LIVER TRANSPLANTATION 21:314–320, 2015
ORIGINAL ARTICLE
Preexisting Atrial Fibrillation and Cardiac Complications After Liver Transplantation Johannes Bargehr,1,2 Jorge F. Trejo-Gutierrez,2 Tushar Patel,1 Barry Rosser,1 Jaime Aranda-Michel,1 Maria L. Yataco,1 and C. Burcin Taner1 1 Department of Transplantation and 2Division of Cardiovascular Diseases, Mayo Clinic Florida, Jacksonville, FL
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with increased cardiovascular morbidity and all-cause mortality. Our aim was to determine the impact of preexisting AF on patients undergoing liver transplantation (LT). A retrospective case-control study was performed. Records from patients who underwent LT between January 2005 and December 2008 at Mayo Clinic Florida were reviewed. Patients with preexisting AF were identified and matched to patients who did not have a diagnosis of AF. Thirty-two of 717 LT recipients (4.5%) had AF before LT. These patients were compared to a control group of 63 LT recipients. Pre-LT left ventricular hypertrophy (P 5 0.03), a history of congestive heart failure (P 5 0.04), and a history of stroke or transient ischemic attack (P 5 0.03) were significantly more prevalent in patients with AF versus controls. Intraoperative adverse cardiac events (P 5 0.02) and AF-related adverse postoperative events (P < 0.001) were more common in the recipients with known AF. Six patients with paroxysmal AF (19%) developed chronic/ persistent AF postoperatively. Graft survival and patient survival were similar in the groups. Although patients with AF had a higher incidence of intraoperative cardiac events, a higher cardiovascular morbidity rate, and a complicated postoperative C 2014 AASLD. course, this did not affect overall graft and patient survival. Liver Transpl 21:314-320, 2015. V Received July 5, 2014; accepted November 23, 2014. Atrial fibrillation (AF) is the most common cardiac arrhythmia with an estimated incidence of 28.3 per 1000 person-years in the United States.1 The prevalence of AF is 0.95% to 2.3% in the general population; however, it is more prevalent in men and older individuals.2-4 AF affects approximately 2.3 million Americans, and it is projected that more than 5.6 million Americans will have this condition by 2050.3 Liver transplantation (LT) outcomes have improved in the last 2 decades, but cardiovascular complications remain a leading cause of death in LT recipients.5-7 These complications have been attributed to immunosuppressive regimens and preexisting cardiac disease.8,9 For this reason, LT candidates undergo an
extensive preoperative cardiac assessment to ensure adequate function.10,11 It is known that AF is associated with an increased risk of stroke, heart failure, and all-cause mortality in the general population; however, the impact of AF on patients undergoing LT is largely unknown.12,13 Our aim in this study was to determine the morbidity and mortality associated with AF in patients undergoing LT.
PATIENTS AND METHODS A retrospective analysis was performed of all patients who underwent LT between January 2005 and December 2008 at our institution. This study was reviewed
Abbreviations: AF, atrial fibrillation; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; DCM, dilated cardiomyopathy; DRI, donor risk index; EF, ejection fraction; LA, left atrium; LT, liver transplantation; LV, left ventricular; LVMI, left ventricular mass index; PCI, percutaneous coronary intervention; RV, right ventricular; STEMI, ST elevation myocardial infarction. Potential conflict of interest: Nothing to report. Johannes Bargehr is currently affiliated with the Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom. Address reprint requests to C. Burcin Taner, M.D., Department of Transplantation, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224. Telephone: 904-956-3261; FAX: 904-956-3359; E-mail: [email protected] DOI 10.1002/lt.24060 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
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and approved by the Mayo Clinic institutional review board. To identify patients with AF, all available electrocardiograms within 2 years before LT were reviewed. Cases were selected if they presented with electrocardiographic changes of AF. In accordance with American Heart Association and American College of Cardiology guidelines, AF was defined as paroxysmal if the episode of AF resolved within 7 days of onset, recurrent if patients had more than 1 episode, and chronic/persistent if AF was present beyond 7 days of onset.14 The patients with AF were subsequently matched to 2 controls according to the following criteria: recipient age 6 5 years, biological Model for End-Stage Liver Disease score 6 5 or both > 30, donor risk index (DRI) 6 0.3, and presence or absence of diabetes mellitus before LT. Data collected from index cases and controls included demographics along with pre-LT and post-LT clinical data. Primary endpoints were graft and patient survival in days. Secondary cardiac endpoints were also assessed (incorporates congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke, vascular disease, age 65-74 and sex category for risk assessment). CHA2DS2-VASc scores were obtained to assess the risk of stroke. For patients who received anticoagulation treatment, CHA2DS2-VASc scores of 1, 2, and 3 corresponded to event rates of hospital admission and death due to thromboembolism of 2.01%, 3.71%, and 5.92% per 100 person-years, respectively.15 Follow-up for all patients was complete as of December 2013.
Statistics Data distribution was accepted as normal if skewness and kurtosis ranged from 21 to 1. Group comparisons of continuous variables between 2 matchedcontrol LT patients (n 5 63) for each member of the AF group were performed with the 2-sample t test when the normality assumption was satisfied and with the Mann-Whitney U test for data that did not demonstrate a normal distribution. For categorical variables, Pearson’s chi-square test was used, and if the validity was violated, Fisher’s exact test was performed. The P value was considered significant if it was less than 0.05. The data are presented as means and standard deviations with medians and ranges (minimum to maximum) for continuous variables and as frequencies and percentages for categorical variables. For patient and graft survival, Kaplan-Meier curves were used to depict the time to the event. Survival data were censored if the patient was still alive. The log-rank test was used to calculate the statistical difference between the 2 groups. Statistical analysis was performed with SPSS 19.0 (SPSS, Inc., Chicago, IL).
