The quintessential form of diastolic heart failure in older adults: Wild type transthyretin cardiac amyloidosis

Abstract

Wild‐type transthyretin cardiac amyloidosis (ATTRwt) is now recognized as a common cause of heart failure with preserved ejection fraction (HFpEF). In this review, we aim to describe the unique epidemiologic, pathophysiologic, and clinical features associated with ATTwt cardiac amyloidosis. Compared to other etiologies of HFpEF, ATTRwt cardiac amyloidosis affects almost exclusively older adults, demonstrating a characteristic age‐dependent penetrance that impacts both the diagnosis and treatment of the disease. In addition, ATTR cardiac amyloidosis demonstrates a unique pathophysiology in contrast to other etiologies of HFpEF, which results in a characteristic phenotype that can raise suspicion for ATTRwt cardiac amyloid in the appropriate demographic. With these distinguishing features in mind, we aim to describe the specific signs, symptoms, and imaging characteristics associated with ATTRwt cardiac amyloidosis, including the role of nuclear scintigraphy that has essentially eliminated the need for biopsy in most patients with suspected disease. Finally, we review the evidence behind the available therapeutic agents, as well as those under investigation, which will change the way we manage older patients with ATTRwt cardiac amyloidosis in the coming years.

A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment

“…Indeed, the increased permeability of the gut mucosa in some predisposed individuals (e.g., older adults) may allow subtilisin, and perhaps other (yet unidentified) bacterial hTTR-cleaving proteases, to pass across the intestinal mucosa into the bloodstream and generate hTTR amyloidogenic fragments, which can deposit as infiltrative fibrils in the heart of SSA patients. The model well accounts for the late and age-dependent onset of SSA in elderly population 12 – 18 and is consistent with recent work showing that patients with hTTR amyloidosis present higher plasma proteolytic activity 68 . The pathogenetic mechanism highlighted in this work also allows to reconsider under a physio-pathological perspective the data of hTTR proteolysis by trypsin, obtained in vitro at high shear stress 9 , 52 .…”

“…Although ATTR is one of the most frequent hereditary protein misfolding diseases worldwide, only about 10,000 cases of genetic ATTR have been estimated in the global population 7,8,16 . At variance, acquired SSA has been recently recognized as a common, albeit underappreciated, cause of cardiomyopathy and heart failure in older adults, with an estimated prevalence as high as 1-3% of elderly people >75 years of age (see also "Introduction" section) [12][13][14][15][16][17][18] . Whereas the pathogenesis of genetic ATTR can be rationalized considering the effects that amino acid mutations have on hTTR tetramer structure and its susceptibility to proteolysis [26][27][28] , the cause of the late onset of SSA in elderly people is much more difficult to decipher and the molecular events leading to the late onset of cardiac hTTR amyloid deposits in older patients remains mysterious, despite normal hTTR circulating in their blood from birth 26 .…”

“…Indeed, hTTR amyloid fibrils were found in 25% of post-mortem hearts from patients >80 years of age 11 . Furthermore, the use of non-invasive imaging techniques recently allowed to reveal the presence of hTTR amyloid deposits in about 15% of older patients with heart failure or aortic stenosis and to estimate a prevalence of hTTR-related cardiomyopathy in 1–3% of elderly people >75 years of age 17 , 18 .…”

“…At variance with ATTR, SSA involves wild type hTTR, more often affects elderly people (usually >75 years), it is generally associated to cardiomyopathic complications, and leads to progressive heart failure 10,11 . Recent data suggest that SSA-related cardiomyopathy has been often overlooked as a common cause of heart failure in older adults [12][13][14][15][16][17][18] . Indeed, hTTR amyloid fibrils were found in 25% of post-mortem hearts from patients >80 years of age 11 .…”