Immune-modulating cells may slow small AAA progression; COVID-19 may quicken it
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Key takeaways:
- IV administration of immune-modulating cells could slow progression of small abdominal aortic aneurysms.
- Prior SARS-CoV-2 infection may cause rapid abdominal aortic aneurysm enlargement.
IV allogeneic mesenchymal stromal cells may reduce inflammatory response and thereby reduce the progression of small abdominal aortic aneurysms, a speaker reported.
A second study presented at the American Heart Association’s Vascular Discovery: From Genes to Medicine Scientific Sessions demonstrated that SARS-CoV-2 infection — in addition to other risk factors — could cause further progression of AAAs.
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Immune-modulating cells to slow AAA progression
“Anyone who has ever overinflated a balloon knows that too much pressure is likely to cause a rupture. In the aorta, this creates a true medical emergency because approximately 70% of people will die before they reach the hospital, and 50% of those who make it to the hospital will die from blood loss before any intervention is possible,” Humraaz S. Samra, MBBCh, BAO, resident in integrated vascular surgery at the Indiana University School of Medicine in Indianapolis, said in a press release.
For ARREST, a phase 1, double-blind, placebo-controlled trial, Samra and colleagues tested the effects of escalating doses of IV allogeneic mesenchymal stromal cells in modulating inflammation in 28 patients with small AAA compared with placebo (mean age, 66 years; 100% men). Small AAA was defined as an aneurysm of less than 5 cm in diameter.
The primary endpoint was 30-day change in T helper 17 (Th17) cell response and type 1 regulatory T (Tr1) cell function measured by mass cytometry. Secondary endpoints included 30-day change in AAA inflammation measured by PET and 1-year change in AAA volume measured by CT. In addition, the researchers measured changes in plasma cytokines using enzyme-linked immunoassay at 0, 7, 14 and 28 days.
Patients assigned to mesenchymal stromal cell therapy received 1 million (low-dose group) or 3 million (high-dose group) mesenchymal stromal cells per kilograms.
Samra and colleagues observed decreased mean percent Th17 cell response relative to increased Tr1 cell function at day 30 compared with placebo in the high-dose group (73.2% vs. 5.5%; P < .05), but not in the low-dose group.
At day 14, they observed decreased average Th17 cells compared with placebo in both high- and low-dose groups (high dose, 11.1% vs. 9.7; low dose, 13.3 vs. 9.7%; P < .05).
At day 7, interleukin 10 was increased in both the high- and low-dose groups compared with placebo (high dose, 28.8 pg/mL vs. 11.9 pg/mL; P = .034; low dose, 42.7 pg/mL vs. 11.9 pg/mL; P = .023).
The decrease in AAA volume at 1 year among patients treated with high-dose mesenchymal stromal cells nearly reached significance compared with placebo (P = .055), and the researchers reported no treatment-related adverse events.
“We believe that a defect in the expression of ... interleukin (IL)-10 is a key event in the formation of abdominal aortic aneurysms. We have confirmed in lab studies that mesenchymal stromal cells have the potential to turn into cells that are profoundly anti-inflammatory and secrete copious amounts of IL-10 when under the right experimental circumstances,” Samra said in the release. “These data are very promising but still early. We hope to obtain more data to develop clinical trials and hopefully change treatment paradigms, more research needs to be done but we have an exciting start.”
AAA progression after SARS-CoV-2 infection
For the second AAA study presented at the meeting, Baohui Xu, MD, PhD, senior research scientist in the department of surgery at the Stanford University School of Medicine, and colleagues evaluated the association between SARS-CoV-2 infection and other risk factors with AAA progression and the influence of SARS-CoV-2 spike proteins on experimental AAAs.
The study included 175 patients with AAA with at least two measurements of AAA diameter aneurysm, of which 26 patients had SARS-CoV-2 infection.
Mean AAA diameter at baseline was 39.1 mm and the median annual enlargement rate was 0.9 mm.
After univariate analysis, Xu and colleagues observed that SARS-CoV-2 infection was the only risk factor associated with rapid AAA enlargement, defined as more than 2.7 mm per year.
After multivariate logistic regression analysis, the researchers observed that SARS-CoV-2 infection (OR = 9.7), chronic kidney disease (OR = 3.8) and ever smoking (OR = 2) were each associated with rapid AAA enlargement.
Moreover, they observed reverse associations between other risk factors, including cancer (OR = 0.2), cerebrovascular disease (OR = 0.3), diameter measurement interval (OR = 0.8) and BMI (OR = 0.9).
“People who have risk factors for developing abdominal aortic aneurysms, and those already known to have abdominal aortic aneurysms who are having their progression monitored, should know that COVID-19 infection may potentially alter the natural course or outcome of abdominal aortic aneurysms,” Xu said in the release.
The researchers evaluated the experimental impact of SARS-CoV-2 spike proteins on AAA progression in wild-type and human ACE2 transgenic mice by injecting SARS-CoV-2 spike proteins.
Xu and colleagues observed that recombinant SARS-CoV-2 spike protein 1 or its receptor binding domain was associated with accelerated AAA progression in wild-type mice and reduced AAA attenuation in human ACE2 transgenic mice.
SARS-CoV-2 spike protein 2 was not associated with AAA progression.
“Large multicenter studies are needed to validate our findings. We previously confirmed that pneumonia associated with the flu also increased the prevalence of abdominal aortic aneurysm, and other research has found an increased abdominal aortic aneurysm risk in people with HIV infection. Thus, it would be interesting to see whether rapid enlargement of abdominal aortic aneurysm in people with COVID-19 infection is specific to COVID-19 or to respiratory viral infections in general,” Xu said in the release.
References:
- Xu B, et al. Presentation #280. Presented at: American Heart Association’s Vascular Discovery: From Genes to Medicine Scientific Sessions; May 10-13, 2023; Boston.
- Abdominal aortic aneurysm: New treatment may reduce size; COVID infection may speed growth. newsroom.heart.org/news/abdominal-aortic-aneurysm-new-treatment-may-reduce-size-covid-infection-may-speed-growth. Published May 10, 2023. Accessed May 10, 2023.
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Samra H, et al. Presentation #111. Presented at: American Heart Association’s Vascular Discovery: From Genes to Medicine Scientific Sessions; May 10-13, 2023; Boston.
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