Argano et al All treatment regimens were generally well tolerated. Side effects were few and transient. Two patients com- plained of asthenia, two of cough and three of dizziness but treatments were not discontinued. DISCUSSION In the present study we hypothesized that complete inhibition of the RAS would be most beneficial in man- agement of left ventricular geometry and function in hy- pertensive patients and might be achieved by a dual blockade with ACEi and ARB. To prove this hypothesis we compared the effects of three treatments (monother- apy with ACEi and ARB and its combination) on blood pressure, left ventricular mass and function in hyperten- sive subjects. This was an independent single-center trial which, compared with multicenter trials, may have some benefits, such as a simple design, strict imple- mentation and constant analysis of clinical and labora- tory data. This is the first study designed to analyze the effects of dual RAS blockade on left ventricular mass and function in hypertensives. Our results indicate an interesting finding. In fact, a more marked reduction in total and indexed left ventric- ular mass without impairment in diastolic and systolic left ventricular function following the combination of ACEi and ARB than either drug alone has been found in hypertensive subjects. In fact, the reduction in LVM/h2.7 after 6 months of combined therapy, was significantly higher than LVM/h2.7 reduction obtained with both sin- gle treatment, both in total hypertensives and in the subset with baseline LVH. This reduction was associat- ed to unchanged EF and to a favorable trend in the mea- surements of diastolic function. It is important to em- phasize that this effect was obtained with strict blood pressure control in all the groups. This finding discounts the suggestion that the differences observed upon the reduction in LVM could be explained only by the sys- temic blood pressure effect. Cardioprotection induced by combined therapy ob- served by us has been reported previously in experi- mental studies and in patients with hypertensive dias- tolic heart failure (25). The exact mechanism of this find- ing is not entirely known but emerging data indicate a strong relationship among Angiotensin II, collagen turnover and left ventricular geometry and function (26). Accordingly, our hypothesis about a better cardiopro- tective effect induced by combined RAS blockade might be related to the well known effects of An- giotensin II both on blood pressure, systemic and car- diac hemodynamics (27, 28) and on inflammatory mark- ers (29). ACEi reduce Angiotensin II but do not com- pletely block the RAS, since Angiotensin II may be pro- duced via other non-ACE-mediated pathways. Block- ade of AT1 by ARB may also reduce the unfavorable ef- fects of Angiotensin II. This might also induce a higher available Angiotensin II to bind with AT2 receptors; the latter may lead to relevant antigrowth and antitissue proliferation actions (27, 28). In particular, ARB also suppress some atherogenesis markers, such as cell-ad- hesion molecules, tumor necrosis factor alfa and super- oxide (29). A combination of both agents may be more effective clinically than either one alone and recent trials show promising results (30, 31). In view of this, our data indicate that the additive car- dioprotection obtained with a combined RAS blockade might be mediated through a concomitant reduction in collagen. This hypothesis might be supported by recent results indicating an important role of TGFβ1 and colla- gen in the occurrence of myocardial fibrosis. In fact, re- cent experimental studies have shown that improve- ment of myocardial stiffness may be due to an inhibition of collagen synthesis rather than to an enhancement of collagen degradation (32). Collagen synthesis is altered by load, activation of RAS, neurohumoral and growth factors. Chronic activation of the RAS increases extra- cellular matrix and fibrillar collagen, promoting myocar- dial stiffness and diastolic dysfunction. The use of treat- ment that blocks RAS might improve diastolic function through a normalization of fibrillar collagen (16). The An- giotensin II type receptor is the target of the RAS sys- tem and its activation promotes ventricular fibrosis and hypertrophy (33). Experimental data demonstrate that a combination of ACEi and ARB have additive favorable effects on ventricular structural abnormalities, diastolic dysfunction and collagen accumulation (34) that are in- dependent of their antihypertensive effectiveness. These effects might be in part due to the decrease of re- active oxygen species (ROS) generation. In fact, AII di- rectly stimulates ROS production promoted by macro- phage infiltration (35) and the blockade of macrophage infiltration stops the production of TGFβ1 (36) and ex- tracellular matrix (37). 45