Moderate alcohol use and health: a consensus document.

AIMS: The aim of this consensus paper is to review the available evidence on the association between moderate alcohol use, health and disease and to provide a working document to the scientific and health professional communities. DATA SYNTHESIS: In healthy adults and in the elderly, spontaneous consumption of alcoholic beverages within 30 g ethanol/d for men and 15 g/d for women is to be considered acceptable and do not deserve intervention by the primary care physician or the health professional in charge. Patients with increased risk for specific diseases, for example, women with familiar history of breast cancer, or subjects with familiar history of early cardiovascular disease, or cardiovascular patients should discuss with their physician their drinking habits. No abstainer should be advised to drink for health reasons. Alcohol use must be discouraged in specific physiological or personal situations or in selected age classes (children and adolescents, pregnant and lactating women and recovering alcoholics). Moreover, the possible interactions between alcohol and acute or chronic drug use must be discussed with the primary care physician. CONCLUSIONS: The choice to consume alcohol should be based on individual considerations, taking into account the influence on health and diet, the risk of alcoholism and abuse, the effect on behaviour and other factors that may vary with age and lifestyle. Moderation in drinking and development of an associated lifestyle culture should be fostered.

Decreased number of circulating endothelial progenitor cells in patients with Graves' hyperthyroidism.

OBJECTIVE: A relevant biological role of circulating endothelial progenitor cells (EPC) was recently demonstrated. EPC are generated in the bone marrow, and interact with damaged endothelium, restoring the integrity of the monolayer. Therefore, aim of the present study was to evaluate EPC in the blood of patients with untreated Graves' hyperthyroidism (GD), in whom an increased oxidative stress was observed. DESIGN AND METHODS: Twenty-three patients with untreated active GD and 18 matched normal controls (NC) were included in the study. Circulating EPC were isolated from peripheral blood. Mononuclear cells were cultured with endothelial basal medium supplemented with EGM SingleQuots, and were identified by positive double staining after 7 days in culture. Circulating levels of C reactive protein, total antioxidant power, interleukin (IL)-6, IL- 18, monocyte chemoattractant protein-1, tumor necrosis facotr- α, soluble vascular cell adhesion molecule (VCAM) and intracellular adhesion molecule were evaluated by enzymelinked immunosorbent assay kit. EPC number was also evaluated in a subgroup of GD patients after restoration of euthyroidism. RESULTS: Systolic blood pressure resulted increased in GD patients compared with control subjects whereas diastolic blood pressure was not significantly different. Patients with GD showed an increase in circulating levels of IL-18 and VCAM-1 and a reduction of total antioxidant power (p<0.05) compared to NC. Moreover, a reduced number of EPC was observed in patients with GD compared to NC (p<0.05) which turned to NC values after restoring euthyroidism. CONCLUSION: Patients with GD showed a reduction in the physiological protective mechanisms against endothelial damage, probably induced by increased inflammation and oxidative stress.

Small artery remodeling in diabetes mellitus.

AIMS: To briefly review available data regarding changes in the structure of microvessels observed in patients with diabetes mellitus, and possible correction by effective treatment. DATA SYNTHESIS: The development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, small arteries' smooth muscle cells are restructured around a smaller lumen and there is no net growth of the vascular wall, while in some secondary forms of hypertension, hypertrophic remodeling may be detected. Moreover, in non-insulin-dependent diabetes mellitus hypertrophic remodeling of subcutaneous small arteries is present. Indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive and diabetic patients, over and above all other known cardiovascular risk factors. Therefore, regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effects on vascular structure. In diabetic hypertensive patients, a significant regression of structural alterations to the small resistance arteries with drugs blocking the renin-angiotensin system (ACE inhibitors, angiotensin II receptor blockers) was demonstrated. CONCLUSION: Alterations in the microcirculation represent a common pathological finding, and microangiopathy is one of the most important mechanisms involved in the development of organ damage as well as of clinical events in patients with diabetes mellitus. Renin-angiotensin system blockade seems to be effective in preventing and/or regressing alterations in the microvascular structure.

Macro and microvasculature in hypertension: therapeutic aspects.

