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Abstract

Objectives:

Atrial fibrillation (AF) often develops in patients with multiple myeloma following autologous stem cell transplantation (ASCT), but the exact incidence of, and the risk factors for AF have not been described. In this study, we sought to determine the incidence of AF in patients with multiple myeloma undergoing ASCT.

Methods:

Patients who received ASCT for multiple myeloma between January 2000 and December 2009 were identified using the ICD-9 codes for multiple myeloma and ASCT, and formed the basis of this report.

Results:

The study included 278 patients (mean age, 63 ± 9.5 years). A total of 75 (27%) patients developed AF at a mean duration of 14.8 days following ASCT. On multiple regression analysis, baseline renal dysfunction (odds ratio 15.2 [confidence interval 5.08–45.6]), left ventricular systolic dysfunction (9.55 [2.78–32.79]), dilated left atrium on echocardiogram (4.97 [1.8–13.78]), and hypertension (3.6 [1.36–9.52]) were significantly associated with the development of AF after ASCT. The presence of light-chain secretion (0.21 [0.07–0.6]) was associated with a lower incidence of AF. Age, gender, and race were not significantly associated with the development of AF after ASCT.

Conclusions:

AF is very frequent in patients with multiple myeloma when they receive ASCT. The presence of abnormal renal function, left ventricular systolic dysfunction, dilated left atrium, or hypertension at baseline identifies patients at high risk of developing AF following ASCT.

Keywords

atrial fibrillation multiple myeloma risk factors stem cell transplantation

Introduction

Atrial fibrillation (AF) is the most common cardiac rhythm disorder [American Heart Association, 2012]. In addition to the well-known risk factors for AF such as age, hypertension, hyperthyroidism, alcohol, ischemic cardiomyopathy, obstructive sleep apnea, etc. [Lloyd-Jones et al. 2004], AF is known to occur at an increased frequency in certain patients. For example, AF has been estimated to occur in 30–50% of patients in the postoperative period following cardiac surgery [Aranki et al. 1996]. In such patients, AF leads to substantial increases in morbidity, mortality, and duration of hospitalization [Mathew et al. 1996]. In this study, we examined the incidence of AF in one such unique patient population, patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) as a part of their oncological treatment.

A high incidence of supraventricular arrhythmias has been reported in patients receiving stem cell transplantation (autologous or allogeneic) for various malignancies such as acute leukemias, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, etc. [Hidalgo et al. 2004; Mileshkin et al. 2005]. ASCT is a standard component of the treatment of patients with multiple myeloma [Barlogie et al. 1986]. Available data suggest that AF occurs more commonly among patients with multiple myeloma [Olivieri et al. 1998]. An unusually high incidence of AF has been noted in these patients following ASCT at our institution, which is a high-volume center specializing in the treatment of patients with multiple myeloma. AF usually occurs within a few days to weeks of ASCT and often necessitates admission to the intensive care unit. There are limited data on the incidence of AF in this patient population. The factors that predispose these patients to AF are also not well described. These could be related to the chemotherapy agents (melphalan), transplanted stem cells, or the effects of the paraproteinemia associated with the myeloma on the myocardium. Here we report the incidence of AF and risk factors in patients with multiple myeloma who received ASCT.

Methods

All patients who were hospitalized at our center between 1 January 2000 and 31 December 2009, and whose hospitalization was associated with the ICD-9 codes for multiple myeloma (203.0) and ASCT (41.04 or 41.07), were initially identified. Patients who had more than one such hospitalization were counted only once. All available electrocardiograms (ECGs) for each of these patients so identified were then reviewed to ascertain those patients who developed AF. Patients who had no recorded ECG, or had AF prior to the diagnosis of multiple myeloma or prior to the first ASCT, and those with a history of significant mitral valve disease or surgery were excluded. Following this, a detailed review of each patient’s electronic medical record was performed. This identified patients who received ASCT as inpatients during the study period and this group comprised the study population.