RESULTS A total of 717 patients underwent LT between January 2005 and December 2008. Thirty-two LT recipients (4.5%) had electrocardiographic changes of AF before LT. The demographic and clinical characteristics of the
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control and study populations are summarized in Table 1. There was no significant difference between the recipients with AF and the control recipients with respect to demographics, comorbid conditions, DRIs, cold ischemia times, warm ischemia times, or retransplantation. There was no statistically significant difference in cardiovascular risk factors such as obesity, hyperlipidemia, hypertension, and diabetes mellitus between the 2 study groups. A history of stroke was present in 3 patients in the group with AF versus 0 in the control group (P 5 0.03). As would be anticipated, there was a significant difference between the AF recipients and the control group in the use of anticoagulants and cardiac glycosides (P 5 0.01 for both). Table 2 illustrates the cardiovascular and echocardiographic characteristics in the pre-LT period. Pre-LT left ventricular (LV) hypertrophy, defined by standard echocardiographic criteria, was significantly more common in AF recipients versus controls (P 5 0.03). The left ventricular mass index (LVMI) qualified for LV hypertrophy in 10 patients with AF (31%) and in 8 patients (13%) in the control group (P 5 0.03). The LV ejection fraction (EF), right ventricular (RV) systolic pressure, and left atrium (LA) size and volume were similar between the 2 groups. The presence of mitral or tricuspid valve regurgitation did not differ between the 2 groups. A history of coronary artery disease (CAD) and a history of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) showed a nonsignificant trend for being more prevalent in recipients with AF (P 5 0.06 and P 5 0.07, respectively). Patients with pre-LT AF were also significantly more likely to exhibit a history of congestive heart failure (CHF; P 5 0.04) and higher CHA2DS2VASc scores (3) than controls (P 5 0.03).
Intraoperative Cardiac Events and Postoperative Complications Table 3 illustrates the intraoperative and postoperative complications. LT recipients with AF had an increased risk of intraoperative cardiac complications, a composite endpoint consisting of ventricular tachycardia, severe intraoperative hemodynamic instability, and cardiac arrest requiring internal cardiac massage (P 5 0.02). Postoperative AF-related complications were present in 9 patients (28%) with preexisting AF versus 1 patient (2%) in the control group (P < 0.001). AF persisted in 18 of 32 patients with preoperative AF and recurred in 9 of 21 patients with a history of AF but sinus rhythm on the day of LT (data not shown). Six of 32 patients (19%) with paroxysmal disease developed chronic AF after LT. Only 1 patient in the control group without any history of AF developed it in the postoperative setting (data not shown). Other cardiovascular complications, including hypertension, ventricular tachycardia, dilated cardiomyopathy (DCM), CHF, and endocarditis, were similar between the 2 groups. There was no significant difference in the occurrence of vascular, biliary, medical, or other complications in the post-LT period between the 2 groups.
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TABLE 1. Demographic and Clinical Characteristics of Patients With AF and Patients in the Control Group
Age (years) Female sex Body mass index (kg/m2) Model for End-Stage Liver Disease score DRI Cold ischemia time (hours) Warm ischemia time (minutes) Reoperation Comorbidities Hypertension Dyslipidemia Diabetes mellitus Obesity Metabolic syndrome History of stroke History of renal insufficiency Cardiovascular medication None Anticoagulation Glycosides Anti-arrhythmic agents Diuretic Antihypertensive Alpha-adrenergic
AF Patients (n 5 32)
Controls (n 5 63)
P Value
58 6 7.7 (58.5, 44-70) 14 (44%) 28.7 6 5.8 (28.1, 18.4-44.8) 25.3 6 11.7 (25.5, 0-43) 1.57 6 0.48 (1.44, 1-3) 6.98 6 2.2 (6.59, 3.1-11.3) 33.2 6 11.7 (34, 17-70) 2 (6%)
58 6 7.0 (58, 42-71) 22 (35%) 29.36 6 6.1 (28, 20.4-46.9) 26.2 6 9.8 (26, 6-45) 1.52 6 0.45 (1.43, 0.89-2.98) 6.82 6 1.72 (6.63, 3.8-11.5) 33.25 6 10 (33, 16-62) 4 (6%)
0.81 0.50 0.59 0.67 0.60 0.69 0.99 >0.99
17 (53%) 1 (3%) 15 (47%) 11 (34%) 5 (16%) 3 (9%) 14 (44%)
28 (44%) 5 (8%) 23 (37%) 26 (41%) 9 (14%) 0 (0%) 21 (33%)
0.52 0.66 0.38 0.66 >0.99 0.03 0.37
3 (9%) 4 (13%) 4 (13%) 2 (6%) 21 (66%) 15 (47%) 0 (0%)
14 (22%) 0 (0%) 0 (0%) 0 (0%) 35 (56%) 23 (37%) 2 (3%)
0.92 0.01 0.01 0.11 0.38 0.38 0.43
NOTE: Categorical values are presented as n (%); other values are presented as means and standard deviations (with medians and ranges in parentheses). Bolded values are significant.
Patient and Graft Survival Kaplan-Meier curves of patient and graft survival are shown in Fig. 1. Patient survival was 1400 6 849 days (median 5 1613 days, range 5 22-2492 days) in the AF recipients and 1446 6 886 days (median 5 1495 days, range 5 0-3155 days) in the control group (P 5 0.44). Graft survival was 1243 6 881 days (median 5 1516 days, range 5 10-2492 days) in AF recipients and 1444 6 889 days (median 5 1495 days, range 5 03155 days) in the control group (P 5 0.14). By the end of the follow-up period, 12 patients (38%) in the AF group had died, whereas 18 patients (29%) had died in the control group (P 5 0.44). Three AF recipients (9%) died from a cardiovascular complication (2 recipients with CHF and 1 recipient with DCM), whereas none of the LT recipients in the control group died of a cardiac event (P 5 0.04). Cardiac death was the commonest reason for death in the AF group (n 5 3). Leading causes of death in the control group were pulmonary causes (n 5 4), including pneumonia and pneumonitis, and hepatic causes (n 5 4), including liver failure and recurrence of primary disease.
