Abstract

Background:

The reduction of coronary flow reserve (CFR) found in arterial hypertension may be due to changes in afterload, left ventricular (LV) structure, and metabolic factors. Also, insulin-like growth factor–1 (IGF-1) may be associated with the magnitude of CFR in relation to its modulating action on cardiac and endothelial function.

Methods:

A total of 44 newly diagnosed, untreated hypertensive patients, who were free of diabetes mellitus and coronary artery disease, underwent M-mode analysis, second-harmonic Doppler echocardiographic assessment of CFR (dipyridamole infusion 0.56 mg/kg intravenously in four patients), determination of circulating free IGF-1, and insulin resistance. Based on CFR levels, hypertensive subjects were divided into two groups: 18 with normal CFR (≥2) and 26 with impaired CFR (<2).

Results:

Patients with normal CFR had lower diastolic blood pressure, heart rate, and LV mass index but higher free circulating IGF-1 than patients with reduced CFR (P < .001). Insulin resistance was not significantly different between the two groups. In a first multilinear regression analysis that included demographic and echocardiographic variables, insulin resistance was independently associated with CFR (standardized β coefficient = −0.31, P < .05) in the overall population. However, in a subsequent model which included also IGF-1, the relationship between insulin resistance and CFR disappeared, whereas IGF-1 was the main independent determinant of CFR (β = 0.51, P < .0002).

Conclusions:

Free IGF-1 circulating levels are independently associated with CFR in hypertensive individuals free of overt coronary artery disease. A possible beneficial effect exerted by IGF-1 on coronary blood flow may be supposed in arterial hypertension.

Insulin-like growth factor–1 (IGF-1) is a single chain polypeptide that is synthesized mainly by the liver under the control of growth hormone, but is also produced by several other organs including the heart and vessels.1 Information about possible cardiac implications of IGF-1 is based both on the epidemiologic observation that acromegalic patients have both elevated circulating IGF-1 levels and a propensity to develop cardiovascular complications2 and on evidence that IGF-1 induces left ventricular (LV) hypertrophy.3 The adverse cardiovascular impact of IGF-1 has been challenged by further data, as IGF-1 improves hemodynamic parameters by modulating endothelium-derived relaxing factor4,5 and intracellular cation concentration.5,6 Our recent experience has shown an inverse association between IGF-1 circulating levels and isovolumic relaxation time in hypertensive patients free of coronary artery disease, underscoring the possible beneficial effect of IGF-1 on LV diastolic function.7

Arterial systemic hypertension is a major risk factor for coronary artery disease, and hypertensive individuals may present with angina pectoris or electrocardiographic signs of myocardial ischemia even in absence of overt coronary artery stenosis.8 Microvessel coronary alterations, which are detectable by a reduction of coronary flow reserve (CFR), have been proposed as a likely mechanism responsible for angina in hypertensive individuals.8,9 Metabolic, hormonal, myocardial, and vascular factors may be involved in impairment of CFR, by a decrease in maximal vasodilation underlying a mismatch between myocardial oxygen demand and coronary blood flow.10

In view of the influence exerted by IGF-1 on both the cardiac structure and function3,7 and, in particular, of its modulator role on endothelium vasodilation,4,6 it can be hypothesized that circulating IGF-1 concentration might also participate in regulating CFR, which is an expression of coronary microvessel response to hyperemic dilation. This issue may be crucial in hypertensive patients who often present with increased circulating IGF-1 levels11 and reduced CFR8,10 in comparison with normotensive subjects. On these grounds, we assessed the possible association between free IGF-1 circulating levels and the degree of CFR in arterial systemic hypertension.

