ATTRwt Amyloidosis (Age-Related)

A major focus of research in the Gerry Laboratory is the study of ATTRwt amyloidosis, an age-related type of amyloid disease caused by deposition of the plasma protein, transthyretin (TTR).  Unlike familial TTR-associated forms of amyloid (ATTRm) which feature TTR gene mutations and amyloid-forming TTR mutant proteins, ATTRwt is a late onset disease that is acquired and not inherited; mutations in the TTR gene are not a cause of ATTRwt.

While in ATTRwt the amyloid deposits accumulate in extracellular compartments of tissues and organs throughout the body, the heart is usually the dominant site of involvement.  The presence of amyloid in the heart disrupts normal cellular processes and tissue functioning.  ATTRwt amyloidosis, frequently diagnosed as a restrictive cardiomyopathy, is most commonly reported in men over the age of 60 years and symptoms include congestive heart failure, arrhythmias, and conduction defects.

A definitive diagnosis of ATTRwt amyloidosis relies on histologic analysis of a biopsy sample from the affected site, i.e. myocardium ideally, but subcutaneous fat or rectal samples are also used. Currently, the etiology of cardiac amyloidosis in ATTRwt remains undefined, the diagnosis of ATTRwt is problematic (there are no biomarkers and disease identification requires the exclusion of all other types of systemic amyloidosis), no accurate measure of disease progression in cardiac amyloidosis is available, and there are no treatment options for patients with ATTRwt. Our research on ATTRwt is aimed at offering contributions and improvements in each of these areas.

With partial support through grant funding from the National Institute on Aging at the National Institutes of Health (1R01 AG031804-01A2), we are conducting a cross-sectional and longitudinal (5-year) study of patients with ATTRwt evaluated at our center.

Patients with ATTRwt are invited to participate in this study.

The goals of this study are to:

  1. Detail the biochemical nature of circulating and deposited forms of TTR in patients with ATTRwt,
  2. Accurately characterize the clinical features of ATTRwt in a large clinical population,
  3. Correlate disease progression to serum markers uniquely present in ATTRwt samples.

Our research is also aimed at defining factors that promote the instability or amyloid-forming potential of TTR, i.e. initiators of ATTRwt disease onset.  At the same time, we are focused on identifying factors that stabilize TTR as these would inhibit aggregation, thereby protecting against disease onset.  Results from these latter investigations should provide a platform for designing therapeutic agents.

Important Contributions to ATTRwt Research:
  • We have precisely detailed the primary structures of TTR purified from the serum and cardiac amyloid deposits of patients diagnosed with ATTRwt.  Our results demonstrated that TTR circulating in blood was quite different from the fibrillar, deposited forms of TTR in the ATTRwt samples.
  • We have found that high molecular weight forms of TTR are present in blood samples from patients with SSA.  In addition, we have gathered data suggesting that there are differences between ATTRwt and age-matched control samples with respect to several molecular chaperones, clusterin (in serum) and αB-crystallin (in tissue).  Preliminary studies provide evidence that serum levels of TTR and clusterin in patients with ATTRwt may be lower than normal levels.
  • Further studies in this area have indicated that clusterin may be important in the pathobiology of ATTRwt.  Specifically, we have reported that clusterin is abundantly present in cardiac tissue with amyloid deposits from patients with ATTRwt, and more precisely, that the clusterin appears to be associated with TTR in the fibrils.