Transthyretin (TTR) protein, which transports thyroid hormone and retinol, can misfold and form amyloid fibrils that deposit in the heart, causing cardiomyopathy, heart failure, arrhythmia, and death. Systemic amyloidosis due to TTR misfolding is the most common type of amyloidosis leading to cardiomyopathy, affecting approximately 50,000 to 150,000 people in the US. The condition can be caused by wild-type or variant TTR genetic sequences. Wild-type TTR amyloidosis primarily manifests as cardiomyopathy, while variant TTR amyloidosis can also cause polyneuropathy. The most common genetic variant is Val122Ile, which is present in about 3.4% of African American individuals. Diagnosis involves serum free light chain assay, immunofixation electrophoresis, and cardiac nuclear scintigraphy. Treatment includes loop diuretics for fluid overload, mineralocorticoid receptor antagonists, and β-blockers for heart failure. Tafamidis, a TTR stabilizer, has been shown to reduce mortality and hospitalizations in patients with ATTR cardiomyopathy, making it the only currently approved therapy. Prognosis is worse for patients with the Val122Ile variant compared to wild-type.Transthyretin (TTR) protein, which transports thyroid hormone and retinol, can misfold and form amyloid fibrils that deposit in the heart, causing cardiomyopathy, heart failure, arrhythmia, and death. Systemic amyloidosis due to TTR misfolding is the most common type of amyloidosis leading to cardiomyopathy, affecting approximately 50,000 to 150,000 people in the US. The condition can be caused by wild-type or variant TTR genetic sequences. Wild-type TTR amyloidosis primarily manifests as cardiomyopathy, while variant TTR amyloidosis can also cause polyneuropathy. The most common genetic variant is Val122Ile, which is present in about 3.4% of African American individuals. Diagnosis involves serum free light chain assay, immunofixation electrophoresis, and cardiac nuclear scintigraphy. Treatment includes loop diuretics for fluid overload, mineralocorticoid receptor antagonists, and β-blockers for heart failure. Tafamidis, a TTR stabilizer, has been shown to reduce mortality and hospitalizations in patients with ATTR cardiomyopathy, making it the only currently approved therapy. Prognosis is worse for patients with the Val122Ile variant compared to wild-type.