Independence Day: Separating Right Ventricular Function From Pulmonary Arterial Hypertension in Systemic Sclerosis

Systemic sclerosis (SSc) describes a range of heterogeneous clinical disorders that are characterized broadly by increased inflammation and auto-immunity, which promote fibrosis in visceral organs as well as the pulmonary and systemic circulatory beds. The pattern of scleroderma (i.e., skin thickening) categorizes patients further as limited cutaneous SSc (which includes the CREST^† syndrome) or diffuse cutaneous SSc. Involvement of the myocardium, pericardium, cardiac conduction system, or pulmonary vasculature is observed in up to 25% of affected patients, but may contribute to the constellation of clinical findings accompanying either disease subtype.¹ However, pulmonary arterial hypertension (PAH), which in this patient population is due to effacement of pulmonary arterioles primarily from severe hypertrophic and fibrotic remodeling, occurs more commonly in patients with limited cutaneous SSc.²

There is important overlap between SSc and primary pulmonary vascular disease, including idiopathic PAH (iPAH). Hyperinflammation, dysregulated humoral autoimmunity, and platelet over-activation are common to both, and in each case mediate endothelial dysfunction, fibrillar collagen deposition, and intimal thickening of pulmonary arterioles. Increased vascular reactive oxygen species accumulation and abnormalities to pathways that involve Wnt ligands, connective tissue growth factor, endothelin-1, and the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ represent just a minority of pathogenetic mechanisms implicated in the development of SSc and the pulmonary vasculopathy of iPAH.^3–6

This overlap is likely to account for elevated PAH prevalence in SSc that by some estimates reaches 12%, which is a substantially higher rate compared to other at-risk subgroups such as those with sickle cell anemia and human immunodeficiency virus for whom PAH affects 3% and 0.5% of patients, respectively.⁷ Based on similarities in vascular pathophenotype, it may also be anticipated that therapeutic efficacy and clinical outcome in SSc-PAH is comparable to iPAH. However, this is not the case. Even in the contemporary era, PAH remains the principal cause of death in SSc, while SSc-PAH is associated with a 3-fold higher risk of death compared to iPAH and 48% mortality rate at 3-years following diagnosis.^2,7 Furthermore, in many clinical trials SSc-PAH appears less responsive to PAH therapy relative to other subgroups.^8,9 The unavailability of PAH treatments that abrogate pulmonary vascular fibrosis effectively or target bona fide SSc-PAH disease-causing pathways is likely to account for this observations to some extent. However, seeking alternative explanations by which to account for the precipitous downward clinical trajectory in SSc-PAH has long been a target of clinical investigation.

In the current edition of Circulation, Hsu and colleagues⁹ provide compelling and much needed insight toward establishing the hallmark features of a right heart pathophysiology that is specific to SSc-PAH. To accomplish this, the authors analyzed differences between rest and exercise (or atrial pacing) in the right ventricular pressure-volume (RV-PV) relationship for 15 patients with SSc-PAH and 9 iPAH patients. Through the rigorous and simultaneous assessment of these two critically important measures–-RV-PV and exercise—analyzing pulmonary vascular disease with respect to derivative changes in RV and clinical function is possible. The principal findings of the study showed a unique RV functional profile during exercise in SSc-PAH that was characterized by i) impaired lusitropy, ii) diminished RV pump efficiency indicated by RV-pulmonary vascular uncoupling and attenuated augmentation of RV contractility, and iii) increased RV volume inferring cavitary dilation.

Perhaps most illuminating was the observation that these deleterious changes to RV function and structure during exercise in SSc-PAH occurred despite a rate of increase in effective arterial elastance (i.e., RV afterload) that was similar in magnitude to iPAH patients. The absence of a meaningful difference in RV afterload at exercise between these two groups might have been expected based on earlier findings from the same research team showing similar pulmonary artery compliance at rest in matched iPAH and SSc-PAH populations.¹⁰ However, by demonstrating transient RV failure induced during exercise in SSc-PAH patients despite RV afterload that was on par with the iPAH cohort, who maintained RV performance during exercise, the investigators provide definitive evidence indicating that the RV-pulmonary vascular relationship is variable across PAH subgroups. Thus, the current work provides a critical clue that may ultimately resolve the unexplained difference in clinical outcome among SSc-PAH patients relative to other pulmonary vascular disease subgroups: intrinsic RV dysfunction as an independent contributor to the larger multi-organ syndrome of SSc.

