ANGIOTENSIN-CONVERTING ENZYME-INHIBITION, AT(1) RECEPTOR INHIBITION, AND COMBINATION THERAPY WITH PACING-INDUCED HEART-FAILURE - EFFECTS ONLEFT-VENTRICULAR PERFORMANCE AND REGIONAL BLOOD-FLOW PATTERNS

Background: AT(1) receptor activation has been demonstrated to cause i ncreased vascular resistance properties which may be of particular imp ortance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of ACE inhibition (ACEI) alone, AT(1) receptor blockade alone and combined ACEI and AT(1) rece ptor blockade on LV pump function, systemic hemodynamics and regional blood flow patterns in the normal state and with the development of pa cing induced CHF, both at rest and with treadmill induced exercise. Me thods and results: Pigs (25 kg) were instrumented in order to measure cardiac output (CO), systemic (SVR) and pulmonary vascular (PVR) resis tance, neurohormonal system activity, and myocardial blood flow distri bution in the conscious state and assigned to one of 4 groups: (1) rap id atrial pacing (240 bpm) for 3 weeks (n = 7); (2) ACEI (benazeprilat , 3.75 mg/day) and pacing (n = 7); (3) AT(1) receptor blockade (valsar tan, 60 mg/day) and rapid pacing (n = 7); and (4) ACEI and AT(1) recep tor blockade (benazeprilat/valsartan, 1/60 mg/day, respectively) and p acing (n = 7). Measurements were obtained at rest and with treadmill e xercise (15 degrees, 3 miles/h; 10 min) in the normal control state an d after the completion of the treatment protocols. With rapid pacing, CO was reduced at rest and with exercise compared to controls. ACEI or AT(1) blockade normalized CO at rest, but remained lower than control values with exercise. Combination therapy normalized CO both at rest and with exercise. Resting SVR in the CHF group was higher than contro ls and SVR fell to a similar degree with exercise; all treatment group s reduced resting SVR. With exercise, SVR was reduced from rapid pacin g values in the ACEI and combination therapy groups. PVR increased by over 4-fold in the rapid pacing group both at rest and with exercise, and was reduced in all treatment groups. In the combination therapy gr oup, PVR was similar to control values with exercise. Plasma catechola mines and endothelin levels were increased by over 3-fold with chronic rapid pacing, and were reduced in all treatment groups. In the combin ation therapy group, the relative increase in catecholamines and endot helin with exercise were significantly blunted when compared to rapid pacing only values. LV myocardial blood flow at rest was reduced in th e rapid pacing only and monotherapy groups, but was normalized with co mbination therapy. Conclusion: These findings suggest that with develo ping CHF, combined ACE inhibition and AT(1) receptor blockade improved vascular resistive properties and regional blood flow distribution to a greater degree than that of either treatment alone. Thus, combined ACEI and AT(1) receptor blockade may provide unique benefits in the se tting of CHF. (C) 1998 Elsevier Science B.V. All rights reserved.