HISTORY, CURRENT ILLNESS AND PHYSICAL EXAMINATION

History
44-year-old woman, who years ago suffered a skin reaction compatible with allergy to ibuprofen and metamizole, without subsequent confirmation by allergology. Active smoker of 10 cigarettes a day for about 20 years (IPA approximately 10), denies alcohol habit. History: hypercholesterolemia, on treatment with atorvastatin 80 mg for 5 years, Graves' disease with mild orbitopathy (at last check-up she was euthyroid) and bronchial asthma being monitored by pulmonology and treated with salmeterol/fluticasone propionate every 12 hours and salbutamol on demand. Family history: father with hypercholesterolemia and type 2 diabetes mellitus. Mother with hypercholesterolemia. Three siblings, no data known. Two children, one 15 years old pending analysis and one 13 years old with LDL 215 mg/dl on treatment by her paediatrician with rosuvastatin 20 mg/ezetimibe 10 mg and pending genetic study of HFHe).

Current illness
She came to the emergency department for clinical symptoms that began 3 weeks earlier, consisting of progressive dyspnoea until minimal effort, increased oedema in the lower limbs, paroxysmal nocturnal dyspnoea crisis, palpitations with a sensation of irradiation to the neck, multiple ecchymosis in the upper and lower limbs and hypoaesthesia in the left lower limb. He denies orthopnoea or diuresis curtailment. She has not presented chest pain. No arthralgias or arthritis, nor oral aphthous ulcers. No fever at home.

Physical examination
Blood pressure 129/84 mmHg, heart rate 85 bpm, respiratory rate 18 rpm, temperature 37.6 oC. Acceptable general condition, conscious, oriented and cooperative. Well hydrated and perfused, normal colour. Slight tachypnoea at rest, with slurred speech although maintaining baseline oxygen saturation 97%, mild dysphonia. Glasgow 15/15. Cardiac auscultation showed rhythmic tones at a good frequency without murmurs, without pericardial friction. Respiratory auscultation showed minimal bibasal crackles and some isolated wheezing. The abdomen is unremarkable. The neurological examination showed isochoric pupils that were normoreactive to light, preserved cranial nerves, diminished gross tactile sensitivity in the left lower limb, more marked in the anterior thigh region. Gait was not examined. The lower limbs showed oedema with fovea up to mid-leg, with signs of chronic venous insufficiency, without signs of deep vein thrombosis, with peripheral pulses present and symmetrical. There were multiple small ecchymoses on the upper and lower limbs.

