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Shorter survival in familial versus idiopathic pulmonary arterial hypertension is associated with hemodynamic markers of impaired right ventricular function.

ABSTRACT: Abstract Although individuals with familial pulmonary arterial hypertension (FPAH) have more severe hemodynamics, compared to individuals with idiopathic PAH (IPAH), it is unclear whether this translates into a survival difference. The influence of right ventricular (RV) function on survival in these groups is also unknown. We reviewed hemodynamic data and health information from a prospective institutional database of 57 FPAH and 66 IPAH patients registered with the Vanderbilt Pulmonary Hypertension Research Cohort. We compared hemodynamics at the time of diagnosis between the two groups and calculated pulmonary arteriolar capacitance (PC) and RV stroke work index (RVSWI). Using survival analysis, we compared freedom from a 5-year composite of death or lung transplantation in FPAH and IPAH patients. The composite outcome of death or transplant at 5 years from diagnosis was significantly increased in FPAH (log rank [Formula: see text]). PC and RVSWI were significantly decreased in FPAH, compared to IPAH ([Formula: see text] for both). In univariate analysis, PC (odds ratio [OR]: 0.17 [95% confidence interval (95% CI): 0.03-0.83]) and RVSWI (OR: 0.86 [95% CI: 0.77-0.95]) were predictors of mortality, as were cardiac index (OR: 0.17 [95% CI: 0.06-0.51]) and PVR (OR: 1.1 [95% CI: 1.01-1.12]). Among FPAH patients, RVSWI was lower in those who died or received a transplant than in survivors ([Formula: see text]), while PC was not ([Formula: see text]). We found significantly worse event-free survival and significantly lower PC and RVSWI in FPAH than in IPAH. In FPAH patients who died or underwent transplantation, RVSWI was lower than that in survivors, suggesting disproportionate RV dysfunction.

SUBMITTER: Brittain EL

PROVIDER: S-EPMC4070798 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

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Project description:RationalePatients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) continue to have an unacceptably high mortality rate despite the progress achieved with pulmonary arterial vasodilator therapies.ObjectivesWe sought to determine whether SSc-PAH is a clinically distinct pulmonary vascular disease phenotype when compared with idiopathic pulmonary arterial hypertension (IPAH) on the basis of progression of echocardiographic right ventricular (RV) dysfunction.MethodsRetrospective analysis of echocardiographic data in 13 patients with SSc-PAH and 11 patients with IPAH was used to delineate the progression of RV dysfunction during single or combination pulmonary arterial vasodilator therapy. All patients had right heart catheterization-confirmed pulmonary arterial hypertension as well as complete baseline (at the time of diagnosis) and follow-up (most recent) echocardiograms. We excluded patients with significant scleroderma-associated interstitial lung disease. Adjusting for time of follow-up and disease duration, we performed mixed model regression analyses comparing the changes between the two groups for different echocardiographic variables: tricuspid annular plane systolic excursion, tricuspid regurgitation jet velocity, right atrial area, and RV diameter.ResultsThe mean ages for the SSc-PAH and IPAH groups were 60.8 and 48.2 years, respectively. The mean follow-up periods for the two groups were 3.8 and 1.95 years, respectively. Tricuspid annular plane systolic excursion did not improve in patients with SSc-PAH, whereas it increased in the patients with IPAH (-0.38 mm, P?=?0.87; vs. +5.6 mm, P?=?0.02). The other echocardiographic variables showed a trend toward worsening in the SSc-PAH group and improvement in the IPAH group.ConclusionsOur results indicate that, in patients with SSc-PAH, echocardiographic RV function does not improve over time compared with that of patients with IPAH, despite institution of pulmonary artery vasodilator therapies.

Project description:BackgroundPatients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function.MethodsCardiac myocytes were isolated from RV septal endomyocardial biopsies from patients with SSc-PAH, IPAH, or SSc with exertional dyspnea but no resting PAH (SSc-d); control RV septal tissue was obtained from nondiseased donor hearts (6-7 per group). Isolated myocyte passive length-tension and developed tension-calcium relationships were determined and correlated with in vivo RV function and reserve. RV septal fibrosis was also examined.ResultsMyocyte passive stiffness from length-tension relations was similarly increased in IPAH and SSc-PAH compared with control, although SSc-PAH biopsies had more interstitial fibrosis. More striking disparities were found between active force-calcium relations. Compared with controls, maximal calcium-activated force (Fmax) was 28% higher in IPAH but 37% lower in SSc-PAH. Fmax in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC50) was similar between control, IPAH, and SSc-d but lower in SSc-PAH. This disparity disappeared in myocytes incubated with the active catalytic subunit of protein kinase A. Myocyte Fmax directly correlated with in vivo RV contractility assessed by end-systolic elastance (R2 =0.46, P=0.002) and change in end-systolic elastance with exercise (R2 =0.49, P=0.008) and was inversely related with exercise-induced chamber dilation (R2 =0.63, P<0.002), which also was a marker of depressed contractile reserve.ConclusionsA primary defect in human SSc-PAH resides in depressed sarcomere function, whereas this is enhanced in IPAH. These disparities correlate with in vivo RV contractility and contractile reserve and are consistent with worse clinical outcomes in SSc-PAH. The existence of sarcomere disease before the development of resting PAH in patients with SSc-d suggests that earlier identification and intervention may prove useful.

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Shorter survival in familial versus idiopathic pulmonary arterial hypertension is associated with hemodynamic markers of impaired right ventricular function.

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