DISCUSSION Survival after LT has steadily improved in the last 2 decades, with an expected 1-year patient survival of more than 90% and a 5-year patient survival of 70%.16 A leading cause of death after LT is cardiovas-
cular complications,5,6 and they are attributed to preexisting cardiovascular disease and long-term immunosuppressive therapy.17 Cirrhotic cardiomyopathy, a recently recognized condition characterized by systolic dysfunction, inadequate stress response, and altered diastolic relaxation, may also contribute to the preexisting cardiovascular risk profile before LT.9 Current standard immunosuppressive regimens, including calcineurin inhibitors, corticosteroids, mycophenolate mofetil, and sirolimus, have been associated with de novo hypertension, hyperlipidemia, metabolic syndrome, and diabetes mellitus.8 Because of the increased risk of cardiovascular complications in the perioperative period and in the long term, LT candidates undergo an extensive cardiac assessment before consideration for LT.7,10,11 AF is the most common arrhythmia in the general population and significantly increases cardiovascular, cerebrovascular morbidity, and all-cause mortality.12,13 Although scientific evidence has shown that CAD, cardiomyopathy, and pulmonary arterial hypertension have a significant influence on LT recipient survival, the impact of AF in LT outcomes has never been studied.11 In the era of donor scarcity, it is of paramount importance to investigate how AF affects the morbidity and mortality of patients after LT. LT is known to impose intense stress on the cardiovascular system with large perioperative fluid shifts, hemodynamic changes, and aggressive fluid and vasopressor management after intraoperative hemorrhage.
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TABLE 2. Pretransplant Cardiovascular and Echocardiographic Characteristics
Type of AF Chronic/persistent Paroxysmal Recurrent LA size (mm) LA volume (cc) LV hypertrophy LV EF (%) LVMI (female > 95 g/m2, male > 115 g/m2) RV systolic pressure (mmHg) Mitral valve regurgitation Tricuspid valve regurgitation History of CAD History of PCI/CABG CHA2DS2-VASc History of CHF Hypertension Age 75 years Diabetes mellitus Prior stroke or transient ischemic attack Vascular disease Age of 65-74 years Female sex CHA2DS2-VASc score 2 3
AF Patients (n 5 32)
Controls (n 5 63)
P Value
9 (28%) 19 (59%) 4 (13%) (42, 30-50) (51, 19-92) 11 (34%) (65, 50-81) 10 (31%) (28, 21-51) 27 (84%) 31 (97%) 8 (25%) 8 (25%)
0 (0%) 0 (0%) 0 (0%) 42.3 6 6.8 (43, 24-61) 52.6 6 18.4 (54, 20-94) 9 (14%) 68.4 6 12 (67, 53-144) 8 (13%) 33.1 6 10.9 (31, 16-69) 52 (83%) 60 (95%) 6 (10%) 5 (8%)
— — — 0.99 0.09 0.03 0.30 0.03 0.10 1.00 1.00 0.06 0.07
4 (13%) 17 (53%) 0 (0%) 15 (47%) 3 (9%) 8 (25%) 7 (22%) 14 (44%)
1 (2%) 28 (44%) 0 (0%) 23 (37%) 0 (0%) 6 (10%) 12 (19%) 22 (35%)
0.04 0.42 — 0.33 0.03 0.06 0.74 0.40
20 (63%) 11 (34%)
30 (48%) 9 (14%)
0.17 0.03
41.5 6 4.4 52.6 6 16.4 65.2 6 8.1 30.6 6 8.5
NOTE: Categorical values are presented as n (%); other values are presented as means and standard deviations (with medians and ranges in parentheses). Bolded values are significant.