Information on the following characteristics was collected for all patients: age, gender, duration and type of myeloma, total number of ASCTs received, history of hypertension, abnormal renal function at baseline (serum creatinine > 114.9 μmol/l), cardiac rhythm and the presence of left ventricular hypertrophy or abnormally low QRS voltage on ECG at baseline, and left ventricular ejection fraction as assessed by echocardiography or radionuclide blood pool imaging. The type of myeloma was classified into heavy-chain disease if only heavy chains (e.g. immunoglobulin G multiple myeloma) were secreted, and into light-chain disease if light chains alone were secreted (e.g. lambda light-chain disease), or light chains were secreted in combination with heavy chains (e.g. immunoglobulin G with free lambda light chains).

Echocardiographic assessment of diastolic interventricular septal thickness (IVSd) (classified as normal, mild, moderate, or severely thickened), evidence of left atrial dilation (classified as normal or dilated), left ventricular diastolic function (classified as normal, grade 1, grade 2, or grade 3 dysfunction), and estimated right ventricular systolic pressure (RVSP) was recorded. Echocardiographic assessment immediately prior to the ASCT was used for analysis in patients who developed AF following ASCT.

In addition, among patients who developed AF, data were collected on the number of ASCTs prior to the occurrence of AF, and the duration in days between the occurrence of AF and preceding ASCT.

The Institutional Review Board at the University of Arkansas for Medical Sciences approved the study. Informed consent was waived as this was a retrospective study based on information collected during the clinical management of the patients included in the study.

Statistical analysis

All continuous variables were expressed as mean and standard deviation or as median with interquartile range as appropriate. Categorical variables were expressed as percentages. Continuous variables were compared using unpaired t-test, and categorical variables were compared using the two-tailed Fisher’s exact test.

A multiple logistic regression model was fit to a model containing all the collected potential risk factors (e.g. age, sex, duration of myeloma, number of ASCTs, time to onset of AF after ASCT, history of hypertension and renal dysfunction at baseline, baseline rhythm, left ventricular ejection fraction, echocardiographic evidence of left ventricular hypertrophy, left atrial dilation, and left ventricular diastolic dysfunction). The Hosmer–Lemeshow purposeful selection algorithm was employed to derive a parsimonious model. Once a parsimonious model was determined with a resultant subset of potential risk factors, age and gender were added as confounders. Odds ratios (ORs) and confidence intervals (CIs) were estimated from the estimated betas in the model. Lastly, each of the risk factors in the final model was fitted into one simple variable logistic regression in order to estimate the unadjusted univariate ODs. A two-tailed p value < 0.05 was considered to be statistically significant. Statistical analyses were performed using graphpad (www.graphpad.com/quickcalcs) and proc logistic in SAS, version 9.2 (SAS Institute, Cary, NC, USA).

Results

Between 1 January 2000 and 31 December 2009, 814 hospitalized patients had the ICD-9 codes for both multiple myeloma and ASCT. Of these, 45 patients did not have an ECG, or had documented evidence of AF prior to the diagnosis of multiple myeloma, or prior to receiving therapy, or had a history of mitral valve disease or repair. A review of the remaining 769 patients identified 278 patients, with a mean age of 63.1 ± 9.5 years, who had received ASCT for multiple myeloma as inpatients. These patients comprised the study population (Figure 1). Two patients from the control group were excluded during multiple logistic regression analysis due to missing data.

Figure 1.

Flowchart displaying the derivation of the study population. AF, atrial fibrillation; ASCT, autologous stem cell transplantation; ECG, electrocardiogram; MM, multiple myeloma.

Patient characteristics analyzed in the study are listed in Table 1.

Table 1.

Baseline characteristics of the study population.

