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Hereditary Links to Aortic Aneurysmal Disease

Key findings

  • Aortic aneurysm and dissection lead to more than 10,000 deaths annually in U.S.
  • Genetic determinants are major factors in determining aneurysmal risk
  • Marfan syndrome patients are at increased risk of cardiovascular death or aortic complications

Aortic aneurysm and dissection lead to more than 10,000 deaths and contribute to more than 17,000 deaths annually in the U.S. Researchers have established that a genetic predisposition to thoracic aortic aneurysm (TAA) and genetic factors play a prominent role in TAA expression. About one-fifth of patients with a TAA have first-degree relatives who have a dilated thoracic aorta.

Researchers, including Massachusetts General Hospital cardiologist Mark Lindsay, MD, PhD, and Eric Isselbacher, MD, director of the Healthcare Transformation Lab, reviewed the literature to evaluate genetic connections to TAA. The results were published in Circulation.

They found that genetic determinants are major factors in determining aneurysmal risk, and genetic testing is a routine procedure to use in the clinic for potential and affected patients. Genetics researchers have found novel aspects of vascular biology that may help identify new therapeutic targets.

Researchers often focus on Marfan syndrome when studying genetically-initiated aortic disease, but that research has also led to advanced findings for TAA, including an established link between progressive aortic growth and aortic dissection.

Marfan syndrome manifests mainly in ocular, skeletal and cardiovascular systems. It is caused by mutations in the gene FBN1, which encodes the protein fibrillin-1. Fibrillins interact with a cell-signaling molecule called transforming growth factor beta (TGF-β).

Researchers found that the gene mutation in Marfan syndrome may significantly affect outcomes. They concluded that among patients with Marfan syndrome and FBN1 mutations, those with haploinsufficient mutations carried a 2.5-fold increased risk for cardiovascular death and a 1.6-fold increased risk for aortic complication when compared to patients with a dominant-matrix mutation.

TGF-βs control multiple features of cellular function, including differentiation and proliferation. Their signaling is associated with aortic aneurysm through mutations in the genes TGFBR1 and TGFBR2, which encode two human TGF-β subunits that cause a TAA condition.

Genetic agitations may lead to loss of TGF-β signaling potency, while loss-of-function mutations may cause aortic disease by upregulating counterregulatory pathways that can directly propel aneurysm.

Some families inherit aneurysmal disease with few outward physical manifestations, and researchers have identified some of these inherited genes. For instance, the gene MYH11, which encodes smooth muscle-specific myosin isoform, has been linked to smooth muscle contraction vasculopathy.

The gene ACTA2, which encodes the smooth muscle-specific isoform of actin, has been definitively linked to familial thoracic aneurysms and dissections.

TAA associated with bicuspid aortic valve (BAV) is probably the most common aortic aneurysm that affects humans, common enough that first-degree relatives are routinely screened in the clinic. BAV is also the most common developmental malformation of the heart. Researcher suggests that BAV/TAA is genetically complex.

Even with a multitude of genetic research studies completed and many links to aortic disease established, there are still many questions to address and challenges to overcome to identify new therapies. Next-generation sequencing has much to offer in addressing these challenges and opportunities.

proportion of classically affected individuals with first-degree relative having dilated thoracic aorta

number of deaths aortic aneurysm and dissection contribute to annually in the US

Refer a patient to the Mass General's Corrigan Minehan Heart Center

Learn more about Mass General’s Thoracic Aortic Center

Related topics


Precision medicine can help answer whether or not current heart disease treatment paradigms optimally address genetic heterogeneity.


Mass General researchers identified 204 cases of recurrent AD from 3,828 AD cases in the International Registry of Acute Aortic Dissection. The study was published in the journal Circulation.