Intermittent left bundle branch block and acute heart failure in trastuzumab-induced cardiotoxicity

Abstract

A 70-year-old woman with HER2+/ER+ breast cancer on adjuvant trastuzumab therapy without a history of cardiovascular disease presented with respiratory failure from influenza and was found to have intermittent left bundle branch block (LBBB) with new onset systolic heart failure. Her course was complicated by polymorphic ventricular tachycardia and recurrent chest pain. Significant investigations included a normal cardiac MRI and cardiac catheterisation with unobstructed coronaries. It was determined that the aetiology of her heart failure was trastuzumab-induced cardiotoxicity after comprehensive workup. This case highlights an uncommon presentation of LBBB and the steps taken to diagnose a rare cardiomyopathy.

Background

Left bundle branch block (LBBB) is a pattern seen on the surface ECG, which results when there is alteration of normal electrical activity in the His-Purkinje fibres.¹ Most often, LBBB occurs from chronic conditions that progressively damage the conduction system (eg, coronary artery disease, hypertension, cardiomyopathy) or more acutely from myocardial ischaemia or myocarditis, among others.^2–4 Infrequently does it manifest in patients with structurally normal hearts without coronary disease and even less commonly does the LBBB appear intermittently.^{5 6}

We present the case of a 70-year-old woman with HER2+/ER+ breast cancer on adjuvant trastuzumab therapy who presented with respiratory failure from influenza and was found to have intermittent LBBB with new onset systolic heart failure in the setting of chemotherapy-induced cardiotoxicity. In patients that present with new LBBB, determining the aetiology can have prognostic importance, especially in those with symptoms of heart failure.^{4 7 8} This case demonstrates an unusual manifestation of LBBB and the challenges faced in diagnosing a rare cardiomyopathy.

Case presentation

A 70-year-old woman with history of asthma, bipolar disorder and breast cancer initially presented to the emergency department with 3 days of shortness of breath, cough and chest pain. The patient was diagnosed with breast cancer almost 1 year prior and underwent lumpectomy with pathology showing grade 2 HER+/ER+ ductal carcinoma. She was almost 6 months into adjuvant chemotherapy with trastuzumab and was being monitored for cardiotoxicity with routine outpatient echocardiograms that showed normal cardiac function. She had already completed therapy with paclitaxel and did not receive anthracycline treatment. The patient had no prior history of cardiovascular disease and recent coronary CT scan demonstrated a coronary artery calcium (CAC) score of 0.

In the emergency department, the patient tested positive for both influenza A and H1N1 virus and demonstrated bilateral consolidations on chest X-ray concerning for secondary bacterial infection. ECG on presentation showed sinus tachycardia and LBBB morphology with a ventricular rate of 124 beats/min, QRS duration of 152 ms and a QTc interval of 476 ms (figure 1). The patient was started on intravenous antibiotics but soon developed respiratory failure necessitating intubation and triage to the medical intensive care unit. On telemetry, it was noted that the patient was no longer demonstrating LBBB morphology, but instead developed frequent premature ventricular complexes that deteriorated into torsades de pointes. The patient received magnesium and cardioversion with restoration of sinus rhythm and was started on amiodarone and lidocaine infusions. Post-arrest ECG demonstrated sinus bradycardia with deep T-wave inversions in the anterior leads and a prolonged QTc interval of 685 ms (figure 2). It was determined that lengthening of the patient’s QTc interval was medication related and her aripiprazole, ondansetron and azithromycin therapies were discontinued.

Figure 1.

ECG on admission showing sinus tachycardia with left bundle branch block.

Figure 2.

Post cardiac arrest ECG showing sinus bradycardia with broad and deep T-wave inversions.

The patient was subsequently extubated and serial ECGs showed normal sinus rhythm with progressively shortening QTc interval. However, the patient’s course was further complicated by acute shortness of breath and chest pain with flash pulmonary oedema. She was given intravenous diuretic and started on non-invasive positive pressure ventilation. A new ECG was obtained which showed recurrence of LBBB with a ventricular rate of 76 beats/min (figure 3). Troponin was elevated to 0.96 ng/mL (normal between 0 and 0.4 ng/mL). A bedside echocardiogram was performed which demonstrated a newly reduced left ventricular ejection fraction (LVEF) of 40%. The patient was started on nitroglycerin and heparin infusions.

