HISTORY, CURRENT ILLNESS AND PHYSICAL EXAMINATION

History
Family history: mother with presbycusis at the age of 68.

Personal history:
Ex-smoker of half a pack of cigarettes a day for 12 years (ICAT 6 packs/year).
Bilateral profound sensorineural deafness with cochlear implantation at 47 years of age, with a baseline electrocardiogram (ECG) compatible with ventricular pre-excitation. Clinically, she presented with self-limited palpitations and was advised to undergo an electrophysiological study and accessory pathway ablation, which the patient refused.
She had no previous cardiological history, nor any other medical or surgical history of interest.

Present illness
A 57-year-old woman presented with dyspnoea in functional class IV, intolerance to decubitus, oliguria and ulcerated oedema in the lower limbs for 3 weeks with a torpid evolution.

Physical examination
Afebrile. Blood pressure (BP) 91/52 mmHg, heart rate (HR) 135 bpm, SatO2 93% room air.
Regular general condition, cooperative and conscious. Not hydrated, delayed capillary refill with acral coldness. Tachypneic with supraclavicular pull. Orthopnoea of 45o. With jugular venous engorgement.
Cardiac and pulmonary auscultation: rapid and rhythmic heart tones, without murmurs or extratones. Vesicular murmur preserved with bibasal crackles.
Abdomen: soft and depressible, not painful on palpation. No signs of peritonism. No masses or megaliths palpable. Hydro-aerial noises present.
Lower limbs (lower limbs): oedema up to the root of the lower limbs with distal ulcers in the second, third, fourth and fifth phalanx of the lower limbs. No signs of deep vein thrombosis (DVT).
Pedal pulses not palpable due to oedema.

COMPLEMENTARY TESTS
Prior to admission to the intensive care unit (ICU)
CBC: haemoglobin 18 g/dl, leukocytes 15,490 cells/mm3 (85% N and 7.5% L), platelets 25,2000, glycaemia 174 mg/dl, creatinine 1.75 mg/dl, urea 176 mg/dl, sodium 130 mEq/l, K 4.70 mEq/l, CPK 1936, LDH 1158 pg/ml, CRP 133 pg/ml. Procalcitonin 7 ng/ml. HsTnI 3,909 pg/ml and BNP 4,915 pg/ml.
Venous blood gases: pH 7.24, CO2 36, HCO3 13.4, lactate 5.9 mmol/l.
Chest X-ray: global cardiomegaly at the expense of the left chambers, double contour sign and slight evidence of pulmonary venous congestion.
During his admission to the ICU
Initial echocardiography: left ventricle with normal internal diameters.
Normal wall thickness, increased echogenicity. Severe global hypokinesia. Severely depressed EF (25% by visual estimation). Large mass in the apical region of the left ventricle, with low mobility, smooth surface, moderate echogenicity, independent of the underlying myocardium without parietal thinning in this region, about 30x 18 mm in diameter. Suggestive of large apical thrombus. Left atrium in normal limits. Right ventricle of normal internal diameters and wall thickness. Reduced longitudinal shortening.
Visual EF moderately depressed. Right atrium in normal limits. Mitral valve with slight thickening of leaflets, good opening. Secondary mild-moderate central insufficiency. Aortic valve without alterations. Right valves without significant structural alterations. Slight tricuspid insufficiency. Thoracic aorta without pathological findings. Inferior vena cava not dilated with normal inspiratory collapse. No pericardial effusion. Estimated normal PSAP. Conclusions: non-dilated left ventricle, with severe global hypokinesia and severely depressed EF. Apical thrombus.
Serology: positive serology for hepatic virus C, as well as IgG and IgM against cytomegalovirus and IgG against Epstein Barr virus. All other tests were negative (enterovirus PCR, HIV, HBV, HSV, Parvovirus B19, Brucella, Rickettsia, Mycoplasma, Chlamydia pneumoniae, Borrelia burgdorferi).
Coronary angiography: non-significant stenosis of distal anterior descending artery (30% without other significant angiographic stenosis.

