Pulmonary Artery Dilatation Correlates With the Risk of Unexpected Death in Chronic Arterial or Thromboembolic Pulmonary Hypertension

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1 CHEST Pulmonary Artery Dilatation Correlates With the Risk of Unexpected Death in Chronic Arterial or Thromboembolic Pulmonary Hypertension Original Research PULMONARY VASCULAR DISEASE Joanna Żyłkowska, MD ; Marcin Kurzyna, MD, PhD ; Michał Florczyk, MD ; Barbara Burakowska, MD, PhD ; Franciszek Grzegorczyk, MD ; Janusz Burakowski, MD, PhD ; Maria Wieteska, MD, PhD ; Karina Oniszh, MD, PhD ; Andrzej Biederman,MD, PhD ; Liliana Wawrzyńska, MD, PhD ; Monika Szturmowicz, MD, PhD, FCCP ; Anna Fijałkowska, MD, PhD ; and Adam Torbicki, MD, PhD Background: Right ventricular failure does not explain all cases of death in patients with chronic pulmonary hypertension. Searching for alternative explanations, we evaluated the prognostic significance of main pulmonary artery (PA) dilatation in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Methods: A retrospective outcome analysis was made of 264 patients (aged years; women, 69%; PAH, 82%) who underwent both CT scan measurement of the PA and right-sided heart catheterization (mean PA pressure, mm Hg) at initial evaluation. Results: The diameter of the PA ranged from 28 to 120 mm (mean, mm; median, 38 mm) and was largest in patients with unrepaired congenital defects ( mm). Pulmonary pulse pressure ( P 5.04), lower age ( P 5.03), and duration of symptoms ( P,.001) were independently but weakly related to PA diameter. During follow-up (median, 38 months), 99 patients (37%) died. Of these 99 deaths, 73 (74%) were due to heart failure or comorbidities, and 26 (26%) were unexpected deaths (UE-Ds). PA diameter (hazard ratio [HR], 1.06 per 1 mm; 95% CI, ), heart rate (HR, 1.30 per 10 beats/min; 95% CI, ), and systolic pulmonary arterial pressure (HR, 1.02 per 1 mm Hg; 95% CI, ) were the only independent predictors of UE-D and differed from the usual predictors found in the study group for all-cause mortality. PA diameter 48 mm had 95% specificity and 39% sensitivity and carried 7.5 times higher risk of UE-D (95% CI, ; P,.0001) during follow-up. Conclusions: PA dilatation emerges as an independent risk factor for death unexplained by right ventricular failure or comorbidities in patients with PAH and CTEPH. The possible mechanisms include, but are not limited to, PA compression of the left main coronary artery, PA rupture, or dissection with cardiac tamponade. CHEST 2012; 142(6): Abbreviations: CHD 5 congenital heart defect; CTD 5 connective tissue disease; CTEPH 5 chronic thromboembolic pulmonary hypertension; HF-D 5 heart failure-related death; HR 5 hazard ratio; IPAH 5 idiopathic pulmonary arterial hypertension; LMCA 5 left main coronary artery; NT-proBNP 5 N-terminal pro B-type natriuretic peptide; PA 5 pulmonary artery; PAH 5 pulmonary arterial hypertension; PAP 5 pulmonary artery pressure; PH 5 pulmonary hypertension; PVR 5 pulmonary vascular resistance; ROC 5 receiver operator characteristic; RV 5 right ventricular; UE-D 5 unexpected death Most deaths in patients with pulmonary arterial hypertension (PAH) can be explained by progressive right ventricular (RV) failure. 1-3 However, some patients die unexpectedly outside the hospital. Little is known about the determinants of these deaths. Dilatation of the pulmonary artery (PA) due 1406 to pulmonary hypertension (PH) has been suggested as a cause of potentially arrhythmogenic left ventricular ischemia. 4 PA dilatation could also lead to dissection of the PA with fatal pericardial tamponade, more frequently than so far believed To further our understanding of the clinical significance of Original Research

2 PA dilatation, we reviewed the outcome of patients with PH followed in our center according to their initial PA diameter. Materials and Methods We retrospectively analyzed the outcome of 300 patients referred to the PH center between 1998 and 2009 who were followed by our team because of the diagnosis of PAH or chronic thromboembolic PH (CTEPH) unsuitable for surgical treatment. The diagnosis was made based on an algorithm including rightsided heart catheterization. The treatment after enrollment followed the best locally available treatment strategy. Two hundred sixteen patients (72%) were treated with targeted therapy, which included a phosphodiesterase type-5 inhibitor (sildenafil), endothelin receptor antagonists (ambrisentan, bosentan, sitaxsentan), and