Frantz, Robert P.

AbstractIntroductionTricuspid valve regurgitation (TR) is a frequent finding in patients with pulmonary arterial hypertension (PAH). However, its prognostic significance and relation to PAH, while suspected, are poorly understood. We assessed 727 consecutive patients with newly diagnosed PAH who underwent transthoracic echocardiographic evaluation of tricuspid valve function.ObjectivesThe study objective was to determine the association of TR presence and severity with patient characteristics, pulmonary artery hemodynamics and outcome.MethodsConsecutive patients with newly diagnosed PAH (N = 727 with group 1 pulmonary hypertension) underwent transthoracic echocardiographic evaluation of tricuspid valve function at diagnosis. The primary study end point was all‐cause mortality or lung transplantation.ResultsIn this population, 702 patients (96.5%) had TR; in 165 patients (23%), TR was severe. Compared with those with no or mild TR by echocardiography criteria, patients with severe TR had shorter mean (SD) 6‐minute walk distances (285 [125] m vs 360 [121] m; P = .02) and higher levels of B‐type natriuretic peptide (695 [672] pg/dL vs 328 [300] pg/dL; P < .05). Severe TR was associated with greater right atrial dilatation (91% vs 47%; P = .004) and right ventricular (RV) dilatation (92% vs 51%; P = .008), greater right atrial pressure (mean [SD] 15 [7] mm Hg vs 10 [6] mm Hg; P < .001) and lower cardiac index (mean [SD], 2.2 [0.7] L/min/m2 vs 2.8 [0.9] L/min/m2; P < .001). Severe TR was strongly predictive of greater 5‐year mortality risk after adjustment for age, sex, functional class, 6‐minute walk distance, diffusing capacity, RV size and pulmonary vascular resistance index (adjusted hazard ratio, 1.83; 95% CI, 1.38‐2.41; P < .001).ConclusionsSevere TR was a significant predictor of long‐term mortality rate in PAH, and TR severity correlated with PAH severity.

Background Pulmonary arterial pressure (PAP) varies considerably in heart failure (HF) despite similar degrees of left ventricular (LV) dysfunction. Bradykinin alters vascular tone and common variations in the kinin B2 receptor (BDKRB2) gene exists. We hypothesized that genetic variation in this receptor would influence PAP in HF. Methods 131 HF patients (>1yr history systolic HF), without COPD, not currently smoking, BMI < 40, without atrial fibrillation completed the study which included a blood draw for genotyping and neurohormones (ACE, A-II, Bradykinin, ANP, BNP, and catecholamines), an echocardiogram for cardiac function and systolic PAP (PAPsys). Results Mean LVEF was 29% ∓ 12%, NYHA class 2 ∓ 1, age 56 ∓ 12 yr, BMI 28 ∓ 5 kg/m 2 . Forty-six patients (35%) were homozygous for the +9 allele, 58 (44%) were heterozygous (+9/-9) and 27 (21%) were homozygous for the -9 allele of the BDKRB2. PAPsys averaged 42 ∓ 13, 38 ∓ 12, and 35 ∓ 11 mmHg for +9/+9, +9/-9 and -9/-9, respectively (p = 0.03). There was a trend towards gene effect for plasma ACE with the highest values in +9/+9 and lowest in -9/-9 patients (9.5 ∓ 10.7, 7.1 ∓ 8.7, and 5.4 ∓ 6.4 U/L, respectively, p = 0.06). There were no differences in plasma bradykinin or A-II, LVEF, or NYHA across genotypes. Conclusion These data suggest the +9/+9 polymorphism of the BDKRB2 receptor influences pulmonary vascular tone in stable HF.

Introduction Submaximal exercise gas exchange may be a useful tool to track responses to therapy in pulmonary arterial hypertension (PAH) patients. Methods Three patients diagnosed with idiopathic PAH, on differing therapies, were included. Standard clinical tests (echocardiography; 6 minute walk) were performed pre and 3-5 months after treatment. Gas exchange was measured during 3 minutes of step exercise at both time points. Results Gas exchange variables, end tidal CO 2 (P ET CO 2 ) and the ratio of ventilation to CO 2 production (V E /VCO 2 ), during submaximal exercise were able to track patient responses to therapy over a 3-5 month period. Two patients demonstrated positive improvements, with an increased P ET CO 2 and decreased V E /VCO 2 during light exercise, in response to an altered therapeutic regime. The third patient had a worsening of gas exchange (decreased P ET CO 2 and increased V E /VCO 2 ) following no changes in the medical regime from the baseline visit. Conclusion Gas exchange variables measured during light submaximal exercise, such as P ET CO 2 and V E /VCO 2 , may be able to better detect small changes in functional status following treatment and could, therefore, be a useful tool to track disease severity in PAH patients. Further study is required to determine the clinical usefulness of these gas exchange variables.