Methods

Based on an initial screening, 147 patients with newly diagnosed, untreated arterial systemic hypertension (World Health Organization/International Society for Hypertension grade 1 to 2) were studied at the outpatient clinic of the Chair of the Emergency Medicine, Department of Clinical and Experimental Medicine of Federico II University of Naples between September 1998 and December 2000. Exclusion criteria were as follows: coronary artery disease (based on the absence of angina pectoris and negative findings on echocardiography (ECG) at rest, ECG at maximal treadmill exercise, and stress myocardial perfusion scintigraphy); diabetes mellitus; congestive heart failure; valvular heart disease; atrial fibrillation; liver or kidney disease; abnormal serum levels of free triiodothyronine, free thyroxine, thyroid-stimulating hormone, prolactin, adrenocorticotropic hormone, and cortisol (8 AM and 6 PM), as well as testosterone and estradiol; abnormal values of 24-h urinary free cortisol; administration of any drug known to interfere with circulating IGF-1 measurements; and echocardiogram of inadequate quality. By this selection, 44 hypertensive patients (28 male, 16 female; mean age 51.6 years) formed the final study group. According to levels of CFR, measured as the ratio between dipyridamole and baseline coronary flow velocities by Doppler ECG of left anterior descendent artery (LAD),12,13 the hypertensive patients were divided into two groups: 18 with normal CFR (≥2) and 26 with impaired CFR (<2).

The study was approved by the Institutional Ethics Committee, and informed consent was obtained from each patient.

Procedures

On the same day, all patients underwent anthropometric and laboratory determinations as well as standard ECG and CFR assessment. Patients were instructed to avoid all caffeine-containing drinks and foods for 12 h before the examinations.

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). All blood samples for circulating free IGF-1, insulin, and glucose were collected on fasting from antecubital vein between 8 and 9 AM. Plasma glucose was determined by the glucose oxidase method (Beckman Glucose Autoanalyzer, Fullerton, CA). Circulating free IGF-1 (Diagnostic System Laboratories, Webster, TX) and insulin (Sorin Biomedica, Milan Italy; intra-assay coefficient of variation 3.1% ± 0.3%) concentrations was measured by commercial radioimmunoassay. Insulin resistance (IR) was calculated according to homeostasis model assessment (HOMA),14 as follows: IR = FI × G/22.5, where IR = insulin resistance, FI = fasting insulin (μU/mL), and G = fasting glucose (mmol/L). The HOMA method has been recently validated as a reliable index of IR in subjects with a broad range of insulin sensitivity, and correlates well with the insulin-mediated glucose uptake calculated by euglycemic hyperinsulinemic glucose clamp.14

Standard M-mode echocardiography

Cuff blood pressure (BP) (mean of three measurements) and heart rate (HR) were estimated at the end of the baseline standard ECG by a physician blinded to echocardiographic and laboratory results. Echocardiography was performed with the Acuson Sequoia ultrasound system (Acuson Corp., Mountain View, CA), using a transducer with second harmonic capability (1.7-MHz transmitting and 3.5-MHz receiving). Echocardiographic examination consisted of standard M-mode analysis and CFR evaluation. The M-mode analysis was performed according to the guidelines of the American Society of Echocardiography.15 Left ventricular mass was indexed for body height powered to 2.7 (Cornell adjustment), and LV mass index >50 g/m2.7 was considered the cut-off point for LV hypertrophy.16 Relative diastolic wall thickness was determined as the ratio between the sum of the septal and posterior wall thickness and the LV internal end-diastolic diameter.

CFR evaluation

The visualization of the distal LAD was performed using a modified, foreshortened, two-chamber view obtained by sliding the transducer on the upper part and medially from an apical two-chamber view, to reach the best alignment to the interventricular sulcus.12,13 Subsequently, coronary flow in the distal LAD was examined by color Doppler flow mapping over the epicardial part of the anterior wall, with color Doppler velocity range set in the range of 12 to 24 cm/sec. A first attempt to record LAD flow was made using a 3.5-MHz, phased-array transducer with second harmonic capability. A 3.5-MHz transducer allowed better evaluation of the coronary flow Doppler signal than a 7-MHz transducer in patients with a suboptimal acoustic window. Contrast flow enhancement of pulsed Doppler was performed as needed using Levovist (SHU-508A; Schering AG, Berlin, Germany), with an infusion pump into the right cubital vein, at a concentration of 300 mg/mL and a rate of 1 mL/min.12 By placing sample volume on the LAD color signal, LAD flow spectral pulsed Doppler showed the characteristic biphasic pattern with larger diastolic and smaller systolic components. Systolic and diastolic peak velocities were measured at baseline and after dipyridamole infusion (0.56 mg/kg over 4 min), averaging the three highest spectral Doppler signals for each velocity. Coronary flow reserve was defined as the ratio between hyperemic and basal diastolic peak velocities. Subjects’ heart rates, BP, and the electrocardiograms were monitored during dipyridamole infusion. All of the images were recorded on a magneto-optical disk, and measurements were made off-line by two observers who were blinded to BP and laboratory results. A total of 20 randomly selected examinations were analyzed twice by the same observer (L.D.S.) at a 2-week interval, as well as by a second observer (S.C.). Intraobserver variability was 2% (L.D.S.) and 3.6% (S.C.), and interobserver variability was 4.5%.

