Elsevier

American Heart Journal

Volume 167, Issue 2, February 2014, Pages 226-234
American Heart Journal

Clinical Investigation
Valvular and Congenital Heart Disease
Short-term hemodynamic effect of angiotensin-converting enzyme inhibition in patients with severe aortic stenosis: A placebo-controlled, randomized study

https://doi.org/10.1016/j.ahj.2013.11.002Get rights and content

Background

In patients with severe aortic stenosis (AS), treatment with angiotensin-converting enzyme inhibitors has previously been considered contraindicated. However, there is a lack of clinical evidence to confirm these potential hemodynamic risks and benefits.

Methods

Forty-four patients with severe AS (aortic valve area <1 cm2) were randomized to treatment with trandolapril 22 mg daily/placebo (1:1). Right heart catheterization and echocardiography were performed at rest and during exercise at baseline and on day 3. Follow-up was performed before valve replacement or after a maximum of 8 weeks, when exercise echocardiography was repeated.

Results

Compared with placebo, systolic blood pressure and systemic arterial compliance significantly changed at day 3 (−14 ± 11 vs −5 ± 13 mm Hg, P = .02, and 0.08 ± 0.16 vs −0.05 ± 0.86 mL/m2 per mm Hg, P = .03, respectively). Changes in left ventricular end systolic volume (LVESV) was nonsignificant (−8 ± 9 vs −3 ± 11 mL, P = .17). At a median of 49 days of follow-up, changes in LVESV and N-terminal pro-brain natriuretic peptide were even lower revealing significant differences between the groups (−7.8 ± 2.6 vs −0.5 ± 2.5 mL, P = .04, and −19 ± 7 vs 0.8 ± 6 pmol/L, P = .04, respectively). No episodes of symptomatic hypotension were noted, and other hemodynamic parameters remained unchanged.

Conclusion

Angiotensin-converting enzyme inhibition in severe AS caused a decrease in LVESV and N-terminal pro-brain natriuretic peptide with other hemodynamic parameters preserved both at rest and during exercise implying hemodynamic improvement with left ventricular unloading.

Section snippets

Study population

Patients with severe AS, defined as an aortic valve area <1 cm2, being in sinus rhythm and without symptoms at rest, who had been referred for aortic valve replacement were recruited at the Department of Cardiology, Rigshospitalet, Denmark, between November 2005 and December 2009. Patients were grouped as symptomatic or asymptomatic. Symptomatic individuals were those with angina pectoris, dizziness, syncope at exertion, or those who were classified as New York Heart Association (NYHA)

Statistics

It was planned to include 64 patients (32 symptomatic and 32 asymptomatic patients) in this study. However, the enrollment was stopped earlier because of the low recruitment rate. Finally, 32 symptomatic and 12 asymptomatic patients were recruited to the study.

Continuous variables are expressed as the mean ± SD, and categorical variables, as the frequency and percentage. Differences in the hemodynamic variables between the ACE-I and placebo groups were assessed with Student independent-samples t

Ethics

The study was approved by the regional ethics committee (J. nr. 02 269334), and all patients gave their written informed consent before inclusion in the study.

Source of funding

The Danish Heart Foundation supported the research fellowship of Dr Dalsgaard, grant number 06-10-B317-A1186-22339.

Baseline characteristics

Forty-four patients with severe AS were studied (32 symptomatic and 12 asymptomatic), 16 of whom (36%) were women. Mean age was 69.9 ± 8.3 years (range, 55-85 years). Thirty (68%) of the patients had at least 1 of the following conditions: hypertension, ischemic heart disease, or diabetes mellitus. Of these, hypertension was the most common (52%). In patients with a history of hypertension, systolic BP was 158 ± 23 mm Hg versus 136 ± 15 mm Hg in the group without a history of hypertension (P =

Discussion

We investigated the short-term hemodynamic effects and safety of treatment with ACE-I in patients with severe symptomatic and asymptomatic AS. At follow-up, LVESV and NT-proBNP were significantly lower than in placebo, implying hemodynamic improvement with LV unloading. The approximate halving of SVR with exercise emphasizes the potential for medical reduction of afterload in these patients.

In the ACE-I group, we found a decrease in afterload, measured as a drop in SVR and BP, which was

Conclusion

Angiotensin-converting enzyme inhibition in severe AS caused a decrease in LVESV and NT-proBNP with other hemodynamic parameters preserved both at rest and during exercise implying hemodynamic improvement with LV unloading.

References (25)

  • E.O. Weinberg et al.

    Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis

    Circulation

    (1994)
  • K.D. O'Brien et al.

    Angiotensin-converting enzyme inhibitors and change in aortic valve calcium

    Arch Intern Med

    (2005)
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    Grants: The Danish Heart Foundation grant no. 06-10-B317-A1186-22339, Copenhagen, Denmark.

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