Macrovasculature, microvasculature and the heart determine the structure and function of the circulatory system. Due to the viscoelastic properties of large arteries, the pulsatile pressure and flow that result from intermittent ventricular ejection is smoothed out, so that microvasculature mediates the delivery of nutrients and oxygen to tissues steadily. The disruption of this function, which occurs when microvascular structure develops in response to hypertension, leads to end-organ damage. Microvascular structure is not only the site of vascular resistance, but also the origin of most of the wave reflections generating increased central systolic blood pressure (SBP) in the elderly. Nowadays many data of the literature suggest that hypertension-related damage to the micro and macrovascular system may be manageable through pharmacological agents. Among them, beta-blocking agents and diuretics poorly modify microvascular structure, whereas angiotensin and calcium entry blockade has an opposite effect, thereby reducing central wave reflections and, finally, causing a selective SBP reduction.

Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke prone, spontaneously hypertensive rats.

While hypertension is a major risk factor for stroke, it is not its sole determinant. Despite similar blood pressures, spontaneously hypertensive rats (SHR) do not share the predisposition to cerebrovascular disease typical of stroke-prone spontaneously hypertensive rats (SHRSP). We investigated vascular function in male SHR and SHRSP as well as in SHRSP/SHR-F2 hybrid animals. Animals were maintained on the appropriate dietary regimen necessary for the manifestation of stroke. Among the hybrid animals, a group of stroke-prone and a group of stroke-resistant rats were selected. Blood pressure was similar in all groups. Endothelium-independent vascular reactivity tested on isolated rings of thoracic aorta and basilar artery after death showed similar contractile and dilatory responses to serotonin and nitroglycerin, respectively, in all groups. In contrast, endothelium-dependent relaxation, in response to acetylcholine or substance P, was markedly reduced in SHRSP compared with SHR. Similarly, reduced vasodilatory responses were present in aortae of F2 rats that had suffered a stroke when compared with SHR or F2 rats resistant to stroke. The observed association and cosegregation of stroke with significant and specific impairment of endothelium-dependent vasorelaxation among SHRSP and stroke-prone F2 hybrids, respectively, suggest a potential causal role of altered endothelium-dependent vascular relaxation in the pathogenesis of stroke.

Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus.

BACKGROUND: It is not presently known whether non-insulin-dependent diabetes mellitus (NIDDM) is associated with the presence of structural alterations in small arteries or whether the combination of hypertension and NIDDM may have an additive effect on endothelial dysfunction. Therefore, we investigated subcutaneous small arteries in 12 normotensive subjects (NT group), 18 patients with essential hypertension (EH group), 13 patients with NIDDM, and 11 patients with NIDDM and EH (NIDDM+EH group). METHODS AND RESULTS: Subcutaneous small arteries were evaluated by a micromyographic technique. The internal diameter, the media-to-lumen ratio, remodeling and growth indices, and the collagen-to-elastin ratio were calculated. Concentration-response curves to acetylcholine, bradykinin, the endothelium-independent vasodilator sodium nitroprusside, and endothelin-1 were performed. The media-to-lumen ratio was higher in the EH, NIDDM, and NIDDM+EH groups compared with the NT group. EH patients showed the presence of eutrophic remodeling, whereas NIDDM and NIDDM+EH patients showed 40% to 46% cell growth. The collagen-to-elastin ratio was significantly increased in the EH and NIDDM+EH groups compared with the NT group. The vasodilatation to acetylcholine and bradykinin was similarly reduced in EH, NIDDM, and NIDDM+EH groups compared with the NT group. The contractile responses to endothelin-1 were similarly reduced in EH, NIDDM, and NIDDM+EH patients. CONCLUSIONS: Our data suggest that the effects of NIDDM and EH on small artery morphology are quantitatively similar but qualitatively different and that the presence of hypertension in diabetic patients has little additive effect on small artery morphology and none on endothelial dysfunction.

Relations between cardiac and vascular structure in patients with primary and secondary hypertension.