COMPLEMENTARY TESTS
On arrival at the ED: Analysis: high sensitivity troponin I 855.40 ng/l (normal 2-15.6) and C-reactive protein 32.7 mg/l (normal < 5). Haemoglobin 14.2 g/dl, leucocytes 10.08 x10^3/μl, with eosinophils 1.68 x10^3/μl (normal 0.02-0.55) and platelets 79 x10^3/μl. Coagulation was normal except for D-dimer 1,785 ng/ml (normal < 500). Electrocardiogram on arrival: sinus rhythm at 93 bpm, PR 0.14 s constant, QRS 0.10 s, electrical axis over +90o, ST depression of 1 mm in II, III, aVF, V3-V6, flattened T waves in inferior leads and negative in V3-V6. Chest X-ray showed no cardiomegaly or parenchymal condensation. Prominent hilarity was present. No pleural effusion or costophrenic sinus impingement was observed. Given the findings, myocardial damage marker serology was requested, as well as a chest CT angiography for suspected pulmonary thromboembolism. Chest CT angiography: no signs of pulmonary thromboembolism were observed, the pulmonary parenchyma showed no alterations, subcentimetric adenopathies of probably reactive appearance were observed at the para-aortic, right paratracheal, hilar and subcarinal levels of 1.5 cm. Control laboratory tests at 4 hours: troponin I increased to 1,770.3 ng/l, with normal CK. During his stay in the intensive care unit and on the internal medicine hospital ward: given the clinical suspicion, an autoimmune panel was urgently requested, in which positive anti-neutrophil cytoplasmic antibodies were found with positive anti-myeloperoxidase antibodies (IgG) (19.1 IU/ml [0-6]), the rest negative. Serialisation of myocardial damage markers was continued, with a peak value of troponin I of 5,065 ng/l. The peak value of brain pro-brain natriuretic peptide was 6,819.8 pg/ml (high probability of heart failure in patients under 55 years of age if > 450 pg/ml). In the routine analysis, extracted 72 hours after admission, glucose 157 mg/dl, LDL cholesterol 261 mg/dl, HDL cholesterol 59 mg/dl, triglycerides 155 mg/dl, lactate dehydrogenase 449 U/l (125-220), complement C3 61 mg/dl (90-180) with normal C4, thyrotropin 0.34 μUI/ml (0.35-4.94), free thyroxine 0.85 ng/dl (0.7-1.48), free triiodothyronine 1.62 pg/ml (1.71-3.71). HIV screening and other infectious immunodiagnostic tests were negative. The bedside echocardiogram performed in intensive care on admission showed a non-dilated left ventricle (LV) with preserved systolic function, even hypercontractile with concentric hypertrophy with an interventricular septum of 14 mm and a posterior wall of 13 mm. Aortic root not dilated. Dilated right ventricle (RV) with a basal diameter of 39 mm, 10 mm lateral wall with hyperechoic image adjacent to the lateral wall. Triscuspid insufficiency with estimated pulmonary arterial systolic pressure (PSAP) of 100 mmHg. Dilated right atrium (RA) with an area of 22 cm2. Normal mitral flow pattern. Mild pericardial effusion adjacent to LV. Echocardiogram performed by cardiology 72 hours after admission showed (body surface area 1.9 m2). Non-dilated LV (DTD 47 mm, 51 ml/m2), without hypertrophy at baseline (IVS 9, PP 9 mm), although progressive thickening from mid segments and especially apex (15 mm), with preserved global systolic function (EF 71% 4C), without evident alterations of segmental contractility. Restrictive mitral filling pattern, with E/A 2.2, e' 6 cm/s, E/e' 14. Dilated right chambers (RV 42 mm basal, RA 18 cm2). RV normocontractile (TAPSE 19 mm, s-wave 12 cm/s). Dilated left atrium (LA) (38 ml/m2). Without good visualisation of the aortic root, apparently not dilated. Dilated inferior vena cava (IVC) (27 mm), with little inspiratory collapse. Dilatation of suprahepatic veins. Slight inferior pericardial effusion (2 mm), with no signs of haemodynamic compromise. No apparent intracavitary thrombus. Trivalve aortic valve with preserved mobility. Normal aortic flow. Normal mitral valve morphology. Mild central mitral insufficiency. Mild tricuspid and pulmonary insufficiency, estimating PSAP of 49 mmHg (V max 2.9 m/s) and PMAP of 30 mmHg (V max 1.9 m/s). Pulmonary TA 105 ms. In short, he presented a pattern of myocardial restriction, non-dilated LV with preserved EF, apical hypertrophy, severe diastolic dysfunction, slightly dilated RV with preserved EF, high probability of pulmonary hypertension, biauricular dilatation, mild mitral and tricuspid insufficiency, mild pericardial effusion. Given the clinical history, compatible with Löffler's endocarditis. After a week of admission, left and right cardiac catheterisation was performed. After obtaining 6F radial access, a good calibre LMCA with no angiographic lesions, a good calibre anterior descending artery (ADA) with no angiographic lesions and good distal flow, a good calibre circumflex artery (Cx) with no angiographic lesions and good distal flow, and a dominant right coronary artery (RCA) with good calibre, no angiographic lesions and good distal flow were visualised. The left ventriculography showed a non-dilated left ventricle with severe apical hypertrophy, preserved systolic function with LVEF 64.5%, mild mitral insufficiency, LV end-diastolic pressure of 29 mmHg. Regarding right catheterisation, AD pressure = 25 mmHg, RV systolic pressure = 43 mmHg, RV diastolic pressure = 11 mmHg, mean RV pressure = 15 mmHg, pulmonary systolic pressure = 45 mmHg, pulmonary diastolic pressure = 28 mmHg, mean pulmonary pressure = 33 mmHg, diastolic transpulmonary gradient = PAMP - PCP = 4 mmHg, concluding in isolated postcapillary pulmonary hypertension. Right ventriculography showed significant apical hypertrophy with preserved ejection fraction (RVEF 52%), mild tricuspid insufficiency and mild pulmonary insufficiency. An endomyocardial biopsy was performed with 3 samples taken (right ventricle). The septal biopsy showed a fibrous cap of normal thickness overlying myocardium, free of inflammatory infiltration, with no histological criteria for endocarditis. The apex biopsy is a minimal fragment of lax fibrous tissue without inflammatory changes and haematic material, unsatisfactory for diagnosis. The basal biopsy is a small fragment of endocardium, without myocardium, with discrete endothelial hyperplasia, suggestive of reactive and slight haematic infiltrate secondary to biopsy, without inflammatory infiltration. Cardiac MRI performed prior to the start of cyclophosphamide showed non-dilated ventricles with preserved systolic function, findings compatible with biventricular endomyocardial fibrosis, with organised left ventricular apical thrombus, secondary to granulomatosis with polyangiitis (late-stage endomyocardial fibrosis), tethering of the inferior papillary muscle and slight hypokinesis of apical segments and apex of the left ventricle, as well as of the apical segment of the right ventricular free wall, biauricular enlargement, tricuspid insufficiency of doubtful significance, pericarditis with signs of active inflammation and slight pericardial effusion. Myocardial septal thickness 10 mm; anterior 11 mm; lateral 10 mm; inferior 11 mm. End-diastolic diameter 49 mm; end-systolic diameter 35 mm. Relative wall thickness 0.24. Indexed mass: 39 g/m2. Cardiac magnetic resonance imaging at 4 months (video 2) showed a significant decrease in the thickness of the distal segments with respect to the previous study, no tethering of the inferior papillary muscle, ventricles with slightly reduced volumes and normal systolic function and slight pericardial effusion. In short, compared to the previous study, there was a great improvement in ventricular thicknesses and apical thrombus, which has disappeared. Measurements: left ventricle: septum 5 mm, posterior wall 5 mm, DTD 48 mm, VTD 119 cc, VTS 53 cc, Systolic volume 67 cc, iVTD 66 cc/m2, iVTS 29 cc/m2, LVEF 56%. Left ventricle: septum 5 mm, posterior wall 5 mm, DTD 48 mm, VTD 119 cc, VTS 53 cc, Systolic volume 67 cc, iVTD 66 cc/m2, iVTS 29 cc/m2, LVEF 56%. Right ventricle: RVT 143 cc, STV 60 cc, Systolic volume 83 cc, iVTD 79 cc/m2, iVTS 33 cc/m2, LVEF 58%. Left atrium: area in 4 chambers 16 cm2. Right atrium: area in 4 chambers 19 cm2. Sinus aorta (diameter in sinuses of Valsalva): 28 mm. Ascending aorta: 25 mm. Descending aorta: 19 mm.

