Echocardiographic markers distinguish combined from isolated postcapillary pulmonary hypertension in systemic sclerosis

Patients with systemic sclerosis who develop heart failure with preserved ejection fraction frequently develop pulmonary hypertension, but the condition can take two distinct hemodynamic forms: isolated postcapillary pulmonary hypertension, in which the pulmonary vascular resistance stays at or below 2 Wood Units, and combined pre- and postcapillary pulmonary hypertension, in which elevated left-sided filling pressures coexist with pulmonary vascular disease. A retrospective single-center cohort study now reports that these two phenotypes, both confirmed by right heart catheterization, can be separated noninvasively using specific echocardiographic measures of right ventricular deformation, right ventricle-pulmonary artery coupling, septal motion and atrial mechanics, and that different sets of these measures tracked mortality within each group.

The study, published in Echo Research & Practice, included 147 adults with systemic sclerosis and heart failure with preserved ejection fraction who were enrolled at the Johns Hopkins Scleroderma Center and Johns Hopkins Pulmonary Hypertension Program. All fulfilled the American College of Rheumatology and European League Against Rheumatism scleroderma classification criteria and had invasive hemodynamic confirmation of pulmonary hypertension status within one year of transthoracic echocardiography. Heart failure with preserved ejection fraction was defined as a pulmonary capillary wedge pressure above 15 mmHg, measured at rest or during standardized supine bicycle exercise provocation, together with a left ventricular ejection fraction above 50 percent on echocardiography. Forty-six patients were classified as having isolated postcapillary pulmonary hypertension and 101 as having the combined form, based on guideline-defined criteria in which the combined phenotype required a pulmonary vascular resistance above 2 Wood Units.

The median interval between right heart catheterization and echocardiography was 97 days, with an interquartile range of 26 to 270 days. Survival was assessed from the date of echocardiography until death or censoring at last known follow-up as of March 1, 2025, with a median follow-up of 4.2 years in the isolated group and 4.0 years in the combined group. The study was approved by the Johns Hopkins University Institutional Review Board, and written informed consent was obtained from all participants upon entry into the registry.

Invasive hemodynamic measurements already pointed to meaningful differences between the groups. Mean pulmonary artery pressure was significantly higher in the combined group at 38.1 versus 25.9 mmHg, and despite preserved left ventricular systolic function, patients with the combined phenotype had significantly lower resting cardiac output, 4.8 versus 5.9 L/min, and lower cardiac index, 2.6 versus 3.2 L/min/m2. The resting ratio of right atrial pressure to pulmonary capillary wedge pressure was also significantly higher in the combined group. Pulmonary function testing showed significantly lower forced vital capacity and diffusing capacity for carbon monoxide in the combined group, although the prevalence of interstitial lung disease, defined by fibrotic changes on high-resolution computed tomography, was similar between groups.

Echocardiographic findings reinforced this separation. Patients with the combined phenotype had significantly higher systolic left ventricular eccentricity index, reflecting greater interventricular septal flattening and right ventricular overload, along with larger left atrial area, lower septal and lateral e-prime velocities, larger right ventricular basal and midventricular diameters, larger right atrial volume index and area, higher peak tricuspid regurgitant velocity and higher estimated pulmonary artery systolic pressure, 54.4 versus 37.5 mmHg. Right ventricular free wall strain was significantly lower in the combined group at -20.7 versus -23.3 percent, and the coupling ratios of right ventricular free wall strain to pulmonary artery systolic pressure and of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure were both significantly reduced. By contrast, patients with isolated postcapillary pulmonary hypertension had larger left ventricular end-diastolic and end-systolic diameters and a higher left ventricular mass index. Tricuspid annular plane systolic excursion and right ventricular fractional area change were not significantly different between groups.

To identify the most discriminating features, the researchers applied a random forest classifier to the imputed dataset, selecting the top ten echocardiographic predictors of the combined phenotype and then testing them with multivariable logistic regression adjusted for age, sex and systemic sclerosis disease duration. Reduced right ventricular free wall strain remained the most robust independent predictor, with an adjusted odds ratio of 1.22 per unit change, followed by a lower ratio of right ventricular free wall strain to pulmonary artery systolic pressure, with an adjusted odds ratio of 0.05. Higher tricuspid regurgitant peak velocity, higher pulmonary artery systolic pressure, lower septal e-prime velocity and higher systolic left ventricular eccentricity index were also independently associated with the combined phenotype. Additional significant predictors included enlarged right ventricular basal and mid-cavity diameters, larger right atrial area and volume index, reduced fractional area change, lower tricuspid annular plane systolic excursion to pulmonary artery systolic pressure ratio, lower fractional area change to pulmonary artery systolic pressure ratio, and reduced right and left atrial reservoir strain.

