Is Blockade of the Renin-angiotensin System Able to Reverse the Structural and Functional Remodeling of the Left Ventricle in Severe Aortic Stenosis?

Abstract

: In experimental aortic stenosis (AS), blockade of the renin-angiotensin system attenuates AS-related left ventricular (LV) dysfunction and improves survival. We tested whether candesartan, an angiotensin II type 1 receptor blocker, favorably influences LV structure and function and improves exercise capacity in AS patients. Fifty-one patients with severe AS were randomized to receive candesartan (target dose 16 mg/d) or placebo. Eight patients discontinued treatment and the remaining 43 patients underwent echocardiography, walking test, and measurement of plasma N-terminal B-type natriuretic peptide (Nt-proBNP) before and after an average of 5-month treatment. No statistically significant changes in LV diameters, mass, or function were seen. The median 6-minute walking distance decreased from 390 to 368 m with candesartan (P = 0.003) and from 380 to 370 m with placebo (P = 0.523), reflecting natural progression of AS. Concomitantly, median Nt-proBNP increased from 319 to 414 ng/L with candesartan (P = 0.170) and from 413 to 561 ng/L with placebo (P = 0.035). No change with candesartan was statistically significantly different from the corresponding change with placebo. In conclusion, candesartan was well tolerated but had no favorable effects on the LV or effort tolerance. The benefits found in experimental AS of blocking the renin-angiotensin system could not be reproduced in patients with severe AS.

Antihypertensive therapies in moderate or severe aortic stenosis: a systematic review and meta-analysis

“…The results also show that different AHT have varying impact on LV function and clinical outcomes. 54 55 60 83 84 Some authors attribute the benefits of AHT in this context to reduction in haemodynamic stress and myocardial ischaemia and to reduction in heart failure symptoms. 55 85 Haemodynamic factors and neurohormonal systems such as the RAAS are implicated in LV hypertrophy and myocardial fibrosis in AS.…”

Current Evidence and Future Perspectives on Pharmacological Treatment of Calcific Aortic Valve Stenosis

“…ARBs were tested in patients with severe CAVS because AT1R are activated and involved in the AV remodeling and fibrosis, a later stage of CAVS. In the prospective ROCK-AS trial, candesartan was well tolerated but failed to show efficacy [105]. In contrast, two consequent studies associated the treatment with ARBs (but not with ACEI) to a reduction in AV remodeling, inflammation, IL-6 expression, and fibrosis score, suggesting that ARBs could halt the fibrotic process by lowering tissue inflammation [106,107].…”

Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design

“… Candesartan vs. placebo Is blockade of the renin–angiotensin system able to reverse the structural and functional remodeling of the left ventricle in severe aortic stenosis? [ 51 ] 2015 51 Patients (>18 years) with severe aortic valve stenosis referred for valve replacement surgery Changes in LV structure and function and improvement of exercise capacity in the eplerenone arm vs. placebo (at 5 months) Candesartan did not have favorable effects on the left ventricle or exercise tolerance. Candesartan vs. placebo ROCK-AS (The Potential of Candesartan to Retard the Progression of Aortic Stenosis) NCT00699452 120 Patients (>18 years) with clinically symptomatic severe aortic valve stenosis, not treated with ACE-inhibitors or AT1R antagonists Inflammation in the valves at 3–5 months Not available Fimasartan vs. placebo ALFA (A Randomized Trial of Angiotensin Receptor bLocker, Fimasarta, in Aortic Stenosis) NCT01589380 100 Patients (20–75 years), with moderate to severe (asymptomatic) aortic valve stenosis (V max 3.0–4.5 m/s, mean gradient 25–49 mmHg or AVA 0.76–1.5 cm 2 ), able to undergo cardiopulmonary exercise testing Change in VO 2max during cardiopulmonary exercise testing at 1 year Not available Tadalafil vs. placebo ASPEN (Aortic stenosis and phosphodiesterase type 5 inhibition: a pilot study) NCT01275339 56 Patients (>18 years) with moderate to severe aortic valve stenosis (AVA < 1.5 cm 2 ), without indications for valve replacement surgery Change in LVM (using CMR at 6 months), change in diastolic function (using tissue Doppler e’ at 12 weeks and 6 months) and change in LV longitudinal peak systolic strain (using echocardiography at 12 weeks and 6 months) Not available.…”