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Hypertension. 2001;38:840-845
doi: 10.1161/hy1001.091776
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(Hypertension. 2001;38:840.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Inverse Association Between Free Insulin-Like Growth Factor-1 and Isovolumic Relaxation in Arterial Systemic Hypertension

Maurizio Galderisi; Giovanni Vitale; Giovanni Lupoli; Michelangela Barbieri; Gina Varricchio; Carlo Carella; Oreste de Divitiis; Giuseppe Paolisso

From Cattedra di Medicina d’Urgenza, Istituto di Medicina e Clinica Sperimentale (M.G., O. de D.) and Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (G. Vitale, G.L.), Università degli Studi di Napoli "Federico II"; and Cattedra di Geriatria (M.B., G. Varricchio, G.P.) and Istituto di Endocrinologia (C.C.), II Università degli Studi di Napoli, Napoli, Italy.

Reprint requests to Prof Giuseppe Paolisso, Cattedra di Geriatria, Seconda Università degli Studi di Napoli, Piazza Miraglia 2, I-80138 Napoli, Italy. E-mail gpaoliss{at}tin.it


*    Abstract
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 *Abstract
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Abstract—— Several trials have suggested that insulin-like growth factor-1 (IGF-1) may have a pathophysiological role in the development of arterial essential hypertension. To verify the possible association of IGF-1 with left ventricular morphological and functional echocardiographic parameters in hypertension, we studied 40 male patients with newly diagnosed hypertension and 15 normotensive control subjects. Doppler echocardiography was performed and circulating free IGF-1 levels were determined in all subjects. Circulating free IGF-1 levels were higher in hypertensives than in control subjects (P<0.01). A significant inverse correlation was observed between free IGF-1 and isovolumic relaxation time in the overall population (r=-0.37, P<0.01) and in hypertensives (r=-0.57, P<0.0001), whereas this relation disappears in normotensives. These results were confirmed by multivariate analysis. The present study confirms that arterial essential hypertension represents a clinical condition associated with an increased synthesis of IGF-1. The observation of an inverse, independent association between free IGF-1 and isovolumic relaxation time suggests 2 alternative hypotheses: a possible beneficial effect of IGF-1 to diastolic relaxation or a resistance to IGF-1 in hypertension.


Key Words: insulin growth factor • hypertension, arterial • echocardiography • diastole • relaxation


*    Introduction
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Arterial hypertension, a major risk factor for stroke and myocardial infarction, is often complicated by left ventricular (LV) hypertrophy and abnormalities of LV function. In particular, LV diastolic dysfunction is an early sign of hypertensive heart disease.1 It is now accepted that several humoral factors (vasoactive substances, hormones, growth factors, and cytokines) participate directly in the development of end-organ damage and metabolic alterations that occur in arterial essential hypertension. Recent reports have underscored the potential role of insulin in the development of cardiac damage,2–4 and a possible influence of insulin-like growth factor-1 (IGF-1) has been supposed.4,5

IGF-1 belongs to a family of single-chain polypeptides with structural homology to proinsulin.6 Circulating IGF-1 is synthesized primarily by the liver under the control of growth hormone (GH).7 However, IGF-1 can be synthesized by many other organs, including heart, and can act as an autocrine or a paracrine factor.8 IGF-1 is a growth factor for cellular proliferation and differentiation, and it exerts both inotropic and growth effects in the heart.9,10 The earliest interest in the relationship between the GH/IGF-1 axis and the cardiovascular system stemmed from the clinical and epidemiological observation that patients with acromegaly and high levels of GH and IGF-1 have an increased propensity to develop cardiovascular complications.11–13 Later, in vitro and in vivo studies demonstrated that IGF-1 induces hypertrophy of cultured ventricular myocytes and participates in the development of LV hypertrophy.10,14

The aim of the present study was to investigate the possible association of circulating IGF-1 levels with Doppler indexes of LV diastolic function in patients affected by arterial essential hypertension.


*    Methods
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Study Design
Forty male patients (mean age, 46.9±7.4 years) with newly diagnosed arterial essential hypertension and a control group of 15 normotensive, insulin-sensitive, healthy male subjects (mean age, 45.4±3.3 years) were enrolled in the study. Informed consent was obtained from all subjects, and the study was approved by the ethics committees of our institutions. Patients were considered hypertensive according to their clinical blood pressure (BP) levels (diastolic BP >90 mm Hg as the mean of 3 separate measurements during >=3 different visits at 1-week intervals). Exclusion criteria were glucose intolerance or diabetes mellitus detected by an oral glucose tolerance test (75 g glucose)15; family history of diabetes, coronary artery disease, congestive heart failure, and valvular heart disease; administration of cardiac medication, glucocorticoids, or any drug known to interfere with the glucose metabolism and circulating IGF-1 measurements; liver and kidney diseases; abnormal serum levels of free triiodothyronine, free thyroxine, thyroid-stimulating hormone, prolactin, adrenocorticotropic hormone, and cortisol (taken at 8:00 AM and 6:00 PM), as well as testosterone and estradiol; abnormal values of 24-hour urinary free cortisol; and poor quality of echocardiograms.

