Ghrelin & Cardiovascular Indexes in Healthly Obese and Lean Men
Ghrelin & Cardiovascular Indexes in Healthly Obese and Lean Men
Objective: Obesity is an increasingly common condition and is associated with excess morbidity and mortality, including clinical and subclinical cardiac dysfunction. The role of hormones involved in energy homeostasis, including ghrelin and leptin, in cardiovascular function remains incompletely understood. Therefore, we sought to evaluate the association between systemic ghrelin and leptin levels with indexes of cardiovascular structure and function.
Design and Measurements: We measured serum ghrelin and leptin levels in 25 clinically healthy obese men and 25 lean controls, using commercially available immunoassays. We also assessed right and left ventricular structure and function using cardiac magnetic resonance imaging. We then investigated the association between serum ghrelin and leptin levels with cardiac indexes, using univariate and multivariate analysis.
Results: There was an independent association between serum ghrelin levels and height-adjusted right ventricular mass (r = -0·324, P = 0·026), right ventricular end-diastolic volume (r = -0·363, P = 0·017) and right ventricular end-systolic volume (r = -0·398, P = 0·009) as well as right ventricular ejection fraction (r = 0·317, P = 0·050). There was no significant association between serum ghrelin and indexes of left ventricular structure or function. We also identified an association between serum leptin levels and resting heart rate (r = 0·391, P = 0·002). There was an association between serum leptin and height-adjusted left ventricular mass on univariate, but not on multivariate, analysis.
Conclusions: Serum ghrelin is associated with right ventricular cardiovascular indexes and serum leptin is associated with resting heart rate. These associations indicate a close interaction between the endocrine and cardiovascular systems in obesity.
Obesity is a major public health problem in Western societies and is associated with excess morbidity and mortality (Flegal et al., 1998; Must et al., 1999; Willett et al., 1999). Data suggest that both subclinical and clinical cardiac abnormalities are associated with obesity (Alpert et al., 1995a,b,c,d, 1997). We have shown recently that otherwise healthy obese men have subtle cardiac abnormalities that can be detected by cardiac magnetic resonance imaging, including increased left and right ventricular mass and increased left and right ventricular end-diastolic volume (Danias et al., 2003). However, the pathophysiology of cardiovascular manifestations in obesity is unclear and the relevant role of endocrine factors remains incompletely understood.
Ghrelin is a 28-amino-acid peptide secreted primarily from endocrine cells in the stomach (Inui, 2001; Kojima et al., 2001). Originally identified as the endogenous ligand for the growth hormone secretagogue receptor, ghrelin has recently been implicated in the regulation of energy homeostasis (Inui, 2001; Kojima et al., 2001). Plasma ghrelin levels increase with decreasing body mass index (BMI) or weight loss in humans (Ravussin et al., 2001; Tschop et al., 2001a). Plasma ghrelin levels increase before meals and decrease rapidly postprandially, and may signal meal initiation and satiety, respectively (Cummings et al., 2001; Tschop et al., 2001b). Central or systemic ghrelin administration to experimental animals leads to increased appetite and weight gain and systemic ghrelin administration leads to increased appetite in humans (Tschop et al., 2000; Wren et al., 2000, 2001a,b; Nakazato et al., 2001). The precise role of ghrelin in the pathophysiology of obesity has not been clearly established.
Recent data indicate that ghrelin may affect cardiovascular function. Short-term administration of ghrelin to healthy volunteers leads to an increase in cardiac index, and stroke volume index, as well as a decrease in mean arterial pressure (Nagaya et al., 2001a). Long-term administration of ghrelin to rats with congestive heart failure leads to increased cardiac output, increased left ventricular fractional shortening, increased posterior left ventricular wall thickness, and inhibition of left ventricular enlargement (Nagaya et al., 2001b).
Leptin is a 16-kDa protein, secreted primarily from white adipose tissue, in direct proportion to BMI and positive energy balance (Flier, 1998; Spiegelman & Flier, 2001). In contrast to ghrelin, systemic leptin levels decline with decreasing BMI as well as in response to negative energy balance (Flier, 1998; Spiegelman & Flier, 2001). Leptin administration to leptin-deficient individuals or rodents leads to a decrease in body adiposity mediated primarily through a decrease in energy intake (Pelleymounter et al., 1995; O'Rahilly, 1998; Farooqi et al., 1999). Available data suggest that central resistance to leptin effects on energy homeostasis occurs in the majority of obese humans (Caro et al., 1996; Flier, 1998). However, the underlying molecular mechanisms have not been clearly established.
Recent evidence suggests that leptin may affect cardiovascular function (Haynes et al., 1997, 1998; Paolisso et al., 1999; Haynes, 2000; Goldberger, 2001; Thakur et al., 2001; Winnicki et al., 2001). There is an association between systemic leptin levels and heart rate, both in autonomically intact humans and in heart transplant recipients who have sustained autonomic denervation (Hirose et al., 1998; Makris et al., 1999; Narkiewicz et al., 1999, 2001; Winnicki et al., 2001).
Cardiovascular magnetic resonance imaging is very reproducible and accurate in the evaluation of cardiovascular anatomy and function, and may allow the detection of small differences in cardiovascular indexes between study groups with a smaller sample size in comparison with echocardiography (Bellenger et al., 2000). In addition, echocardiography is often inadequate in the evaluation of obese individuals, due to limited acoustic penetration (Schirmer et al., 1999; Chuang et al., 2001).
In the present study, we sought to examine the association between systemic ghrelin and leptin levels with a priori specified indexes of cardiovascular structure and function, evaluated by cardiovascular magnetic resonance imaging, in a population of clinically healthy obese and age-matched lean young adult men. We also measured serum levels of insulin, cortisol, GH, IGF-I, thyroid hormones and testosterone, and used these data to adjust for potential confounders in analysis.
