Antonio Salvetti

Data from controlled clinical studies comparing active drugs versus placebo or comparing different classes of drugs and their meta-analysis seem to indicate that although more subtle differences in the effects of various antihypertensive drugs cannot be ruled out, the protective effects against cardiovascular morbidity and mortality of all classes of drugs, including conventional therapy based on diuretics and beta-blockers and their combination, are largely explained by the extent of blood pressure (BP) reduction. Therefore BP control is still the main target of antihypertensive therapy. The benefits of diuretics have been well documented, particularly when these drugs are used at appropriate and/or optimal doses to achieve the optimal antihypertensive effect with the least occurrence of side effects, including negative metabolic effects. Therefore they must still be included among first line antihypertensive drugs. By contrast, beta-blockers seem recently to have lost their previously favored status as initial therapy for hypertension owing to their lower preventive effects against cardiovascular events as compared with diuretics in elderly hypertensive patients and against stroke as compared with other treatments, and to their negative metabolic effects. However, although evidence-based data must be taken into account, the choice of antihypertensive therapy aimed at BP control in individual patients must be made according to clinical characteristics. We believe that a wide range of choices among various antihypertensive drugs, above all diuretics and also beta-blockers, offers an appropriate possibility of selecting the right drug and the right combinations according to the clinical profile of the individual patient.

The endothelium plays a crucial role in modulating vascular function and structure. In healthy conditions, nitric oxide produced by endothelial cells exerts not only vasodilating properties, but also several other protective actions toward the vessel wall against the development of atherosclerosis and thrombosis. Traditional cardiovascular risk factors are characterized by endothelial dysfunction caused by an enhanced production of oxidative stress leading to destroy nitric oxide, thus reducing its availability. Abdominal obesity is associated with endothelial dysfunction, through direct mechanisms, such as insulin resistance and the association with risk factors (including diabetes mellitus, hypertension and dyslipidemia), and direct, by the production of adipokines and pro-inflammatory cytokines, which in turn induce oxidative stress leading to a reduced nitric oxide availability. A reduced endothelium-dependent relaxation is a predictor of cardiovascular events in high-risk patients and represents a putative clinical parameter to stratify the cardiovascular risk and a useful marker for therapy efficacy. Weight loss and a modification of lifestyle ameliorate endothelial function in obese patients, an effect due not only to a better glycemic profile, but also secondary to reduced plasma levels of inflammatory markers and adipokines. At present, whether an improvement of endothelial dysfunction secondary to weight loss is significantly associated with a better cardiovascular prognosis is still unknown. (G Ital Cardiol 2006; 7 (11): 715-723)

Thiazide diuretics were the first tolerated efficient antihypertensive drugs that significantly reduced cardiovascular morbidity and mortality in placebo-controlled clinical studies. Although these drugs today still are considered a fundamental therapeutic tool for the treatment of hypertensive patients, the following considerations should be taken into account. Although there are some indications that chlorthalidone can offer additional advantages as compared with other compounds, a recent meta-analysis of placebo-controlled trials suggested that the beneficial effects of thiazide diuretics could be a class effect. Thiazide diuretics must be used at appropriate and/or optimal doses to achieve the optimal antihypertensive effect with the smallest occurrence of side effects, including alterations in glucose and lipid profiles and hypokalemia. Moreover, because thiazide diuretics can increase the incidence of new-onset diabetes, especially when combined with β blockers, caution is advised in using these drugs above all in patients who are at high risk for developing diabetes, in whom thiazide diuretics should be used at the lowest active dose and possibly in combination with drugs that block the renin-angiotensin system. Finally, the current debate on whether thiazide diuretics are the first-choice drug for most patients with uncomplicated hypertension, as stated in the Seventh Joint National Committee Report, or are included in the major classes of antihypertensive agents that are suitable for initiation and maintenance of therapy, as reported in the European Society of Hypertension–European Society of Cardiology Guidelines, derives from different interpretations of controlled clinical trial data on drug class comparison and of cost-benefit analyses. However, considering that the benefit of antihypertensive drugs seems to be due principally to BP lowering per se without definitive evidence of the superiority of a particular drug class and that there is no cost-benefit analysis showing the superiority of thiazide diuretics, it is believed that these drugs should not be considered as the only first-choice drug but included among first-choice drugs.

