Vascular Ehlers Danlos Syndrome: Exploring the Role of Inflammation in Arterial Disease

Vascular-type Ehlers-Danlos syndrome (vEDS) is an autosomal dominant disease that affects the arteries, bowels, uterus, and skin. Affected individuals can have spontaneous rupture of the hollow organs, such as the bowels or gravid uterus, along with arterial dissections and ruptures that lead to premature death. The arterial disease seen in individuals with vEDS is diffuse, involving small to medium arteries and the aorta ^{1, 2}. The median lifespan of vEDS patients is only 48 years with the majority of deaths attributed to vascular complications ^{3, 4}. Surgical treatment of the vascular diseases in vEDS patients had been limited due to the friable and fragile tissues. However, a human treatment trial using, celiprolol, a cardioselective β-adenergic blocking agent with β2 agonist properties, was shown to reduce the number of vascular events in vEDS patients ⁵. Although there were limitations to the treatment trial, this study provided the first possible medical therapy for vEDS. While much of the morbidity and mortality of this condition is still due to the spontaneous rupture of non-dilated arteries, reports of progressive arterial aneurysms have been reported suggesting that there is a greater role for noninvasive imaging, elective surgery and medical therapy than previously thought^{6, 7}.

Type III collagen is composed of three α1(III) polypeptide chains coiled into a triple helix structure. Each polypeptide chain in the triple helix portion of the protein contains a domain of approximately 330 -Gly-X-Y- repeats. Disruption of this triple-helical structure leads to abnormal protein folding thereby resulting in pathogenicity ⁸. Alterations in the glycine codons leading to substitutions for glycine in the triple helical domain account for the majority of disease causing mutations and leads to misfolding of type III collagen in the endoplasmic reticulum and retention of the 7/8^th of the misfolded procollagen trimers in the cell ⁹. This type of mutation produces a dominant negative effect on the protein thereby inhibiting the extracellular accumulation of mature type III collagen^{10, 11}. Unlike the dominant negative effect of missense mutations on type III collagen, nonsense and frameshift mutations in COL3A1 lead to premature termination of translation and nonsense-mediated decay causing half the normal amount of type III collagen to be secreted which typically produces a milder clinical phenotype ^{12, 13}.

The clinical manifestations observed in individuals with vEDS has historically been attributed to tissue “fragility” based on the fact that there are decreased amounts of type III collagen secreted by these cells. ^{4, 14}. Questions were raised as to whether this tissue fragility was the responsible factor for the vascular manifestations observed in patients with vEDS after data emerged from a type III collagen deficient mouse (Col3a^-/-). When compared with their wild-type littermates, these mice developed spontaneous skin lesions and organ rupture, which limited their life-span to 20% of their wild-type counterparts ¹⁵. Interestingly, the heterozygous Col3a1^+/- mice did not demonstrate a predisposition to arterial or organ rupture and had a normal life-span ¹⁵. Additionally, biomechanical manipulation of Col3a1^+/- aortas showed that they could equally withstand rupture similar to wild-type tissues under extreme and supraphysiologic pressures (>800mgHg) ¹⁶. Altogether, this suggests that the frank concept of tissue fragility caused by decreased levels of type III collagen may not fully explain the austere clinical manifestations observed in vEDS.

In this issue of Circulation: Cardiovascular Genetics, Moriessette et al.¹⁷ provide to further support that the vascular disease in patients with vEDS is not merely due to tissue fragility. They sought to quantify circulating biomarkers involved in vascular inflammation (TGF-β1, TGF-β2, MCP-1, C-reactive protein (CRP), ICAM-1 and VCAM-1, in patients with vEDS. The study participants (n = 41) were all confirmed to have disease-causing COL3A1 mutations; the control group (n = 74) was age-, gender- and body mass index (BMI)-matched to the vEDS participants. The majority of the cases were the first family member diagnosed (n = 28); 13 participants were family members of index cases. The markers of vascular inflammation were significantly elevated in the patients with vEDS compared with matched controls. In addition, TGF-β1 and TGF-β2 levels were also increased. Platelets store TGF-β1 and therefore the increased turnover of platelets could be responsible for the increased circulating levels of this growth factor. Interestingly, circulating IL-8 levels, a cytokine typically classified as proinflammatory, were decreased in the vEDS patients when compared to controls.