Postoperatively, these changes result in a marked increase in arterial pressure and peripheral vascular resistance.18 It is conceivable that the mere absence of atrial and ventricular synchronicity could have a major hemodynamic impact at the time of surgical stress. This hypothesis is amenable for intervention trials that would aim to establish and maintain sinus rhythm before and during the intraoperative transplantation phase. It has recently been reported that development of AF in the postoperative period after kidney transplantation can be predicted by recipient age, a history of myocardial infarction, and combined liver/kidney transplantation.19 The pathophysiological mechanisms that trigger postoperative AF remain unclear, but ischemia/reperfusion events, resulting in the formation of oxidative stress and a systemic inflammatory response, have been shown to cause structural modifications of myocardial tissue and atrial remodeling.20-22 The American Heart Association and the American College of Cardiology currently recommend betamimetic blockers for the prevention of postoperative AF in patients undergoing cardiac surgery.14 Pharmaceutical prevention of AF could also prove useful for patients with preexisting paroxysmal AF. Because postoperative chronic/persistent AF is an established predictor for long-term mortality, prevention of AF may be important.23-25
This study suggested that LT recipients with a history of AF were more likely to have LV hypertrophy, a history of CHF, and a history of cerebrovascular events. Patients with AF were significantly more likely to exhibit high CHA2DS2-VASc scores (3). Our finding of a higher incidence of LV hypertrophy in AF patients correlates with previous publications.25 However, we did not find a significant difference in other key structural parameters, such as LV EF, LA size and volume, and RV systolic pressure, that are thought to be associated with cardiovascular morbidity. In the current study, we found that LT recipients with a history of AF before transplantation were significantly more likely to develop intraoperative cardiac events than the patients in the control group. This, perhaps, provides indirect evidence that AF should be embedded more thoroughly into surgical risk management and used to predict the assignment of the care location after LT. Taken collectively, the clinical risk profile of patients with a history of AF has several implications: preoperative cardiologic and anesthetic assessment of LT recipients is paramount. Importantly, alertness by the anesthesia team during surgery and by the medical team in the postoperative period is required to prevent any adverse outcomes.26 The postoperative course of patients with a history of AF is intricate: it may require cardiac expertise and a multidisciplinary approach to handle
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TABLE 3. Intraoperative and Postoperative Complications
Intraoperative complications (n) Hypotension Ventricular tachycardia Bradycardia Cardiac arrest Hemodynamic instability STEMI RV dysfunction Postoperative AF-related complications Postoperative medical complications Cardiac Hypertension Ventricular tachycardia Rapid AF DCM CHF Endocarditis Postoperative stroke Infectious Pulmonary Renal Endocrine Gastrointestinal Neurological Vascular Biliary
AF (n 5 32)
Controls (n 5 63)
P Value
9 (28%) 5 (16%) 2 (6%) 1 (3%) 1 (3%) 1 (3%) 0 (0%) 0 (0%) 9 (28%) 24 (75%) 15 (46%) 9 (28%) 1 (3%) 2 (6%) 1 (3%) 2 (6%) 0 (0%) 0 (0%) 8 (25%) 4 (12%) 8 (25%) 16 (50%) 9 (28%) 3 (9%) 5 (16%) 3 (9%)
3 (5%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) 0 (0%) 1 (2%) 1 (2%) 1 (2%) 56 (89%) 18 (29%) 16 (25%) 0 (0%) 0 (0%) 1 (2%) 1 (2%) 1 (2%) 0 (0%) 27 (43%) 13 (21%) 27 (43%) 34 (54%) 13 (21%) 9 (14%) 10 (16%) 12 (19%)
0.02 — — — — — — — 0.99 0.25
NOTE: Categorical values are presented as n (%). Bolded values are significant.
Figure 1.
Graft and patient survival.
chronic/persistent AF, a rapid ventricular response to AF, and addressing the complex issue of the need for anticoagulation in those with chronic/persistent AF.
This study found no statistically significant differences in graft and patient survival between the 2 study groups, and this suggests that AF in isolation from
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other recognized cardiac contraindications to transplant does not increase mortality or graft loss independently of other noncardiac factors. However, we observed that LT recipients with AF had a trend of a higher rate of death due to cardiac reasons in comparison with their matched controls. Because of statistical power limitations in the current study, confirmation of our results in larger cohorts is warranted to determine the influence of AF on candidacy for LT. Despite an initial population count of 717 LT recipients, only 32 of these patients were found to have a history of AF. The low number of patients in both groups did not allow for a multivariate analysis due to overfitting of the model, which is a weakness of this study. It is possible that patients who had an increased risk for mortality after LT may have been denied listing and that our group of AF patients was “the best of the worst.” A lack of data on potential candidates who were denied candidacy for LT because of AF or other preexisting cardiac conditions is a shortcoming of this study. A multi-institutional study with a larger study population may illustrate problems related to AF itself or to AF as a cardiovascular marker for complications in the posttransplant period. Future studies are needed to corroborate our findings and to establish whether AF has major implications in the selection criteria for LT recipients as well as intraoperative and long-term care of such patients. In conclusion, this retrospective case-control analysis shows that preexisting AF in LT recipients is associated with intraoperative cardiac events and cardiovascular morbidity in the medium to long term.
REFERENCES 1. Piccini JP, Hammill BG, Sinner MF, Jensen PN, Hernandez AF, Heckbert SR, et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes 2012;5:85-93. 2. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469-473. 3. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370-2375. 4. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042-1046. 5. Pruthi J, Medkiff KA, Esrason KT, Donovan JA, Yoshida EM, Erb SR, et al. Analysis of causes of death in liver transplant recipients who survived more than 3 years. Liver Transpl 2001;7:811-815. 6. Madhwal S, Atreja A, Albeldawi M, Lopez R, Post A, Costa MA. Is liver transplantation a risk factor for cardiovascular disease? A meta-analysis of observational studies. Liver Transpl 2012;18:1140-1146. 7. Johnston SD, Morris JK, Cramb R, Gunson BK, Neuberger J. Cardiovascular morbidity and mortality
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after orthotopic liver transplantation. Transplantation 2002;73:901-906. 8. Canzanello VJ, Schwartz L, Taler SJ, Textor SC, Wiesner RH, Porayko MK, Krom RA. Evolution of cardiovascular risk after liver transplantation: a comparison of cyclosporine A and tacrolimus (FK506). Liver Transpl Surg 1997; 3:1-9. 9. Timoh T, Protano MA, Wagman G, Bloom M, Vittorio TJ. A perspective on cirrhotic cardiomyopathy. Transplant Proc 2011;43:1649-1653. 10. Raval Z, Harinstein ME, Skaro AI, Erdogan A, DeWolf AM, Shah SJ, et al. Cardiovascular risk assessment of the liver transplant candidate. J Am Coll Cardiol 2011; 58:223-231. 11. Lentine KL, Costa SP, Weir MR, Robb JF, Fleisher LA, Kasiske BL, et al.; for American Heart Association Council on the Kidney in Cardiovascular Disease and Council on Peripheral Vascular Disease; American Heart Association; American College of Cardiology Foundation. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation. Circulation 2012;126:617-663. 12. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/ Paisley study. Am J Med 2002;113:359-364. 13. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995;98:476-484. 14. Fuster V, Ryd en LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al.; for American College of Cardiology Foundation/American Heart Association Task Force. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011;123:e269-367. 15. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. 16. Roberts MS, Angus DC, Bryce CL, Valenta Z, Weissfeld L. Survival after liver transplantation in the United States: a disease-specific analysis of the UNOS database. Liver Transpl 2004;10:886-897. 17. Gonwa TA. Hypertension and renal dysfunction in longterm liver transplant recipients. Liver Transpl 2001; 7(suppl 1):S22-S26. 18. Navasa M, Feu F, Garcıa-Pag an JC, Jim enez W, Llach J, Rimola A, et al. Hemodynamic and humoral changes after liver transplantation in patients with cirrhosis. Hepatology 1993;17:355-360. 19. La Manna G, Boriani G, Capelli I, Marchetti A, Grandinetti V, Spazzoli A, et al. Incidence and predictors of postoperative atrial fibrillation in kidney transplant recipients. Transplantation 2013;96:981-986. 20. Van Wagoner DR. Molecular basis of atrial fibrillation: a dream or a reality? J Cardiovasc Electrophysiol 2003;14: 667-669. 21. Van Wagoner DR. Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target. J Cardiovasc Pharmacol 2008;52: 306-313.