Statistical analysis

Data are presented as mean ± SD. To approximate normal distributions, plasma insulin and IR (HOMA) were logarithmically transformed and used as is in all calculations. Analysis of variance by Scheffé's post hoc test was used for intergroup differences. Univariate relations were assessed by Pearson's method. Multiple linear regression analyses were used for independent effects of potential determinants that were not obviously related to each other (eg, septal wall thickness and LV mass) on CFR. Differences were considered significant at P < .05. All statistical analyses were performed on an IBM-type personal computer using SPSS software, version 10 (SPSS Inc., Chicago, IL).

Results

The main characteristics of the study population are listed in Table 1. The hypertensive patients were slightly overweight, with a higher proportion of men than women. The prevalence of LV hypertrophy (LV mass index >50 g/m2.7 according to Cornell criteria)16 was 40.9% (18/44).

Table 1

Main characteristics of the study population

Variable Mean ± SD (Range) 
Sex (male/female) 28/16 
Age (y) 51.6 ± 6.1 (37–63) 
BMI (kg/m227.7 ± 2.9 (22–34.6) 
HR (beats/min) 74.4 ± 8.7 (56–98) 
Systolic BP (mm Hg) 149.0 ± 10.0 (135–170) 
Diastolic BP (mm Hg) 100.0 ± 3.7 (95–100) 
Mean BP (mm Hg) 116.2 ± 5.1 (108.3–130.0) 
Plasma glucose (mmol/L) 5.2 ± 0.9 (3.4–7.3) 
Plasma insulin (mU/L) 12.3 ± 3.6 (4.5–19.4) 
2-h Plasma glucose (mmol/L) 6.66 ± 0.3 (5.6–7.5) 
IR (HOMA) 2.89 ± 1.1 (0.83–6.18) 
IGF-1 (pg/mL) 0.44 ± 0.04 (0.04–1.51) 
LV mass index (g/m2.747.1 ± 9.3 (29.4–68) 
RDWT 0.35 ± 0.07 (0.21–0.49) 
Baseline CFDPV (m/sec) 0.30 ± 0.08 (0.14–0.50) 
Dipyridamole CFDPV (m/sec) 0.55 ± 0.16 (0.25–1.20) 
Coronary flow reserve 1.90 ± 0.51 (1.11–3.27) 
Variable Mean ± SD (Range) 
Sex (male/female) 28/16 
Age (y) 51.6 ± 6.1 (37–63) 
BMI (kg/m227.7 ± 2.9 (22–34.6) 
HR (beats/min) 74.4 ± 8.7 (56–98) 
Systolic BP (mm Hg) 149.0 ± 10.0 (135–170) 
Diastolic BP (mm Hg) 100.0 ± 3.7 (95–100) 
Mean BP (mm Hg) 116.2 ± 5.1 (108.3–130.0) 
Plasma glucose (mmol/L) 5.2 ± 0.9 (3.4–7.3) 
Plasma insulin (mU/L) 12.3 ± 3.6 (4.5–19.4) 
2-h Plasma glucose (mmol/L) 6.66 ± 0.3 (5.6–7.5) 
IR (HOMA) 2.89 ± 1.1 (0.83–6.18) 
IGF-1 (pg/mL) 0.44 ± 0.04 (0.04–1.51) 
LV mass index (g/m2.747.1 ± 9.3 (29.4–68) 
RDWT 0.35 ± 0.07 (0.21–0.49) 
Baseline CFDPV (m/sec) 0.30 ± 0.08 (0.14–0.50) 
Dipyridamole CFDPV (m/sec) 0.55 ± 0.16 (0.25–1.20) 
Coronary flow reserve 1.90 ± 0.51 (1.11–3.27) 

