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Changes in Left Ventricular Mass During Treatment with Minoxidil and Cilazapril in Hypertensive Patients with Left Ventricular Hypertrophy

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Changes in Left Ventricular Mass During Treatment with Minoxidil and Cilazapril in Hypertensive Patients with Left Ventricular Hypertrophy Journal of Human Hypertension (1997) 11, 149–156 1997 Stockton Press. All rights reserved 0950-9240/97 $12.00 Changes in left ventricular mass during treatment with minoxidil and cilazapril in hypertensive patients with left ventricular hypertrophy G Poga´tsa-Murray1, L Varga2, A Varga2,GyA´braha´m1, I Nagy1, T Forster2, M Csana´dy2 and S Sonkodi1 11st and 22nd Departments of Medicine, A Szent-Gyo¨rgyi Medical University, Szeged, Hungary Attainment of the regression of hypertension-associa- kind of therapy decreased the arterial pressures to a ted left ventricular hypertrophy (LVH) seems to be a similar degree. The 1-year treatment with the cilazapril- desirable goal of blood pressure (BP)-reducing therapy. based regimen resulted in a significantly diminished Since antihypertensive drugs of differing types may LVMI (from a mean ± s.d. of 173 ± 38 to 152 ± 22 g/m2; exhibit markedly different abilities to modulate LVH, we P , 0.05). On the other hand, the minoxidil-based ther- examined the effects of the angiotensin-converting apy led to a significant increase in LVMI (from 148 ± 19 enzyme inhibitor cilazapril, and the potassium channel to 170 ± 35 g/m2; P , 0.05). There were no significant activator minoxidil, alone or in combination with each LVMI changes in patients receiving the combined, cilaz- other, on the left ventricular mass (LVM) in patients with april + minoxidil-based treatment (172 ± 34 vs the pre- severe essential hypertension who had LVH detected by treatment 183 ± 54 g/m2). The results confirm that long- echocardiography. All patients received the same base term treatment with cilazapril is effective both in reduc- therapy of bopindolol and guanfacine. After a run-in per- ing BP and in reducing LVM. In spite of yielding a satis- iod, they were treated with: (1) cilazapril (n = 10); (2) factory reduction of BP, minoxidil therapy, even in com- minoxidil, combined with a diuretic (n = 10); or (3) both bination with a diuretic and a b-blocker, may lead to an cilazapril and monoxidil (n = 6) for 12 months. The LVM aggravation of pre-existing LVH; this effect of minoxidil index (LVMI; LVM per body surface area) was estimated could be prevented by the simultaneous administration every 3 months by means of echocardiography. Each of cilazapril. Keywords: left ventricular hypertrophy; angiotensin-converting enzyme inhibitor; cilazapril; minoxidil; vasodilator Introduction in LVM has been found to be accompanied by approximately a 1.5-fold enhanced relative risk of Left ventricular hypertrophy (LVH), which occurs in cardiovascular disease and by a doubled risk of car- approximately 15–20% of adult hypertensive diovascular mortality.5 1 patients, is not simply an incidental compensatory Regression of hypertension-associated LVH can be phenomenon in response to the increased overload, achieved by the long-term administration of antihy- but is recognized as a potent independent risk factor pertensive agents6–8 and there is preliminary evi- 1–5 for cardiovascular morbidity and mortality. The dence that the reversal of LVH might reduce the risk main cardiovascular events related to LVH in hyper- of cardiovascular events.9,10 Clinical and experi- tensive patients are coronary heart disease, cardiac mental studies suggest that antihypertensive drugs failure, stroke and sudden death. In the Framingham may differ in their potencies to reduce LVH; in this Study, electrocardiographically detected LVH was sense, angiotensin-converting enzyme (ACE) inhibi- found to be associated with a relative risk of cardio- tors seem to be the most powerful drug class, fol- vascular disease as high as for hypercholesterole- lowed by calcium antagonists, b-blockers and 2 mia, cigarette smoking and diabetes together. How- diuretics, while vasodilators exhibit less or no effi- ever, anatomical LVH is more sensitively detected cacy.6–8,11,12 Moreover, experimental studies showed by echocardiography than by electrocardiography or that, in spite of its excellent blood pressure (BP)- 3 X-ray examination. Recent echocardiographic stud- lowering potency, minoxidil, a direct vasodilator ies confirmed that the left ventricular mass (LVM) acting via activation of the ATP-sensitive potassium predicts a progressively increasing risk of mortal channels, can even induce or aggravate LVH, pre- 4,5 2 and morbid cardiac events; each 50 g/m increase sumably due to reflexive activation of the sympath- etic and renin-angiotensin systems and the volume overload.12–15 In clinical studies, minoxidil in com- Correspondence: Dr Sa´ndor Sonkodi, 1st Department of Medi- bination with other antihypertensive drugs proved cine, A Szent-Gyo¨ rgyi Medical University, Szeged, P.O.B. 469, H- 6701, Hungary effective in the treatment of