Roberto Pedrinelli

Insulin Resistance in Essential Hypertension

High blood pressure is prevalent in obesity and in diabetes, both conditions with insulin resistance. To test whether hypertension is associated with insulin resistance independently of obesity and glucose intolerance, we measured insulin sensitivity (using the euglycemic insulin-clamp technique), glucose turnover (using [3H]glucose isotope dilution), and whole-body glucose oxidation (using indirect calorimetry) in 13 young subjects (38 +/- 2 years [+/- SEM]) with untreated essential hypertension (165 +/- 6/112 +/- 3 mm Hg), normal body weight, and normal glucose tolerance. In the postabsorptive state, all measures of glucose metabolism were normal. During steady-state euglycemic hyperinsulinemia (about 60 microU per milliliter), hepatic glucose production and lipolysis were effectively suppressed, and glucose oxidation and potassium disposal were normally stimulated. However, total insulin-induced glucose uptake was markedly impaired (3.80 +/- 0.32 vs. 6.31 +/- 0.42 mg per minute per kilogram of body weight in 11 age- and weight-matched controls, P less than 0.001). Thus, reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis) accounted for virtually all the defect in overall glucose uptake (1.19 +/- 0.24 vs. 3.34 +/- 0.44 mg per minute per kilogram, P less than 0.001). Total glucose uptake was inversely related to systolic or mean blood pressure (r = 0.76 for both, P less than 0.001). These results provide preliminary evidence that essential hypertension is an insulin-resistant state. We conclude that this insulin resistance involves glucose but not lipid or potassium metabolism, is located in peripheral tissues but not the liver, is limited to nonoxidative pathways of intracellular glucose disposal, and is directly correlated with the severity of hypertension.

Microalbuminuria and endothelial dysfunction in essential hypertension

Microalbuminuria (urinary albumin excretion between 20 and 200 micrograms/min) and endothelial dysfunction coexist in patients with essential hypertension. To evaluate whether the two phenomena are related and the determinants of that association, we recruited 10 untreated males with essential hypertension and microalbuminuria without diabetes to be compared with an equal number of matched patients with essential hypertension excreting albumin in normal amounts and 10 normal controls. The status of endothelial function was inferred from circulating von Willebrand Factor antigen (vWF), a glycoprotein secreted in greater amounts when the vascular endothelium is damaged. vWF concentrations were higher in hypertensive patients with microalbuminuria than in hypertensive patients without and controls. Individual vWF and urine albumin-excretion values were correlated (r = 0.55, p < 0.002). Blood pressure correlated with both urinary albumin excretion and vWF. Left ventricular mass index and minimal forearm vascular resistances were comparable in patients with hypertension and higher than in controls; total and low-density lipoprotein cholesterol, triglycerides, lipoprotein-a, Factor VII, and plasminogen activator inhibitor-1 did not differ. Fibrinogen was higher and creatinine clearance lower in microalbuminurics. Albuminuria in essential hypertension may reflect systemic dysfunction of the vascular endothelium, a structure intimately involved in permeability, haemostasis, fibrinolysis, and blood pressure control. This abnormality may have important physiopathological implications and expose these patients to increased cardiovascular risk.

Soluble Vascular Cell Adhesion Molecule-1 as a Biohumoral Correlate of Atherosclerosis

