Antonio Cittadini

Growth Hormone Attenuates Early Left Ventricular Remodeling and Improves Cardiac Function in Rats With Large Myocardial Infarction

OBJECTIVES We sought to investigate the cardiac effects of growth hormone (GH) administration during the early phase of pathologic remodeling in a rat model of large myocardial infarction (MI). BACKGROUND Recent evidence suggests that exogenous administration of GH evokes a hypertrophic response and increases left ventricular (LV) function in vivo in rats with normal or chronically failing hearts. We hypothesized that these effects would attenuate ventricular remodeling early after MI. METHODS Fifty-eight male rats underwent sham operation (n = 19) or had induced MI (n = 39). The day after the operation, the infarcted rats were randomized to receive 3 weeks of treatment with GH, 3 mg/kg body weight per day (n = 19) or placebo (n = 20). Echocardiography, catheterization and isolated whole heart preparations were used to define cardiac structure and function. RESULTS Growth hormone caused hypertrophy of the noninfarcted myocardium in a concentric pattern, as noted by higher echocardiographic relative wall thickness at 3 weeks and by morphometric histologic examination. Left ventricular dilation was reduced in the GH-treated versus placebo group (echocardiographic LV diastolic diameter to body weight ratio 2.9 +/- 0.1 vs. 3.5 +/- 0.2 cm/kg; p < 0.05). In vivo and in vitro cardiac function was improved after GH treatment. Despite elevated insulin-like growth factor-1 (IGF-1) serum levels in GH-treated rats, myocardial IGF-I messenger ribonucleic acid was not different among the three groups, suggesting that an increase in its local expression does not appear necessary to yield the observed effects. CONCLUSIONS These data demonstrate that early treatment of large MI with GH attenuates the early pathologic LV remodeling and improves LV function.

Insulin-like Growth Factor-1 but Not Growth Hormone Augments Mammalian Myocardial Contractility by Sensitizing the Myofilament to Ca2+ Through a Wortmannin-Sensitive Pathway : Studies in Rat and Ferret Isolated Muscles

A growing body of evidence has been accumulated recently suggesting that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) affect cardiac function, but their mechanism(s) of action is unclear. In the present study, GH and IGF-1 were administered to isolated isovolumic aequorin-loaded rat whole hearts and ferret papillary muscles. Although GH had no effect on the indices of cardiac function, IGF-1 increased isovolumic developed pressure by 24% above baseline. The aequorin transients were abbreviated and demonstrated decreased amplitude. The positive inotropic effects of IGF-1 were not associated with increased intracellular Ca2+ availability to the contractile machinery but to a significant increase of myofilament Ca2+ sensitivity. Accordingly, the Ca2+-force relationship obtained under steady-state conditions in tetanized muscle was shifted significantly to the left (EC50, 0.44+/-0.02 versus 0.52+/-0.03 micromol/L with and without IGF-1 in the perfusate, respectively; P<0.05); maximal Ca2+-activated tetanic pressure was increased significantly by 12% (211+/-3 versus 235+/-2 mm Hg in controls and IGF-1-treated hearts, respectively; P<0.01). The positive inotropic actions of IGF-1 were not associated with changes in either pHi or high-energy phosphate content, as assessed by 31P nuclear magnetic resonance spectroscopy, and were blocked by the phosphatidylinositol 3-kinase inhibitor wortmannin. Concomitant administration of IGF binding protein-3 blocked IGF-1-positive inotropic action in ferret papillary muscles. In conclusion, IGF-1 is an endogenous peptide that through a wortmannin-sensitive pathway displays distinct positive inotropic properties by sensitizing the myofilaments to Ca2+ without increasing myocyte [Ca2+]i.

Exogenously Administered Growth Hormone and Insulin-like Growth Factor-I Alter Intracellular Ca2+ Handling and Enhance Cardiac Performance: In Vitro Evaluation in the Isolated Isovolumic Buffer-Perfused Rat Heart