severe, refractory hyper- Received 6 March 1996; revised 12 December 1996; accepted 2 tension.16,17 There is only scanty experience on the January 1997 effect of minoxidil on LVM in human hypertensives; Minoxidil, cilazapril and cardiac mass G Poga´tsa-Murray et al 150 some early studies18,19 and one involving an echo- Roche, Basel, Switzerland; n = 10), depending on the cardiographic assessment of LVM20 demonstrated an BP response, besides the bopindolol and guanfacine aggravating effect of minoxidil on LVH, whereas they were already taking. All minoxidil-treated another echocardiographic investigation did not.21 patients were given a diuretic (clopamide, 10 mg The primary aim of the present study, therefore, daily) to counteract fluid retention. When necessary, was to investigate the effect of the long-term admin- the dose of clopamide was increased throughout the istration of minoxidil on echocardiographically study. A third group of patients (n = 6) received both detected LVH in patients with severe hypertension minoxidil (15–30 mg/day) and cilazapril (3–5 in comparison with that of cilazapril, a new, long- mg/day) in addition to the bopindolol+guanfacine acting ACE inhibitor,22 the two drugs also being therapy. The application of clopamide in this group applied as combination therapy. was ceased if possible. During the first month of treatment, the doses of cilazapril and minoxidil Subjects and methods were titrated to achieve the target DBP of less than 100 mm Hg. Thereafter, BP, heart rate and clinical Subjects status were controlled every month. Echocardiogra- phy, electrocardiography and routine blood chemis- All patients (n = 26) selected for the study had sev- try analyses were performed before randomization ere essential hypertension and LVH. Their diastolic and every 3 months during the treament for 12 BP (DBP) levels amounted to 115 mm Hg on three months. separate occasions when they were not on antihy- pertensive therapy (baseline BP; Table 1). The cri- teria for LVH, detected by echocardiography, were BP measurements a mean wall thickness (the average of the posterior wall thickness [PWT] and the interventricular sep- Systolic BP (SBP) and DBP were measured after tum thickness [IVST]) >11 mm and an LVM index 15 min of rest in the sitting position, using a stan- (LVMI; LVM per body surface area) >110 g/m2 in dard mercury sphygmomanometer. BP was meas- women and >134 g/m2 in men.23,24 Secondary ured five times on the occasion of each ambulatory causes of hypertension were excluded by standard control between 8 am and 4 pm. The BP data clinical and laboratory tests. Patients with evident reported in this study are the average values heart or renal failure were excluded. Informed con- observed before each echocardiographic examin- sent was obtained from all patients before the study. ation. Mean arterial pressure (MAP) was calculated as (SBP + 2DPB)/3. In patients with unstable BP, automated BP monitoring (24–48 h) was performed Study protocol to help dose optimization. The protocol was planned in a randomized, pro- spective, open-labelled fashion because of the Echocardiography potentially adverse cardiac effects of minoxidil. As a run-in period, all patients were treated for 4 weeks M-mode echocardiography was performed by using with the b-receptor blocker bopindolol (1–2 mg/day) an Ultramark 9 HDI echocardiograph (ATL, USA) and with the centrally acting agent guanfacine (1–2 with a 3-2 MHz transducer. All echocardiograms mg/day). This run-in period was intended to make were taken by the same investigator. Recordings the pre-trial antihypertensive therapy comparable, were made at a paper speed of 50 mm/second. All since those patients with severe hypertension could echocardiograms were videorecorded. The internal not be deprived of drug treatment,25 for ethical dimension of the left ventricle (LVIDd), IVST and reasons. PWT at end-diastole were measured according to the After the 4-week period, patients were randomly recommendations of the American Society of Echo- allocated to treatment with either a dose of 15– 40 cardiography.26 All recordings were read by two mg/day minoxidil (Loniten, Upjohn, Crawley, UK; independent observers who were blind to the n = 10) or up to 5 mg/day cilazapril (Inhibace, patient’s treatment status. All measurements were Table 1 Baseline clinical characteristics in the three patient groups (checked before the run-in period) Minoxidil Cilazapril Minoxidil+cilazapril (n = 10) (n = 10) (n = 6) Female/male 4/6 4/6 2/4 Age (years) 52.3 ± 6.3 47.2 ± 8.2 51.3 ± 5.6 Weight (kg) 96.2 ± 14.9 85.6 ± 10.6 96.5 ± 13.7 Body surface area (m2) 2.09 ± 0.22 1.98 ± 0.19 2.10 ± 0.25 Duration of hypertension (years) 13.6 ± 6.6 12.6 ± 5.1 12.0 ± 3.2 SBP (mm Hg) 204 ± 15 199 ± 15 206 ± 17 DBP (mm Hg) 130 ± 14 123 ± 16 127 ± 15 LVMI (g/m2) 149 ± 23 171 ± 34 179 ± 48 Values are means ± s.d. SBP = systolic blood pressure; DBP = diastolic blood pressure; LVMI = left ventricular mass index. For all parameters, there were no significant differences between the groups (x2-test or Kruskal-Wallis test).
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