Peripheral microangiopathy in Eisenmenger syndrome: A nailfold video capillaroscopy study☆
Graphical abstract
Introduction
Eisenmenger syndrome (ES) comprises the extreme end of the pulmonary arterial hypertension (PAH) spectrum, associated with congenital heart disease. It occurs in patients with large, unrepaired intra- or extracardiac shunts, and is associated with poor long-term prognosis, despite recent advances in medical management [1]. An initially present left-to-right shunt, leads to increased right ventricular (RV) volume and pressure and culminates in disturbed pulmonary blood flow, posing a shear stress on pulmonary endothelium [2]. The ensuing endothelial dysfunction and pulmonary vascular remodeling, results in the irreversible increase of pulmonary vascular resistance (PVR) and eventually in the development of PAH with subsequent shunt reversal [3].
Although research in PAH and ES has been traditionally focused on the pulmonary vascular bed [4,5], interest has been recently diverted towards the possibility of a co-existing peripheral microangiopathy. Nailfold video-capillaroscopy (NVC) is an established, validated, non-invasive imaging technique for the assessment of peripheral microcirculation in patients with Raynaud's phenomenon contributing to the differential diagnosis of the different types of structural and functional microvascular abnormalities observed in patients with systemic autoimmune diseases [6]. Limited amount of capillaroscopic evidence suggests the presence of systemic microvascular dysfunction in patients with PAH associated with systemic sclerosis (SSc), PAH associated with systemic lupus erythematosus (SLE) and idiopathic PAH (IPAH) [[7], [8], [9], [10], [11], [12]]. Recently Arvanitaki et al. demonstrated significant NVC changes, namely a reduction in capillary density and an increase in capillary dimensions, in patients with IPAH and chronic thromboembolic pulmonary hypertension (CTEPH) compared to healthy controls [13], reinforcing the hypothesis that peripheral microangiopathy parallels pulmonary microangiopathy in patients with precapillary pulmonary hypertension (PH) [12]. There have been no similar studies so far in patients with ES.
The aim of the present study was to investigate whether peripheral microvascular abnormalities are present in patients with ES using NVC and to identify potential correlations of certain nailfold capillaroscopic characteristics with non-invasive markers of systemic organ function.
Section snippets
Study design, setting, participants
This was a cross-sectional sub-study of a larger study which took place at a tertiary center for PH and adult congenital heart disease (ACHD) in collaboration with a tertiary center for rheumatic diseases with expertise in NVC in Northern Greece [13,14]. Adult patients with ES and age- and sex-matched healthy controls were enrolled between March 2019 and February 2020. Written informed consent was obtained from all participants. The study received approval from the Aristotle University of
Baseline characteristics
Demographics of ES patients and healthy controls are presented in Table 1. One individual with ES and two healthy controls were excluded from the analysis as they had at least one nailfold traumatized, that precluded adequate image acquisition from the corresponding finger. In total, 17 consecutive patients with ES [median age was 40 (18–65) years, median body mass index was 21.5 (15.0–36.2) kg/m2, while 11 (64.7%) were women] and 17 age- and sex-matched healthy controls [median age was 42
Discussion
The main finding of our study is the manifestation of peripheral microvascular impairment assessed by NVC in patients with ES. In particular, ES individuals demonstrated both reduced capillary density and increased capillary dimensions compared to controls, whilst microhaemorrhages, thrombi and shape abnormalities, usually reported in SSc [22], − a condition characterized by systemic microcirculatory changes - were also observed. To the best of our knowledge, this is the first time that such
Conclusion
This study demonstrated significant NVC microvascular changes in patients with ES suggestive of impaired peripheral microcirculation and altered neovascularisation. The similarities of nailfold capillaroscopic features with other forms of precapillary PH, favor pulmonary vascular disease as the trigger factor of peripheral endothelial dysfunction, further supporting the hypothesis that microangiopathy in ES may not be strictly restricted in the pulmonary vascular bed. On the contrary, the
Funding
This study was funded by the Greek Society of Rheumatology & Professional Association of Rheumatologists (protocol number 856).
Conflicts of interest
None declared.
Acknowledgements
Alexandra Arvanitaki is the recipient of the International Training and Research Fellowship EMAH Stiftung Karla Voellm, Krefeld, Germany. We thank Konstantinos Arvanitakis for English language editing.
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All authors listed take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.