prostanoids (inhaled iloprost and subcutaneous treprostinil). Combination therapy was used in 97 cases (32%). After initial diagnosis, the patients were followed by our center, which served as a key national referral center for PH. The patients were regularly contacted at 1- to 6-month intervals for monitoring required by the national therapeutic program, clinical trials, or to reassess indictions for lung transplantation. The patients and their families were also advised to contact our center if complications or comorbidities emerged. Ultimately, three patients were lost to follow-up; however, the assessment of survival status for all the patients was completed. For purposes of the survival analysis, death was considered unexpected ( unexpected death [UE-D]) if a patient with PAH or inoperable CTEPH either died suddenly (according to information received) or: did not demonstrate severe or progressive RV dysfunction requiring treatment escalation during recent routine follow-up contact and/or visit, and did not call our center to report signs/symptoms consistent with progression of RV dysfunction, new comorbidities, or complications of PH, and was not known to acquire other diseases or conditions with potentially deleterious consequences in patients with PH, such as infection, hyperthyroidosis, hemoptysis, arrhythmias, or pregnancy. Manuscript received November 12, 2011; revision accepted May 1, Affiliations : From the Department of Pulmonary Circulation and Thromboembolic Diseases (Drs Żyłkowska, Kurzyna, Florczyk, Wieteska, and Torbicki), Medical Center of Postgraduate Education, European Health Centre, Otwock; Department of Radiology (Drs Burakowska, Oniszh, and Fijałkowska), Cardio-Pulmonary Intensive Care Medicine (Dr Burakowski), Department of Chest Medicine (Dr Wawrzyńska), and the I Department of Pneumonology (Dr Szturmowicz), Institute of Tuberculosis and Lung Diseases, Warsaw; the I Chair and Department of Cardiology (Dr Grzegorczyk), Medical University of Warsaw; and the Department of Cardiac Surgery (Dr Biederman), Praski Hospital, Warsaw, Poland. Drs Żyłkowska and Kurzyna contributed equally to this article. Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Adam Torbicki, MD, PhD, Department of Pulmonary Circulation and Thromboembolic Diseases, Medical Center of Postgraduate Education, ECZ-Otwock, Poland, ul. Borowa 14/18, Otwock, Poland; adam.torbicki@ ecz-otwock.pl 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest Death in the remaining patients was considered as explicable by RV failure or comorbidities (heart failure-related death [HF-D]), as suggested by the signs/symptoms or information received. The classification of death as unexpected was done prior to analysis of the clinical and laboratory data and, thus, without any knowledge of the baseline data set, including results of initial PA diameter measurements. Since all correlations between variables were assessed retrospectively from already available data, neither patients consents nor approval of internal review board were applied for. CT Scan Angiography Protocol Until 2003, angiography-ct scan studies of the chest were performed using a single-detector spiral unit (PICKER PQS; Picker International Inc) and thereafter with a multidetector scanner (Somatom Sensation 16; Siemens AG). The standard CT scan angiographic protocol consisted of administration of 80 ml of the nonionic contrast material, injected at a rate of 4 ml/s with bolus tracking. The threshold level for triggering scanning was achieved when the attenuation of the pulmonary trunk reached 80 Hounsfield units. Axial scanning was performed from the lung apices to the diaphragm in inspiration. The section thickness was mm. The PA diameter was determined as the internal width of the pulmonary trunk in the contrast-enhanced image. It was measured on horizontal scans, perpendicularly to the long axis of the pulmonary trunk in the plane of transition to the right PA, directly on the monitor screen using an electronic cursor in the mediastinum window ( Figs 1A, 1B ). A PA diameter of 29 mm was considered as the upper limit of normal in healthy individuals. 