Micah R. Fisher

Accuracy of Doppler Echocardiography in the Hemodynamic Assessment of Pulmonary Hypertension

RATIONALE Transthoracic Doppler echocardiography is recommended for screening for the presence of pulmonary hypertension (PH). However, some recent studies have suggested that Doppler echocardiographic pulmonary artery pressure estimates may frequently be inaccurate. OBJECTIVES Evaluate the accuracy of Doppler echocardiography for estimating pulmonary artery pressure and cardiac output. METHODS We conducted a prospective study on patients with various forms of PH who underwent comprehensive Doppler echocardiography within 1 hour of a clinically indicated right-heart catheterization to compare noninvasive hemodynamic estimates with invasively measured values. MEASUREMENTS AND MAIN RESULTS A total of 65 patients completed the study protocol. Using Bland-Altman analytic methods, the bias for the echocardiographic estimates of the pulmonary artery systolic pressure was -0.6 mm Hg with 95% limits of agreement ranging from +38.8 to -40.0 mm Hg. Doppler echocardiography was inaccurate (defined as being greater than +/-10 mm Hg of the invasive measurement) in 48% of cases. Overestimation and underestimation of pulmonary artery systolic pressure by Doppler echocardiography occurred with a similar frequency (16 vs. 15 instances, respectively). The magnitude of pressure underestimation was greater than overestimation (-30 +/- 16 vs. +19 +/- 11 mm Hg; P = 0.03); underestimates by Doppler also led more often to misclassification of the severity of the PH. For cardiac output measurement, the bias was -0.1 L/min with 95% limits of agreement ranging from +2.2 to -2.4 L/min. CONCLUSIONS Doppler echocardiography may frequently be inaccurate in estimating pulmonary artery pressure and cardiac output in patients being evaluated for PH.

Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension

Combination therapy has been recommended for the treatment of pulmonary arterial hypertension (PAH). However, there is scant information on combination therapy after failure of monotherapy, particularly in patients with scleroderma-associated PAH (PAH-SSD). From a group of 82 consecutive patients with PAH who received initial bosentan monotherapy, a total of 13 idiopathic PAH (IPAH) and 12 PAH-SSD patients requiring additional therapy with sildenafil were studied. Sildenafil was added for clinical deterioration based upon symptoms, New York Heart Association (NYHA) classification or 6-min walk distance (6MWD). Clinical data and haemodynamics were collected at baseline. Assessments were made at 1–3-month intervals. At baseline, there were no differences in demographics, NYHA classification, haemodynamics or 6MWD between the two groups. After initiation of bosentan, both groups experienced clinical improvement but ultimately deteriorated (median time to monotherapy failure 792 versus 458 days for IPAH and PAH-SSD patients, respectively). After addition of sildenafil, more IPAH patients tended to improve in NYHA class (five out of 13 versus two out of 12) and walked further (mean difference in 6MWD 47±77 m versus -7±40 m) compared with PAH-SSD patients. In conclusion, addition of sildenafil after bosentan monotherapy failure improved New York Heart Association class and 6-min walk distance in idiopathic pulmonary arterial hypertension patients but failed to improve either parameter in scleroderma-associated pulmonary arterial hypertension patients. Additional studies are needed to assess the tolerability and efficacy of this combination in patients with scleroderma-associated pulmonary arterial hypertension.

Hyponatremia Predicts Right Heart Failure and Poor Survival in Pulmonary Arterial Hypertension

RATIONALE Hyponatremia is associated with decompensated heart failure and poor prognosis in patients with left ventricular systolic dysfunction. OBJECTIVES We sought to determine if hyponatremia is associated with right heart failure and worse prognosis in patients with pulmonary arterial hypertension (PAH). METHODS We prospectively followed 40 patients with PAH and examined the relationship between serum sodium and right heart function as well as survival. MEASUREMENTS AND MAIN RESULTS Subjects with hyponatremia (Na < or = 136 mEq/L) were more symptomatic (11/13 World Health Organization [WHO] class III/IV vs. 12/27 WHO class III/IV; P = 0.02), had more peripheral edema (69 vs. 26%; P = 0.009), and had higher hospitalization rates (85 vs. 41%; P = 0.009) than normonatremic subjects. Hyponatremic subjects had higher right atrial pressure (14 +/- 6 vs. 9 +/- 3 mm Hg; P < 0.001), lower stroke volume index (21 +/- 7 vs. 32 +/- 10 ml/m(2); P < 0.01), larger right ventricular:left ventricular area ratio (1.8 +/- 0.4 vs. 1.3 +/- 0.4; P < 0.001), and lower tricuspid annular plane systolic excursion (1.4 +/- 0.3 vs. 2.0 +/- 0.6 cm; P = 0.001), despite similar mean pulmonary artery pressure (49 +/- 10 vs. 47 +/- 12 mm Hg; P = 0.60). The 1- and 2-year survival estimates were 93% (95% confidence interval [CI], 73-98%) and 85% (95% CI, 65-94%), and 38% (95% CI, 14-63%) and 15% (95% CI, 2-39%) for normonatremic and hyponatremic subjects, respectively (log-rank chi(2) = 25.19, P < 0.001). The unadjusted risk of death (hazard ratio) in hyponatremic compared with normonatremic subjects was 10.16 (95% CI, 3.42-30.10, P < 0.001). Hyponatremia predicted outcome after adjusting for WHO class, diuretic use, as well as right atrial pressure and cardiac index. CONCLUSIONS Hyponatremia is strongly associated with right heart failure and poor survival in PAH.

