The predictive capabilities of a novel cardiovascular magnetic resonance derived marker of cardiopulmonary reserve on established prognostic surrogate markers in patients with pulmonary vascular disease: results of a longitudinal pilot study

Blood flow velocity through the main pulmonary artery is thought to decline in PAH due to impeded passage of cardiac output through remodelled microcirculation, dilation of proximal pulmonary vessels and eventually, impaired RV function [7]. Not surprisingly therefore, mean pulmonary arterial blood flow velocity (meanPAvel) measured at rest has been shown to correlate with measures of RV function, arterial load and exercise capacity, which are all important determinants of prognosis in PAH [7–11]. This study adds to our knowledge by demonstrating correlation between our non-invasive measure of ‘cardiopulmonary’ reserve (meanPAvel at peak hyperemia, [1]) and validated invasively and non-invasively derived surrogate prognostic markers at baseline and six month follow-up. This marker was superior to meanPAvel when measured at rest. This data would support further studies being undertaken with hard clinical endpoints, to establish if this novel marker would provide incremental prognostic information in patients with PAH or at high risk for incident PAH.

PAH is principally defined by the plexogenic pulmonary vasculopathy that underlies its genesis, increasing RV afterload and stress. These two compartments (the RV and pulmonary vasculature) are integrally related and not surprisingly therefore, measures of RV afterload (static e.g. PVR, and oscillatory e.g. pulmonary arterial stiffness, components), stress (e.g. NTpBNP), and functional adaptation (e.g. RVEF, RVESVI) all provide independent prognostic information. In isolation however, each parameter tends to provide a limited picture of the state of the ‘cardiopulmonary’ unit as a whole. In our study, meanPAvel at peak hyperemia correlated significantly with measures of RV afterload (e.g. PVRI and elastic modulus), RV functional adaptation (e.g. RVEF/RVESVI) and VA coupling (defined as the ratio of maximal systolic RV elastance: effective arterial elastance), suggesting a capacity to simultaneously interrogate the pulmonary vasculature, the RV, and their interaction in a simple, non-invasive fashion. The capacity to assess the RV and pulmonary vasculature as a collective unit may translate to improved ability to discriminate changes in ventricular function, arterial load, or both when compared to, for example, RVEF, a serial CMR measure that conveys consistent prognostic information in PAH patients [3, 12, 13].

‘Traditional’ prognostic parameters are generally measured at rest and are subject to the influence of unrelated systemic factors such as anxiety, hypertension and sedation which may be compounded by serial assessment. Moreover, they lack the capacity to assess physiological reserve, that is, they provide a static measure of a dynamic disease process. Our protocol, like other physiological stress tests, negates the influences of unrelated systemic factors whilst permitting assessment of reserve as it pertains to PAH, that is, the degree of functional pulmonary circulation recruitable by endothelial independent mechanisms with IV adenosine (‘vascular reserve’) and the capacity of the RV to increase blood flow in response to downstream circulatory recruitment (‘RV reserve’: chronotropic/inotropic). We postulate that the generally closer association found between meanPAvel at peak hyperemia with validated prognostic parameters, compared with meanPAvel measured at rest, was due to the capacity to assess the cardiopulmonary unit as whole and its’ reserve while ameliorating the impact of unrelated systemic processes.

Acknowledging the above, not all validated prognostic comparators correlated significantly with meanPAvel at peak hyperemia. Most notably, NTpBNP levels measured at initial assessment did not correlate with meanPAvel measured at the same assessment or at follow-up, although the relative change in NTpBNP correlated with the change in meanPAVel at peak hyperemia over time. Previous studies have demonstrated association between baseline NTpBNP levels, resting hemodynamics, lung function, peak VO2 and prognosis, CMR-derived measures of RV function, and association between change in NTpBNP over time and survival [14–19]. The discordant findings of strong correlation between meanPAVel at peak hyperemia, resting hemodynamics and markers of RV functional adaptation (RVEF, RVESVI) but no correlation with NTpBNP levels in absolute terms were unexpected and difficult to explain biologically: they may therefore reflect a statistical anomaly. A lack of correlation between change in meanPAvel and change in PVRI over time was likely due to the small sample size undergoing repeat RHC (N?=?10) or, as earlier discussed, the impact of unrelated systemic factors on resting measures that may compound with serial assessment. No correlation between change in meanPAvel at peak hyperemia and change in 6MWD over time may reflect the inherent limitations of serial 6MWDs and is in keeping with registry data showing a decline in 6MWD is prognostically relevant whereas an increase is not [6]. Closer association between these variables in the subset of patients that experienced a decline in 6MWD (n?=?9: R?=?0.59, P?=?0.22) is in keeping with our other findings, acknowledging that statistical significance was not met, likely due to a small sample size.