, among 324 developed cardiac failure. Among the men and women who had coronary disease or left ventricular hypertrophy, those with FVCs in the lower quartile were at substantially increased risk of developing cardiac failure. For men, comparing the lowest quartile with men whose FVCs were in the highest quartile (<2.7 L vs >5.6 L), the risk ratio was 1.8; for women with FVCs <1.7 L, the risk was 2.3 times those with FVCs of > or = 3.5L. The excess risk of cardiac failure imposed by a low FVC was similar in those with coronary disease and left ventricular hypertrophy. The simple FVC is an inexpensive and robust predictor of cardiac failure in persons predisposed by coronary disease or left ventricular hypertrophy. FVC determination should help identify candidates for cardiac failure needing echocardiographic examination for ventricular dysfunction.

Aged↗
PubMed1995

Heart rate-dependent characteristics of diastolic ventricular filling in the developing chick embryo.

The contributions of the early (passive) and late (active) components of ventricular filling have been reported to decrease and increase, respectively, during chick embryo cardiac development. We hypothesized that the observed changes in ventricular filling during early cardiac development results from a decrease in cycle length. We studied the effect of development and cycle length on atrioventricular inflow in 28 chick embryos, Hamilton-Hamburger stages 17, 24, and 26. Cycle length was perturbed (range 240-1040 ms) in ovo by transiently heating or cooling the sinus venosus. Atrioventricular inflow and dorsal aortic velocities were obtained by 20-MHz pulsed Doppler flow-meter and digitally recorded at 500 samples per second. Stroke volume was calculated from dorsal aortic velocity and cross-sectional area. The atrioventricular inflow wave form was integrated and partitioned by area and percentage of total into early (passive) and late (active) components using three methods. Regardless of method, the proportion of filling volume due to the early and late components was cycle length and stage dependent (p < 0.05). The early and late filling volumes were large in the older embryos, and during cycle length decrease (heart rate increase) the early filling volume decrease was greater than the late filling volume decrease. When compared with the percentage of intrinsic heart rate, the percentage of stroke volume due to early filling decreased as heart rate increased and was greater in younger embryos at all heart rates. That due to late filling increased as the percentage of intrinsic heart rate increased. Ventricular filling characteristics are both developmentally determined and cycle length dependent.

Animals↗
PubMed2006

Selenoprotein expression is essential in endothelial cell development and cardiac muscle function.

LoxP-Cre technology was used to remove the selenocysteine tRNA gene, trsp, in either endothelial cells or myocytes of skeletal and heart muscle to elucidate the role of selenoproteins in cardiovascular disease. Loss of selenoprotein expression in endothelial cells was embryonic lethal. A 14.5-day-old embryo had numerous abnormalities including necrosis of the central nervous system, subcutaneous hemorrhage and erythrocyte immaturity. Loss of selenoprotein expression in myocytes manifested no apparent phenotype until about day 12 after birth. Affected mice had decreased mobility and an increased respiratory rate, which proceeded rapidly to death. Pathological analysis revealed that mice lacking trsp had moderate to severe myocarditis with inflammation extending into the mediastinitis. Thus, ablation of selenoprotein expression demonstrated an essential role of selenoproteins in endothelial cell development and in proper cardiac muscle function. The data suggest a direct connection between the loss of selenoprotein expression in these cell types and cardiovascular disease.

Animals↗
PubMed2002

Influence of hypoxia and of hypoxemia on the development of cardiac activity in zebrafish larvae.

Cardiac activity and anaerobic metabolism were analyzed in zebrafish larvae raised under normoxia (PO(2) = 20 kPa) and under chronic hypoxia (PO(2) = 10 kPa) at three different temperatures (25, 28, and 31 degrees C). Heart rate increased with development and with temperature. Under normoxia, cardiac output increased significantly at high temperature (31 degrees C), but not at 28 or at 25 degrees C. Under chronic hypoxia, however, heart rate as well as cardiac output increased at all temperatures in larvae at about hatching time or shortly thereafter. Cardiac activity of larvae raised for 2 wk after fertilization with a reduced hemoglobin oxygen-carrying capacity in their blood (hypoxemia; due to the presence of CO or of phenylhydrazine in the incubation water) was not different from control animals. Whole body lactate content of these animals did not increase. Thus there was no indication of a stimulated anaerobic energy metabolism. The increase in cardiac activity observed during hypoxia suggests that at about hatching time receptors are present that sense hypoxic conditions, and this information can be used to induce a stimulation of convective oxygen transport to compensate for a reduction in bulk oxygen diffusion in the face of a reduced oxygen gradient between environmental water and tissues. Under normoxia, however, the PO(2) gradient between environmental water and tissues and diffusional oxygen transport assure sufficient oxygen supply even if hemoglobin oxygen transport in the blood is severely impaired. Thus, under normoxic conditions and with a normal metabolic rate of the tissues, convective oxygen transport is not required until approximately 2 wk after fertilization.

