Pulmonary hypertension across the spectrum of left heart and lung disease

Abstract

Aims: Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2-3), but this group is not well-characterized.

Methods and results: Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2-3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2-3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2-3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2-3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2-3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.86), and patients with G2-3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38-0.86).

Conclusions: Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2-3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease.

Clinical trial registration: ClinicalTrials.gov NCT02980887.

Keywords: Combined post‐ and pre‐capillary pulmonary hypertension; Heart failure; Left heart disease; Lung disease; Pulmonary hypertension; Pulmonary vascular resistance.

Figure 1.. Participant flow and distribution.

Distribution of patients with primary groups 2 and 3, as well as secondary group designations. The letter x indicates secondary contribution from a group other than 2 or 3 (i.e., 1, 4, or 5).

Figure 2.. Lung structure and function.

[A, B] Patients with Group 3 (G3) PH displayed more severe impairments in forced expiratory volume in 1 second (FEV1) and greater impairment in lung diffusing capacity for carbon monoxide (DL_CO) compared with G2 and G2–3, but FEV1 and DLCO were both significantly reduced compared to age and sex-predicted normative values I graded fashion in the latter groups, expressed as percent predicted. [C] High resolution chest computed tomography revealed ground glass opacities to be common in all 3 groups, with no statistically significant differences.

Figure 3.. Pulmonary vasodilation with inhaled Nitric Oxide.

Most patients in all 3 groups displayed a reduction in pulmonary vascular resistance (PVR) in response to acute inhaled nitric oxide (iNO), with no significant between-group differences observed.

Figure 4.. Outcomes.

Kaplan Meier curve showing survival free of death or heart and/or lung transplantation, which was significantly poorer in patients with G3 compared with G2 and G2–3 (log rank P = 0.0016), who did not differ from one another (log rank P = 0.83).