Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.

Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 µg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.

Pulmonary Hypertension Association's 2022 International Conference Scientific Sessions Overview.

The considerable progress made in recent years in the diagnosis, risk stratification, and treatment of pulmonary hypertension was highlighted during the most recent edition of the Pulmonary Hypertension Association Scientific Sessions, which was held in Atlanta, Georgia from June 9 to 11, 2022, with the theme: Vision for the PHuture: The Evolving Science and Management of PH. Content presented over the 3-day conference focused on scientific and management updates since the last sessions were held in 2018 and included didactic talks, debates, and roundtable discussions across a broad spectrum of topics related to pulmonary hypertension. This article aims to summarize the key messages from each of the session talks.

l-Carnitine therapy improves right heart dysfunction through Cpt1-dependent fatty acid oxidation.

Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that decreased fatty acid oxidation and increased lipid accumulation in the failing RV is driven, in part, by a relative carnitine deficiency. We then tested whether supplementation of l-carnitine can reverse lipotoxic RV failure through augmentation of fatty acid oxidation. In vivo in transgenic mice harboring a human BMPR2 mutation, l-carnitine supplementation reversed RV failure by increasing RV cardiac output, improving RV ejection fraction, and decreasing RV lipid accumulation through increased PPARγ expression and augmented fatty acid oxidation of long chain fatty acids. These findings were confirmed in a second model of pulmonary artery banding-induced RV dysfunction. In vitro, l-carnitine supplementation selectively increased fatty acid oxidation in mitochondria and decreased lipid accumulation through a Cpt1-dependent pathway. l-Carnitine supplementation improves right ventricular contractility in the stressed RV through augmentation of fatty acid oxidation and decreases lipid accumulation. Correction of carnitine deficiency through l-carnitine supplementation in PAH may reverse RV failure.

Echocardiographic Assessment of Right Ventricular Function and Response to Therapy in Pulmonary Arterial Hypertension.

Echocardiography is a key tool in the management of patients with pulmonary arterial hypertension (PAH), but many potential parameters could be used to assess response to therapy. In this retrospective study of 48 patients with severe PAH at baseline, we examined echocardiographic variables before and after initiation of PAH-specific therapy to evaluate which measures of right ventricular (RV) function best correlated with clinical response to therapy as assessed by 6-minute walk distance (6MWD) and 3-year all-cause mortality. Tricuspid annular plane systolic excursion (TAPSE), mid-RV and basal-RV diameters, RV systolic pressure, and RV global longitudinal strain were all found to significantly improve after initiation of a PAH therapy. Decreases in right atrial area (r = -0.50, p = 0.002) and mid-RV diameter (r = -0.36, p = 0.03) were most strongly correlated with improvement in 6MWD. Pretreatment values of RA area (hazard ratio [HR] per 1 SD: 2.72; 95% confidence interval [CI] 1.58, 4.69), mid-RV diameter (HR 2.03; 1.20, 3.45), basal-RV diameter (HR 2.27; 1.40, 3.70), and RV global longitudinal strain (HR 2.36; 1.22, 4.56) were all associated with mortality risk. 6MWD and TAPSE were the 2 variables for which pretreatment measures (6MWD - HR 0.35; 0.17, 0.72; TAPSE - HR 0.41; 0.21, 0.82) and change with treatment (6MWD - HR 0.26; 0.10, 0.64; TAPSE - HR 0.40; 0.21, 0.77) were both significantly associated with 3-year mortality. Change in RV systolic pressure with treatment was significantly associated with mortality (HR 2.55; 1.23, 5.28,) but pretreatment baseline had no association (HR 1.48; 0.72, 3.06). Although many echocardiographic parameters change with initiation of PAH treatment, the strong association of both baseline TAPSE and change in TAPSE with mortality supports the ongoing use of TAPSE as an important measure in the assessment of disease severity and treatment response in PAH.

Upper Extremity Pulse Pressure Predicts Amputation-Free Survival after Lower Extremity Bypass.

Increased pulse pressure reflects pathologic arterial stiffening and predicts cardiovascular events and mortality. The effect of pulse pressure on outcomes in lower extremity bypass patients remains unknown. We thus investigated whether preoperative pulse pressure could predict amputation-free survival in patients undergoing lower extremity bypass for atherosclerotic occlusive disease. An institutional database identified 240 included patients undergoing lower extremity bypass from 2005 to 2014. Preoperative demographics, cardiovascular risk factors, operative factors, and systolic and diastolic blood pressures were recorded, and compared between patients with pulse pressures above and below 80 mm Hg. Factors were analyzed in bi- and multivariable models to assess independent predictors of amputation-free survival. Kaplan-Meier analysis was performed to evaluate the temporal effect of pulse pressure ≥80 mm Hg on amputation-free survival. Patients with a pulse pressure ≥80 mm Hg were older, male, and had higher systolic and lower diastolic pressures. Patients with pulse pressure <80 mm Hg demonstrated a survival advantage on Kaplan-Meier analysis at six months (log-rank P = 0.003) and one year (P = 0.005) postoperatively. In multivariable analysis, independent risk factors for decreased amputation-free survival at six months included nonwhite race, tissue loss, infrapopliteal target, and preoperative pulse pressure ≥80 mm Hg (hazard ratio 2.60; P = 0.02), while only tissue loss and pulse pressure ≥80 mm Hg (hazard ratio 2.30, P = 0.02) remained predictive at one year. Increased pulse pressure is independently associated with decreased amputation-free survival in patients undergoing lower extremity bypass. Further efforts to understand the relationship between increased arterial stiffness and poor outcomes in these patients are needed.