HISTORY, CURRENT ILLNESS AND PHYSICAL EXAMINATION

History
Hereditary family diseases:
Father died at 78 years of age suddenly with unspecified heart disease.
There were 7 siblings, 5 of them died approximately in the neonatal period. Surviving is an older brother aged 70 with unspecified heart disease, not a carrier of Val26Ala in the emerin gene mutation (EMD).
She has 3 children, the first of whom died suddenly at the age of 38, diagnosed with DCM. The second is a 39 year old male who is not a carrier and has no heart disease. Finally, a 27 year old male, a carrier and apparently without heart disease.

Previous illnesses:
No known drug allergies. Toxic habits: non-smoker and non-drinker. No cardiovascular risk factors. Fibromyalgia.
Chronic venous insufficiency in lower limbs. Cardiological history:
Dilated cardiomyopathy diagnosed in 2007. Val26Ala mutation in DME in heterozygosis.
Last transthoracic echocardiogram (TTE): severe LVSD (LVEF 27%), right ventricle (RV) with mildly depressed systolic function, severe functional MR, severe functional tricuspid regurgitation (TR). Pattern of
Pulmonary hypertension (PH) at least moderate. Advanced heart failure with poor prognostic data: restrictive filling.
Ergospirometry with O2 consumption of 10.8 ml/kg/min (56% of predicted theoretical), class C-D.
Refractory congestion with need for high dose diuretics.
Cardiorenal syndrome type 2 with frequent episodes of renal function deterioration with intolerance to neurohormonal drugs.
Persistently elevated biomarkers despite optimal medical treatment. NT- proBNP 7739 pg/ml.
Left bundle branch block (LBBB) with implantation of Boston ICD-resynchroniser in 2013 in primary prevention. Events related to ventricular arrhythmias: one episode of ventricular tachycardia (VT) requiring therapies.
Paroxysmal AF.
Medication: bisoprolol 1.25 mg one tablet every 12 hours; furosemide 40 mg one tablet every 24 hours; torasemide 10 mg one tablet every 8 hours; levosulpiride 25 mg every 8 hours; lormetazepam 1 mg at dinner; omeprazole 20 mg at breakfast; sintrom 4 mg as prescribed.

Present illness
60-year-old woman with the previously described history, who in the last year required admission on three occasions due to HF and low cardiac output, requiring levosimendan perfusion and intensive diuretic treatment with good response. After three attempts at titration, sacubitril/valsartan was discontinued due to progressive deterioration of renal function up to Cr 3.18 mg/dl and GFR 20 ml/min.
In view of the poor prognosis data, a pre-transplant study was started at his reference centre and he was transferred to our centre to assess treatment options. On admission to our centre she was clinically and haemodynamically stable with no evidence of low cardiac output. Currently in NYHA functional class (FC) III. He climbed two flights of stairs without dyspnoea, no orthopnoea, bendopnoea, DPN. No oedema in the lower limbs, no increase in abdominal perimeter, no weight gain (weight 68 kg) and no decrease in diuresis rate since discharge from the last admission a month ago.

Physical examination
Systolic blood pressure (SBP) 85 mmHg, diastolic blood pressure (DBP) 48 mmHg, mean arterial blood pressure (MAP) 57 mmHg, heart rate (HR) 61 bpm, SpO2: 96%. Temperature 35.4 o C. Weight 68 kg.
Conscious, alert and oriented. Good general condition. Well perfused.
PVC: Normal.
Cardiac auscultation: rhythmic, systolic murmur II-III/VI in tricuspid and mitral focus, 3R. Pulmonary auscultation: preserved vesicular murmur (VCM) without added noise. Abdomen: RHA+, soft, depressible, not painful on palpation, no masses or megaliths. No signs of peritonism.
Lower limbs: no oedema or signs of deep vein thrombosis (DVT). Pedial pulses present and symmetrical.

COMPLEMENTARY TESTS
Laboratory tests:
CBC: red cells 4.01 xmill/μl, haemoglobin 11.5 g/dl, haematocrit 34.2%, MCV 85.3 fl, MCH 28.7 pg, MCHC 33.6 g/dl, RDW 17.0 %, platelets 141 x1000/μl, MPV 10.2 fl, leukocytes 6.3 x1000/μl, neutrophils 3.9 x1000/μl, neutrophils % 62.1%, lymphocytes 1.6 x1000/μl, lymphocytes % 25.2%, monocytes 0.4 x1000/μl, monocytes % 6.3%, eosinophils 0.4 x1000/μl, eosinophils % 5.7%, basophils 0.0 x1000/μl, basophils % 0.7%.
Coagulation: prothrombin activity 20%, prothrombin time 38.0 sec, INR (lab) 3.34, TTP 41 sec, fibrinogen (derivative) 370 mg/dl.
Biochemistry 14/08/2019: creatinine 1.77 mg/dl, glomerular filtration rate (ckd-epi) 31 ml/min/1.73m , sodium 144 mEq/l, potassium 3.68 mEq/l, chlorine 103 mEq/l, calcium 9.1 mg/dl, ALT (GPT) 16 U/l, AST (GOT) 17 U/l, gamma-GT 55 U/l, alkaline phosphatase 58 U/l, bilirubin 1.1 mg/dl, CK 31 U/l, C-reactive protein 0.16 mg/dl. NT-proBNP 7051 pg/ml. Iron profile: ferritin 103 ng/ml, iron 49 μg/dl, transferrin 249 mg/dl, % transferrin saturation 14.0%, TIBC 351 μg/dl. Glycaemic profile: glycated Hb (DCCT) 5.7%, glycated Hb (IFCC) 38.8 (mmol/mol). Lipid profile: cholesterol 139 mg/dl, triglycerides 74 mg/dl, HDL 43 mg/dl, LDL (Friedewald estimation) 81 mg/dl, LDL/HDL ratio 1,90, cholesterol/HDL ratio 3,25.
Chest X-ray: increased cardiothoracic index (CTI), vascular redistribution. ICD-CRT generator in the left pectoral region with electrocatheters normally positioned in the RA, RV and coronary sinus.
Electrocardiogram (ECG): sinus rhythm with ventricular stimulation at 70 bpm. Isolated monomorphic ventricular extrasystoles. Paced QRS of 160 ms.
Echocardiogram 20/8/2019: left ventricle (LV) dilated, remodelled, with severe systolic dysfunction (LVEF 24%). Elevated filling pressures. Reduced stroke volume. Right ventricle (RV) slightly dilated with mild systolic dysfunction. Severe functional mitral regurgitation (MR). Moderate tricuspid insufficiency (TI) (III/IV), in relation to annular dilatation and with electrode. Moderately elevated pulmonary pressures. Mild aortic insufficiency.
Left catheterisation: right dominance. Coronary tree without significant lesions.
Right catheterisation: moderate postcapillary pulmonary hypertension (56/27/37 mmHg). Pressure in RA slightly elevated (8 mmHg). Elevated PCP (27 mmHg). Cardiac output decreased. PVR at high limit.