It has been proposed that chronic treatment with growth hormone (GH) or insulin-like growth factor-I (IGF-I) in the rat may enhance cardiac function in vivo. To confirm these findings and elucidate the mechanisms by which cardiac function is modulated, we studied isolated buffer-perfused rat hearts after 4 weeks of treatment with high doses of GH and IGF-I alone or in combination. Mechanical parameters were measured at 50% of the intracardiac balloon volume at which maximal developed pressure (DevP) occurred. EC50 of the force-Ca2+ relationship and maximal Ca(2+)-activated systolic wall stress (max sigma s) were assessed by increasing Ca2+ in the perfusate in a stepwise fashion and plotting systolic wall stress (sigma s) versus intracellular peak systolic Ca2+, measured by the aequorin bioluminescence method. We found a marked increase of systolic pressure (Ps), DevP, and (+dP/dt)/DevP in the treated groups compared with the control group. The combination group showed a blunted effect. sigma s was increased in all treated groups for a perfusate Ca2+ concentration of > 1.5 mmol/L. The enhanced systolic performance can be explained by an increase of the overall Ca2+ responsiveness due to an increased maximal response to Ca2+ even though the EC50 of the Ca(2+)-dose response was also slightly increased. Ps was further enhanced by an increase of the relative wall thickness induced by the treatment. Diastolic pressure, diastolic Ca2+, and the amplitude and time course of the Ca2+ transient were not influenced by any treatment protocol. All treatments caused increases of body and heart weight. These data support the hypothesis that both IGF-I and GH directly affect cardiac performance by altering cardiac geometry as well as by enhancing max sigma s.

Cardiac Morphology and Function in Senescent Rats: Gender-Related Differences

OBJECTIVES We sought to better understand the effects of aging and gender on left ventricular (LV) structure and function. BACKGROUND Cardiovascular disease in older persons is associated with increased mortality and morbidity. The influence of gender on age-related cardiac changes is incompletely characterized. METHODS We studied 34 senescent, male and female, normotensive Fischer rats with transthoracic Doppler echocardiography and morphometric and histopathologic analyses. RESULTS Male rats were larger (396 +/- 31 g vs. 282 +/- 35 g), and LV mass in males was greater (1.04 +/- 0.22 g vs. 0.67 +/- 0.13 g). However, wall and chamber dimensions normalized to body weight revealed proportionately thicker anterior and posterior walls in females. Relative wall thickness ratio (2 [Diastolic posterior wall thickness]/Diastolic LV internal chamber diameter) was greater in females, but abnormal fractional shortening and diastolic filling (E/A ratio) patterns were more common in males. Significant mitral regurgitation (MR) was sevenfold more common among males (88% vs. 12%, p < 0.001). Histopathologic analysis showed that the cardiac myocytes were larger, and there was greater LV fibrosis in males (both p < 0.001). CONCLUSIONS Gender-related morphologic and functional differences are important to consider in cardiovascular assessment. Very old rats show significant gender differences in LV size and function. Male rat hearts are larger, thinner and more fibrotic and have indexes of diminished performance. The high prevalence of MR in male rats may play a crucial role in these gender differences.

Cardiovascular Abnormalities in Transgenic Mice With Reduced Brown Fat An Animal Model of Human Obesity

BACKGROUND A new model of murine obesity has recently been developed through transgenic ablation of brown adipose tissue that manifests typical metabolic complications of obesity, including insulin resistance and non-insulin-dependent diabetes mellitus. The cardiovascular phenotype has not been defined. METHODS AND RESULTS Transthoracic echocardiography, aortic catheterization, isolated whole-heart studies, and morphometric histology defined cardiac structure and function in 30 transgenic mice with reduced brown fat and 30 matched wild-type controls. Obesity was indicated by a 77% increase in body weight and was accompanied by elevated systemic pressures (mean aortic blood pressure 85+/-1 versus 66+/-2 mm Hg; P<0.01), left ventricular dilation and hypertrophy (mass/body weight 4.0+/-0.2 versus 2.7+/-0.3 mg/g; P<0.01), and high cardiac output (cardiac index 3.2+/-0.4 versus 2.4+/-0.1 mL x kg(-1) x min(-1); P<0.01). Baseline functional parameters assessed in vitro were not different, but after imposition of zero-flow ischemia, significant relaxation impairment developed in obese mice. Although morphometrically determined myocyte diameters were similar, the percentage of interstitial fibrosis was significantly increased in transgenic mice compared with wild-type controls (7.5+/-2% versus 4. 2+/-0.2%; P<0.01). CONCLUSIONS Transgenic ablation of brown adipose tissue is associated not only with obesity but also with systemic hypertension, left ventricular hypertrophy with eccentric remodeling and fibrosis, and high cardiac output, a unique constellation of findings strikingly similar to that seen in human obesity. Mice with reduced brown fat may serve as a new model for the cardiovascular morbid complications associated with obesity in humans.