13 The radiologic team (B. B. and K. O.) remained unaware of the clinical outcome of the evaluated cases. In 36 patients (12%), no baseline CT scans were available for analysis. A random sample of 50 CT scan studies was chosen for the assessment of interobserver variability between the two radiologists (B. B. and K. O.). Bland-Altman analysis calculated the interobserver agreement of 0.12 mm (SD, 1.24 mm). Right-Sided Heart Catheterization Protocol In 299 patients, right-sided heart catheterization was performed during the initial hospitalization. The PA pressures (systolic, diastolic, mean), mean right atrial pressures, pulmonary occlusion pressure, and mixed venous oxygen saturation were assessed. Pulmonary vascular resistance (PVR) and cardiac index were calculated based on thermodilution or Fick measurements of pulmonary flow, whichever was appropriate. One patient died suddenly after noninvasive evaluation, including CT scan, but before scheduled right-sided heart catheterization. Echocardiography revealed unequivocal signs of significant precapillary PH with tricuspid systolic pressure gradient. 100 mm Hg and marked domination of right over left heart chamber dimensions. Statistical Analysis Continuous variables were summarized by mean SD. Correlations between PA diameter and other variables were assessed with the Spearman R method. Backward stepwise multivariate regression analysis was performed to evaluate the relationship between PA diameter and demographic and hemodynamic variables. For categorical variables, the differences between the groups were compared using Yates corrected x 2 test. For continuous variables, Student t test or Mann-Whitney U test was used, depending on the character of distribution. Normality of distribution was tested with the Shapiro-Wilk test. The ability of the PA diameter to predict death was tested using receiver operating characteristic (ROC) curves. The proportion of patients surviving was estimated by the Kaplan-Meier method. Observations on patients who journal.publications.chestnet.org CHEST / 142 / 6 / DECEMBER

3 available baseline CT scans were initially classified as World Health Organization (WHO) functional class III (n 5 147, 55%) or functional class II (n 5 105, 40%). They presented with significantly compromised exercise tolerance (mean distance of 6-min walk test, m) and elevated concentration of N-terminal pro B-type natriuretic peptide (NT-proBNP) (mean, 2,095 2,543 pg/ml; median, 1,300 pg/ml). The mean PA diameter ranged from 28 to 120 mm (mean, mm; median, 38 mm). In 259 patients (98.1%), the PA diameter was greater than the predefined upper limit of normal ( Fig 2 ). Figure 1. A, Example of moderate (42 mm) dilatation of the pulmonary artery evaluated by CT scan. B, Example of large (57 mm) dilatation of the pulmonary artery evaluated by CT scan. underwent lung transplantation were censored at the time of the procedure, and observations on all patients 7 years from baseline assessment were not considered in the Kaplan-Meier analysis. Survival for the groups with PA diameter above and below the proposed cutoff point was compared using the logrank test. Univariate and multivariate Cox proportional hazard analysis of selected variables was performed to identify factors independently related to all-cause mortality and sudden death, controlling for possible confounders. A multivariate model was constructed from a set of variables, which were of prognostic significance in univariate analysis. Results are expressed as hazard ratios (HRs) with 95% CI. Interobserver variability of CT scan readings was assessed by Bland-Altman analysis. P value was considered statistically significant when All analyses were performed using STATISTICA 9.0 (StatSoft, Inc) computer software. Results Basic Characteristics and Hemodynamic Data Clinical and hemodynamic data of 264 patients included in the analysis and 36 (12%) excluded from the trial because of unavailable baseline CT scans are presented in Table 1. Most of the 264 patients with Risk Factors Predisposing to PA Dilatation The correlations of PA diameter and PAP were weak ( r 50.18, P 5.003; r 50.16, P 5.01; r 50.18, P 5.004; r 50.12, P 5.05 for systolic/diastolic/mean/pulse PAP, respectively). PA diameter correlated negatively with age ( r , P 5.02) and positively with duration of symptoms before baseline evaluation ( r , P,.001). PA diameter did not correlate with weight, height, body surface area, WHO functional class, NT-proBNP concentration, or right atrial pressure. Multiple regression analysis revealed pulmonary pulse pressure ( b, 0.12; P 5.04), age ( b, 20.12; P 5.03), and duration of symptoms ( b, 0.28; P,.001) as factors independently related to PA diameter. Patients with PAH associated with unrepaired congenital heart defects (CHDs) were characterized by the largest PA diameter ( mm, P 5.01; vs