TAPSE powerfully reflects RV function and prognosis in PAH.

Background Right ventricular (RV) failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (RPA) and compliance (CPA) are consistently and inversely related regardless of age, pulmonary hypertension (PH), or interstitial fibrosis, and that this relation may be changed by elevated pulmonary capillary wedge pressure (PCWP), augmenting RV pulsatile load. Methods and Results Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the RPA-CPA relationship with PH, pulmonary fibrosis, patient age, and varying PCWP. Patients with suspected or documented PH (n=1009) and normal PCWP displayed a consistent RPA-CPA hyperbolic (inverse) dependence; CPA=0.564/(0.047+RPA), with a near constant resistance-compliance product (RC) (0.48±0.17 seconds). In the same patients, the systemic RC was highly variable. Severe pulmonary fibrosis (n=89) did not change the RPA-CPA relation. Increasing patient age led to a very small though statistically significant change in the relation. However, elevation of the PCWP (n=8142) had a larger impact, significantly lowering CPA for any RPA, and negatively correlating RC (p<0.0001). Conclusions PH and pulmonary fibrosis do not significantly change the hyperbolic dependence between RPA and CPA, while patient age has only minimal affects. This fixed relationship helps explain the difficulty of reducing total RV afterload by therapies that have modest impact on mean RPA. Higher PCWP appears to enhance net RV afterload by elevating pulsatile, relative to resistive load, and may contribute to RV dysfunction.

Objective. Pulmonary arterial hypertension related to scleroderma (PAH-Scl) is associated with high morbidity and mortality as well as poorer response to therapy and worse outcomes compared with the idiopathic form of PAH (IPAH). Scleroderma is an autoimmune disease that can affect left and right heart function directly through inflammation and fibrosis and indirectly through systemic and pulmonary hypertension. This study tested the hypothesis that an increased prevalence of left heart disease might explain the higher mortality in patients with PAH-Scl compared with patients with IPAH.Methods. The study was designed as a retrospective cohort study comparing the baseline clinical data from 91 consecutive patients (41 with IPAH and 50 with PAH-Scl). Cox proportional hazards models were used to predict the effect of clinical covariates on patient survival.Results. Patients with PAH-Scl had a lower mean pulmonary artery pressure (46.6 mm Hg versus 54.4 mm Hg in patients with IPAH; P ‫؍‬ 0.002) despite similar levels of cardiac dysfunction (cardiac index 2.2 and 2.1 liters/minute/m 2 , respectively; P ‫؍‬ 0.19). Echocardiography revealed similar degrees of right ventricular dysfunction in the 2 groups, whereas a predominance of left heart dysfunction was observed in patients with PAH-Scl. One-and three-year survival estimates were 87.8% and 48.9%, respectively, in patients with PAH-Scl and 95.1% and 83.6%, respectively, in those with IPAH. Patients with PAH-Scl were 3.06 times more likely to die than were patients with IPAH, after controlling for the presence of pericardial effusion; there was no significant change in increased risk of death in PAH-Scl after controlling for left heart disease.Conclusion. The results confirm that there are significant clinical and survival differences between IPAH and PAH-Scl. The presence of left heart disease, although more common in PAH-Scl, was not predictive of the higher mortality in these patients.

This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.

Background Systemic sclerosis associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared to idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often due to right ventricular (RV) failure. We tested if SScPAH or systemic sclerosis related pulmonary hypertension with interstitial lung disease (SSc-ILD-PH) imposes a greater pulmonary vascular load than IPAH and/or leads to worse RV contractile function. Methods and Results We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 SSc-ILD-PH, 67 IPAH). An inverse relation between pulmonary resistance (RPA) and compliance (CPA) was similar for all three groups, with a near constant resistance × compliance product. RV pressure-volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7) as well as SSc without PH (SSc-no-PH, n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of right ventricular load (arterial elastance [Ea]), and RV-pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (RPA=7.0±4.5 vs. 7.9±4.3 Wood units; Ea=0.9±0.4 vs. 1.2±0.5 mmHg/mL; CPA=2.4±1.5 vs. 1.7±1.1 mL/mmHg; p>0.3 for each). Though SScPAH did not have greater vascular stiffening compared to IPAH, RV contractility was more depressed (Ees=0.8±0.3 vs. 2.3±1.1, p<0.01; Msw=21±11 vs. 45±16, p=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0±0.5 vs. 2.1±1.0, p=.03). This ratio was higher in SSc-no-PH (Ees/Ea = 2.3±1.2, p=0.02 vs. SScPAH). Conclusions RV dysfunction is worse in SScPAH compared to IPAH at similar afterload, and may be due to intrinsic systolic function rather than enhanced pulmonary vascular resistive and/or pulsatile loading.