The availability of newer oral agents for therapy of pulmonary arterial hypertension entails both opportunity and uncertainty. There is the opportunity for less intrusive therapy and the potential to further lessen risk of disease progression, but there is also uncertainty regarding optimal role of these agents, concern about their expense, and risk of preventable deterioration if these agents are used in settings that clearly warrant parenteral prostanoids. Among the newer agents, the evidence is strongest for the use of the prostacyclin receptor agonist selexipag, which has been shown to reduce events in functional class II and III patients, even in the setting of background therapy with a phosphodiesterase type 5 (PDE5) inhibitor and an endothelin receptor antagonist. Riociguat is a soluble guanylate cyclase stimulator that has been shown to be beneficial, including in combination with an endothelin receptor antagonist, and may be a useful alternative to a PDE5 inhibitor in properly selected patients. It has also been shown to be beneficial in inoperable or residual thromboembolic pulmonary hypertension. Oral treprostinil has been shown to improve 6-minute walk distance as monotherapy, and has been used to transition from inhaled or parenteral treprostinil in carefully selected patients also on other agents. Herein we discuss the mechanisms of action, side effect profiles, and clinical trial data for these agents, followed by a practical approach to their use, integrating the available data with real-world experience.

Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when pulmonary emboli fail to resolve with anticoagulation. For patients with inoperable or residual CTEPH, riociguat is currently the only therapy approved by the United States Food and Drug Administration. However, some patients with CTEPH may require therapy beyond riociguat, such as intravenous prostacyclins, which can present significant administration challenges in patients with complex comorbid conditions. We describe a 42‐year‐old man with T12 paraplegia complicated by CTEPH (functional class IV with substantial right ventricular dysfunction) and severe pressure ulcers. In order to facilitate goals of care (hospital discharge to a skilled nursing facility where parenteral prostanoids could not be administered), he underwent rapid transition from intravenous treprostinil to oral selexipag in the form of a cross‐taper over 6 days. The patient required readmission due to worsening symptoms and was transitioned back to intravenous treprostinil; he tolerated conversion to oral treprostinil for approximately 4 months, but it was subsequently discontinued due to nausea and modified goals of care. The patient underwent transition to hospice care 3 months later and eventually died from clinical deterioration. To our knowledge, this is the first report to describe transition from intravenous treprostinil to selexipag as well as conversion from parenteral treprostinil to oral treprostinil in a patient with CTEPH and illustrates the approaches to and potential issues with prostanoid transitions. Additional observations are necessary to better understand the relative roles of selexipag and oral treprostinil regarding comparative efficacy and tolerability.

Abstract The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics” (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.

Renal function improves early after left ventricular assist device (LVAD) implantation but later decline has been observed. We sought to determine the occurrence and evaluate possible causes for this decline. In 62 consecutive patients with HeartMateII LVAD with available calculated glomerular filtration rate (GFR, ml/min/1.73 m2) 1 year after implant, GFR was assessed repeatedly and possible predictors for decline from 3 to 12 months were investigated. Post-mortem renal specimens for patients supported with an LVAD were evaluated. GFR 54.5 ± 19.5 at admission increased to 66.4 ± 22.3 preoperatively and to 79.2 ± 30.1 ~1 month after implantation. Subsequently at ~3 months GFR declined to 74.7 ± 25.4, at ~6 months to 68.8 ± 23.1, and ~1 year after implant to 63.9 ± 17.7. Glomerular filtration rate at 1 year was significantly lower (p < 0.0001, p < 0.0001, p = 0.005) than GFR 1, 3, and 6 months after implant. Early rise in GFR after surgery was not associated with late decline. Shorter bypass time (β = −0.09, p = 0.048) and higher albumin 3 months after LVAD (β = 14.4, p = 0.025) were significantly associated with less later decline in GFR. Arteriosclerosis was identified in autopsy renal specimens. In conclusion, early gains in renal function after LVAD implant are not sustained in many patients. Patient, device, and operative factors may influence long-term renal function in these patients.