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Supraventricular Arrhythmias in Patients With Pulmonary Arterial Hypertension
Supraventricular Arrhythmias in Patients With Pulmonary Arterial Hypertension Margherita Cannillo, MDa,*, Walter Grosso Marra, MDa, Sebastiano Gili, MDa, Fabrizio D’Ascenzo, MDa, Mara Morello, MDa, Lorena Mercante, MDb, Elisa Mistretta, MDa, Davide Salera, MDa, Domenica Zema, MDa, Arianna Bissolino, MDa, Enrico Fusaro, MDc, Sebastiano Marra, MDc,d, Daniela Libertucci, MDb, and Fiorenzo Gaita, MDa The onset of supraventricular arrhythmias (SVA) may be associated with clinical worsening in patients with pulmonary arterial hypertension (PAH). However, limited data have been reported, especially at long-term follow-up. Aim of this study was to investigate the incidence of SVA in our patients with PAH, the risk factors correlated to their onset and the prognostic impact. All consecutive patients with PAH without history of SVA were enrolled. Incidence of new SVA was investigated and also the risk factors for SVA. Primary end point of the study was the impact of SVA on a composite of all-cause mortality and re-hospitalization, whereas mortality was the secondary end point. Seventy-seven patients were enrolled. No significant differences in the clinical or instrumental baseline characteristics between the 2 study groups were reported. During a median follow-up of 35 months (interquartile range 21.5 to 53.5), 17 (22%) patients experienced SVA. Development of SVA was associated with worsening of prognostic parameters at the follow-up: increasing of World Health Organization (WHO) functional class (p [ 0.005) and N-terminal-pro-brain natriuretic peptide (NT-proBNP) (p [ 0.018) and reduction of 6-minute walking distance (p [ 0.048), tricuspid annular plane systolic excursion (TAPSE) (p [ 0.041), and diffusing capacity of the lung for carbon monoxide (p [ 0.025). The primary end point occurred in 13 patients (76%) in the SVA group and in 22 patients (37%) in the group without SVA (p [ 0.004), whereas 9 patients (53%) among those with SVA died during the follow-up compared with 8 (13%) among those without (p [ 0.001). At multivariate analysis, development of SVA was independently associated with an increased risk to meet the both primary (hazard ratio 2.13; 95% confidence interval 1.07 to 4.34; p [ 0.031) and secondary (hazard ratio 4.1; 95% confidence interval 1.6 to 10.6; p [ 0.004) end points. In conclusion, during the 3-year follow-up period, 1/3 of patients with PAH developed SVA, which was related to worsening of hemodynamic and functional parameter and independently predicted adverse prognosis. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;-:-e-)
This study investigated the incidence and the risk factors for supraventricular arrhythmias (SVA) and the prognostic significance of the development of these arrhythmias in a cohort of patients with pulmonary arterial hypertension (PAH) followed at the Pulmonary Hypertension Service of the Città della Salute e della Scienza of Turin. Methods This is a retrospective, single-center, cohort study enrolling patients with PAH followed from January 2008 to January 2015 in the Registry of Pulmonary Hypertension Service of the Città della Salute e della Scienza of Turin. a Division of Cardiology, University of Turin, Città Della Salute e Della Scienza, Turin, Italy; and Divisions of bPneumology, cRheumatology, and d Cardiology, Città Della Salute e Della Scienza, Turin, Italy. Manuscript received June 18, 2015; revised manuscript received and accepted September 25, 2015. See page 7 for disclosure information. *Corresponding author: Tel: (þ39) 338-710-7679; fax: (þ39) 0116336015. E-mail address: [email protected] (M. Cannillo).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.09.039
Inclusion criteria were (1) diagnosis of PAH according to the current guidelines, including right-sided cardiac catheterization demonstrating a mean pulmonary artery pressure 25 mm Hg, pulmonary vascular resistance >3 UW, and a mean pulmonary arterial capillary pressure 15 mm Hg1; (2) PAH classified as group 1, PAH group 3, or group 4 (without indication to thromboendarterectomy [TEA] or with residual PAH after TEA) according to the updated classification of pulmonary hypertension2; (3) a follow-up of at least 6 months; and (4) sinus rhythm at baseline. Exclusion criteria were (1) other types of pulmonary hypertension and (2) patients with preexisting SVA. Demographic characteristics, cardiovascular risk factors, World Health Organization functional class (WHO-FC), 6minute walking distance (6MWD), electrocardiographic (ECG) and echocardiographic features, N-terminal-pro-brain natriuretic peptide (NT-proBNP), diffusing capacity for carbon monoxide (DLCO), right-sided cardiac catheterization data, the REVEAL score, and pharmacologic history were collected for all patients at baseline and at follow-up. The primary end point was the occurrence of a morbidity end point, composed by death for any cause and www.ajconline.org
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Table 1 Baseline characteristics of study population, expressed as median (IQR) or number and percentages (%), in relation to insurgence of supraventricular arrhythmia Variable Age at diagnosis (years) Female BMI (Kg/m2) Systemic hypertension Diabetes Dyslipidemia Idiopathic and Heritable PAH Drug and toxin induced PAH PAH associated with Connective tissue disease PAH associated with HIV infection PAH associated with Portal Hypertension PAH associated with Congenital heart disease Chronic thromboembolic pulmonary hypertension Pulmonary Hypertension due to lug disease and/or hypoxia (out of proportion) Systemic systolic pressure (mmHg) Heart rate (bpm) SaO2 (%) Clinical evidence of RV failure Rapid progression of symptoms Syncope WHO I WHO II WHO III WHO IV QRS duration (sec) Right axis deviation Signe of right overload RBB QTc 6MWD (metres) NT-proBNP (pg/ml) DLCO (%) Left Ventricle EF (%) Left atrial dilatation Right ventricle dilatation Right atrial dilatation TAPSE (mm) PAPs (mmHg) D-shape Pericardial effusion Right atrial pressure (mmHg) PAPs (mmHg) PAPm (mmHg) Arteriolar pulmonary resistance (UW) Cardiac Index (l/min/m2) REVEAL Score 1-7 REVEAL Score 8 REVEAL Score 9 REVEAL Score 10-11 REVEAL Score 12
All patients (n ¼ 77)
Supraventricular arrhythmia þ (n ¼ 17)
Supraventricular arrhythmia - (n ¼ 60)
