Familial amyloid cardiomyopathy

Transthyretin Amyloid Cardiomyopathy (ATTR-CM), or Familial Amyloid Cardiomyopathy (FAC), results from the aggregation of mutant and/or wild-type transthyretin protein in the heart.[1] Both mutant and wild-type transthyretin comprise the aggregates because the TTR blood protein is a tetramer composed of mutant and wild-type TTR subunits in heterozygotes. The TTR tetramer has to dissociate in a rate-limiting step before the monomer can misfold and become aggregation competent.[2] Senile systemic amyloidosis,[3] a highly related cardiomyopathy, results from the aggregation of wild-type transthyretin exclusively.[4][5] In these maladies, TTR amyloid fibrils infiltrate the myocardium, leading to diastolic dysfunction. Eventually, progression to restrictive cardiomyopathy and heart failure is seen.[6] Several mutations in TTR are primarily associated with FAC, including V122I, V20I, P24S, A45T, Gly47Val, Glu51Gly, I68L, Gln92Lys, and L111M. One common mutation (V122I), which is a substitution of isoleucine for valine at position 122, occurs with high frequency in African-Americans, with a prevalence of approximately 3.5%.

Clinical presentation

The onset of FAC caused by aggregation of the V122I mutation and wild-type TTR, and senile systemic amyloidosis caused by the exclusive aggregation of wild-type TTR, typically occur after age 60. Greater than 40% of these patients present with carpal tunnel syndrome before developing ATTR-CM. Cardiac involvement is often identified with the presence of conduction system disease (sinus node or atrioventricular node dysfunction) and/or congestive heart failure, including shortness of breath, peripheral edema, syncope, exertional dyspnea, generalized fatigue, or heart block.[7][8] Unfortunately, echocardiographic findings are indistinguishable from those seen in AL amyloidosis, and include thickened ventricular walls (concentric hypertrophy, both right and left) with a normal-to-small left ventricular cavity, increased myocardial echogenicity, normal or mildly reduced ejection fraction (often with evidence of diastolic dysfunction and severe impairment of contraction along the longitudinal axis), and bi-atrial dilation with impaired atrial contraction. Unlike the situation in AL amyloidosis, the ECG voltage is often normal, although low voltage may be seen (despite increased wall thickness on echocardiography). Marked axis deviation, bundle branch block, and AV block are common, as is atrial fibrillation.

Therapeutic strategies

Although not based on a human clinical trial, the only currently accepted disease-modifying therapeutic strategy available for familial amyloid cardiomyopathy is a combined liver and heart transplant. Treatments aimed at symptom relief are available, and include diuretics, pacemakers, and arrhythmia management. Thus, Senile systemic amyloidosis and familial amyloid polyneuropathy are often treatable diseases that are misdiagnosed.[9][10][11] Recently, the European Medicines Agency approved the drug Tafamidis or Vyndaqel[12] to slow the progression of familial amyloid polyneuropathy, a related disease caused by TTR aggregation that first presents as an autonomic and/or peripheral neuropathy (later progressing to a cardiomyopathy).[13][14][15][16] Some believe that Vyndaqel may be useful in slowing the progression of familial amyloid cardiomyopathy, although this has not been demonstrated by a placebo controlled clinical trial.

Currently, there are active clinical trials recruiting patients in the United States and world wide. The DISCOVERY trial is a screening study evaluating the prevalence of TTR mutations in patients suspected of having cardiac amyloidosis with the goal of identifying and facilitating the diagnosis of FAC.[17] Two Phase III trials are being conducted to evaluate drugs which may block amyloid formation: ENDEAVOUR, evaluating revusiran, an investigational medicine, in the treatment of familial TTR-induced cardiomyopathy,[18] and ATTR-ACT, evaluating tafamidis in the treatment of TTR-induced cardiomyopathy.[19]

Additionally, the THAOS registry is currently enrolling patients with TTR amyloidosis in order to track outcomes.[20]

References

  1. ↑ Jacobson, D. R., Pastore, R. D., Yaghoubian, R., Kane, I., Gallo, G., Buck, F. S. & Buxbaum, J. N. (1997). Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis that occurs in black Americans. The New England Journal of Medicine 336, 466-73.
  2. ↑ Colon, W. & Kelly, J. W. (1992). Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654-60.
  3. ↑ Westermark, P., Sletten, K., Johansson, B. & Cornwell, G. G., 3rd. (1990). Fibril in Senile Systemic Amyloidosis is derived from normal transthyretin. Proceedings of the National Academy of Sciences of the United States of America 87, 2843-5.
  4. ↑ Ng, B., Connors, L. H., Davidoff, R., Skinner, M. & Falk, R. H. (2005). Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med 165, 1425-9.
  5. ↑ Westermark, P., Bergstrom, J., Solomon, A., Murphy, C. & Sletten, K. (2003). Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid 10 Suppl 1, 48-54.
  6. ↑ "Familial". Amyloidosis Foundation. Retrieved 23 August 2013.
  7. ↑ Falk, R. H. & Elkayam, U. (2010). Cardiomyopathy: the importance of recognizing the uncommon diagnosis. Prog Cardiovasc Dis 52, 262-3.
  8. ↑ Snyder, M. E., Haidar, G. R., Spencer, B. & Maurer, M. S. (2011). Transthyretin cardiac amyloidosis diagnosed by analyzing a prostatic tissue sample: a case report. J Am Geriatr Soc 59, 1745-7.
  9. ↑ Falk, R. H. (2011). Cardiac amyloidosis: a treatable disease, often overlooked. Circulation 124, 1079-85.
  10. ↑ Bhuiyan, T., Helmke, S., Patel, A. R., Ruberg, F. L., Packman, J., Cheung, K., Grogan, D. & Maurer, M. S. (2011). Pressure-volume relationships in patients with transthyretin (ATTR) cardiac amyloidosis secondary to V122I mutations and wild-type transthyretin. Transthyretin cardiac amyloid study (TRACS). Circ.: Heart Failure 4, 121-128.
  11. ↑ Miller, A. L., Falk, R. H., Levy, B. D. & Loscalzo, J. (2010). A heavy heart. N. Engl. J. Med. 363, 1464-1470.
  12. ↑ Hammarstrom, P., Wiseman, R. L., Powers, E. T. & Kelly, J. W. (2003). Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299, 713-6.
  13. ↑ Coelho, T. (1996). Familial amyloid polyneuropathy: new developments in genetics and treatment. Current opinion in neurology 9, 355-9.
  14. ↑ Olofsson, B. O., Backman, C., Karp, K. & Suhr, O. B. (2002). Progression of cardiomyopathy after liver transplantation in patients with familial amyloidotic polyneuropathy, Portuguese type. Transplantation 73, 745-51
  15. ↑ Benson, M. D. (1989). Familial Amyloidotic polyneuropathy. Trends in neurosciences 12, 88-92.
  16. ↑ Schulze, P. C. & Maurer, M. S. (2010). Transthyretin Val30Met mutation in an African American with cardiac amyloidosis. Congest Heart Fail 16, 73-6.
  17. ↑ https://clinicaltrials.gov/ct2/show/NCT02252653?term=discovery+cardiac&rank=2
  18. ↑ https://clinicaltrials.gov/ct2/show/NCT02319005?term=revusiran&rank=2
  19. ↑ https://clinicaltrials.gov/ct2/show/NCT01994889
  20. ↑ http://www.thaos.net/