Improvement of Cardiac Structure And Function In Hereditary Transthyretin Amyloidosis Cardiomyopathy With Inotersen: A Case Report

Introduction Hereditary transthyretin amyloidosis (hATTR) is a progressive, fatal disease caused by systemic deposition of misfolded transthyretin (TTR) fibrils resulting in cardiomyopathy (CM) and polyneuropathy (PN). Treatment options include stabilizers (tafamidis) to prevent TTR tetramer dissociation, silencers (inotersen, patisiran) that inhibit hepatic TTR synthesis, or liver transplantation. Silencers have favorable outcomes in PN, with limited data on CM. This case highlights improvement in hATTR-CM in a patient treated with inotersen. Patient Case A 68 year old female with a family history of hATTR presented for evaluation as a heterozygous carrier of the p.T80A (T60A) TTR mutation. She experienced refractory nausea, vomiting, diarrhea alternating with constipation, weight loss (10 kg) over the preceding 6 months, and 2 months of new onset exertional dyspnea and was in NYHA Class 2 heart failure. ECHO showed severe concentric hypertrophy (septal and posterior walls, 2.1 cm and 1.9 cm), moderate reduction in left ventricular systolic function with a left ventricular ejection fraction (LVEF) of 32%, and moderate pericardial effusion. BNP and troponin I levels were 532 pg/mL and 0.05 ng/mL. Diffuse 4-chamber delayed gadolinium enhancement was noted on cardiac MRI (A). Nerve conduction studies confirmed sensorimotor neuropathy with an estimated neuropathy impairment score of 10. Furosemide and spironolactone resulted in a 6.4 kg diuresis with improved dyspnea. Right heart catheterization showed right atrial pressure of 6 mm Hg, pulmonary artery pressure of 39/16 mm Hg, and pulmonary capillary wedge pressure of 10 mm, with a cardiac index of 2. Episodic orthostatic hypotension precluded initiation of beta blockers and vasodilators. She was initiated on inotersen for symptoms of neuropathy. After 6 months, LVEF increased to 45% and diastolic function improved from stage 2 to 1. The pericardial effusion resolved. Six minute walk distance showed an increasing trend over 10 months (B). BNP levels were 108 pg/mL after 1 year on inotersen, and modified BMI stabilized. Conclusion Inotersen was associated with improvements in cardiac function in this patient with hATTR-CM who could not be treated with guideline-directed heart failure therapy. For hATTR-CM with no convincing benefit from conventional therapy beyond symptom control, inotersen may offer a treatment option to alter the natural history of this fatal disease.