Arterial stiffness is associated with cardiovascular risk factors such as hypertension and sedentary lifestyle. The aim of this study was to evaluate the relationship between habitual physical activity and arterial stiffness in hypertensive (HT) and normotensive subjects (NT). In 190 subjects (age range: 21-73 years, 112 HT, 78 NT) augmentation index (AIX), a marker of arterial stiffness, was measured by pulse wave analysis (PWA) in the radial artery (SphygmocorR). Brachial artery diameter was measured by high resolution ultrasounds. Habitual physical activity was evaluated with a modified Baecke questionnaire, which assesses work activity score (WAS), sports activity score (SAS) and leisure time activity score (LAS). The total activity score (TAS) of habitual physical activity was calculated from the individual scores. In a subgroup of 40 subjects cardiorespiratory fitness (VO₂ max) was assessed with a graded exercise (cycle ergometer) test. AIX (adjusted for heart rate) was higher in HT (26.0±9.8) (p2 max between these groups. VO₂ max correlated with TAS (r=0.40, p=0.01) and SAS (r=0.47, p=0.005), but not with WAS or LAS. In NT, AIX correlated with TAS (r=-0.32, p=0.004) and SAS (r=-0.29, p=0.01), brachial artery diameter (r=-0.34, p=0.003), age (r=0.54, p2=0.64). In HT, AIX correlated with TAS (r=-0.22, p=0.02) and SAS (r=-0.19, p=0.05), brachial artery diameter (r=-0.41, p2=0.50). VO₂ max was significantly related to AIX (r=-0.60, p= 0.004) in NT, whereas no relationship was found in HT. In conclusion, habitual physical activity is inversely related to arterial stiffness, this relationship is more pronounced in normotensive subjects than in hypertensive patients.

Uremic patients have an increased incidence of cardiovascular disease (CVD), endothelial dysfunction and oxidative stress that can contribute to cardiovascular (CV) events. To assess the relationship between endothelial dysfunction, oxidative stress and renal failure severity, we studied 40 patients (age 57 +/- 7 yrs, 24 males) affected by chronic kidney disease (CKD) K/DOQI stage 3-5 (serum creatinine (Cr) 5.6 +/- 2.2 mg/dL) on conservative treatment, 20 uremic patients (age 57 +/- 12 yrs, 13 males) on hemodialysis (HD) and 30 healthy controls (56 +/- 12 yrs, 20 males). Before and 2 hr after oral vitamin C (2 g) administration, we measured brachial artery endothelium-dependent vasodilation (flow mediated dilation (FMD)) to reactive hyperemia following 5 min of forearm ischemia and the response to sublingual glyceril trinitrate (GTN). Measurements were made by high-resolution ultrasound and computerized analysis. FMD was lower in CKD patients than in controls (5.3 +/- 2.2 vs. 6.9 +/- 2.8%; p<0.01) and was further reduced in HD patients (3.6 +/- 2.7; p<0.01 vs. CKD patients). Response to GTN was similar in all groups. FMD was related to Cr clearance (r=0.42; p<0.01) in CKD patients, while it related inversely to Kt/V(urea) (r=-0.52; p<0.05) in HD patients. After vitamin C administration, FMD was significantly enhanced in HD (4.7 +/- 2.4%; p<0.01 vs. baseline), but not in CKD patients. Response to GTN was unaffected. However, vitamin C load reduced oxidative stress markers, and increased plasma antioxidant capability in both groups. In conclusion, the reduced endothelium-dependent dilation in the brachial artery of CKD patients is related to renal failure severity. HD patients showed a more marked alteration, which seems to be related, at least in part, to increased oxidative stress.