idiopathic PAH [IPAH], P vs CTEPH), whereas those with PAH associated with connective tissue disease were a subgroup with the least PA dilatation ( mm; P,.001 vs unrepaired CHD, P 5.04 vs corrected CHD, P 5.01 vs IPAH). Patients with IPAH, CTEPH, and repaired CHD presented moderate PA dilatation: mm, mm, and mm, respectively. Survival Status Of the 264 patients who were followed for a mean of months (median 38 months), 99 (37%) died after 0.4 to 83 months (mean, months; median, 22 months). Four patients (2.2%) underwent double lung transplantation. The mean follow-up period of the 165 survivors was (range, 5-84; median, 49 months). The cumulative survival rate of all patients was 87% (95% CI, 83%-91%) at 12 months, 71% (95% CI, 65%-77%) at 3 years, and 57% (95% CI, 50%-64%) at 5 years. Compared with survivors, patients who died were characterized by higher heart rate (85 15 beats/min vs beats/min, P,.001), lower systolic BP ( mm Hg vs mm Hg, P 5.003), lower stroke volume (53 18 ml vs ml, 1408 Original Research

4 Table 1 Baseline Clinical, Functional, and Hemodynamic Characteristics of Patients With Available CT Scans and Subjects Excluded From Analysis Because of the Lack of CT Scans Characteristic Baseline CT Scans Available (n 5 264) Baseline CT Scans Unavailable (n 5 36) P Value Age, y NS Sex, male (female) 81 (183) 7 (29) NS Height, cm NS Weight, kg NS BMI NS Follow-up length, mo NS Cause of PH.003 Idiopathic and hereditary PAH 130 (49) 17 (47) PAH associated with CHD, unrepaired 23 (9) 1 (3) PAH associated with CHD, repaired 19 (7.2) 0 (0) PAH associated with connective tissue disease 44 (17) 10 (28) Other forms of PAH 1 (0.4) 3 (8) Pulmonary venoocclusive disease 1 (0.4) 0 (0) Chronic thromboembolic PH 46 (17) 5 (14) Heart rate, bpm NS Systolic arterial pressure, mm Hg NS Diastolic arterial pressure, mm Hg NS Systolic PAP, mm Hg Diastolic PAP, mm Hg Mean PAP, mm Hg Mean right atrial pressure, mm Hg NS Pulmonary artery occlusion pressure, mm Hg NS Cardiac output, L/min NS Cardiac index, L/min/m NS Pulmonary vascular resistance, Wood units NS Mixed venous O 2 saturation, % Aortic blood O 2 saturation, % NS Unexplained deaths 26 (9.9) 2 (5.6) NS Right-sided heart failure related deaths 73 (28) 10 (28) NS All-cause mortality 99 (38) 12 (33) Data are presented as mean SD or No. (%) unless otherwise noted. bpm 5 beats per min; CHD 5 congenital heart defect; NS 5 not significant; O 2 5 oxygen; PAH 5 pulmonary arterial hypertension; PAP 5 pulmonary arterial pressure; PH 5 pulmonary hypertension. P,.001), and lower mixed venous oxygen saturation (56.4% 9.4% vs 62.8% 8.9%, P,.001) at baseline. Nonsurvivors also presented with higher mean right atrial pressure ( mm Hg vs mm Hg, P,.001), higher PVR ( Wood units vs Wood units, P 5.002), and higher NT-proBNP concentration (2,846 3,040 pg/ml vs 1,671 2,100 pg/ml, P,.001) at admission. Figure 2. Distribution of pulmonary trunk diameter in the studied population of patients with arterial (n 5 218) or chronic thromboembolic pulmonary hypertension (n 5 46). journal.publications.chestnet.org CHEST / 142 / 6 / DECEMBER

5 Univariate and multivariate Cox proportional hazard analysis identified several well-recognized factors related to all-cause mortality ( Table 2 ). Heart rate, systolic arterial pressure, mean right atrial pressure, mixed venous saturation, and diagnosis of PAH associated with connective tissue disease (CTD) were independent predictors of survival. PA diameter was not related to all-cause mortality. However, among seven patients presenting with PA diameter 56 mm, six individuals died, all of them unexpectedly. Risk Factors for Unexpected Death In the group of 99 patients who died during follow-up, 26 deaths (26%) were classified as unexpected (UE-D). Such unexpected deaths occurred in 12 patients with IPAH, five with CTD, four with CTEPH, three with corrected CHD, and two with Eisenmenger syndrome. Those numbers corresponded to the relative prevalence of the respective etiologies in the whole studied group ( Table 1 ). Autopsies were performed in only two patients with IPAH who died unexpectedly. In both cases, cardiac tamponade due to dissection of dilated PA was found. Compared with patients who died because of progressive right-sided heart failure or comorbidities, patients who died unexpectedly were characterized at baseline by greater PA diameter ( mm vs mm, P,.001); higher systolic, diastolic, and mean PA pressure ( mm Hg vs mm Hg, P,.001; mm Hg vs mm Hg, P 5.006; and mm Hg vs mm