Right Ventricular Pulmonary Coupling as a Therapeutic Target in Heart Failure With Preserved Ejection Fraction.

Abstract

HomeCirculation ResearchVol. 124, No. 2Right Ventricular Pulmonary Coupling as a Therapeutic Target in Heart Failure With Preserved Ejection Fraction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBRight Ventricular Pulmonary Coupling as a Therapeutic Target in Heart Failure With Preserved Ejection Fraction Thomas R. Cimato and John M. CantyJr Thomas R. CimatoThomas R. Cimato From the VA WNY Health Care System and the Departments of Medicine, Pharmacology and Toxicology, Physiology and Biophysics, and Biomedical Engineering, and The Clinical and Translational Research Center of the University at Buffalo, NY. Search for more papers by this author and John M. CantyJrJohn M. CantyJr Correspondence to John M. Canty Jr, MD, Jacobs School of Medicine and Biomedical Sciences, Clinical and Translational Research Center, University at Buffalo, Suite 7030, 875 Ellicott St, Buffalo, NY 14203. Email E-mail Address: [email protected] From the VA WNY Health Care System and the Departments of Medicine, Pharmacology and Toxicology, Physiology and Biophysics, and Biomedical Engineering, and The Clinical and Translational Research Center of the University at Buffalo, NY. Search for more papers by this author Originally published17 Jan 2019https://doi.org/10.1161/CIRCRESAHA.118.314356Circulation Research. 2019;124:186–188This article is a commentary on the followingThe β-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection FractionAlthough there have been considerable advances in the diagnosis and therapy of heart failure when ejection fraction is reduced, at least half of patients have heart failure with a preserved ejection fraction or HFpEF.1 This frequency is probably an underestimate because the emerging gold standard test to diagnose HFpEF is currently invasive exercise hemodynamics. Although not yet widely utilized, detailed exercise hemodynamics along with cardiopulmonary stress testing has contributed to a better characterization of central (eg, exercise elevations in pulmonary capillary wedge pressure and pulmonary vascular resistance) versus peripheral mechanisms (eg, deconditioning) contributing to the HFpEF syndrome. Despite an improved understanding of pathophysiology, as well as complexity of the HFpEF phenotype,2 no specific treatments have emerged other than diuretics to reduce preload and improve dyspnea and peripheral edema. Exercise training seems to improve peak exercise capacity and quality of life in subjects with HFpEF but does not significantly change underlying systolic and diastolic dysfunction.3 Although therapies directed at reducing neurohormonal activation have reduced symptoms and improved survival in heart failure with a reduced ejection fraction, their prophylactic use in HFpEF has demonstrated no clear clinical impact. Likewise, clinical trials using novel therapies specifically directed at HFpEF pathophysiology, including cGMP phosphodiesterase inhibitors,4 aldosterone antagonists (spironolactone),5 and more recently inhaled nitrite,6 have all convincingly shown no improvement in symptoms, exercise capacity, or other clinical endpoints. The failure to translate positive results observed in small single-center clinical trials in larger multicenter randomized trials is not unique to HFpEF, and it may in part reflect the multiple biological phenotypes of HFpEF which pose a challenge for clinical trial design. Some of this variability may arise from modulating factors, such as diabetes mellitus, obesity, and systemic inflammation. Other factors contributing to variability in therapeutic responses may relate to the presence and extent of pulmonary and systemic hypertension, as well as epicardial and microvascular coronary artery disease.Article, see p 306Exercise hemodynamic and echocardiographic evaluation has significantly advanced our understanding of the diverse hemodynamic alterations that contribute to the symptoms associated with HFpEF. In prior studies, Andersen et al7 and Borlaug et al8 have demonstrated that subjects with HFpEF have preserved right ventricular (RV) systolic and diastolic function at rest with impaired measures of left ventricular (LV) systolic and diastolic function using tissue Doppler echocardiography. During exercise, subjects with HFpEF exhibit a rapid elevation in pulmonary wedge pressure along with an impaired rise in both stroke volume and heart rate. These lead to impaired exercise-induced pulmonary artery (PA) vasodilation resulting in postcapillary as well as precapillary pulmonary hypertension. As a result, the increase in RV afterload depresses RV systolic and diastolic function during exercise. These changes have led to the hypothesis that the abnormal pulmonary vascular response and impaired RV-PA coupling may be a major contributor to exercise intolerance in HFpEF. In support of this, β-adrenergic stimulation with the nonselective β-agonist dobutamine has been demonstrated to improve cardiac output, reduce left atrial pressure, and reduce pulmonary vascular resistance in patients with HFpEF.7In this issue of Circulation Research, Reddy et al9 extend their prior work to test whether β2-adrenergic stimulation with inhaled albuterol can improve pulmonary vascular hemodynamics in HFpEF. In a small proof-of-concept trial in patients with compensated HFpEF (baseline pulmonary capillary wedge pressure 15 to 17 mm Hg), resting and exercise hemodynamics were measured by right heart catheterization. Patients were randomized to receive albuterol or placebo via a high-efficiency nebulizer. The results demonstrate that inhaled albuterol reduced pulmonary vascular resistance during exercise which was the primary end point of the study. Albuterol also significantly reduced systemic vascular resistance and increased cardiac output during exercise through increases in stroke volume without significant changes in heart rate. Despite pulmonary and systemic vasodilation, there was no change in pulmonary capillary wedge pressure