A 51-year-old woman was referred to a heart failure clinic for the evaluation of progressive cardiomegaly. She underwent dual-chamber pacemaker (Adapta ADD01 [the last generator change in 2015], Medtronic, MN, USA) implantation because of a high-degree atrioventricular block (AVB) 24 years ago and was followed up by an electrophysiology specialist. She was also treated for Type 2 diabetes mellitus for 23 years and underwent right total thyroidectomy for papillary thyroid cancer. She was taking subcutaneous insulin glargine 8 units once daily, metformin 1000 mg once daily, alogliptin 25 mg once daily, and glimepiride 4 mg once daily for Type 2 diabetes mellitus. Under these medications, her haemoglobin A1c level was 7.1%. She had been using hearing aids for 12 years after being diagnosed with sensorineural hearing loss and had been receiving antibiotic treatment, including azithromycin and ethambutol, for non-tuberculous mycobacterial lung disease for 2 years prior to this medical event. She had no family history of cardiac disease or genetic syndrome. A chest radiography revealed that her heart size increased progressively over the past 2 years (Figure 1).
When visiting a heart failure clinic, she complained of dyspnoea on exertion for 1 month. She also suffered from paraesthesia of her upper and lower extremities. Her blood pressure was 139/75 mmHg, and her pulse rate was 89 b.p.m. On physical examination, no abnormal finding other than a chronic ill-looking appearance was observed. A regular heartbeat without a murmur was observed, and her lung sounds were clear.
A transthoracic echocardiography revealed severe global hypokinesia of the left ventricle (LV) with an enlargement of the cardiac chambers (LV end-diastolic dimension was 56 mm); LV ejection fraction was estimated to be 26%. The myocardium showed a sparkling texture with fine bright particles, and the thickness of the interventricular septum and LV posterior wall increased to 11 mm from an echocardiography measurement of 7 mm in 2012. A small pericardial effusion was also noted. No valvular dysfunction was observed, except for Grade 1 mitral regurgitation. Mitral inflow showed a pseudonormalization pattern with elevated LV filling pressure (E/e' 20.2) (see Supplementary material online, Video). Interrogation from her pacemaker showed a 100% ventricular pacing record with an underlying complete AVB rhythm, which suggested complete dependency on the pacemaker. Her thyroid function was within the normal range in laboratory tests, but her serum sodium level was slightly low (126 mmol/L), whereas N-terminal pro-B-type natriuretic peptide (1961 pg/mL; reference range, 0-249 pg/mL) and troponin-T (39 pg/mL; reference range, 0-14 pg/mL) levels increased. Urinary tests showed heavy proteinuria (spot urine protein-to-creatinine ratio, 7.22 g/gCr; albumin-to-creatinine ratio, 5811 mg/gCr). Urine electrophoresis of 24-h-collected urine showed non-selective proteinuria. A nerve conduction velocity study confirmed the presence of bilateral sensorimotor polyneuropathy.
Several diagnostic examinations were performed for cardiac amyloidosis or other infiltrative diseases. Screening tests for Fabry disease revealed normal alpha-galactosidase activity. Serum and urine immunofixation revealed no abnormal monoclonal band, and the ratio of serum kappa and lambda light chains was also within the normal range (1.0; reference range, 0.26-1.65). 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy showed no definite DPD uptake in the myocardium. Cardiac magnetic resonance imaging could not be carried out because of the old-generation pacemaker leads. Coronary angiography was performed to exclude ischaemic cardiomyopathy, and a concomitant EMB was performed to investigate the possibility of unusual cardiomyopathy or chronic myocarditis. Coronary angiography revealed no significant stenosis in either the right or left coronary artery systems. Myocardial tissue of the right ventricle was obtained and analysed. Haematoxylin-eosin staining showed hypertrophy of myocytes (Figure 2A), and an electron microscopy revealed a disarrangement of mitochondrial cristae (Figure 2B), which were compatible with mitochondrial cardiomyopathy; Congo red staining was negative. Genetic testing was performed to identify genes related to cardiomyopathy. Although common mutations known to cause dilated cardiomyopathy, such as those in TTN, LMNA, MYH7, and TNNT2, were not found in next-generation sequencing, the m.3243A > G heterozygote mutation of the MT-TL1 gene was confirmed by Sanger sequencing (see Supplementary material online, Figure S1). However, no mutation of the MT-TL1 gene was identified in her mother. Of note, the patient never suffered from stroke-like episodes, serum lactic acid levels were found to be within the normal range (1.5 mmol/L; reference range, 0.5-2.2 mmol/L), and she never complained about headaches or recurrent vomiting episodes during the recent follow-ups.
The patient was prescribed guideline-directed medical treatment for heart failure, including sacubitril-valsartan (49/51 mg twice a day), carvedilol (12.5 mg twice a day), spironolactone (12.5 mg once daily), and dapagliflozin (10 mg once daily). Although upgrade to cardiac resynchronization therapy could be considered, given the high dependency on pacemaker, it was not proceeded because the patient was tolerable without exacerbation of any heart failure symptoms. In addition, 1 year after being on the guideline-directed medical treatment, a transthoracic echocardiography showed improved LV ejection fraction from 26 to 46%, but the LV wall remained thick.