BMI = body mass index; HR = heart rate; BP = blood pressure; IR = insulin resistance; HOMA = homeostasis model assessment; IGF-1 = insulin growth factor–1; LV = left ventricular; RDWT = relative diastolic wall thickness; CFDPV = coronary flow diastolic peak velocity.

All patients had normal ECG at rest. During dypiridamole stress test, no patient complained of chest discomfort. In addition, no ECG ischemic ST-segment changes and no two-dimensional echocardiographic regional wall motion abnormalities were observed during the test.

The clinical, metabolic, and echocardiographic characteristics of the entire hypertensive population according to CFR magnitude are reported in Table 2. The higher CFR presented by hypertensive subjects with normal CFR (≥2) in comparison with those having impaired CFR (<2) was due to both lower baseline and higher dipyridamole coronary diastolic peak velocity. Patients with normal CFR had lower HR and diastolic BP (both P < .05) as well as higher free IGF-1 circulating levels (P < .001). No difference in plasma glucose levels and IR (HOMA) degree was found between the two groups. Because of the lower septal wall thickness, LV mass index was marginally reduced in this group.

Table 2

Clinical, metabolic, and echocardiographic differences between hypertensive subjects with normal and impaired coronary flow reserve

Variable CFR ≥ 2 (n = 18) CFR <2 (n = 26) P Value 
Sex (male/female) 11/7 17/9 NS 
Age (y) 51.6 ± 6.2 51.7 ± 6.1 NS 
BMI (kg/m227 ± 2.6 28.2 ± 3.1 NS 
Systolic BP (mm Hg) 147 ± 8.4 150 ± 11 NS 
Diastolic BP (mm Hg) 98 ± 2.8 101 ± 4.0 <.05 
Mean BP (mm Hg) 114.9 ± 4.0 117.2 ± 5.7 <.05 
HR (beats/min) 69.6 ± 7.6 77.7 ± 13.4 <.05 
Plasma glucose (mmol/L) 4.8 ± 1.0 5.3 ± 0.9 NS 
Plasma insulin (mU/L) 11.6 ± 4.1 12.5 ± 3.4 NS 
IR (HOMA) 2.54 ± 1.0 3.06 ± 1.2 NS 
Free IGF-1 (pg/mL) 0.75 ± 0.5 0.29 ± 0.2 <.001 
IVST (mm) 10.6 ± 1.9 11.5 ± 1.4 <.05 
PWT (mm) 8.7 ± 1.3 9.1 ± 1.3 NS 
LVIDD (mm) 52 ± 5.7 51 ± 3.5 NS 
LV mass (g) 183.8 ± 51.5 208.0 ± 48.5 NS 
LV mass index (g/m2.742.9 ± 9.1 49.9 ± 8.5 <.05 
RDWT 0.34 ± 0.07 0.35 ± 0.05 NS 
Baseline CFDPV (m/sec) 0.27 ± 0.09 0.32 ± 0.08 <.02 
Dipyridamole CFDPV (m/sec) 0.64 ± 0.20 0.49 ± 0.09 <.005 
Variable CFR ≥ 2 (n = 18) CFR <2 (n = 26) P Value 
Sex (male/female) 11/7 17/9 NS 
Age (y) 51.6 ± 6.2 51.7 ± 6.1 NS 
BMI (kg/m227 ± 2.6 28.2 ± 3.1 NS 
Systolic BP (mm Hg) 147 ± 8.4 150 ± 11 NS 
Diastolic BP (mm Hg) 98 ± 2.8 101 ± 4.0 <.05 
Mean BP (mm Hg) 114.9 ± 4.0 117.2 ± 5.7 <.05 
HR (beats/min) 69.6 ± 7.6 77.7 ± 13.4 <.05 
Plasma glucose (mmol/L) 4.8 ± 1.0 5.3 ± 0.9 NS 
Plasma insulin (mU/L) 11.6 ± 4.1 12.5 ± 3.4 NS 
IR (HOMA) 2.54 ± 1.0 3.06 ± 1.2 NS 
Free IGF-1 (pg/mL) 0.75 ± 0.5 0.29 ± 0.2 <.001 
IVST (mm) 10.6 ± 1.9 11.5 ± 1.4 <.05 
PWT (mm) 8.7 ± 1.3 9.1 ± 1.3 NS 
LVIDD (mm) 52 ± 5.7 51 ± 3.5 NS 
LV mass (g) 183.8 ± 51.5 208.0 ± 48.5 NS 
LV mass index (g/m2.742.9 ± 9.1 49.9 ± 8.5 <.05 
RDWT 0.34 ± 0.07 0.35 ± 0.05 NS 
Baseline CFDPV (m/sec) 0.27 ± 0.09 0.32 ± 0.08 <.02 
Dipyridamole CFDPV (m/sec) 0.64 ± 0.20 0.49 ± 0.09 <.005 

