EFFECTS OF EARLY AND LATE THERAPY WITH PERINDOPRIL ON SURVIVAL AND MYOCARDIAL INOTROPIC STATE IN EXPERIMENTAL DILATED CARDIOMYOPATHY

We wished to test (a) whether single-drug therapy with a low dose of the angiotensin-converting enzyme (ACE) inhibitor perindopril has the capacity to improve early survival of the cardiomyopathic Syrian hamster (CSH); (b) whether early treatment with perindopril modifies CSH survival to a greater extent than perindopril treatment initiated later in the course of the disease; and (c) the effects of early and late perindopril therapy on the intrinsic contractility of left ventricular (LV) papillary muscle. We studied CSH from the Bio 53.58 dilated strain (n = 76), in which myocardial necrosis is known to develop from age 30 days, whereas congestive heart failure (CHF) is observed only after age 6 months. Animals were randomly assigned to three groups. In early-treated animals, perindopril (1 mg/kg body weight once daily in distilled water) was administered by force-feeding from age 1 month to 9 months (PE1, n = 21). Animals receiving delayed treatment received distilled water from age 1 month to 6 months, followed by 1 mg/kg body weight from age 6 to 9 months (PE2, n = 34). Controls received distilled water from age 1 month to 9 months (C, n = 21). At endpoint (9 months), mechanical properties of LV papillary muscles and serum ACE activity were studied in a subgroup of 32 CSH (C, n = 8; PE1, n = 10; and PE2, n = 14). Maximum unloaded shortening velocity, maximum extent of systolic shortening in twitch with preload only, and normalized peak of isometric active force were measured. Mortality was observed from weeks 23, 34, and 32 of treatment in C, PEI, and PE2, respectively. At endpoint (9 months), the three groups were different with regards to survival rate (14 of 21 in C, 20 of 21 in PE1, and 32 of 34 in PE2) (p = 0.003), with no difference between PE1 and PE2. The three mechanical indexes measured were similar in C, PE1, and PE2. Inhibition of serum ACE activity of 76.6 and 69.6% was obtained in PE1 and PE2 as compared with C values (p < 0.001 each). Age-matched golden Syrian hamsters from the F1B strain were also studied (survival rate = 16 of 16 at endpoint). Single-drug therapy with a low dose of perindopril was efficient in experimental cardiomyopathy, with similar benefits of early and late ACE inhibition with regard to delayed occurrence and decreased rate of fatal events at endpoint (9 months). Lack of intrinsic negative inotropic effect of ACE inhibition was also demonstrated in this model.-