Renal transplant patients (RTP) are at high cardiovascular risk, and evidence exists that soy protein diet has cardiovascular and renal benefits. To evaluate the effect of soy on endothelial function, we measured brachial artery flow mediated dilation (FMD) and endothelium-independent vasodilation induced by sublingual nitroglycerine (GTN, 25 μg) at baseline and after 5 weeks of a soy-diet in 20 stable RTP (age: 55±11years, 11 males, serum creatinine 1.7±0.6 mg/dl). Dietary counselling was given individually with the aim to substitute 25 g of animal protein with 25 g of soy-protein, using common commercially available soy-foods. Changes in serum lipids and oxidative stress markers (lipid peroxides, LOOH) were also evaluated. FMD was induced by reactive hyperemia (RH) to 5 minutes of forearm ischemia (cuff inflated at 250 mmHg). Diameter was measured by an automatic edge detection system from end-diastolic scans (high resolution ultrasounds, Esaote AU5 Armonic) acquired on personal computer. Vascular responses were calculated as the maximal percentage change in diameter above baseline. Blood flow velocity was measured by pulsed Doppler to calculate RH after ischemia. Soy diet significantly reduced total cholesterol (from 229±41 to 212±41 mg/dL, p=0.02) and LDL cholesterol (from 142± 38 to 126±32 mg/dL, p=0.004), and actual protein intake remained unchanged (from 0.97±0.16 to 0.95±0.22 g/Kg/day). LOOH did not significantly change (from 5.3±3.9 to 4.1±4.9 mmol/L). After soy diet, brachial artery diameter (5.01±0.72 vs 4.99±0.75 mm), RH (439±253% vs 466±222%) and response to GTN (7.3±2.1% vs 7.3±2.9%), were unchanged, while FMD was significantly improved as compared to baseline (from 4.6±2.1 to 3.3±1.8%; p=0.03; area under the curve of increase 338±201 vs 220±162 units, p=0.006). No correlation was found between FMD and cholesterol serum levels, at baseline and after the soy diet. Moreover, improvement in FMD was not related to total or LDL cholesterol reduction or to changes in oxidative stress markers. In conclusion, 5 weeks of a soy protein diet improves endothelium-dependent vasodilation. This effect seems to be independent of cholesterol lowering and might be related to the influence of phyto-estrogen. These results suggest that implementation of a soy-protein diet could be useful in the nutritional management of renal transplant patients. Am J Hypertens (2004) 17, 69A–69A; doi: 10.1016/j.amjhyper.2004.03.176

Endothelium-derived nitric oxide is not only a potent vasodilator but also inhibits platelet aggregation, vascular smooth muscle cell migration and proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall from the development of atherosclerosis and thrombosis. Major cardiovascular risk factors are associated with endothelial dysfunction, which involves enhanced production of oxygen free radicals, that can destroy nitric oxide and reduce its availability, and release of endothelium-derived contracting factors including prostanoids and endothelin-1. Endothelial dysfunction is a promoter of atherosclerotic and thrombotic damage and in prospective studies on patients with high cardiovascular risk impaired endothelium-dependent vasodilation is associated with an increased incidence of cardiovascular events. However, endothelial function cannot yet be included among the surrogate endpoints which need to be measured for cardiovascular risk stratification. This limitation springs from the fact that available tests to assess endothelium-dependent vasodilation are invasive or, if noninvasive, they have no sufficient sensitivity and specificity to be proposed for clinical practice. Moreover, no study is available demonstrating that reversal of endothelial dysfunction, which can be obtained by appropriate treatment, is independently associated with a better clinical outcome. However it is conceivable that in the future, by the utilization of a non-invasive method such as the determination of brachial artery flow-mediated dilation, large-scale multicenter trials might provide a definitive answer to the real prognostic value of endothelial dysfunction, in terms of cardiovascular risk and therapeutic approach.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Study, the largest double-blind, randomized trial in hypertensive patients, confirmed and strengthened the clinical relevance of thiazide diuretics in the treatment of hypertension but did not prove the superiority of these drugs. Its claim of the superiority of chlorthalidone was based on some secondary outcomes, principally represented by (1) an increased incidence of stroke in the doxazosin and lisinopril arms, an effect that might be explained by differences in systolic BP; (2) greater morbidity but not mortality for congestive heart failure (CHF) in the doxazosin, amlodipine, and lisinopril arms, a finding that might reflect poor accuracy in the diagnosis and/or especially the switching from diuretic treatment in 90% of patients. Moreover, the ALLHAT study has other limitations, and its conclusions are in contrast with data from overall controlled clinical trials indicating that given the same BP reduction, the benefit of different drug classes is similar. As to whether the ALLHAT study will influence ongoing guidelines concerning the choice of antihypertensive drugs, the answer is “yes” if interpretation of its data in favor of diuretics and cost of drugs become the preponderant considerations, as it was in recent JNC VII guidelines. However, the more liberal approach based on the choice of all available drug classes seems still to be valid, as is in the ESH-ESC guidelines, if the preponderant consideration is that the real benefit of antihypertensive therapy is due to efficient BP control and not to a particular benefit of a single drug class.