Figure 3.

ECG obtained during acute chest pain episode showing normal sinus rhythm with recurrence of left bundle branch block.

Investigations

There was concern for acute coronary syndrome with new LBBB. However, initial cardiac catheterisation was deferred because the patient’s chest pain was convincingly described as pleuritic which was consistent with her active pulmonary disease. Furthermore, she had a recent CAC score of 0. The elevated troponin was considered to be from a type II myocardial infarction due to a mismatch in myocardial oxygen supply and demand. Although her symptoms subsided, she was noted on continuous telemetry to sporadically transition in and out of LBBB morphology with continued ventricular ectopy (figure 4). The appearance of LBBB was not rate dependent and recurrent episodes were asymptomatic. A formal echocardiogram was obtained that demonstrated an ejection fraction of 45% and mild global hypokinesis with more severe hypokinesis of the anterior septal and apical walls. There was no evidence of apical ballooning suggestive of stress cardiomyopathy. At this juncture, the differential for new-onset heart failure and intermittent LBBB included viral myocarditis, ischaemic cardiomyopathy, tachycardia mediated cardiomyopathy and chemotherapy induced cardiotoxicity. A cardiac MRI was pursued that did not show mid-wall delayed gadolinium enhancement characteristic of myopericarditis. Given these negative results, cardiac catheterisation was performed to more definitively rule out obstructive coronary disease given intermittent ECG changes, T-wave inversions and QTc interval variability in the setting of elevated troponin and mild left ventricular dysfunction. The left heart catheterisation demonstrated no significant coronary disease and left ventriculogram did not show apical ballooning.

Figure 4.

Telemetry strip indicating axis change from left bundle branch block to normal morphology without change in heart rate (HR).

Differential diagnosis

While viral myocarditis and ischaemia were our leading differentials for acute heart failure and intermittent LBBB, these aetiologies were excluded by cardiac MRI and left heart catheterisation, respectively. Stress-induced cardiomyopathy was also considered given the patient’s age and gender; however, echocardiogram findings at onset of symptoms and subsequent ventriculogram findings were not characteristic. The regional wall motion abnormalities on echocardiogram were likely artefact of LBBB and MRI did not demonstrate infiltrative disease or any other causes of intraventricular conduction disturbance. It was likely that the persistent T-wave inversions on ECG were from cardiac memory following abnormal ventricular activation. We also entertained the possibility of tachycardia-mediated cardiomyopathy from torsades de pointes and ventricular tachycardia; however, the lack of improvement in LVEF despite returning to normal sinus rhythm made this diagnosis unlikely. Furthermore, the patient presented with LBBB on admission ECG before developing cardiac arrest indicating that myocardial damage preceded the ventricular tachycardia. Therefore, we arrived at the diagnosis of trastuzumab-induced cardiotoxicity based on exclusion of the aforementioned possibilities. While conduction disease with intermittent LBBB is a rare manifestation of this adverse medication effect, it was the most unifying diagnosis in our patient without long-standing hypertensive, ischaemic or structural heart disease.

Treatment

Treatment was aimed at symptom management and avoidance of medications that could exaggerate QTc interval and precipitate arrhythmia. The patient was started on medications for systolic heart failure including lisinopril and torsemide as well as propranolol for prevention of recurrent arrhythmia. Trastuzumab therapy was also suspended. The patient was discharged with a wearable defibrillator given continued electrical abnormalities in the setting of recent cardiac arrest.

Outcome and follow-up

The patient was discharged alive and scheduled for close follow-up in a multispecialty cardio-oncology clinic. Approximately 4 weeks after discharge, a repeat echocardiogram showed recovery of LVEF after stopping trastuzumab therapy. An ECG obtained at that time showed normal sinus rhythm without LBBB morphology and a normal QTc interval.