Hg, P,.001, respectively); and higher PVR ( mm Hg vs mm Hg, P 5.04) (Table 3 ).14 When compared with survivors, patients who died unexpectedly had higher heart rate; lower systolic BP, cardiac index, and stroke volume; but also higher pulmonary arterial pressures and PVR and greater PA diameter ( Table 3 ). Univariate and multivariate Cox proportional hazard analyses confirmed an unusual panel of independent prognostic determinants of unexpected death: PA diameter (HR, 1.06 per 1 mm; 95% CI, ), heart rate (HR, 1.30 per 10 beats/min; 95% CI, ), and systolic pulmonary arterial pressure (HR, 1.02 per 1 mm Hg; 95% CI, ) ( Table 4 ). Increasing dimension of the PA, expressed in quartiles, was related to increasing contribution of unexpected deaths to all-cause mortality (Fig 3 ). The ROC curve (area under the curve, 0.73; 95% CI, ) identified a PA diameter of 48 mm as a useful cutoff point, with 95% specificity and 39% sensitivity for prediction of UE-D dur ing follow-up ( Fig 4 ). Kaplan-Meier survival analysis ( Fig 5 ) showed significant differences in unexpected death-free survival (log-rank test, P,.001) between patients with PA diameter 48 mm compared with those with PA diameter, 48 mm. Among 23 patients with PA diameter 48 mm, 10 (43%) died unexpectedly compared with 16 of 241 patients (6.6%, P,.001) with PA diameter, 48 mm. Patients having a PA diameter 48 mm were characterized by greater than seven times higher risk of unexpected death compared with those having a PA diameter, 48 mm (HR, 7.5; Table 2 Univariate and Multivariate Cox Proportional Hazard Analysis of Factors Related to All-Cause Mortality Univariate Cox Proportional Hazard Analysis Multivariate Cox Proportional Hazard Analysis x , P,.001 Parameter HR 95% CI P Value HR 95% CI P Value PA diameter, per 1 mm NS Heart rate, per 10 bpm , ,.001 Systolic arterial pressure, per 10 mm Hg , , min walk distance, per 50 m Baseline NT-proBNP, per 1,000 pg/ml ,.001 Baseline troponin T, per 0.1 ng/ml Pulmonary artery systolic pressure, per 1 mm Hg NS Pulmonary artery diastolic pressure, per 1 mm Hg Pulmonary artery mean pressure, per 1 mm Hg NS Mean right atrial pressure, per 1 mm Hg , Cardiac output, per 1 L/min Cardiac index, per 1 L/min/m Stroke volume, per 1 ml ,.001 Mixed venous saturation, per 1% , Pulmonary vascular resistance, per 1 Wood unit PAH associated with connective tissue disease , ,.001 PAH associated with congenital heart defect Treatment with targeted therapy NS HR 5 hazard ratio; NT-proBNP 5 N-terminal pro B-type natriuretic peptide; PA 5 pulmonary artery. See Table 1 legend for expansion of other abbreviations Original Research

6 Table 3 Baseline Clinical, Functional, and Hemodynamic Characteristics for the Subgroup According to Outcome Survivors, Unexplained Death, and Death Related to Right-Sided Heart Failure Characteristics Survivors (n 5 165) P Value SUR vs UE-D Unexpected Deaths (n 5 26) P Value UE-D vs HF-D HF-Related Deaths (n 5 73) P Value SUR vs HF-D Age, y NS Female, No. (%) 115 (70%) NS 21 (81) NS 47 (64) NS BMI NS NS Symptoms duration, mo 52 70; median, 29 NS 50 56; median, 36 NS 35 38; median, 24 NS Heart rate, bpm NS 84 14,.001 Systolic BP, mm Hg NS Diastolic BP, mm Hg NS NS WHO functional class I-II 69 (42) NS 14 (54) NS 24 (33) NS III 90 (55) 11 (42) 46 (63) IV 6 (3) 1 (4) 3 (4) Mean WHO functional class NS NS 6MWT distance, m NS NT-proBNP serum concentration, pg/ml 1,671 2,100; median,1,102 NS 2,556 3,377; median, 1,443 NS 2,958 2,923; median,1,929,.001 Troponin T serum concentration, pg/ml NS NS Treated with targeted therapy, % 165 (74) NS 22 (85) NS 51 (70) NS Pulmonary artery diameter, mm , , NS Pulmonary hemodynamics Systolic PAP, mm Hg 83 23, , NS Diastolic PAP, mm Hg NS Mean PAP, mm Hg 56 17, , NS Mean right atrial pressure, mm Hg NS NS ,.001 Pulmonary artery occlusion pressure, mm Hg NS NS NS Cardiac index, L/min/m NS Stroke volume, ml NS 52 18,.001 Arterial O 2 saturation, % NS NS NS Mixed venous O 2 saturation, % ,.001 Pulmonary vascular resistance, Wood units , Survival probability at 1 y, a % NS , ,.001 Survival probability at 3 y, a % NS , ,.001 Survival probability at 5 y, a % NS , ,8,.001 Data are presented as mean SD or No. (%) unless otherwise noted. 6MWT 5 6-min walk test; HF-D 5 heart failure-related death; SUR 5 survivor; UE-D 5 unexpected death. WHO 5 World Health Organization. See Table 1 and 2 legends for expansion of other abbreviations. a According to Reference 14. journal.publications.chestnet.org CHEST / 142 / 6 / DECEMBER