CFR = coronary flow reserve; NS = not significant; IVST = interventricular septal wall thickness; PWT = posterior wall thickness; LVIDD = left ventricular internal end-diastolic diameter; other abbreviations as in Table 1.

Univariate relations of CFR with demographic, metabolic, and echocardiographic variables were tested in the overall population. The CFR was not related to BMI (P = .07, NS), whereas the correlation with HR (r = −0.33, P < .05), diastolic BP (r = −0.38, P < .01), and, in particular, mean BP (r = −0.45, P < .001) were all significant. Thus, the subsequent relationships were tested adjusting CFR for mean BP. Adjusted CFR was significantly marginally related with fasting plasma glucose (r = −0.32) and 2-h plasma glucose (r = −0.30, both P < .05) but not with plasma insulin levels (r = −0.15, NS). The relation of adjusted CFR with IR (HOMA) did not achieve the statistical significance (r = −0.28, P = .09, NS) but a positive association was found between adjusted CFR and free IGF-1 circulating levels (r = 0.51, P < .001) (Fig. 1). Adjusted CFR also had inverse relationships with LV mass (r = −0.33, P < .02) and LV mass index (r = −0.30, P < .05). However, among components of LV mass formula, adjusted CFR was significantly related to septal wall thickness (r = −0.33, P < .02) but not to LV internal end-diastolic diameter (r = −0.11, NS) or to posterior wall thickness (r = −0.10, NS).

Scatter plots and regression line of the relation between circulating levels of free insulin growth factor–1 (IGF-1) and adjusted coronary flow reserve (CFR) for mean blood pressure in the overall hypertensive population.

In a first multiple linear regression analysis (Table 3, upper panel), performed to assess independent associations of CFR in the overall population (including sex, age, BMI, HR, mean BP, septal wall thickness and insulin resistance as potential determinants), HR, septal wall thickness, and IR were independently associated with CFR (R2 = 0.39, P < .001). Of note, by replacing septal wall thickness by LV mass or LV mass index in the model, both of these variables were not significantly associated with CFR.

Table 3

Multiple linear regression analyses with coronary flow reserve as dependent variable in the overall hypertensive population