p value
63 41 24.2 46 14 11 16 1 18 2 9 5 14 12
(48; 70,7) (53%) (22; 27.3) (60%) (18%) (14%) (21%) (1%) (23%) (3%) (12%) (6%) (18%) (16%)
62 8 23.4 10 2 1 4 1 4 0 3 1 2 2
(48; 69.5) (47%) (22; 27.3) (62%) (12%) (6%) (23%) (6%) (23%) (0%) (18%) (6%) (12%) (12%)
63 33 24.3 37 6 11 12 0 14 2 6 4 12 10
(48; 70.7) (55%) (21.9; 27.4) (61%) (22%) (18%) (20%) (0%) (23%) (3%) (10%) (7%) (20%) (17%)
0.81 0.56 0.73 0.85 0.49 0.44 0.33
120 76 93 48 43 7 2 27 42 6 0.08 21 42 15 439 340 893 40 60 39 62 62 18 70 49 15 9 70 44 5.9 2.6 21 9 12 21 13
(113.5; 135) (68.5; 86) (89; 95) (62%) (56%) (9%) (3%) (35%) (54%) (8%) (0.08; 0.10) (27%) (54%) (19%) (413.7; 460.7) (188.7; 428.7) (201; 2905) (29; 58.5) (60; 65) (51%) (80%) (80%) (15.5; 21) (58; 85) (64%) (19%) (6; 12) (50; 82) (35; 54) (3.7; 10) (2.2; 3.4) (27%) (12%) (16%) (29%) (17%)
120 75 94 12 9 1 0 7 9 1 0.09 2 6 4 447 380 1370 45 63 9 12 13 17 65 8 2 10 70 45 4.88 2.9 2 3 1 6 5
(110; 140) (65; 80) (93; 95.5) (71%) (53%) (6%) (0%) (41%) (53%) (6%) (0.08; 0.095) (12%) (35%) (23%) (416; 465) (232.5; 415) (376.5; 3611) (36.5; 55.5) (60; 65) (53%) (71%) (76%) (14.5; 22.5) (37.5; 90) (47%) (12%) (7.5; 1.,5) (42.5; 88) (30; 52) (2.6; 10.3) (2.3; 3.6) (12%) (18%) (6%) (35%) (29%)
120 77 93 36 34 6 2 20 33 5 0.08 19 36 11 439 318 795 37,5 60 30 50 49 18 70 41 13 9 70 43 6.05 2.57 19 6 11 16 8
(112.7; 134.5) (70; 88) (89; 95) (60%) (57%) (10%) (3%) (33%) (55%) (8%) (0.08; 0.1) (32%) (60%) (18%) (402; 456) (185; 430) (200.5; 2920.7) (27.3; 59.3) (60; 65) (50%) (83%) (82%) (16; 20) (60; 83.7) (68%) (22%) (6; 11.5) (53; 79) (36; 54) (4.7; 9.7) (2.1; 3.2) (32%) (10%) (18%) (27%) (13%)
0.78 0.35 0.09 0.42 0.78 0.5 0.8
hospitalization for heart failure/respiratory insufficiency. The secondary end points were all-cause mortality and hospitalization for heart failure/respiratory insufficiency. Analysis was stratified on the basis of the development of SVA during the follow-up period. SVA were specified to include (a) atrial fibrillation (AF), classified as permanent,
0.73 0.13 0.07 0.7 0.32 0.63 0.48 0.23 0.34 0.87 0.3 0.63 0.83 0.67 0.1 0.5 0.15 0.67 0.82 0.27 0.11 0.22
persistent or paroxysmal AF, (b) atrial flutter, or (c) paroxysmal SVA (as definite by current guidelines3,4). SVA were detected by means of a routine electrocardiogram performed during the follow-up, by an electrocardiogram performed during hospitalizations for heart failure or for SVA-related symptoms, or by ECG Holter performed
Arrhythmias and Conduction Disturbances/Supraventricular Arrhythmias as Marker of Prognosis in PAH Table 2 Supraventricular arrhythmias patient history ID patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
SVA
Persistent AF Permanent AF Right atrial flutter Paroxymal AF PSVA Persistent AF Persistent AF PSVA Persistent AF Persistent AF PSVA Permanent AF Permanent AF Persistent AF Persistent AF Right atrial flutter Persistent AF
Rhythm Recurrence Death Time from SVA control occurrence to strategy death (month) þ 0 þ þ þ þ þ 0 þ þ þ 0 0 þ þ þ þ
þ 0 þ 0 þ þ 0 þ þ þ 0 0 þ þ
þ 0 þ þ 0 þ þ 0 þ þ 0 þ 0 0 0 0 þ
9.1 2.3 3.5 21.2 0.3 50.36 0.8 1.6 7.2
- ¼ not applicable.
because of the occurrence of palpitations. No preplanned ECG Holter were performed to screen asymptomatic SVA. Data about the SVA treatment with drugs, electric cardioversion or transcatheter ablation, and their effectiveness to restore sinus rhythm were collected. The study was performed according to good clinical practice and in compliance with the Declaration of Helsinki. Continuous variables were expressed as median with interquartile ranges (IQR), and categorical variables were expressed as number and percentages (%). Correlations between parameters and study groups were tested in cross tabulation tables by means of Pearson’s chi-square test or Fisher’s exact test for categorical variables and by MannWhitney nonparametrical analysis for continuous variables. Survival analysis was performed by Cox regression analysis and by Kaplan-Meier survival curves, whereas multivariate models for each study end point were run including variables relating to those same end points at univariate analysis. A 2-sided p value <0.05 was considered as statistically significant; all analysis were performed with SPSS 21.0 (IBM Corporation, Armonk, New York). Results One hundred six patients were followed at the Pulmonary Hypertension Service of the Città della Salute e della Scienza of Turin from January 2008 to January 2015. Twentynine patients did not meet inclusion criteria and were excluded: 9 for follow-up <6 months, 5 for successful pulmonary TEA without residual PAH, 11 for out of proportion group 2 PAH, and 4 for preexisting SVA. Overall, 77 patients met eligibility criteria and were included in the present analysis. During a median follow-up of 35 months (IQR 21.5 to 53.5), 17 patients (22%) experienced SVA. Persistent AF was the more frequent rhythm disturbance (8 patients, 47%), followed by permanent AF (3, 17%), paroxysmal SVA (3,
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17%: 2 atrial ectopic tachycardia and 1 atrioventricular nodal re-entry tachycardia), right atrial flutter (2, 12%), and paroxysmal AF (1, 6%). Patients who experienced SVA had a median age of 67.7 years (IQR 56 to 70.2) at the time of the arrhythmia presentation and arrhythmias occurred after a median of 15. 1 months (IQR 11.3 to 43.2) from the diagnosis of PAH. Detection of SVA occurred occasionally during the routine follow-up in 4 cases (23%), during hospitalization for the onset of palpitations or dizziness in 4 patients (23%), during hospitalization for heart failure or respiratory insufficiency in 7 patients (41%), and in 2 cases (12%) during ECG Holter monitoring executed for palpitations. The baseline characteristics of the study population, in relation to insurgence of SVA, are reported in Table 1. No significant differences between the 2 study groups were reported, with no clinical or instrumental characteristics at baseline able to predict development of SVA during follow-up. Concerning arrhythmia management, a rhythm control strategy was attempted in 13 patients (76%): 10 with drugs (3 patients with sotalol, 4 with amiodarone, and 2 with Ic antiarrhythmic drugs), 8 with electrical cardioversion, and 3 with radiofrequency transcatheter ablation (1 patient underwent atrioventricular nodal re-entry tachycardia transcatheter ablation 1 month