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Background: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21-24 mmHg)., Methods: The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks., Discussion: The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP., Trial Registration: ClinicalTrials.gov Identifier NCT04797286., (© 2024. The Author(s).)

Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2 , which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2 . Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target. NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

Background: Scleroderma is a serious chronic autoimmune disease in which a patient's disease state manifests in several irregularly spaced longitudinal measures of lung, heart, skin, and other organ systems. Threshold crossings of pulmonary and cardiac measures indicate potentially life-threatening key clinical events including interstitial lung disease (ILD), cardiomyopathy, and pulmonary hypertension (PH). The statistical challenge is to accurately and precisely predict these events by using all of the clinical history for the patient at hand and for a reference population of patients., Methods: We use a Bayesian mixed model approach to simultaneously characterize each individual's future trajectories for several biomarkers. We estimate this model using a large population of patients from the Johns Hopkins Scleroderma Center Research Registry. The joint probabilities of critical lung and heart events are then calculated as a byproduct of the mixed model., Results: The performance of this approach is substantially better than standard, more common alternatives. In order to predict an individual's risks in a clinical setting, we also develop a cross-validated, sequential prediction (CVSP) algorithm. As additional data are observed during a patient's visit, the algorithm sequentially produces updated predictions for the future longitudinal trajectories and for ILD, cardiomyopathy, and PH. The updated prediction distributions with little additional computing, for example within an electronic health record (EHR)., Conclusions: This method that generates real-time personalized risk estimates has been implemented within the electronic health record system for clinical testing. To our knowledge, this work represents the first approach to compute personalized risk estimates for multiple scleroderma complications., (© 2021. The Author(s).)