All subjects underwent fasting free IGF-1 determination and echocardiographic examination.

Anthropometric and Laboratory Determinations
Body weight and height were measured by standard technique, and body mass index (BMI) was derived as weight divided by height squared (kg/m2). Serum free IGF-1 (Diagnostic Systems Laboratories)16 and glucose (enzymatic method) determinations were made on fasting subjects.

Doppler Echocardiographic Examination
Doppler echocardiographic examinations were performed according to recommendations of the American Society of Echocardiography.17 Relative diastolic wall thickness (RDWT) was determined as the ratio between the sum of interventricular septal thickness and posterior wall thickness and LV end-diastolic diameter. Endocardial fractional shortening was calculated as the percentage change in the internal LV dimension between systole and diastole. LV mass (LVM) was estimated according to the Penn convention,18 and LVM index was defined as the LVM (g) divided by the height (m).19 Pulsed Doppler evaluation of LV inflow tract was performed from the apical 4-chamber view, with the sample volume placed at the level of the mitral annulus.20 Measurements of LV diastolic filling and of the isovolumic relaxation time (IVRT) were determined as reported elsewhere.2,21

Statistical Analyses
Statistical analyses were performed by use of the SPSS/PC for Windows release 6.0 statistical package. All results are expressed as mean±SD. Student’s t test for unpaired data was used to compare the results between the 2 groups. Simple and partial correlations by Pearson’s method were used to assess the univariate relations. Stepwise forward multiple linear regression analysis allowed us to weigh the independent contribution of each covariate to the change in LV diastolic parameters. A value of P<0.05 was considered statistically significant.

An expanded Methods section can be found in an online data supplement available at http://hypertensionaha.org.


*    Results
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Anthropometric and Laboratory Determinations
The anthropometric and laboratory data of the study population are listed in Table 1. No significant differences in age, heart rate, and fasting plasma glucose levels were found between the control group and hypertensives. BMI (P<0.05), waist-to-hip ratio (WHR; P<0.0001), and systolic and diastolic BPs (both P<0.0001) were significantly higher in hypertensives than in control subjects. Fasting circulating free IGF-1 levels were higher in hypertensives than in control subjects (P<0.01).


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  		Table 1. Anthropometric Characteristics and Laboratory Determinations of the Study Population

Doppler Echocardiographic Examination
Posterior wall thickness (P<0.0001), interventricular septal thickness (P<0.0005), RDWT (P<0.0005), and LVM index (P<0.005) were higher in hypertensives than in control subjects, whereas LV end-diastolic diameter, LV end-systolic diameter, and fractional shortening were not significantly different between the 2 groups (Table 2).


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  		Table 2. Doppler Echocardiographic Analysis

Doppler examination showed lower E peak velocity (P<0.05), higher A peak velocity (P<0.0001), greater atrial filling fraction, and lower peak velocity E/A ratio (P<0.0001) in hypertensives than in control subjects. E-wave deceleration time did not differ significantly between the 2 groups, but IVRT was significantly longer (P<0.05) in hypertensives.

Determinants of IVRT
In the overall population, among Doppler-derived LV diastolic indexes, no significant associations of E and A peak velocities, E/A ratio, and E wave deceleration time with free IGF-1 were found. On the other hand, free IGF-1 was inversely associated with IVRT in the overall population (the Figure) as in the hypertensive group but not in the control group.



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  		Scatterplot and regression line in the overall population between IGF-1 and IVRT.

Univariate relations of IVRT with several variables in the overall population and separately in hypertensive are shown in Table 3. In the whole population, IVRT was related to BMI (r=0.43, P<0.005), WHR (r=0.47, P<0.005), diastolic BP (r=0.33, P<0.05), heart rate (r=-0.27, P<0.05), LVM index (r=0.58, P<0.0001), and free IGF-1 (r=-0.37, P<0.01). A scatterplot and regression line of the inverse correlation between IGF-1 and IVRT in the overall population are depicted in the Figure. Of note, among the other Doppler-derived LV diastolic indexes, E and A peak velocities, E/A ratio, and E-wave deceleration time were not related to IGF-1. Also in hypertensives, IVRT was related significantly to free IGF-1 (r=-0.57, P<0.0001), whereas this relation did not achieve statistical significance in the normotensive control group. Of note, no significant relation of IGF-1 with endocardial fractional shortening and LVM index was found in the overall population, normotensives, or hypertensive patients.