after lung transplantation, 1 patient underwent cavotricuspid isthmus ablation for common atrial flutter, and 1 patient underwent cavotricuspidal isthmus and pulmonary vein isolation for common atrial flutter and AF with the need of a subsequent redo AF ablation procedure with pulmonary vein isolation). Sinus rhythm restoration was obtained in 11 cases (65%), and recurrent episodes of SVA were reported in 9 patients (see Table 2). Development of SVA was associated with worsening of prognostic parameters at follow-up: SVA group presented a significant worsening of WHO-FC (p ¼ 0.005), a reduction of 6MWD (p ¼ 0.048), tricuspid annular plane systolic excursion (TAPSE) (p ¼ 0.041), and DLCO (p ¼ 0.025), and higher values of NT-proBNP (p ¼ 0.018) compared with those who did not develop SVA (Table 3). The primary composite morbidity end point was reached by 35 patients (45%), of whom 13 (76%) in the SVA group compared with 22 (37%) in the group without SVA (p ¼ 0.004). Other parameters relating to occurrence of the composite end point were DLCO (p ¼ 0.002) and the clinical evidence of RV failure at baseline (p ¼ 0.014). Secondary end points were analyzed (Table 4, Figure 1): concerning mortality, 17 patients (22%) died during the follow-up, 9 (53%) among those with SVA, 8 (13%) among those who did not develop SVA (p ¼ 0.001). In the SVA group, median time from arrhythmia occurrence to death was 3.5 months (IQR 1.7 to 9.1). Eight patients (66%) of 12 with permanent AF or recurrent SVA died compared with 1 (20%) of 5 without SVA recurrences. No other factors predicted an increased risk for mortality except PAH duration (p ¼ 0.029). Hospitalization for heart failure/respiratory insufficiency occurred in 33 patients (43%), 11 patients (65%) with SVA, and 22 patients (37%) without SVA (p ¼ 0.019). Other parameters relating to occurrence of hospitalization for heart failure/respiratory insufficiency were DLCO (p ¼ 0.02) and clinical evidence of RV failure at baseline (p ¼ 0.014).
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Table 3 Characteristics of study population at the end of the follow-up, expressed as median (IQR) or number and percentages (%), in relation to insurgence of supraventricular arrhythmia Supraventricular arrhythmia þ (n ¼ 17)
Variable Systemic systolic pressure (mmHg) Heart rate (bpm) SaO2 (%) WHO-FC worsening at follow-up 6MWD variation (metres) NT-proBNP variation (pg/ml) DLCO variation (10%) TAPSE variation (mm) Pericardial effusion Right atrial pressure variation (mmHg) PAPm variation (mmHg) Cardiac Index variation (l/min/m2)
105 90 89 8 45 þ635 -10 -2 6 þ1 0 þ0.03
(100; 140) (75; 117.5) (88; 95) (47%) (-207.5; -1.25) (-80; þ4042) (-19.5; -5) (-3; þ2) (35%) (-7.5; þ5) (-4; þ2) (-2.13 - þ1.22)
Table 4 Recurrence of end points in relation to insurgence of supraventricular arrhythmia Variable
Supraventricular arrhythmia þ (n ¼ 17)
Supraventricular arrhythmia (n ¼ 60)
p value
Morbidity end point Death for any cause Hospitalization for heart failure/respiratory insufficiency
76.5 % (13 pz) 52.9 % (9 pz) 64.7 % (11 pz)
36.7 % (22 pz) 13.3 % (8 pz) 36.7 % (22 pz)
0.004 0.001 0.03
Figure 1. Distribution of the end point in the 2 groups.
Figures 2 to 4 show Kaplan-Meier curves comparing incidence of primary composed mobility end point (Cox regression hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.07 to 4.34; p ¼ 0.031), mortality (Cox regression HR 4.1; 95% CI 1.6 to 10.6; p ¼ 0.004), and hospitalization for heart failure/respiratory insufficiency (Cox regression HR 2.1; 95% CI 1.1 to 4.2; p ¼ 0.031) in patients developing SVA compared with those not developing SVA.
Supraventricular arrhythmia - (n ¼ 60) 120 80 93 9 0 -84 1 þ1 9 þ2 0 þ0.15
(110; 128.7) (70; 95) (88.2; 95) (15%) (-55.5; þ72.5) (-1544; þ261.5) (-9; þ7.5) (-1.2; þ4) (15%) (-4; þ6) (-7; þ15) (-0.13; þ0.7)
p value 0.82 0.07 0.24 0.005 0.048 0.018 0.025 0.041 0.06 0.5 0.82 0.5
After controlling for potential confounding factors by Cox regression survival analysis, development of SVA was confirmed to independently relate with the occurrence of the primary composite morbidity end point (HR 2.82; 95% CI 1.2 to 6.6; p ¼ 0.018); also 6MWD (HR 0.86 for each increase of 50 meters of test results; 95% CI 0.75 to 0.99; p ¼ 0.036), and DLCO (HR 0.97 (95% CI 0.94 to 0.99); p ¼ 0.037) emerged as independent predictors of the primary end point. Discussion This study shows that (1) the incidence of SVA in patients with PAH is relatively high; (2) no demographic, clinical, and instrumental data at baseline may help to predict occurrence of SVA, which are associated with the worsening of functional and prognostic parameters; (3) sinus rhythm could be successfully restored in patients with PAH but with high rates of recurrences; and (4) SVA are associated with an increased risk of a composite morbidity end point and of death. In our cohort during a median follow-up of 35 months, 22% patients had almost 1 episode of SVA, confirming the data about high incidence of SVA in patients with PAH (from 10% to 25% in 6 years of follow-up) reported by other authors.5e8 The right chamber dilation, and the associated electrical remodeling of right atria, could be the substrate of SVA insurgence in PAH with the iperactivation of the sympathetic nervous system.9 Our study confirms that in patients with PAH, the SVA onset could be a warning sign. On one hand, SVA could further deteriorate the right ventricular function leading to prognostic worsening, as discussed in other works5e8: once SVA happens, reduction of atrial contraction, loss of atrioventricular synchrony, and rapid heart rate may compromise cardiac function, resulting in reductions of diastolic filling and cardiac output.5 In contrast, SVA onset could be a marker of deteriorating right ventricular function and progression of PAH. Indeed, in our cohort, as in the population previously analyzed by Olsson et al,8 SVA were detected mainly after patients’ request of medical attention because of aggravation of symptoms related to PAH and right-sided cardiac failure (41% of patients with SVA), instead of for
Arrhythmias and Conduction Disturbances/Supraventricular Arrhythmias as Marker of Prognosis in PAH
5
Figure 2. Kaplan-Meier estimates of occurrence of the morbidity end point in patients with PAH. Patients who developed SVA had more events (green line) than who did not develop SVA (blue line), p ¼ 0.031.