On the ward
Complete blood count: glycaemia 146 mg/dl, HbA1c 7.5%, creatinine 0.82 mg/dl, K 4.4 meq/l, Na 139 meq/l, Cl 105 meq/l, Ca 9.9, phosphorus 4, magnesium 2.2. LDH 555 U/l. Iron 107 ug/dl, ferritin 747 ng/ml, IST 28.2%. Total cholesterol 157 mg/dl, HDL 51, LDL 86. TG 103 mg/dl. TSH 3.33 IU/ml. BNP 1479 (decreasing). CRP 2.9 mg/l. Troponins 2354 pg/ml.
Normal proteinogram: albumin 3.6, percentage albumin 53.8%, alpha-1 globulins 0.3, percentage 5.2%, alpha-2 0.7, percentage 10.8%, beta globulins 0.7 (percentage 11.2%), gamma globulins 1.3 (percentage 19%). Light chains: free kappa chains 64.15, free lambda chains 31.5.

24-hour urine protein: light chains normal. Kappa chains < 1.85 mg/dl, lambda chains < 5 mg/dl.
CBC: haemoglobin 13.7 g/dl, haematocrit 42.8%, mean corpuscular volume 90fKl, leucocytes 9150/microL, neutrophils 54.8%, platelets 279000/microL.
GSV: pH 7.3242. pCO2 39.5, bicarbonate 30.1mmHg, lactic acid 3.7.
Echocardiography after ICU discharge: left ventricle with slightly reduced internal diameters. Slightly increased wall thickness diffusely in relation to the diameter of the cavity and increased echogenicity. Mild global hypokinesia.
Moderately depressed ejection fraction (41%) by Simpson biplane. Restrictive mitral filling pattern. E/e ratio ́ 16. Muscular trabeculae at the apical level without intraventricular thrombus. Slightly dilated left atrium. Right ventricle of normal diameter and walls with decreased longitudinal shortening and depressed ejection fraction (TAPSE 10). Slightly dilated right atrium. Thin leaflet aortic valve with mild central regurgitation. Mitral valve with diffuse mild leaflet thickening, moderate central insufficiency, with an ERO of 0.2, 5 mm vena contracta, regurgitant volume of 22 ml and PISA radius of 0.6. Tricuspid valve with fine leaflets, good opening and moderate central insufficiency. Aortic root and ascending aorta without pathological findings.
Dilated inferior vena cava with reduced inspiratory collapse. No pericardial effusion. Estimated PSAP of 44 mmHg. Free fluid in the abdominal cavity. Conclusions: left ventricle with slightly thickened walls in relation to the diameter of the cavity, with increased echogenicity. Global hypokinesia with moderately depressed ejection fraction. Signs of advanced diastolic dysfunction. Right ventricle of normal wall and diameter with depressed ejection fraction. Moderate central mitral regurgitation. Mild pulmonary hypertension.

Thrombophilia and autoimmunity study: negative lupus anticoagulant, normal protein C and S, no resistance to activated protein C, normal coagulation factors V, VII and von Willebrand and antithrombin. No mutations in prothrombin genes, factor V Leiden gene, MTHFR gene, factor XII gene. Normal anti-cardiolipin and anti-beta-2 glycoprotein antibodies.
Rectal biopsy: rectal mucosa without relevant morphological changes. No abnormal deposits are observed after staining with Congo red and the rectal mucosa without relevant morphological changes.
Subcutaneous fat biopsy: Congo red techniques were performed on serial sections and immunohistochemistry for amyloid A, immunoglobulin heavy and light chains with negative results.

