HISTORY, CURRENT ILLNESS AND PHYSICAL EXAMINATION

History
Cardiovascular risk factors (CVRF): untreated dyslipidaemia, overweight grade 2.
Cardiological history: 11 years ago an echocardiogram was performed which showed no abnormalities during an admission for pneumonia.

Other history:
Chronic hepatitis C virus genotype 1 liver disease, non-responsive to interferon and ribavirin therapy.
Treatment was started with ledipasvir and sofosbuvir with prior withdrawal of omeprazole from her usual treatment to avoid interaction.
She finished treatment 2 months ago, totally asymptomatic, with sustained viral response.
Systemic sarcoidosis secondary to treatment with interferon, which was treated with corticosteroids and interruption of interferon therapy, with no current activity.
Usual treatment: omeprazole 20 mg 1 tablet per day.

Current disease
A 74-year-old female patient was being followed up by hepatology outpatients for chronic HCV infection.
During a follow-up visit to the hepatology outpatient clinic (2 months after finishing treatment with anti-HCV), the patient reported deterioration of functional class to dyspnoea on moderate exertion, with two-pillow orthopnoea, peripheral oedematisation and subjective decrease in daily diuresis volume, for which reason she was referred to cardiology.
She reported no chest pain at rest or on exertion, no presyncopal episodes and no infectious symptoms due to equipment.
At the cardiology outpatient clinic, anamnesis was performed, in accordance with the above, and NT- proBNP and transthoracic echocardiogram was requested, which showed dilated cardiomyopathy with severe left ventricular dysfunction.
Treatment was started with sacubitril/valsartan 24/26 mg every 12 hours, bisoprolol 2.5 mg daily, furosemide 40 mg 1 tablet every 12 hours and atorvastatin/ezetimibe 80/10 mg daily.
Due to evidence of iron deficiency anaemia in decompensated heart failure (HF), treatment was started with IV iron carboxymaltose in 15 minutes each dose (1,500 mg in total; 1,000 mg in the first week and 500 mg in the following week).
Cardiac magnetic resonance imaging (MRI) is requested and a new appointment is made in one month.

Physical examination
Conscious and oriented in the three spheres, normohydrated, cutaneous-mucosal pallor, good general condition.
Blood pressure 107/65 mmHg, heart rate 75 bpm, O2 saturation 98% room air, temperature 36.3 oC.
Cardiac auscultation: regular, third sound, no murmurs. Pulmonary auscultation: preserved vesicular murmur (VCM), humid bibasal crackles.
Extremities: tibiomalleolar oedema with fovea, no signs of deep vein thrombosis (DVT).

COMPLEMENTARY TESTS
AP chest X-ray: signs of venous congestion, with perihilar interstitial infiltrate, no pinching of costophrenic sinuses, cardiothoracic index (CTI) not assessable by projection.
Electrocardiogram (ECG): RS at 75 bpm, PR 160 ms, QRS 100 ms, Axis 0o, LVH criteria (Sokolov-Lyon), flattened T-waves in V5-V6, aVL

Blood tests:
CBC: red blood cells 4.52 10*12/l. Haemoglobin 9.6 g/dl. Haematocrit 32.8%. MCV 77.3 fl. MCH 22.1 pg. MCHC 26.4 g/dl. ADE 14%. Leukocytes 6.8 10*9/l. Neutrophils 3.3 10*9/l. Lymphocytes 2.9 10*9/l. Monocytes 0,4 10*9/l. Eosinophils 0,2 10*9/l. Basophils 0.1 10*9/l. Platelets 280 10*9/l.
Haemostasis: prothrombin time (PT) 11.1 sec. Quick index 100%. INR 0.97. APTT 26.9 sec. Ratio (aPTT) 0.9. Derived fibrinogen 311 mg/dl.
Biochemistry: glucose 105 mg/d. Sodium 141 mEq/l. Potassium 5 mEq/l. Chlorine 103 mEq/l. Total birubin 0.54 mg/dl. Aspartate aminotransferase GOT 26 U/l. Alanine aminotransferase GPT 13 U/l. Alkaline phosphatase 73 U/. Gamma-glutamyl transferase 13 U/l.
Creatinine 0.94 mg/dl. Estimated GFR CKD-EPI 60.8 ml/min/1.73 m. Uric acid 4.8 mg/dl.
Protein 7.2 g/dl. Creatine phosphokinase 119 U/l.
Iron profile: ferritin 54 μg/l. Iron 94 μg/dl. Total Fe fixation capacity 371 ug/dl. Transferrin saturation index 12.3%. Latent Fe binding capacity 277 ug/dl.
Immunological markers: rheumatoid factor 9 U/ml. C-reactive protein 0.0 mg/dl. Lactate dehydrogenase 374 U/l. Angiotensin converting enzyme 60 U/l.
Congestion markers: NT-proBNP 3407 pg/ml. Ag. Carbohydrate 125 (CA125) 107 IU/ml.
Lipid profile: total cholesterol 319 mg/dl. Triglycerides 90 mg/dl. HDL cholesterol 72 mg/dl. LDL cholesterol 229 mg/dl. Total cholesterol/HDL cholesterol 4.4.
Hormones: thyrotropin (TSH) 1.77 uIU/ml.
Calciuria 24 hours: within normal limits.

