New Lessons on the Great Vessel

When a center performs the world’s largest volume of aortic surgeries, the abundance of cases offers unique opportunities to study underlying causes of aortic disease and new therapeutic approaches. Cleveland Clinic’s Aorta Center is running with those opportunities, as reflected in a flurry of new research papers on diverse aspects of inflammatory disease of the aorta.

A multidisciplinary imperative

Over the past 15 years, Cleveland Clinic has grown its thoracic aorta surgical volumes sixfold, making its aortic surgery program the largest in the world. The program’s overall 4 percent operative mortality rate (in-hospital or 30-day, whichever is longer) is likewise one of the lowest in the world despite a challenging patient mix: 29 percent of the 1,196 aorta operations performed in 2014 were emergency procedures. For elective operations — e.g., elective ascending aorta or root operations — the mortality rate is 0.5 to 1.0 percent.

Yet surgery is only the capstone of the Aorta Center’s multidisciplinary offerings, which draw on the expertise of Cleveland Clinic rheumatologists, pathologists, genetic counselors and other specialists in addition to cardiologists and cardiothoracic and vascular surgeons.

“We believe aortic disease should be treated like cancer, with a multidisciplinary team and lifelong care,” says thoracic and cardiovascular surgeon Eric Roselli, MD, Director of the Aorta Center. “This approach is particularly valuable for inflammatory and autoimmune diseases of the aorta, where we collaborate on patient care and in exciting research with world leaders in vasculitis.”

Leveraging premier vasculitis expertise

He’s speaking of the Center for Vasculitis Care and Research in the Department of Rheumatic and Immunologic Diseases, directed by Carol Langford, MD, MHS.

“Any time our surgical colleagues make an unexpected diagnosis of aortitis during surgery, they can reach our vasculitis specialists immediately,” says Dr. Langford. “We work closely with our vascular pathology colleagues to confirm the diagnosis and then plan the patient’s medical evaluation and need for medical management.”

Aortitis is seen in 5 to 15 percent of thoracic aneurysms and is speculated to be an autoimmune process. It may occur as a process limited to the thoracic aorta, as a secondary vasculitis due to a range of illnesses or as a component of primary systemic large-vessel vasculitis, most commonly giant cell arteritis (GCA) or Takayasu arteritis (TAK).

“In patients with known GCA or TAK, we consult with the surgeon to coordinate the timing of surgery with ongoing medical treatment to optimally manage their blood vessel inflammation and damage,” Dr. Langford notes.

New classification of aortitis patterns

This intersection of long-standing leadership in vasculitis and aortic surgery enabled Cleveland Clinic experts to recently publish an analysis in the Journal of Thoracic and Cardiovascular Surgery of the largest reported series of patients undergoing surgery for ascending or aortic arch disease — 7,551 such patients from 1996 to 2012.

They found that 156 of these patients (2 percent) had histologically confirmed aortitis. Using observations in these patients along with earlier reports, the researchers developed a classification of aortitis types to enable better targeting of treatment (see table and figure).

Figure. New classification of aortitis types, from type 1 on the left through type 4 on the right. See table above for an overview of each type.

The researchers concluded that good results for patients with aortitis are achievable with surgery, and that intervention should be based on the clearest possible understanding of the histologic pattern and extent of disease.

“The aim of surgical intervention is to correct the anatomic problem, reduce the risk of pseudoaneurysm formation, prevent paravalvular leaks, prevent continued destruction from the disease and prepare for later disease progression,” explains Dr. Roselli, who co-authored the paper.

Anticipating future surgeries

In view of the chronic nature of aortic disease, Dr. Roselli and his fellow Aorta Center surgeons also take a “great vessel tailored” approach to treatment that plans for the likelihood of future surgeries.

Because many patients with an aneurysm in one section of the aorta have disease in other segments, they may need another surgery within five years. The surgeons often prepare for the second operation during the first one.

“Extending the repair into the arch with bypasses to the carotid arteries and leaving a cuff of graft or performing a prophylactic elephant trunk repair eliminates the need for two more open surgeries,” says Dr. Roselli. It also allows the second operation to be done endovascularly with placement of a stent graft into the previously placed surgical graft.