The lung is a common site of complications of systemic connective tissue disease (CTD), and lung involvement can present in several ways. Interstitial lung disease (ILD) and pulmonary hypertension are the most common lung manifestations in CTD. Although it is generally thought that interstitial lung disease develops later on in CTD it is often the initial presentation ("lung dominant" CTD). ILD can be present in most types of CTD, including rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD associated ILD (CTD-ILD) can differ greatly from that of other forms of ILD, such as idiopathic pulmonary fibrosis. Pulmonary hypertension (PH) can present as a primary vasculopathy in pulmonary arterial hypertension or in association with ILD (PH-ILD). Therefore, detailed history, physical examination, targeted serologic testing, and, occasionally, lung biopsy are needed to diagnose CTD-ILD, whereas both non-invasive and invasive assessments of pulmonary hemodynamics are needed to diagnose pulmonary hypertension. Immunosuppression is the mainstay of treatment for ILD, although data from randomized controlled trials (RCTs) to support specific treatments are lacking. Furthermore, treatment strategies vary according to the clinical situation-for example, the treatment of a patient newly diagnosed as having CTD-ILD differs from that of someone with an acute exacerbation of the disease. Immunosuppression is indicated only in select cases of pulmonary arterial hypertension related to CTD; more commonly, selective pulmonary vasodilators are used. For both diseases, comorbidities such as sleep disordered breathing, symptoms of dyspnea, and cough should be evaluated and treated. Lung transplantation should be considered in patients with advanced disease but is not always feasible because of other manifestations of CTD and comorbidities. Clinical trials of novel therapies including immunosuppressive therapies are needed to inform best treatment strategies.

Rationale: Pulmonary arterial hypertension (PAH) related to systemic sclerosis (SSc) has a poorer prognosis compared with other forms of PAH for reasons that remain unexplained. Objectives: To identify risk factors of mortality in a well-characterized cohort of patients with PAH related to systemic sclerosis (SSc-PAH). Methods: Seventy-six consecutive patients with SSc (64 women and 12 men; mean age 61 6 11 yr) were diagnosed with PAH by heart catheterization in a single center, starting in January 2000, and followed over time. Kaplan-Meier estimates were calculated and mortality risk factors were analyzed. Measurements and Main Results: Forty (53%) patients were in World Health Organization functional class III or IV. Mean pulmonary artery pressure was 41 6 11 mm Hg, pulmonary vascular resistance (PVR) was 8.6 6 5.6 Wood units, and cardiac index was 2.4 6 0.7 L/min/m 2 . Median follow-up time was 36 months, with 42 deaths observed. Survival estimates were 85%, 72%, 67%, 50%, and 36% at 1, 2, 3, 4, and 5 years, respectively. Multivariate analysis identified PVR (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03-1.18; P , 0.01), stroke volume index (HR, 0.94; 95% CI, 0.89-0.99; P 5 0.02), and pulmonary arterial capacitance (HR, 0.43; 95% CI, 0.20-0.91; P 5 0.03) as strong predictors of survival. An estimated glomerular filtration rate less than 60 ml/min/1.73 m 2 portended a threefold risk of mortality. Conclusions: Our results suggest that specific components of right ventricular dysfunction and renal impairment contribute to increased mortality in SSc-PAH. Understanding the mechanisms of right ventricular dysfunction in response to increased afterload should lead to improved targeted therapy in these patients.

Objective. Pulmonary hypertension (PH) is an important cause of mortality in systemic sclerosis (SSc), where it can be isolated (pulmonary arterial hypertension [PAH]) or associated with interstitial lung disease (ILD). This study was undertaken to characterize determinants of survival among SSc patients with either type of PH who received PAH-specific therapy.Methods. Consecutive SSc patients with PAH or ILD-associated PH confirmed by right heart catheterization were included in the study. Kaplan-Meier and Cox proportional hazards models were used to compare survival between SSc patients with PAH and those with ILD-associated PH and to identify predictors of survival.Results. Fifty-nine patients (39 with PAH and 20 with ILD-associated PH) were identified. The majority (15 of 20 with ILD-associated PH and 27 of 39 with PAH) received an endothelin receptor antagonist as initial therapy. Median followup time was 4.4 years (range 2.7-7.4 years). Survival was significantly worse in SSc patients with ILD-associated PH than in those with PAH (1-, 2-, and 3-year survival rates 82%, 46%, and 39% versus 87%, 79%, and 64%, respectively; P < 0.01 by log rank test). In a multivariable analysis, ILD-associated PH was associated with a 5-fold increase in risk of death compared with PAH. Pulmonary vascular resistance index was also an independent predictor of mortality in the overall cohort (hazard ratio 1.05, P < 0.01) and was a significant univariable risk factor in each group separately. Type of initial PAH therapy and the use of warfarin were not related to survival.Conclusion. Survival in SSc complicated by PH remains poor despite currently available treatment options. While therapy may be associated with improved survival in PAH compared with historical controls, the prognosis for patients with ILD-associated PH is particularly grim. Early diagnosis and treatment may improve outcomes since worsening hemodynamic factors were associated with reduced survival.