Patient characteristic	Cases	Controls	p value
Males	72% (54/75)	63.5% (129/203)	0.2
Age (years)	64.4 ± 8.1	63.1 ± 9.9	0.28
White race	94.7% (71/75)	87.2% (177/203)	0.08
Light-chain disease	42.6% (32/75)	36.5% (74/203)	0.4
Duration of multiple myeloma (days)	1796 ± 1265	3392 ± 753	0.0001
Time between autologous stem cell transplantation and atrial fibrillation onset (days)	14.8 ± 18.7	NA
Number of autologous stem cell transplantations	2 ± 1	2.3 ±1	0.01
Abnormal renal function at baseline	53.3% (40/75)	14.9% (30/202)	0.0001
Hypertension at baseline	42.6% (32/75)	45.5% (92/202)	0.69
Left ventricular hypertrophy on baseline electrocardiogram	5.3% (4/75)	12.3% (25/203)	1.0
Low QRS voltage on baseline electrocardiogram	1.3% (1/75)	2% (4/203)	1.0
Abnormal left ventricular ejection fraction	27.6% (16/74)	6.5% (13/201)	0.0007
Increased interventricular septal diastolic thickness at baseline	29.3% (22/75)	25.7% (48/187)	0.54
Dilated left atrium at baseline	30.7% (23/75)	19.7% (37/188)	0.07

Of the 278 patients, 75 (27%) developed AF at a mean duration of 14.8 days following ASCT. The prevalence of abnormal left ventricular systolic function (p < 0.0007) and abnormal renal function (p < 0.0001) at baseline was significantly higher in patients who developed AF after ASCT (versus those who did not develop AF). A trend toward a higher prevalence of a dilated left atrium at baseline (p 0.07) was also noted.

Patients in the case cohort received a mean of 1.97 ± 1.07 ASCTs before AF occurred. In comparison, patients in the control group received 2.3 ± 0.97 ASCTs (p < 0.01). AF occurred most commonly after the first (n = 30) or second (n = 28) ASCT among cases.

There were no significant gender-specific differences in the incidence of AF. The mean age of patients in both groups was not significantly different. The study population was predominantly White. No significant race-specific difference was noted in the incidence of AF. The prevalence of hypertension at baseline or left ventricular hypertrophy (assessed by measuring the IVSd) was not significantly different among cases and controls.

On multiple logistic regression analysis (Table 2), multiple myeloma with light-chain secretion (OR 0.21, 95% CI 0.07–0.6) was associated with a lower incidence of AF after ASCT. There was a small but statistically significant association between the duration of multiple myeloma and the development of AF after ASCT. The presence of abnormal renal function at baseline (15.2 [5.08–45.6]), left ventricular systolic dysfunction at baseline (9.55 [2.78–32.79]), and a dilated left atrium on baseline echocardiogram (4.97 [1.8–13.78]) were significantly associated with the development of AF after ASCT. The presence of hypertension at baseline was found to be significantly associated with the development of AF after ASCT (3.6 [1.36–9.52]).

Table 2.

Odds ratio estimates from multiple regression analysis.

Patient characteristic	Odds ratio	95% Wald confidence limits
Light-chain secretion	0.21	0.7–0.64
Duration of multiple myeloma	0.998	0.998–0.999
Abnormal renal function at baseline	15.2	5.1–45.6
Baseline hypertension	3.6	1.4–9.5
Baseline abnormal left ventricular ejection fraction	9.5	2.8–32.8
Baseline dilated left atrium	4.9	1.8–13.8
Age	1.03	0.9–1.1
Female gender	0.9	0.4–2.2

Discussion

In this paper, we present our findings on the incidence of AF in patients with multiple myeloma who received ASCT. We noted an extremely high incidence of AF (27%) in this patient population, comparable with other high-risk groups such as patients undergoing cardiac surgery. The incidence of AF after ASCT was significantly and independently associated with baseline renal dysfunction, abnormal left ventricular systolic function, dilated left atrium, and history of hypertension. A lower incidence of AF after ASCT was associated with multiple myeloma involving the secretion of light chains.

