(Hypertension. 1999;34:1047-1052.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Plasma Leptin Level Is Associated With Myocardial Wall Thickness in Hypertensive Insulin-Resistant Men
From the Department of Geriatric Medicine (G.P., M.R.T., G.A.Z., M.V.) and the Institute of Endocrinology 2nd (C.C.), University of Naples, and Chair of Emergency Medicine (M.G., A.P., O.d.D.), Department of Clinical and Experimental Medicine, University of Naples "Federico II," Naples, Italy.
Correspondence to Giuseppe Paolisso, MD, Department of Geriatric Medicine and Metabolic Diseases, Servizio di Astanteria Medica, P.zza Miraglia, 2, 80138 Napoli, Italy. E-mail gpaoliss{at}tin.it
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Abstract |
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Abstract—Leptin, the product of the ob gene, has been shown to increase heart rate and blood pressure through a stimulation of cardiac sympathetic nervous system activity, a phenomenon also involved in the pathogenesis of left ventricular hypertrophy in hypertensives. Thus, we hypothesize that plasma leptin concentration is associated with left ventricular hypertrophy. Forty hypertensive males and 15 healthy male subjects underwent anthropometric and echocardiographic evaluations, assessment of insulin sensitivity through euglycemic glucose clamp combined with indirect calorimetry, and determination of fasting plasma leptin concentration. Fasting plasma leptin levels were higher in hypertensives than in controls (6.48±2.9 versus 4.62±1.5 ng/mL, P<0.05); these results were unchanged after adjustment for body mass index (P<0.05). In the whole group of patients (n=55), fasting plasma leptin concentration was correlated with body mass index (r=0.46, P<0.001) and waist/hip ratio (r=0.50, P<0.001); independent of body mass index and waist/hip ratio, fasting plasma leptin concentration was correlated (n=55) with whole-body glucose disposal (r=-0.27, P<0.04), interventricular septum thickness (r=0.34, P<0.001), posterior wall thickness (r=0.38, P<0.003), and the sum of wall thicknesses (r=0.68, P<0.001). In a multivariate analysis (n=55), age, body mass index, fasting plasma leptin concentration, plasma Na+ concentration, whole-body glucose disposal, and diastolic blood pressure explained 68% of the variability of the sum of wall thicknesses with fasting plasma leptin concentration (P<0.03), whole body glucose disposal (P<0.002), and diastolic blood pressure (P<0.001), which were significantly and independently associated with the sum of wall thicknesses. In conclusion, our study demonstrates that fasting plasma leptin levels are associated with increased myocardial wall thickness independent of body composition and blood pressure levels in hypertensives.
Key Words: leptin • hypertension, essential • hypertension, arterial • insulin
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Introduction |
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Leptin, the product of the ob gene,1 is a peptide hormone produced by adipose tissue involved in body weight control through a decrease in food intake and an increase in energy expenditure.2 Several studies have shown leptin to increase in insulin-resistant states such as obesity3 and hypertension.4 Nevertheless, a direct relation between plasma leptin concentration and the cardiovascular system needs to be investigated. The possibility that leptin plays a role in the cardiovascular system is strengthened by the evidence that chronic leptin infusion has been shown to increase heart rate and blood pressure through stimulation of sympathetic nervous system activity.5 6 Interestingly, this latter phenomenon is also involved in the pathogenesis of left ventricular (LV) hypertrophy.7 8 Thus, we hypothesize that plasma leptin concentration is associated with the presence of LV hypertrophy. To determine the accuracy of this hypothesis, we evaluated the possible association between plasma leptin levels and echocardiographic parameters of LV measurements in hypertensive patients.
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Methods |
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Patients
Forty consecutive male patients with newly diagnosed slightly to moderate essential arterial hypertension and 15 adult male healthy subjects were enrolled after their informed consent was obtained. Patients were considered to be hypertensive according to their clinic blood pressure levels (diastolic blood pressure [DBP] >90 mm Hg, calculated as the mean of 3 different measurements in at least 3 different visits at 1-week intervals). Exclusion criteria from the study were a family history of diabetes and obesity, coronary artery disease, impaired glucose tolerance, and diabetes mellitus. All patients were free from cardiac medication and drugs known to interfere with glucose metabolism, and all had a similar sedentary lifestyle. More detailed information concerning the population studied is given in Table 1. The study was approved by the ethical committees of our institutions.