Anaerobiosis↗
PubMed2003

Angiopoietin-1 protects against the development of cardiac allograft arteriosclerosis.

BACKGROUND: Angiopoietin (Ang)-1 is an angiogenic growth factor that counteracts the permeability and proinflammatory effects of vascular endothelial growth factor and other proinflammatory cytokines. Recently, we demonstrated that vascular endothelial growth factor enhances cardiac allograft arteriosclerosis. Here, we studied the roles of Ang1, its natural antagonist Ang2, and their receptor Tie2 in rat cardiac allograft arteriosclerosis. METHODS AND RESULTS: Heterotopic cardiac allografts and syngrafts were transplanted from Dark Agouti (DA) to Wistar-Furth rats and from DA to DA rats, respectively. Immunohistochemistry disclosed that only a few mesenchymal cells expressed Ang1 in normal hearts and syngrafts, whereas no immunoreactivity was found in cardiac allografts undergoing chronic rejection. Ang2 and Tie2 immunoreactivity was induced mainly in capillaries and postcapillary venules in chronic allografts when compared with syngeneic controls, but no immunoreactivity was found in arterial endothelium. Intracoronary perfusion of cardiac allografts with a clinical-grade adenoviral vector encoding human Ang1 (Ad.Ang1) protected against the development of allograft arteriosclerosis. Ad.Ang1 perfusion reduced Ang2 expression in microcirculation, the numbers of graft-infiltrating leukocytes, and the level of immunoactivation and interstitial fibrosis, as well as both the incidence and intensity of intimal lesions. Ad.Ang1 perfusion also increased CD34+ stem cell counts in peripheral blood. CONCLUSIONS: Our findings suggest that the antiinflammatory properties of Ang1 may offer an entirely new therapeutic approach to prevent cardiac allograft arteriosclerosis.

Adenoviridae↗
PubMed2000

Thyroid hormones differentially modulate enolase isozymes during rat skeletal and cardiac muscle development.

During muscle development, an isozymic transition of the glycolytic enzyme enolase occurs from the embryonic and ubiquitous alphaalpha-isoform to the muscle-specific betabeta-isoform. Here, we demonstrate a stimulatory role of thyroid hormones on these two enolase genes during rat development in hindlimb muscles and an inhibitory effect on the muscle-specific enolase gene in cardiac muscle. In hindlimb muscles the ubiquitous alpha-transcript level is diminished by hypothyroidism, starting at birth. On the contrary, the more abundant muscle-specific beta-transcript is insensitive to hypothyroidism before establishment of the functional diversification of fibers and is greatly decreased thereafter. Our data support the hypothesis of a role of thyroid hormones in coordinating the expressions of contractile proteins and metabolic enzymes during muscle development. The subcellular localization of isoenolases, established here, is not modified by hypothyroidism. Our results underline the specificity of action of thyroid hormones, which modulate differentially two isozymes in the same muscle and regulate, in opposite directions, the expression of the same gene in two different muscles.

Animals↗
PubMed2001

Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure.

BACKGROUND: Ghrelin is a novel growth hormone (GH)-releasing peptide that may also induce vasodilation and stimulate feeding through GH-independent mechanisms. We investigated whether ghrelin improves left ventricular (LV) dysfunction and attenuates cardiac cachexia in rats with chronic heart failure (CHF). METHODS AND RESULTS: Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, rat ghrelin (100 microg/kg SC BID) or saline was administered for 3 weeks. Echocardiography and cardiac catheterization were performed. Serum GH and insulin-like growth factor-1 were significantly higher in both CHF and sham rats treated with ghrelin than in those given placebo (P<0.05 for both). CHF rats given placebo showed an impaired increase in body weight compared with sham rats given placebo (P<0.05). CHF rats treated with ghrelin, however, showed a significantly greater increase in body weight than those given placebo (+10% versus +3%, P<0.05). They showed significantly higher cardiac output (315+/-49 versus 266+/-31 mL. min(-1). kg(-1), P<0.05) and LV dP/dt(max) (5738+/-908 versus 4363+/-973 mm Hg/s, P<0.05) than CHF rats given placebo. Ghrelin increased diastolic thickness of the noninfarcted posterior wall, inhibited LV enlargement, and increased LV fractional shortening in CHF rats (from 15+/-3% to 19+/-3%, P<0.05). CONCLUSIONS: Chronic subcutaneous administration of ghrelin improved LV dysfunction and attenuated the development of LV remodeling and cardiac cachexia in rats with CHF.

Animals↗