Pathophysiology
There are data to suggest prognosis in AL amyloidosis is poor due to myocardial light chain toxicity.13 Pathophysiology due to ATTR amyloidosis is probably related to infiltration alone, with concomitant cell hypertrophy contributing to increased wall thickening.14 New insights into the pathogenic processes involved in ATTR amyloidosis have been reported. Transthyretin, a transporter protein for thyroxine and retinol in the blood, is formed from four subunits.15 Instability of the tetrameric transthyretin protein has been shown to increase the likelihood of forming amyloid fibrils.16 Proteostasis in all ATTR types may be as important as the point mutations causing ATTRm, as evidenced by overexpression of extracellular chaperones in ATTR patients.17 Proteolytic cleavage has been identified as an important step in destabilisation of the TTR tetramer. The mechano-enzymatic mechanism described by Marcoux et al. is common to several amyloidogenic variants and is particularly important in the heart where shear stress, a process increasing susceptibility to proteolytic cleavage, is greatest.18 The findings are encouraging for the development of therapies targeting inhibition of transthyretin amyloidogenesis.
The Importance of ATTR Cardiac Amyloidosis
Two separate post-mortem series reported a high incidence (25 %) of transthyretin amyloid deposits in the myocardium of elderly subjects at the time of death.19,20 It is not yet known whether the presence of transthyretin amyloid in the heart of very elderly subjects is part of a general aging process or represents under-diagnosis of the clinical phenotype pre-mortem. ATTRwt is associated with an isolated cardiac phenotype, presenting as diastolic heart failure in the eighth decade, with approximately 9:1 male:female ratio.7 Wildtype ATTR amyloidosis is increasingly recognised as an important, yet often unrecognised, cause of heart failure with preserved ejection fraction (HFpEF), a likely heterogeneous group with differing aetiologies. Nuclear imaging with technetium-99m-labelled (99mTc) 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) was used to screen 120 HFpEF patients and 16 patients (13.3 %) showed significant cardiac uptake, later confirmed as ATTRwt following genetic testing and endomyocardial biopsy.21 Unlike the vast majority of studies on ATTRwt, there was no difference in sex in the HFpEF patients with cardiac amyloidosis, suggesting the diagnosis by other methods is often missed in women.22 Undiagnosed ATTRwt has been suggested as a possible cause of poor outcomes in patients undergoing transcutaneous aortic valve replacement (TAVR).23 Coexistent degenerative aortic stenosis and ATTRwt has been reported in a small series of 5/43 patients undergoing aortic valve replacement, with confirmed wild-type TTR on endomyocardial biopsy.24 The authors propose larger prospective studies to determine the role of screening for cardiac amyloidosis with Tc-DPD to aid risk stratification in patients being selected for aortic valve interventions.
Over 100 TTR gene mutations have been associated with systemic amyloidosis, a condition with autosomal dominant inheritance.25 The V122I variant, in which valine is substituted for isoleucine at position 122, has been the focus of significant interest in recent years. V122I amyloidosis was first reported in 1989 and the clinical phenotype is identical to ATTRwt, with isolated cardiac involvement.26,27 V122I allele frequency was first reported as 3.9 % in African Americans in 1996 and has more recently been re-calculated in a study analysing DNA from 1688 New York State African American newborns.28,29 TTR V122I was detected in 65/3376 alleles and, through expansion of the analysis to include samples from a ‘wellness’ study in San Diego, the authors calculated 3.43 % of African Americans under 65 carry at least one copy of the amyloidogenic allele. Disease onset is reported from 65 years and thus, with the aging population, and improving detection techniques, ATTR V122I is expected to be confirmed as the cause of heart failure in increasing numbers of elderly black patients. In January 2015, it was reported by Quarta et al. in The New England Journal of Medicine that there was no significant difference in mortality for V122I carriers and the prevalence of overt cardiac abnormalities was low, following an interim analysis of the Atherosclerosis Risk in the Communities (ARIC) study.30 Final follow-up, totalling 21.5 years, took place before the median age of presentation with ATTR V122I.31,32 As a result, the authors may have underestimated the true burden of cardiac amyloidosis due to ATTR V122I.33