Independence Day
2016; Lippincott Williams & Wilkins; Volume: 133; Issue: 24 Linguagem: Holandês
10.1161/circulationaha.116.023237
ISSN1524-4539
Autores Tópico(s)Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
ResumoHomeCirculationVol. 133, No. 24Independence Day Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBIndependence DaySeparating Right Ventricular Function From Pulmonary Arterial Hypertension in Systemic Sclerosis Bradley A. MaronMD Bradley A. MaronBradley A. Maron From Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Department of Cardiology, Boston VA Healthcare System, Boston, MA. Originally published11 May 2016https://doi.org/10.1161/CIRCULATIONAHA.116.023237Circulation. 2016;133:2345–2347Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 14, 2016: Previous Version 1 Systemic sclerosis (SSc) describes a range of heterogeneous clinical disorders that are characterized broadly by increased inflammation and autoimmunity, which promote fibrosis in visceral organs and the pulmonary and systemic circulatory beds. The pattern of scleroderma (ie, skin thickening) categorizes patients further as limited cutaneous SSc (which includes the CREST [calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia] 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 attributable to effacement of pulmonary arterioles primarily from severe hypertrophic and fibrotic remodeling, occurs more commonly in patients with limited cutaneous SSc.2Article, see p 2413There is important overlap between SSc and primary pulmonary vascular disease, including idiopathic PAH (iPAH). Hyperinflammation, dysregulated humoral autoimmunity, and platelet overactivation 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-γ represent just a minority of pathogenetic mechanisms implicated in the development of SSc and the pulmonary vasculopathy of iPAH.3–6This overlap is likely to account for elevated PAH prevalence in SSc that by some estimates reaches 12%, which is a substantially higher rate compared with other at-risk subgroups such as those with sickle cell anemia and HIV, of whom PAH affects 3% and 0.5% of patients, respectively.7 On the basis of 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, whereas SSc-PAH is associated with a 3-fold higher risk of death compared with iPAH and a 48% mortality rate at 3 years after diagnosis.2,7 Furthermore, in many clinical trials, SSc-PAH appears less responsive to PAH therapy relative to other subgroups.8 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 this edition of Circulation, Hsu and colleagues9 provide compelling and much needed insight into establishing the hallmark features of a right-sided 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 (RV) pressure-volume relationship for 15 patients with SSc-PAH and 9 iPAH patients. Through the rigorous and simultaneous assessment of these 2 critically important measures, RV pressure-volume 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 impaired lusitropy, diminished RV pump efficiency indicated by RV–pulmonary vascular uncoupling and attenuated augmentation of RV contractility, and increased RV volume implying cavitary dilation.Perhaps most illuminating was the observation that these deleterious changes in RV function and structure during exercise in SSc-PAH occurred despite a rate of increase in effective arterial elastance (ie, RV afterload) that was similar in magnitude to that in iPAH patients. The absence of a meaningful difference in RV afterload at exercise between these 2 groups might have been expected from 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 that in 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 present 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 multiorgan syndrome of SSc.These findings have a number of important ramifications on the cardiopulmonary disease field. First, it is evident now more than ever that RV function must be regarded beyond its current role as primarily a marker of prognosis. Findings from the present 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, which remains incompletely characterized in PAH, but enhanced consideration of the primary disease substrate (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 comorbid 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 pressure-volume 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 because 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 explanations for the study findings. The presence of RV hypertrophy has been implicated as both adaptive and maladaptive in PAH.15 Thus, although the RV midventricular free wall thickness was increased somewhat in SSc-PAH compared with 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 indexes does not seem justified. Similarly, the authors' observation that patients with SSc-PAH 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 the involvement of sarcoplasmic endoplasmic reticulum calcium (Ca2+) ATPase, 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 requires further study; therefore, an indirect yet important consequence of the present work is rekindled emphasis on characterizing RV cardiomyocyte biology in SSc.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 pressure-volume 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 with a functional profile that is dynamic and disease specific. In this way, the present study leads an emerging movement18–20 contemporizing the framework by which SSc-PAH specifically and pulmonary vascular disease in general are defined and considered clinically.Sources of FundingDr Maron has received funding from the National Institutes of Health (1K08HL11207-01A1), American Heart Association (15GRNT25080016), Pulmonary Hypertension Association, Cardiovascular Medical Research and Education Fund, and Klarman Foundation at Brigham and Women's Hospital.DisclosuresDr Maron receives funding from Gilead Sciences to research pulmonary hypertension.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Bradley A. Maron, MD, 77 Ave Louis Pasteur, NRB Room 0630-N, Boston, MA 02115. E-mail [email protected]References1. Deswal A, Follansbee WP. Cardiac involvement in scleroderma.Rheum Dis Clin North Am. 1996; 22:841–860.CrossrefMedlineGoogle Scholar2. 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