Transthyretin cardiac amyloidoses in older North Americans

Abstract

The amyloidoses are a group of hereditary or acquired disorders caused by the extracellular deposition of insoluble protein fibrils that impair tissue structure and function. All amyloidoses result from protein misfolding, a common mechanism for disorders in older persons, including Alzheimer's disease and Parkinson's disease. Abnormalities in the protein transthyretin (TTR), a serum transporter of thyroxine and retinol, is the most common cause of cardiac amyloidoses in elderly adults. Mutations in TTR can result in familial amyloidotic cardiomyopathy, and wild-type TTR can result in senile cardiac amyloidosis. These underdiagnosed disorders are much more common than previously thought. The resulting restrictive cardiomyopathy can cause congestive heart failure, arrhythmias, and advanced conduction system disease. Although historically difficult to make, the diagnosis of TTR cardiac amyloidosis has become easier in recent years with advances in cardiac imaging and more widespread use of genetic analysis. Although therapy has largely involved supportive medical care, avoidance of potentially toxic agents, and rarely organ transplantation, the near future brings the possibility of targeted pharmacotherapies designed to prevent TTR misfolding and amyloid deposition. Because these disease-modifying agents are designed to prevent disease progression, it has become increasingly important that older persons with TTR amyloidosis be expeditiously identified and considered for enrollment in clinical registries and trials.

Figure 1

Prevailing theory of pathogenesis of transthyretin amyloidosis. The tetrameric transthyretin molecule dissociates into four monomers (only one shown for simplicity). The monomer misfolds, aggregates with like molecules, and ultimately organizes into thread-like amyloid fibrils that are resistant to degradation and deposit in tissues. Image courtesy of Jeffery W. Kelly, PhD.

Figure 2

Representative electrocardiograms from patients with familial amyloidotic cardiomyopathy due to the Val122Ile mutation. (A) Sinus bradycardia with 1^st degree AV block, low limb lead QRS voltage, poor precordial R-wave progression (cannot rule out anterior MI); (B) Atrial fibrillation, anterolateral and inferior infarcts (pseudo-infarcts); (C) Marked sinus bradycardia, inferior infarct (pseudo-infarct); (D) Sinus rhythm with marked 1^st degree AV block, low limb lead QRS voltage, left bundle branch block.

Figure 3

Characteristic imaging findings in patients with cardiac transthyretin amyloidosis. (A) Echocardiogram in patient without cardiac disease. LA - left atrium, LV - left ventricle, RV - right ventricle, A_o - aorta. Interventricular septum (IVS), shown by arrowhead, is normal in thickness. (B) Echocardiogram in patient with familial amyloidotic cardiomyopathy due to Val122Ile mutation demonstrates markedly thickened Interventricular septum. (C) Cardiac MRI in patient with transthyretin amyloidosis showing short axis of heart. (D) Identical short axis view from the same patient demonstrates diffuse subendocardial late gadolinium enhancement of both ventricles that is characteristic of amyloid deposition. Panels (E), (F), and (G) show differences in cardiac retention of a technetium-pyrophosphate-99 radiotracer in subjects with heart failure and a preserved ejection fraction in hypertension (panel E) and AL amyloid (panel F) demonstrating no cardiac tracer retention compared to the subject with cardiac transthyretin amyloidosis in panel (G).