*First Model: Sex, Age, BMI, HR, mean BP, IVSWT, and IR as potential determinants 
Dependent Variable Independent Predictor Standardized β-Coefficient t P Value 
CFR HR −0.41 −2.92 <.01 
 IVST −0.42 −2.99 <.005 
 IR −0.31 −2.24 <.05 
 Age 0.11 0.70 NS 
 Sex −0.02 −0.10 NS 
 BMI 0.16 0.89 NS 
 Mean BP −0.04 −0.27 NS 
Second Model: Sex, Age, BMI, HR, mean BP, IVSWT, IR, and free IGF-1 as potential determinants 
CFR IGF-1 0.51 4.23 <.0002 
 HR −0.36 −3.01 <.005 
 IVST −0.32 −2.58 <.01 
 IR −0.11 −0.68 NS 
 Age 0.11 1.23 NS 
 Sex −0.07 −0.55 NS 
 BMI 0.05 0.29 NS 
 Mean BP −0.04 −0.31 NS 
*First Model: Sex, Age, BMI, HR, mean BP, IVSWT, and IR as potential determinants 
Dependent Variable Independent Predictor Standardized β-Coefficient t P Value 
CFR HR −0.41 −2.92 <.01 
 IVST −0.42 −2.99 <.005 
 IR −0.31 −2.24 <.05 
 Age 0.11 0.70 NS 
 Sex −0.02 −0.10 NS 
 BMI 0.16 0.89 NS 
 Mean BP −0.04 −0.27 NS 
Second Model: Sex, Age, BMI, HR, mean BP, IVSWT, IR, and free IGF-1 as potential determinants 
CFR IGF-1 0.51 4.23 <.0002 
 HR −0.36 −3.01 <.005 
 IVST −0.32 −2.58 <.01 
 IR −0.11 −0.68 NS 
 Age 0.11 1.23 NS 
 Sex −0.07 −0.55 NS 
 BMI 0.05 0.29 NS 
 Mean BP −0.04 −0.31 NS 

Abbreviations as in Tables 1 and 2.

*

R2 = 0.40; SE = 0.41; P < .001.

R2 = 0.55; SE = 0.36; P < .00001.

In a subsequent multivariate model (Table 3, lower panel), by the additional inclusion of free circulating IGF-1, this last variable (standardized β coefficient = 0.51, P < .0002), HR and septal wall thickness were independent determinants of CFR (cumulative R2 = 0.55, P < .00001), whereas the partial relation coefficients of IR and the other variables versus CFR were not significant.

Discussion

Our study demonstrates that 1) free IGF-1 circulating concentration is lower in hypertensive patients with impaired CFR, and 2) an independent, positive association is evident between free IGF-1 levels and CFR in the hypertensive population overall.

A reduction of CFR has been previously reported in arterial systemic hypertension.8–10 Increased LV afterload, changes in cardiac structure such as LV remodeling and hypertrophy, and impairment of endothelium-mediated vasodilation have been considered as possible mechanisms underlying the CFR decrease in hypertensive patients who are free of coronary artery disease.8,9,10,13,17,18

In our study, the overall hypertensive population was divided into two groups according to CFR levels. The choice to consider normal a CFR ≥2 was based on the findings of previous studies, which used both coronary Doppler flow wire19 and the same second-harmonic Doppler method.20 By this subdivision and in accordance with previous reports,17,18,21 the patients with impaired CFR had higher LV mass than those with normal CFR. This was due to a greater septal thickness, whereas both the posterior wall thickness and LV end-diastolic diameter were comparable between the two groups. The metabolic profile (plasma glucose, insulin, and IR) was similar in hypertensive subjects with normal or impaired CFR. Free IGF-1, however, was increased in the presence of normal CFR, its mean concentration being more than twice in comparison with patients with an impaired CFR. This last finding was further supported by the positive univariate relation found between the same IGF-1 circulating levels and CFR (adjusted for mean BP) in the overall population.

In the same population, a negative association of IR with CFR was not significant by adjusting CFR for mean BP; however, it did reach statistical significance in a first multivariate model including demographic and echocardiographic variables but not free IGF-1 as potential determinants. Of note, multivariate analyses take into account only the independent effect of each single factor on a dependent variable. Insulin resistance has emerged as a true coronary risk factor in non–insulin dependent diabetes mellitus, obesity, hyperlipidemia, and arterial hypertension.22 It is involved in the atherosclerosis progression because of its significant relationship with the incidence of atherosclerotic complications.23 Yokoyama et al24 showed that hyperglycemia itself, rather than IR, is related to reduced CFR in non–insulin dependent diabetes mellitus. Nevertheless, such patients might have greater tissue damage due to hyperglycemia, whereas the negative impact of IR might be more evident in nondiabetic hypertensive subjects. Insulin resistance might be critical in the genesis of coronary artery disease by inducing frequent activation of the sympathetic nervous system.25

