Author + information
- aDepartment of Internal Medicine, Chicago Medical School, Rosalind Franklin University, North Chicago, Illinois
- bDepartment of Bioengineering, College of Engineering (Bioengineering), College of Medicine, University of Illinois, Chicago, Illinois
- cCollege of Medicine, University of Illinois, Rockford, Illinois
- dAdvocate Heart Institute, Advocate Lutheran General Hospital, Park Ridge, Illinois
- eShands Medical Center Department of Pediatrics, University of Florida, Gainesville, Florida
- ↵∗Address for correspondence:
Dr. Marc Ovadia, Advocate Heart Institute, Lutheran General Hospital, Parkside Pavilion 605, 1875 Dempster Street, Park Ridge, Illinois 60068.
- chronic thromboembolic pulmonary hypertension
- pulmonary angiogram
- pulmonary arterial hypertension
- V/Q SPECT imaging
- lung allocation score
- lung transplantation
Despite a plethora of novel pulmonary vasodilators, patients with pulmonary hypertension (PAH) continue to succumb to their disease. Although the newer drugs have resulted in an improved intermediate-term prognosis for many patients (1), they are of limited use for others, and of no use whatsoever in certain PAH subtypes (e.g., group 3 or in those with sickle cell anemia).
The role of lung transplantation (LTX)—the one approach which in effect cures PAH—continues to be poorly defined, particularly with respect to its timing. For PAH patients failing medical management, lung transplantation (LTX) offers the sole meaningful chance for survival (2). (In patients with pulmonary hypertension plus right or left ventricular dysfunction, or pulmonary hypertension plus congenital heart defect, it is heart and lung transplantation that constitutes the sole therapeutic option that may lead to survival.) A recent consensus suggests certain triggers for referring PAH patients for transplantation and others for placing them on a waiting list (3), but as we will discuss later, there are difficulties with this approach. Most experts favor LTX for those PAH patients who are within 1 to 2 years of death (3), but such prognostication is difficult or impossible in the present state of clinical science because of unpredictability of the course of PAH, and this is difficult to operationalize in the United States because of the current approach to lung allocation.
In this issue of iJACC, Chan et al. (4), of the UK National Pulmonary Hypertension Service, present what may be a useful insight into the pathophysiology and clinical assessment of PAH. Using ventilation and perfusion single-photon emission computed tomography (V/Q-SPECT) they appear to demonstrate the existence of a clinically and radiologically distinct group of PAH characterized by diffuse vascular damage as imaged by this modality. This may represent a previously unappreciated phase of PAH or the final common pathway of its multiple pathophysiologic subtypes, including idiopathic pulmonary hypertension (IPAH), PAH associated with systemic sclerosis and nonsclerodermatous connective tissue diseases (5), and others. This may even represent a distinct nosologic type of PAH. The importance of this finding is that these patients are characterized by a dramatically increased risk of death. Here, we review the authors’ data and conclusions. Furthermore, from a U.S. perspective, which must take into account LTX and the optimization of organ allocation, we propose the more far-reaching conclusion that these V/Q-SPECT findings may have use as the trigger for LTX, which may improve patient survival.
To probe the meaning of V/Q-SPECT findings in adults with PAH, Chan et al. (4) studied 136 sequentially evaluated patients and correlated their V/Q-SPECT patterns with their outcomes and other work-up. The patients all had PAH diagnosed by heart catheterization, but no heart or parenchymal lung disease, and after V/Q-SPECT scintigraphy, they underwent CT arteriography, and subsequently conventional pulmonary arteriography and targeted invasive pulmonary angiography, where relevant, to exclude distal thromboembolism. What caught the attention of the authors is that 75 patients showed significant perfusion deficits, but in fact had no evidence of thromboembolism on the corroborating angiographies.
Hypothesizing that SPECT scintigraphy might be providing unexpected insight into nonthromboembolic pathophysiology of PAH, Chan et al. reanalyzed scans in a blinded fashion, classifying them as: 1) normal scans without perfusion defects; 2) those with focal perfusion defects indicative of segmental or subsegmental obstruction; and 3) those with global perfusion defects. This disjunction was robust, with minimal discrepancies, and an interclass correlation coefficient of 98% (95% confidence interval: 0.97 to 0.99).
The study disclosed perfect correspondence of the novel V/Q-SPECT categories with hemodynamic severity: PAH was mild in patients with focal defects, moderate in those with normal scintigraphy, and most severe in those with bilateral perfusion defects (“global perfusion defects”). By analysis of variance there were significant differences among the 3 groups in mean pulmonary arterial pressure (p < 0.00015) and in pulmonary vascular resistance (p < 0.004). As a higher incidence of scleroderma was present in the global perfusion defect group (p < 0.05), those patients were analyzed separately, and the same findings were confirmed among patients with systemic sclerosis. On follow-up for 373 ± 200 days, the global perfusion defect group fared far worse than the others, with far higher mortality and an extremely high hazard ratio for death of 5.63 by Mantel-Haenszel (chi-square) treatment compared with the rest of the patients (Figure 1A).
The authors concluded that the global perfusion defect subgroup stood alone as a readily identifiable set of patients at high mortality risk, and they hypothesized that such V/Q-SPECT findings “could reflect obliteration of distal pulmonary vessels, a pathological feature that precede[s] progression to right heart failure”—and, we add, perhaps other processes as well that may lead to death. The Mantel-Haenszel graph makes clear that the data are dense enough to corroborate the authors’ assertion. Though the median survival point is not reached, the unimodality of the slope implies it is 700 to 800 days in the global perfusion defect group in comparison with median survival of more than double that in the other group. In fact, all the mortality was in the global perfusion defect group, occurring in more than 1 PAH subtype, including IPAH, PAH associated with systemic sclerosis, and PAH of nonsclerodermatous connective tissue diseases. Importantly, the pattern of mortality in the V/Q-SPECT global perfusion defect group is a continuing unremitting drop-off, far different from that after LTX for PAH, where primary graft failure, infections, and perhaps left heart failure account for an early survival disadvantage, followed, 6 to 12 months post-LTX, by a markedly reduced rate of mortality among the survivors of that early phase (2). This early survival disadvantage may be unique to recipients with PAH, specifically to those with IPAH (Figure 1). The reason for this may be that a chief risk factor for primary graft failure (grade ≥3) is idiopathic pulmonary hypertension of the recipient (7,8).