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Anthropometric Determinations
Weight and height were measured by standard techniques. Body fat
and fatty free mass were measured using a 4-terminal bioimpedance
analyzer (RJL Spectrum Bioelectrical Impedance, BIA 101/SC
Akern, RJL-System).9 Body mass index (BMI) was calculated
as body weight divided by height squared. Waist circumference was
measured at the midpoint between the lower rib margin and the iliac
crest (normally the umbilical level), and hip circumference was
measured at the trochanter level. Both circumferences were measured to
the nearest 0.5 cm with plastic tape, and the ratio between them
provided the waist/hip ratio (WHR).
Echocardiographic Determinations
Doppler echocardiographic examinations using
a 2.5-MHz transducer connected to a Sector Imager 5000 (Ote-Biomedica)
were performed with patients in a partial left decubitus position and
recorded on strip-chart paper. At the end of the study, heart rate
and cuff blood pressure (as the mean of 3 determinations) were
estimated by a physician using a sphygmomanometer who was blinded to
the results of the echocardiographic examination.
Consecutive coded Doppler echocardiographic
tracings were examined for 
3 cardiac cycles by 2 experienced
observers who were unaware of blood pressure and metabolic
data of the subjects. M-mode measurements of the LV were performed at
end diastole according to the recommendations of the
American Society of
Echocardiography.10 The sum of wall
thicknesses (SWT) was calculated as the sum of
interventricular septum thickness (IVST) and posterior wall
thickness (PWT). Relative diastolic wall thickness (RDWT)
was determined as the ratio between SWT and LV
end-diastolic diameter (LVEDD). Fractional shortening was
calculated as the percentage of change in the internal LV dimension
between systole and diastole. LV mass (LVM) was estimated
by the Penn convention11 and corrected for height in
meters (LVM/height).12 According to the values of LVM
index, the study population was divided into 2 groups: one with LV
hypertrophy (LVM index >141 g/m according to the
Framingham criteria for men)13 and one without LV
hypertrophy. Echocardiographic
cardiovascular determinations were carried out by
investigators unaware of the metabolic data. Finally,
cardiovascular and metabolic investigations
were performed on different days.
Metabolic Determinations
All subjects had a normal glucose tolerance, which was assessed
by oral glucose tolerance test (75 g glucose).14 On a
different day, a test involving a euglycemic
hyperinsulinemic glucose clamp15 was
carried out. In this latter test, a fixed insulin infusion rate (7.1
pmol/kg per minute for 120 minutes) was set, and a variable amount
of glucose (as 20% solution) was delivered. Whole-body glucose
disposal (WBGD) was calculated during the final 60 minutes of the clamp
procedure according to the following formula: WBGD=glucose infusion
rate+pool correction (as described elsewhere16 ). This
calculation is valid when no entry of glucose in plasma from the liver
occurs. In nondiabetic subjects17 and hypertensive
patients,18 hepatic glucose output has been found to be
fully suppressed during a glucose clamp, test at this insulin infusion
rate. Furthermore, in preliminary clamps, an insulin infusion rate of
7.1 pmol/kg per minute fully suppressed (but without negative numbers)
hepatic glucose output.
In the basal state (from -60 to 0 minutes) and during the last 60 minutes of the clamp procedure, indirect calorimetry estimated substrate oxidation.19 A computerized open-circuit system to measure gas exchange through a 25-L PVC plastic canopy (Deltatrac, Datex) was used. The monitor has a precision of 2.6% for oxygen and 2.1% for carbon dioxide production. Protein oxidation was calculated from urea nitrogen excretion before and at the end of the glucose clamp procedure and corrected for the changes in urea pool.19 Substrate oxidation rate was calculated from the oxygen consumption, the carbon oxide production, and the nitrogen urinary excretion rate according to Ferrannini.19 Nonoxidative glucose metabolism (NOGM) was calculated as the difference between WBGD and oxidative glucose metabolism calculated by indirect calorimetry.19 Metabolic tests were carried out by investigators unaware of the cardiovascular data.