Discussion

Cardiac diseases resulting from chemotherapy agents have become an increasingly important issue given the emergence of novel medical therapies with unique mechanisms of action. Cardiotoxicity occurs in about 4% of patients receiving trastuzumab without concomitant anthracycline therapy and typically presents as asymptomatic left ventricular dysfunction that is usually reversible.⁹ The above case is unique in that not only did the patient present with symptoms of overt heart failure, but she also developed intermittent LBBB on ECG and continuous telemetry. Only a few cases in the literature have described non-myopathic adverse effects of trastuzumab-induced cardiotoxicity including conductive disturbances such as LBBB.^10–12 Tahir et al described a patient who developed functional, or tachycardia-induced LBBB along with asymptomatic left ventricular dysfunction from trastuzumab therapy without evidence of obstructive disease on left heart catheterisation.¹¹ This patient was noted to have continued presence of intermittent LBBB 1 year after the initial ECG and 5 months after recovery of left ventricular systolic function. In the current case report, our patient developed LBBB that was independent of heart rate as evidenced in the overnight telemetry strip (figure 4). There have also been reports of non-intermittent LBBB presenting as acute coronary syndrome in patients with trastuzumab-related disease who were found to have no evidence of coronary obstruction on immediate cardiac catheterisation.^{10 12} Taken collectively, these cases demonstrate the challenges of risk stratifying patients that develop this rare side effect of chemotherapy. The underlying mechanism of trastuzumab-induced cardiotoxicity is still unclear but may involve defective HER2 signalling, immune-mediated destruction of cardiomyocytes and changes in expression of BCL-X proteins that lead to contractile dysfunction without changing cellular structure.9 11 13 14

The prognosis in patients with LBBB is influenced by the type and severity of any concomitant underlying heart disease and to the possible presence of additional conduction disturbances.⁴ In patients with heart failure, the presence of LBBB is associated with a higher risk of cardiovascular events and mortality.^{3 4 7} In this subset of patients, even in the absence of structural heart disease, LBBB is associated with left ventricular dyssynchrony, which can over time lead to decreased efficiency of ventricular contraction.⁴ Rarely does LBBB appear intermittently as in our patient, and most documented cases are heart rate dependent while only a few have been observed in a variety of unrelated medical conditions.^{5 6} The significance and mechanisms of intermittent LBBB in these scenarios are still poorly understood, but prior studies have demonstrated that many will progress to permanent LBBB and sometimes advanced atrioventricular block.^{5 6} Independent of the presence of electrical disturbance, expert recommendation for treatment of trastuzumab-induced cardiotoxicity includes first-line heart failure medications and at least temporary discontinuation of trastuzumab therapy with follow-up echocardiography.⁹ Our patient was discharged on lisinopril, propranolol and torsemide, all of which were started inpatient. Given continued QTcinterval variability despite discontinuation of offending medications, she was discharged with a wearable defibrillator and scheduled for close electrophysiology follow-up. It remains possible that the iatrogenic prolonged QTc interval may have been potentiated by her chemotherapy-related disease.

In closing, we highlight a case of complex decision-making where our differential diagnosis was continuously challenged in light of new data and developments in a critically ill patient. This report calls attention to a rare, non-myopathic complication of trastuzumab-induced cardiotoxicity that may become apparent in more patients as anticancer therapy becomes increasingly prevalent. It will be important that these patients are closely followed for complications from both cardiac and oncological perspectives. Future studies should attempt to disambiguate the mechanisms of action related to these toxicities to help prognosticate outcomes and target potential therapies.

Learning points.

• Intermittent left bundle branch block (LBBB) is a rare complication of trastuzumab-induced cardiotoxicity.

• In new onset LBBB, careful consideration must be given to ischaemic aetiology as well as alternative diagnoses.

• For patients receiving cancer therapies with potential for cardiovascular complications, incorporation of cardio-oncology into clinical oncology patient care is paramount in optimising outcomes and improving quality of life for patients.