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to report that are related to the reported content of this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Right ventricular (RV) capacity to adapt to increased afterload is the main determinant of outcome in pulmonary hypertension, a common morbidity seen in systemic sclerosis (SSc). We hypothesized that supine bicycle echocardiography (SBE), coupled with RV longitudinal systolic strain (RVLSS), improves detection of limitations in RV reserve in SSc. 56 SSc patients were prospectively studied during SBE with RV functional parameters compared at rest and peak stress. We further dichotomized patients based on resting RV systolic pressure (RVSP) to determine the effects of load on contractile response. Our pooled cohort analysis revealed reduced global RVLSS at rest (-16.2 ± 3.9%) with normal basal contractility (-25.6 ± 7.7%) and relative hypokinesis of the midventricular (-14.1 ± 6.0%) and apical (-8.9 ± 5.1%) segments. With exercise, global RVLSS increased significantly (p = 0.0005), however despite normal basal contractility at rest, there was no further augmentation with exercise. Mid and apical RVLSS increased with exercise suggestive of RV contractile reserve. In patients with resting RVSP < 35 mmHg, global and segmental RVLSS increased with exercise. In patients with resting RVSP ≥ 35 mmHg, global and segmental RVLSS did not increase with exercise and there was evidence of exertional RV dilation. Exercise provocation in conjunction with RVLSS identified differential regional contractile response to exercise in SSc patients. We further demonstrate the effect of increased loading conditions on RV contractile response exercise. These findings suggest subclinical impairments in RV reserve in SSc that may be missed by resting noninvasive 2DE-based assessments alone., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Right ventricular (RV) contractile reserve shows promise as an indicator of occult RV dysfunction in pulmonary vascular disease. We investigated which measure of RV contractile reserve during exercise best predicts occult RV dysfunction and clinical outcomes., Methods: We prospectively studied RV contractile reserve in 35 human subjects referred for right heart catheterization for known or suspected pulmonary hypertension. All underwent cardiac magnetic resonance imaging, echocardiography, and supine invasive cardiopulmonary exercise testing with concomitant RV pressure-volume catheterization. Event-free survival was prospectively adjudicated from time of right heart catheterization for a 4-year follow-up period., Results: RV contractile reserve during exercise, as measured by a positive change in end-systolic elastance (Ees) during exertion, was associated with elevation in pulmonary pressures but preservation of RV volumes. Lack of RV reserve, on the other hand, was tightly coupled with acute RV dilation during exertion (R 2  = 0.76, p< 0.001). RV Ees and dilation changes each predicted resting RV-PA dysfunction. RV ejection fraction during exercise, which captured exertional changes in both RV Ees and RV dilation, proved to be a robust surrogate for RV contractile reserve. Reduced exercise RV ejection fraction best predicted occult RV dysfunction among a variety of resting and exercise RV measures, and was also associated with clinical worsening., Conclusions: RV ejection fraction during exercise, as an index of RV contractile reserve, allows for excellent identification of occult RV dysfunction, more so than resting measures of RV function, and may predict clinical outcomes as well., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: In cross-sectional studies, pulmonary hypertension (PH) and ischemic digital lesions are 2 scleroderma vascular outcomes associated with abnormalities in biomarkers of angiogenesis. The clinical usefulness of these biomarkers is unknown, in part due to lack of data on longitudinal measurement. This prospective longitudinal study was undertaken to evaluate vascular biomarker measurements in patients with systemic sclerosis (SSc) over time., Methods: We conducted a prospective cohort study of 300 patients with SSc who were followed up for at least a 5-year period and lacked evidence of PH and/or active ischemic digital lesions at enrollment. Levels of hepatocyte growth factor (HGF), soluble Flt-1 (sFlt-1), soluble endoglin, endostatin, and placental growth factor (PLGF) were obtained at multiple time points and assessed for their ability to predict the development of PH/ischemic digital lesions. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated., Results: Forty-six patients (15%) developed PH and 69 patients (23%) developed an ischemic digital lesion. In time-to-event analyses, the following 3 biomarkers measured at cohort entry were found to be significantly associated with the development of PH: HGF (HR 1.99 [95% CI 1.24-3.17], P = 0.004), sFlt-1 (HR 3.04 [95% CI 1.29-7.14], P = 0.011), and PLGF (HR 2.74 [95% CI 1.32-5.69], P = 0.007). As time approaching PH diagnosis decreased, there was no corresponding increase in any biomarker level. Upon converting each continuous vascular biomarker into a binary variable, a dose-response relationship was observed for the number of elevated biomarkers at cohort entry and the risk of developing PH. With each additional elevated biomarker at cohort entry, there was a 78% increase in the risk of developing PH (HR 1.78 [95% CI 1.2-2.6], P = 0.004)., Conclusion: These data suggest that molecules involved in angiogenesis reflect vascular perturbation, and that elevations in these biomarkers at first encounter can indicate patients who are at risk of PH development., (© 2020, American College of Rheumatology.)

Objective: To evaluate whether global peak systolic strain (PSS) and peak systolic strain rate (PSSR) derived from velocity vector imaging (VVI) allow early recognition of regional and global right ventricular (RV) dysfunction and the impact of this on left ventricular (LV) function in patients with pulmonary hypertension (PHT)., Background: RV function is an important determinant of prognosis in patients with heart failure, pulmonary hypertension, heart transplant, and congenital heart diseases. However, evaluation of the right ventricle is often limited by its complex geometry and inadequate visualization of RV free wall. Furthermore, the impact of RV dysfunction on the LV function is not well elucidated., Methods: Ninety-nine participants, 35 control patients with normal RV systolic pressure (RVSP) (<30 mm Hg) and 64 patients with PHT (25 with mild-to-moderate increase in RVSP [≥36 and <60 mm Hg] and 39 with severe increase in RVSP [≥60 mm Hg]), underwent comprehensive echo-Doppler assessment and velocity vector imaging (VVI) for strain rate analysis. RV regional peak systolic and diastolic tangential velocity, strain, and strain rate were obtained from the basal, mid and apical segments of the RV free wall and interventricular septum (IVS) from apical 4-chamber view at end-expiration. Similar data were obtained from eighteen LV segments from apical 4-chamber, 2-chamber, and long-axis views., Results: Peak systolic strain, strain rate, and tangential velocity at all segments in the RV free wall and IVS were decreased compared to controls in patients with PHT (P < 0.001). Significant correlation (r > 0.60; P < 0.001) was noted between RVSP and systolic and diastolic strain and strain rate at basal segment in IVS and global RV function. Peak early diastolic strain rate at all segments was also decreased in PHT patients compared with control patients (P < 0.01). Furthermore, RV systolic and diastolic strain and strain rate were lower in group 2 with mild-to-moderate hypertension while the conventional echo parameters were normal. Except for IVS segments, other LV segments had no statistical differences in systolic and diastolic velocity, strain, and strain rate compared to controls. However, they were lower than the published normal range., Conclusions: Strain and strain rate derived from VVI demonstrates early recognition of systolic and diastolic RV dysfunction in patients with PHT compared to controls. PHT is associated with global and regional RV systolic and diastolic dysfunction. Systolic and diastolic strain and strain rate from LV was lower compared to controls but were not statistically significant. This may indicate subclinical LV dysfunction in these patients, suggesting that conventional LV function parameters may not be sensitive to recognize subclinical LV dysfunction., (© 2019 Wiley Periodicals, Inc.)

Two major complications in scleroderma patients that cause substantial morbidity and mortality are ischemic digital lesions (DL) and pulmonary hypertension (PH). The clinician's ability to predict which patients will develop these complications is imperfect. We conducted a prospective observational cohort study of 300 patients with scleroderma who were followed for at least a 5-year period. At baseline, patients lacked evidence of PH and were without a current DL. At each 6-month visit, the patient was examined for signs/symptoms of PH and/or a DL. The primary outcomes were (1) PH defined as a mean pulmonary artery pressure ≥ 25 mmHg by right heart catheterization and (2) ≥ 1 DL defined as new onset of severe vascular compromise. Thirty patients (10%) developed PH (11 group 1/PAH, 4 group II, 15 group III) and 69 developed DL. The average time from enrollment until diagnosis of PH was 3.2 ± 2 years. In multivariable analyses, patients who developed PH were more likely to have diffuse disease (HR 3.2, p = 0.004), a forced vital capacity (FVC)/diffusing capacity of the lungs for carbon monoxide (DLCO) ratio > 1.6 (HR 1.7, p = 0.008), and elevated RVSP (HR = 1.07, p = 0.007). Patients who developed PAH were more likely to have a FVC/DLCO ratio > 1.6 (HR = 5.8, p = 0.014), and patients who developed group III PH were less likely to have an elevated FVC (HR = 0.92, p = 0.001). Patients were more likely to develop a DL if they had a history of prior DL (HR = 7.0, p < 0.001), or were men (HR = 2.3, p = 0.007). In a prevalent cohort of scleroderma patients, individuals who develop PH or DL have simple to measure clinical features that can predict these complications years before they occur.

Background: Patients 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., Methods: Cardiac 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., Results: Myocyte 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 (F max ) was 28% higher in IPAH but 37% lower in SSc-PAH. F max in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC 50 ) 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 F max directly correlated with in vivo RV contractility assessed by end-systolic elastance ( R 2 =0.46, P =0.002) and change in end-systolic elastance with exercise ( R 2 =0.49, P =0.008) and was inversely related with exercise-induced chamber dilation ( R 2 =0.63, P <0.002), which also was a marker of depressed contractile reserve., Conclusions: A 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., (© 2018 American Heart Association, Inc.)