All four patient characteristics noted to be associated with AF in our study population have been well documented as risk factors for developing AF in general [Lloyd-Jones et al. 2004; Kannel et al. 1998]. However, there are significant differences between our study patients and the general population. The incidence of AF in this patient population appears to be markedly higher than that reported in the general population in the presence of these risk factors [Benjamin et al. 1994]. In addition, the mean age of the patients in this study was disproportionately low (63.3 years). For example, the incidence of AF is estimated to increase with age, reaching as high as 9% in people over 80 years old [Kannel et al. 1998; Benjamin et al. 1994], in comparison with the 27% incidence noted in our study population. Hypertension is estimated to increase the risk of AF by 1.4 to 1.6 times. In comparison, the OR for developing AF after ASCT in our study population was 3.6 in the presence of a history of hypertension. The adjusted OR for developing AF in the presence of heart failure is estimated to be 4.5–6.0. The adjusted OR for developing AF after ASCT in our study population in the presence of reduced left ventricular systolic function was 9.5. Recent data suggest an increased risk of developing AF proportionate to the degree of renal dysfunction. The adjusted OR of developing AF after ASCT in our study was 15.2, comparable with the OR of 13.1 in patients with severely reduced estimated glomerular filtration rate and macroalbuminuria [Alonso et al. 2011]. A dilated left atrium was associated with a hazard ratio of 1.39 for every 5 mm increase in left atrial diameter [Vaziri et al. 1994]. In our study, a dilated left atrium was associated with an adjusted OR of 4.9 for developing AF after ASCT.

The substantially greater odds of developing AF in the presence of these risk factors in this patient subset are likely related to the other factors unique to multiple myeloma and its therapy. Although the risk attributable to each of these other factors cannot be determined from our analysis, certain features are noteworthy. Multiple myeloma involves unregulated proliferation of plasma cells, and usually, excessive production of immunoglobulin heavy chains, light chains, or both. Deposition of light chains in the myocardium is a well-recognized form of cardiac amyloidosis, and AF is one of the manifestations of this disease [Falk, 2005]. In our study, we noted a negative association between the presence of light-chain secretion and the incidence of AF following ASCT. It is possible that patients with light-chain deposition disease developed AF prior to receiving ASCT and were excluded from the study. This could have spuriously resulted in the negative association noted. The higher incidence of AF despite the absence of light-chain secretion is nevertheless consistent with the finding that the myocardium is affected by multiple myeloma even in the absence of cardiac amyloidosis. For example, delayed enhancement on cardiac magnetic resonance imaging due to endomyocardial fibrosis has been noted in the presence of multiple myeloma without amyloidosis [Brahmbhatt et al. 2008]. Similarly, patients with multiple myeloma can develop restrictive cardiomyopathy and diastolic heart failure [Schattner et al. 1995; Mitchell et al. 1993]. High circulating levels of immunoglobulins leading to hyperviscosity [Mehta and Singhal, 2003], and the presence of associated anemia can also contribute to the development of congestive heart failure as well as ischemia in the presence of underlying coronary artery disease. Paradoxically, a high output cardiac state with resultant congestive heart failure can also develop in some patients. These factors are conducive to the creation of a substrate for developing AF [McBride et al. 1988].

Chemotherapy for multiple myeloma can also affect the myocardium and increase the risk of developing AF. Patients at our institution typically undergo induction therapy consisting of bortezomib, dexamethasone, thalidomide or lenalidomide, cisplatin, adriamycin, cyclophosphamide, and etoposide followed by the harvesting of peripheral stem cells. They then undergo myeloablative therapy with melphalan followed by ASCT. They subsequently undergo maintenance therapy with agents used for induction [Nair et al. 2010]. The chemotherapy agents used for induction as well as myeloablation are known to have cardiac effects. For example, bortezomib has been reported to cause myocardial scarring and heart failure [Foley et al. 2010]. Feliz and colleagues reported an association between AF and other supraventricular arrhythmias and melphalan use during autologous and allogeneic stem cell transplantation for a variety of hematological malignancies including multiple myeloma [Feliz et al. 2011]. Many patients also receive granulocyte colony-stimulating factor during the course of their treatment to enhance neutrophil proliferation, minimize the duration of neutropenia, and treat infections. Its use has been associated with the incidence of supraventricular tachycardia [Lee et al. 2000]. Severe systemic illness and sepsis in these patients as a result of the induction and myeloablative chemotherapy also increases the risk of AF. A 6–20% incidence of AF in such patients has been reported [Walkey et al. 2011; Arora et al. 2007; Annane et al. 2008; Meierhenrich et al. 2010]. Advanced age, severity of illness, and increased markers of inflammation were associated with incidence of AF in these patients.