Figure 3. Kaplan-Meier estimates of survival in patients with PAH. Patients who developed SVA had significantly worse outcomes (green line) than those who did not develop SVA (blue line), p ¼ 0.004.
symptoms related to the arrhythmia. Moreover, the median interval between PAH diagnosis and onset of SVA was relatively long (15.1 months; IQR 11.3 to 43.3), suggesting
that these arrhythmias are mostly manifestation of longstanding PAH, as reported also by Tonges et al6 and by Ruiz-Cano et al.7 Furthermore, SVA insurgence was
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Figure 4. Kaplan-Meier estimates of occurrence of hospitalization for heart failure/respiratory insufficiency in patients with PAH. Patients who developed SVA had more events (green line) than those who did not develop SVA (blue line), p ¼ 0.031.
associated with worsening of parameters traditionally related to a negative prognosis: WHO-FC, 6MWD, DLCO, TAPSE, and NT-proBNP. All these elements taken together suggest that SVA onset could be a marker of the progression of the natural history of PAH to the end-stage phase, more than a factor decisively contributing to this negative evolution. From this perspective, the association between SVA onset and high rate of death and hospitalization for heart failure/ respiratory insufficiency comes than hardly unexpected. Therefore, physicians should be careful in the management of patients with PAH and SVA. In the contest of a goaloriented therapy strategy, the SVA occurrence is a negative prognostic factor and the SVA onset may underline a PAH progression with the need to increase PAH-specific drugs, as suggested by the experience of Ruiz-Cano et al.7 Moreover, the sinus rhythm restoration should be desirable to improve the RV performance. Indeed, in larger cohorts, an improvement of clinical status after sinus rhythm restoration has been described and a worse prognostic outcome in patients with PAH with permanent AF compared with those with transient AF.5e8 Concerning the rhythm control strategy, we have demonstrated that sinus rhythm could be restored in most patients with PAH (11 of 13 patients). In this cohort of patients, all tools for the rhythm control strategy have been safely applied: to the best of our knowledge, this is the first work in which it has been reported the use of Ic antiarrhythmic drugs in patients with PAH without adverse events. Moreover, for the first time in our study, we report the use of AF transcatheter ablation in patients with PAH: despite the many doubts about feasibility and safety of these interventions in patients with PAH, AF ablation in left atria might be a charming option in this population, even if
substrate for AF in these patients may be different than in general population as it could primarily involve the right atrium more than the left.8 In our study, there was not a correlation between left atria dilation and the insurgence of SVA, as in other previous reports,8 and an increased inducibility of AF on right atrial stimulation in idiopathic PAH has been also described.10 Although these data seem to suggest that the source of AF in patients with PAH might be in the right atrium, further studies are needed to determine the pathophysiological basis of AF in this population and the best ablation strategy in patients with PAH. Although an aggressive rhythm control strategy, the rate of recurrence of SVA was very high, and it did not improve the prognosis of patients, probably because SVA occurred in patients with advanced stages of the disease and irreversible right-sided cardiac dysfunction. Maybe, as in left ventricular dysfunction,11,12 in patients with PAH, a rhythm control strategy could be effective only if performed early in the natural evolution of the right-sided cardiac failure. This study has several limitations: first of all the sample size. The retrospective design may have lead to the underestimation of the true incidence of the SVA, even if our data are similar to finding of more wild prospective study.5,7 Furthermore, although electrocardiogram were monitored regularly during the routine follow-up, the lack of closer rhythm monitoring (e.g., ECG Holter or loop recorded) may have led to the underdetection of several asymptomatic selflimiting tachyarrhythmias. Moreover, patients with right-sided cardiac failure and aggressive forms of PAH were more frequently hospitalized and underwent more often to clinical evaluation compared with those with milder forms, potentially leading to a higher
Arrhythmias and Conduction Disturbances/Supraventricular Arrhythmias as Marker of Prognosis in PAH
detection bias of SVA in patients with advanced PAH. However, all patients were regularly and closely followed up, so we can hypothesize that no clinically relevant episodes of SVA were missed in our cohort. Disclosures The authors have no conflicts of interest to disclose. 5. 1. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493e2537. 2. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62(25 Suppl):D34eD41. 3. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071e2104. 4. Blomström-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW, Stevenson WG, Tomaselli GF, Antman EM, Smith SC Jr, Alpert JS, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Hiratzka LF, Hunt SA, Jacobs AK, Russell RO Jr, Priori SG, Blanc JJ, Budaj A, Burgos EF, Cowie M, Deckers JW, Garcia MA, Klein WW, Lekakis J, Lindahl B, Mazzotta G, Morais JC, Oto A, Smiseth O, Trappe HJ; European Society of Cardiology
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Committee; NASPE-Heart Rhythm Society. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPE-Heart Rhythm Society. J Am Coll Cardiol 2003;42:1493e1531. Wen L, Sun ML, An P, Jiang X, Sun K, Zheng L, Liu QQ, Wang L, Zhao QH, He J, Jing ZC. Frequency of supraventricular arrhythmias in patients with idiopathic pulmonary arterial hypertension. Am J Cardiol 2014;114:1420e1425. Tongers J, Schwerdtfeger B, Klein G, Kempf T, Schaefer A, Knapp JM, Niehaus M, Korte T, Hoeper MM. Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J 2007;153:127e132. Ruiz-Cano MJ, Gonzalez-Mansilla A, Escribano P, Delgado J, Arribas F, Torres J, Flox A, Riva M, Gomez MA, Saenz C. Clinical implications of supraventricular arrhythmias in patients with severe pulmonary arterial hypertension. Int J Cardiol 2011;146:105e106. Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial flutter and fibrillation in patients with pulmonary hypertension. Int J Cardiol 2013;167:2300e2305. Rajdev A, Garan H, Biviano A. Arrhythmias in pulmonary arterial hypertension. Prog Cardiovasc Dis 2012:180e186. Medi C, Kalman JM, Ling LH, Teh AW, Lee G, Lee G, Spence SJ, Kaye DM, Kistler PM. Atrial electrical and structural remodeling associated with longstanding pulmonary hypertension and right ventricular hypertrophy in humans. J Cardiovasc Electrophysiol 2012;23: 614e620. Anselmino M, Matta M, D’Ascenzo F, Bunch TJ, Schilling RJ, Hunter RJ, Pappone C, Neumann T, Noelker G, Fiala M, Bertaglia E, Frontera A, Duncan E, Nalliah C, Jais P, Weerasooriya R, Kalman JM, Gaita F. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2014;7:1011e1018. Handoko ML, de Man FS, Allaart CP, Paulus WJ, Westerhof N, VonkNoordegraaf A. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur Respir Rev 2010;19:72e82.