Analytical Methods
Plasma glucose was immediately determined by the plasma glucose
method (Autoanalyzer, Beckman). Blood samples for insulin
measurements were collected in heparinized tubes. After
centrifugation, serum insulin was determined by a
commercially available radioimmunoassay kit (coefficient of variation
3.2±0.3%, Sorin, Biomedical). At baseline and at the end of
the glucose clamp procedure, blood samples for plasma leptin
concentration were drawn, and leptin concentrations were determined by
radioimmunoassay (coefficient of variation 4.3±0.5%, Linco
Research).
Calculation and Statistical Analysis
Mean blood pressure was calculated as DBP plus one-third pulse
pressure. To approximate normal distribution, plasma leptin and plasma
insulin were log-transformed (used in all calculations) and then
back-transformed (used in the presentation of the results).
All results are mean±SD. ANOVA with the Scheffé test were used
to compare the results between the groups. Simple correlations by the
Pearson method allowed us to assess the univariate
relations. ANCOVA was used for investigating the impact of BMI on
differences in plasma leptin concentration. Multiple regression
analysis allowed us to investigate the different contribution
of each covariate to the variability in myocardial wall thickness. A
value of P<0.05 was considered statistically significant. All
statistical analyses were made on IBM PC computers by the SOLO
software package (BMDP).
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Results |
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Clinical characteristics of the study groups are reported in Table 1. Patients and controls were adults and had a prevalent central body fat distribution without significant differences between the 2 groups. In contrast, hypertensive patients had worse insulin action (lower level of WBGD) than did control subjects. Fasting plasma (FP) leptin levels were higher in hypertensives than in control subjects, and such results were unchanged after adjustment for BMI (P<0.05). Insulin infusion did not affect baseline plasma leptin levels for either group (Figure 1).
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According to the presence of LV hypertrophy, hypertensives were categorized into 2 groups. Despite slight differences in BMI, plasma Na+ concentrations, and insulin action, plasma leptin levels did not differ in patients with and without LV hypertrophy (data not shown).
Because FP leptin levels were different in controls and hypertensives, the correlation analysis was made in the whole population (n=55) as well as in the control (n=15) and hypertensive (n=40) groups separately (Table 2). In the whole population, FP leptin concentration was correlated positively with BMI, WHR, FP insulin, and basal lipid oxidation and negatively with WBGD and NOGM (Table 2). By group, all these correlations, except basal lipid oxidation, remained significant (Table 2). Independent of BMI and WHR, FP leptin concentration was still correlated with WBGD (all groups, r=-0.27, P<0.04; controls, r=-0.52, P<0.03; and hypertensives, r=-0.42, P<0.01) and NOGM (all groups, r=-0.26, P<0.05; controls, r=-0.52, P<0.03; and hypertensives, r=-0.40, P<0.01). According to echocardiographic characteristics (Figure 2), hypertensive patients had greater LVM/height, IVST, PWT, RDWT, and SWT than did controls. As far as the relation between FP leptin concentrations and cardiovascular variables is concerned (Table 3), FP leptin concentration correlated positively with DBP, IVTS, PWT, SWT, RDWT, and plasma Na+ concentration in the whole population. In the hypertensive group, all these correlations, except DBP, remained significant, whereas in the control group no correlation reached statistical significance (Table 3). After adjustment for BMI and WHR, the correlations between FP leptin concentrations and IVST (all groups, r=0.34, P<0.001; hypertensives, r=0.39, P<0.01), PWT (all groups, r=0.38, P<0.003; hypertensives, r=0.34, P<0.03), and SWT (all groups, r=0.68, P<0.001; hypertensives, r=0.48, P<0.001) (Figure 3) remained significant. Such correlations did not remain significant in controls.
