Design of the β3-Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure Trial

Abstract

Combined pre-and post-capillary hypertension (CpcPH) is a relatively common complication of heart failure (HF) associated with a poor prognosis. Currently, there is no specific therapy approved for this entity. Recently, treatment with beta-3 adrenergic receptor (β3AR) agonists was able to improve pulmonary hemodynamics and right ventricular (RV) performance in a translational, large animal model of chronic PH. The authors present the design of a phase II randomized clinical trial that tests the benefits of mirabegron (a clinically available β3AR agonist) in patients with CpcPH due to HF. The effect of β3AR treatment will be evaluated on pulmonary hemodynamics, as well as clinical, biochemical, and advanced cardiac imaging parameters. (Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure [SPHERE-HF]; NCT02775539).

Keywords: CCT, cardiac computed tomography; CMR, cardiac magnetic resonance; CpcPH, combined pre- and post-capillary pulmonary hypertension; ECG, electrocardiography; HF, heart failure; ITT, intention to treat; IpcPH, isolated post-capillary pulmonary hypertension; LHD, left heart disease; LV, left ventricular; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NYHA, New York Heart Association; PAP, pulmonary artery pressure; PH, pulmonary hypertension; PP, Per protocol; PVR, pulmonary vascular resistance; RV, right ventricle; adrenoreceptors; cGMP, cyclic guanosine monophosphate; imaging; pulmonary hypertension; treatment; β3AR, beta-3 adrenoreceptor.

Graphical abstract

Figure 1

Summary of the Study Conduct

Figure 2

Multimodality Imaging Evaluation of RV Performance in SPHERE-HF Trial (A) Right ventricular (RV) speckle tracking−derived strain from an apical 4-chamber view on echocardiography. (B and C) End-diastolic and end-systolic frames from the cine sequence at the mid-ventricular level to calculate biventricular volumes and ejection fraction with cardiac magnetic resonance (CMR). (D and E) T1 maps before (D) and 15 min after contrast administration (E) for estimation of extracellular volume using CMR. (F and G) Cardiac computed tomographic images from end-diastolic and end-systolic frames to calculate biventricular volumes and ejection fraction in a patient who could not undergo CMR due to an implantable cardiac resynchronization therapy device. SPHERE-HF = β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure.