Resident University Of Toronto Toronto, Ontario, Canada
Case background: An 82-year-old female presented with a two-week history of progressive shortness of breath, bilateral leg swelling, and orthopnea. Her past medical history was significant for ER+/PR+/HER2- metastatic breast cancer, type 2 diabetes, and hypertension. Her home medications included Letrozole 2.5mg daily, Hydrochlorothiazide 25mg daily, Valsartan 160mg daily, Metformin 1000mg twice daily, Gliclazide 60mg daily, Sitagliptin 500mg daily, and Canagliflozin 100mg daily. She had no prior history of hospital presentations for cardiac disease. She was a non-smoker and had no history of alcohol or illicit drug use. She lived alone and was functionally independent.
At the time of her initial presentation, she was tachycardic (117 bpm), tachypneic (26 breaths per minute), and normotensive (117/79 mmHg). Physical examination was remarkable for elevated jugular venous pressure at 14 cm above the sternal angle, bilateral crackles throughout her lung fields and bilateral pitting edema to her knees. Initial laboratory tests showed hemoglobin 104 g/L, leukocytes 13.3 10*9/L, platelets 323 10*9/L, sodium 116 mmol/L, potassium 4.9 mmol/L, creatinine 68 µmol/L, lactate 7.3 mmol/L, NT-proBNP 7845 pg/mL, serial troponins four hours apart were negative (13 to 16 ng/L). Respiratory viral swabs were negative.
Electrocardiogram showed sinus tachycardia at 124 bpm, left bundle branch block, and left atrial enlargement. Chest X-ray showed bilateral pulmonary venous congestion with increased interstitial markings and bibasilar pulmonary edema. Transthoracic echocardiogram (TTE) demonstrated severely dilated left ventricle (LV) with severely reduced systolic function, biplane LV ejection fraction (EF) was estimated at 14%, normal right ventricular size with mild-moderately reduced systolic function, mild aortic insufficiency, moderate mitral and moderate to severe tricuspid regurgitation, right ventricular systolic pressure was elevated at 49 mmHg, no pericardial effusion was present (Figure 1).
Initial clinical presentation was consistent with cardiogenic shock requiring admission to the coronary care unit. The patient required intravenous (IV) inodilator (milrinone) and IV furosemide as part of her initial management. Given her age, the leading differential for her cardiomyopathy included an ischemic etiology, although, non-ischemic causes including acute myocarditis, and idiopathic dilated were also considered. She underwent coronary angiography which only revealed mild luminal irregularities in her coronary arteries, and no significant stenosis. Right heart catheterization revealed right atrial pressure of 9 mmHg, pulmonary artery pressure 53/27 mmHg (mean of 37 mmHg), pulmonary capillary wedge pressure of 16 mmHg. Cardiac output and cardiac index were both reduced at 2.0 L/min and 1.5 L/min/m², respectively. She subsequently underwent cardiac magnetic resonance (CMR) imaging to investigate the non-ischemic causes of her cardiomyopathy. CMR revealed severe biventricular dilation with severely reduced biventricular global systolic function, no regional wall motion abnormalities, moderate functional mitral regurgitation with apical tethering of mitral valve leaflets, moderate tricuspid regurgitation, mild aortic regurgitation, diffusely elevated T1 values suggestive of diffuse fibrosis, and non-specific late gadolinium enhancement (LGE) that was not suggestive of any specific cardiomyopathy (Figure 2). Letrozole was then discontinued given the association with adverse cardiovascular effects and potential letrozole induced cardiotoxicity.
Guideline-directed medical therapy for heart failure was challenging to initiate given symptomatic hypotension. She underwent a repeat TTE three weeks from admission which demonstrated moderately dilated LV with severe global systolic function, and LVEF of 20%. She was transferred to an inpatient rehabilitation on maximally-tolerated doses of guideline-direct medical therapy (GDMT) which included bisoprolol 1.25mg daily, empagliflozin 10mg oral daily, ramipril 1.25mg oral twice daily, and spironolactone 25mg daily.
She followed up in the Cardiotoxicity and Prevention Clinic after two months. She had some residual deconditioning from her prolonged hospital stay but reported near complete resolution of her symptoms. A repeat TTE demonstrated minimal improvement in LV function with LVEF of 26%.
Management Challenges: Letrozole, a nonsteroidal aromatase inhibitor (AI), is a commonly used adjuvant treatment for hormone receptor-positive breast cancer. It has been associated with adverse cardiovascular effects and increased incidence of heart failure and hypertension in postmenopausal women. This is thought to occur due to reduced estrogen levels leading to endothelial dysfunction, increased arterial stiffness and subsequent development or exacerbation of hypertension and left ventricular dysfunction. AIs also increase the risk of myocardial infarction leading to ischemic cardiomyopathy.
Diagnosing letrozole-induced cardiomyopathy presents a significant clinical challenge due to the lack of specific imaging or clinical findings. Furthermore, letrozole-induced cardiomyopathy may only be partially reversible upon discontinuation of the drug further leading to diagnostic uncertainty. Patients on letrozole are typically older adults with baseline cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes, all of which independently increase the risk of cardiac dysfunction.
While this patient had baseline risk factors of hypertension and diabetes, they were well managed. She had no prior hospital admissions for cardiac complaints, no evidence of left ventricular hypertrophy on ECG or TTE to suggest uncontrolled hypertension. There was no evidence of arrythmia on telemetry and her tachycardia was likely compensatory in the setting of low cardiac output. Attributing her cardiomyopathy to letrozole is challenging, but was considered following exclusion of all other causes, warranting a trial of stopping Letrozole. She had mild improvement in her biventricular function after cessation of Letrozole and initiation of minimal GDMT.
Letrozole-induced cardiomyopathy is rare but an important consideration in patients presenting with new-onset heart failure while on AI. Diagnostic dilemma lies in the nonspecific presentation, confounding comorbidities, and absence of definitive biomarkers or diagnostic features. The diagnosis relies on clinical suspicion, exclusion of other causes, and close monitoring after drug withdrawal. In patients with predisposing cardiovascular risk factors, selective estrogen receptor modulators (SERMs) might be considered as potentially lower risk option but come at the cost of oncologic efficacy.