CLINICAL EVOLUTION
He was admitted to our centre on 13/08/2019 in a situation of haemodynamic stability with no data of low CO or decompensated HF. In CF III of the NYHA, INTERMACS 6. Renal function stable with creatinine around 1.7 mg/dl with good diuresis rate under his usual oral diuretic treatment.
The iron profile showed ferritin 103 ng/ml with transferrin saturation 14.0% and haemoglobin 11.5 mg/dl, so 1000 mg of iron carboxymaltose were administered.
A right heart catheterisation was performed in euvolemic conditions, showing slightly elevated filling pressures with moderate post-capillary pulmonary hypertension with decreased CO (thermodilution: CO 3.41 l/min- CI 1.82 l/min/m. Fick: CO 4.1 l/min-IC 219 l/min/m2) with PVR at the high limit with PWG of 10 mmHg.
The patient has been evaluated by the familial heart disease unit as a carrier of the Val26Ala mutation in the emerin gene in heterozygosis (detected in a Sanger). However, the age at presentation and sex raise doubts about a possible secondhit. Moreover, the family history is also inconsistent with the finding of only one emerin, so a complete genetic panel is requested.
The genetic study by NGS panel only reports the previously described mutation, with no evidence of a secondhit. In this context, it is possible that the picture corresponds to random X inactivation with involvement (possible but unlikely) in a heterozygous female. For the moment, without other positive results, it is considered that this mutation is responsible for the family history
After completing the pre-transplant study, confirming the presence of data on advanced heart failure, and given the absence of significant comorbidity (only stable CKD with mild proteinuria in probable relation to type 2 cardiorenal syndrome) on 23/08/2019 she was presented at the multidisciplinary session and included on the elective waiting list for heart transplant.
One month later, the patient was readmitted with decompensation after catarrhal symptoms (sputum culture and rhinovirus negative) with increased dyspnoea of 3 days' evolution until becoming resting and marked orthopnoea without peripheral congestion.
During the first weeks of admission, he presented clinical worsening with fine B lines of significant size in the lung ultrasound and data of low postprandial output. For all these reasons, and after optimising diuretic treatment, it was decided to start dobutamine at low doses (2.5 mg) with evident clinical improvement, which was maintained for a week. Subsequently, she received a new course of levosimendan.
Given the patient's evolution and the presence of severe MI, she was assessed for MitraClip implantation, which was performed without incident on 16/10/2019, leaving mild to moderate MI.
After this, intravenous diuretics were withdrawn and the patient was discharged euvolaemic, without orthopnoea, in CF-II and having observed a decrease in NT-proBNP. ARA-II was reintroduced at low doses with good clinical and analytical tolerance. At discharge, treatment was as follows: candesartan 4 mg (half a tablet) at dinner, hydralazine 25 mg every 8 hours, furosemide 40 mg one tablet at breakfast and another at lunch with a flexible regimen, spironolactone 100 mg every 24 hours at lunch, levosulpiride 25 mg every 8 hours, lormetazepam 1 mg one tablet at dinner, omeprazole 20 mg one capsule at breakfast, Mastical D 1.500/1,000U one tablet every 24 hours and sintrom 4 mg (according to INR control).

DIAGNOSIS
Main diagnosis:
Advanced chronic heart failure CF III NYHA - INTERMACS 6 due to familial dilated cardiomyopathy (Val26Ala mutation in the EMD gene in heterozygosis) with severe LVSD (LVEF 24%) and included in elective waiting list for heart transplantation.

Other diagnoses:
Severe functional mitral insufficiency and moderate functional tricuspid insufficiency. MitraClip holder.
Moderate postcapillary pulmonary hypertension.
Carrier of ICD-CRT Boston in primary prevention. NSMVT on Holter.
Paroxysmal atrial fibrillation.
Chronic renal failure (G3A2) due to cardiorenal syndrome type 2.