During outpatient follow-up
Echocardiography last check-up, prior to readmission: left ventricle with slightly thickened walls in relation to the diameter of the cavity, absolute diameters within the normal range, with increased echogenicity. Global hypokinesia with severely depressed ejection fraction (27%). Signs of advanced diastolic dysfunction. Mass in the apex compatible with thrombus. Right ventricle of normal wall and diameter with depressed ejection fraction. Moderate secondary mitral insufficiency. Severe tricuspid insufficiency.
PET-CT scan: no cervical, supraclavicular or mediastinal hypercapillary lymphadenopathy with lambdoid pattern suggestive of lymph node sarcoidosis. There are no pulmonary lesions suspicious of pulmonary sarcoidosis. No pleural or pericardial effusion or hyperenhancement suspicious for active pleuritis or pericarditis. Diffuse myocardial hyperenhancement of mild intensity (SUVmax=2.3) and very homogeneous, suggesting a non-specific dilated cardiomyopathy that could be of viral origin (CMV) among other possibilities. Conclusions: there are no PET findings suggestive of pulmonary, lymph node or cardiac sarcoidosis. Nonspecific diffuse cardiomyopathy that could be of viral origin (CMV IgM+).
DPD scan: no pathological uptake in the cardiac projection area. No foci of pathological bone uptake were seen in the rest of the bone scan. Conclusion: negative study for detection of cardiomyopathy due to TTR amyloid deposition.
Laboratory tests: glucose 133 mg/dl, urea 51 mg/dl, creatinine 1.32 mg/dl, total protein 6.6 g/dl, total bilirubin 1.35 mg/dl, direct bilirubin 0.65 mg/dl, aspartate transaminase (GOT) 37 U/, alanine transaminase (GPT) 39 U/l, gamma glutamyl transferase (GGT) 67 U/l, alkaline phosphatase (ALP) 103 U/l, alpha amylase 34 U/l, CPK 253 U/l, lactate dehydrogenase (LDH) 402 U/l, sodium 139 mEq/l, potassium 4.90 mEq/l, chlorine 108 mEq/l. C-reactive protein 10.4 mg/l.
Brain natriuretic peptide (BNP): 1579 pg/ml (previos 370--150--429).
Troponin I (high sensitivity): 2044.3 pg/ml (previous 2384--650--1500-1196).
Genetic study of mitochondrial disease: detection of the most frequent mutations associated with mitochondrial encephalopathy type MELAS. The presence of the m.3243A>Gen mutation in the MT-TL1 gene has been detected. This variant has been found in heteroplasmy with 13% of the mutated G allele.
Endomyocardial biopsy: numerous cox-negative fibres (> 50%). Although an increase in COX-negative cardiomyocytes attributed to age is reported, such a high percentage could be compatible with a disease of mitochondrial origin.

