Bradycardia and Bradyarrhythmias with Conventional Chemotherapies and Targeted Agents

Bradyarrhythmias have been reported in patients treated with alkylating agents. Four out of 39 patients with breast cancer, previously treated with anthracyclines and receiving high-dose chemotherapy with cyclophosphamide before stem cell transplantation, developed some degree of atrioventricular block (AVB).2 Two of them developed complete heart block (CHB) managed with isoproterenol infusion, but in all cases, the conduction abnormality was transient, and the patients were able to complete the scheduled regimen. Nevertheless, other reports of CHB required discontinuation of cyclophosphamide and/or temporary as well as permanent pacemaker implantation.34 Arrhythmias related to alkylating agents are thought to arise from direct cardiotoxicity to myocytes and ischemic damage caused by coronary vasospasm and vascular endothelial injury with subsequent intracapillary microthrombi. An increased vagal tone has also been proposed as a mechanism given that some patients have uncontrolled emesis associated with CHB.56

Anthracyclines are traditionally associated with cardiomyopathy/left ventricular dysfunction, with arrhythmias resulting from the former. In a prospective study of patients receiving doxorubicin, 3.4% developed bradycardia detected by 24-hour Holter monitoring with one patient developing CHB requiring permanent pacing.7 There have been no specific studies addressing the mechanisms of bradyarrhythmias due to anthracyclines. Anthracyclines can have a direct electrophysiological effect by interfering with cardiac Ca²⁺ channels. They also generate, lead to the accumulation of and increase cardiomyocyte’s susceptibility to reactive oxygen species. Abnormal Ca²⁺ homeostasis due to abnormal functioning of sarcoplasmic reticulum calcium–ATPase can cause intracellular Ca²⁺ overload and subsequent myocardial necrosis. Reduction in adenosine monophosphate-activated protein kinase expression can lead to myocardial apoptosis. Cardiac accumulation of doxorubicinol, a toxic metabolite of doxorubicin, may be involved in some of these mechanisms.56

Cisplatin infusion is associated with sinus bradycardia (SB) which can start immediately during infusion, can be marked, and tends to recur with each cycle.891011 Coronary vasospasm, endothelial damage, and electrolyte disturbances are postulated mechanisms for cisplatin cardiotoxicity.56 Cisplatin deposition in the sinoatrial (SA) node and the vasculature supplying it are likely to be the cause of the bradycardia.8

There have been isolated case reports of SB related to 5-fluorouracil (5-FU) treatment with a published case series of six patients that developed asymptomatic SB with a heart rate below 50 bpm. Two of them required repeated interruptions of the infusion, and two of them required discontinuation of the drug due to sustained bradycardia in the second cycle of drug administration.12 In a second case series of six patients, one of them developed Mobitz type I and another one SB with first-degree AVB. Interestingly there were no ST-segment changes, and troponin levels were normal.13 A relatively large retrospective study showed that 5-FU induced SB occurred in 12% of the patients (36 out of 301 patients), and it was the most common cardiotoxicity.14 In a prospective study including patients treated with either 5-FU or oral capecitabine, 26 out of 644 (4.03%) had cardiotoxicity, and three of them had conduction abnormalities that included either Mobitz type II or CHB, with one death occurring because of high-grade AVB and subsequent cardiac arrest.15 The classic mechanism of 5-FU mediated cardiotoxicity is coronary vasospasm either through a direct toxic effect involving endothelial nitric oxide synthase or through endothelium-independent protein kinase C vasoconstriction. Another postulated mechanism is ischemia due to arteritis and/or thrombosis.56 There is a paucity of data regarding bradycardia and other drugs of the antimetabolites class with only one case report of symptomatic SB with cytarabine.16

The most common paclitaxel-related arrhythmia is SB, which can occur in as much as 29% of the patients (13 out of 45 patients in one prospective study) but is usually transient and asymptomatic.17 More advanced AVB is infrequent. In the National Cancer Institute database, including more than 4,000 patients, only four had second- or third-degree AVB. Paclitaxel-induced conduction abnormalities might be explained by reduced coronary blood flow due to vasoconstriction. Histamine-induced release can also cause bradycardia and atrioventricular (AV) conduction delays.56

CHB requiring pacing to continue arsenic trioxide treatment has been described, but it is infrequent, and the most common described cardiotoxicity of this drug still is QT interval changes.18 Arsenic trioxide increases Ca²⁺ currents, inhibits K⁺ channels, and reduces surface expression of the human ether-a-go-go-related K⁺ channels, although these actions are more clearly related to the QTc changes previously mentioned.56

