Against the Odds: Risk Stratification with Cardiac Magnetic Resonance Imaging in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare, heterogeneous disease characterized by a distinct microvascular remodeling with a concomitant increase of pulmonary arterial pressure and resistance (1). As a central pathophysiological element, the right ventricle eventually reacts to the increased load, leading from adaptation to maladaptation and beyond as eventually failure ensues (2). The state-of-the-art therapeutic strategy to address this pathophysiological progression is based on individual risk stratification (3). This risk assessment integrates pulmonary hemodynamics, symptoms, functional capacity, laboratory values, and echocardiographic parameters to classify the patient as low, intermediate, or high risk (3). Although the included variables, number of patients, geographical heterogeneity, and definition of the average low-risk score vary among studies, recent analyses of large PAH registries have proven the clinical and therapeutic relevance of this risk assessment (3).

Cardiac magnetic resonance imaging (CMRI) is currently considered the gold-standard technique to evaluate right ventricular (RV) volumes and function (4), and is recommended for the follow-up of patients with pulmonary hypertension (5), but it has not been integrated into risk stratification. One might argue that this is overdue, as CMRI-derived volumetric measures, including stroke volume (SV), RV end-diastolic volume, and RV end-systolic volume (ESV), mirror the RV adaptational process, have prognostic value, and are easy to assess. The RV ejection fraction (EF) and the SV/ESV ratio have also been shown to have prognostic value (6, 7), and a low SV index at baseline and a reduction in the SV index during treatment have both been associated with increased mortality (8). Assessment of RV mass is also of great importance; it provides a valuable prognostic parameter when combined with volume in a mass/volume ratio, as lower mass/volume ratios (signifying eccentric hypertrophy) are associated with more severe functional impairment (9) and independently predict clinical worsening. Furthermore, RV mass was recently shown to predict outcomes in PAH (10). Although longitudinal relaxation time mapping has the potential to be a marker of fibrosis (11) and could allow early detection of myocardial involvement in pulmonary hypertension, it was not found to be prognostic independently of RV size and function in patients with PAH.

The evaluation and validation of CMRI for risk stratification in PAH by Lewis and coworkers (pp. 458–468) in this issue of the Journal (12) might pave the way for CMRI to become part of risk assessment. Using a referral center registry, the authors carefully analyzed CMRI data in a large population of patients with PAH at baseline and, for a proportion of the patients, at the first follow-up. The majority of the included patients ultimately received PAH-specific combination therapy. Overall 1-year mortality was 8.7%, although the majority of patients entered the study in an advanced state of disease (72% of the patients were in functional class ≥III) and a substantial proportion were classed as high risk at baseline. This indicates the following: first, the call for early combination therapy has reached daily clinical practice; second, 1-year survival of this incurable disease has improved dramatically during the last decade; and third, the goal of earlier disease recognition and identification of patients at lower risk (13) has not yet been realized (although the results might be biased by the fact that the authors included a population of patients with incident and prevalent PAH).

The authors were able to identify patients at low, intermediate, and high risk of 1-year mortality based on the RV EF, whereas only patients at low and high risk were identified using the RV ESV index % predicted and left ventricular (LV) end-diastolic volume index. In addition, transition to or maintenance of a lower RV ESV or higher RV EF was associated with better survival at follow-up. Besides representing the gold standard for volume assessment, what might be the added value of CMRI in the assessment of patients with PAH?

The findings by Lewis and coworkers fit perfectly into the current pathophysiological concept of RV–arterial coupling in PAH. To remain “coupled” and maintain an end-systolic/arterial elastance (Ees/Ea) ratio of 0.8, the right ventricle reacts to chronic pressure overload with homeometric adaptation (increased contractility) and heterometric adaptation (increased dimensions) (14). However, evaluation of Ees/Ea based exclusively on CMRI RV volume measurements has been reported, with Ees/Ea simplified as SV/ESV (15). Alterations of SV/ESV are necessarily associated with an increase in RV volumes to maintain SV. Interestingly, the parameters proposed by the authors mirror an additional important fact: during RV maladaptation to chronic pressure overload, RV hypertrophy and dilation lead to septal bowing and compression of the left ventricle, resulting in impairment of LV filling (RV–LV interdependence). Reduced RV SV and progressive remodeling of the pulmonary vasculature may also impair LV filling. CMRI is probably the best possible way to determine RV adaptation and maladaptation in pulmonary hypertension because of its ability to provide a holistic assessment of RV and LV volumes and function.

The authors are to be commended for their work, which hopefully will introduce CMRI parameters into risk stratification in PAH. CMRI parameters such as SV/ESV, RV mass, measures of RV deformation such as feature-tracking strain, four-dimensional flow in the right ventricle including assessment of vorticity, late enhancement, and longitudinal relaxation time and transverse relaxation time mapping, in combination with right atrial phase assessment with strain imaging, are promising tools to be explored in the future in terms of prognosis and perhaps risk stratification.