Frequency of and Prognostic Significance of Cardiac Involvement at Presentation in Hereditary Transthyretin-Derived Amyloidosis and the Value of N-Terminal Pro-B-Type Natriuretic Peptide

Abstract

The aim of this study is to assess the prevalence of cardiac involvement in hereditary transthyretin-derived (ATTRm) amyloidosis at the time of diagnosis and to determine the diagnostic and clinical value of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The University Medical Center Groningen is the national center of expertise for amyloidosis. All consecutive patients between 1994 and 2016 with ATTRm amyloidosis were followed prospectively. Baseline was set at the time of the first positive biopsy. All patients underwent a standard cardiac and neurologic work-up. Cardiac involvement was defined by otherwise unexplained left and/or right ventricular wall hypertrophy on cardiac ultrasound and/or advanced conduction disturbances. Seventy-seven patients had ATTRm amyloidosis and were included in the study. The TTR V30M mutation was present in 30 patients (39%). In both the V30M and the non-V30M groups, the neurologic presentation dominated (77% vs 51%), whereas cardiac presentation was infrequent (7% vs 15%). Clinical work-up showed that cardiac involvement was present at baseline in 51% of all patients irrespective of genotype and was associated with increased overall mortality (hazard ratio 5.95, 95% confidence interval 2.12 to 16.7), independent from clinical confounders. At a cutoff level of 125 ng/L, NT-proBNP had a sensitivity of 92% for establishing cardiac involvement. In conclusion, irrespective of the frequent noncardiac presentation of ATTRm amyloidosis, cardiac involvement is already present at diagnosis in half of the patients and is associated with increased mortality. NT-proBNP is a useful marker to determine cardiac involvement in this disease.

Hereditary transthyretin-related amyloidosis

“…Echocardiography and cardiac MRI typically show myocardial thickening, including the interatrial septum. 13 TTR-CA is the major cause of death in patients with 1 In a study of 263 patients with TTR-CA, cardiac MRI revealed asymmetric hypertrophy associated with hypertrophic cardiomyopathy as the commonest pattern of ventricular remodeling in ATTR-CA.…”

“…8 TTR-CA is already present at the time of the first positive biopsy in 51% of the patients. 13 TTR-CA most frequently manifests clinically as heart failure with normal systolic function, conduction blocks, ventricular arrhythmias, or sudden cardiac death (SCD). 14…”

“…16 It is well established that TTR-CA is associated with an increased mortality. 13 TTR-CA is the major cause of death in patients with…”

Non‐Val30Met mutation, septal hypertrophy, and cardiac denervation in patients with mutant transthyretin amyloidosis

“…2,3 Mutant ATTR was once believed to be a rare autosomal dominant disease, restricted to an endemic presence in specific areas; however, with the progression of molecular and biochemical analyses, it has become clear that this disease occurs worldwide. [8][9][10][11] Because TTR-derived amyloid fibril deposition causes peripheral and autonomic polyneuropathy, it is reasonable to speculate that the cardiac neuronal homeostasis is altered in patients with ATTRm amyloidosis. 4 To date, over 140 TTR mutations have been identified, 5 with ATTRm amyloidosis symptoms varying according to the TTR mutation.…”

“…[7][8][9][10] In particular, cardiac involvement causes heart failure and cardiac arrhythmias due to infiltrative and restrictive cardiomyopathy and impacts the prognosis of patients with ATTR. [8][9][10][11] Because TTR-derived amyloid fibril deposition causes peripheral and autonomic polyneuropathy, it is reasonable to speculate that the cardiac neuronal homeostasis is altered in patients with ATTRm amyloidosis. A reduced heart-to-mediastinum uptake (HM) ratio on 123-iodine metaiodobenzylguanidine ( 123 I-MIBG) imaging, which is a noninvasive tool for assessing cardiac sympathetic nerve activity, has been reported to predict a poor prognosis in patients with ATTRm amyloidosis.…”