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Effects of Phosphodiesterase Type 5 Inhibition on Systemic and Pulmonary Hemodynamics and Ventricular Function in Patients with Severe Aortic Stenosis

B. R. Lindman

A. Zajarias

J. A. Madrazo

J. Shah

B. F. Gage

E. Novak

Murali Chakinala

T. A. Hohn

M. Saghir

D. L. Mann


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Lindman BR, Zajarias A, Madrazo JA, Shah J, Gage BF, Novak E, Johnson SN, Chakinala MM, Hohn TA, Saghir M, Mann DL.

Washington University School of Medicine, St. Louis, Missouri, USA.

BACKGROUNDPatients with aortic stenosis (AS) often present with advanced heart failure symptoms and abnormal hemodynamics characterized by pulmonary venous congestion, pulmonary hypertension (PH), afterload mismatch, and low cardiac output. PH worsens heart failure symptoms and increases operative risk in patients with AS undergoing valve replacement. When pulmonary vascular resistance (PVR) is particularly elevated in these patients, they may be deemed inoperable. Phosphodiesterase type 5 (PDE5) inhibition may decrease PH and PVR in these patients and help reverse their decompensated clinical state, thereby potentially reducing operative risk and improving symptoms. However, the use of PDE5 inhibitors in patients with AS is controversial because of concerns about vasodilation and hypotension.

METHODSDuring cardiac catheterization, we evaluated the hemodynamic response of subjects with severe symptomatic AS (aortic valve area [AVA] <1.0 cm2) to a single oral dose of sildenafil (40mg or 80mg). Measurements were taken at baseline and 60 minutes after sildenafil. Data are shown as mean±SD and % change reported is the median.

RESULTSWe enrolled 20 subjects with mean age 86 years, AVA 0.7±0.2 cm2 and ejection fraction 60±14%. Fifty percent were female, 65% had coronary disease, and 90% were NYHA functional class III or IV. After 60 minutes, sildenafil reduced systemic (from 27±8 to 22±6 Wood units, 12%, p<0.001) and pulmonary (3.5±2.8 to 2.2±1.1 Wood units, 29%, p=0.002) vascular resistance, mean pulmonary artery (37±11 to 27±9 mmHg, 25%, p<0.001) and wedge (24±7 to 19±8 mmHg, 17%, p<0.001) pressure. Likewise, sildenafil increased systemic (0.57±0.2 to 0.66±0.2 ml/mmHg, +13%, p<0.001) and pulmonary (2.1±1.1 to 2.8±1.2 ml/mmHg, +45%, p<0.001) vascular compliance and stroke volume index (29±6 to 31±6 ml/m2, +8%, p=0.01). There was a similar decrease in mean pulmonary artery pressure (mPAP) in subjects with “passive” (mPAP ≥25, PVR <3, n=10) vs. “reactive” (mPAP ≥25, PVR ≥3, n=7) PH. Among those with PH and PVR ≥3 on baseline measurements (n=7), sildenafil reduced PVR 52% (6.5±2.7 to 3.0±1.2 Wood units, p<0.05). The increase in stroke volume was strongly associated with a decrease in systemic and pulmonary vascular afterload resulting from sildenafil administration. The changes in hemodynamic measurements were not dose dependent. Sildenafil modestly decreased mean systemic arterial pressure (108±15 to 94±16 mmHg, 11%, p<0.001), but was well-tolerated without symptomatic hypotension.

CONCLUSIONSThis study shows for the first time that a single dose of a PDE5 inhibitor is safe and well-tolerated in patients with severe AS and is associated with acute improvements in pulmonary and systemic hemodynamics resulting in biventricular unloading. These findings support the need for longer-term studies to evaluate the role of PDE5 inhibition as adjunctive medical therapy in patients with AS and suggest that they may be particularly beneficial in patients with a concomitant increase in pulmonary vascular load.