Modern Age Pathology of Pulmonary Arterial Hypertension

Abstract

Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives: To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Methods: Assessment of pulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions: Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH. Keywords: pulmonary circulation; vessel remodeling; angiogenesis; inflammationThe modern treatment of pulmonary arterial hypertension (PAH) has led to substantive advancements in patients' quality of life and survival, significantly improving on the grave prognosis historically associated with the disease (1, 2). With the restrictions regarding obtaining lung tissue for diagnosis, the endpoints for effectiveness of the current therapies are largely based on assessments of exercise performance and reported quality of life, time to clinical deterioration, and/or measured physiological performance (e.g., 6-min walk test). Whether prostacyclin and its analogs, endothelin receptor blockers, and phosphodiesterase type 5 inhibitors modify the spectrum of pulmonary vascular lesions in PAH has not been addressed with a large cohort of lungs with the disease.Several large series, heavily reliant on autopsy samples, highlighted pulmonary vascular alterations that characterize the pulmonary vascular remodeling in idiopathic PAH (IPAH) and PAH associated with congenital heart disease (CHD) (3-14) (see Table E1 in the online supplement). Eccentric and obliterative intima thickening are largely composed of smooth muscle cells and myofibroblasts. A similar cell composition underlies media thickening, which is regarded as the signature process in pulmonary hypertension (15). In addition, most of the cau...

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“…correlates with the disease severity, and in particular with pulmonary vascular wall remodelling and thickness [38,39]. Using neonatal, chronic hypoxia-induced PH models, FRID et al [40] found that pulmonary adventitial remodelling was due to the robust recruitment of monocyte/macrophage lineage cells expressing α-SMA that can produce collagen.…”

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

“…The perivascular infiltrate surrounding each pulmonary artery was quantified as follows: 0: absent, 1: minimal with a single layer clustering of inflammatory cells; 2: moderate, with localized clustering of inflammatory cells; and 3: abundant, with large clusters of inflammatory cells extending from the perivascular region toward adjacent alveoli. The final inflammatory score was the result of the following: [0 Â n vessels with 0 score þ 1 Â n vessels with score of 1 þ 2 Â n vessels with score of 2 þ 3 Â n vessels with score of 3]/number of analyzed vessels, as described elsewhere; 40 100 AE 36 vessels were examined per lung.…”

Lung Function, Inflammation, and Endothelin‐1 in Congenital Heart Disease–Associated Pulmonary Arterial Hypertension

“…Circulating levels of serum cytokines including interleukin (IL)‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, and tumor necrosis factor α are significantly elevated when compared with controls 22, 23. IPAH shares a number of features with CHD‐APAH,24 and inflammation could develop in CHD‐APAH because of the high stresses associated with increased pulmonary blood flow and hypoxemia 25. Evidence of inflammation in CHD‐APAH includes inflammatory cell infiltrates around remodeled vessels,26, 27 and elevated circulating levels of IL‐6, tumor necrosis factor α,.MCP‐1, and C‐reactive protein have also been demonstrated 26, 27, 28…”