Do thiazide diuretics reduce central systolic blood pressure in hypertension?

Hypertension reduction strategies use blood pressure (BP) in the brachial artery as the primary end point. Individuals who achieve target BP reduction with antihypertensive treatment have residual cardiovascular risk attributed to the difference in pressure between the aorta and brachial artery. Measurement of central systolic BP (CSBP), although not part of the routine stratification of patients with hypertension, is of increasing interest because of its predictive value of cardiovascular events, as well as to assess the effects of the different classes of antihypertensive agents on CSBP compared with the traditionally determined brachial arterial pressure.1 One of the first publications to draw attention of the scientific community to the role of CSBP in cardiovascular outcomes, regardless of peripheral BP, was the CAFE (Conduit Artery Function Evaluation) study published in 2006.2 In this study, patients with hypertension who obtained higher reductions in the systolic component of central pressure for similar reductions in the arterial BP measured using the conventional evaluation had a lower incidence of cardiovascular events. In that same year, the European Society of Cardiology published a position report drawing attention to the fact that brachial measures overestimate central BP values and that the systolic component of central pressure as well as the central pulse pressure are better predictors of cardiovascular outcomes in patients with hypertension and chronic kidney disease.3 Other publications also drew attention to this superiority even when the central BP measures were compared with brachial arterial measurements obtained by ambulatory BP monitoring.4 However, a recent meta-analysis of 11 longitudinal studies showed that both CSBP and central pulse pressure are independent markers of outcome and cardiovascular mortality but were no better than the values obtained by conventional measurements (brachial pressure assessment) (P = .057).5, 6 The aortic wall has endocrine, autocrine, and paracrine functions, and is capable of undergoing rapid changes in its morphology and elasticity. Complex mechanisms of regulation controlled by hemodynamic factors, local and systemic responses, neurohumoral activation, and changes in vascular reactivity promote changes in the structure and function of the arterial wall, thereby stimulating the development of arterial stiffness.7, 8 Arterial stiffness is a major determinant of increased pulse pressure and CSBP. Antihypertensive treatment affects the intrinsic properties of the vascular wall and arterial stiffness markers and consequently the central pressure. Hypertension reduction strategies use BP in the brachial artery as the primary end point. Individuals who achieve target BP reduction with antihypertensive treatment have residual cardiovascular risk attributed to the difference in pressure between the aorta and brachial artery. The clinical implications of this discrepancy suggest that individuals with normal peripheral but high central BP should not receive antihypertensive drugs that act on the central pressure. Therefore, they remain at greater cardiovascular risk. Fernandes and colleagues9 evaluated the effect of treatment using low doses of the thiazide diuretic chlorthalidone plus amiloride or angiotensin II receptor blockers on CSBP in patients with stage 1 hypertension. Twenty-five patients were randomized to the initial dose of chlorthalidone plus amiloride (12.5/2.5 mg/d) and 25 patients received losartan (50 mg/d). After 3 months, chlorthalidone plus amiloride and losartan were doubled if necessary for patients who did not have controlled BP with the initial dose: chlorthalidone 25 mg/amiloride 5 mg/d and losartan up to 100 mg/d. The CSBP and augmentation index at 75 beats per minute (AIx75) were assessed using applanation tonometry. The thiazide and losartan groups were compared using the paired t test at baseline and after 6 months of treatment. The chlorthalidone 25 mg/amiloride 5 mg group showed significant reductions in CSBP (123.3 ± 14.2 mm Hg vs 113.4 ± 111.4 mm Hg, P = .01) and AIx75 (87.7 ± 9.6 vs 83.8 ± 8.9, P = .03) after 6 months of active treatment. The administration of losartan 50/100 mg did not reduce CSBP and there were no significant changes in AIx75. The results of this work contradict studies that have shown that diuretics appear to have no beneficial effect on central hemodynamics. Several agents, including thiazide diuretics, were shown to have a neutral effect on the reduction of CSBP and a neutral effect on the amplification of the pressure waveform moving from the aorta to the radial artery.10-13 Consistent data are available for bendrofluazide and indapamide, which also have neutral effects on AIx75 and pulse wave velocity, respectively.14 Some benefits of chlorthalidone in experimental and human studies have been shown beyond the reduction in BP. These benefits include a reduction in oxidative stress, improved endothelial function, decreased vascular permeability and platelet aggregation, and stimulating angiogenesis, which plays a key role in the restoration of arterial stiffness and vascular remodeling, components that are significantly involved in the genesis of elevated central pressure.15 Several clinical studies have been performed investigating the effects of angiotensin II type 1 receptor blockers on CSBP. The EXPLOR (Effect of the Fixed Dose Combination Amlodipine/Valsartan on Central Aortic Blood Pressure in Uncontrolled Essential Hypertension With Amlodipine 5 mg) study compared the association of valsartan/amlodipine versus amlodipine/atenolol, with similar reductions in the brachial artery pressure being found with both drug combinations. Significant reductions in pulse wave velocity and AIx75 were shown in the valsartan/amlodipine group compared with the amlodipine/atenolol group.16 Telmisartan,17 candesartan,18 eprosartan, and other angiotensin II type 1 receptor blockers were studied and showed similar results. Laurent and coworkers19 investigated patients with hypertension who had metabolic syndrome and demonstrated an efficient reduction of CSBP with olmesartan. In the J-TOP (Japan Morning Surge-Target Organ Protection) study, Shimizu and colleagues20 highlight the importance of using CSBP as an adjunct measure of antihypertensive therapy. The authors showed an association between the reduction in CSBP and decreased urinary albumin excretion (a marker of endothelial dysfunction) and left ventricular mass index (target organ damage) in patients with hypertension treated with antihypertensive drugs. The relevance and potential of this method lies in the importance of the difference found between the CSBP and peripheral brachial BP in all age groups as demonstrated by McEniery and colleagues21 in the ACCT II (Anglo-Cardiff Collaborative Trial II). In addition, the influence of antihypertensive therapy leading to improvements in CSBP of patients with stage 1 hypertension cannot be excluded. Fuchs and colleagues22 showed that the use of a fixed combination of low-dose chlorthalidone and amiloride also produced a substantial and highly significant reduction in the incidence of hypertension and a reduction in left ventricular mass in patients with prehypertension, These authors concluded that the use of low-dose diuretics in patients with prehypertension might be an effective option to reduce the burden of hypertension and its cardiovascular consequences. Thus, taken together, the results of the current study reinforce the importance of early pharmacological interventions in patients with stage 1 hypertension to reduce peripheral BP, and low doses of chlorthalidone and amiloride have a beneficial effect within 6 months of therapy by acting on CSBP. This may be an additional mechanism of cardiovascular protection for patients with hypertension treated with diuretics. The authors do not have any conflicts of interest to disclose.