Tricuspid Annular Plane Systolic Excursion Is a Robust Outcome Measure in Systemic Sclerosis-associated Pulmonary Arterial Hypertension

Objective. The tricuspid annular plane systolic excursion (TAPSE) strongly reflects right ventricular (RV) function and predicts survival in idiopathic pulmonary arterial hypertension (PAH). But its role in systemic sclerosis (SSc)-associated PAH has not been established. Our objective was to validate the TAPSE in the assessment of RV function and prediction of survival in SSc-PAH. Methods. Fifty consecutive patients with SSc-PAH who underwent echocardiography with TAPSE measurement within 1 h of clinically indicated right heart catheterization were followed prospectively. The relationship between TAPSE and measures of RV function and measures of survival was assessed. Results. The majority of the cohort were women in New York Heart Association class III/IV with severe PAH (mean cardiac index 2.4 ± 0.8 l/min/m2). RV function was significantly impaired (mean cardiac index 2.1 ± 0.7 vs 2.9 ± 0.8 l/min/m2; p < 0.01) and RV afterload was significantly greater (mean pulmonary vascular resistance 11.1 ± 5.1 vs 5.8 ± 2.5 Wood units; p < 0.01) in subjects with a TAPSE ≤ 1.7 cm. The proportion surviving in the low TAPSE group was significantly lower [0.56 (95% CI 0.37–0.71) and 0.46 (95% CI 0.28–0.62) vs 0.87 (95% CI 0.55–0.96) and 0.79 (95% CI 0.49–0.93), 1- and 2-year survival, respectively]. TAPSE ≤ 1.7 cm conferred a nearly 4-fold increased risk of death (HR 3.81, 95% CI 1.31–11.1, p < 0.01). Conclusion. TAPSE is a robust measure of RV function and strongly predicts survival in patients with PAH-SSc. Future studies are needed to identify the responsiveness of TAPSE to PAH-specific therapy and to assess its diagnostic utility in PAH-SSc.

SAFETY AND TOLERABILITY OF TRANSITION FROM INHALED TREPROSTINIL TO ORAL SELEXIPAG IN PULMONARY ARTERIAL HYPERTENSION: RESULTS FROM THE TRANSIT-1 STUDY

BACKGROUND A long-term trial showed that the oral prostacyclin (PGl2) receptor (IP) agonist, selexipag, delayed disease progression in patients with pulmonary arterial hypertension (PAH). Transition to selexipag in patients treated with more burdensome inhaled therapies that target the prostacyclin pathway may be considered by patients and physicians. The Phase 3b, prospective, open-label TRANSIT-1 (Tolerability and Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Patients With Pulmonary Arterial Hypertension) study evaluated the safety and tolerability of transition from inhaled treprostinil to oral selexipag. METHODS Patients receiving non-prostanoid oral PAH therapy and inhaled treprostinil at stable doses, in World Health Organization Functional Class II/III, with 6-minute walk distance ≥ 300 meters were enrolled. The 16-week main treatment period included downtitration of inhaled treprostinil over 8 weeks and parallel uptitration of selexipag over 12 weeks. Sustained treatment transition at Week 16 was defined as (1) receiving selexipag at Week 16; (2) no selexipag interruption(s) totaling ≥ 8 days; and (3) no inhaled treprostinil or other prostanoids after Week 8. Clinical parameters and patient-reported treatment satisfaction outcomes were assessed at Week 16. RESULTS All 34 enrolled patients completed the study. At Week 16, 32 patients (94.1%) had stopped inhaled treprostinil and were receiving selexipag. Twenty-eight patients (82.4%) met all criteria for sustained treatment transition. During the study, 3 patients discontinued selexipag due to adverse events. Overall, most adverse events were typical of prostanoid therapies and started during the uptitration phase. In general, patients remained clinically stable throughout treatment and reported improved convenience. CONCLUSIONS Transition to oral selexipag from inhaled treprostinil in PAH patients was successful and well tolerated in most patients, and associated with greater convenience. CLINICAL TRIAL NUMBER NCT02471183.

Chronic Thromboembolic Pulmonary Hypertension: Advances in Therapy

&NA; Chronic thromboembolic pulmonary hypertension is a progressive disease characterized by obstruction of the pulmonary vascular bed by insufficient resolution of thromboemboli leading to increased pulmonary vascular resistance with resultant right heart dysfunction and poor long‐term survival. Estimates of cumulative incidence after an acute pulmonary embolism range from 1 to 4% within 2 years of an initial event. Current recommendations focus on screening patients being evaluated for pulmonary hypertension with ventilation/perfusion scans and then considering them for potentially curative surgery consisting of a pulmonary endarterectomy. Outcomes at high‐volume surgical centers continue to improve and overall perioperative mortality is close to 2 to 4% with excellent reported long‐term survival. Unfortunately, adherence with guidelines remains poor and patients with this potentially remediable disease are being missed. In addition, a significant number of patients who are diagnosed are not felt to be operative candidates based on location of disease, hemodynamics, or comorbidities. Several new advances may improve outcomes for such patients who are not operative candidates or who have persistent pulmonary hypertension after surgery, including medical therapy and balloon pulmonary angioplasty. Further studies are needed to answer questions about how best to incorporate these advances into our overall treatment algorithm.