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  		Table 3. Univariate Correlations of IVRT With Main Anthropometric, Laboratory, and Echocardiographic Variables in the Whole Population and Separately in Hypertensives and Normotensives

In a subsequent multiple linear regression analysis performed in the whole population, including age, BMI, WHR, diastolic BP, heart rate, LVM index, and free IGF-1 as potential determinants, free IGF-1 (standardized ß=-0.40, P<0.0001), WHR (ß=0.40, P<0.0005), and LVM index (ß=0.39, P<0.0005) were independent predictors of IVRT (cumulative R2=0.56, SE=7.42 ms, P<0.0001). After the effects of free IGF-1, WHR, and LVM index were removed, the partial relation coefficients of age, BMI, WHR, diastolic BP, and heart rate with IVRT were not significant. In hypertensives, free IGF-1 (standardized ß=-0.45, P<0.0005), WHR (ß=0.37, P<0.005), and LVM index (ß=0.33, P<0.01) were independent determinants of IVRT (cumulative R2=0.59, SE=7.37 ms, P<0.0001). In normotensives, only heart rate (ß=-0.85, P<0.0001) was independently associated with IVRT (cumulative R2=0.68, SE=4.91 ms, P<0.0001).


*    Discussion
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This study shows that (1) free IGF-1 is higher in hypertensives than in normotensive subjects; (2) a significant inverse association is found between free IGF-1 and isovolumic relaxation in the overall population and in the hypertensive group but not in the control group; and, importantly, (3) after adjustment for several confounders in separate multiple linear regression models, this association remains significant in hypertensives although it is not evident in normotensives.

Free IGF-1 Increase in Arterial Systemic Hypertension
In the present study, we found a significant increase in free IGF-1 levels in patients with arterial hypertension. This finding is consistent with previous reports in which circulating levels of IGF-1 were higher in hypertensives than in normotensive subjects. Despite abnormally higher compared with the control groups, IGF-1 levels of hypertensive patients were below the established lower limit of patients affected by active acromegaly,5,22 even in the absence of overt GH hypersecretion.23 It has to be taken into account that this increase could be due to a reduction in serum concentration of IGF-1–binding proteins. However, IGF-1–binding protein 3, primarily responsible for regulating serum IGF-1 levels because it is linked to {approx}75% of the total IGF-1, has been reported to be normal or increased in hypertensive patients.24,25

Inverse Association of Free IGF-1 and IVRT
Our results showed that among Doppler indexes of LV diastolic function, only IVRT was significantly associated with free IGF-1 in an inverse fashion in the overall population, whereas the other measurements of LV diastolic filling did not show any relation with free IGF-1. IVRT represents a reliable marker of isovolumic relaxation, which is the active diastolic phase preceding LV filling. It includes the decline in LV pressure from its peak until its value falls below that of left atrial pressure while LV volume remains constant.26 Recent studies showed that IVRT is an early marker of LV dysfunction in arterial systemic hypertension.27 IVRT is influenced by several physiological and pathological factors that control LV filling (mainly age, heart rate, preload and afterload changes, and LV hypertrophy).28–32 In addition, a substantial link between IVRT and 2 other metabolic parameters, insulin resistance and cytosolic calcium concentration, is recognized. In fact, insulin resistance is positively associated with IVRT,2 whereas an increase in cytosolic calcium levels induces a prolongation of the IVRT.32,33

In the present study, the univariate inverse relation between free IGF-1 levels and IVRT was significant in the whole population and in hypertensives, but this relation disappeared in the normotensive group. These results were confirmed by multivariate analyses, which provided additional information. After adjustment for clinic and echocardiographic confounders in separate multivariate models, WHR, LVM index, and free IGF-1 were independent determinants of IVRT in the whole population and in hypertensives. On the contrary, heart rate was the only independent determinant of IVRT in healthy normotensives. The positive association of WHR with IVRT might be expected because of the well-known adverse influence exerted by obesity on diastolic isovolumic relaxation.34 In addition, the relation of LVM index with IVRT is in agreement with previous findings.32 On the other hand, the inverse relation observed between free IGF-1 and IVRT is apparently unexpected, because previous reports observed prolonged IVRT in acromegalic patients.35,36 Myocardial hypertrophy and interstitial fibrosis, induced by high levels of IGF-1, have been reported to induce LV diastolic dysfunction in acromegalics.37–39 IGF-1 has also been reported to increase inositol 1,4,5-tris-phosphate levels40; to activate tyrosine kinase phosphatase, phosphatidylinositol-3-kinase, and protein kinase C41–43; and to increase intracellular calcium level or sensitivity,43–45 suggesting another mechanism for IVRT prolongation in case of IGF-1 overproduction.

However, some studies reported beneficial effects of IGF-1, describing improvement in LV diastolic function in patients with heart failure during GH therapy.46,47 In addition, Li et al48 showed that IGF-1 constitutive overexpression prevents the activation of myocyte death in the surviving myocardium of the postinfarcted mouse heart, limiting LV dilatation, wall stress, and reactive hypertrophy. Therefore, we can hypothesize that IGF-1 hypersecretion in hypertensives could improve LV diastolic relaxation, thus justifying the inverse correlation between free IGF-1 and IVRT found in the present study.

In a recent report, Ren et al49 demonstrated a resistance in myocardial contractile response to IGF-1 in patients with arterial hypertension and advanced age. In addition, the normal positive response of intracellular calcium to IGF-1 showed an opposite trend in the presence of hypertension. A decrease in intracellular calcium transient changes has been observed to progress hand in hand with a parallel increase in IGF-1 concentration in ventricular myocytes of spontaneously hypertensive rats. The mechanisms explaining this opposite responsiveness to IGF-1 in hypertensives are still not clear. According to Ren et al,49 the following hypotheses can be put forth: (1) a decrease in myocardial IGF-1 receptor or signal trasduction,50 (2) altered expression of IGF-1/insulin hybrid receptors,50 (3) overexpression of NO able to inhibit the voltage-dependent calcium channel,51,52 (4) intracellular calcium overload,53,54 and (5) diminished ß-adrenergic activity.55

Therefore, the positive and negative effects of IGF-1 on intracellular calcium modulation in normotensives and hypertensives, respectively, provide another potential explanation for the apparent discrepancy of our data about the inverse correlation between free IGF-1 and IVRT.

Study Limitations
In view of the fact that circulating free IGF-1 levels do not reflect cardiomyocyte production of this hormone, circulating free IGF-1 levels could not provide reliable estimation of their autocrine and paracrine effects. Cardiomyocyte IGF-1 overexpression plays a significant role in the functional adaptation to the failing heart.48,56,57 This notwithstanding, even circulating IGF-1 levels have been shown to affect LV function.11–14 Furthermore, an assessment of cardiomyocyte IGF-1 might not have been ethically justified in uncomplicated hypertensive patients without signs of overt heart failure such as those included in the population of the present study.

Another limitation is that the possible role exerted by both the renin-angiotensin system and the sympathetic nervous system on LV diastolic function was not evaluated. The greater BMI and WHR of hypertensives in the present study could have stimulated both these systems and induced a greater hepatic production of IGF-1, thus worsening LV diastolic relaxation. However, according to our data, the higher levels of IGF-1 were related to a shortening of IVRT, which may be interpreted as an improvement in diastolic relaxation. In addition, the association between IGF-1 and IVRT in the present study was independent of the effect of both BMI and WHR in the multilinear regression analyses. Key experimental studies58,59 have reported that IGF-1 overexpression downregulates rather than upregulates both the renin-angiotensin and sympathetic nervous systems. Thus, it is unlikely that the association between IGF-1 and IVRT might be mediated by overweight and central obesity. Finally, in our multivariate analyses, in both the overall population and hypertensive patients, the association of IGF-1 with IVRT was independent of the effect exerted by heart rate, a crude index of sympathetic nervous system activity. Interestingly, heart rate was the only independent determinant of IVRT in the normotensive control group.

In conclusion, the present study confirms that arterial essential hypertension represents a clinical condition associated with an increased synthesis of IGF-1. The observation of an inverse and independent association between free IGF-1 concentrations and IVRT length occurring in hypertensives supports a possible beneficial effect exerted by IGF-1 on LV diastolic relaxation. An alternative explanation of our findings is a possible resistance to IGF-1 that can induce a decrease in intracellular calcium and a consecutive shortening of IVRT. Further clinical and molecular studies are need to clarify this interesting issue.

Received December 21, 2000; first decision January 16, 2001; accepted March 26, 2001.


*    References
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 *References
 

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