Objective: Obesity is an increasingly common condition and is associated with excess morbidity and mortality, including clinical and subclinical cardiac dysfunction. The role of hormones involved in energy homeostasis, including ghrelin and leptin, in cardiovascular function remains incompletely understood. Therefore, we sought to evaluate the association between systemic ghrelin and leptin levels with indexes of cardiovascular structure and function.
Design and Measurements: We measured serum ghrelin and leptin levels in 25 clinically healthy obese men and 25 lean controls, using commercially available immunoassays. We also assessed right and left ventricular structure and function using cardiac magnetic resonance imaging. We then investigated the association between serum ghrelin and leptin levels with cardiac indexes, using univariate and multivariate analysis.
Results: There was an independent association between serum ghrelin levels and height-adjusted right ventricular mass (r = -0·324, P = 0·026), right ventricular end-diastolic volume (r = -0·363, P = 0·017) and right ventricular end-systolic volume (r = -0·398, P = 0·009) as well as right ventricular ejection fraction (r = 0·317, P = 0·050). There was no significant association between serum ghrelin and indexes of left ventricular structure or function. We also identified an association between serum leptin levels and resting heart rate (r = 0·391, P = 0·002). There was an association between serum leptin and height-adjusted left ventricular mass on univariate, but not on multivariate, analysis.
Conclusions: Serum ghrelin is associated with right ventricular cardiovascular indexes and serum leptin is associated with resting heart rate. These associations indicate a close interaction between the endocrine and cardiovascular systems in obesity.
Obesity is a major public health problem in Western societies and is associated with excess morbidity and mortality (Flegal et al., 1998; Must et al., 1999; Willett et al., 1999). Data suggest that both subclinical and clinical cardiac abnormalities are associated with obesity (Alpert et al., 1995a,b,c,d, 1997). We have shown recently that otherwise healthy obese men have subtle cardiac abnormalities that can be detected by cardiac magnetic resonance imaging, including increased left and right ventricular mass and increased left and right ventricular end-diastolic volume (Danias et al., 2003). However, the pathophysiology of cardiovascular manifestations in obesity is unclear and the relevant role of endocrine factors remains incompletely understood.
Ghrelin is a 28-amino-acid peptide secreted primarily from endocrine cells in the stomach (Inui, 2001; Kojima et al., 2001). Originally identified as the endogenous ligand for the growth hormone secretagogue receptor, ghrelin has recently been implicated in the regulation of energy homeostasis (Inui, 2001; Kojima et al., 2001). Plasma ghrelin levels increase with decreasing body mass index (BMI) or weight loss in humans (Ravussin et al., 2001; Tschop et al., 2001a). Plasma ghrelin levels increase before meals and decrease rapidly postprandially, and may signal meal initiation and satiety, respectively (Cummings et al., 2001; Tschop et al., 2001b). Central or systemic ghrelin administration to experimental animals leads to increased appetite and weight gain and systemic ghrelin administration leads to increased appetite in humans (Tschop et al., 2000; Wren et al., 2000, 2001a,b; Nakazato et al., 2001). The precise role of ghrelin in the pathophysiology of obesity has not been clearly established.
Recent data indicate that ghrelin may affect cardiovascular function. Short-term administration of ghrelin to healthy volunteers leads to an increase in cardiac index, and stroke volume index, as well as a decrease in mean arterial pressure (Nagaya et al., 2001a). Long-term administration of ghrelin to rats with congestive heart failure leads to increased cardiac output, increased left ventricular fractional shortening, increased posterior left ventricular wall thickness, and inhibition of left ventricular enlargement (Nagaya et al., 2001b).
Leptin is a 16-kDa protein, secreted primarily from white adipose tissue, in direct proportion to BMI and positive energy balance (Flier, 1998; Spiegelman & Flier, 2001). In contrast to ghrelin, systemic leptin levels decline with decreasing BMI as well as in response to negative energy balance (Flier, 1998; Spiegelman & Flier, 2001). Leptin administration to leptin-deficient individuals or rodents leads to a decrease in body adiposity mediated primarily through a decrease in energy intake (Pelleymounter et al., 1995; O'Rahilly, 1998; Farooqi et al., 1999). Available data suggest that central resistance to leptin effects on energy homeostasis occurs in the majority of obese humans (Caro et al., 1996; Flier, 1998). However, the underlying molecular mechanisms have not been clearly established.
Recent evidence suggests that leptin may affect cardiovascular function (Haynes et al., 1997, 1998; Paolisso et al., 1999; Haynes, 2000; Goldberger, 2001; Thakur et al., 2001; Winnicki et al., 2001). There is an association between systemic leptin levels and heart rate, both in autonomically intact humans and in heart transplant recipients who have sustained autonomic denervation (Hirose et al., 1998; Makris et al., 1999; Narkiewicz et al., 1999, 2001; Winnicki et al., 2001).
Cardiovascular magnetic resonance imaging is very reproducible and accurate in the evaluation of cardiovascular anatomy and function, and may allow the detection of small differences in cardiovascular indexes between study groups with a smaller sample size in comparison with echocardiography (Bellenger et al., 2000). In addition, echocardiography is often inadequate in the evaluation of obese individuals, due to limited acoustic penetration (Schirmer et al., 1999; Chuang et al., 2001).
In the present study, we sought to examine the association between systemic ghrelin and leptin levels with a priori specified indexes of cardiovascular structure and function, evaluated by cardiovascular magnetic resonance imaging, in a population of clinically healthy obese and age-matched lean young adult men. We also measured serum levels of insulin, cortisol, GH, IGF-I, thyroid hormones and testosterone, and used these data to adjust for potential confounders in analysis.
Source...