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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.

Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the in vivo environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease.

Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. Are risk scores originally developed for PAH predictive in PH groups 1 through 4? We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including the Registry to Evaluate Early and Long-Term PAH Disease Mangement (REVEAL) Lite 2, REVEAL 2.0, European Society of Cardiology/European Respiratory Society 2022, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 3-strata, and COMPERA 4-strata. Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (interquartile range, 33-52 mm Hg) and pulmonary vascular resistance of 7 Wood units (WU) (interquartile range, 4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH). This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups. ClinicalTrials.gov; No.: NCT05329714; URL: www.clinicaltrials.gov [ABSTRACT FROM AUTHOR]

BACKGROUND: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. METHODS: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (?11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO2peak)>15 mL/ (kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance. RESULTS: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P=0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (logrank P=0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P=0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise. CONCLUSIONS: RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise. [ABSTRACT FROM AUTHOR]

In this 4D flow cardiovascular magnetic resonance (CMR) study, vortical blood flow in the main pulmonary artery (MPA) is quantified using circulation (ᴦ), a metric used in fluid dynamics to quantify the rotational components of flow. Circulation (ᴦ) is a 4D flow CMR metric that quantifies the vortical blood flow pattern in the MPA of patients with pulmonary hypertension (PH), distinguishes them from healthy controls, and shows high correlation with invasive markers of PH severity. [ABSTRACT FROM AUTHOR]

The article presents the case study on the hemodynamic response to Right Atrial pacing in a cohort of patients with Pulmonary Arterial Hypertension by performing a prospective, single-center study in subjects referred for right heart catheterization (RHC) or suspected Pulmonary Arterial Hypertension (PAH) between January 2013 and April 2016. The research protocol was approved by the Johns Hopkins Medical Institutional Review Board.

Background: The effect of heart rate (HR) and body surface area (BSA) on pulmonary RC time and right ventricular (RV) load is unknown. Methods: To determine the association of HR and BSA with the pulmonary RC time and measures of RV load, we studied three large patient cohorts including subjects with 1) known or suspected pulmonary arterial hypertension (PAH) (n = 1008), 2) pulmonary hypertension due to left heart disease (n = 468), and 3) end-stage heart failure with reduced ejection fraction (n = 150). To corroborate these associations on an individual patient level, we performed an additional analysis using high-fidelity catheters in 22 patients with PAH undergoing right atrial pacing. Results: A faster HR inversely correlated with RC time (p<0.01 for all), suggesting augmented RV pulsatile loading. Lower BSA directly correlated with RC time (p<0.05) although the magnitude of this effect was smaller than for HR. With incremental atrial pacing, cardiac output increased and total pulmonary resistance (TPR) fell. However, effective arterial elastance, its mean resistive component (TPR/heart period; 0.60±0.27 vs. 0.79±0.45;p = 0.048), and its pulsatile component (0.27±0.18 vs 0.39±0.28;p = 0.03) all increased at faster HR. Conclusion: Heart rate and BSA are associated with pulmonary RC time. As heart rate increases, the pulsatile and total load on the RV also increase. This relationship supports a hemodynamic mechanism for adverse effects of tachycardia on the RV. [ABSTRACT FROM AUTHOR]

The article identifies the unique predictors of mortality in patients with pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) using the Registry to Evaluate Early and Long-Term PAH Management in the U.S. Findings include the high mortality rate in patients with PAH associated with SSc, and the high risk of death for elderly men, patients with low baseline systolic blood pressure, and those who have poor exercising capacity.

