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].