Vascular cell adhesion molecule-1 (VCAM-1) is a protein expressed on the surface of activated endothelial cells and expressed in early atherosclerosis. Because part of the protein is shed in the circulation and can be detected in peripheral plasma [soluble (s) VCAM-1], we hypothesized that sVCAM-1 may be a circulating marker of the presence and severity of atherosclerosis in humans. We selected 11 patients with essential hypertension plus peripheral vascular disease (PVD) and matched them for age, gender, body mass index, and smoking habits with 11 patients with uncomplicated essential hypertension (UH) and 11 healthy controls. We evaluated plasma concentrations of sVCAM-1 along with those of the soluble form of two other endothelial leukocyte adhesion molecules [sE-selectin and s-intercellular adhesion molecule-1 (sICAM-1)] and other markers of endothelial dysfunction/ damage [s-thrombomodulin, plasminogen activator inhibitor type I, and von Willebrand factor (vWF)]. We also measured insulin, glucose, fibrinogen, total and HDL cholesterol, and the urinary albumin excretion (UAE), which may also be related to atherosclerosis. Results of these assays were related to the echographic assessment of the maximum intima-media thickness (IMTmax) at the carotid bifurcation, as an index of atherosclerosis in the carotids. PVD patients had a clearly elevated IMTmax [2.7 (1.1-3.1) mm, median (range)] compared with both UH patients [1.2 (0.8-2.4) mm] and controls [1 (0.6-2) mm]. sVCAM-1 was clearly higher in PVD patients [990 (273-1808) ng/mL, median (range)] versus 340 (236-975) ng/mL in UH and 386 (204-835) ng/mL in controls, and it separated clinical categories better than sICAM-1, vWF, glucose, insulin, UAE, triglycerides, or total, LDL or HDL cholesterol, sVCAM-1 was also the best biohumoral correlate of IMTmax (R = .59; P < .001) in univariate analysis. Because many of the biohumoral variables assessed were mutually intercorrelated, they were entered in a multivariate analysis to assess their contribution in explaining IMTmax variability. sVCAM-1 remained the only independent predictor of IMTmax and totally abolished the contribution of other variables to IMTmax variability. Thus, sVCAM-1 is a good biohumoral correlate of overt atherosclerosis, independent of underlying hypertension, and may be an in vivo marker of endothelial activation. Its potential value as a surrogate for global risk assessment and its behavior in intervention studies remain to be determined.

Effects of Insulin on Hemodynamics and Metabolism in Human Forearm

We investigated the vascular response (blood flow and resting vascular resistance) and the metabolic response (exchange of metabolites and respiratory gases) to local insulin administration in the forearms of healthy young volunteers with the use of the perfused-forearm technique. In the postabsorptive state, the deep tissues of the forearm (mostly skeletal muscle) took up glucose (mean +/- SE 1.09 +/- 0.17 mumol.min-1.dl-1 forearm vol), beta-hydroxybutyrate (0.267 +/- 0.130 mumol.min-1.dl-1), and O2 (9.96 +/- 1.02 mumol.min-1.dl-1) and released lactate (0.284 +/- 0.098 mumol.min-1.dl-1), glycerol (0.029 +/- 0.012 mumol.min-1.dl-1), citrate (0.091 +/- 0.030 mumol.min-1.dl-1), alanine (0.184 +/- 0.044 mumol.min-1.dl-1), CO2 (7.36 +/- 0.97 mumol.min-1.dl-1), and protons (12.1 +/- 1.4 pmol.min-1.dl-1). Forearm blood flow (by venous occlusion plethysmography) was 2.95 +/- 0.18 ml.min-1.dl-1, and intra-arterial systolic/diastolic blood pressure was 116 +/- 3/76 +/- 2 mmHg. Local indirect calorimetry indicated dominance of fat as the oxidative substrate (RQ 0.76 +/- 0.09) and an energy expenditure rate of 1.03 +/- 0.11 cal.min-1.dl-1 forearm vol. One hundred minutes of intra-arterial insulin infusion (deep venous plasma insulin concn of 125 +/- 11 microU/ml) had no detectable effect on forearm blood flow, resting forearm vascular resistance, heart rate, or blood pressure. Local hyperinsulinemia significantly stimulated glucose uptake (to 4.79 +/- 0.61 mumol.min-1.dl-1 forearm vol, P less than 0.001), lactate and pyruvate release (to 0.710 +/- 0.093 and 0.032 +/- 0.016 mumol.min-1.dl-1 forearm vol, respectively; P less than 0.01 for both), potassium uptake (0.76 +/- 0.22 mueq.min-1.dl-1, P less than 0.001), and free fatty acid uptake (0.123 +/- 0.041 mumol.min-1.dl-1 forearm vol, P less than 0.05); glycerol balance switched to a net uptake (P less than 0.001), alanine release was restrained by 33% (P less than 0.05), and beta-hydroxybutyrate and citrate release were unchanged. Despite these metabolic changes, local rates of substrate oxidation and energy expenditure were not altered by insulin. In contrast, forearm proton release was significantly stimulated by insulin (to 14.8 +/- 1.4 pmol.min-1.dl-1, P less than 0.02). Proton release was also found to be directly related to resting forearm vascular resistance independent of the effect of insulin (multiple r = 0.64, P less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Microalbuminuria and Pulse Pressure in Hypertensive and Atherosclerotic Men