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indicates controls; 
, hypertensives.Among the different echocardiographic indexes, SWT is the most expressive index of the increase in myocardial wall thickness. For this reason, SWT was chosen as a dependent variable in the multiple linear stepwise regression analysis. Such analysis allowed us to investigate the independent role of main anthropometric and cardiovascular covariates on SWT variability (Table 4). In the whole population, a model that incorporated age, BMI, FP leptin concentration, plasma Na+ concentration, WBGD, and DBP explained 68% of SWT variability. In such a model, plasma leptin concentration (P<0.03), WBGD (P<0.002), and DBP (P<0.001) were significantly and independently associated with SWT. The same model was used for the hypertensive group, and it explains 53% of SWT variability. In this model, only plasma leptin (P<0.01) and WBGD (P<0.04) were significantly and independently associated with SWT.
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Discussion |
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The present study demonstrates that plasma leptin concentration (1) was higher in hypertensives patients than in control subjects, (2) did not correlate with LVM but was associated with echocardiographic indexes of increased wall thickness, (3) had the strongest association with SWT, and (4) was not affected by acute hyperinsulinemia.
The higher FP leptin concentration found in hypertensive patients could be due to the occurrence of insulin resistance in this group. In fact, in the whole population compared with the hypertensive group, FP leptin concentration had a negative correlation with WBGD.
To the best of our knowledge, this is the first evidence showing a relation between plasma leptin levels and LV wall thickness (SWT). The evidence that leptin concentration did not correlate with LVM but with SWT was not unexpected. In fact, LV hypertrophy can be attributable to the increase of either wall thickness (concentric hypertrophy) or LVEDD (eccentric hypertrophy) or both, and no relation between plasma leptin levels and LVEDD was found. Because plasma leptin correlated with BMI and some of our patients were overweight, one could argue that the impact of plasma leptin on myocardial wall thickness was mainly driven by body weight. This was not the case. In fact, the relation between FP leptin levels and SWT was independent of anthropometric characteristics as well as of blood pressure levels; thus, FP leptin levels are independently associated with SWT variability.
Recently, SWT has been found to be associated to insulin resistance in arterial hypertension.20 Because insulin resistance and leptin were also found to be associated in the present study, one could hypothesize that the link between plasma leptin levels and myocardial wall growth might be driven by insulin resistance. However, although much of the variability in SWT found in the present study was explained by insulin resistance, leptin remained independently associated with SWT in the multivariate model, even after adjusting for insulin action. This finding suggests that the effect of leptin on the myocardial wall is at least partially independent of insulin action.
Why a relation between plasma leptin levels and myocardial wall thickness occurs requires deeper investigation. Previous studies have reported that leptin may exert different effects on cardiovascular and neurohormonal systems.21 22 23 24 Briefly, leptin has been found to increase sympathetic nerve activity in the brown adipose tissue, kidney, hindlimb, and adrenal gland22 in anesthetized Sprague-Dawley rats; this effect was dose dependent and slow in onset22 but did not affect the cardiovascular system because of the presence of anesthesia. Later on, Shek et al6 showed that chronic leptin infusion also increases arterial pressure and heart rate in conscious rats. The authors hypothesized that plasma leptin could affect heart rate and blood pressure through an increase in sympathetic activity or a withdrawal of parasympathetic tone. The relation between plasma leptin and the autonomic nervous system is strengthened by evidence of a direct relation between muscle sympathetic nerve activity and plasma leptin concentration.21 Since sympathetic nervous system overactivity can play a role in increasing LVM in hypertensive patients,7 8 25 one could hypothesize leptin-induced sympathetic activation to have a role in the myocardial wall thickness of hypertensive patients. In the present study, plasma leptin concentration did not correlate with arterial blood pressure, most likely because of the very narrow range of the blood pressure levels in the hypertensive group.
On the other hand, leptin has been demonstrated to induce proliferation, differentiation, and functional activation of hemopoietic and embryonic cells.26 27 28 29 Thus, one could hypothesize that leptin might play a role in the functional activation of the cell at the myocardial level also. Nevertheless, only longitudinal studies designed to address the impact of plasma leptin levels on changes in cardiac function and structure will provide a strong evidence for a cause-effect relationship.