7 Table 4 Univariate and Multivariate Cox Proportional Hazard Analysis of Factors Related to Unexpected Mortality Univariate Cox Proportional Hazard Analysis Multivariate Cox Proportional Hazard Analysis x , P,.001 Parameter HR 95% CI P Value HR 95% CI P Value PA diameter, per 1 mm , ,.001 Heart rate, per 10 bpm Systolic arterial pressure, per 10 mm Hg min walk distance, per 50 m NS Baseline NT-proBNP, per 1,000 pg/ml NS Baseline troponin T, per 0.1 ng/ml NS Pulmonary artery systolic pressure, per 1 mm Hg , Pulmonary artery diastolic pressure, per 1 mm Hg Pulmonary artery mean pressure, per 1 mm Hg ,.001 Cardiac output, per 1 L/min NS Cardiac index, per 1 L/min/m NS Stroke volume, per 1 ml Mixed venous saturation, per 1% NS Pulmonary vascular resistance, per 1 Wood unit PAH associated with connective tissue disease NS PAH associated with congenital heart defect NS Treatment with targeted therapy NS See Table 1 and 2 legends for expansion of abbreviations. 95% CI, ; P,.0001) and by a mod erately increased risk of all-cause mortality (HR, 1.84; 95% CI, ; P 5.04). Discussion RV failure resulting in low cardiac output is the main cause of death in patients with PAH. 1,2,15 However, with growing experience of referral centers, new potentially life-threatening complications are being recognized. Supraventricular arrhythmias, 16 recur- rent haemoptysis, 17 angina due to compression of the main left coronary artery, 4 and management of PAH in pregnancy and labor 18 exemplify new challenges faced by clinical teams caring for patients with PAH. Moreover, some otherwise clinically stable patients with PH die unexpectedly outside the hospital. A recent prospective registry reported sudden death in 28% (seven out of 25) of patients with PAH who died within 3 years of initial diagnosis. 15 Little is known about the causes of such deaths. The current study found pulmonary artery dilatation to be independently related to the risk of Figure 3. Relationship of the incidence of unexpected deaths and deaths that could be explained by right ventricular failure and/or comorbidities (right-sided heart failure-related deaths) with PA diameter (presented as quartiles). PA 5 pulmonary artery Original Research

8 Figure 4. Receiver operating characteristic curve of PA diameter as a prognostic marker of risk of unexpected death in the studied population. See Figure 3 legend for expansion of abbreviation. UE-D in patients with PAH or inoperable CTEPH. This risk was highest in patients in whom dilatation of the PA coincided with high systolic PAP and heart rate. Neither indices of RV failure nor etiology of PH were independently related to the risk of UE-D. At baseline CT examination, PA dilatation correlated with pulmonary arterial pressures, age, and duration of symptoms. The relationship of PA diameter, as assessed by magnetic resonance, with intraluminal PAP pressure and duration of the disease in patients with PAH was recently reported by Boerrigter et al. 19 The inverse correlation with age is a new finding, probably reflecting age-related fibrosis of the PA wall, making it less prone to dilatation. PA diameter was not related to the risk of all-cause mortality. In fact, an optimal risk-predicting model for all-cause mortality included well-recognized variables related to hemodynamic compromise as well as the presence of PAH associated with CTD. Together with all-cause mortality at around 10%/y, this indirectly validated the study population as comparable with other currently reported cohorts of patients with PAH.20 There seem to be two potential main mechanisms linking dilatation of the PA in the setting of severe PH with UE-D: potentially arrhythmogenic PA compression of the left main coronary artery (LMCA), or PA rupture/dissection with cardiac tamponade. The latter explanation is new but appealing because of the presence of systolic PA pressure in the multivariate prognostic model and an obvious analogy with the consequences of aneurysms of the ascending aorta Although in the present study autopsies were performed in only two of 26 patients with PAH who died Figure 5. Kaplan-Meier unexpected death-free survival curves for patients with PA diameter 48 mm and, 48 mm. See Figure 3 legend for expansion of abbreviation. journal.publications.chestnet.org CHEST / 142 / 6 / DECEMBER