Mortality analyses used separate random forest models for each hemodynamic group, with the top five predictors in each group then examined using Cox proportional hazards regression, again adjusted for age, sex and disease duration. In the isolated postcapillary group, mortality was independently associated with a lower fractional area change to pulmonary artery systolic pressure ratio, higher left ventricular mass index, lower left ventricular global longitudinal strain, higher pulmonary artery systolic pressure and lower right ventricular free wall strain. In the combined group, mortality was independently associated with higher left ventricular eccentricity index, larger right ventricular internal diastolic diameter, lower left atrial reservoir strain, lower right atrial reservoir strain and a reduced fractional area change to pulmonary artery systolic pressure ratio. Reduced fractional area change relative to pulmonary artery systolic pressure emerged as a shared predictor across both phenotypes, underscoring the prognostic weight of right ventricle-pulmonary artery uncoupling.

Survival comparisons were complicated by early crossover of the Kaplan-Meier curves and violation of the proportional hazards assumption, so the researchers used restricted mean survival time analysis over a 10-year horizon as the primary comparative method. The mean restricted mean survival time was 87.7 months in the isolated group and 76.5 months in the combined group, a between-group difference of 11.1 months that was statistically significant. Survival curves showed numerically lower survival in the combined group throughout follow-up, and the authors interpreted the restricted mean survival time result as confirming a survival disadvantage for patients with the combined phenotype.

The authors noted several limitations. As a retrospective single-center study from a tertiary referral hospital, the findings may be subject to selection bias and may not generalize to broader systemic sclerosis populations, and the higher prevalence of advanced disease may have influenced cohort severity. The unequal group sizes, particularly the larger combined subgroup, may have affected comparative analyses. Image quality occasionally limited strain measurement availability despite the use of standardized vendor-independent software. The inclusion of patients with an echocardiography-to-catheterization interval of up to 12 months introduces potential variability, since hemodynamic and loading conditions may change over time. The subset undergoing exercise hemodynamic testing was relatively small, limiting statistical power to detect exercise-specific differences, and residual confounding remains possible, including unmeasured effects of comorbidities such as interstitial lung disease or medication use. Cause-specific mortality data were unavailable, and echocardiographic data were limited to a single time point, preventing assessment of longitudinal remodeling or disease progression.

The study’s conclusion is that strain-derived indices of right ventricular function, right ventricle-pulmonary artery interaction and atrial mechanics provide incremental value for differentiating combined from isolated postcapillary pulmonary hypertension in systemic sclerosis with preserved ejection fraction and for identifying patients at highest risk of adverse outcomes. The authors suggest that maladaptive right heart remodeling in this disease reflects not only increased afterload but also intrinsic myocardial and vascular pathology that parallels the fibrotic and microvascular processes characteristic of systemic sclerosis, and that integrating advanced echocardiographic metrics may improve classification of pulmonary hypertension due to left heart disease, inform the timing of invasive evaluation and guide individualized therapeutic strategies.

Subject of Research: Echocardiographic differentiation of combined and isolated postcapillary pulmonary hypertension in systemic sclerosis with preserved ejection fraction

Article Title: Echocardiographic characterization of combined postcapillary and precapillary pulmonary hypertension in systemic sclerosis with preserved ejection fraction

Article References: Daoud, A., Goldin, G., Goren, L., Bagga, A., Mombeini, H., Osgueritchian, R., Jani, V. P., Hsu, S., Wigley, F. M., Lammi, M. R., Hassoun, P. M., Shah, A. A., Mathai, S. C., & Mukherjee, M. (2026). Echocardiographic characterization of combined postcapillary and precapillary pulmonary hypertension in systemic sclerosis with preserved ejection fraction. Echo Research & Practice, 13(1), Article 18. https://doi.org/10.1186/s44156-026-00116-4

Image Credits: AI Generated

DOI: 10.1186/s44156-026-00116-4

Keywords: systemic sclerosis, pulmonary hypertension, HFpEF, echocardiography, right ventricle, strain imaging, RV-PA coupling, right heart catheterization, random forest, mortality risk, atrial strain, postcapillary PH