Novel pharmacological approaches in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.

The hepatoprotective potential of resveratrol in an experimental model of ruptured abdominal aortic aneurysm via oxidative stress and apoptosis.

The mortality rate in ruptured abdominal aortic aneurysms can today be reduced through cardiovascular surgery. However, ischemia and reperfusion-induced tissue damage develop due to aortic cross-clamping applied during surgery. The present study aimed to reduce oxidative stress-induced hepatic damage resulting from ischemia and reperfusion due to aortic cross-clamping during surgery by means of resveratrol administration. Forty male Sprague-Dawley rats were randomly assigned into four groups: control (healthy), glycerol+ischemia/reperfusion (I/R) (sham), I/R, and I/R + Resveratrol. In all groups scheduled for I/R, 60 min of shock was followed by 60 min of ischemia. In the I/R + Resveratrol group, 10 mg/kg of resveratrol was administered 15 min before ischemia and immediately before reperfusion via the intraperitoneal route. In addition, 120 min of reperfusion was applied under anesthesia after ischemia in all groups. Intralobar and interlobar necrosis, vascular congestion, and edematous fields resulting from aortic occlusion were present. Liver tissue malondialdehyde (MDA) levels and cleaved caspase-3 positivity increased, while glutathione (GSH) levels decreased. However, resveratrol administration reduced intralobular and interlobar necrosis, vascular congestion and edematous fields, cleaved caspase-3 positivity, and MDA levels, and increased GSH levels. Our findings suggest that resveratrol is effective against aortic occlusion-induced liver injury by reducing oxidative stress and apoptosis.

Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model.

Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

IgG4-Aortopathy: An Underappreciated Cause of Non-Infectious Thoracic Aortitis.

IgG4 related thoracic aortitis is a recent addition to the differential diagnosis for inflammatory aortic disease - a condition which is often underappreciated until complications arise such as aneurysmal formation or aortic dissection. Currently, IgG4 aortitis remains a post-surgical diagnosis reliant on positive immunohistochemistry findings. Management is guided by the extent of disease involvement, which can be gauged by serum IgG4 levels and radiological findings. Options include surgical resection, corticosteroid therapy and steroid-sparing agents to prevent relapses.

Mineralocorticoid receptor agonists induce mouse aortic aneurysm formation and rupture in the presence of high salt.

OBJECTIVE: Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in patients with heart failure. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown. APPROACH AND RESULTS: We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or aldosterone and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin-converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt-induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt- or aldosterone and salt-induced aortic aneurysm. CONCLUSIONS: The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms.

Research advances in drug therapy for abdominal aortic aneurysms over the past five years: An updated narrative review.

BACKGROUND: Abdominal aortic aneurysms (AAA) rupture can lead to patient death. Surgical treatment is currently the optimal treatment for AAA with large diameter (≥50 mm). For AAA with small diameter (30-50 mm), how to administer effective pharmacological treatment to reduce aneurysm expansion rate and rupture risk is the current focus in the field of vascular surgery. There is still no effective drug for the treatment of asymptomatic AAA. METHODS: This article searches the PubMed, Web of Science, Embase, and Cochrane databases for clinical studies on the drug treatment of abdominal aortic aneurysms in the past 5 years. The latest progress in the drug treatment of AAA was reviewed, including antibiotics, antihypertensive drugs, antiplatelet drugs, hypoglycemic drugs, hypolipidemic drugs, mast cell inhibitors and corticosteroids. RESULTS: 25 studies were included in this narrative review. Among them, metformin revealed therapeutic effect in 2 prospective cohort study and 3 retrospective cohort study. The therapeutic effect of statins was controversial in 3 retrospective cohort study. However, the definite therapeutic effects of antihypertensive agents, antibiotics, mast cell inhibitors, antiplatelet agents and corticosteroids on abdominal aortic aneurysms have not been verified in prospective studies. CONCLUSION: Metformin provided a positive effect in reducing expansion rate, rupture risk, and perioperative mortality. The therapeutic effect of statins was controversial, which warrant further validation in prospective cohorts. However, there is still a lack of effective agents for the treatment of AAA based on recent studies.

Targeted Drug Delivery of Microbubble to Arrest Abdominal Aortic Aneurysm Development: A Simulation Study Towards Optimized Microbubble Design.