9 unexpectedly, in both cases cardiac tamponade due to dissection of the dilated PA was found. We are aware of. 70 published cases of PA dissection. 5-9,12 In most of them it occurred in the setting of PH (including 26 patients with CHD and 13 with primary PH), and the diagnosis could only be made at autopsy. Degano et al 5 described a CT scan diagnosis of dissection of the dilated right PA in a patient with IPAH, with sudden fatal outcome within 72 h. An autopsy, however, was not performed. Another possible explanation is LMCA compression by an enlarged PA resulting in potentially arrhythmogenic ventricular ischemia. 4,24 We were not able to assess the presence and significance of coronary ischemia and ventricular arrhythmias in the studied population. However, in the international survey, Hoeper et al 25 reported ventricular fibrillation as a cause of cardiac arrest only in a minority (8%) of 132 patients with PAH in whom cardiopulmonary resuscitation was instituted. The electromechanical dissociation, more compatible with PA rupture or cardiac tamponade, was observed in 28% of cases. 25 Study Limitations Several limitations were due to the retrospective character of our trial, which should be considered as hypothesis generating rather than conclusive. We used measurements of PA diameter taken routinely during CT scan evaluation of patients with PH at our center. 26 Although interobserver reproducibility of such measurements was acceptable, we did not attempt to improve it by additional three-dimensional image reconstructions. Imaging of the LMCA was not attempted. Autopsy data in 24 of 26 cases were missing, since most unexpected deaths occurred outside the hospital. Therefore, the cause of 24 deaths that occurred unexpectedly cannot be unequivocally identified and remain speculative. We were not systematically following the changes in PA diameter with CT scan in individual patients, and thus we were unable to evaluate prognostic significance of such changes. It is possible that the rate of PA remodeling differs between patients regardless of similar levels and duration of PH. This could have modified the risk of fatal outcome, as assessed from baseline PA measurement. There is a place for echocardiography both for monitoring PA diameter and for exploring its relationship with pulmonary valve regurgitation, which was not systematically analyzed in our trial. The definition of UE-D created for the purpose of this trial was arbitrary. However, it resulted in the emergence of two distinct subgroups, significantly differing in their baseline characteristics and prognostic determinants. This indirectly validated the criteria that had been used. On the other hand, the characteristics of the whole studied group, as well as all-cause annual mortality rate and its predictors, were comparable with other reported PAH/CTEPH cohorts.3,14,15 Although we analyzed consecutive patients referred to our center, some of the subtypes of PAH (HIV, drugs/toxins, portopulmonary hypertension) were not widely represented in our series. This may partly reflect the gaps in targeted drug reimbursement rules in our country, limiting referrals of those subgroups to PAH centers. Our observations may, therefore, not be applicable to those subtypes of PAH that were underrepresented in our series. Consequently, 48-mm diameter of the PA, which separated patients according to the prevalence of unexpected death, although identified based on ROC analysis, cannot be understood as universally applicable. Research and Clinical Implications To our knowledge, the correlation between PA diameter and the risk of unexpected death, whatever its cause, has never been previously reported in patients with PH and requires independent confirmation. We hope that our report will encourage the undertaking of prospective studies assessing in more detail the prevalence and consequences of PA dilatation in PH. However, already now impending PA dissection and left ventricular ischemia should be considered in the case of any new chest pain in patients with significantly dilated PA. In contrast to stenting of a compressed LMCA, management strategies for a patient with PH complicated by acute PA dissection are unclear. Successful surgical treatment has been reported, but this provided only a bridge to lung transplantation rather than definitive therapy. 