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.