This study investigated the incidence and the risk factors for supraventricular arrhythmias (SVA) and the prognostic significance of the development of these arrhythmias in a cohort of patients with pulmonary arterial hypertension (PAH) followed at the Pulmonary Hypertension Service of the Città della Salute e della Scienza of Turin. Methods This is a retrospective, single-center, cohort study enrolling patients with PAH followed from January 2008 to January 2015 in the Registry of Pulmonary Hypertension Service of the Città della Salute e della Scienza of Turin. a Division of Cardiology, University of Turin, Città Della Salute e Della Scienza, Turin, Italy; and Divisions of bPneumology, cRheumatology, and d Cardiology, Città Della Salute e Della Scienza, Turin, Italy. Manuscript received June 18, 2015; revised manuscript received and accepted September 25, 2015. See page 7 for disclosure information. *Corresponding author: Tel: (þ39) 338-710-7679; fax: (þ39) 0116336015. E-mail address: [email protected] (M. Cannillo).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.09.039
Inclusion criteria were (1) diagnosis of PAH according to the current guidelines, including right-sided cardiac catheterization demonstrating a mean pulmonary artery pressure 25 mm Hg, pulmonary vascular resistance >3 UW, and a mean pulmonary arterial capillary pressure 15 mm Hg1; (2) PAH classified as group 1, PAH group 3, or group 4 (without indication to thromboendarterectomy [TEA] or with residual PAH after TEA) according to the updated classification of pulmonary hypertension2; (3) a follow-up of at least 6 months; and (4) sinus rhythm at baseline. Exclusion criteria were (1) other types of pulmonary hypertension and (2) patients with preexisting SVA. Demographic characteristics, cardiovascular risk factors, World Health Organization functional class (WHO-FC), 6minute walking distance (6MWD), electrocardiographic (ECG) and echocardiographic features, N-terminal-pro-brain natriuretic peptide (NT-proBNP), diffusing capacity for carbon monoxide (DLCO), right-sided cardiac catheterization data, the REVEAL score, and pharmacologic history were collected for all patients at baseline and at follow-up. The primary end point was the occurrence of a morbidity end point, composed by death for any cause and www.ajconline.org
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Table 1 Baseline characteristics of study population, expressed as median (IQR) or number and percentages (%), in relation to insurgence of supraventricular arrhythmia Variable Age at diagnosis (years) Female BMI (Kg/m2) Systemic hypertension Diabetes Dyslipidemia Idiopathic and Heritable PAH Drug and toxin induced PAH PAH associated with Connective tissue disease PAH associated with HIV infection PAH associated with Portal Hypertension PAH associated with Congenital heart disease Chronic thromboembolic pulmonary hypertension Pulmonary Hypertension due to lug disease and/or hypoxia (out of proportion) Systemic systolic pressure (mmHg) Heart rate (bpm) SaO2 (%) Clinical evidence of RV failure Rapid progression of symptoms Syncope WHO I WHO II WHO III WHO IV QRS duration (sec) Right axis deviation Signe of right overload RBB QTc 6MWD (metres) NT-proBNP (pg/ml) DLCO (%) Left Ventricle EF (%) Left atrial dilatation Right ventricle dilatation Right atrial dilatation TAPSE (mm) PAPs (mmHg) D-shape Pericardial effusion Right atrial pressure (mmHg) PAPs (mmHg) PAPm (mmHg) Arteriolar pulmonary resistance (UW) Cardiac Index (l/min/m2) REVEAL Score 1-7 REVEAL Score 8 REVEAL Score 9 REVEAL Score 10-11 REVEAL Score 12
All patients (n ¼ 77)
Supraventricular arrhythmia þ (n ¼ 17)
Supraventricular arrhythmia - (n ¼ 60)
p value
63 41 24.2 46 14 11 16 1 18 2 9 5 14 12
(48; 70,7) (53%) (22; 27.3) (60%) (18%) (14%) (21%) (1%) (23%) (3%) (12%) (6%) (18%) (16%)
62 8 23.4 10 2 1 4 1 4 0 3 1 2 2
(48; 69.5) (47%) (22; 27.3) (62%) (12%) (6%) (23%) (6%) (23%) (0%) (18%) (6%) (12%) (12%)
63 33 24.3 37 6 11 12 0 14 2 6 4 12 10
(48; 70.7) (55%) (21.9; 27.4) (61%) (22%) (18%) (20%) (0%) (23%) (3%) (10%) (7%) (20%) (17%)
0.81 0.56 0.73 0.85 0.49 0.44 0.33
120 76 93 48 43 7 2 27 42 6 0.08 21 42 15 439 340 893 40 60 39 62 62 18 70 49 15 9 70 44 5.9 2.6 21 9 12 21 13
(113.5; 135) (68.5; 86) (89; 95) (62%) (56%) (9%) (3%) (35%) (54%) (8%) (0.08; 0.10) (27%) (54%) (19%) (413.7; 460.7) (188.7; 428.7) (201; 2905) (29; 58.5) (60; 65) (51%) (80%) (80%) (15.5; 21) (58; 85) (64%) (19%) (6; 12) (50; 82) (35; 54) (3.7; 10) (2.2; 3.4) (27%) (12%) (16%) (29%) (17%)
120 75 94 12 9 1 0 7 9 1 0.09 2 6 4 447 380 1370 45 63 9 12 13 17 65 8 2 10 70 45 4.88 2.9 2 3 1 6 5
(110; 140) (65; 80) (93; 95.5) (71%) (53%) (6%) (0%) (41%) (53%) (6%) (0.08; 0.095) (12%) (35%) (23%) (416; 465) (232.5; 415) (376.5; 3611) (36.5; 55.5) (60; 65) (53%) (71%) (76%) (14.5; 22.5) (37.5; 90) (47%) (12%) (7.5; 1.,5) (42.5; 88) (30; 52) (2.6; 10.3) (2.3; 3.6) (12%) (18%) (6%) (35%) (29%)
120 77 93 36 34 6 2 20 33 5 0.08 19 36 11 439 318 795 37,5 60 30 50 49 18 70 41 13 9 70 43 6.05 2.57 19 6 11 16 8
(112.7; 134.5) (70; 88) (89; 95) (60%) (57%) (10%) (3%) (33%) (55%) (8%) (0.08; 0.1) (32%) (60%) (18%) (402; 456) (185; 430) (200.5; 2920.7) (27.3; 59.3) (60; 65) (50%) (83%) (82%) (16; 20) (60; 83.7) (68%) (22%) (6; 11.5) (53; 79) (36; 54) (4.7; 9.7) (2.1; 3.2) (32%) (10%) (18%) (27%) (13%)
0.78 0.35 0.09 0.42 0.78 0.5 0.8
hospitalization for heart failure/respiratory insufficiency. The secondary end points were all-cause mortality and hospitalization for heart failure/respiratory insufficiency. Analysis was stratified on the basis of the development of SVA during the follow-up period. SVA were specified to include (a) atrial fibrillation (AF), classified as permanent,
0.73 0.13 0.07 0.7 0.32 0.63 0.48 0.23 0.34 0.87 0.3 0.63 0.83 0.67 0.1 0.5 0.15 0.67 0.82 0.27 0.11 0.22
persistent or paroxysmal AF, (b) atrial flutter, or (c) paroxysmal SVA (as definite by current guidelines3,4). SVA were detected by means of a routine electrocardiogram performed during the follow-up, by an electrocardiogram performed during hospitalizations for heart failure or for SVA-related symptoms, or by ECG Holter performed
