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Transthyretin Amyloidosis Cardiomyopathy

Hereditary transthyretin amyloidosis cardiomyopathy (hATTR-CM) is an autosomal-dominant cardiac disease caused by a mutation in the TTR gene that results in a substitution of isoleucine for valine at position 122 (TTR Val122Ile) in transthyretin, which is also called thyroxine and retinol transport protein. This substitution causes a conformational change in the tetrameric subunits of transthyretin that leads to their dissociation. Misfolded subunits are reconstituted into amyloid fibrils that are deposited in the extracellular spaces among myocardial cells. Accumulation of amyloid in the heart can lead to life-threatening cardiomyopathy, arrhythmias, and heart failure.

The median time from onset of heart failure symptoms to diagnosis of hATTR-CM is approximately 3 years. Successful treatments such as Tafamidis, and other amyloid-disrupting therapies, are now available for hATTR-CM. Earlier detection could provide greater therapeutic benefit.

To date, pyrophosphate scanning is the most helpful noninvasive imaging for the diagnosis of hATTR-CM. However, use of the pyrophosphate scan requires negative screening for monoclonal light chain via urine or serum immunofixation electrophoresis and measurement of serum-free light chains.

The population frequency for the TTR Val122Ile allele is 3% to 4%. Widespread population screening beyond cases of unexplained left ventricular hypertrophy or left ventricular functional abnormalities is problematic because of the incomplete penetrance of of TTR Val122Ile, meaning that only a minority of individuals with the allele would be ultimately affected by disease. The variable penetrance of the TTR Val122Ile variant influenced the decision made by the American College of Medical Genetics and Genomics to withhold the inclusion of this genetic variant from the list of medically actionable genes of the clinical exome. Genetic counseling consultation may be helpful in supporting joint patient-physician decision-making for relatives of known clinical cases, carriers of the risk allele, or both.


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Parcha V, Malla G, Ivin MR, et al. Association of transthyretin Val122Ile variant with incident heart failure among Black individuals.JAMA. Published online April 4, 2022. doi:10.1001/jama.2022.2896

Nayak A, Hicks AJ, Morris AA. Understanding the complexity of heart failure risk and treatment in Black patients.Circ Heart Fail. 2020;13(8):e007264. doi:10.1161/CIRCHEARTFAILURE.120.007264

Stern LK, Kittleson MM. Updates in cardiac amyloidosis diagnosis and treatment.Curr Oncol Rep. 2021;23(4):47. doi:10.1007/s11912-021-01028-8

Damy T, Garcia-Pavia P, Hanna M, et al. Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study.Eur J Heart Fail. 2021;23(2):277-285. doi:10.1002/ejhf.2027

Echols MR and Taylor H. Heart Failure, Precision Medicine, and Incremental Equity: The Case of Hereditary Amyloid Cardiomyopathy. JAMA 2022;327:1341-1343.

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