Interestingly, weight loss may reduce both plasma leptin30 concentration and LVM.31 Whether weight loss affects LVM through a reduction in plasma leptin concentration is a fascinating hypothesis. Unfortunately, the present study had a cross-sectional design; thus, only future studies will be able to respond to the possible pathophysiological link reported above.
An indirect finding of the present study was the lack of effect of acute hyperinsulinemia on plasma leptin concentration. Indeed, contrasting data regarding the possible influence of hyperinsulinemia on leptin levels have been reported. In fact, some32 33 34 but not all35 studies have shown plasma leptin levels to be unmodified by acute hyperinsulinemia. Differences in doses and length of insulin infusion, as well as in clinical characteristics of the population studied, might explain the discrepancy between the results found.
It is noteworthy that in the multivariate model, DBP was an independent determinant of SWT in the whole population but not in hypertensive patients alone. This could be explained by the wide range of DBP values in the whole population compared with the narrow range of the same parameter in the hypertensive group.
In conclusion, the present study demonstrates that FP leptin levels are associated with increased myocardial wall thickness independent of body composition and blood pressure levels in hypertensive insulin-resistant men. A leptin-induced sympathetic activation and/or cell proliferation could account for this effect of leptin on myocardial wall thickness.
Received February 4, 1999; first decision February 25, 1999; accepted June 30, 1999.
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 F.-P. Xu, M.-S. Chen, Y.-Z. Wang, Q. Yi, S.-B. Lin, A. F. Chen, and J.-D. Luo Leptin Induces Hypertrophy via Endothelin-1-Reactive Oxygen Species Pathway in Cultured Neonatal Rat Cardiomyocytes Circulation, September 7, 2004; 110(10): 1269 - 1275. [Abstract] [Full Text] [PDF]
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 P. Tajmir, R. B. Ceddia, R.-K. Li, I. R. Coe, and G. Sweeney Leptin Increases Cardiomyocyte Hyperplasia via Extracellular Signal-Regulated Kinase- and Phosphatidylinositol 3-Kinase-Dependent Signaling Pathways Endocrinology, April 1, 2004; 145(4): 1550 - 1555. [Abstract] [Full Text] [PDF]
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 K. Rahmouni and W. G. Haynes Leptin and the Cardiovascular System Recent Prog. Horm. Res., January 1, 2004; 59(1): 225 - 244. [Abstract] [Full Text]
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V. Rajapurohitam, X. T. Gan, L. A. Kirshenbaum, and M. Karmazyn The Obesity-Associated Peptide Leptin Induces Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., August 22, 2003; 93(4): 277 - 279. [Abstract] [Full Text] [PDF]
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S. Sader, M. Nian, and P. Liu Leptin: A Novel Link Between Obesity, Diabetes, Cardiovascular Risk, and Ventricular Hypertrophy Circulation, August 12, 2003; 108(6): 644 - 646. [Full Text] [PDF]
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A. K. M. T. Zaman, S. Fujii, H. Sawa, D. Goto, N. Ishimori, K. Watano, T. Kaneko, T. Furumoto, T. Sugawara, I. Sakuma, et al. Angiotensin-Converting Enzyme Inhibition Attenuates Hypofibrinolysis and Reduces Cardiac Perivascular Fibrosis in Genetically Obese Diabetic Mice Circulation, June 26, 2001; 103(25): 3123 - 3128. [Abstract] [Full Text] [PDF]
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M. A. Weber, J. M. Neutel, and D. H. G. Smith Contrasting clinical properties and exercise responses in obese and lean hypertensive patients J. Am. Coll. Cardiol., January 1, 2001; 37(1): 169 - 174. [Abstract] [Full Text] [PDF]
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 G. Fantuzzi and R. Faggioni Leptin in the regulation of immunity, inflammation, and hematopoiesis J. Leukoc. Biol., October 1, 2000; 68(4): 437 - 446. [Abstract] [Full Text]
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M. W. Nickola, L. E. Wold, P. B. Colligan, G.-J. Wang, W. K. Samson, and J. Ren Leptin Attenuates Cardiac Contraction in Rat Ventricular Myocytes : Role of NO Hypertension, October 1, 2000; 36(4): 501 - 505. [Abstract] [Full Text] [PDF]
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