Isolated cases of varying degrees of AVB have been described with interleukin-2, and it has been speculated that lymphoid infiltration of the AV node or the conduction system of the heart might be at its origin.19

In a phase II multicenter study, three out of 131 patients with mantle-cell lymphoma developed bradycardia related with rituximab, requiring some form of treatment.20 Two case reports of CHB have been published, but one of the patients had previous conduction disease, and the other was an aged patient; hence the causality is difficult to ascertain.2122 It was postulated that rituximab might affect the cardiac conduction system by inhibiting Ca²⁺ channel properties of the CD20 antigen on cardiac myocytes.22

In an extension of a phase II study, including 63 relapsed multiple myeloma patients treated with bortezomib, one case of nonspecified and CHB was reported.23 In another study, two out of 69 patients with multiple myeloma treated with bortezomib developed nonspecified and CHB, leading to pacemaker implantation.24 Bortezomib upregulates the adrenergic G-protein-coupled receptor kinase 2 (GRK2), which can predispose to bradyarrhythmia and AV conduction abnormalities.56

SB is a common cardiotoxicity of thalidomide and occurred in as many as 53% of the patients included in one study. Although it usually resolved with discontinuation of the drug, some patients required pacemaker implantation.2526 AVB is limited to rare case reports.27 It has been hypothesized that thalidomide inhibits dorsal motor neurons of the nucleus of the vagus nerve by reducing TNF-alfa levels, with subsequent parasympathetic over-reactivity. Bradycardia has also been associated with thalidomide-induced hypothyroidism.56

Tyrosine kinase inhibitors (TKIs) are implicated in the modulation of growth factor signaling and, as such, play an essential role in targeted cancer therapy. However, they are not entirely selective for protein kinases in cancer cells. SB is therefore observed with various TKIs but is particularly common with ALK-TKIs. In a retrospective analysis of two multinational trials, SB occurred in 42% of the patients treated with crizotinib, with an average decrease in heart rate of 25 bpm. The likelihood of experiencing SB was higher among patients with a pretreatment heart rate of less than 70 bpm.28 Alectinib treatment resulted in a mean decrease of heart rate of 11 to 13 beats per minute. In approximately 5% of the patients, bradycardia or SB’s adverse events were reported, but when analyzing electrocardiograms (ECG), 20% of the patients had heart rates below 50 bpm. Bradycardia is usually transient and asymptomatic and does not require discontinuation of the drug.29 The occurrence of AVB needing further management is low. In a phase II trial of 295 patients who received lorlatinib, 1% experienced AVB, and 0.3% experienced Grade 3 AVB and underwent pacemaker placement.30 Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% (three out of 449) of the patients treated with ponatinib.31 Arrhythmias including AVB are described as common with the use of nilotinib, but the specific percentage of each arrhythmia type is not specified.32

Table 1 summarizes the type and incidence of bradycardia/bradyarrhythmia with each class of agents, as well as the mechanism behind it.

Bradycardia and Bradyarrhythmias with Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) are part of a relatively novel drug category which has demonstrated efficacy in prolonging overall survival in numerous cancers with previous poor prognosis. Conceptually, cancer cells can evade the patient’s immune system. ICIs aim to restore antitumor immune response by blocking immune checkpoints, i.e., intrinsic downregulation of immunity, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte-associated protein 4 (CTLA-4). By suppressing immune regulation and tolerance, ICIs are traditionally associated with immune-related adverse events (irAEs). There are concerns that cardiovascular events were not consistently reported in randomized control trials of ICIs.33 Moreover, there are other cardiotoxic effects related to ICIs besides myocarditis that were likely not identified in registration trials, owing to their limited power.34 Cardiovascular toxicity is infrequent when compared with other irAEs, but now it is increasingly reported in the literature, and with the rapidly expanding indications of ICIs, we should expect to see these more often.

There are no retrospective studies regarding bradyarrhythmias and the use of ICIs. Most of the published data in relation to cardiovascular toxicities have focused on myocarditis, with some of them reporting concomitant conduction disease but not in a systematic fashion, so the type of bradyarrhythmia, risk factors, treatment, and the outcome are not always clear.

Escudier et al published in 2017 a review of 30 cases of ICIs cardiotoxicity from their cardio-oncology clinic combined with selected cases from a literature review. Of those, 17% (n = 5) had conduction abnormalities. Cardiotoxicity was diagnosed 65 (2–454) days after the initiation of ICIs. Cardiovascular mortality was significantly associated with conduction abnormalities (80 vs. 16%; p = 0.003).35

In a retrospective study conducted using VigiBase, which is the World Health Organization’s global database of individual case safety reports, Salem et al. reported an incidence of ICI-related cardiac conductive disorders of 0.12%, similar to the incidence in the entire database.36

In a multicenter observational study that included 35 patients with ICI-associated myocarditis, three had hemodynamically significant CHB. Myocarditis was diagnosed at a median of 34 days after initiation of ICIs. Diabetes, sleep apnea, obesity, and combination checkpoint blockade were all identified as risk factors for myocarditis.