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22. Korantzopoulos P, Kolettis TM, Galaris D, Goudevenos JA. The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation. Int J Cardiol 2007;115: 135-143. 23. Villareal RP, Hariharan R, Liu BC, Kar B, Lee VV, Elayda M, et al. Postoperative atrial fibrillation and mortality after coronary artery bypass surgery. J Am Coll Cardiol 2004;43:742-748. 24. Mathew JP, Fontes ML, Tudor IC, Ramsay J, Duke P, Mazer CD, et al.; for Investigators of the Ischemia Research and Education Foundation and Multicenter
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Study of Perioperative Ischemia Research Group. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 2004;291:1720-1729. 25. El-Chami MF, Kilgo P, Thourani V, Lattouf OM, Delurgio DB, Guyton RA, et al. New-onset atrial fibrillation predicts long-term mortality after coronary artery bypass graft. J Am Coll Cardiol 2010;55:1370-1376. 26. Bargehr J, Trejo-Gutierrez JF, Rosser BG, Patel T, Yataco ML, Pungpapong S, et al. Liver transplantation in patients with atrial fibrillation. Transplant Proc 2013;45: 2302-2306.
ORIGINAL ARTICLE
Preexisting Atrial Fibrillation and Cardiac Complications After Liver Transplantation Johannes Bargehr,1,2 Jorge F. Trejo-Gutierrez,2 Tushar Patel,1 Barry Rosser,1 Jaime Aranda-Michel,1 Maria L. Yataco,1 and C. Burcin Taner1 1 Department of Transplantation and 2Division of Cardiovascular Diseases, Mayo Clinic Florida, Jacksonville, FL
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with increased cardiovascular morbidity and all-cause mortality. Our aim was to determine the impact of preexisting AF on patients undergoing liver transplantation (LT). A retrospective case-control study was performed. Records from patients who underwent LT between January 2005 and December 2008 at Mayo Clinic Florida were reviewed. Patients with preexisting AF were identified and matched to patients who did not have a diagnosis of AF. Thirty-two of 717 LT recipients (4.5%) had AF before LT. These patients were compared to a control group of 63 LT recipients. Pre-LT left ventricular hypertrophy (P 5 0.03), a history of congestive heart failure (P 5 0.04), and a history of stroke or transient ischemic attack (P 5 0.03) were significantly more prevalent in patients with AF versus controls. Intraoperative adverse cardiac events (P 5 0.02) and AF-related adverse postoperative events (P < 0.001) were more common in the recipients with known AF. Six patients with paroxysmal AF (19%) developed chronic/ persistent AF postoperatively. Graft survival and patient survival were similar in the groups. Although patients with AF had a higher incidence of intraoperative cardiac events, a higher cardiovascular morbidity rate, and a complicated postoperative C 2014 AASLD. course, this did not affect overall graft and patient survival. Liver Transpl 21:314-320, 2015. V Received July 5, 2014; accepted November 23, 2014. Atrial fibrillation (AF) is the most common cardiac arrhythmia with an estimated incidence of 28.3 per 1000 person-years in the United States.1 The prevalence of AF is 0.95% to 2.3% in the general population; however, it is more prevalent in men and older individuals.2-4 AF affects approximately 2.3 million Americans, and it is projected that more than 5.6 million Americans will have this condition by 2050.3 Liver transplantation (LT) outcomes have improved in the last 2 decades, but cardiovascular complications remain a leading cause of death in LT recipients.5-7 These complications have been attributed to immunosuppressive regimens and preexisting cardiac disease.8,9 For this reason, LT candidates undergo an
extensive preoperative cardiac assessment to ensure adequate function.10,11 It is known that AF is associated with an increased risk of stroke, heart failure, and all-cause mortality in the general population; however, the impact of AF on patients undergoing LT is largely unknown.12,13 Our aim in this study was to determine the morbidity and mortality associated with AF in patients undergoing LT.