Arrhythmias and Conduction Disturbances/Supraventricular Arrhythmias as Marker of Prognosis in PAH Table 2 Supraventricular arrhythmias patient history ID patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
SVA
Persistent AF Permanent AF Right atrial flutter Paroxymal AF PSVA Persistent AF Persistent AF PSVA Persistent AF Persistent AF PSVA Permanent AF Permanent AF Persistent AF Persistent AF Right atrial flutter Persistent AF
Rhythm Recurrence Death Time from SVA control occurrence to strategy death (month) þ 0 þ þ þ þ þ 0 þ þ þ 0 0 þ þ þ þ
þ 0 þ 0 þ þ 0 þ þ þ 0 0 þ þ
þ 0 þ þ 0 þ þ 0 þ þ 0 þ 0 0 0 0 þ
9.1 2.3 3.5 21.2 0.3 50.36 0.8 1.6 7.2
- ¼ not applicable.
because of the occurrence of palpitations. No preplanned ECG Holter were performed to screen asymptomatic SVA. Data about the SVA treatment with drugs, electric cardioversion or transcatheter ablation, and their effectiveness to restore sinus rhythm were collected. The study was performed according to good clinical practice and in compliance with the Declaration of Helsinki. Continuous variables were expressed as median with interquartile ranges (IQR), and categorical variables were expressed as number and percentages (%). Correlations between parameters and study groups were tested in cross tabulation tables by means of Pearson’s chi-square test or Fisher’s exact test for categorical variables and by MannWhitney nonparametrical analysis for continuous variables. Survival analysis was performed by Cox regression analysis and by Kaplan-Meier survival curves, whereas multivariate models for each study end point were run including variables relating to those same end points at univariate analysis. A 2-sided p value <0.05 was considered as statistically significant; all analysis were performed with SPSS 21.0 (IBM Corporation, Armonk, New York). Results One hundred six patients were followed at the Pulmonary Hypertension Service of the Città della Salute e della Scienza of Turin from January 2008 to January 2015. Twentynine patients did not meet inclusion criteria and were excluded: 9 for follow-up <6 months, 5 for successful pulmonary TEA without residual PAH, 11 for out of proportion group 2 PAH, and 4 for preexisting SVA. Overall, 77 patients met eligibility criteria and were included in the present analysis. During a median follow-up of 35 months (IQR 21.5 to 53.5), 17 patients (22%) experienced SVA. Persistent AF was the more frequent rhythm disturbance (8 patients, 47%), followed by permanent AF (3, 17%), paroxysmal SVA (3,
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17%: 2 atrial ectopic tachycardia and 1 atrioventricular nodal re-entry tachycardia), right atrial flutter (2, 12%), and paroxysmal AF (1, 6%). Patients who experienced SVA had a median age of 67.7 years (IQR 56 to 70.2) at the time of the arrhythmia presentation and arrhythmias occurred after a median of 15. 1 months (IQR 11.3 to 43.2) from the diagnosis of PAH. Detection of SVA occurred occasionally during the routine follow-up in 4 cases (23%), during hospitalization for the onset of palpitations or dizziness in 4 patients (23%), during hospitalization for heart failure or respiratory insufficiency in 7 patients (41%), and in 2 cases (12%) during ECG Holter monitoring executed for palpitations. The baseline characteristics of the study population, in relation to insurgence of SVA, are reported in Table 1. No significant differences between the 2 study groups were reported, with no clinical or instrumental characteristics at baseline able to predict development of SVA during follow-up. Concerning arrhythmia management, a rhythm control strategy was attempted in 13 patients (76%): 10 with drugs (3 patients with sotalol, 4 with amiodarone, and 2 with Ic antiarrhythmic drugs), 8 with electrical cardioversion, and 3 with radiofrequency transcatheter ablation (1 patient underwent atrioventricular nodal re-entry tachycardia transcatheter ablation 1 month after lung transplantation, 1 patient underwent cavotricuspid isthmus ablation for common atrial flutter, and 1 patient underwent cavotricuspidal isthmus and pulmonary vein isolation for common atrial flutter and AF with the need of a subsequent redo AF ablation procedure with pulmonary vein isolation). Sinus rhythm restoration was obtained in 11 cases (65%), and recurrent episodes of SVA were reported in 9 patients (see Table 2). Development of SVA was associated with worsening of prognostic parameters at follow-up: SVA group presented a significant worsening of WHO-FC (p ¼ 0.005), a reduction of 6MWD (p ¼ 0.048), tricuspid annular plane systolic excursion (TAPSE) (p ¼ 0.041), and DLCO (p ¼ 0.025), and higher values of NT-proBNP (p ¼ 0.018) compared with those who did not develop SVA (Table 3). The primary composite morbidity end point was reached by 35 patients (45%), of whom 13 (76%) in the SVA group compared with 22 (37%) in the group without SVA (p ¼ 0.004). Other parameters relating to occurrence of the composite end point were DLCO (p ¼ 0.002) and the clinical evidence of RV failure at baseline (p ¼ 0.014). Secondary end points were analyzed (Table 4, Figure 1): concerning mortality, 17 patients (22%) died during the follow-up, 9 (53%) among those with SVA, 8 (13%) among those who did not develop SVA (p ¼ 0.001). In the SVA group, median time from arrhythmia occurrence to death was 3.5 months (IQR 1.7 to 9.1). Eight patients (66%) of 12 with permanent AF or recurrent SVA died compared with 1 (20%) of 5 without SVA recurrences. No other factors predicted an increased risk for mortality except PAH duration (p ¼ 0.029). Hospitalization for heart failure/respiratory insufficiency occurred in 33 patients (43%), 11 patients (65%) with SVA, and 22 patients (37%) without SVA (p ¼ 0.019). Other parameters relating to occurrence of hospitalization for heart failure/respiratory insufficiency were DLCO (p ¼ 0.02) and clinical evidence of RV failure at baseline (p ¼ 0.014).