These findings cast a number of important ramifications on the cardiopulmonary disease field. First, it is evident now more than ever before that RV function must be regarded beyond its current role as primarily a marker of prognosis. Findings from the current study pave the way for careful consideration to the RV itself as a differential target of end-organ damage. Detecting RV vulnerability is likely still to hinge on RV-pulmonary vascular mechanics, perhaps via RV myocardial ischemic burden that remains incompletely characterized in PAH, but enhanced consideration to the primary disease substrate (i.e., RV targeting by inflammation, neurohumoral cardiac effectors, etc.) as an independent mediator of RV dysfunction now seems warranted.

Second, these data introduce an empirical basis, through induced RV-pulmonary vascular uncoupling during exercise, to potentially explain earlier observations linking exercise intolerance to SSc patients even when resting pulmonary artery pressure is within the current range of normal or only mildly increased.¹¹ Given the importance of co-morbid PAH on mortality in SSc, recent clinical trial data supporting early aggressive therapy in this patient population,¹² fresh reports identifying the limitations of conventional cardiopulmonary hemodynamics for assigning clinical risk,¹³ and an overarching mandate in the field emphasizing approaches for PAH prevention,¹⁴ it would seem that findings from this study justify further investigation of RV-PV as a useful tool for SSc-PAH risk stratification early in the disease course. Indeed, additional investigations are needed to characterize the relevance of inducible RV-pulmonary vascular uncoupling to hard clinical end-points across a broader spectrum of SSc-PAH, as the majority of patients under investigation in this study had severe heart failure symptoms and a substantially decreased peak volume of oxygen consumption on exercise testing.

Third, these data stimulate a priority for investigating pathophysiological and pathobiological mechanisms that delineate RV dysfunction in SSc from other PAH syndromes. In this study, no difference between patient groups was observed at rest for RV end-diastolic volume or pattern of late-gadolinium enhancement distribution, thereby eliminating grossly abnormal baseline RV structure or fibrosis burden as reasons by which to explain the study findings. The presence of RV hypertrophy has been implicated as both adaptive and maladaptive in PAH.¹⁵ Thus, although the RV mid-ventricular free wall thickness was increased somewhat in SSc-PAH compared to iPAH patients in this study, attributing impaired RV performance in SSc-PAH to this finding in the absence of differences in RV mass or other geometric indices does not seem justified. Similarly, the authors’ observation that SSc-PAH patients exhibit a decrease in RV recirculation fraction, which is an indirect measure of calcium cycling in the cardiomyocyte sarcoplasmic reticulum, is consistent with recent reports identifying involvement of SERCA2a, phospholamban, and other calcium handling proteins in the RV myocardium to the pathogenesis of PAH.^16,17 Determining the relevance of these intermediaries to SSc-PAH will require further study, and, therefore, an indirect yet important consequence of the current work is rekindled emphasis on characterizing RV cardiomyocyte biology in SSc.

Taken together, Hsu and colleagues have pioneered a new path toward understanding SSc-PAH and, more broadly, expose the importance of rigorous RV physiological assessment for elucidating the clinical profile of cardiopulmonary disease. Through meticulous analysis of RV-PV studies, the investigators provide potential insight into the troubling association between SSc-PAH and dismal outcome: impaired RV functional reserve decreasing the threshold for developing RV failure. The specific clinical utility of these findings remains forthcoming, as does elucidation of the mechanisms regulating RV dysfunction in SSc-PAH relative to other PAH subgroups. Nonetheless, findings from this work crystallize the RV as an independent contributor to cardiopulmonary disease whose functional profile is dynamic and disease-specific. In this way, the current study leads an emerging movement^18–20 contemporizing the framework by which SSc-PAH, in specific, and pulmonary vascular disease, in general, are defined and considered clinically.