Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. OBJECTIVES: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). METHODS: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. MEASUREMENTS AND MAIN RESULTS: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. CONCLUSIONS: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

Do Patients With Low-Risk Pulmonary Arterial Hypertension Really Benefit From Upfront Combination Therapy?: Insight From the AMBITION Trial.

BACKGROUND: Based on results of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, upfront combination therapy is recommended for treatment-naive patients with low-risk pulmonary arterial hypertension (PAH). However, conflicting data exist whether adopting this treatment strategy in this risk group is beneficial or well tolerated. RESEARCH QUESTION: Do patients with low-risk PAH really benefit from upfront combination therapy? STUDY DESIGN AND METHODS: Using the data from the original AMBITION trial, patients with PAH were classified as low, intermediate, or high risk using the Registry to Evaluate Early and Long-term PAH Disease Management 2.0 (REVEAL 2.0) score and the Pulmonary Hypertension Outcomes and Risk Assessment (PHORA) tool. The primary end point was time to clinical worsening (including death, hospitalization for PAH worsening, and disease progression) censored at 1- and 3-year post-enrollment. Side effects that led to withdrawal of treatment were also considered. RESULTS: Patients with low-risk PAH categorized by REVEAL 2.0 and PHORA did not see a statistically significant benefit of upfront combination therapy vs monotherapy for time to clinical worsening at 1 and 3 years' post-enrollment using Cox proportional analysis (3-year hazard ratio of 0.40 [95% CI, 0.15-1.06; P = .07] and 0.55 [95% CI, 0.26-1.18; P = .12] for REVEAL 2.0 and PHORA, respectively) or considering time to clinical worsening or side effects (3-year hazard ratio of 0.75 [95% CI, 0.39-1.47; P = .4] and 0.87 [95% CI, 0.49-1.54; P = .63] for REVEAL 2.0 and PHORA). Patients with low-risk PAH on upfront combination therapy experienced a higher but not significant incidence of side effects using REVEAL 2.0 and PHORA. In contrast, patients at intermediate or high risk saw a statistically significant benefit of upfront combination therapy considering each of the end points regardless of side effects. INTERPRETATION: This analysis suggests that perhaps some patients with low-risk PAH should be further stratified using other modalities prior to committing to upfront combination therapy, especially when the occurrence of side effects is considered. Further prospective data are needed to validate this hypothesis prior to changes in current guideline directed therapy are contemplated.

Integrated use of cardiac MRI and the CardioMEMS™ HF system in PAH: the utility of coincident pressure and volume in RV failure-the NHLBI-VITA trial.

BACKGROUND: This study aims to study the feasibility and safety of measuring volumetric and pressure parameters noninvasively using simultaneous cardiovascular magnetic resonance (cMR) volumetric data and time-resolved pressure waveforms from previously implanted CardioMEMS devices in pulmonary arterial hypertension (PAH) patients. Opportunities to intervene during clinically occult phases in PAH promise to herald a key transformation in our current practice for treating this complex population. Currently, it is possible and convenient to monitor daily pulmonary arterial (PA) pressures in PAH patients using the CardioMEMS device to determine clinically silent progression. Supplementation of these pressures with other prognostic measurements of right ventricular (RV) contractility, PA resistance and RV/PA coupling could add further predictive capabilities. METHODS: PAH patients (n=17) with New York Hospital Association (NYHA) class III or IV heart failure (HF) and recent HF related hospitalizations were implanted with the CardioMEMS device as part of a NHLBI sponsored Trial. Implanted patients were then assessed using cMR imaging of the right ventricle (RV) along with measurement of pulmonary artery flow. Patients were imaged at one-month post implant (baseline) and at 4-month follow-up time (n=12). At baseline, patients were studied at rest and then under three different physiologic conditions: inhaled nitric oxide (INO), dobutamine (Dob) stress and volumetric stress (Vol), using a multiple slice short-axis imaging and a rapid imaging protocol. RESULTS: All patients were safely imaged, with no artifacts obscuring the cMR images. RV volumes were measured successfully at rest and under each stress condition using a reduced scan approach that required calibration for each patient which achieved a correlation r2 of 0.98. Variables measured included the maximal pulmonary artery elastance (Ea), maximal RV myocardial elastance (Emax) and ventricular-vascular coupling ratio (VVC). The response to stressors was determined on a patient basis. No complications occurred during the cMRI examination. CONCLUSIONS: It is safe and feasible to perform cMR imaging with simultaneous pulmonary artery pressure readings from the CardioMEMS device. A reduced scan approach was developed to allowed measurement of RV volumes during stress conditions. Volumetric and pressure measurements can be combined to assess fundamental myocardial properties (e.g., Emax, Ea and VVC) in PAH patients serially over time. In the future, these parameters can be tested as serial predictors of outcome and response to therapies in PAH.