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Table 3 Characteristics of study population at the end of the follow-up, expressed as median (IQR) or number and percentages (%), in relation to insurgence of supraventricular arrhythmia Supraventricular arrhythmia þ (n ¼ 17)
Variable Systemic systolic pressure (mmHg) Heart rate (bpm) SaO2 (%) WHO-FC worsening at follow-up 6MWD variation (metres) NT-proBNP variation (pg/ml) DLCO variation (10%) TAPSE variation (mm) Pericardial effusion Right atrial pressure variation (mmHg) PAPm variation (mmHg) Cardiac Index variation (l/min/m2)
105 90 89 8 45 þ635 -10 -2 6 þ1 0 þ0.03
(100; 140) (75; 117.5) (88; 95) (47%) (-207.5; -1.25) (-80; þ4042) (-19.5; -5) (-3; þ2) (35%) (-7.5; þ5) (-4; þ2) (-2.13 - þ1.22)
Table 4 Recurrence of end points in relation to insurgence of supraventricular arrhythmia Variable
Supraventricular arrhythmia þ (n ¼ 17)
Supraventricular arrhythmia (n ¼ 60)
p value
Morbidity end point Death for any cause Hospitalization for heart failure/respiratory insufficiency
76.5 % (13 pz) 52.9 % (9 pz) 64.7 % (11 pz)
36.7 % (22 pz) 13.3 % (8 pz) 36.7 % (22 pz)
0.004 0.001 0.03
Figure 1. Distribution of the end point in the 2 groups.
Figures 2 to 4 show Kaplan-Meier curves comparing incidence of primary composed mobility end point (Cox regression hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.07 to 4.34; p ¼ 0.031), mortality (Cox regression HR 4.1; 95% CI 1.6 to 10.6; p ¼ 0.004), and hospitalization for heart failure/respiratory insufficiency (Cox regression HR 2.1; 95% CI 1.1 to 4.2; p ¼ 0.031) in patients developing SVA compared with those not developing SVA.
Supraventricular arrhythmia - (n ¼ 60) 120 80 93 9 0 -84 1 þ1 9 þ2 0 þ0.15
(110; 128.7) (70; 95) (88.2; 95) (15%) (-55.5; þ72.5) (-1544; þ261.5) (-9; þ7.5) (-1.2; þ4) (15%) (-4; þ6) (-7; þ15) (-0.13; þ0.7)
p value 0.82 0.07 0.24 0.005 0.048 0.018 0.025 0.041 0.06 0.5 0.82 0.5
After controlling for potential confounding factors by Cox regression survival analysis, development of SVA was confirmed to independently relate with the occurrence of the primary composite morbidity end point (HR 2.82; 95% CI 1.2 to 6.6; p ¼ 0.018); also 6MWD (HR 0.86 for each increase of 50 meters of test results; 95% CI 0.75 to 0.99; p ¼ 0.036), and DLCO (HR 0.97 (95% CI 0.94 to 0.99); p ¼ 0.037) emerged as independent predictors of the primary end point. Discussion This study shows that (1) the incidence of SVA in patients with PAH is relatively high; (2) no demographic, clinical, and instrumental data at baseline may help to predict occurrence of SVA, which are associated with the worsening of functional and prognostic parameters; (3) sinus rhythm could be successfully restored in patients with PAH but with high rates of recurrences; and (4) SVA are associated with an increased risk of a composite morbidity end point and of death. In our cohort during a median follow-up of 35 months, 22% patients had almost 1 episode of SVA, confirming the data about high incidence of SVA in patients with PAH (from 10% to 25% in 6 years of follow-up) reported by other authors.5e8 The right chamber dilation, and the associated electrical remodeling of right atria, could be the substrate of SVA insurgence in PAH with the iperactivation of the sympathetic nervous system.9 Our study confirms that in patients with PAH, the SVA onset could be a warning sign. On one hand, SVA could further deteriorate the right ventricular function leading to prognostic worsening, as discussed in other works5e8: once SVA happens, reduction of atrial contraction, loss of atrioventricular synchrony, and rapid heart rate may compromise cardiac function, resulting in reductions of diastolic filling and cardiac output.5 In contrast, SVA onset could be a marker of deteriorating right ventricular function and progression of PAH. Indeed, in our cohort, as in the population previously analyzed by Olsson et al,8 SVA were detected mainly after patients’ request of medical attention because of aggravation of symptoms related to PAH and right-sided cardiac failure (41% of patients with SVA), instead of for
Arrhythmias and Conduction Disturbances/Supraventricular Arrhythmias as Marker of Prognosis in PAH
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Figure 2. Kaplan-Meier estimates of occurrence of the morbidity end point in patients with PAH. Patients who developed SVA had more events (green line) than who did not develop SVA (blue line), p ¼ 0.031.