Background: Systemic sclerosis–associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared with idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often caused by right ventricular (RV) failure. We tested whether SScPAH or systemic sclerosis–related pulmonary hypertension with interstitial lung disease imposes a greater pulmonary vascular load than IPAH and 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 systemic sclerosis–related pulmonary hypertension with interstitial lung disease, and 67 IPAH). An inverse relation between pulmonary resistance and compliance was similar for all 3 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 (n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of RV load (arterial elastance [Ea]), and RV pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (pulmonary vascular resistance=7.0±4.5 versus 7.9±4.3 Wood units; Ea=0.9±0.4 versus 1.2±0.5 mm Hg/mL; pulmonary arterial compliance=2.4±1.5 versus 1.7±1.1 mL/mm Hg; P>0.3 for each). Although SScPAH did not have greater vascular stiffening compared with IPAH, RV contractility was more depressed (Ees=0.8±0.3 versus 2.3±1.1, P<0.01; Msw=21±11 versus 45±16, P=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0±0.5 versus 2.1±1.0; P=0.03). This ratio was higher in SSc without PH (Ees/Ea=2.3±1.2; P=0.02 versus SScPAH)., Conclusions: RV dysfunction is worse in SScPAH compared with IPAH at similar afterload, and may be because of intrinsic systolic function rather than enhanced pulmonary vascular resistive and pulsatile loading.

Objectives: Annual echocardiography screening is widely used in scleroderma, but the utility of longitudinal assessment is unknown. We evaluated whether change in right ventricular systolic pressure (RVSP) was a risk factor for mortality and development of pulmonary arterial hypertension (PAH) in a cohort of scleroderma patients., Methods: The study population consisted of scleroderma patients who had at least three echocardiograms and pulmonary function tests (PFTs) over ≥1 year as part of routine care. The annual rate of change in RVSP was determined for each subject. Cox proportional hazards regression was performed to assess the association between PAH and mortality and change in RVSP/year, adjusted for relevant covariates., Results: 613 scleroderma patients with 3244 echocardiograms were studied. The adjusted relative hazards of PAH and mortality were 1.08 (95% CI 1.05-1.11) and 1.12 (95% CI 1.08-1.15) per 1 mm Hg increase in RVSP/year, respectively. Compared with patients with a stable RVSP, the relative hazards for the development of PAH were 1.90 (95% CI 0.91-3.96), 5.09 (95% CI 2.53-10.26) and 6.15 (95% CI 3.58-10.56) for subjects whose RVSP increased at rates of 1-1.99, 2-2.99 and 3+ mm Hg/year. Compared with the same reference group, the relative hazards for death were 0.92 (95% CI 0.48-1.73), 2.16 (95% CI 1.16-4.01) and 5.05 (95% CI 3.47-7.34) for subjects whose RVSP increased at rates of 1-1.99, 2-2.99 and 3+ mm Hg/year., Conclusions: In a population of scleroderma patients, the rate of increase in RVSP is a risk factor for mortality and PAH even after adjustment for clinical characteristics and longitudinal PFT data.

Objective: Clinical markers are needed to identify scleroderma patients at risk for pulmonary arterial hypertension (PAH) since early therapy may improve survival. We investigated whether increased numbers of telangiectases in scleroderma associate with measures of pulmonary vascular disease., Methods: One hundred forty-seven consecutive adult patients with scleroderma were enrolled in this cross-sectional study and scored for the presence of matted telangiectases on 11 body areas. Per body area, telangiectases were scored as 0 if none were present, 1 if there were fewer than 10 telangiectases, and 2 if 10 or more telangiectases were counted. Linear regression analysis was performed to assess the association between right ventricular systolic pressure (RVSP) and telangiectasia score, adjusted for age, race, smoking status, scleroderma subtype, disease duration, and autoantibody status. Logistic regression analysis was performed with PAH by right-heart catheterization (RHC) as the dependent variable., Results: The mean telangiectasia score was 6.0 (SD 4.5, range 0-20). RVSP and telangiectasia score were positively correlated (r = 0.271, p = 0.001). The mean RVSP increased by 10.9 mm Hg for every 10-point increase in telangiectasia score (95% CI 3.6-18.3 mm Hg, p = 0.004), adjusted for potential confounders. The adjusted relative odds of PAH by RHC were 12.4 for patients with a 10-point increase in telangiectasia score (95% CI 1.78-85.9, p = 0.01)., Conclusion: Increased numbers of telangiectases strongly associate with the presence of pulmonary vascular disease. Telangiectases may be a clinical marker of more widespread aberrant microvascular disease in scleroderma.