CLINICAL EVOLUTION
In the ED, with clinical suspicion of subacute onset heart failure of uncertain aetiology but with severe current situation with hypotension and peripheral hypoperfusion in addition to infectious analytical parameters and marked increase in markers of myocardial damage, infusion of volume expanders and initiation of oxygen therapy with Ventimask FiO2 31% and i.v. antibiotic therapy were decided.
In the absence of response to initial emergency measures, the patient was admitted to the ICU in cardiogenic shock requiring support with vasoactive drugs (dobutamine and noradrenaline).
On admission, an urgent echocardiogram was performed showing severe biventricular systolic dysfunction (LVEF 15%) with severe secondary mitral regurgitation and an apical ventricular thrombus, for which anticoagulation with enoxaparin was initiated and levosimendan perfusion was started. An emergency coronary angiography ruled out coronary artery disease and the patient was labelled cardiogenic shock in the context of probable acute myocarditis. During the first hours of ICU stay, the patient was sleepy but reactive and conscious, maintaining AMT 75 mmHg with a heart rate of around 80 bpm, but requiring vasoactive support. Some improvement in renal function with polyuria as well as from the respiratory point of view, requiring support only with nasal cannulas.
Acceptable distal perfusion with good gasometric controls but with persistently high lactic acid.
During the following 7-10 days the patient remained stationary, dependent on vasoactive drugs (VAD), with persistently elevated troponins and BNP levels (although slightly decreasing) and no improvement in cardiac ventricular function. During her admission to the ICU she was also assessed by angiology, who considered it necessary to perform a metatarsophalangeal amputation of the second-fourth MII phalanges in a few weeks, due to necrosis of the same, probably secondary to low cardiac output, high doses of VAD and ventricular thrombus embolism.
Given the suspicion of myocarditis with a possible infectious aetiology due to the data of severe global dysfunction and elevated cardiac markers and acute phase reactants, serological tests were requested, with positive liver virus C, as well as IgG and IgM against cytomegalovirus and IgG against Epstein-Barr virus, and the rest of the tests were negative. Blood cultures were requested and were negative. CardioMRI with LGE was requested, but as the patient had a cochlear implant it was not possible to perform it.
After a month of admission to the coronary unit, with slow but progressive improvement, remaining haemodynamically stable after withdrawal of vasoactive drugs, she was finally transferred to the hospital ward. A new echocardiogram was performed which showed an improvement in biventricular function (LVEF 41%), with no intraventricular thrombus visible. At the myocardial level, slight concentric hypertrophy of the left ventricle was observed, which appeared hyperechogenic and with a reduced ventricular cavity size and data of advanced diastolic dysfunction with increased filling pressures and left atrial size, with no other valvular alterations other than the aforementioned mitral insufficiency. The data were suggestive of deposit or infiltrative disease, with an inflammatory/viral origin being less likely.
Given these findings, an extensive aetiological study was continued, ruling out autoimmune diseases (negative autoantibody battery) and prothrombotic diseases (special coagulation study with heterozygosity for mutation in the gene for factor XII, methyltetrahydrofolate reductase and factor V Leiden).
For the study of possible infiltrative disease, cardiac amyloidosis, both AA, AL and by transthyretin (TTR), was the first study target. Urine proteinogram and urine light chains were negative, and a rectal and subcutaneous fat biopsy with Congo red staining were negative. To rule out familial or senile transthyretin amyloidosis, a technetium-99 diphosphonate scan was performed, which did not identify abnormal TTR deposits. For the study of possible cardiac sarcoidosis, a whole-body PET-CT scan with 18 fluorodeoxyglucose was performed, which showed a diffuse, homogeneous circumferential uptake in the entire left ventricular myocardium, suggestive of deposit disease rather than inflammatory, but not compatible with the typical cardiac involvement of sarcoidosis, which is usually patchy. A blood test ruled out the presence of haemochromatosis (normal ferritin, transferrin and transferrin saturation index), as well as Wilson's disease and Fabry's disease.
The patient was discharged in good functional class, after more than 2 months of hospitalisation, with a diagnosis of cardiomyopathy of unaffiliated origin, and reviewed in consultation every three months.
Initially she presented clinical and analytical improvement; however, from the eighth month after discharge, there was a progressive worsening with an increase in BNP and troponin, as well as a decrease in LVEF and the need for a new admission due to recurrence of the intraventricular thrombus.
For this reason, treatment was started with apixaban 5 mg every 12 hours and diuretic and heart failure treatment was optimised.
After discharge from hospital, the patient was referred to the outpatient clinic for family heart disease in order to clarify whether she might have a cardiomyopathy of this type. On closer examination, the patient's short stature (126 cm), the presence of sensorineural hearing loss and Wolff-Parkinson-White syndrome (WPW) were noted, leading to the suspicion of mitochondrial MELAS disease. A genetic study was then requested to confirm this and indeed it showed an m.3243A>G mutation in the MT-TL1 gene, with heteroplasmy of 13% in peripheral blood, this being the variant most frequently associated with mitochondrial diseases, and in particular with MELAS syndrome (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes).
In order to demonstrate a greater degree of heteroplasmy at the myocardial level and the possible association of myocarditis as a possible trigger for such a marked worsening of cardiac function, an endomyocardial biopsy was performed, which confirmed this suspicion. The patient has also been referred for neurological assessment and a matrilineal family study has been initiated.

DIAGNOSIS
Possible acute myocarditis on underlying heart disease presenting as cardiogenic shock with favourable evolution.
MELAS mitochondrial disease with m.3243A>G mutation in MT-TL1 gene.
Hypertrophic cardiomyopathy secondary to MELAS.
WPW syndrome (left latera tract).
Recurrent intraventricular thrombus with peripheral embolism (necrosis and amputation of lower phalanges).
