HISTORY, CURRENT ILLNESS AND PHYSICAL EXAMINATION

BACKGROUND
Male patient aged 77 years.
No known allergic reactions to medication.
Cardiovascular risk factors: hypertension, dyslipidaemia.
Chronic obstructive pulmonary disease (COPD) secondary to bilateral calcific pachypleuritis (flour factory worker), with no need for home oxygen therapy.
Mild cor pulmonale.
Ischaemic stroke in the territory of the left middle cerebral artery in November 2016.
Stage 3A chronic kidney disease.
Spinal canal stenosis, right hip prosthesis.

Usual treatment
Rabeprazole 20 mg (every 24 hours), bisoprolol 2.5 mg (every 24 hours), diosmin 500 mg (every 12 hours), acetylsalicylic acid 300 mg (every 24 hours), atorvastatin 40 mg (every 24 hours), enalapril 5 mg (every 24 hours), glycopyrronium bromide 44 mcg (1 inhalation every 24 hours), vilanterol/fluticasone 22/92 mcg (1 inhalation every 24 hours).

CURRENT ILLNESS
The patient presented to the emergency department with an increase in dry cough with no change in the usual sputum for the past week. He also presented with a progressive increase in his baseline dyspnoea to the point of minimal effort. Since two days before, he presented fever up to 38.4 oC, without chills.


PHYSICAL EXAMINATION
Temperature 36 ̊C. Blood pressure (BP) 159/83 mmHg. Heart rate (HR) 70 bpm; SatO2 91% with nasal goggles at 1.5 l and after bronchodilators. Cardiac auscultation rhythmic, without murmurs.
Pulmonary auscultation with crackles in both bases and some isolated wheezing. Abdominal examination showed no palpable organomegaly, hepatojugular reflux was negative and there was no semiology of ascites. The lower limbs were oedematous up to the middle third of the lower extremities, with fovea.

COMPLEMENTARY TESTS
Chest X-ray (posteroanterior and lateral projections): increased cardiothoracic index. Right costophrenic sinus impingement. Pleural and probably pericardial plaques. Increased bronchoalveolar tract.
CBC: leucocytes 8900 u/ml, haemoglobin 13.3 g/dl, platelets 145.000 u/l, ESR 28 mm; no coagulation alterations, basal glucose 73 mg/dl, urea 83 mg/dl, creatinine 1.3 mg/dl, estimated glomerular filtration rate (MDRD-4) 53 ml/min/1.73m2, total bilirubin 0.6 mg/dl, GOT 18 UI/l, CPK 47 UI/l, Na 144 mmol/l, potassium 4.7 mmol/l, corrected calcium 9.1 mg/dl, basal TSH 1.34 mcU/ml, total cholesterol 184 mg/dl, HDL-C 50 mg/dl, LDL-c 109 mg/dl, triglycerides 126 mg/dl, immunoglobulins in normal range.
Proteinogram: total protein 6.60 g/dl, albumin 3.19 g/dl (48.3%); B-globulins 10.2%, gamma-globulins 21.8%; serum B2-microglobulin 5.19 ug/ml, (ref. value 0.8-3.1 ug/ml). Serum light chains: Kappa 18.5 mg/dl (ref. value 3.3-19.4 mg/dl), Lambda 17.9 mg/dl (ref. value 5.7-26.3). Urine light chains: negative, amyloid A > 8.0 mg/l (ref. value < 5), NT-Pro-BNP 11,562 pg/ml (ref. value < 125 pg/ml).
Electrocardiogram (ECG) during admission: sinus rhythm at 65 bpm, first degree atrioventricular block (PR 245 ms), intraventricular conduction disturbance (QRS 105 ms). Posteroinferior hemiblock. Image of pseudoinfarction in the anterior face. QTc 461 ms.
Transthoracic echocardiography: end-diastolic volume 132 ml, end-systolic volume 86 ml. Left ventricular ejection fraction (LVEF) 35% by Simpson biplane.
Left ventricle not dilated, severely hypertrophied, with moderately depressed global systolic function. Generalised hypokinesia, without segmental alterations.
Septal hyperrefringence. Restrictive filling pattern. Mild mitral insufficiency of central origin, without notable alterations in the aortic valve. Dilated left atrium (48 mm in M mode). End-diastolic velocity of pulmonary insufficiency 17 mmHg, allowing calculation of a diastolic pulmonary artery pressure (PAP) of 27 mmHg. Slightly dilated right ventricle without hypertrophy with preserved systolic function. Right atrium not dilated. No tricuspid insufficiency. Pericardium with posterior effusion of 5 mm. Inferior vena cava 21 mm, with respiratory collapse greater than 50%.
Cardiac magnetic resonance imaging (MRI): right atrium 63 x 54 mm.
Right ventricle (RV) 94 x 51 x 69 mm. Left atrium 69 x 56 mm. Left Ventricle (LV) 48 x 49 x 93 mm. Interatrial Septum 8 mm. Minimal circumferential pericardial fluid tab. LVEF 35%. Beat volume 33.4 ml/m2, cardiac output 5.1 l/min; end-diastolic volume (EDV) 96.6 ml/m2, end-systolic volume (ESV) 63.2 ml/m2. LV wall mass 155.6 g/m2. RV ejection fraction 27%; LV stroke volume 57.2 ml/m2; cardiac output 4.3 l/min; end-diastolic volume 106.1 ml/m2, end-systolic volume 77.5 ml/m2. LV with moderate-severe concentric hypertrophy, predominantly septal hypertrophy, with wall thickness in IVS up to 23 mm, anterolateral segment 18 mm and inferior segment 15 mm at baseline. Global generalised hypocontractility, more accentuated at the basal level of the RV with hypertrophy up to 6-7 mm thick. After intravenous contrast administration, diffuse global subendocardial pathological enhancement is observed, as well as transmural enhancement in septobasal.
T1 values: mid-level levels of 1194 ± 103 ms in the lateral aspect showing some focal areas within the lateral aspect levels of up to 1224 ± 85 ms, ECV 48.1% in the lateral aspect and up to 54.7% in focal areas of the lateral aspect.
Pyrophosphate scintigraphy: increased uptake of the radiotracer at cardiac level, more intense than in bone structures, compatible with transthyretin amyloidosis (Perugini grade 3).
Genetic test: negative result for genetic variants related to cardiac amyloidosis.

CLINICAL EVOLUTION
The patient was admitted to the pulmonology department with suspected acute COPD.
During his admission he did not present complete symptomatic resolution and a chest computed tomography (CT) scan was requested to assess the progression of his disease. This test showed the presence of pericardial effusion and signs of heart failure, so transthoracic echocardiography was performed. After finding an echocardiographic pattern suggestive of cardiac amyloidosis, the patient was transferred to the cardiology department.
Cardio-MRI was requested, which again showed a pattern compatible with cardiac amyloidosis. In addition, a fat biopsy was requested (the patient refused a rectal biopsy), which was negative, a 48-hour Holter recording with no alterations, a proteinogram and detection of light chains in serum and urine, which was negative, and a scintigraphy with technetium-99-diphosphonate (Tc99-DPN) with intense uptake. With these results (see section on complementary tests) the patient was diagnosed with cardiac amyloidosis due to transthyretin. A genetic study was performed which did not detect any pathogenic variants and the diagnosis was therefore made as senile or wild-type.
The patient was discharged with furosemide 80 mg every 24 hours and bisoprolol 2.5 mg every 12 hours, in addition to his usual treatment. Spironolactone and renin-angiotensin axis antagonists could not be added due to impaired renal function and hyperkalaemia.
At the outpatient level, the patient was in New York Heart Association (NYHA) functional class III. Treatment of systolic dysfunction was optimised by adding low doses of sacubitril/valsartan, as the patient reported no evidence of orthostatic hypotension or other manifestations of dysautonomia. On subsequent examinations, renal function remained stable, as well as blood pressure and potassium levels, so he was maintained on sacubitrile/valsartan 24/26 m /12 hours. He did not present orthostatic hypotension and finally low doses of eplerenone every 48 hours could be added to the treatment. The patient reported relative clinical improvement, as well as a decrease in NT-proBNP levels from 11,562 pg/ml to 6,244 pg/ml. The same treatment was continued and to date the patient has not been admitted to hospital.

DIAGNOSIS
Heart failure with depressed LVEF.
Cardiac amyloidosis due to transthyretin, senile form.
