Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs

Abstract

Transthyretin-cardiac amyloidoses (ATTR-CA) are an underdiagnosed but increasingly recognized cause of heart failure. Extracellular deposition of fibrillary proteins into tissues due to a variety of inherited transthyretin mutations in ATTRm or due to advanced age in ATTRwt eventually leads to organ failure. In the heart, amyloid deposition causes diastolic dysfunction, restrictive cardiomyopathy with progressive loss of systolic function, arrhythmias, and heart failure. While traditional treatments have consisted of conventional heart failure management and supportive care for systemic symptoms, numerous disease-modifying therapies have emerged over the past decade. From organ transplantation to transthyretin stabilizers (diflunisal, tafamidis, AG-1), TTR silencers (ALN-ATTR02, ISIS-TTR(Rx)), and degraders of amyloid fibrils (doxycycline/TUDCA), the potential for effective transthyretin amyloid therapy is greater now than ever before. In light of these multiple agents under investigation in human clinical trials, clinicians should be familiar with the systemic cardiac amyloidoses, their differing pathophysiology, natural histories, and unique treatment strategies.

Fig. 1

Distribution of phenotypic variation between neuropathic and cardiomyopathic symptoms according to ATTRm mutation

Fig. 2

Proposed progression of ATTR-cardiac amyloidosis by clinical and biomarker parameters. In the preclinical phase, myocardial infiltration is minimal, while functional status and ejection fraction (EF) are normal. Symptomatic patients begin to experience a decline in functional status as amyloid fibrils infiltrate the myocardium and other organs. Ejection fraction initially remains normal, but diastolic function ensues and cardiac biomarkers begin to rise. As myocardial infiltration plateaus, patients continue to decline, functional status advances to a debilitated state, EF eventually drops steeply and then progresses slowly in a terminal phase leading to death

Fig. 3

Emerging disease-modifying therapeutic opportunities within the TTR amyloidogenesis cascade target suppression/silencing of TTR synthesis, stabilization, and degradation of TTR