PATIENTS AND METHODS A retrospective analysis was performed of all patients who underwent LT between January 2005 and December 2008 at our institution. This study was reviewed
Abbreviations: AF, atrial fibrillation; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; DCM, dilated cardiomyopathy; DRI, donor risk index; EF, ejection fraction; LA, left atrium; LT, liver transplantation; LV, left ventricular; LVMI, left ventricular mass index; PCI, percutaneous coronary intervention; RV, right ventricular; STEMI, ST elevation myocardial infarction. Potential conflict of interest: Nothing to report. Johannes Bargehr is currently affiliated with the Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom. Address reprint requests to C. Burcin Taner, M.D., Department of Transplantation, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224. Telephone: 904-956-3261; FAX: 904-956-3359; E-mail: [email protected] DOI 10.1002/lt.24060 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
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and approved by the Mayo Clinic institutional review board. To identify patients with AF, all available electrocardiograms within 2 years before LT were reviewed. Cases were selected if they presented with electrocardiographic changes of AF. In accordance with American Heart Association and American College of Cardiology guidelines, AF was defined as paroxysmal if the episode of AF resolved within 7 days of onset, recurrent if patients had more than 1 episode, and chronic/persistent if AF was present beyond 7 days of onset.14 The patients with AF were subsequently matched to 2 controls according to the following criteria: recipient age 6 5 years, biological Model for End-Stage Liver Disease score 6 5 or both > 30, donor risk index (DRI) 6 0.3, and presence or absence of diabetes mellitus before LT. Data collected from index cases and controls included demographics along with pre-LT and post-LT clinical data. Primary endpoints were graft and patient survival in days. Secondary cardiac endpoints were also assessed (incorporates congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke, vascular disease, age 65-74 and sex category for risk assessment). CHA2DS2-VASc scores were obtained to assess the risk of stroke. For patients who received anticoagulation treatment, CHA2DS2-VASc scores of 1, 2, and 3 corresponded to event rates of hospital admission and death due to thromboembolism of 2.01%, 3.71%, and 5.92% per 100 person-years, respectively.15 Follow-up for all patients was complete as of December 2013.
Statistics Data distribution was accepted as normal if skewness and kurtosis ranged from 21 to 1. Group comparisons of continuous variables between 2 matchedcontrol LT patients (n 5 63) for each member of the AF group were performed with the 2-sample t test when the normality assumption was satisfied and with the Mann-Whitney U test for data that did not demonstrate a normal distribution. For categorical variables, Pearson’s chi-square test was used, and if the validity was violated, Fisher’s exact test was performed. The P value was considered significant if it was less than 0.05. The data are presented as means and standard deviations with medians and ranges (minimum to maximum) for continuous variables and as frequencies and percentages for categorical variables. For patient and graft survival, Kaplan-Meier curves were used to depict the time to the event. Survival data were censored if the patient was still alive. The log-rank test was used to calculate the statistical difference between the 2 groups. Statistical analysis was performed with SPSS 19.0 (SPSS, Inc., Chicago, IL).
RESULTS A total of 717 patients underwent LT between January 2005 and December 2008. Thirty-two LT recipients (4.5%) had electrocardiographic changes of AF before LT. The demographic and clinical characteristics of the
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control and study populations are summarized in Table 1. There was no significant difference between the recipients with AF and the control recipients with respect to demographics, comorbid conditions, DRIs, cold ischemia times, warm ischemia times, or retransplantation. There was no statistically significant difference in cardiovascular risk factors such as obesity, hyperlipidemia, hypertension, and diabetes mellitus between the 2 study groups. A history of stroke was present in 3 patients in the group with AF versus 0 in the control group (P 5 0.03). As would be anticipated, there was a significant difference between the AF recipients and the control group in the use of anticoagulants and cardiac glycosides (P 5 0.01 for both). Table 2 illustrates the cardiovascular and echocardiographic characteristics in the pre-LT period. Pre-LT left ventricular (LV) hypertrophy, defined by standard echocardiographic criteria, was significantly more common in AF recipients versus controls (P 5 0.03). The left ventricular mass index (LVMI) qualified for LV hypertrophy in 10 patients with AF (31%) and in 8 patients (13%) in the control group (P 5 0.03). The LV ejection fraction (EF), right ventricular (RV) systolic pressure, and left atrium (LA) size and volume were similar between the 2 groups. The presence of mitral or tricuspid valve regurgitation did not differ between the 2 groups. A history of coronary artery disease (CAD) and a history of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) showed a nonsignificant trend for being more prevalent in recipients with AF (P 5 0.06 and P 5 0.07, respectively). Patients with pre-LT AF were also significantly more likely to exhibit a history of congestive heart failure (CHF; P 5 0.04) and higher CHA2DS2VASc scores (3) than controls (P 5 0.03).
Intraoperative Cardiac Events and Postoperative Complications Table 3 illustrates the intraoperative and postoperative complications. LT recipients with AF had an increased risk of intraoperative cardiac complications, a composite endpoint consisting of ventricular tachycardia, severe intraoperative hemodynamic instability, and cardiac arrest requiring internal cardiac massage (P 5 0.02). Postoperative AF-related complications were present in 9 patients (28%) with preexisting AF versus 1 patient (2%) in the control group (P < 0.001). AF persisted in 18 of 32 patients with preoperative AF and recurred in 9 of 21 patients with a history of AF but sinus rhythm on the day of LT (data not shown). Six of 32 patients (19%) with paroxysmal disease developed chronic AF after LT. Only 1 patient in the control group without any history of AF developed it in the postoperative setting (data not shown). Other cardiovascular complications, including hypertension, ventricular tachycardia, dilated cardiomyopathy (DCM), CHF, and endocarditis, were similar between the 2 groups. There was no significant difference in the occurrence of vascular, biliary, medical, or other complications in the post-LT period between the 2 groups.
