Dataset Information

Differences in Right Ventricular Functional Changes during Treatment between Systemic Sclerosis-associated Pulmonary Arterial Hypertension and Idiopathic Pulmonary Arterial Hypertension.

ABSTRACT:

Rationale

Patients 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.

Objectives

We 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.

Methods

Retrospective 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.

Results

The 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.

Conclusions

Our 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.

SUBMITTER: Argula RG

PROVIDER: S-EPMC5802595 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Differences in Right Ventricular Functional Changes during Treatment between Systemic Sclerosis-associated Pulmonary Arterial Hypertension and Idiopathic Pulmonary Arterial Hypertension.

Argula Rahul G RG Karwa Abhijit A Lauer Abigail A Gregg David D Silver Richard M RM Feghali-Bostwick Carol C Schanpp Lynn M LM Egbert Kim K Usher Bruce W BW Ramakrishnan Viswanathan V Hassoun Paul M PM Strange Charlie C

Annals of the American Thoracic Society 20170501 5

<h4>Rationale</h4>Patients 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.<h4>Objectives</h4>We 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) dysfun ...[more]

PMID: 28282243

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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.

Project description:Right ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca(2+) sensitivity underlie diastolic dysfunction in PAH. This study investigates protein modifications contributing to cellular diastolic dysfunction in PAH.RV samples from PAH patients undergoing heart-lung transplantation were compared to non-failing donors (Don). Titin stiffness contribution to RV diastolic dysfunction was determined by Western-blot analyses using antibodies to protein-kinase-A (PKA), C? (PKC?) and Ca(2+)/calmoduling-dependent-kinase (CamKII?) titin and phospholamban (PLN) phosphorylation sites: N2B (Ser469), PEVK (Ser170 and Ser26), and PLN (Thr17), respectively. PKA and PKC? sites were significantly less phosphorylated in PAH compared with donors (P<0.0001). To test the functional relevance of PKA-, PKC?-, and CamKII?-mediated titin phosphorylation, we measured the stiffness of single RV cardiomyocytes before and after kinase incubation. PKA significantly decreased PAH RV cardiomyocyte diastolic stiffness, PKC? further increased stiffness while CamKII? had no major effect. CamKII? activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca(2+) sensitivity is mediated by sarcomeric troponin I (cTnI) phosphorylation. We observed increased unphosphorylated cTnI in PAH compared with donors (P<0.05) and reduced PKA-mediated cTnI phosphorylation (Ser22/23) (P<0.001). Finally, alterations in Ca(2+)-handling proteins contribute to RV diastolic dysfunction due to insufficient diastolic Ca(2+) clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (P<0.05).Increased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca(2+) handling proteins contribute to RV diastolic dysfunction in PAH.

Dataset Information

Differences in Right Ventricular Functional Changes during Treatment between Systemic Sclerosis-associated Pulmonary Arterial Hypertension and Idiopathic Pulmonary Arterial Hypertension.

Rationale

Objectives

Methods

Results

Conclusions

Publications

Differences in Right Ventricular Functional Changes during Treatment between Systemic Sclerosis-associated Pulmonary Arterial Hypertension and Idiopathic Pulmonary Arterial Hypertension.

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