Further, the incidence of mortality in the global perfusion defect group is in the range of those to whom LTX modalities are offered in American clinics.
The identification by V/Q-SPECT of a clinically unique and pathophysiologically meaningful subgroup of adult PAH patients with far greater mortality than the rest of the cohort (hazard ratio: 5.6) is certainly of interest in the context of interpreting these studies, and it contributes as well to a description of the natural history of PAH. However, far beyond that, it is of game-changing importance in LTX for PAH.
Now a sound decision on the timing of referral and listing for, and ultimately the performance of, LTX hinges on the ability to prognosticate each patient’s survival on his or her current therapy (especially in relation to the estimated wait time) versus that patient’s survival following lung or heart–lung transplantation. In an ideally timed LTX, the candidate should have enough reserve to survive to transplant and recover from it. Such LTX is neither too early (thereby imposing on the recipient its own actuarial survival and its own effects on quality of life, which may be worse than those of his or her PAH), nor too late, jeopardizing the recipient’s chances of recovery and possibly denying another candidate access to the scarce organ (9). In the United States, this approach is operationalized by the use of the lung allocation score (LAS) to govern access to transplantable lungs in adult recipients. LAS, the arithmetic difference between a term intended to quantitate the probability and duration of post-transplant survival and a corresponding term for survival while waiting for transplant, each calculated based on a small number of disease-specific metrics, serves as a single means for comparison of the likely benefit from LTX across diverse pulmonary diseases and cardiologic morbidities.
Yet it is now accepted that LAS may discriminate against candidates recipients with IPAH versus those with idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), or cystic fibrosis (2).
The seminal results that Chan et al. (4) present may offer a lasting and substantive remedy for the problem. By offering an efficacious and readily available tool (V/Q-SPECT) that predicts mortality, Chan et al. (4) place prognostication in PAH on a firm footing, similar to that enjoyed by chronic obstructive pulmonary disease, cystic fibrosis, and pulmonary fibrosis—3 members of the family of diseases that compete for the same donor organs for LTX. In those diseases, excellent predictors of mortality exist: the BODE (body mass index, airflow obstruction, dyspnea and exercise capacity index) prognostication score (10) for COPD is highly predictive of mortality, and the BODE score is rightly regarded as a “landmark” development in the field (10,11); in cystic fibrosis, multiple organ system indices are similarly predictive—though only some pulmonary function indices are predictive (e.g., forced expiratory volume in 1 s, but not Forced Vital Capacity [FVC] FVC) (12,13)—and in idiopathic pulmonary fibrosis the GAP score (14) is of comparable efficacy. (The GAP score refers to the Gender, Age and two lung Physiologic variables, FVC and DLCO, multidimensional index .) In PAH, so useful a predictor of mortality has hitherto been lacking. These V/Q-SPECT observations could provide such a predictor.
If the results of Chan et al. are corroborated, one must conclude that the identification of global perfusion defects (in the absence of thromboembolism) should be used as a trigger for LTX, so that LTX can be expedited for the PAH patients with the global perfusion defects on V/Q-SPECT that identify so greatly increased a risk of death (hazard ratio: 5.6). Corroboration of the data will require prospective data gathering and serial studies to confirm robustness of the trifold disjunction. The effect on scintigraphy of comorbid conditions and of vasodilator and other disease-modifying drug therapies must be identified and atlased. For example, in IPF (15), 20% to 45% have pulmonary hypertension—45% if they come to LTX—and drug therapies evaluated must include not only the vasodilators but also the antifibrotic drugs pirfenidone and nintedanib (16). From the U.S. perspective, in the context of the LAS framework, incorporation of V/Q-SPECT findings into a revised LAS should be implemented, a strong and serious recommendation from the editorial pages of JACC: Cardiovascular Imaging. This would put V/Q-SPECT results in the same class as the BODE score in COPD (10); multiple indices of pulmonary, hepatic, and pancreatic function for cystic fibrosis; and the GAP in IPF. For COPD and IPF, the chief of these are already incorporated into the LAS.
We do not know the underlying anatomic pathology of the subgroup of patients with global perfusion deficit on V/Q-SPECT, but this should not be disconcerting to the clinician, as in end-stage PAH it is probably unimportant which pathologic process predominated early in pathogenesis. The present situation may be similar to how cardiac transplant clinicians were slow to distinguish between idiopathic dilated cardiomyopathy and cardiomyopathy of ischemic origin before 1982, but once this was done, the field advanced rapidly. For it turned out that very few etiologic distinctions were necessary in the adult within the idiopathic dilated group, to choose life-saving therapy (e.g., tachycardia cardiomyopathy and hemochromatosis are to be distinguished, but little else). The same is true for PAH, based on the conclusions of this study. If these V/Q-SPECT results do prove robust, and if they can be used to prioritize LTX in PAH patients on, or failing, medical therapy, then they may lead to improved survival in these patients, and ultimately represent a giant leap in the field of LTX for PAH.
The authors acknowledge C. Ovadia of Asterisk, Inc., for redrawing the figures, and Margaret E. Billingham, MBChB, our teacher in lung transplant pathology.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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