In a 2018 systematic review of published case series and case reports, Mir et al concluded that myocarditis was the most commonly observed cardiovascular irAE, corresponding to 45% (n = 45) of the cases. Conduction disease was present in 12% (n = 12) of the patients with cardiovascular toxicities. Of those, three had isolated rhythm disturbances, and nine had another toxicity. The overall mortality rate was 35%, and 50% in patients presenting with CHB or other conduction abnormalities.34

In a 2019 review by Atallah-Yunes et al, of 42 myocarditis cases related to pembrolizumab, nivolumab, or ipilimumab use, CHB occurred in 36% of them. In agreement with previously published data, 33% of the myocarditis cases occurred after a single ICI dose and 29% after two doses. Notably, CHB occurred in 64% of the patients that died, and 60% of those who developed CHB died.37

A recent study by Zlotoff et al. found that QRS duration is increased in ICI myocarditis and is associated with an increased risk of major adverse cardiac events, including CHB (HR 3.28, 95% CI 1.98–5.62, p < 0.001).38

The large majority of bradycardia cases related to ICIs use are due to CHB, with most of the patients having concomitant myocarditis. Table 2 describes the characteristics and outcomes of ICIs-related bradycardia case reports and case series. Most strikingly, half of the patients with bradyarrhythmia died; however, it is not clear if this association only denotes the severity of the myocarditis behind it. Definitive pacemakers were inserted in almost two-thirds of the patients, but there are three reported cases of recovery of intrinsic sinus rhythm after steroid therapy.394041

The exact mechanism(s) of ICI-related conduction disease is not fully understood. It is postulated that myocarditis, pre-existing cardiovascular diseases, past cardiotoxic chemotherapy, myocardial metastases, old age, and systemic inflammatory conditions could all contribute to arrhythmias in cancer patients treated with PD-1/PDL-1 inhibitors.42 Lyon et al hypothesized that ventricular myocarditis, inflammation of the His-Purkinje conduction system, either via direct T-cell-Purkinje interactions or via activation of local macrophages resident in the Purkinje system, increased systemic inflammatory state (without myocarditis), left ventricular impairment due to noninflammatory functional cardiotoxicity, or inflammation of myocardial metastases (if present) could all be at the origin of arrhythmias in the context of ICIs use.43 In murine models, the deletion of PD-1 leads to autoimmune dilated cardiomyopathy.44 Later studies detected circulating autoantibodies against cardiac troponin I in PD-1 knockout mice.45 CTLA-4 knockout mice also develop autoimmune myocarditis with CD4+ and CD8+ T lymphocyte infiltration of the myocardium.46 In mice models of T cell-mediated myocarditis, there is upregulation of myocardial PD-L1. ICIs can interfere with this likely cytokine-induced cardioprotective mechanism by blocking PD-L1.47 Johnson et al. described a robust T-cell infiltration, activation, and clonal expansion across the myocardium, striated muscle, and tumor tissue, with shared high-frequency T-cell receptors, in their two reported cases of myocarditis with ICIs use. They then postulated that T cells could either be targeting an antigen shared by those tissue types or that the same T-cell receptor was targeting a tumor antigen and a different but homologous muscle antigen. Backing the first possibility was the fact they observed high levels of muscle-specific antigens (desmin and troponin) in tumors from both patients. However, they still considered the possibility that their finding of clonal, high-frequency, T-cell receptor sequences across tumor and muscle samples could be misleading and that distinct T-cell receptors were targeting dissimilar antigens.48