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TABLE 1. Demographic and Clinical Characteristics of Patients With AF and Patients in the Control Group
Age (years) Female sex Body mass index (kg/m2) Model for End-Stage Liver Disease score DRI Cold ischemia time (hours) Warm ischemia time (minutes) Reoperation Comorbidities Hypertension Dyslipidemia Diabetes mellitus Obesity Metabolic syndrome History of stroke History of renal insufficiency Cardiovascular medication None Anticoagulation Glycosides Anti-arrhythmic agents Diuretic Antihypertensive Alpha-adrenergic
AF Patients (n 5 32)
Controls (n 5 63)
P Value
58 6 7.7 (58.5, 44-70) 14 (44%) 28.7 6 5.8 (28.1, 18.4-44.8) 25.3 6 11.7 (25.5, 0-43) 1.57 6 0.48 (1.44, 1-3) 6.98 6 2.2 (6.59, 3.1-11.3) 33.2 6 11.7 (34, 17-70) 2 (6%)
58 6 7.0 (58, 42-71) 22 (35%) 29.36 6 6.1 (28, 20.4-46.9) 26.2 6 9.8 (26, 6-45) 1.52 6 0.45 (1.43, 0.89-2.98) 6.82 6 1.72 (6.63, 3.8-11.5) 33.25 6 10 (33, 16-62) 4 (6%)
0.81 0.50 0.59 0.67 0.60 0.69 0.99 >0.99
17 (53%) 1 (3%) 15 (47%) 11 (34%) 5 (16%) 3 (9%) 14 (44%)
28 (44%) 5 (8%) 23 (37%) 26 (41%) 9 (14%) 0 (0%) 21 (33%)
0.52 0.66 0.38 0.66 >0.99 0.03 0.37
3 (9%) 4 (13%) 4 (13%) 2 (6%) 21 (66%) 15 (47%) 0 (0%)
14 (22%) 0 (0%) 0 (0%) 0 (0%) 35 (56%) 23 (37%) 2 (3%)
0.92 0.01 0.01 0.11 0.38 0.38 0.43
NOTE: Categorical values are presented as n (%); other values are presented as means and standard deviations (with medians and ranges in parentheses). Bolded values are significant.
Patient and Graft Survival Kaplan-Meier curves of patient and graft survival are shown in Fig. 1. Patient survival was 1400 6 849 days (median 5 1613 days, range 5 22-2492 days) in the AF recipients and 1446 6 886 days (median 5 1495 days, range 5 0-3155 days) in the control group (P 5 0.44). Graft survival was 1243 6 881 days (median 5 1516 days, range 5 10-2492 days) in AF recipients and 1444 6 889 days (median 5 1495 days, range 5 03155 days) in the control group (P 5 0.14). By the end of the follow-up period, 12 patients (38%) in the AF group had died, whereas 18 patients (29%) had died in the control group (P 5 0.44). Three AF recipients (9%) died from a cardiovascular complication (2 recipients with CHF and 1 recipient with DCM), whereas none of the LT recipients in the control group died of a cardiac event (P 5 0.04). Cardiac death was the commonest reason for death in the AF group (n 5 3). Leading causes of death in the control group were pulmonary causes (n 5 4), including pneumonia and pneumonitis, and hepatic causes (n 5 4), including liver failure and recurrence of primary disease.
DISCUSSION Survival after LT has steadily improved in the last 2 decades, with an expected 1-year patient survival of more than 90% and a 5-year patient survival of 70%.16 A leading cause of death after LT is cardiovas-
cular complications,5,6 and they are attributed to preexisting cardiovascular disease and long-term immunosuppressive therapy.17 Cirrhotic cardiomyopathy, a recently recognized condition characterized by systolic dysfunction, inadequate stress response, and altered diastolic relaxation, may also contribute to the preexisting cardiovascular risk profile before LT.9 Current standard immunosuppressive regimens, including calcineurin inhibitors, corticosteroids, mycophenolate mofetil, and sirolimus, have been associated with de novo hypertension, hyperlipidemia, metabolic syndrome, and diabetes mellitus.8 Because of the increased risk of cardiovascular complications in the perioperative period and in the long term, LT candidates undergo an extensive cardiac assessment before consideration for LT.7,10,11 AF is the most common arrhythmia in the general population and significantly increases cardiovascular, cerebrovascular morbidity, and all-cause mortality.12,13 Although scientific evidence has shown that CAD, cardiomyopathy, and pulmonary arterial hypertension have a significant influence on LT recipient survival, the impact of AF in LT outcomes has never been studied.11 In the era of donor scarcity, it is of paramount importance to investigate how AF affects the morbidity and mortality of patients after LT. LT is known to impose intense stress on the cardiovascular system with large perioperative fluid shifts, hemodynamic changes, and aggressive fluid and vasopressor management after intraoperative hemorrhage.
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TABLE 2. Pretransplant Cardiovascular and Echocardiographic Characteristics
Type of AF Chronic/persistent Paroxysmal Recurrent LA size (mm) LA volume (cc) LV hypertrophy LV EF (%) LVMI (female > 95 g/m2, male > 115 g/m2) RV systolic pressure (mmHg) Mitral valve regurgitation Tricuspid valve regurgitation History of CAD History of PCI/CABG CHA2DS2-VASc History of CHF Hypertension Age 75 years Diabetes mellitus Prior stroke or transient ischemic attack Vascular disease Age of 65-74 years Female sex CHA2DS2-VASc score 2 3
AF Patients (n 5 32)
Controls (n 5 63)
P Value
9 (28%) 19 (59%) 4 (13%) (42, 30-50) (51, 19-92) 11 (34%) (65, 50-81) 10 (31%) (28, 21-51) 27 (84%) 31 (97%) 8 (25%) 8 (25%)
0 (0%) 0 (0%) 0 (0%) 42.3 6 6.8 (43, 24-61) 52.6 6 18.4 (54, 20-94) 9 (14%) 68.4 6 12 (67, 53-144) 8 (13%) 33.1 6 10.9 (31, 16-69) 52 (83%) 60 (95%) 6 (10%) 5 (8%)
— — — 0.99 0.09 0.03 0.30 0.03 0.10 1.00 1.00 0.06 0.07
4 (13%) 17 (53%) 0 (0%) 15 (47%) 3 (9%) 8 (25%) 7 (22%) 14 (44%)
1 (2%) 28 (44%) 0 (0%) 23 (37%) 0 (0%) 6 (10%) 12 (19%) 22 (35%)
0.04 0.42 — 0.33 0.03 0.06 0.74 0.40
20 (63%) 11 (34%)
30 (48%) 9 (14%)
0.17 0.03
41.5 6 4.4 52.6 6 16.4 65.2 6 8.1 30.6 6 8.5
NOTE: Categorical values are presented as n (%); other values are presented as means and standard deviations (with medians and ranges in parentheses). Bolded values are significant.