Consequences of Growth Hormone Deficiency on Cardiac Structure, Function, and β-Adrenergic Pathway: Studies in Mutant Dwarf Rats1

To evaluate GH’s role in cardiac physiology and its interrelationship with the β-adrenergic system, we studied GH-deficient dwarf (dw/dw) and control rats in 4 groups of 20 each: dwarf group receiving placebo, dwarf-GH group receiving 2 mg/kg GH, dwarf-GH-propranolol group receiving 2 mg/kg GH and 750 mg/liter propranolol, and a control group of Lewis rats receiving placebo. Dwarf rats showed reduced left ventricular weight and myocyte cross-sectional area, and impaired cardiac performance in vitro. Left ventricular pressure-volume curves showed a shift upward and leftward, indicating reduced distensibility. These abnormalities reversed after GH treatment regardless of concomitant propranolol administration. Although isoproterenolol responsiveness was reduced in dwarf rats, there were no differences in β-adrenergic receptor density, affinity, Na+,K+-adenosine triphosphatase activity, or adenylyl cyclase activity. In summary, myocyte size, cardiac structure, myocardial contractility, and distensibility are...

Optimal determination of right ventricular filling dynamics in systemic hypertension

To determine the optimal method of normalizing peak filling rate (PFR) determinations and apply it to the assessment of right ventricular (RV) and left ventricular (LV) filling characteristics and their interactions, 41 subjects with hypertension and 40 matched normals underwent echo-Doppler and nuclear study. Conventional normalization of PFR to end-diastolic volume (EDV) yielded poor correlations between nuclear- and echo-derived PFR (RV, r = 0.34; LV, r = 0.42), whereas nuclear and echo PFR normalized to stroke volume (SV) were closely correlated (RV, r = 0.87; LV, r = 0.92). Further, use of PFR normalized to SV revealed to close relation between RV and LV filling characteristics. Multivariate analysis confirmed that, in contrast to normalization to EDV or early to late filling-velocity ratios (E/A), peak filling rate normalized to SV was independent of ejection fraction and heart rate. In addition, RV filling impairment was related to LV filling impairment, and the effects of hypertension eliminated the independent influence of age on both LV and RV filling. In conclusion, normalization of PFR to SV may be preferable to use of EDV or E/A in evaluating RV and LV filling dynamics.

Does the Growth Factor Approach Have a Future in the Treatment of Human Heart failure

Until recently, the physiologic role of growth hormone (GH) and its tissue effector insulin-like growth factor I (IGF-I) was restricted to the control of linear growth and energetic metabolism, and to the maintenance of skeletal muscle growth and performance (1). Over the past few years, a wealth of data from both animal and human studies have enlarged the spectrum of GH’s action even further. GH is now well recognized to be essential for cardiac development and for preserving cardiac structure and performance in adult life (2). IGF-I is rightly included in the list of the many factors that are implicated in cardiac hypertrophy in response to pressure or volume overload.

THE CELLULAR AND MOLECULAR BASIS FOR GROWTH HORMONE ACTION ON THE HEART

Despite a series of elegant studies perfonned by Beznak in the fifties clearly demonstrating Growth Honnone (GH)s role in maintaining a nonnal hypertrophic response following experimental aortic constriction (1-3), the cardiovascular role of the GHlIGF-1 axis was largely overlooked. In fact, until few years ago, GH was classically regarded as the principal mediator of bone linear growth, in addition to its well known actions on glucose homeostasis and skeletal muscle mass, and the heart was not generally considered as a target tissue (4). It is now well established that not only does GH play an essential role in maintaining a nonnal cardiac muscle mass and function, but also that its growth-promoting and positive inotropic actions may be beneficial in the setting of heart failure and ischemic syndromes.

Heart Failure: Potential Benefit of Growth Hormone Therapy

Until a few years ago, growth hormone (GH) was considered essential in the control of linear growth, glucose homeostasis, and skeletal muscle mass. More recently, a series of studies have unequivocally proven that the heart is a target organ for the GH/IGF-I axis, which modulates cardiac structure and function. The importance of the GH/IGF-I axis is also supported by several lines of experimental evidence demonstrating that GH/IGF-I affects the determinants of cardiac output (preload, afterload, and contractility), through direct and indirect mechanisms. The therapeutic options available for the treatment of heart failure are few, and the overall prognosis for this disease remains very poor. Recent studies employing growth factors, which activate myocardial growth by inducing a physiological kind of hypertrophy, seem exciting. In this regard, GH and IGF-I may be the best candidates to produce a growth response in the heart. The large amount of novel information derived from the experimental and clinical studies on GH and cardiac function suggests that this field of research will be an important area of future investigations. Basic research is needed to discover the complex intracellular pathways of GH and IGF-I and to clarify their growth-promoting and positive inotropic actions. Furthermore, survival animal studies employing GH may potentially address whether the beneficial hemodynamic effects of GH in experimental heart failure would translate into a better prognosis for human heart failure.