Twisted arteries in neck in vEDS tied to greater cardiovascular risk

Having elongated and twisted arteries — called tortuous arteries — in the neck is tied to greater cardiovascular risk in people with vascular Ehlers-Danlos syndrome (vEDS), a new study reports.

Moreover, the rate of cardiovascular events was higher among vEDS patients younger than 40 with high-risk mutations in the COL3A1 gene that underlie the rare genetic disorder.

These findings suggest that measuring vertebral arterial tortuosity, or the degree to which these arteries are twisted or lengthened, “may be a useful biomarker for prognosis when evaluated in conjunction with genotype [genetic profile] and age,” the researchers wrote.

Further, the scientists suggest that “longitudinal imaging surveillance,” or long-term monitoring with scans for assessment — “risk stratification,” the team wrote — “can benefit children and adults with vascular Ehlers‐Danlos syndrome.”

The study, “Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers‐Danlos Syndrome,” was published in the Journal of the American Heart Association.

Elongated and twisted arteries a known cardiovascular risk factor

Ehlers-Danlos syndrome (EDS) refers to a group of genetic disorders characterized by defects in the connective tissue that provides support to joints, skin, blood vessels, and other tissues and organs in the body.

vEDS, which affects blood vessels and internal organs, is typically considered the most severe form of the disorder. Most cases of vEDS are caused by mutations in the COL3A1 gene, which provides instructions for making type III collagen. Collagens are proteins that strengthen and support skin, tissues, and organs.

While a patient’s disease onset and severity depend on the type of COL3A1 mutation, the variable presentation of EDS within the same family — meaning when relatives have the disease but with different symptoms — can only be explained by the existence of additional factors.

Arterial tortuosity, which refers to elongated and distorted arteries, is a known risk factor for worse outcomes in patients with other connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome.

However, “the clinical utility of tortuosity in patients with vEDS has not been evaluated,” the researchers wrote.

Now, a team led by scientists at Texas Children’s Hospital examined whether the presence of arterial tortuosity was linked to a higher risk of cardiovascular or extracardiac events, such as organ ruptures, in children and adults with vEDS.

To that end, the scientists assessed arterial tortuosity with VTI-h, or the height-adjusted vertebral artery tortuosity index. The vertebral arteries carry blood to the brain and upper spinal cord.

The researchers hypothesized that an increased VTI-h would be associated with a higher incidence, or more new cases, of life-threatening events.

35 vEDS patient experienced 59 cardiovascular events in study

Altogether, data were analyzed from 65 vEDS patients with a mutation in the COL3A1 gene enrolled from four longitudinal groups. Longitudinal studies collect data over an extended period of time.

Just more than half (54%) of the patients were male, and the median age at diagnosis was 10.5 years.

Overall, 18 patients (28%) had a low-risk COL3A1 gene mutation, while 40 individuals (62%) had a high-risk mutation.

VTI-h was calculated from magnetic resonance angiography (MRA) and computed tomography angiography (CTA). Both exams evaluate the body’s blood vessels: MRA is a type of MRI, whereas CTA combines a CT scan with an injection of a special dye to visualize blood vessels.

Specifically, the study analyzed associations between VTI-h and cardiovascular or organ events, specifically a collapsed lung, or pneumothorax, or a perforation/rupture of a hollow organ. Cardiovascular events were defined as arterial dissection or rupture, aneurysm — which is a bulge in a weakened area of a blood vessel — requiring surgical intervention, or stroke.

In total, 32 patients (49%) experienced 59 events. These were 28 arterial or aortic dissections, five arterial ruptures, four aneurysms requiring intervention, four strokes, 11 hollow organ ruptures, and seven pneumothoraxes. One patient died as a result of these events.

The overall rate of new cardiovascular events was 2.38 per 100 person-years and was 0.88 per 100 person-years for organ events. Person-years is a measure that considers the number of people in a study as well as the amount of time they spent in the study.

The median VTI-h of the 65 total patients was 12. VTI-h showed a mild predictive value for events before age 30, reaching an area-under-the-curve (AUC) value of 0.64. AUC is a test of how well a measure can differentiate between two groups. Values can range from 0.5 to 1, with higher values indicating a better ability to tell the two groups apart.

The predictive power of VTI-h was better (higher) when considering only cardiovascular events before age 30, with an AUC value of 0.71. In contrast, VTI-h had no predictive ability for extravascular organ events before age 30.

Cardiovascular risk found higher for those younger than 40 with mutations

Based on these findings, the team conducted further analysis focusing on the relationship between VTI-h and cardiovascular events.

A cut-off VTI-h value equal to or higher than 15.5 was able to identify 75.4% of patients at risk of cardiovascular events, with a sensitivity of 70% and a specificity 76.4%. A test’s sensitivity is its ability to correctly identify those with a given disease, while specificity refers to correctly identifying those without it.

A total of 20 patients had a high VTI-h, whereas 45 were below the 15.5 threshold. In a subsequent analysis, a high VTI-h was associated with significantly higher rate of cardiovascular events compared with a low VTI-h (3.78 vs. 1.57). The risk of cardiovascular events also was higher among non-Hispanic white patients than among Hispanic patients (2.97 vs. 1.02).

When stratifying patients by age groups, the results showed a slower increase in risk with increasing age among those with low versus high VTI‐h.

When limiting the analysis to patients with high-risk COL3A1 mutations and considering the first four decades of life, the risk of cardiovascular events was significantly increased — 4.14 higher in patients in the high VTI-h group.

Overall, these findings show that, in vEDS patients, an increase in twisted or elongated arteries is associated with a higher incidence of cardiovascular events.

“Prospective studies that include more racially and ethnically diverse subjects are needed to evaluate VTI’s predictive ability in this high‐risk population,” the researchers wrote.