Bradycardia and Bradyarrhythmias with Radiation Therapy

Radiation therapy for thoracic malignancies such as Hodgkin’s lymphoma, left-sided breast cancer, lung cancer, and other mediastinal tumors can lead to radiation-associated cardiac disease due to unwanted cardiac exposure.49 SB and bradyarrhythmia can develop from the direct effects of irradiation on the conduction system and myocardium, often manifesting years to decades after the radiation treatment.50 In 48 patients with Hodgkin’s lymphoma treated with mediastinal irradiation, 75% had conduction defects on ECG with a mean follow-up of 14 years.51 Case series for other patients with irradiation for Hodgkin’s lymphoma 10 to 20 years prior described the development of CHB, predominantly due to infranodal conduction block.525354 Other types of bradyarrhythmia after mediastinal irradiation include first-degree and Mobitz type II AVB.54 Right bundle branch block was also commonly observed due to its anterior location.5255 Second- and third-degree AVB have also been reported after irradiation for left-sided breast cancer 18 to 23 years prior.56 Valvular disease is also a latent consequence of radiation therapy. Radiation-associated valvular thickening and calcification can lead to stenosis or regurgitation, more commonly affecting left-sided valves. The mechanism for radiation-associated bradyarrhythmia is primarily driven by damage to the conduction system from chronic, progressive fibrosis.49 Reactive oxygen species are formed from radiation exposure, creating an inflammatory response.57 Subsequently, progressive fibrosis and endothelial dysfunction are enhanced by the induction of transforming growth factor-β expression.58 Experiments of irradiation in animal models have shown increased deposition of collagen in the myocardium, which exacerbates over time.59 Similar findings are observed in patients with CHB who underwent autopsy. Microscopic examination of the conduction system of patients with CHB after mediastinal irradiation showed sclerosis of the SA node arterioles and arteries, moderate fibrosis near the SA and AV nodes, and substantial fibrosis of both right and left bundle branches.5354

Interaction between Anticancer Agents and Nodal Blocking Drugs

A drug–drug interaction occurs when the combined administration of drugs leads to an adverse pharmacological or clinical response in patients.60 Patients with cancer have an increased risk of potential drug–drug interactions due to polypharmacy among anticancer therapies and medications for comorbidities as well as age-related physiologic changes that alter drug absorption or excretion.6061 In particular, drug–drug interactions have been reported in 14 to 16% of patients receiving anticancer therapy.6263 Pharmacodynamic interactions occur when two or more drugs have similar physiological outcomes, leading to excessive response or toxicity. Pharmacokinetic interactions occur when one drug alters the absorption, distribution, metabolism, or elimination of another drug. Commonly, metabolism by cytochrome P450 enzymes in the liver, such as the CYP34A isozyme, can be affected by drugs that act as inhibitors or inducers.60 Calcium-channel blockers are substrates for CYP34A isozymes, and several β-blockers are substrates for CYP2D6 isozymes.6465 Another common mechanism of interaction involves the P-glycoprotein (P-gp), an efflux pump that enables the transport of drugs across cell membranes for excretion.60 Substrates for P-gp include many anticancer therapies, digoxin, and calcium-channel blockers.65

Drug databases are frequently used to identify potentially harmful drug interactions, with reported sensitivities and specificities over 80%.666768Fig. 4 shows the risk of bradycardia and bradyarrhythmia with drug–drug interactions between nodal blocking agents and anticancer therapies, including data from Lexi-Interact (Wolters Kluwer) and Micromedex (IBM Corporation).6970 Among conventional chemotherapies, cases of additive bradycardia have been reported from pharmacodynamic drug–drug interactions between thalidomide and β-blockers, particularly in elderly patients with cardiac comorbidities.7172 Further, many targeted agents such as TKIs are known to interact with medications that affect CYP3A4 metabolism, leading to the risk of pharmacokinetic drug–drug interactions with calcium-channel blockers in particular.7374 For example, there are moderate to severe interactions between calcium-channel blockers and the TKIs imatinib, nilotinib, or vemurafenib from the inhibition of CYP3A4-mediated metabolism leading to increased calcium-channel blocker concentration. Ibrutinib and vemurafenib, in particular, also have pharmacokinetic drug–drug interactions with digoxin due to P-gp-mediated digoxin efflux transport inhibition. Among histone deacetylase inhibitors, panobinostat has a minor pharmacokinetic interaction with metoprolol due to inhibition of CYP2D6-mediated metabolism. On the other hand, no formal pharmacokinetic drug–drug interactions have been conducted for nivolumab, pembrolizumab, and ipilimumab.757677 Further evaluation is needed to better define drug–drug interactions with nodal blocking agents and ICIs, especially given case reports of high-grade AVB in ICI-associated myocarditis.4048787980

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Fig. 4: Drug–Drug interactions between anticancer and nodal blocking agents (created by biorender.com).

