Breast Cancer Patient Develops Heart Palpitations and Dyspnea

What has caused this young woman in her 20s to develop heart palpitations and shortness of breath? That’s what Xuhong Geng, MD, of Fourth Hospital of Hebei Medical University in China, and colleagues needed to determine when the patient presented the day after onset of these symptoms, they reported in JAMA Internal Medicine.

Importantly, the patient had breast cancer and had undergone a total mastectomy of the right breast, followed by five cycles of dual anti-HER2 therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta).

The patient had no history of cardiovascular disease, nor was there any family history of sudden death or hereditary arrhythmia syndromes. Clinicians had ordered an ECG and an echocardiogram prior to starting the patient on anti-HER2 treatment; results were normal.

When the patient presented to the emergency department, her heart rate was 209/min, blood pressure was 90/60 mm Hg, respiratory rate was 31/min, and oxygen saturation was 92% on room air.

Troponin I level was 0.017 ng/mL (reference range <0.034 ng/mL), N–terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) level was 3,600 ng/L (reference range <125 ng/L), and levels of serum electrolytes were normal.

Findings of a transthoracic echocardiogram showed that the patient’s left ventricular ejection fraction (LVEF) was mildly reduced, at 46%. Geng and team described findings of the ECG performed upon her presentation in the emergency department as “a regular, relatively narrow, wide QRS complex tachycardia at a rate of 177/min, with a QRS duration of 132 milliseconds, atypical right bundle-branch block (RBBB) pattern, and superior left-axis deviation.”

Initially, clinicians suspected that the patient had supraventricular tachycardia with RBBB and left anterior fascicular block aberrancy. However, upon further assessment of leads II and V1, they noted atrioventricular dissociation and fusion beats, which were consistent with a diagnosis of left posterior fascicular ventricular tachycardia (LPF-VT).

In light of the patient’s hemodynamic instability, clinicians provided direct electrical cardioversion, which resolved the LPF-VT.

Fascicular ventricular tachycardias (FVTs) can develop in people with structurally normal or abnormal hearts, Geng and colleagues explained. When it occurs in patients with structurally normal hearts, it is referred to as idiopathic FVT. FVTs have also been noted in the setting of ischemic heart disease or digoxin intoxication.

In this patient’s case, neither traditional cardiovascular risk factors or exposure to digoxin were involved. The observed elevation in NT-proBNP level and decrease in LVEF that developed following five cycles of trastuzumab and pertuzumab suggested that the heart dysfunction was related to the patient’s use of dual anti-HER2 therapy, which has been associated with an arrhythmogenic effect.

Clinicians discontinued treatment with trastuzumab and pertuzumab and provided heart failure therapy as per guideline recommendations. Within 2 weeks, the patient’s NT-proBNP level had fallen to 116.0 ng/L and her LVEF was restored to 59%.

A follow-up ECG showed that her sinus rhythm had returned to normal. The team advised the patient to undergo electrophysiological testing, but she declined. She had no further FVT events for the remainder of her time in the hospital, or during 2 years of follow-up. Her breast cancer was treated with pyrotinib.

Discussion

First described around 50 years ago, FVT is a relatively rare form of VT of poorly understood etiology, the authors said. Proposed mechanisms for idiopathic FVT “involve a macro-reentry basis … with the reentry circuit involving a slow conduction zone with verapamil sensitivity,” they wrote; thus, it is also called verapamil-sensitive idiopathic left VT. In the setting of ischemic heart disease, FVT occurs due to abnormal automaticity, while triggered activity has been implicated in FVT associated with digoxin toxicity.

“Because of the involvement of the fascicular system, FVTs are commonly narrow (110-140 milliseconds in QRS duration),” they wrote of the three types of FVTs that have been described in the literature.

LP-FVT occurs most commonly, accounting for 90% of cases. Of the other two types, left anterior FVT makes up 10% of cases, and left upper septal FVT is seen even less often, accounting for less than 1% of cases. Because left posterior FVT presents as a wide complex tachycardia with an RBBB and superior left-axis pattern, it “can be easily misdiagnosed as supraventricular tachycardia with RBBB and left anterior fascicular block, especially in the settings without atrioventricular dissociation, capture, or fusion beats,” Geng and colleagues noted.

A novel prediction model has been proposed to differentiate LPF-VT from supraventricular tachycardia with RBBB and left anterior fascicular block.

A diagnosis of LPF-VT should be considered if at least three of the following criteria are met:

• Positive QRS in aVR
• QRS of 140 ms or less
• An R/S ratio of 1 or less in V6
• An atypical RBBB pattern in V1

Given its capacity to inhibit the HER2 signaling pathway more fully, dual anti-HER2 therapy “represents a promising treatment option” for HER2-positive breast cancers, the authors said. Unfortunately, its use is often limited by its potential cardiotoxicity, they added.

In addition to the documented adverse effects on cardiac function, anti-HER2 therapy — particularly trastuzumab — also has an arrhythmogenic effect. Given that the HER2 pathway is integral to antioxidative activity, preservation of myofibrillar integrity, and withstanding cardiac stress, targeting HER2 “could lead to accumulation of reactive oxygen species,” Geng and team noted.

“Increased reactive oxygen species can lead to malfunction of intracellular ionic homeostasis and abnormal functioning of myocardial ion channels, which could induce reentry, triggered activity, and automaticity, thus eliciting different types of arrhythmias, such as FVT,” they explained. In addition, anti-HER2 therapy has been implicated in the development of other arrhythmias, including atrial fibrillation, sick sinus syndrome, and nonsustained VT. Anti-HER2 treatment-related cardiotoxicity is characterized by a high rate of reversibility after treatment is stopped, as was noted in this patient.

The authors said that clinicians should be aware of the potential cardiac effects of anti-HER2 treatment, and emphasized the importance of adding routine ECG monitoring to echocardiography in patients receiving trastuzumab or dual anti-HER2 therapy.