Effects of Sildenafil on Ventricular and Vascular Function in Heart Failure with Preserved Ejection Fraction

Barry A Borlaug, Gregory D. Lewis, Steven E. McNulty, Marc J. Semigran, Martin Lewinter, Horng Haur Chen, Grace D Lin, Anita Deswal, Kenneth B. Margulies, Margaret May Redfield

Research output: Contribution to journalArticle

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Abstract

Background-Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction. Methods and Results-A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus-0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV-52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus-6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure. Conclusions-In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Original languageEnglish (US)
Pages (from-to)533-541
Number of pages9
JournalCirculation: Heart Failure
Volume8
Issue number3
DOIs
StatePublished - May 4 2015

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Ventricular Function
Blood Vessels
Heart Failure
Phosphodiesterase 5 Inhibitors
Placebos
Hyperemia
Pulmonary Artery
Blood Pressure
Sildenafil Citrate
Left Ventricular Function
Endothelium
Arm
Stroke
Clinical Trials
Prospective Studies
Exercise
Therapeutics

Keywords

  • diastolic heart failure
  • heart failure
  • vascular function
  • ventricular function

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Effects of Sildenafil on Ventricular and Vascular Function in Heart Failure with Preserved Ejection Fraction. / Borlaug, Barry A; Lewis, Gregory D.; McNulty, Steven E.; Semigran, Marc J.; Lewinter, Martin; Chen, Horng Haur; Lin, Grace D; Deswal, Anita; Margulies, Kenneth B.; Redfield, Margaret May.

In: Circulation: Heart Failure, Vol. 8, No. 3, 04.05.2015, p. 533-541.

Research output: Contribution to journalArticle

Borlaug, Barry A ; Lewis, Gregory D. ; McNulty, Steven E. ; Semigran, Marc J. ; Lewinter, Martin ; Chen, Horng Haur ; Lin, Grace D ; Deswal, Anita ; Margulies, Kenneth B. ; Redfield, Margaret May. / Effects of Sildenafil on Ventricular and Vascular Function in Heart Failure with Preserved Ejection Fraction. In: Circulation: Heart Failure. 2015 ; Vol. 8, No. 3. pp. 533-541.
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abstract = "Background-Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction. Methods and Results-A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus-0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11{\%} to 16{\%} with sildenafil compared with placebo (ΔPWR/EDV-52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus-6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure. Conclusions-In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.",
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T1 - Effects of Sildenafil on Ventricular and Vascular Function in Heart Failure with Preserved Ejection Fraction

AU - Borlaug, Barry A

AU - Lewis, Gregory D.

AU - McNulty, Steven E.

AU - Semigran, Marc J.

AU - Lewinter, Martin

AU - Chen, Horng Haur

AU - Lin, Grace D

AU - Deswal, Anita

AU - Margulies, Kenneth B.

AU - Redfield, Margaret May

PY - 2015/5/4

Y1 - 2015/5/4

N2 - Background-Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction. Methods and Results-A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus-0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV-52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus-6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure. Conclusions-In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

AB - Background-Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction. Methods and Results-A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus-0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV-52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus-6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure. Conclusions-In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

KW - diastolic heart failure

KW - heart failure

KW - vascular function

KW - ventricular function

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