BACKGROUND: Data on cardiac and vascular structure in secondary hypertension are generally scarce, and no data on the interrelations between cardiac mass and structural characteristics of the vessel wall, both in large and in small resistance arteries, are presently available. OBJECTIVES: The aim of this study was to investigate the relation between structural changes in subcutaneous small arteries, left ventricular mass and wall thickness of the common carotid artery in patients with primary and secondary hypertension. METHODS: Seventy-four subjects were included in the study: 11 patients with pheochromocytoma, 14 with primary aldosteronism (PA), 19 with renovascular hypertension (RVH), 18 with essential hypertension (EH) and 12 normotensive (NT) control subjects. All subjects were submitted to a biopsy of subcutaneous fat. Morphologic characteristics of subcutaneous small resistance arteries (relaxed diameter <300 microm) were directly evaluated using a micromyographic technique. All subjects were submitted to calculation of left ventricular mass index (LVMI) and common carotid artery intima-media thickness (CCIMT), using ultrasound technique. RESULTS: The correlation coefficients between the media to lumen ratio in subcutaneous small arteries (M/L) and LVMI or between M/L and CCIMT were closer in RVH than in pheochromocytoma, EH or NT; in PA the correlation coefficients were slightly less close than those in RVH. An excess prevalence of carotid plaques in RVH was observed. CONCLUSIONS: A close relation between small resistance artery morphology and cardiac or carotid artery structure may be observed in those hypertensive patients in whom the renin-angiotensin-aldosterone system is activated. In constrast, in NT, EH and pheochromocytoma no significant correlation between M/L and LVMI or CCIMT was observed.

Effects of low and high doses of fosinopril on the structure and function of resistance arteries.

It has been suggested that angiotensin-converting enzyme inhibitors may induce a significant regression of cardiovascular hypertrophy not only through blood pressure reduction but also as a possible consequence of growth factor inhibition. The aim of this study was to evaluate the effects of the angiotensin-converting enzyme inhibitor fosinopril, given either at a hypotensive high dose or a nonhypotensive low dose, on structural and functional alterations of mesenteric resistance arteries and on cardiac mass in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats. Fosinopril was administered in the drinking water from 6 to 12 weeks of age. Rats were killed at 12 weeks, and the ratio of heart weight to body weight was measured. Mesenteric arterioles were dissected and mounted on a micromyograph (Mulvany's technique). Vascular morphology (media-lumen ratio, media thickness) and endothelial function (response to acetylcholine) were then assessed. During the 6 weeks of treatment, systolic pressure in SHR treated with high-dose fosinopril was significantly lower compared with that in untreated SHR, whereas no difference was observed with low-dose fosinopril. In SHR treated with both high-dose and low-dose fosinopril, a statistically significant reduction of vascular structural alterations, in terms of both media-lumen ratio and media thickness, was observed. The ratio of heart weight to body weight was reduced only in SHR treated with high-dose fosinopril. An improvement in the endothelium-dependent relaxation to acetylcholine was observed in SHR treated with high-dose fosinopril compared with untreated SHR, whereas in SHR treated with low-dose fosinopril no improvement in endothelial function was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed development of hypertension after short-term nitrendipine treatment.

In this study we evaluated the delayed effects of a calcium entry blocker on blood pressure and on vascular structural and functional alterations in mesenteric resistance arteries of spontaneously hypertensive rats (SHR). The calcium entry blocker nitrendipine was administered (30 mg/kg per day) according to three different schedules: in one group of SHR from 4 to 8 weeks of age (n = 12), in a second group from 8 to 12 weeks of age (n = 12), and in a third group from 4 to 12 weeks of age (n = 12). Twelve untreated SHR and 12 untreated Wistar-Kyoto rats served as controls. Half the animals of each group were killed at 13 weeks, and the remaining were killed at 38 weeks. After death, relative left ventricular mass was calculated. Vascular morphology and function (responses to norepinephrine and acetylcholine) in mesenteric small arteries were then assessed using a micromyographic technique. Nitrendipine treatment delayed the development of hypertension and determined the regression of structural alterations of mesenteric resistance arteries in SHR. These favorable effects were maintained for several weeks after treatment withdrawal, provided that treatment was started at 4 weeks of age. Considering the functional alterations of mesenteric arteries in SHR (responses to norepinephrine and acetylcholine), nitrendipine treatment determined an improvement of both these dysfunctions as long as reductions of the media-to-lumen ratio and blood pressure, respectively, were maintained.

Cellular hypertrophy in subcutaneous small arteries of patients with renovascular hypertension.

Structural alterations of small arteries in patients with essential hypertension are characterized by inward eutrophic remodeling. However, small arteries in patients with secondary hypertension, as well as in experimental models of hypertension with high circulating renin, are characterized by inward hypertrophic remodeling, which is characterized by smooth muscle cell hypertrophy in animal models. The aim of our study was to determine whether remodeling of subcutaneous small arteries in patients with secondary forms of hypertension is associated with smooth muscle cell hypertrophy and/or alterations in the elastic modulus of the vessel wall. Fifteen patients with renovascular hypertension, 9 with primary aldosteronism, and 13 with essential hypertension and 9 normotensive subjects were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small arteries were dissected, and morphology was determined on a micromyograph. Unbiased estimates of cell volume and number were made in fixed material. From the resting tension-internal circumference relation of the small arteries, the incremental elastic modulus was calculated and plotted as a function of wall stress. Blood pressure was greater in patients with essential hypertension, renovascular hypertension, or primary aldosteronism than in normotensive subjects, but no significant difference was observed among the 3 groups of hypertensive patients. The media/lumen ratio, the medial cross-sectional area, and the smooth muscle cell volume were significantly greater in patients with renovascular hypertension than in normotensive subjects and patients with essential hypertension. No difference in cell number or in the elastic properties was observed among the 4 groups of subjects. In conclusion, our data demonstrate for the first time that a pronounced activation of the renin-angiotensin-aldosterone system is associated with vascular smooth muscle cell hypertrophy in human hypertension in a manner similar to that found in animal models.

Angiotensin II type 1 receptor A/C1166 polymorphism. Relationships with blood pressure and cardiovascular structure.

The angiotensin II type 1 (AT1) receptor has a key role in mediating the vasoconstrictor and growth-promoting effects of angiotensin II. It has been reported that a polymorphism of the AT1 receptor gene (an A/C transversion at position 1166) may be associated with cardiovascular phenotypes, such as arterial blood pressure and aortic stiffness, that underlie a condition of increased cardiovascular risk. We examined a sample of 212 subjects randomly selected from a general population in northern Italy to investigate the role of AT1 receptor gene polymorphism, in the regulation of blood pressure and cardiovascular growth. We measured blood pressure (both clinic and 24-hour ambulatory recording), left ventricular mass (echocardiography), and carotid artery wall thickness (B-mode ultrasound); we assessed the AT1 receptor genotype by polymerase chain reaction and allele-specific oligonucleotide hybridization. Blood pressure values were lower in CC homozygotes than in heterozygotes and AA homozygotes; the difference was statistically significant for clinic measurements (mean difference for mean blood pressure, -6.6 mm Hg, P = .01; 95% confidence interval, -1.6 to -11.7 mm Hg) but not for ambulatory blood pressure measurements. CC homozygotes also presented a lower incidence of a positive family history of hypertension (P = .027). No statistically significant differences among AT1 receptor A/C1166 genotypes were observed for left ventricular mass or carotid artery wall thickness. We conclude that the present study does not support a major role of the AT1 receptor gene A/C1166 polymorphism as a marker of conditions associated with increased cardiovascular risk.

Vascular hypertrophy and remodeling in secondary hypertension.

It has been proposed that several neurohumoral factors may be involved in the genesis of vascular structural changes (remodeling or hypertrophy) frequently observed in essential hypertension. Therefore, in this study we investigated vascular structural alterations of subcutaneous small resistance arteries in patients with secondary forms of hypertension. The study included 70 participants: 11 with pheochromocytoma, 13 with primary aldosteronism, and 17 with renovascular hypertension; 13 normotensive subjects and 16 patients with essential hypertension served as controls. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on a micromyograph, and media-lumen ratio, media thickness, remodeling index, and growth index were evaluated. Endothelial function was evaluated according to the dose-response curve to acetylcholine. In patients with either primary aldosteronism or renovascular hypertension, a marked increase in media-lumen ratio was observed, whereas in patients with pheochromocytoma, the extent of vascular structural alterations was similar to that observed in patients with essential hypertension. The increase in media-lumen ratio in patients with essential hypertension and with pheochromocytoma was mainly due to vascular remodeling (remodeling index, 93% to 94%), whereas in patients with renovascular hypertension, there was vascular growth (remodeling index, 70%; growth index, 53%). Patients with primary aldosteronism had an intermediate pattern compared with the other two forms of secondary hypertension. An evident impairment of endothelial function was observed in all four hypertensive groups. In conclusion, the renin-angiotensin-aldosterone system seems to be more powerful than the adrenergic system in inducing vascular growth.

Endothelial dysfunction in hypertension is independent from the etiology and from vascular structure.

The aim of our study was to evaluate the relationships between endothelial function, small resistance artery structure, and blood pressure in patients with primary or secondary hypertension. Sixty subjects were included in the study: 9 patients with pheochromocytoma, 10 with primary aldosteronism, 17 with renovascular hypertension, and 13 with essential hypertension with 11 normotensive subjects who served as controls. Clinic and 24-hour ambulatory blood pressure (ABPM) were evaluated. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on a micromyograph and the media/lumen ratio was calculated. A dose-response curve to acetylcholine was performed at cumulative concentrations from 10(-9) to 10(-5) mol/L. The vasodilator response to acetylcholine was similarly impaired in the four groups of hypertensive patients (ANOVA P<.05 versus normotensive controls), without any significant difference among them. In subcutaneous small arteries of patients with either primary aldosteronism or renovascular hypertension, a marked increase in media:lumen ratio was observed, while in patients with pheochromocytoma, the extent of vascular structural alterations was similar to that observed in essential hypertension. No significant correlation between media-lumen ratio or clinic blood pressure and maximum acetylcholine-induced vasodilatation was observed. On the contrary, a significant, albeit not very close, correlation between ABPM values and maximum acetylcholine-induced vasodilatation was observed (r=34, P<.05 with 24-hour systolic blood pressure, r=0.36, P<.05 with 24-hour diastolic blood pressure). In conclusion, endothelial dysfunction seems to be independent from the degree of vascular structural alterations and from the etiology of hypertension, and it is probably more linked to the hemodynamic load.

Effects of losartan and enalapril on small artery structure in hypertensive rats.

We evaluated the effects on cardiovascular structure of the angiotensin-converting enzyme (ACE) inhibitor enalapril and of the angiotensin II receptor blocker losartan, administered either at hypotensive or nonhypotensive dosage in spontaneously hypertensive rats (SHR). SHR were treated from ages 4 to 12 weeks with low-dose (1 mg x kg(-1) x d(-1)) enalapril, low-dose (0.5 mg x kg(-1) x d(-1)) losartan, high-dose (25 mg x kg(-1) x d(-1)) enalapril, or high-dose (15 mg x kg(-1) x d(-1)) losartan. Untreated WKY and SHR were also studied. Rats were killed at 13 weeks of age, and the heart was weighed. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of media thickness and lumen diameter. In fixed arteries, cell volume, number of cells per segment length, and number of cell layers were measured using the unbiased "disector" method. Systolic blood pressure was significantly reduced by the high doses of both drugs, but the hypotensive effect was greater with enalapril than with losartan (P<0.05). In the high-dose enalapril and losartan groups, there were similar reductions in relative left ventricular mass, media/lumen ratio, and number of cell layers of resistance arteries; however, there were no differences in the cell volume or number of cells per segment length of resistance arteries. Low-dose enalapril did not affect systolic blood pressure or any of the structural parameters. The results show that the hypotensive effects of both losartan and enalapril were associated with outward remodeling of resistance arteries at the cellular level. The effect of losartan on resistance artery structure was equal to that of enalapril, despite the smaller hypotensive effect.

Cardiac and vascular structural changes. Prevalence and relation to ambulatory blood pressure in a middle-aged general population in northern Italy: the Vobarno Study.

The aims of this study were to determine the prevalence of structural changes in the carotid arteries and heart and the correlation between these changes and the commonly recognized cardiovascular risk factors in the general population. Structural changes in the carotid arteries were defined as the intima-media thickness of the artery measured by B-mode ultrasound. Changes in the heart were defined as left ventricular mass index (LVMI) measured by echocardiography. LVMI values greater than 134 g/m2 in men and greater than 110 g/m2 in women were considered abnormal, indicating the presence of left ventricular hypertrophy. Blood pressure (BP) was measured in the clinic setting with a mercury sphygmomanometer and by 24-hour noninvasive ambulatory monitoring. Hypertension was defined as a sustained systolic BP greater than or equal to 160 mm Hg and/or diastolic BP increase greater than or equal to 95 mm Hg. The study population consisted of 225 subjects (107 women and 118 men) 48 to 64 years old. Prevalence of intima-media thickening (intima-media thickness > 1 mm) was 11% in normotensive subjects and 44% in hypertensive subjects. The presence of plaque (wall thickening with either mineralization or focal protrusion in the lumen at least 50% greater than the surrounding wall, usually > 2 mm) was observed in 35% of normotensive subjects and 44% of hypertensive subjects. The prevalence of left ventricular hypertrophy was 13% in normotensive subjects and 19% in hypertensive subjects. Intima-media thickness in the common and bifurcation segments of carotid arteries correlated well with LVMI (r = .20 and r = .19, respectively; P < .01). Intima-media thickness and LVMI were both positively related to 24-hour monitored BP (P < .01). However, in the multivariate analysis, body mass index (P = .027), sex (P < .001), and 24-hour mean BP (P = .025) were the most significant determinants of LVMI, whereas carotid artery intima-media thickness was found to be associated best with age (P < .001), cigarette smoking (P = .009), serum cholesterol (P = .025), serum glucose (P = .038), and nighttime systolic BP (P = .006). Logistic regression analysis confirmed the association between the presence of plaque and age (P < .001), nighttime systolic BP (P < .05), and cigarette smoking (P < .05); a negative association between plaque and the decrease in mean systolic BP daytime to nighttime was also observed (P < .001). In conclusion, in a general population of unselected middle-aged subjects, carotid wall thickness and LVMI were associated with each other and related to 24-hour BP levels although the major determinants of carotid wall and cardiac structure were different.

Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension.

off aim of our study was to evaluate the effect of antihypertensive treatment on flow-mediated dilation (FMD)of a large artery, a noninvasive estimate of endothelial function, in hypertensive patients. In 78 consecutive hypertensive patients (40%men; age range, 42 to 67 years) we measured by a high-resolution ultrasound system the changes of brachial artery diameter during reactive hyperemia and after sublingual glyceryl trinitrate (400 microg); brachial artery flow velocity was measured by pulsed Doppler. The results of 2 studies are reported. In the first study, this procedure was repeated in 58 patients after 6 and 12 months of treatment with a combination of antihypertensive drugs; in a second study, the FMD was assessed in 20 patients after 2 months of monotherapy with either nifedipine or hydrochlorothiazide. In the first study, FMD was significantly increased after treatment compared with baseline (from 3.1+/-3% at baseline to 6.5+/-4.5% at 6 months and to 8.12+/-4. 6% at 12 months; P<0.001 by ANOVA), concomitant with blood pressure reduction (from 162+/-24/102+/-13 mm Hg to 141+/-12/89+/-6 mm Hg and to 141+/-9/89+/-6 mm Hg; P<0.001 by ANOVA); significant changes of endothelium-independent dilation were also observed, but only after 12 months of treatment (from 14.2+/-4.8 at baseline to 15.5+/-4.7 at 6 months and 16.8+/-5.9% at 12 months; P=0.03 by ANOVA). In the second study, FMD was significantly increased during nifedipine treatment as compared with baseline (from 5+/-6.18% at baseline to 9. 45+/-3.94%, P<0.001), while it did not change in patients receiving hydrochlorothiazide (from 5.15+/-5.28% at baseline to 4.69+/-4.34%, NS). No significant changes of endothelium-independent dilation were observed with both drugs (from 17.10+/-2.4% to 18.14+/-3.76% and from 18.73+/-4.07% to 17.46+/-4.27% during nifedipine and hydrochlorothiazide, respectively, NS). Thus, in essential hypertensive patients an improvement of the impaired FMD of the brachial artery, evaluated by noninvasive ultrasound, may be observed after long-term, effective blood pressure reduction, suggesting a beneficial effect of antihypertensive treatment on endothelial function. It seems that beyond blood pressure control, a calcium antagonist may be more effective than a diuretic in this respect.

The smoothness index: a new, reproducible and clinically relevant measure of the homogeneity of the blood pressure reduction with treatment for hypertension.

OBJECTIVE: To introduce a new method, the smoothness index, for assessing the homogeneity of 24 h blood pressure reduction by antihypertensive treatment and to compare it with the trough : peak ratio; and to assess the ability of both indices to predict a reduction in the left ventricular mass index induced by treatment. PATIENTS AND METHODS: In 174 patients with essential hypertension and left ventricular hypertrophy, enrolled in the Study on Ambulatory Monitoring of Pressure and Lisinopril Evaluation (SAMPLE), aged 20-65 years, we measured clinic blood pressure, 24 h ambulatory blood pressure and the left ventricular mass index (echocardiography) before and after treatment with lisinopril at 20 mg with the addition of 12.5 or 25 mg hydrochlorothiazide as needed to reach a sufficient blood pressure reduction. The following parameters were computed for systolic and diastolic ambulatory blood pressure: (1) hourly and 24 h blood pressure averages (+/- SD) at baseline and after 3 and 12 months of treatment; (2) hourly blood pressure changes from baseline after 3 and 12 months of treatment, and their average (+/- SD) over 24 h; (3) the trough : peak ratio after 3 and 12 months of treatment; and (4) the smoothness index after 3 and 12 months of treatment Similar calculations were also performed at the end of a final study month during which active treatment was withdrawn and placebo was substituted (n = 164). RESULTS: The smoothness index for systolic and diastolic ambulatory blood pressure computed after 3 months of treatment was more closely related to its corresponding values after 12 months of treatment than the trough : peak ratio values computed after the same time periods were (r = 0.68 versus 0.38 for systolic and 0.68 versus 0.42 for diastolic blood pressure, respectively). The smoothness index showed an inverse correlation with the 24 h standard deviation of systolic and diastolic blood pressure (r = -0.25 and -0.16, P < 0.01 and < 0.05, respectively, for 12 months of treatment), while the trough : peak ratio did not (r = -0.01 to -0.12, NS). A treatment-induced reduction in the left ventricular mass index was related to the smoothness index for systolic and diastolic blood pressure (r = -0.35 and -0.32, P< 0.001 with 12 months of treatment), but not to the corresponding trough : peak ratios. CONCLUSIONS: The smoothness index identifies the occurrence of a balanced 24 h blood pressure reduction with treatment and correlates with the favourable effects of treatment on left ventricular hypertrophy better than the commonly used trough : peak ratio.

Association of change in left ventricular mass with prognosis during long-term antihypertensive treatment.

OBJECTIVE: The aim of the present study was to assess the prognostic value of changes in left ventricular hypertrophy in hypertensive patients with time. DESIGN: Two hundred and fifteen uncomplicated hypertensive patients underwent a high-quality baseline echocardiogram for left ventricular anatomy evaluation and in 151 of those patients the echocardiographic examination was repeated 10 +/- 1.4 years after the initial study. METHODS: Left ventricular mass index changes were evaluated, in relation to the incidence of non-fatal cardiovascular events, adjusted for traditional cardiovascular risk factors. RESULTS: According to the presence or absence of left ventricular hypertrophy (left ventricular mass index > 134 g/m2 in men and > 110 g/m2 in women) at baseline and at the end of follow-up study, patients were divided into four groups: with normal left ventricular mass at both examinations (n = 78), with regression of left ventricular hypertrophy (n = 32), with persistence of left ventricular hypertrophy (n = 34) and with hypertrophy development (n = 7). After adjustment for traditional cardiovascular risk factors, the cumulative incidence of non-fatal cardiovascular events was significantly higher in the group of patients without regression of left ventricular hypertrophy. Cox survival analysis showed the presence of left ventricular hypertrophy at the end of follow-up study to be the most important factor related to cardiovascular events. CONCLUSIONS: The present findings strongly indicate that the lack of decrease or the increase of left ventricular mass after antihypertensive treatment can be associated with a higher risk for cardiovascular events, which is significantly reduced and almost normalized by complete regression of left ventricular hypertrophy.

The vasoconstriction induced by endothelin-1 is mediated only by ET(A) receptors in mesenteric small resistance arteries of spontaneously hypertensive rats and Wistar Kyoto rats.

OBJECTIVE: To evaluate the functional responses of mesenteric small resistance arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rat controls to endothelin-1 (ET-1), in the presence and absence of an ET(A) receptor antagonist drug as well as to an ET(B) receptor agonist. METHODS: Twenty rats aged 12 weeks were studied. They were 10 SHR and 10 WKY rats. Mesenteric small resistance arteries (relaxed diameter 100-180 microm) were dissected and mounted on a micromyograph (Mulvany's technique). A dose-response curve for response to ET-1 was plotted for cumulative concentrations (from 10(-11) to 10(-8) mol/l) in the presence and absence of 10(-6) mol/l FR 139317 (a selective antagonist of ET(A) receptors). In addition, the effects of 10(-7) mol/l N-succinyl-[Glu9, Ala11,15]-endothelin 1 fragment 8-21 (IRL 1620, a selective agonist of ET(B) receptors) were evaluated. RESULTS: The response of ET-1 was greater in WKY rats than it was in SHR. Almost all the vasoconstrictor effect of ET-1 could be prevented by addition of FR 139317, whereas the agonist of ET(B) receptors had no effect (no change in active force). CONCLUSIONS: The contractile effects of ET-1 on mesenteric small resistance arteries of SHR and WKY rats are mediated mostly by ET(A) receptors, whereas ET(B) receptors play a minor role, if any. It is possible, however, that a vasoconstrictor effect of ET(B) receptors on the smooth muscle could be masked by the concomitant stimulation of endothelial ET(B) vasodilator receptors.

Various ways of calculating echocardiographic left ventricular mass and their relative prognostic values.

OBJECTIVE: To compare the calculations of left ventricular mass according to thick-wall [American Society of Echocardiography (ASE) and Penn convention] and thin-wall (Wikstrand formula) models. METHODS: We have reexamined the data from the cross-sectional study on the general population sample of Vobarno and from a prospective longitudinal study of hypertensive patients assessing the prognostic significance of changes in left ventricular mass during a follow-up period of 10 years on average (Brescia population). RESULTS: For the Vobarno and Brescia populations, we found a close relationship between values of left ventricular mass calculated by using a thin-wall ellipsoidal model (Wikstrand formula) and those calculated using a thick-wall model with Penn convention or ASE left ventricle measurements (r = 0.99, for both the Vobarno and Brescia populations). Highest values of Penn left ventricle mass were slightly underestimated by use of the thin-wall formula. The numbers of nonfatal cardiovascular events and the relative risks, evaluated by Cox proportional hazard models for 151 patients seen at follow-up did not differ for patients with persistence of left ventricular hypertrophy (LVH), those with regression of LVH, and those with normal left ventricle mass, both at baseline and at follow-up, when these different ways of measuring left ventricle mass and partition values for LVH were used. CONCLUSIONS: The calculation of left ventricle mass according to the ASE recommendations or to the Penn convention, both of which are based on the assumption that the left ventricle can be represented by a prolate ellipsoid with both the internal and external long axes twice the short axis, produces results similar to those obtained using an alternate formula for the calculation of left ventricle mass, considering wall thickness constant around the ellipsoidal cavity. The cardiovascular risk stratification, in relation both to baseline left ventricular mass and to its change during long-term antihypertensive treatment, does not differ significantly among the results of these three different calculations.