Introduction:
Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor used in
the treatment of various B-cell malignancies, including chronic
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), relapsed or
refractory Mantle cell lymphoma, relapsed or refractory marginal zone
lymphoma, Waldenstrom macroglobulinemia, chronic graft-versus-host
disease and additional off-label uses [1, 2]. Ibrutinib has been
associated with the development of atrial fibrillation (AF) in
approximately 6-16% of patients [1], though a recent prospective
multicenter cohort study suggests the incidence of ibrutinib-related
atrial fibrillation (IRAF) may be as high as 38% at 2 year follow up
[3]. A systematic review and meta-analysis of four randomized
control trials noted the pooled relative risk of AF in ibrutinib
recipients was 3.5 (95% confidence interval 1.8-6.9, p <
0.0001) [4]. Cardiovascular adverse events related to ibrutinib were
associated with a 10-20% fatality rate (with the exception of
ibrutinib-associated hypertension), as per a retrospective international
analysis of 303 ibrutinib-associated cardiovascular deaths [5].
Various studies have sought to identify risk factors that predict future
development of IRAF. In a large study of 4 randomized control trials,
1505 patients with CLL and Mantle cell lymphoma, a multivariate analysis
showed that use of ibrutinib, prior history of AF and age >
65 were associated with higher risk of AF [1]. A retrospective
analysis demonstrated a history of AF and higher Framingham Heart Study
AF risk score were significantly associated with IRAF [6]. Another
retrospective analysis noted that among various clinical,
electrocardiographic, and echocardiographic parameters, only the
presence of left atrial (LA) abnormality on electrocardiogram and prior
history of heart failure were independently associated with IRAF in a
paired Cox regression model [2]. A prospective analysis of 43
patients receiving ibrutinib for CLL demonstrated that male gender, the
presence of one or more cardiac comorbidities, LA diameter and LA area
on transthoracic echocardiogram predicted future development of IRAF
[7]. These studies highlight the need to better identify clinical
and echocardiographic parameters to reliably stratify the risk of IRAF.
Two-dimensional speckle tracking echocardiography (2DSTE) provides a
quantitative measure of myocardial deformation, and there is growing use
of STE in analyzing LA deformation, measured as LA strain [8]. LA
strain is measured across the cardiac cycle and averaged between four-
and two-chamber apical views. Peak atrial longitudinal strain (PALS), is
measured immediately following atrial filling, with a normal reference
range across healthy adults of approximately 39% (95% CI 38-41%)
[9, 10]. Peak atrial contraction strain (PACS), is measured
immediately prior to atrial contraction, with a normal reference range
of 17% (95% CI 16-19%) [9, 10]. Conduit strain is defined as the
difference between PALS and PACS, with a normal reference range of 23%
(95% CI 21-25%). Current work suggests LA strain may hold predictive
value for the development of AF [11]. We sought to identify whether
LA strain is associated with development of AF for patients on ibrutinib
therapy.