CLINICAL EVOLUTION
After first-level complementary tests were performed in the emergency department with the findings described, pulmonary thromboembolism was suspected, which was ruled out by angio-CT. Given the clinical picture and the analytical data, it was decided to admit the patient to intensive care. This unit consulted with internal medicine for assessment. Due to his history (sinusitis, hypereosinophilia), clinical manifestations (dyspnoea, oedema in the lower limbs, etc.), analyses (elevated cardiac enzymes, thrombopenia, eosinophilia, etc.) and echocardiographic data of myocardial infiltration compatible with Löffler's endocarditis, it was suspected that it could be APEEG, and an urgent ANCA ELISA study was requested, which was positive (myeloperoxidase). Steroid treatment was started immediately with boluses of 1 g of 6-methylprednisolone for 3 consecutive days, with significant clinical improvement reflected in the analytical parameters (thrombopenia, eosinophilia and troponin), to be continued with 60 mg of prednisone daily. After 7 days of hospitalisation, cyclophosphamide was administered in boluses of 500 mg (fixed dose) every 15 days, which were programmed to complete 6 boluses. Right and left cardiac catheterisation was performed with biopsy, which did not clarify the diagnosis. Clinically and haemodynamically stable, she was discharged from hospital after 2 weeks of admission, under treatment with prednisone 60 mg at breakfast (which was progressively reduced to 15 mg), calcium 600 mg/cholecalciferol 1.000 IU (1 tablet daily), ibandronic acid (1 tablet monthly at fasting), torasemide 5 mg (1 tablet at breakfast), acetylsalicylic acid 100 mg (1 tablet at lunch), omeprazole (1 capsule at breakfast) and atorvastatin 80 mg (1 tablet at dinner).

Outpatient follow-up showed total cholesterol 413 mg/dl, non-HDL cholesterol 326 mg/dl and triglycerides 308 mg/dl, and treatment was started with anti-PCSK9 (evolocumab 140 mg subcutaneous every 2 weeks) and omega-3 acid ethyl esters (two capsules every 12 hours). The response was spectacular, with LDL cholesterol reduced to 62 mg/dl, HDL cholesterol 66 mg/dl and triglycerides 125 mg/dl. Dyspnoea did not return and acute phase reactants remained normal, with no eosinophilia.

DIAGNOSIS
Congestive heart failure and isolated postcapillary pulmonary hypertension related to acute myocarditis (Loeffler's endocarditis) with myocardial restriction pattern and severe diastolic dysfunction in the context of eosinophilic granulomatosis with polyangiitis. Apical thrombus in the left ventricle resolved.
Moderate thrombopenia of autoimmune origin resolved.
Euthyroid patient syndrome. Primary familial hypercholesterolemia (very probable HFHe).
Secondary hypertriglyceridaemia.