at rest or during exercise. In contrast, right atrial pressure decreased and multiple echocardiographic indices of RV systolic function increased reflecting improved RV-PA coupling. Reddy et al9 conclude that albuterol-induced pulmonary vasodilation improves pulmonary vascular reserve primarily through reducing right-sided pressures and improving RV-PA coupling.This is a well-conceived and carefully performed human investigation. Although the authors have clearly demonstrated an improvement in pulmonary hemodynamics with albuterol, there are other potential mechanisms that may be contributing to the favorable hemodynamic response. First, while administered into the pulmonary circulation, inhaled albuterol likely enters the circulation and causes systemic vasodilation. The resulting systemic β2-mediated vasodilation may be important in the integrative response to albuterol because without it, pulmonary vasodilation could cause pulmonary capillary wedge pressure to rise. Second, albuterol may also increase LV contractility. Echocardiographic assessment in the present study was restricted to assessing detailed RV coupling, and LV systolic and diastolic function was not reported. Prior studies have identified a role for β2-mediated inotropic effects in the heart that may increase when β1 signaling is downregulated as in heart failure.10 In addition, studies in normal volunteers have demonstrated that echocardiographic indices of LV function increase after inhaled albuterol.11 Although the improved systolic function could reflect a β2-mediated inotropic effect and reduction in afterload because of systemic vasodilation, a more recent study has demonstrated modest increases in circulating norepinephrine in conjunction with increased cardiac output which could reflect β1 mediated inotropic effects.12 Thus, improved LV contractility may also contribute to the overall effects of albuterol in HFpEF.The findings on the favorable effects of β2 stimulation on hemodynamics also have some theoretical ramifications on the use of β antagonists in HFpEF. Many patients with HFpEF are empirically placed on β blockers or receive them for other indications like atrial fibrillation, hypertension, or angina. Some studies have demonstrated a deterioration in exercise performance after β blockers which could reflect a blunted heart rate response to exercise. Although speculative, nonselective β antagonists, such as carvedilol, could also negatively impact pulmonary vasodilation and exacerbate PA-RV coupling in HFpEF.The present study provides data to support a promising new approach to treat a common disorder with little other evidence-based pharmacological therapies available. That said, it is a proof-of-concept study designed to assess exercise hemodynamics at a fixed workload rather than determine whether albuterol improves exercise capacity or reduces symptoms. Unfortunately, it is unclear whether demonstrating short-term hemodynamic benefits is a surrogate of reduced symptoms with longer-term therapy in HFpEF. A few prior interventions focused on improving hemodynamics in HFpEF, and their subsequent impact on clinical outcomes are summarized in the Table. Sildenafil was initially found to produce prominent reductions in right-sided pressures, as well as pulmonary capillary wedge pressure.13 Unfortunately, the subsequent RELAX trial (Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial)4 evaluating functional outcomes after sildenafil did not demonstrate any effects on exercise capacity, symptoms, or composite end points. More recently, nitrite therapy demonstrated promising hemodynamic effects with reductions in exercise pulmonary capillary wedge pressure, as well as right-sided filling pressures.14 Nevertheless, short-term improvement in exercise hemodynamics were not associated with long-term improvement in symptoms or exercise capacity in the INDIE-HFpEF trial (Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial).6Table. Hemodynamic Effects of HFpEF Therapies vs Impact on Functional CapacityTreatmentRight Heart HemodynamicsSystemic HemodynamicsChronic Functional CapacityPCWPPA systolicRAPVRCOSVRPeak Vo2Clinical BenefitSildenafil (rest)4,13DecreaseDecreaseDecreaseDecreaseIncreaseIncreaseNo effectNo effectInhaled nitrite (exercise)6,14DecreaseNo effectDecreaseNo effectNo effectNo effectNo effectNo effectInhaled albuterol (exercise)9No effectDecreaseDecreaseDecreaseIncreaseDecrease??CO indicates cardiac output; HFpEF, heart failure with a preserved ejection fraction; PA systolic, pulmonary artery systolic pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RA, right atrial pressure; and SVR, systemic vascular resistance.Whether inhaled albuterol will effect an improvement in symptoms and functional capacity remains to be answered. Although it has a favorable effect on RV-PA coupling and increases cardiac output in patients with HFpEF, an important consideration is whether exercise capacity in HFpEF can improve without a reduction in pulmonary capillary wedge pressure. Future clinical studies using inhaled albuterol (or long-acting inhaled β2 agonists like salmeterol or formoterol) along with objective functional testing after short-term, as well as chronic administration, will be required to address this. The carefully performed human physiological study of Reddy et al9 provides a sound basis to advance this new approach to clinical trials and bolster our therapeutic armamentarium for a disease where we have had a paucity of successes.AcknowledgmentsSupported by the National Heart Lung and Blood Institute (HL-61610, HL-130266), the National Center for Advancing Translational Sciences (UL1TR001412), the Department of Veterans Affairs (1IO1BX002659), The Mae Stone Good Trust, and the Albert and Elizabeth Rekate Fund in Cardiovascular Medicine.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to John M. Canty Jr, MD, Jacobs School of Medicine and Biomedical Sciences, Clinical and Translational Research Center, University at Buffalo, Suite 7030, 875 Ellicott St, Buffalo, NY 14203. Email [email protected]edu