Author + information
- Jane A. Leopold, MD∗ ()
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Jane A. Leopold, Brigham and Women’s Hospital, Division of Cardiovascular Medicine, 77 Avenue Louis Pasteur, NRB0630K, Boston, Massachusetts 02115.
Pulmonary hypertension (PH) associated with cardiovascular disease and left heart dysfunction is now recognized as a complex pathophenotype that, when present, may portend an increased susceptibility to adverse events and worse clinical outcome (1). PH associated with left heart disease (PH-LHD) occurs because of the backward transmission of high left-sided filling pressures directly to the post-capillary pulmonary vessels, and thereby, to the rest of the pulmonary circulation. This pattern is reflected in the hemodynamic definition of PH-LHD: a mean pulmonary artery pressure ≥25 mm Hg and a pulmonary artery wedge pressure >15 mm Hg (2). In ∼12% to 38% of patients with PH-LHD, the diastolic pulmonary vascular pressure gradient is ≥7 mm Hg, and/or the pulmonary vascular resistance is >3 Wood units (3). These hemodynamic findings indicate that there is a pre-capillary contributor to the pulmonary hypertensive phenotype and suggest that pulmonary vascular remodeling has occurred. Patients with PH-LHD who have this hemodynamic profile were once described as having PH “out of proportion” to their left heart disease. This has now been taken into account, and they have been reclassified as a distinct sub-phenotype of PH-LHD and referred to as having combined pre- and post-capillary PH (Cpc-PH).
The European Cardiology Society and European Respiratory Society recognize Cpc-PH as a unique subset of PH-LHD (2), although the clinical characteristics that are associated with and predict Cpc-PH, the etiology and natural history of the disease, and its pathobiology remain incompletely understood. These knowledge gaps have occurred, in part, because of the limited data available on patients with Cpc-PH. Some clinical information has been gathered from re-analysis of PH-LHD patient registries and prospective studies; however, phenotyping studies that provide biological evidence to understand the pathogenesis of Cpc-PH are lacking.
There is a growing recognition that Cpc-PH shares some clinical and hemodynamic characteristics with pulmonary arterial hypertension (PAH). A previous retrospective single center study that included 1,063 unselected patients with chronic heart failure demonstrated that 12% of PH-LHD patients should be reclassified as Cpc-PH (4). The prevalence of Cpc-PH did not differ between patients with diastolic or systolic heart failure, which suggests that the type of heart failure or severity was not the mechanism underlying Cpc-PH. In this cohort, patients with Cpc-PH had a shorter overall survival compared with patients with isolated post-capillary PH-LHD, especially those who presented with diastolic heart failure (median: 54 months vs. 102 months; p = 0.0004). Interestingly, patients with Cpc-PH had worse indexes of right ventricular−pulmonary artery coupling than patients with isolated post-capillary PH-LHD (4). This suggests that pulmonary artery remodeling and right ventricular dysfunction occurred more frequently in Cpc-PH patients, which is similar to what is observed in PAH.
Additional evidence that Cpc-PH exhibits features of PAH came from a recent analysis of the COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) study (5). In the highly selected group of patients enrolled in this study, patients with PH-LHD due to heart failure with preserved ejection fraction (PH-HFpEF), many of whom could be reclassified as having Cpc-PH, were compared with patients with idiopathic PAH (iPAH) who were stratified further on the basis of risk factors for left heart disease (i.e., coronary artery disease, arterial hypertension, diabetes mellitus, body mass index >30 kg/m2, and atrial fibrillation) and referred to as typical (<3 factors) or atypical (≥3 factors). Comparison of the 3 groups of patients revealed that PH-HFpEF closely resembled atypical iPAH with respect to age, body mass index, natriuretic peptide levels, 6-minute walking distance, and other comorbidities while having a similar mean pulmonary artery pressure and cardiac index as typical iPAH (5).
When considered together, these observations led to the theory that PH, as a disease entity, exists as a continuum that spans from PAH to PH-LHD with atypical iPAH and Cpc-PH located in between (3,5). This concept is not entirely without merit because of the clinical and hemodynamic similarities observed between atypical iPAH and PH-HFpEF. It is also supported by histopathological evidence of pulmonary vascular remodeling in Cpc-PH that recapitulates some of the vascular changes in PAH. In Cpc-PH, there is distal pulmonary artery hypertrophic remodeling, fibrosis, and luminal occlusion, although typical plexiform lesions pathognomonic of PAH are not present (6,7). In Cpc-PH, this degree of pulmonary vascular remodeling likely contributes to the increased pulmonary vascular resistance and decreased pulmonary artery compliance, similar to what is seen in PAH. Thus, these observations move the relationship between PAH and Cpc-PH closer, but they are also missing the biological link to explain the overlap of disease features that stem from a remodeled pulmonary vasculature.