Further important information was obtained, however, by adding free IGF-1 in a second multilinear regression analysis. In this model, the relationship between IR and CFR disappeared, whereas free IGF-1 resulted as the main independent predictor of CFR; this, combined with HR and septal wall thickness, explained 55% of the CFR variability. Thus, one could conclude that IGF-1 has a more major role than that exerted by IR to modulate CFR in arterial hypertension. Of note, the inverse association of LV mass and CFR also disappeared in the multivariate models. It is still controversial whether CFR reduction occurs as consequence of LV hypertrophy or of increased afterload itself in hypertensive patients.17,21,26 In addition, in the present study, the independent association of CFR with septal wall thickness and not with LV mass is not surprising, as septal thickness is part of LV mass itself and is directly perfused by LAD when the same CFR was measured.

Our data provide clinical support for the results of Li et al,27 showing in vitro that IGF-1 attenuates detrimental impact of nonocclusive coronary artery constriction on the heart. In particular, IGF-1 overexpression of hypertensive individuals12 strongly blunts cell necrosis after coronary artery occlusion,27 interferes with the activation of myocytes necrosis during ischemic reperfusion injury28 and myocardial infarction,29 and increases the vascular component of the myocardium.27 The possible positive impact of IGF-1 serum levels on CFR is not totally unexpected in a population of recently diagnosed hypertensive individuals such as those included in the present study. It can be hypothesized that the cellular growth effect due to increased IGF-1 levels does not have the right time to exert its negative influence on myocardial blood flow after a short-term exposure. The association between IGF-1 and CFR should also be tested in different populations such as as hypertensive individuals with longer-standing diagnoses as well as acromegalic patients, in whom a longer exposure length to increased IGF-1 levels induces detrimental effects on cardiac structure and function.3,30–32

Worthy of note is that the possible positive impact of free IGF-1 on CFR may be explained by different effects of IGF-1 on intracellular cation concentrations as well as endothelial function and regulation.22

The effect of IGF-1 on CFR might be modulated by intracellular cation concentrations, which, in turn, may influence vascular reactivity and resistance. Elevated intracellular calcium levels are associated with increased vascular resistance and vascular hyperactivity.6 Both IGF-1 and insulin may reduce intracellular calcium concentration by the direct activation of calcium-dependent K+ channels, which indirectly decrease calcium influx via voltage-operated channels, and by the stimulation of Na/K ATPase pump through both transcriptional and posttranslational modifications of the pump.22

Another possible mechanism of IGF-1–induced vasodilation in coronary microvascular vessels is that mediated by hyperpolarization through K+ channels.33 In addition, IGF-1 stimulates cytosolic free magnesium levels in both normal and hypertensive persons, improving tissue insulin sensitivity. Magnesium appears to be able to activate several hormonal and biochemical mechanisms modulating cellular glucose use. In insulin-resistant conditions (eg, arterial hypertension and type 2 diabetes), an intracellular magnesium deficiency that is able to increase peripheral vascular resistance has been observed. On these grounds, IGF-derived stimulation of intracellular magnesium levels may, at least in part, explain the previously reported beneficial effects of IGF-1 on microvessels.34

Finally, IGF-1 vascular actions could also be mediated by nitric oxide, as IGF-1 stimulates nitric oxide production by inducing vascular relaxation or blunting vasoconstrictive responses.4,22,35,36

In conclusion, our study provides evidence that free IGF-1 circulating levels are independently and positively associated with CFR in hypertensive individuals, in the absence of overt coronary artery disease. Future longitudinal studies will be needed to demonstrate the beneficial effect of circulating IGF-1 on coronary blood flow and its possible prognostic role in preventing coronary artery diseases in arterial hypertension.

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