10,11 Decisions about whether and which surgical intervention should be performed in PH because of a dilated PA are very difficult and should be made on a case-by-case basis. Reconstruction can perhaps be considered in those few patients who have very good RV function and a maintained pulmonary vascular reactivity (eg, responders), bilateral lung transplantation could be probably feasible in most patients, and heart and lung transplantation might be considered in patients in whom vascular anastomoses would be particularly difficult. Although monitoring the diameter of a dilated PA seems reasonable, pharmacologic prevention used in patients with a severely dilated ascending aorta cannot be easily extrapolated to patients with marked PA dilatation. As an example, b -blockers are currently contraindicated in patients with PAH and CTEPH because of potentially deleterious systemic hypotension. 27 On the other hand, moderate hemodynamic effects of current PAH therapies are unlikely to affect the progression of PA remodeling Original Research

10 Risk of catheter-induced PA dissection in patients with PH and PA dilatation is probably negligible, 28,29 judging from the excellent safety record of right-sided heart catheterization in patients with PAH. 30 Whether and when dilatation of the PA should lead to listing for lung transplantation is another emerging question. This should probably be considered only at the extremes of dilatation in view of the lack of a clear correlation between moderately increased PA diameter and all-cause mortality. Such a decision in otherwise stable patients with PH would be particularly difficult. Conclusions PA dilatation emerges as an independent risk factor for death unexplained by RV failure or comorbidities in patients with PAH or inoperable CTEPH. Possible mechanisms include the consequences of LMCA compression and also PA rupture or dissection with cardiac tamponade. Further studies on the clinical significance of PA dilatation are required to understand the causes of death and, we hope, to improve the outcome of patients with PH. Acknowledgments Author contributions: Drs Żyłkowska, Kurzyna, and Torbicki had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of data analysis. Dr Żyłkowska: contributed to conception and design of the study, analysis and interpretation of data, drafting part of the manuscript and revising it critically for important intellectual content, and giving final approval of the manuscript before submission. Dr Kurzyna: contributed to conception and design of the study, analysis and interpretation of data, drafting parts of the manuscript, revising it critically for important intellectual content, and giving final approval of the manuscript before submission. Dr Florczyk: contributed to analysis and interpretation of data, revising the manuscript for important intellectual content, and giving final approval of the manuscript submitted. Dr Burakowska: contributed to analysis and interpretation of data, drafting part of the manuscript dedicated to radiologic methodology, revising the manuscript for important intellectual content, Dr Grzegorczyk: contributed to analysis and interpretation of data, revising the manuscript for important intellectual content, Dr Burakowski: contributed to analysis and interpretation of data, revising the manuscript critically for important intellectual content, Dr Wieteska: contributed to analysis and interpretation of data, revising the manuscript critically for important intellectual content particularly related to chronic thromboembolic pulmo nary hypertension, Dr Oniszh: contributed to analysis and interpretation of data, revising the manuscript critically for important intellectual content particularly related to radiologic aspects, and giving final approval of the manuscript submitted. Dr Biederman : contributed to analysis and interpretation of data, revising the manuscript critically for important intellectual content particularly related to surgical aspects and potential similarities of consequences of pulmonary artery and aortic dilatation, Dr Wawrzyńska: contributed to analysis and interpretation of data, revising the work critically for important intellectual content, Dr Szturmowicz: contributed to analysis and interpretation of data, revising the work critically for important intellectual content, Dr Fijałkowska: contributed to analysis and interpretation of data, revising the work critically for important intellectual content, and giving final approval of the manuscript submitted. Dr Torbicki: contributed to conception and design of the study, analysis and interpretation of data, drafting parts of the manuscript, revising it critically for important intellectual content, and giving final approval of the manuscript prior to submission. 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