Familial amyloid cardiomyopathy

Familial amyloid cardiomyopathy (FAC) or Transthyretin (TTR) Amyloid Cardiomyopathy or TTR amyloid cardiomyopathy (ATTR-CM) results from the aggregation of mutant and/or wild type transthyretin protein. 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. Senile systemic amyloidosis, a highly related cardiomyopathy, results from the aggregation of wild type transthyretin exclusively. In these maladies TTR amyloid fibrils infiltrate the myocardium, leading to diastolic dysfunction progressing to restrictive cardiomyopathy and heart failure. Several mutations in TTR are primarily associated with FAC including V122I,V20I, P24S, A45T, Gly47Val, Glu51Gly, I68L, Gln92Lys, and L111M. One common mutation, V122I (substitution of isoleucine for valine at position 122), occurs with high frequency (prevalence of approximately 3.5%) in African-Americans.

Clinical Presentation
The onset of FAC caused by aggregation of the V122I mutation and wild-type TTR and senile systemic amyloidosis caused by aggregation of wild type TTR typically occurs after age 60. Greater than 40% of patients present with carpal tunnel syndrome before developing ATTR-CM. Cardiac involvement can present with conduction system disease (sinus node or atrioventricular node dysfunction) or congestive heart failure including shortness of breath, peripheral edema, syncope, exertional dyspnea, generalized fatigue or with heart blocks. Unfortunately, the echocardiographic findings are indistinguishable from those seen in AL (primary immunoglobulin light chain) 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 voltage on the ECG is often normal, although low voltage may be seen despite the increased wall thickness on echocardiography. Marked axis deviation, bundle branch block and AV block is common, as is atrial fibrillation.

Therapeutic Strategies
The only currently accepted (not based on a human clinical trial) disease modifying therapeutic strategy available for Familial amyloid cardiomyopathy is a combined liver and heart transplan, although treatments aimed at symptom relief are available; including diuretics, pacemakers, and arrhythmia management. Thus Senile systemic amyloidosis and familial amyloid polyneuropathy are often treatable diseases that are misdiagnosed. Recently, the European Medicines Agency approved the drug Tafamidis or Vyndaqel 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, that progresses to a cardiomyopathy. 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. Patients should check the following website to discern whether the Tafamidis or vyndaqel cardiomyopathy clinical trial has begun (http://www.clinicaltrials.gov/).