Discussion:
LA mechanics are increasingly important prognostic markers of AF development. We applied measures of PALS and PACS to a unique cohort of patients who have a well-recognized risk of developing AF on ibrutinib. This is the first study to demonstrate that measures of LA strain prior to initiation of ibrutinib therapy help identify patients at risk for developing IRAF. On univariate analysis, age, ibrutinib dose, E/e’, and PALS were associated with IRAF. On multivariate regression analysis, age and PACS had notably strong associations with IRAF. On multivariate regression analyses of ibrutinib dose and echocardiographic parameters, both PALS and PACs were associated with IRAF.
The pathophysiology of IRAF is as yet unknown [13]. Experimental studies on rat models suggest ibrutinib activity inhibits the PI3K-Akt signaling pathway in cardiac myocytes, which increases susceptibility to AF [14]. Further work with mouse models has suggested that ibrutinib induces structural remodeling and calcium handling disorders in atria, leading to increased arrhythmogenicity [15]. Additional work has suggested the possibility of a two-hit hypothesis, due to which patients with structural abnormalities are increasingly susceptible to PI3K-Akt downregulation by ibrutinib [2]. Our findings corroborate this theory, as they indicate a relationship between impaired LA myocardial mechanics prior to ibrutinib initiation and subsequent IRAF. This highlights opportunities for translational studies of patients with abnormal LA strain and investigating underlying mechanisms of IRAF.
A meta-analysis of LA strain across healthy adults estimated PALS is approximately 39% (38-41) across 40 studies and PACS is 17% (16-19) across 18 studies [9]. Our patient population had a lower than average PALS of 34.2%, and a PACS of 17.3%, which approximated that of this meta-analysis. We suspect the decreased average PALS of our patient population reflects increased baseline population rates of concomitant heart failure and other cardiac comorbidities. Figure 1 shows LA strain mechanics of two patients in our cohort: a patient without AF who has normal PALS and PACS, versus a patient with IRAF with decreased PALS and PACS. This figure delineates the patient who develops IRAF has notable loss of a well-defined atrial contraction pattern, calculated as PACS, which predates the occurrence of IRAF.
PALS was significantly associated with IRAF on univariate regression analysis, though was not significant on multivariate analyses when accounting for patient age. We suspect that while PALS is an echocardiographic marker associated with IRAF, impairment in PALS may be a function of increasing population age and other comorbidities. In contrast, PACS was not associated with IRAF on univariate analysis, though had a significant association with IRAF in multivariate regression modeling with age. This suggests that impaired PACS can identify patients with poorer atrial contractile function, which predisposes them to the development of IRAF independent of patient age. Taken together, the relationship between these measures of LA strain and IRAF suggests that significant impairments in LA mechanics detect LA myopathy, which may predispose patients to the development of IRAF.
LA strain may be able to discern various cardiac pathologies, though further work remains to be done within this realm [16]. One study of patients with non-ischemic cardiomyopathy noted decreased PACS was an independent and incremental predictor of ventricular arrhythmia [17]. It was proposed that in diseased ventricular states, PACS has increased importance as it helps maintain cardiac output and control pulmonary capillary wedge pressure [17]. The relationship between LA mechanics, IRAF and concurrent HF merits further evaluation. In our work, patients who developed IRAF had increased E/e’, which may suggest the presence of subclinical HF. Both PALS and PACS demonstrated stronger associations with the development of IRAF than E/e’. However, the impact of HF and elevated filling pressures on impaired LA mechanics in the development of IRAF needs to be further explored.
Prior work has suggested the importance of PALS in patients with AF, as this specifically reflects atrial compliance [11]. Studies have indicated a relationship between PALS and risk of stroke in patients with permanent AF [18] as well as a relationship between improved PALS and maintenance of sinus rhythm after AF ablation [19]. Of note, PACS can only be measured in patients with sinus rhythm, and it is thought that in adults without a history of atrial arrhythmia, impaired PACS may reflect the initial structural remodeling which ultimately leads to the development of AF [20]. Our work suggests a complex interplay of both these measures of LA strain, as related to age and other comorbidities in the development of IRAF.
Management of IRAF poses unique challenges given the increased risk of bleeding associated with ibrutinib and various medication interactions [21, 22]. It is estimated that ibrutinib is associated with bleeding in 3-5% of patients, likely mediated by platelet dysfunction [23], and potentially compounded by underlying thrombocytopenia in the setting of hematologic malignancy [24]. The majority of ibrutinib-related bleeding events tend to be mild and do not require medication interruption or dose modification [23]. However, this known bleeding risk complicates decisions regarding initiation of anticoagulation and procedural intervention for IRAF. It is worth noting that one patient in our cohort who developed IRAF had a concurrent intraparenchymal hemorrhage, not on any anticoagulation or antiplatelet therapy. Furthermore, ibrutinib is primarily metabolized by hepatic cytochrome P450 3A4 which complicates choice of anticoagulant given known metabolic interactions [24]. Better understanding of AF risk, incorporating clinical and echocardiographic variables such as LA strain, may inform anticoagulation management and warrants further exploration.
As a retrospective analysis, our work carries a risk of selection bias. Specifically, at the time during which our patients were initiated on ibrutinib, there were no specific guidelines for echocardiographic screening prior to treatment. Therefore, patients who had echocardiograms within our database likely had concern for underlying cardiac pathology, as suggested by the high baseline rate of HF seen in our population. Our work also demonstrates an inverse relationship between ibrutinib dose and IRAF rate. Ibrutinib dose was decreased for patients who demonstrated intolerance to higher doses due to a variety of adverse events (neutropenia, GI symptoms), and these patients may have been more likely to develop cardiac toxicity as well. We recognize that the specific strain values used in this study apply to our population and strain software, and may not be universally translated, owing to the software-dependent variability of strain findings.
Our study was limited by a small patient population, though notably within which 33.3% of the population developed IRAF. Larger studies will assist in validating the relationship between LA strain and IRAF, and determining predictive markers which have greater sensitivity for detecting IRAF. Our findings suggest a complex interplay between age, ibrutinib dose, LA myocardial dynamics and IRAF, which merits further prospective evaluation. Results are forthcoming from the CITE-LA trial (NCT03751410), a prospective, observational cohort study assessing LA strain of patients on chronic ibrutinib therapy, which may elucidate this relationship further [25].