Lastly, there appears to be an association between stem cells and the propensity to develop AF. Siu and colleagues noted an association between the recurrence of AF following successful cardioversion and higher numbers of circulating endothelial precursor cells [Siu et al. 2010]. Feliz and colleagues noted an 8% incidence of AF following hematopoietic stem cell transplantation and melphalan-based chemotherapy [Feliz et al. 2011]. Similarly, Hidalgo and colleagues noted a 12% incidence of AF after hematopoietic stem cell transplantation [Hidalgo et al. 2004]. These studies however included a more heterogeneous patient population receiving stem cell transplants for reasons other than multiple myeloma. Interestingly, pre-existing cardiac comorbidities were associated with arrhythmias in both these studies, and an association with elevated serum creatinine and dilated left atrium was also noted in the former. In patients with multiple myeloma and non-Hodgkin’s lymphoma receiving high-dose chemotherapy and stem cell transplantation, Mileshkin and colleagues noted an incidence of AF that was similar (22.5%) to that noted in our study [Mileshkin et al. 2005]. AF occurred in the presence of electrolyte abnormalities or sepsis, and more than half had pre-existing cardiac comorbidities. The incidence of AF in patients with multiple myeloma was not separately quantified in their study. We specifically sought to quantify the incidence of AF in patients with multiple myeloma and this may explain the differences in incidence noted in our study and in previously published studies. Although data from multiple small studies involving patients with myocardial infarction receiving stem cells suggest no increased risk of arrhythmias [Bartunek et al. 2005; Adler et al. 2011], these studies fundamentally differ from ours in that they aimed to study the cardiac effects of stem cells in patients with myocardial scarring. Stem cell transplantation in these patients is not associated with the chemotherapy regimens or the inflammatory and metabolic milieus experienced by patients with multiple myeloma.

Limitations

This is a retrospective study based on patient data collected primarily during the clinical care of these patients at a single large-volume center specializing in the management of multiple myeloma. As such, there was no standardization in the manner the information was collected and stored. We also identified patients for inclusion in this study on the basis of the ICD-9 codes associated with hospitalizations at our institution during the study period. Due to the inherent limitations of this method, not all eligible patients may have been included in the study. Although it is the second most common hematological malignancy, multiple myeloma is still a relatively rare disorder. This perforce necessitates a retrospective approach to study the problems associated with the management of this arrhythmic complication in these patients. AF can be diagnosed only when patients become symptomatic and an ECG is obtained, or when they are already being monitored on telemetry for any reason. As such, asymptomatic AF would not have been detected in our study. This however will only underestimate the incidence of AF and the strength of our findings. At our center, a significant proportion of the patients undergo ASCT in the outpatient setting. Our study findings may not be applicable to this subset of patients. It is possible that other parameters such as C-reactive protein, platelet count, white blood cell count, b-type natriuretic peptide levels, etc., are associated with incidence of AF in this population. We purposefully included only those patient characteristics that can potentially identify the risk at presentation for developing AF after ASCT.

Conclusion

Atrial fibrillation frequently complicates the course of patients with multiple myeloma, occurring in over a quarter of such patients after they receive ASCT in the inpatient setting. This complication is associated with pre-existing hypertension, kidney dysfunction, decreased left ventricular ejection fraction, and a dilated left atrium. Appropriate patient selection and the correction of risk factors when feasible (such as optimizing renal function and volume status) may prevent AF in this population. Prophylactic use of beta-blockers, amiodarone, etc., may be helpful in high-risk patients. Further research is needed to elucidate the merits of such measures.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

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Atrial fibrillation following autologous stem cell transplantation in patients with multiple myeloma: incidence and risk factors

Abstract

Objectives:

Methods:

Results:

Conclusions:

Keywords

Introduction

Methods

Statistical analysis

Results

Discussion

Limitations

Conclusion

Footnotes

Funding

Conflict of interest statement

References