Figure 3. Kaplan-Meier estimates of survival in patients with PAH. Patients who developed SVA had significantly worse outcomes (green line) than those who did not develop SVA (blue line), p ¼ 0.004.
symptoms related to the arrhythmia. Moreover, the median interval between PAH diagnosis and onset of SVA was relatively long (15.1 months; IQR 11.3 to 43.3), suggesting
that these arrhythmias are mostly manifestation of longstanding PAH, as reported also by Tonges et al6 and by Ruiz-Cano et al.7 Furthermore, SVA insurgence was
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Figure 4. Kaplan-Meier estimates of occurrence of hospitalization for heart failure/respiratory insufficiency in patients with PAH. Patients who developed SVA had more events (green line) than those who did not develop SVA (blue line), p ¼ 0.031.
associated with worsening of parameters traditionally related to a negative prognosis: WHO-FC, 6MWD, DLCO, TAPSE, and NT-proBNP. All these elements taken together suggest that SVA onset could be a marker of the progression of the natural history of PAH to the end-stage phase, more than a factor decisively contributing to this negative evolution. From this perspective, the association between SVA onset and high rate of death and hospitalization for heart failure/ respiratory insufficiency comes than hardly unexpected. Therefore, physicians should be careful in the management of patients with PAH and SVA. In the contest of a goaloriented therapy strategy, the SVA occurrence is a negative prognostic factor and the SVA onset may underline a PAH progression with the need to increase PAH-specific drugs, as suggested by the experience of Ruiz-Cano et al.7 Moreover, the sinus rhythm restoration should be desirable to improve the RV performance. Indeed, in larger cohorts, an improvement of clinical status after sinus rhythm restoration has been described and a worse prognostic outcome in patients with PAH with permanent AF compared with those with transient AF.5e8 Concerning the rhythm control strategy, we have demonstrated that sinus rhythm could be restored in most patients with PAH (11 of 13 patients). In this cohort of patients, all tools for the rhythm control strategy have been safely applied: to the best of our knowledge, this is the first work in which it has been reported the use of Ic antiarrhythmic drugs in patients with PAH without adverse events. Moreover, for the first time in our study, we report the use of AF transcatheter ablation in patients with PAH: despite the many doubts about feasibility and safety of these interventions in patients with PAH, AF ablation in left atria might be a charming option in this population, even if
substrate for AF in these patients may be different than in general population as it could primarily involve the right atrium more than the left.8 In our study, there was not a correlation between left atria dilation and the insurgence of SVA, as in other previous reports,8 and an increased inducibility of AF on right atrial stimulation in idiopathic PAH has been also described.10 Although these data seem to suggest that the source of AF in patients with PAH might be in the right atrium, further studies are needed to determine the pathophysiological basis of AF in this population and the best ablation strategy in patients with PAH. Although an aggressive rhythm control strategy, the rate of recurrence of SVA was very high, and it did not improve the prognosis of patients, probably because SVA occurred in patients with advanced stages of the disease and irreversible right-sided cardiac dysfunction. Maybe, as in left ventricular dysfunction,11,12 in patients with PAH, a rhythm control strategy could be effective only if performed early in the natural evolution of the right-sided cardiac failure. This study has several limitations: first of all the sample size. The retrospective design may have lead to the underestimation of the true incidence of the SVA, even if our data are similar to finding of more wild prospective study.5,7 Furthermore, although electrocardiogram were monitored regularly during the routine follow-up, the lack of closer rhythm monitoring (e.g., ECG Holter or loop recorded) may have led to the underdetection of several asymptomatic selflimiting tachyarrhythmias. Moreover, patients with right-sided cardiac failure and aggressive forms of PAH were more frequently hospitalized and underwent more often to clinical evaluation compared with those with milder forms, potentially leading to a higher
Arrhythmias and Conduction Disturbances/Supraventricular Arrhythmias as Marker of Prognosis in PAH
detection bias of SVA in patients with advanced PAH. However, all patients were regularly and closely followed up, so we can hypothesize that no clinically relevant episodes of SVA were missed in our cohort. Disclosures The authors have no conflicts of interest to disclose. 5. 1. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493e2537. 2. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62(25 Suppl):D34eD41. 3. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071e2104. 4. Blomström-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW, Stevenson WG, Tomaselli GF, Antman EM, Smith SC Jr, Alpert JS, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Hiratzka LF, Hunt SA, Jacobs AK, Russell RO Jr, Priori SG, Blanc JJ, Budaj A, Burgos EF, Cowie M, Deckers JW, Garcia MA, Klein WW, Lekakis J, Lindahl B, Mazzotta G, Morais JC, Oto A, Smiseth O, Trappe HJ; European Society of Cardiology
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Committee; NASPE-Heart Rhythm Society. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPE-Heart Rhythm Society. J Am Coll Cardiol 2003;42:1493e1531. Wen L, Sun ML, An P, Jiang X, Sun K, Zheng L, Liu QQ, Wang L, Zhao QH, He J, Jing ZC. Frequency of supraventricular arrhythmias in patients with idiopathic pulmonary arterial hypertension. Am J Cardiol 2014;114:1420e1425. Tongers J, Schwerdtfeger B, Klein G, Kempf T, Schaefer A, Knapp JM, Niehaus M, Korte T, Hoeper MM. Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J 2007;153:127e132. Ruiz-Cano MJ, Gonzalez-Mansilla A, Escribano P, Delgado J, Arribas F, Torres J, Flox A, Riva M, Gomez MA, Saenz C. Clinical implications of supraventricular arrhythmias in patients with severe pulmonary arterial hypertension. Int J Cardiol 2011;146:105e106. Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial flutter and fibrillation in patients with pulmonary hypertension. Int J Cardiol 2013;167:2300e2305. Rajdev A, Garan H, Biviano A. Arrhythmias in pulmonary arterial hypertension. Prog Cardiovasc Dis 2012:180e186. Medi C, Kalman JM, Ling LH, Teh AW, Lee G, Lee G, Spence SJ, Kaye DM, Kistler PM. Atrial electrical and structural remodeling associated with longstanding pulmonary hypertension and right ventricular hypertrophy in humans. J Cardiovasc Electrophysiol 2012;23: 614e620. Anselmino M, Matta M, D’Ascenzo F, Bunch TJ, Schilling RJ, Hunter RJ, Pappone C, Neumann T, Noelker G, Fiala M, Bertaglia E, Frontera A, Duncan E, Nalliah C, Jais P, Weerasooriya R, Kalman JM, Gaita F. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2014;7:1011e1018. Handoko ML, de Man FS, Allaart CP, Paulus WJ, Westerhof N, VonkNoordegraaf A. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur Respir Rev 2010;19:72e82.