Abdominal aortic aneurysm (AAA) is an irreversible bulge in the artery with higher prevalence among the elderlies. Increase of the aneurysm diameter by time is a fatal phenomenon which will lead to its sidewall rupture. Invasive surgical treatments are vital in preventing from AAA development. These approaches however have considerable side effects. Targeted drug delivery using microbubbles (MBs) has been recently employed to suppress the AAA growth. The present study is aimed to investigate the surface adhesion of different types of drug-containing MBs to the inner wall of AAA through ligand-receptor binding, using fluid-structure interaction (FSI) simulation by using a patient CT-scan images of the vascular system. The effect of blood flow through AAA on MBs delivery to the intended surface was also addressed. For this purpose, the adherence of four types of MBs with three different diameters to the inner surface wall of AAA was studied in a patient with 40-mm diameter aneurysm. The effects of the blood mechanical properties on the hematocrit (Hct) percentage of patients suffering from anemia and diabetes were studied. Moreover, the impact of variations in the artery inlet velocity on blood flow was addressed. Simulation results demonstrated the dependency of the surface density of MBs (SDM) adhered on the AAA lumen to the size and the type of MBs. It was observed that the amount of SDM due to adhesion on the AAA lumen for one of the commercially-approved MBs (Optison) with a diameter of 4.5 µm was higher than the other MBs. Furthermore, we have shown that the targeted drug delivery to the AAA lumen is more favorable in healthy individuals (45% Hct) compared to the patients with diabetes and anemia. Also, it was found that the targeted drug delivery method using MBs on the patients having AAA with complicated aneurysm shape and negative inlet blood flow velocity can be severely affected.

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-α 1 chain of collagen III. Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. We created 2 mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glycine substitutions analogous to those found in patients, and we showed that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase) are major mediators of vascular pathology. Treatment with pharmacologic inhibitors of ERK1/2 or PKCß prevented death due to spontaneous aortic rupture. Additionally, we found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, was rescued by attenuation of oxytocin and androgen signaling, respectively. Taken together, our results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.

Turning back the clock: regression of abdominal aortic aneurysms via pharmacotherapy.

Abdominal aortic aneurysm (AAA) is a common disease that causes progressive expansion and rupture of the aorta with high mortality. There is a large and unmet need for nonsurgical treatment for AAA. Research has shown that an intricate network of inflammatory cells and interstitial cells contributes to the formation of AAA by producing pro-inflammatory mediators that activate enzymes to degrade the extracellular matrix (ECM) and impair ECM biosynthesis. Pharmacological agents such as statins and angiotensin-converting enzyme inhibitors may promote tissue stabilization in AAA by diminishing pro-inflammatory signaling and normalizing metabolism of the ECM. Our recent experiments in animal models demonstrate that inhibition of c-Jun N terminal kinase (JNK) inhibits multiple pathological processes and causes regression of established AAA. Thus, emerging evidence indicates that pharmacological intervention targeting pro-inflammatory signaling and abnormal ECM metabolism is a promising strategy for treatment of AAA.

A Salmonella infection complicated with suppurative thyroiditis and ruptured aortic mycotic aneurysm in a renal transplant recipient.

We report a renal transplant recipient who presented with fever and chills for 2 days. The blood and stool cultures revealed the growth of Salmonella enteriditis. A whole-body gallium scan played an important role in the subsequent diagnosis of suppurative thyroiditis. To our knowledge, this is the first report of acute S. enteriditis thyroiditis in a renal transplant recipient. Despite vigorous antibiotic use and a partial thyroidectomy, he experienced recurrent S. enteriditis infection, resulting in a ruptured thoracic mycotic aneurysm 1 month later. Finally the patient was successfully cured with aneurysm resection, in situ reconstruction of the thoracic aorta, and prolonged antibiotics.

Current Status and Perspectives on Pharmacologic Therapy for Abdominal Aortic Aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA), a common disease involving the segmental expansion and rupture of the aorta, has a high mortality rate. Therapeutic options for AAA are currently limited to surgical repair to prevent catastrophic rupture. Non-surgical approaches, particularly pharmacotherapy, are lacking for the treatment of AAA. OBJECTIVE: We review both basic and clinical studies and discuss the current challenges to developing medical therapy that reduces AAA progression. RESULTS: Studies using animal models of AAA progression and human AAA explant cultures have identified several potential targets for preventing AAA growth. However, no clinical studies have convincingly confirmed the efficacy of any pharmacologic treatment against the growth of AAA. Thus, there is as yet no strong recommendation regarding pharmacotherapy to reduce the risk of AAA progression and rupture. CONCLUSION: This review identifies concerns that need to be addressed for the field to progress and discusses the challenges that must be overcome in order to develop effective pharmacotherapy to reduce AAA progression in the future.

[Optimizing medical treatment of abdominal aortic aneurysm: Interest of vascular centers]. / Optimiser le traitement médical de l'anévrysme de l'aorte abdominale : intérêt des centres vasculaires.

Diagnosis of abdominal aortic aneurysm (AAA) at preoperative stage is increasingly frequent. It carries both a local risk of rupture and an increased global cardiovascular risk. Patients with AAA have indeed a 20 times higher risk of dying from myocardial infarction or stroke than from a ruptured aneurysm. Cardiovascular risk factors control is therefore essential, particularly smoking cessation. