Arrhythmia and device assessment during cancer treatments

Atrial fibrillation and other supraventricular arrhythmias

Atrial arrhythmias, especially atrial fibrillation (AF) are frequently observed in patients undergoing cancer therapy. The “REasons for Geographic and Racial Differences in Stroke” (REGARDS) cohort of more than 15,000 patients reported a 20% higher adjusted risk of AF in patients with cancer, especially within the first year of diagnosis. This can be for multiple reasons, ranging from the malignancy itself and the associated inflammatory state (breast, colorectal, and hematologic malignancies are all associated with higher rates of AF), to specific cancer treatments, including chemo- and targeted therapies. Additionally, patients with cancer and AF have worse outcomes with a two-fold higher risk for thromboembolic complications, a 6-fold higher adjusted risk for heart failure, and a 10-fold higher risk of adjusted 30-day mortality compared with patients not having cancer. It is essential to identify and manage aggressively those patients with cancer with AF, whereas providing appropriate treatment can be challenging and often requires a nuanced, multidisciplinary approach in order for patients to have the best oncologic and CV outcomes.

Anthracyclines

Although heart failure and left ventricular dysfunction are the most common cardiotoxicities of doxorubicin and other anthracyclines, arrythmias are also frequently encountered. For example, rates of AF with doxorubicin infusion are reported between 6% and 10% in the absence of other cardiovascular pathology. ^, Moreover, also found are increased rates of AF in the setting of anthracycline-mediated cardiomyopathy, with a prevalence of more than 50%, which is similar to other nonischemic cardiomyopathy etiologies. ^, The arrhythmic mechanism is not clear, but is likely caused by impaired intracellular signaling, damage from free radicals and other toxins, and/or direct myocardial injury.

Alkylating agents and stem cell transplantation

Alkylating agents, including melphalan and cyclophosphamide, are a class of cytotoxic chemotherapeutics that disrupt the DNA double helix and are used in the treatment of various solid and hematologic malignancies. Moreover, melphalan is a common agent used in stem cell transplant (SCT) preconditioning regimens. In one study, 11% of patients who received melphalan prior to SCT developed atrial arrhythmias, including AF, which was significantly higher than in patients who received other treatment regimens. Moreover, SCT itself increases the likelihood of developing AF, with rates as high as 27%. Risk factors for the development of AF after transplant include renal failure, hypertension, and exposure to melphalan. Moreover, the development of AF during transplant portends a worse prognosis, with elevated rates of intensive care unit admissions as well as 30-day and 1-year mortality compared with those patients without arrhythmias.

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKI) affect intracellular pathways that regulate cell growth. A variety of cardiotoxicities are observed with these agents, including AF and other arrhythmias. In one study, the incidence of AF with the TKI sorafenib was reported at 5%. Similarly, arrhythmias can be seen with TKIs used to treat chronic myeloid leukemia that target the BCR-ABL protein. Although vascular toxicities, raging from stroke to myocardial infarction, are most often associated with these TKIs, arrhythmias can also occur. For example, in the EPIC study, the incidence of AF associated with ponatinib use was reported at 3%, compared with 0% for the imatinib treated group. Similarly, rates of AF are around 2% with bosutinib. Whereas the mechanism of arrhythmia remains unclear, it may be related to off-target effects on the phosphoinositide 3-kinase (PI3K) pathway.

Ibrutinib is the TKI most associated with the development of AF. This is a small molecule inhibitor of the Bruton’s tyrosine kinase, used to treat various B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom’s macroglobulinemia, as well as chronic graft-versus-host disease. Rates of AF have been reported between 10% and 15%, with ibrutinib itself identified as an independent risk factor for the development of AF. Other risk factors include a prior history of AF, left atrial enlargement, and an elevated Framingham Heart Study AF risk score. As other Bruton’s tyrosine kinase inhibitors, such as acalabrutinib, are associated with a significantly lower incidence of AF, off-target effects of ibrutinib have been postulated, among these. Inhibition of the PI3K pathway, enhanced left atrial fibrosis, and/or impaired sarcoplasmic reticulum calcium handling.

Proteasome inhibitors

Proteasomes are essential in the elimination of the majority of intracellular proteins, including those modified by oxidative stress and tagged for degradation by the ubiquitin system. Proteasome inhibitors (PIs) block the proteolytic activity of the proteasome complex, leading to protein accumulation, even aggregation, and the activation of apoptotic pathways and cell death. PIs are used primarily in the treatment of multiple myeloma and AL amyloidosis. AF is quite common in patients with multiple myeloma, with a prevalence of 14.6%. This is caused, in part, to PI exposure, particularly to carfilzomib, in which the associated incidence of AF/atrial flutter (AFL) is between 3% and 4%.