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In reverse, nodal blocking agents can also potentiate anticancer therapies’ concentration due to similar pharmacokinetic mechanisms. For example, doxorubicin, paclitaxel, vincristine, and vinblastine are P-gp substrates.65 Thus, their drug concentrations can be increased in patients who are taking carvedilol, a moderate P-gp inhibitor. Similarly, diltiazem is a potent CYP3A4 inhibitor, and co-administration with CYP3A4 substrates such as doxorubicin, ibrutinib, busulfan, imatinib, vincristine, and vinblastine can increase the systemic concentration of such anticancer therapies.6064 For example, venetoclax exposure is increased with the concurrent use of both CYP3A4 inhibitors or P-gp inhibitors, such as carvedilol and diltiazem, that can result in increased neutropenia and risk of tumor lysis syndrome. Alternative nodal blocking agents should be considered to avoid such chemotherapy toxicities.81

Diagnosis and Management

The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) bradycardia clinical practice guidelines define a sinus rate <50 bpm and/or a sinus pause >3 seconds as potential components of sinus node dysfunction (SND). For the acute management of bradycardia related to moderate or severely symptomatic SND, symptomatic second- or third-degree AVB believed to be at the AV nodal level or any of the above resulting in hemodynamic compromise, atropine can be helpful to transiently increase sinus rate, and is a reasonable first step. If symptoms persist despite this and given atropine’s short duration of action, β-adrenergic agonists such as isoproterenol, dopamine, dobutamine, or epinephrine may be considered to increase heart rate and/or improve AV conduction and/or symptoms. In the presence of symptoms or hemodynamic compromise refractory to medical therapy, temporary transvenous pacing is reasonable, and temporary transcutaneous pacing may be considered until a temporary transvenous, or permanent pacemaker is placed.82 The need for temporary pacing is more likely when AV block is infra-Hisian.

There are no specific bradycardia-management guidelines produced by the European Society of Cardiology (ESC). Instead, there are guidelines related to cardiac pacing indications. They state that temporary transvenous pacing shall only be used in bradycardia refractory to positive chronotropic drugs. Temporary transvenous pacing should also be limited to cases of high-degree AVB without escape rhythm or life-threatening bradyarrhythmias.83

As per the ACC/AHA/HRS guidelines, for the management of bradycardia attributable to AVB in the chronic setting, such as the one related to radiation therapy, class I indications for permanent pacemaker implantation include Mobitz type II AVB, high-grade AVB, or CHB that is not attributable to reversible causes. For bradycardia attributable to SND, class I indication for permanent pacemaker implantation includes symptoms directly attributable to SND.82 The ESC pacing guidelines recommend permanent pacemaker implantation (Class I recommendation) in patients whose symptoms are attributable to SND and patients with third- or second-degree type 2 AVB.83

Fig. 5 represents a proposed algorithm for managing patients with cancer treatment-related bradycardia/bradyarrhythmia, with a special focus on ICI- and radiation-induced conduction abnormalities.

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Fig. 5: Proposed algorithm for the management of bradycardia/bradyarrhythmia, with a special focus on ICI- and radiation-induced conduction abnormalities49979899w100 (created by biorender.com). CK, creatine kinase; CMR, cardiac magnetic resonance; CRP, C-reactive protein; CXR, chest X-ray; ECG, electrocardiogram; EMB, endomyocardial biopsy; ESR, erythrocyte sedimentation rate; NT proBNP, N-terminal pro-brain natriuretic peptide; TTE, transthoracic echocardiography; WBC, white blood cell count.

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Future Directions

There is a limited body of literature regarding the true incidence of bradycardia and bradyarrhythmia related to chemotherapeutic agents, targeted molecular therapies, immunotherapies, and radiation. This is partially explained by the lack of systematic cardiac monitoring and reporting of arrhythmic events. In our view, a structured cardiac surveillance strategy with a homogenous classification of the arrhythmic events to be reported should be applied to clinical trials investigating the safety and efficacy of new cancer drugs. Databases/registries could also be established to obtain real-world quantitative data. Research of the possible mechanisms behind this type of cardiotoxicity is as well much needed. The already published evidence has mainly focused on arrhythmias in general, and there is a lack of data regarding the pathophysiology behind cancer drug-related bradycardia/bradyarrhythmia. Such knowledge could help develop evidence-based models to predict the patients who are more at risk of developing bradycardia/bradyarrhythmia and define the ones who may benefit from tighter monitoring strategies. Longer-term follow-up data are essential to determine the role of bradycardia on cancer patients’ overall outcomes. In particular, in ICI-myocarditis patients presenting with CHB who frequently undergo pacemaker implantation, long-term data regarding the percentage of pacing would be helpful to evaluate the degree of temporal recovery of these conduction abnormalities if at all. The rapid advances in pharmacotherapy in oncology show no signs of abating and if we are to understand the nuances of the adverse effects of these drugs on the cardiovascular system then the future mandates much closer collaboration between cardiologists and oncologists to optimize patient outcomes.