Postoperatively, these changes result in a marked increase in arterial pressure and peripheral vascular resistance.18 It is conceivable that the mere absence of atrial and ventricular synchronicity could have a major hemodynamic impact at the time of surgical stress. This hypothesis is amenable for intervention trials that would aim to establish and maintain sinus rhythm before and during the intraoperative transplantation phase. It has recently been reported that development of AF in the postoperative period after kidney transplantation can be predicted by recipient age, a history of myocardial infarction, and combined liver/kidney transplantation.19 The pathophysiological mechanisms that trigger postoperative AF remain unclear, but ischemia/reperfusion events, resulting in the formation of oxidative stress and a systemic inflammatory response, have been shown to cause structural modifications of myocardial tissue and atrial remodeling.20-22 The American Heart Association and the American College of Cardiology currently recommend betamimetic blockers for the prevention of postoperative AF in patients undergoing cardiac surgery.14 Pharmaceutical prevention of AF could also prove useful for patients with preexisting paroxysmal AF. Because postoperative chronic/persistent AF is an established predictor for long-term mortality, prevention of AF may be important.23-25
This study suggested that LT recipients with a history of AF were more likely to have LV hypertrophy, a history of CHF, and a history of cerebrovascular events. Patients with AF were significantly more likely to exhibit high CHA2DS2-VASc scores (3). Our finding of a higher incidence of LV hypertrophy in AF patients correlates with previous publications.25 However, we did not find a significant difference in other key structural parameters, such as LV EF, LA size and volume, and RV systolic pressure, that are thought to be associated with cardiovascular morbidity. In the current study, we found that LT recipients with a history of AF before transplantation were significantly more likely to develop intraoperative cardiac events than the patients in the control group. This, perhaps, provides indirect evidence that AF should be embedded more thoroughly into surgical risk management and used to predict the assignment of the care location after LT. Taken collectively, the clinical risk profile of patients with a history of AF has several implications: preoperative cardiologic and anesthetic assessment of LT recipients is paramount. Importantly, alertness by the anesthesia team during surgery and by the medical team in the postoperative period is required to prevent any adverse outcomes.26 The postoperative course of patients with a history of AF is intricate: it may require cardiac expertise and a multidisciplinary approach to handle
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TABLE 3. Intraoperative and Postoperative Complications
Intraoperative complications (n) Hypotension Ventricular tachycardia Bradycardia Cardiac arrest Hemodynamic instability STEMI RV dysfunction Postoperative AF-related complications Postoperative medical complications Cardiac Hypertension Ventricular tachycardia Rapid AF DCM CHF Endocarditis Postoperative stroke Infectious Pulmonary Renal Endocrine Gastrointestinal Neurological Vascular Biliary
AF (n 5 32)
Controls (n 5 63)
P Value
9 (28%) 5 (16%) 2 (6%) 1 (3%) 1 (3%) 1 (3%) 0 (0%) 0 (0%) 9 (28%) 24 (75%) 15 (46%) 9 (28%) 1 (3%) 2 (6%) 1 (3%) 2 (6%) 0 (0%) 0 (0%) 8 (25%) 4 (12%) 8 (25%) 16 (50%) 9 (28%) 3 (9%) 5 (16%) 3 (9%)
3 (5%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) 0 (0%) 1 (2%) 1 (2%) 1 (2%) 56 (89%) 18 (29%) 16 (25%) 0 (0%) 0 (0%) 1 (2%) 1 (2%) 1 (2%) 0 (0%) 27 (43%) 13 (21%) 27 (43%) 34 (54%) 13 (21%) 9 (14%) 10 (16%) 12 (19%)
0.02 — — — — — — — 0.99 0.25
NOTE: Categorical values are presented as n (%). Bolded values are significant.
Figure 1.
Graft and patient survival.
chronic/persistent AF, a rapid ventricular response to AF, and addressing the complex issue of the need for anticoagulation in those with chronic/persistent AF.
This study found no statistically significant differences in graft and patient survival between the 2 study groups, and this suggests that AF in isolation from
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other recognized cardiac contraindications to transplant does not increase mortality or graft loss independently of other noncardiac factors. However, we observed that LT recipients with AF had a trend of a higher rate of death due to cardiac reasons in comparison with their matched controls. Because of statistical power limitations in the current study, confirmation of our results in larger cohorts is warranted to determine the influence of AF on candidacy for LT. Despite an initial population count of 717 LT recipients, only 32 of these patients were found to have a history of AF. The low number of patients in both groups did not allow for a multivariate analysis due to overfitting of the model, which is a weakness of this study. It is possible that patients who had an increased risk for mortality after LT may have been denied listing and that our group of AF patients was “the best of the worst.” A lack of data on potential candidates who were denied candidacy for LT because of AF or other preexisting cardiac conditions is a shortcoming of this study. A multi-institutional study with a larger study population may illustrate problems related to AF itself or to AF as a cardiovascular marker for complications in the posttransplant period. Future studies are needed to corroborate our findings and to establish whether AF has major implications in the selection criteria for LT recipients as well as intraoperative and long-term care of such patients. In conclusion, this retrospective case-control analysis shows that preexisting AF in LT recipients is associated with intraoperative cardiac events and cardiovascular morbidity in the medium to long term.
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