Available data indicate that blood pressure (BP) is reduced below 140-90 mmHg in less than 30% of hypertensive patients. This poor control of BP derives from lack of diagnosis (unawareness of hypertension), lack of treatment of aware hypertensive patients and lack of efficacy of treatment. Systolic BP (SBP) is now considered as the most important parameter for diagnosis and stadiation of hypertension, above all in elderly patients, and the most frequent cause of unsatisfactory control of BP in the population. Lack of SBP control is caused both by physicians attitude and difficulty in reducing SBP. Physicians are more prone to consider diastolic BP as the most important parameter for diagnosis and stadiation of hypertension, decision to treat and intensification of treatment and therefore SBP is often forgotten and-or misinterpreted in this decision making process. On the other hand, since current antihypertensive drugs are equally effective in lowering SBP and DBP and-or less effective in lowering SBP more than DBP, SBP is often uncontrolled in treated patients with isolated systolic hypertension or prevalent increase in SBP. The possibility of obtaining better control of SBP in the future is linked to better education of physicians, who need to pay greater attention to SBP as a parameter for diagnosing, treating and intensifying treatment, and to the development of new drugs more active in reducing SBP.

Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxidative stress-induced nitric oxide (NO) breakdown and compensatory production of a hyperpolarizing factor. To test whether calcium antagonist treatment can restore NO availability and prevent hyperpolarization through antioxidant properties, in 15 healthy subjects and 15 patients with essential hypertension, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial bradykinin (5, 15, 50 ng/100 mL per minute), an endothelium-dependent vasodilator, in basal conditions, during infusion of N ^G -monomethyl- l -arginine (L-NMMA, 100 μg/100 mL per minute), an NO-synthase inhibitor, and ouabain (0.72 μg/100 mL per minute), an Na ⁺ -K ⁺ ATPase inhibitor to prevent hyperpolarization. These infusions were repeated in the presence of the antioxidant vitamin C (8 mg/100 mL/min). The response to sodium nitroprusside was also evaluated. In controls, vasodilation to bradykinin was inhibited by L-NMMA and remained unchanged by ouabain or vitamin C. In hypertensive patients, vasodilation to bradykinin was blunted and resistant to L-NMMA but sensitive to ouabain. Vitamin C increased the response to bradykinin and restored the inhibiting effect of L-NMMA while preventing the effect of ouabain. In hypertensive patients, infusions were repeated after 3-month treatment with lercanidipine (10 to 20 mg daily). Lercanidipine decreased plasma lipoperoxides, isoprostanes, and malondialdehyde and increased plasma antioxidant capacity. Moreover, lercanidipine increased the vasodilation to bradykinin and restored the inhibiting effect of L-NMMA on bradykinin-induced vasodilation while preventing the effect of ouabain. Finally, vitamin C no longer exerted its facilitating activity. These results indicate that in essential hypertension, lercanidipine increases endothelium-dependent vasodilation by restoring NO availability and preventing hyperpolarization, an effect probably determined by antioxidant activity.