Background--Right ventricular 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, or interstitial fibrosis and that this relation may be changed by elevated pulmonary capillary wedge pressure, augmenting right ventricular pulsatile load. Methods and Results--Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the RPA-CPA relationship with pulmonary hypertension, pulmonary fibrosis, patient age, and varying pulmonary capillary wedge pressure. Patients with suspected or documented pulmonary hypertension (n= 1009) and normal pulmonary capillary wedge pressure displayed a consistent RPA-CPA hyperbolic (inverse) dependence, CPA=0.564/(0.047+RPA), with a near-constant resistance-compliance product (0.48±0.17 seconds). In the same patients, the systemic resistance-compliance product was highly variable. Severe pulmonary fibrosis (n=89) did not change the RPA-CPA relation. Increasing patient age led to a very small but statistically significant change in the relation. However, elevation of the pulmonary capillary wedge pressure (n=8142) had a larger impact, significantly lowering CPA for any RPA and negatively correlating with the resistance-compliance product (P<0.0001). Conclusions--Pulmonary hypertension and pulmonary fibrosis do not significantly change the hyperbolic dependence between RPA and CPA, and patient age has only minimal effects. This fixed relations, hip helps explain the difficulty of reducing total right ventricular afterload by therapies that have a modest impact on mean RPA. Higher pulmonary capillary wedge pressure appears to enhance net right ventricular afterload by elevating pulsatile, relative to resistive, load and may contribute to right ventricular dysfunction. [ABSTRACT FROM AUTHOR]

The article presents the conducted study to analyze the clinical features of patients with connective tissue disease-associated pulmonary arterial hypertension (PAH). The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) was used in the analysis. It claims that PAH is a common complication of patients with connective tissue diseases (CTD), which specifically affects patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and mixed CTD (MCTD).

The article presents the results of a study on the experience of two health care centers in New York in the management of patients with sarcoidosis-associated pulmonary arterial hypertension (PAH). According to the authors, 22 patients with sarcoidosis treated with PAH-specific therapies experienced an increase in their mean six-minute walk distance, a greater increment in exercise capacity, and reduce in mean pulmonary artery pressure. They add that the survival rates of one- and three-year transplant free patients ranged from 74 to 90 percent.

The article discusses the study which determines the survival of systemic sclerosis (SS) patients with pulmonary arterial hypertension (PAH) for therapy. The study used fifty-five patients with PAH and 20 respondents with interstitial lung disease (ILD) associated with proportional hazards to identify predictors of survival as endothelin receptor antagonist. The study suggests for early diagnosis and treatment to improve outcome and avoid the worsening of hemodynamic factors.

The authors discuss a study which described the use of synchrotron radiation microangiography (SRA) to assess the distal pulmonary vasculature in patients with pulmonary arterial hypertension (PAH), by Schwenke and colleagues, published within the issue. The study showed the clinical benefits of utilizing SRA. The authors commend the researchers to demonstrating the usefulness of SRA in patients with PAH, but they also cite the limitations of the study.

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 (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.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. [ABSTRACT FROM AUTHOR]

Background: Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients.Methods and Results: RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-systolic elastance) whereas IPAH did (P<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, P=0.004, and +19±4% versus -1±6%, P<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort.Conclusions: RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients. [ABSTRACT FROM AUTHOR]

The article discusses studies on the use of noninvasive imaging in the assessment of the right ventricular (RV) function in pulmonary arterial hypertension (PAH) patients and the advances in echocardiography, cardiac magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging. Topics include the role of computed tomography angiography in evaluating chronic thromboembolic pulmonary hypertension (PH), the RV ejection fraction (RVEF), and transthoracic echocardiography.

The article presents a study on the repressive effect of imatinib on platelet-derived growth factor signaling and its effectives in pulmonary arterial hypertension (PAH) treatment. It states that imatib in pulmonary vascular resistance patients were evaluated using Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES). Results show that imatinib improved hemodynamics in patients with advanced PAH, however, drug discontinuance and serious untoward events are common. INSET: CLINICAL PERSPECTIVE.

Background--Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly upregulated in several experimental models of PH. In this study, we test the hypothesis that ARC expression is essential for the development of chronic hypoxia-induced PH. Methods and Results--Experiments in which cells or mice were rendered ARC-deficient revealed that ARC not only protected pulmonary arterial smooth muscle cells from hypoxia-induced death, but also facilitated growth factor-induced proliferation and hypertrophy and hypoxia-induced downregulation of selective voltage-gated potassium channels, the latter a hallmark of the syndrome in humans. Moreover, ARC-deficient mice exhibited diminished vascular remodeling, increased apoptosis, and decreased proliferation in response to chronic hypoxia, resulting in marked protection from PH in vivo. Patients with PH have significantly increased ARC expression not only in remodeled vessels but also in the lumen-occluding lesions associated with severe disease. Conclusions--These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome. [ABSTRACT FROM AUTHOR]