Choice of surgical approach is always individualized. High-risk patients and those unlikely to need a second repair may be treated with less-invasive techniques. In patients with multiple comorbidities, only the immediate threat may be addressed.

Identifying a novel autoantigen in aortitis

Other collaborations between the Aorta Center’s cardiovascular staff and Dr. Langford’s team of vasculitis experts include ongoing studies of biomarkers and clinical trials of new treatments. “We’re focused on trying to understand the underlying basis of these diseases,” Dr. Langford says. “There’s much we have yet to learn, and knowing the triggers could provide insights into better treatments.”

One avenue of research initiated and being advanced by Center for Vasculitis Care and Research founder Gary Hoffman, MD, recently culminated in the discovery of a novel autoantigen that appears to play a role in the pathogenesis of aortitis (Arthritis Rheumatol. 2015;67:1913-1921).

“We found that 78 percent of patients with large-vessel vasculitis produced antibodies to aortic proteins in the 14-3-3 family,” says the paper’s lead author, Ritu Chakravarti, PhD, of Cleveland Clinic’s Lerner Research Institute. “In contrast, patients with noninflammatory aortic conditions were usually 14-3-3 antibody-negative.” (The 14-3-3 family of proteins perform important cell signaling functions.) “We’re hopeful this novel finding may lead to use of 14-3-3 antibodies as a noninvasive biomarker for diagnosis and disease activity.”

Another avenue of investigation in large-vessel vasculitis has involved international collaborations with the NIH-funded Vasculitis Clinical Research Consortium. These involve biomarker/genetic studies and investigations of patient-reported outcomes, imaging techniques and novel therapeutics. A recent NIH-funded clinical trial funded is evaluating the safety and effectiveness of the biologic agent abatacept (CTLA4-Ig) in GCA and TAK.

Another focus: Marfan and other genetic syndromes

Care of patients with Marfan syndrome and other connective tissue disorders is another focus of the Aorta Center’s multidisciplinary team. Because these patients are at heightened risk for aortic aneurysms and valve disease, they are treated with appropriate medications and monitored closely. When surgery is needed to repair an aneurysm or repair or replace a valve, Aorta Center surgeons provide innovative, expert care.

Aortic root aneurysms are a common complication of Marfan syndrome. Affected patients are offered the modified David reimplantation procedure. Developed by Lars Svensson, MD, PhD, Chairman of Cleveland Clinic’s Sydell and Arnold Miller Family Heart & Vascular Institute, this technique enables the aneurysm to be repaired while preserving the patient’s native valve. It improves outcomes by determining the appropriately sized aorta graft and maintaining the left ventricular outflow tract. For the 655 patients who have undergone modified reimplantations at Cleveland Clinic, substudies have shown a mortality rate of less than 0.5 percent and a 10-year freedom-from-reoperation rate of 95 percent.

The diagnosis of Marfan syndrome is confirmed with a genetic test, after which close medical supervision is provided to manage complications. The Aorta Center advises patients’ family members to be tested as well, and genetic counselors work with patients and families to help them understand how the syndrome may be passed to future generations.

The gene mutations responsible for Marfan syndrome are among a group of at least eight mutation types associated with aortic disease. For this reason, tissue and blood samples are preserved from aortic surgery patients who agree to participate in one of several tissue banking efforts offered by the Miller Family Heart & Vascular Institute. “If we learn of a new gene mutation, we can screen the samples again,” Dr. Roselli explains.

Enhancing follow-up and data collection

Genetic counselors likewise figure into the Aorta Center’s efforts to enhance its Aortic Follow-Up Clinic, where patients are closely monitored after surviving an aortic emergency. “Thirty to 40 percent of these patients will require another surgery, so they need to be followed by their surgeon and by a cardiologist for blood pressure management,” says Dr. Roselli. “We also engage genetic counselors to advise patients and families, and we’ve been working to make that process more seamless and improve preventive care for patients and family members.”

The Aorta Center has also begun collecting data on patients who haven’t yet had surgery, to better understand the natural history of aortic disease. That effort aligns with a newly created database specifically for patients with aortic disease that features a structured reporting mechanism created in concert with Cleveland Clinic cardiovascular imaging specialists. “It allows us to harvest and analyze data more easily,” Dr. Roselli notes.

The aim is accelerated research efforts. So stay tuned: More insights are likely on the way.