Transthoracic echocardiography (TTE): severely dilated left ventricle (LV) with severe systolic dysfunction (LVEF 30%) due to global hypokinesia. Normal sized atria. Mild central functional mitral regurgitation. Aortic valve without findings of interest. Right ventricle (RV) slightly dilated at baseline with preserved contractility. Trivial TR with PAPs 25 mmHg. Inferior vena cava not dilated.

Cardiac MRI (videos 2, 3, 4 and 5): LV volumes at the upper limit of normal (IVTDVI = 93 l/m; IVTSVI = 52 ml/m) with eccentric hypertrophy (IMVI = 84 g/m) and moderately depressed systolic function (LVEF = 44%). Generalised mild hypokinesia. Absence of myocardial oedema. Normal RV volumes (IVTDVD = 69 ml/m2; IVTSVD = 26 ml/m2) with normal systolic function (RVEF = 62%). Atria and great vessels of normal size. Lung resistance within normal values (2.6 U. Wood). First-pass perfusion at rest with e.v. gadolinium. - meglumine gadoterate 0.15 mmol/kg - no complications. Absence of significant perfusion defects. Focal late gadolinium enhancement in the medial inferior septum at the intersection with the right ventricle. Although small necrosis cannot be ruled out as it also affects the subendocardium, it could also be a focal sarcoid lesion. In summary: findings of dilated cardiomyopathy (DCM) of uncertain origin, probably not ischaemic although it presents a focal lesion compatible with necrosis vs. sarcoid lesion.

Catheterisation: right dominance. Coronary tree without angiographically significant lesions.

High-resolution pulmonary CT scan: mediastinal structures centred with small right paratracheal lymph node not exceeding one centimetre in maximum diameter, without appreciable lymph node growths in the hilar or axillary hollows. No pleural or pericardial effusions. No pulmonary nodules, masses or intraparenchymal infiltrates. Free main tracheobronchial tree.
Cardiac MRI (control in 6 months): LV of normal volumes (VTD 70 ml/m, VTS 34 ml/m, IMVI 74 g/m2) without significant hypertrophy of its walls or alterations of segmental contractility at rest and with slightly depressed global systolic function (LVEF 51%).
Abnormal septal motion. Non-dilated RV (RVOT 66 ml/m, STV 25 ml/m) with preserved global systolic function (LVEF 62%). Aorta and great vessels of normal diameter and morphology. Atria of normal dimensions. Normal pulmonary vascular resistance (mean pulmonary velocity 14.3 cm/sec). Compared with the August 2017 examination, the LV volumes improved, as did LVEF.

CLINICAL EVOLUTION
Continuing with the study of the left ventricular dysfunction detected at the outpatient level, cardiac MRI was performed 3 weeks after the consultation, showing improvement in ventricular function, with moderate dysfunction, and catheterisation was performed (due to the late gadolinium enhancement image suggestive of necrosis), which showed no significant angiographic lesions.
The patient did not report catarrhal or other symptoms prior to the current process suggestive of myocarditis prodrome. Only the introduction and completion of HCV antivirals coincided in time.
Given the findings of late gadolinium enhancement that could be partially explained by sarcoidosis in a patient with a history of iatrogenic sarcoidosis secondary to the use of interferon, a high-resolution CT scan of the lungs was performed, which showed no data suggestive of pulmonary or adenopathic sarcoidosis, nor analytical data of activity (ACE, calciuria or elevation of acute phase reactants).
A literature search was conducted on cardiotoxicity due to direct antivirals against HCV. Although there is no reference to toxic myocarditis in the data sheet, articles were found referring to toxicity from drugs that act on the same targets and were withdrawn from clinical trials, reversible global longitudinal destrain worsening after sofosbuvir and exclusion of patients with heart disease and without adequate controls (with echocardiography) of cardiovascular safety in pivotal trials of antiviral drugs against HCV. Because of this, left ventricular dysfunction is attributed to the use of HCV antivirals.
After starting treatment, the patient was asymptomatic, with no dyspnoea for activities of daily living.
A follow-up cardiac MRI was requested after 6 months, showing normalisation of left ventricular volumes without hypertrophy and improvement in left ventricular function, with mild dysfunction remaining.
Subsequently, in echocardiographic controls up to the present, LVEF has normalised and diameters are at the upper limit of normality.
The study of iron deficiency anaemia showed three polyps in the right colon at colonoscopy, which were removed without significant histopathological findings.
In summary, this is a case of severe left ventricular dysfunction secondary to reversible dilated cardiomyopathy. Although the findings could be explained by a past asymptomatic myocarditis, we consider more likely the possibility of toxic myocarditis related to direct antivirals against HCV, a pathology little studied in our environment, and with drugs widely used in our health system.

DIAGNOSIS
Non-ischaemic dilated cardiomyopathy with severe left ventricular dysfunction, recovered.
Suspected toxic myocarditis due to HCV antivirals.
Iron deficiency anaemia secondary to colonic polyps.
Dyslipidaemia.
