HISTORY, CURRENT ILLNESS AND PHYSICAL EXAMINATION

History
We present a 78-year-old male patient, non-smoker, with no known cardiovascular risk factors (CVRF) or other toxic habits. In 2013 he presented an episode of paroxysmal atrial fibrillation, with no alterations in the echocardiogram or ergometry, for which he was discharged. The patient was not anticoagulated as he had a CHA2DS2-Vasc of 1 point at that time. Since then, the patient's only treatment was occasional lorazepam.

Oncological history:
In October 2016, the patient started with intermittent dysphonia. Computed tomography (CT) scan showed a lung mass in the right hemithorax measuring approximately 33 mm and multiple homolateral hilar and mediastinal hilar adenopathies. A right pleural effusion with multiple pseudonodular images and segmental atelectasis in the middle lobe were also seen.
Due to these findings, the patient was referred to the pulmonologist, who performed bronchoscopy with aspiration and positron emission tomography (PET), which confirmed a hypermetabolic mass in the right upper lobe compatible with a primary pulmonary neoplasm. The patient also presented hypermetabolic adenopathies at different levels, including a right supraclavicuar adenopathy, a right pleural effusion and hypermetabolic lesions in the sixth costal arch.
Anatomo-pathological study revealed adenocarcinoma (ADC) of the lung, and genetic analysis identified ALK translocation, which has been found to be strongly associated with the genesis of this type of tumour.
Finally, the patient was diagnosed with stage IV lung adenocarcinoma (T2aN2M1) with ALK translocation, and first-line palliative treatment with crizotinib, a tyrosine kinase inhibitor, was initiated.
After two cycles of chemotherapy, a control CT scan showed a partial response with reduction of the lung mass (20 mm), reduction of the size of the paratracheal adenopathies and disappearance of the pleural effusion. From January 2017 to June 2017, he received a total of 6 cycles of crizotinib (500 mg/24 hours) and the patient achieved stable disease. During this period, the patient had no relevant adverse events.
Since then, the patient was clinically monitored every month and a follow-up CT scan was performed every six months. He had no adverse effects related to the oncological treatment and the disease remained stable according to RECIST criteria.

Current disease
In November 2019, during a follow-up oncology consultation, the patient reported slow but progressive onset of oedema in the lower extremities and weight gain of up to 5 kg in the last few months. He also reported noticing an even slower heart rate than usual, around 30-40 beats per minute without dizziness or syncope, and mild dyspnoea without clear orthopnoea.
A follow-up CT scan showed that the lung mass remained stable, but a mild pleural effusion, a laminar pericardial effusion and a periportal hypodensity compatible with oedema were observed.
It was decided to temporarily suspend crizotinib, treatment with a loop diuretic was started and the patient was referred to the cardio-oncology department to rule out congestive heart failure.

Physical examination
At the first visit to the cardio-oncology department, the patient was hypertensive (187/91 mmHg) and oxygen saturation was normal. Physical examination revealed no jugular plethora but he had hepatojugular reflex and oedema with pitting in both lower extremities. Cardiac auscultation was rhythmic at about 40 beats per minute, with no murmurs.

COMPLEMENTARY TESTS
The electrocardiogram showed sinus rhythm at 43 beats per minute, with first degree atrioventricular block and normal QT (QTc 422 ms).
No significant alterations were evident in the blood tests: glucose 82 mg/dl, urea 38 mg/dl, creatinine 1.15 mg/dl, glomerular filtration rate (CKD-EPI) 60 ml/min/1.73 m , sodium 145 mEq/l, potassium 4.6 mEq/l, magnesium 2.2 mg/dl, albumin 3.8 g/dl, cholesterol 177 mg/dl, haemoglobin 14 g/dl, leucocytes 4.41 x 103/ml, platelets 149 x 103/ml.
NT-proBNP was determined once diuretic treatment had been started and the patient's clinical situation had improved, and the value was 115 pg/ml (normal range 0 to 300 pg/ml).
An echocardiogram was also performed and showed mild to moderate septal hypertrophy with preserved left ventricular ejection fraction (LVEF) (estimated LVEF 58%). The aortic root was mildly dilated (42 mm ascending aorta) with mild aortic and mitral valve regurgitation.
The left atrium was mildly dilated. The right ventricle was normal in size and function. There was mild tricuspid regurgitation without significant pulmonary hypertension, and mild pericardial effusion.

CLINICAL EVOLUTION
After the first visit, the patient's condition was suspected to be heart failure secondary to bradycardia. Bradycardia is a common cardiovascular adverse effect of crizotinib, which can also cause heart failure.
According to the Framingham criteria for heart failure, the patient met two major and three minor criteria. The diagnosis was further supported by echocardiographic findings of mild-to-moderate septal hypertrophy with preserved LVEF and mild pericardial effusion.
Differential diagnosis was made with other entities that could cause systemic congestion:
Systemic congestion can be caused by both renal disturbances and nephrotic syndrome. The association between lung cancer and paraneoplastic syndromes is frequent, including nephrotic syndrome. As we can see from the laboratory results, the patient's renal function was normal and albumin and cholesterol were within normal ranges.
Liver failure can also be a cause of oedema, but the patient had no history of ethylism, and both bilirubin and liver enzymes were normal.
It should also be noted that venous compression due to tumour progression could cause oedema in the lower extremities. However, no abdomino-pelvic or inguinal adenopathies were seen on the follow-up CT scan in October 2019.
Some medications that are part of the different oncological treatments can cause systemic congestion (e.g. corticosteroids, analgesics such as ibruprofen, naproxen...). Our patient, however, was not receiving treatment with any of them.
By the time the patient was referred to the cardio-oncology department, crizonitib had already been discontinued and the loop diuretic was started. Since then, the patient progressed favourably, losing up to 2-3 kilograms. In addition, enalapril 5 mg/24 hours daily was started due to the hypertension observed in the consultation.
The patient was finally diagnosed with symptomatic bradycardia secondary to crizotinib and congestive heart failure with preserved LVEF.
After one week of treatment the patient lost 5 kg and had no congestive signs. He also reported an increased heart rate. Holter blood pressure monitoring showed that the patient had grade 1 hypertension, and treatment was adjusted.
The loop diuretic could be withdrawn because the patient evolved favourably, the congestive signs resolved, no serious heart disease was observed in the tests performed, and his heart rate was around 60 beats per minute. After a multidisciplinary consultation, and considering the spectacular response he had previously shown, it was decided to restart crizotinib with close monitoring.

DIAGNOSIS
Heart failure with preserved LVEF secondary to sinus bradycardia. Sinus bradycardia secondary to crizotinib.
Stage IV lung adenocarcinoma with ALK translocation.
