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WSU Medical School

Training Level

Medical Student


Wayne State University


Introduction: Transthyretin (TTR) amyloidosis is a life-threatening disease characterized by extracellular deposition of hepatocyte derived TTR with hereditary and acquired variants. Although there are over 120 genetic mutations in the (TTR) gene, only a few are responsible for hereditary TTR amyloidosis. The most common mutation in African-Americans is Val142Ile substitution, occurring with a frequency of 3.5%. Accumulation of misfolded TTR within the myocardium results in cardiac restriction and dysfunction, most commonly presenting as heart failure with preserved ejection fraction. Delay of diagnosis is associated with elevated cardiac biomarkers, worsening patient outcomes, and an unfavorable prognosis in a potentially treatable and reversible disease. Tafamidis was approved by the FDA in 2019 and prevents progression of disease by stabilizing misfolded protein fibrils. Liver transplant is the definitive therapy in patients diagnosed at a young age. Our case describes a patient who presented with advanced nonischemic systolic heart failure with subsequent diagnosis of hereditary TTR amyloidosis.

Case: A 72 year old African-American male with a past medical history of worsening nonischemic heart failure diagnosed 20 years ago status post AICD placement in 2016 presented as a transfer with NYHA III systolic heart failure symptoms. His family reported he was experiencing worsening fatigue, generalized weakness, and exertional dyspnea limiting ambulation without assistance for two weeks prior to presentation. Significant bilateral lower extremity edema was also noted. Family history revealed his father and uncle died of heart failure. At the outside hospital, he required dobutamine for persistent hypotension with systolic blood pressure 70-80s. BNP was 2,443 pg/mL, EKG demonstrated low-voltage tracings and echocardiogram showed decreased right ventricular function with pulmonary artery pressure of 46 mmHg, ventricular wall hypertrophy with biatrial enlargement and an ejection fraction of 25%. Dobutamine was weaned after a normal right heart catheterization with recurrence of hypotension to 60/40s with mean arterial pressures in the 40s and norepinephrine infusion was started and subsequently changed to midodrine 5mg three times daily after achieving hemodynamic stability. Genetic testing was obtained, identifying a valine to isoleucine substitution at position 142 (Val142Ile) in the TTR protein. Goals of care were discussed with family who decided to pursue comfort measures, thus the patient was discharged home.

Discussion: TTR cardiac amyloidosis is the hereditary or acquired extracellular deposition of misfolded TTR proteins in the myocardium resulting in restriction and dysfunction, most commonly presenting as heart failure with preserved ejection fraction. The Val142Ile mutation has a frequency of approximately 3.5% in African-Americans and is likely to be underdiagnosed, resulting in an unfavorable prognosis and poor patient outcomes. Subtle clinical and imaging signs include a constellation of ventricular hypertrophy with a low amplitude voltage EKG, biatrial enlargement, heart failure with preserved ejection fraction, and arrhythmias. The most sensitive and specific test for cardiac amyloidosis is 99Tc-pyrophosphate scintigraphy. With advances in genetic testing, it is possible to diagnose hereditary disease early with the potential of reversal with medical therapy and definitive treatment with transplantation. Delay in diagnosis is associated with elevated BNP, troponins, development of systolic heart failure, and fatal arrhythmias. Although most patients present with heart failure with preserved ejection fraction, our patient developed symptoms of advanced systolic heart failure prior to his diagnosis of TTR amyloidosis. As such, cardiac amyloidosis should be considered in patients with worsening heart failure symptoms despite appropriate medical therapy with subtle clinical findings associated with the disease.

Presentation Date


Advanced systolic heart failure in undiagnosed cardiac amyloidosis