Monitoring Pulmonary Arterial Hypertension Using an Implantable Hemodynamic Sensor.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disease that ultimately progresses to right-sided heart failure (HF) and death. Close monitoring of pulmonary artery pressure (PAP) and right ventricular (RV) function allows clinicians to appropriately guide therapy. However, the burden of commonly used methods to assess RV hemodynamics, such as right heart catheterization, precludes frequent monitoring. The CardioMEMS HF System (Abbott) is an ambulatory implantable hemodynamic monitor, previously only used in patients with New York Heart Association (NYHA) class III HF. In this study, we evaluate the feasibility and early safety of monitoring patients with PAH and right-sided HF using the CardioMEMS HF System. METHODS: The CardioMEMS HF sensors were implanted in 26 patients with PAH with NYHA class III or IV right-sided HF (51.3 ± 18.3 years of age, 92% women, 81% NYHA class III). PAH therapy was tracked using a minimum of weekly reviews of CardioMEMS HF daily hemodynamic measurements. Safety, functional response, and hemodynamic response were tracked up to 4 years with in-clinic follow-ups. RESULTS: The CardioMEMS HF System was safely used to monitor PAH therapy, with no device-related serious adverse events observed and a single preimplant serious adverse event. Significant PAP reduction and cardiac output elevation were observed as early as 1 month postimplant using trends of CardioMEMS HF data, coupled with significant NYHA class and quality of life improvements within 1 year. CONCLUSIONS: The CardioMEMS HF System provided useful information to monitor PAH therapy, and demonstrated short- and long-term safety. Larger clinical trials are needed before its widespread use to guide therapy in patients with severe PAH with right-sided HF.

Hemodynamic response to treatment of iron deficiency anemia in pulmonary arterial hypertension: longitudinal insights from an implantable hemodynamic monitor.

Despite new therapeutic options, pulmonary arterial hypertension (PAH) remains a progressive disease associated with substantial morbidity and mortality. As such, additional strategies for monitoring and adjunctive management of this disease are important. A 59-year-old woman with scleroderma-associated PAH received an implantable hemodynamic monitor (IHM) as part of a research protocol at our institution. Pulmonary artery pressures, heart rate, and cardiac output (sensor-based algorithm) were measured on a daily basis, and parameters of right ventricular (RV) performance and afterload were calculated. At the time of IHM implant, the patient had functional class III symptoms, was receiving triple-drug therapy, and had normal hemoglobin levels. Four months after implant, and with further optimization of prostacyclin therapy, she had improvement in her symptoms. However, shortly thereafter, while the patient was receiving stable drug therapy, her case regressed with worsening symptoms, and the patient received a new diagnosis of iron deficiency anemia. Oral iron supplementation resulted in normalization of hemoglobin levels and improvement in the patient's iron profile. A gradual and sustained reduction in pulmonary pressures was noted after initiation of oral iron accompanied by increased RV performance and favorable reduction in RV afterload. The patient had significant symptomatic improvement. Iron deficiency is an underappreciated yet easily treatable risk factor in PAH. Use of IHM in this case longitudinally illustrates the optimization of pulmonary hemodynamics and RV afterload in tandem with clinical improvement achieved by a simple therapy.