To identify the biological covariates of microalbuminuria (albuminuria >/=15 microg/min) in nondiabetic subjects, brachial blood pressure, echocardiographic left ventricular mass, and other cardiovascular and metabolic parameters were evaluated in 211 untreated males (38 normal controls, 109 uncomplicated stage 1 to 3 essential hypertensives, and 64 patients with clinically stable atherosclerotic peripheral vascular disease either with [n=44] or without [n=20] essential hypertension) with normal cardiac and renal function. Compared with normoalbuminuric subjects, microalbuminuric subjects (n=67) were characterized by higher systolic blood pressure, comparable diastolic blood pressure, and, therefore, wider pulse pressure. Greater prevalence of hypertension, peripheral vascular disease, left ventricular hypertrophy, and reduced HDL cholesterol values further distinguished microalbuminuric from normoalbuminuric subjects in univariate comparisons. The risk of microalbuminuria increased by ascending pulse pressure quintiles in age-corrected logistic regression models, in which pulse pressure was more predictive than systolic pressure and was independent of mean pressure. When microalbuminuric status was regressed against a series of dichotomous (vascular and active smoker status) and continuous (age, pulse and mean pressure, left ventricular mass index, and HDL and LDL cholesterol) variables, only pulse pressure, left ventricular mass index, and smoking status were independent predictors. The association of increased albuminuria with wider pulse pressure, a correlate of the pulsatile hemodynamic load and conduit vessel stiffness as well as an important cardiovascular risk factor, may explain why microalbuminuria predicts cardiovascular events in nondiabetic subjects. The independence from concomitant vascular disease also suggests that wider pulse pressure, rather than representing a simple marker for atherosclerotic disease, influences albuminuria directly.

Homogeneously Reduced Versus Regionally Impaired Myocardial Blood Flow in Hypertensive Patients: Two Different Patterns of Myocardial Perfusion Associated With Degree of Hypertrophy

OBJECTIVES The aim of this study was to quantitatively measure regional and global myocardial blood flow and coronary reserve in hypertensive patients without coronary artery disease and to assess the correlation with left ventricular mass. BACKGROUND The effect of left ventricular hypertrophy on regional vasodilating coronary capability in arterial hypertension is controversial, and no quantitative method has been applied to assess a possible correlation. METHODS Positron emission tomography was performed in 50 untreated hypertensive patients and 13 normotensive subjects. Blood flow at baseline and after dipyridamole was globally and regionally measured by using nitrogen-13 ammonia; coronary reserve and resistance were calculated. Left ventricular mass was assessed by two-dimensional echocardiography. RESULTS In hypertensive patients, flow at baseline was similar to that of normotensive subjects (p = 0.21), but values were reduced after pharmacologic vasodilation (p < 0.05). This impairment of maximal coronary flow was not correlated with left ventricular mass (p = 0.13). Among hypertensive patients, we identified a group with a homogeneous distribution of perfusion and a group with a heterogeneous flow pattern. Flow was globally reduced in the former group, but it was abnormal only at the site of perfusion defects in the latter. Patients with regional defects showed the highest likelihood of having an increased left ventricular mass. CONCLUSIONS In arterial hypertension, left ventricular mass is not correlated with global myocardial blood flow. Nevertheless, patients with ventricular hypertrophy are likely to show a heterogeneous flow pattern with regional defects and almost normal blood flow in nonaffected regions. In hypertensive patients with a homogeneous perfusion pattern during stress, myocardial blood flow frequently shows a diffuse reduction.

Quantification of topological changes in retinal vascular architecture in essential and malignant hypertension.

Objective Grading of hypertension severity by fundoscopic appearance is difficult and inaccurate. We investigated whether essential hypertension (EHT) and malignant phase hypertension (MHT) were associated with quantifiable abnormalities of the topology and architecture of the retinal circulation. Methods The topology and architecture of the retinal microvasculature were compared in images from 20 normotensive subjects, 20 patients with EHT and 20 patients with MHT. Digitized retinal photographs were analysed by a novel multiscale image analysis method using a semi-automated program to quantify geometrical and topological properties of arteriolar and venular trees. Results EHT was associated with an increase in the arteriolar length-to-diameter ratio (P < 0.01). There were also alterations in arteriolar topology indicative of rarefaction, including a marked reduction in the number of terminal branches in EHT (P < 0.01). These changes in the arteriolar network were exaggerated in MHT and there was also increased venular tortuosity and venular rarefaction in MHT compared with normotensive subjects. Conclusions Hypertension is associated with marked topological alterations in the retinal vasculature, and quantification of these changes may be a useful novel approach to the assessment of target organ damage in hypertension.

Low-Grade Inflammation and Microalbuminuria in Hypertension

Background—Albuminuria and C-reactive protein (CRP), a marker of systemic low-grade inflammation, are frequently elevated in essential hypertension and predict cardiovascular prognosis independent of conventional risk factors. However, in spite of their potentially important links, the interrelationships between the 2 parameters have not been explored in depth in hypertensive patients. Methods and Results—Albuminuria (the mean of 3 overnight urine collections), high-sensitive CRP (hs-CRP), 24-hour blood pressure (BP), weight, lipids, poststimulative (75 g PO) plasma glucose, insulin, and insulin sensitivity by the homeostasis model assessment model were evaluated in 220 never treated, nondiabetic, uncomplicated essential hypertensive men. Albuminuria ≥15 &mgr;g/min was defined as microalbuminuria and hs-CRP values above and below median (2.3 mg/L) as high and low, respectively. Concentric left ventricular hypertrophy was diagnosed by echocardiography, and a full-blown metabolic syndrome was identified in presence of hypertension and at least 3 of following: obesity, subclinical hyperglycemia, low high-density lipoprotein (HDL) and high triglycerides. Microalbuminuria was present in 54 patients, 29 with high hs-CRP characterized by higher 24-hour systolic BP, postload glucose, body mass index, lower HDL cholesterol, more frequent metabolic syndrome, concentric LVH, and active smoking than those with either isolated microalbuminuria (n=27) or normoalbuminuria. Conclusions—Microalbuminuria accompanied by evidence of subclinical inflammation is a strong correlate of metabolic abnormalities in essential hypertension and identifies a patient subset at very high cardiovascular risk. In contrast, isolated microalbuminuria may represent a distinct pathophysiological condition characterized by a more benign profile and possibly a better prognosis.

Non-diabetic microalbuminuria, endothelial dysfunction and cardiovascular disease

Subclinical increases in albuminuria (microalbuminuria) predict morbid events, but the reasons for that are still not understood in full. This paper reviews the existing evidence regarding the relationships of non-diabetic microalbuminuria and cardiovascular disease, the underlying assumption being that endothelial dysfunction contributes both to atherosclerotic macrovascular disease and renal microvascular disease of which albuminuria is a marker. Much data support that concept, and suggest a preferential link with endothelial activation in response to acute and subclinical inflammatory stimulation, although further studies are needed to establish the exact cause-effect mechanisms. Epidemiological studies also show associations with cardiovascular events, and some recent prospective results also indicate the power of micro-albuminuria to predict risk independently from conventional atherogenic factors. Thus, micro-albuminuria might be considered as an integrated marker of cardiovascular risk sensitive to systemic vascular status in addition to other parameters such as blood pressure levels, glucose metabolism, smoking habits, a profile rather unique among the prognostic predictors available to stratify risk in hypertensive patients.

Interaction between oxprenolol and indomethacin on blood pressure in essential hypertensive patients.

SummaryA double-blind, cross-over study in 16 patients with essential hypertension was carried out, to evaluate any possible interference by indomethacin, a known prostaglandin-synthetase inhibitor, with the antihypertensive effect of oxprenolol, a non-selective beta-adrenoceptor blocking agent. Both indomethacin and oxprenolol, as well as the two drugs combined, inhibited plasma renin activity; no change was found in urinary sodium excretion or body weight. Oxprenolol alone caused a highly significant decrease in the systolic (−10.4 mmHg,p<0.001), diastolic (−7.4 mmHg,p<0.001) and mean (−7.7 mmHg,p<0.01) blood pressures, whereas indomethacin did not influence blood pressure. When the two drugs were given in combination, blood pressure decreased (systolic: −5.9 mmHg; diastolic: −4.0 mmHg; mean: −4.6 mmHg), but the changes induced in blood pressure were reduced by about 50% when compared with those in the oxprenolol alone period. The data show that indomethacin seems to interfere with the antihypertensive effect of oxprenolol, by an action which may be due to the inhibition of prostaglandin synthesis.