In this issue of the Journal, Assad et al. (8) advance our understanding of Cpc-PH by providing a robust clinical data set and the first biological evidence to position Cpc-PH closer to PAH than isolated post-capillary PH-LHD on the PH disease spectrum. To define the study population for this retrospective study, the investigators accessed the Vanderbilt Synthetic Derivative to identify 564 PAH patients, 364 patients with Cpc-PH, and 1,456 patients with isolated post-capillary PH-LHD on the basis of right heart catheterization data. This database, which has been linked to a DNA biorepository, is a powerful tool for clinical studies, and there are few single-center databases that rival this resource. Although Cpc-PH patients shared demographic characteristics with PAH patients (younger age, greater percentage of women), they had a comorbidity profile that either had intermediate characteristics between PAH and PH-LHD or more closely resembled isolated post-capillary PH-LHD. Thus, although we gained some clarity regarding the clinical profile of Cpc-PH patients, no distinct set of characteristics emerged to distinguish Cpc-PH patients from those with isolated post-capillary PH-LHD. This, perhaps, speaks to the heterogeneity in left heart diseases associated with Cpc-PH and the overlapping phenotype with other types of PH.
The available echocardiographic data from 82% of patients revealed that there were similarities in the degree of left ventricular structural remodeling and wall stress in Cpc-PH and isolated post-capillary PH-LHD patients that were not shared by PAH patients. This led to the premise that Cpc-PH patients had a predisposition to exaggerated pulmonary vascular remodeling, which is important because patients with Cpc-PH and a pulmonary vascular resistance >3 Wood units had increased mortality compared with those with isolated post-capillary PH-LHD. In the current study, the investigators did not report any right ventricular structural or functional data from the echocardiograms. In this case, it would be interesting to know if there was evidence of right ventricular dysfunction or failure to explain the increase in mortality.
To test the hypothesis that Cpc-PH and PAH have a shared genetic risk, the investigators used previously sequenced samples from 254 subjects to identify 75 exonic single nucleotide polymorphisms in 73 genes that were differentially expressed among PAH, Cpc-PH, and isolated post-capillary PH-LHD. Using expression quantitative trait loci mapping, the list of relevant genes was expanded to 141. Gene ontology analysis demonstrated that the gene set was enriched for biological processes relevant to PAH and vascular remodeling, including cytoskeletal structure and immune function. This is of interest because it puts the genetic and shared risk focus on vascular remodeling. It also identifies vascular remodeling as the key phenotypic feature in the overlap between Cpc-PH and PAH.
Although the sequencing data represents the first evidence of shared genetic risk and lends biological plausibility to a pathophysiological overlap between Cpc-PH and PAH, there are still not enough data to make this claim with any certainty. As noted by the investigators, the genetic analysis was limited by the small number of sequenced samples available (only 36 for Cpc-PH), restriction to an European American ancestry, and the use of whole exome sequencing as opposed to whole genome sequencing, which would allow for a deeper examination of the shared genetic risk. It should also be noted that although the relevant genes were expressed at high levels in lung tissue, the analysis did not differentiate between lung parenchymal and vascular tissue. Furthermore, because the relevant genes were expressed at higher levels in at least 5 other tissues, it would be of interest to know the identity of these tissues and if there was any unexpected overlap between Cpc-PH and diseases relevant to these tissues. This will require a more advanced data set and systems biology methodology. Finally, the investigators are likely correct in their assumption that Cpc-PH represents a subset of PH-LHD that has a genetic (or epigenetic) predisposition to develop early and aggressive pulmonary vascular remodeling in concert with left heart disease. Whether this genetic susceptibility is observed in any disease associated with pulmonary vascular remodeling or is restricted to a previously identified PAH gene program requires additional study.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
This work was supported by NIH/NHLBI U01 125512-02 and the Thomas W. Smith MD Foundation.
Dr. Leopold has reported that she has no relationships relevant to the contents of this paper to disclose.
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