Lower Limb Malperfusion in Acute Type A Dissection

Abstract

We have previously shown that patients with abdominal aortic aneurysm (AAA) have decreased number and diminished immune suppressive function of regulatory type 1 T cells (Tr1) and increased numbers of activated effector Th17 cells. The objective of this clinical trial was to assess the efficacy of allogeneic mesenchymal stem cells (MSCs) in inducing Tr1 cells and suppressing AAA inflammation. Methods: The AneuRysm Repression with mEsenchymal STem cells (ARREST) trial is a blinded, placebo-controlled phase 1 study in which patients with small AAA (30-to 50-mm diameter) are randomized to intravenous infusion of placebo (plasmalyte A), 1 million MSCs/kg, and 3 million MSCs/kg (n ¼ 12/group). Blood samples are collected at baseline and at days 3, 7, 14, 28, and 60 and yearly. The primary end point is change in the ratio of Tr1:Th17 cells at 14 days after treatment using flow cytometry. Secondary end points are changes in FoxP3 + T-regulatory cells, myeloid-derived suppressor cells, microRNA profiles, serum cytokine levels, changes in AAA inflammation as measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography, and changes in aneurysm diameter and volume at years 1 to 5. Results: Twenty-one patients have been enrolled to date. There have been no treatment-related adverse events, and one patient withdrew after discovery of an occult pulmonary malignant neoplasm on baseline positron emission tomography/computed tomography. At day 14, the ratio of Tr1:Th17 cells increased by 20.3 6 1.3-fold from baseline for the highdose MSC group (n ¼ 7) compared with 4.3 6-fold for the low-dose group (n ¼ 7; P < .01) and À10 .66 2.3-fold for the placebo group (n ¼ 7; P ¼ .001; Fig). There was a decrease in 18-fluorodeoxyglucose uptake as measured by standard uptake values by 5.6% 61.3% in the combined MSC group (n ¼ 7) compared with an increase in standard uptake values of 4.1% 6 1.0% in the placebo group (n ¼ 4; P < .05). Although the sample size was too small for statistical comparison, the average increase in maximal transverse diameter of AAA at 12 months after treatment was À1.6 6 0.6 mm in the combined MSC group (n ¼ 4) and 4.3 6 0.9 mm in the placebo group. Conclusions: The results of the ARREST trial demonstrate a significant increase in Tr1 cells concurrent with a decrease in cytotoxic effector Th17 cells in an MSC dose-dependent fashion, achieving the primary end point. Preliminary data suggest that aneurysm inflammation and expansion are decreased with MSC treatment.

Malperfusion in Acute Type A Aortic Dissection: Management Strategies

“…12,39 Rteil and colleagues support this approach as 61% of limb malperfusion in 62 of their patients resolved with a simple proximal arch repair of the dissection itself, without any need for further intervention. 25 However, a quarter of patients in this study required further vascular intervention to reperfuse the lower limbs with cannula driven bypass. 25 Other investigations also confirm if persistent post-operative ischaemia remains, more radical management may be required, such as limb amputation.…”

“…25 However, a quarter of patients in this study required further vascular intervention to reperfuse the lower limbs with cannula driven bypass. 25 Other investigations also confirm if persistent post-operative ischaemia remains, more radical management may be required, such as limb amputation. 40,41 There are few authors that advocate a lag to intervention because the risk of mortality associated with an aggressive approach is high, despite the chance of limb preservation.…”

“…25 However, a quarter of patients in this study required further vascular intervention to reperfuse the lower limbs with cannula driven bypass. 25 Other investigations also confirm if persistent post-operative ischaemia remains, more radical management may be required, such as limb amputation. 40,41…”

“…Limb malperfusion in ATAAD has an incidence of 15-40% (Table 1) but the consequences ultimately are less severe than other malperfusion syndromes. 12,25 Its presence still confers a risk of mortality to the patient, so effectively timed management remains crucial. 23 Clinically, in addition to the classic tearing chest pain associated with aortic dissection, weak or absent pulses and blood pressure variation in the limbs is an early indication of limb malperfusion, confirmed with CT angiography.…”

“…12 However, the presence of limb malperfusion makes it more likely for other malperfusion syndromes to manifest. 12,25,42 Superimposed onto the lower limb malperfusion, the mortality rates become worse and the likelihood of further complex management on top of the arch repair is more likely. In some cases, loss of the affected limb is a potentially devastating outcome for patients.…”