Emerging Treatments and Technologies N A L A R T I C L E Beneficial Impact of Ramipril on Left Ventricular Hypertrophy in Normotensive Nonalbummuric NIDDM Patients FLEMMING S. NIELSEN, MD ASAKO SATO, MD SAMIR ALI, MD LISE TARNOW, MD ULLA M. SMIDT JENS KASTRUP, MD, DMSC HANS-HENRIK PARVING, MD, DMSC OBJECTIVE— To evaluate the effect of the ACE inhibitor ramipril as compared with placebo on left ventricular mass index (LVMl) in normotensive, nonalbuminuric NIDDM patients with left ventricular hypertrophy (LVH). Patients with NIDDM are characterized by excessive cardiovascular morbidity and mortality, and LVH, an independent risk factor for car- diac events, is often present in NIDDM patients. RESEARCH DESIGN AND METHODS— A total of 38normotensive, nonalbuminuric (albuminuria <100 mg/24 h) NIDDM patients with LVH (LVMl >131 g/m 2 in men and >100 g/m 2 in women) were enrolled in a 6-month randomized, double-blind parallel group study to compare the effects of ramipril (5 mg/day) with placebo on LVMl (echocardiography, Vingmed CFM725, Diasonics Sonotron), QT C dispersion determined as the interlead variation in QT C interval on standard electrocardiogram (ECG), and 24-h ambulatory blood pressure (A&D TM2420, Tokyo, Japan). A total of 16 ramipril (10 men, 60 ± 9 years [mean ± SD]) and 15 placebo-treated (8 men, 55 ± 10 years) patients completed the study, and their data are presented. RESULTS— Ambulatory blood pressure was almost identical at baseline (132/76 ± 3/1 vs. 133/74 ± 5/2 mmHg [mean ± SEM]) and remained stable during follow-up (134/76 ± 3/1 vs. 136/74 ± 6/2 mmHg) in the ramipril and placebo group, respectively. LVMl was comparable at baseline (137.1 ± 7.0 vs. 129.6 ± 3.7 g/m 2 ) in the ramipril and placebo group, respectively, and decreased significantly more in the ramipril group as compared with the placebo group (17.6 ± 3.0 vs. 5.7 ± 4.6 g/m 2 , respectively, 11.9 [0.7-23.1] g/m 2 , mean difference [95% CI]; P = 0.037). QT C dispersion was comparable at baseline (60.2 [5.5] vs. 64.1 [6.5] ms) and did not change significantly during follow-up: —2.5 [7.0] vs. —12.2 [9.5] ms; mean difference 9.8 (—14.2 to 33.8 ms) in the ramipril and placebo group, respectively. CONCLUSIONS — Ramipril induces regression of LVH in normotensive, nonalbuminuric NIDDM patients, independent of reduction in systemic blood pressure. P atients with NIDDM have excessive cardiovascular morbidity and mortal- ity even in the absence of albuminuria and hypertension (1). Left ventricular hypertrophy (LVH), which is an ominous prognostic sign and an independent risk factor for cardiac events, is often present in NIDDM patients (2,3). The preliminary results of three prospective studies indicate that reversal of LVH reduces the increased cardiovascular risk in patients with essen- tial hypertension and LVH (4-6). This indi- cates that left ventricular mass index (LVMl) can be used as an intermediate or From the Steno Diabetes Center (F.S.N., A.S., L.T., U.M.S., H.-H.P), Gentofte; and the Department of Car- diology (S.A., J.K.), the Heart Centre Rigshospitalet, Copenhagen, Denmark. Address correspondence and reprint requests to Flemming S. Nielsen, MD, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. Received for publication 7 July 1997 and accepted in revised form 27 January 1998. Abbreviations: ECG, electrocardiogram; LVDD, left ventricular end-diastolic diameter; LVH, left ven- tricular hypertrophy; LVMl, left ventricular mass index; PWTD, posterior wall thickness in diastole; RPWT, relative posterior wall thickness; STD, ventricular septum thickness; WHO, World Health Organization. "surrogate" end point in the management of LVH in patients with essential hyperten- sion. Surrogate end points are end points that correlate with or predict a principal end point. A principal end point is defined as an end point that is of benefit to the patient if improved (e.g., cardiac morbidity and mortality). Most antihypertensive drugs reduce left ventricular mass in hyper- tensive patients but ACE inhibitors seem to offer a reduction beyond that explained by their blood pressure-lowering properties as reviewed by Schmieder et al. (7). Further- more, LVH is associated with abnormalities in the electrophysiology of the heart, rec- ognized as prolonged QT C interval and increased QT C dispersion (interlead varia- tions in the QT C interval) on standard elec- trocardiogram (ECG). Prolonged QT C interval and increased QT C dispersion have been shown to be independent predictors of cardiac death in apparently healthy sub- jects (8), various patient groups (9,10), and in NIDDM (11) and IDDM patients (12). An increased QT C dispersion may be a more important parameter than the pro- longed QT C interval because it reflects regional repolarization differences in the heart, which may predispose to reentry arrhythmias (13). Recently, it has been demonstrated that ACE inhibitors reduce the QT C dispersion in patients with essen- tial hypertension in parallel with reversion of LVH (14). Both reductions of LVH and QT C dispersion have been shown to occur within 6 months of ACE inhibition (7,14). Therefore, the aim of our 6-month prospective, randomized parallel study was to compare the effects of ramipril and placebo on LVMl and QT C dispersion in normotensive, nonalbuminuric NIDDM patients with LVH. RESEARCH DESIGN AND METHODS — A total of 146 nor- motensive (repeated arterial blood pressure < 140/90 mmHg and no present or previ- ous antihypertensive treatment), nonalbu- minuric (urinary albumin excretion rate <100 mg/24 h) consecutive NIDDM 804 DIABETES CARE, VOLUME 21, NUMBER 5, MAY 1998