Thus, many of the established biomarkers of vascular inflammation, including markers of endothelial dysfunction, such as VCAM-1, ICAM-1 and MCP-1, and an acute phase reactant, CRP, are increased in the vEDS patients. The first and a critical question that these data evoke is whether these markers will have clinical utility. Specifically, will they aid is predicting the life-threatening vascular complications in vEDS? CRP has proven to be a robust marker for predicting coronary artery disease, in part because it has a large dynamic range and long half-life. Although CRP is a marker for risk for atherosclerosis, the role of this protein in progression of the disease is not as clearly delineated. Interestingly, although VCAM-1 clearly plays a pathologic role in atherosclerosis, plasma V-CAM levels are not as predictive of coronary events as CRP ¹⁸.

Therefore, can one or more of these inflammatory markers play a role in predicting vascular events in vEDS patients? Although the friable tissues hinder surgical repair, recent studies indicate that surgical repair of vEDS patients in an elective setting improve surgical outcomes⁷. Therefore, a clinically useful biomarker would aid in the timing of elective repair of aneurysms and stable dissections. However, spontaneous dissection or rupture of a non-dilated artery also occurs in vEDS patients and these vascular complications are difficult to prevent. Additionally, such biomarkers can be useful in treatment trials. Therefore, it would be useful to investigate if levels of the inflammatory markers decreased in vEDS patients treated with celiprolol.

These data also raise the question as to why these inflammatory markers are increased in patients in vEDS. Vascular inflammatory markers are increased in many conditions that predispose the vascular events. With atherosclerosis, circulating levels of inflammatory markers increase due to ongoing atherosclerotic pathology in the arterial wall^19,20. Levels of CRP, VCAM-1 and ICAM-1 are elevated in obstructive sleep apnea through a different mechanism. The hypoxia associated with sleep apnea leads to the vascular oxidative stress, inflammation, endothelial dysfunction, thereby decreasing nitric oxide production and increasing platelet activation²¹. VCAM-1, ICAM-1 and CRP are also elevated in patients with sickle cell disease at baseline²². Microvascular occlusion and chronic inflammation are the hallmarks of vaso-occlusive crises in these patients. Although the details of the underlying pathophysiology remains unclear, it is thought to be the result of a complex and dynamic interplay between sickled red blood cells (RBCs), endothelial cells, leukocytes, platelets, and various plasma proteins. Interestingly, evidence suggests that in patients with sickle cells disease, circulating platelets are chronically activated in the non-crisis steady state²³.

Why would decreased production of type III collagen lead to increased markers of vascular inflammation and platelet turnover? Cutaneous manifestations of vEDS suggest that there is an aberrant wound healing response with loss of type III collagen. Thin, translucent skin with dehiscence of surgical wounds, fistulas, and wide atrophic or papyraceous scars indicate an aberrant response to tissue injury that may also occur when the arterial wall is injured. Tissue injury initiates the wound healing program, a well-described phenomenon involving three overlapping phases: acute hemostasis and early inflammation, subacute proliferative of myofibroblasts and the formation of highly vascularized granulation tissue, and prolonged remodeling and contraction of matrix scar^24,25. Thus, injury of an artery may lead to increased levels of inflammatory markers. It is also interesting to note that recent investigations have drawn parallels between traditional cutaneous wound healing and the resolution of intravascular thrombi. Similar to a wound, clot resolution begins with polymerized fibrin at the injury site forming a nidus for recruitment of inflammatory cells, followed by a wave of migrating fibromuscular cells entering the clot to synthesize, remodel, and contract provisional matrix into collagenous scar tissue and vascularization of the clot, and then the resolution into intimal lesions of smooth muscle cells^26-28. Since type III collagen is required for a proper wound healing response, it may play a similar role in thrombus resolution. Thus, decreased type III collagen could delay thrombus resolution, thereby leading to elevated markers of vascular inflammation and increased platelet turnover. In contrast to sickle cell disease and sleep apnea, vascular complications in patients with vEDS involve large to small arteries but not the microvascular bed. Therefore, it is unlikely that the microvasculature would be involved in this disease.

As is the rule in research, the current study showing increased markers of vascular inflammation and platelet turnover in vEDS raises further questions about whether these markers could play a role in predicting the arterial complications in patients with vEDS. Although the initial study provided some encouraging preliminary data suggesting that the markers could potentially correlate with severity of disease, further prospective studies are needed. Additionally, exploring why these markers are increased at baseline in patients with vEDS may provide novel insight into the molecular pathology driving the vascular disease, another step to improving the medical treatment to prevent vascular disease and premature deaths in these patients.