Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the SMAD3 gene.

Julie De Backer,Alan C Braverman

doi:10.1002/mgg3.396

Abstract

BackgroundPredominant cardiovascular manifestations in the spectrum of Heritable Thoracic Aortic Disease include by default aortic root aneurysms‐ and dissections, which may be associated with aortic valve disease. Mitral‐ and tricuspid valve prolapse are other commonly recognized features. Myocardial disease, characterized by heart failure and/or malignant arrhythmias has been reported in humans and in animal models harboring pathogenic variants in the Fibrillin1 gene.MethodsDescription of clinical history of three cases from one family in Ghent (Belgium) and one family in St. Louis (US).ResultsWe report on three cases from two families presenting end‐stage heart failure (in two) and lethal arrhythmias associated with moderate left ventricular dilatation (in one). All three cases harbor a pathogenic variant in the SMAD3 gene, known to cause aneurysm osteoarthritis syndrome, Loeys‐Dietz syndrome type 3 or isolated Heritable Thoracic Aortic Disease.ConclusionsThese unusual presentations warrant awareness for myocardial disease in patients harboring pathogenic variants in genes causing Heritable Thoracic Aortic Disease and indicate the need for prospective studies in larger cohorts.

Highlights

In recent years, both the genetic and clinical spectrum of Heritable Thoracic Aortic Disease (H-TAD) has expanded substantially
H-TAD comprises a heterogeneous group of disorders with as a common denominator aortic aneurysm or dissection on one or several levels of the aorta (Pyeritz, 2014)
The latter group can be divided into genes encoding various proteins involved in TGFb signaling (TGFBR15*190181), TGFBR2 (*190182), TGFB2 (*190220), TGFB3 (*190230), SMAD3 (*603109) and genes encoding proteins involved in vascular smooth muscle cell contractility (ACTA2 (*102620), MYH11 (*160745), MYLK (*600922), PRKG1 (*176894), FLNA (*300017))

Summary

| INTRODUCTION

Both the genetic and clinical spectrum of Heritable Thoracic Aortic Disease (H-TAD) has expanded substantially. Components (FBN1(*134797), COL3A1 (*120180), MFAP5 (*601103), ELN (*130160), EFEMP2 (*604633)) and those that affect the ability to modify structure in response to changes in mechanical load imposed on the aortic wall The latter group can be divided into genes encoding various proteins involved in TGFb signaling (TGFBR15*190181), TGFBR2 (*190182), TGFB2 (*190220), TGFB3 (*190230), SMAD3 (*603109) and genes encoding proteins involved in vascular smooth muscle cell contractility (ACTA2 (*102620), MYH11 (*160745), MYLK (*600922), PRKG1 (*176894), FLNA (*300017)). One small study investigated the genotype in relation to left ventricular (LV) function and noticed that LV dilatation in MFS patients is more often seen in patients with a nonmissense FBN1 pathogenic variant and in those patients without an FBN1 pathogenic variant (Aalberts et al, 2014) Whether this latter group included patients harboring variants in other H-TAD genes is not known. We report two families (three cases) with a pathogenic SMAD3 variant displaying severe heart failure (two cases) and sudden cardiac death (one case), indicating a possible relationship between SMAD3 pathogenic variants and these manifestations to heighten awareness of this association and to further evaluate in larger series

| ETHICAL COMPLIANCE

Findings

| DISCUSSION