Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the SMAD 3 gene

Background Predominant 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. Methods Description of clinical history of three cases from one family in Ghent (Belgium) and one family in St. Louis ( US ). Results We 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 SMAD 3 gene, known to cause aneurysm osteoarthritis syndrome, Loeys‐Dietz syndrome type 3 or isolated Heritable Thoracic Aortic Disease. Conclusions These 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.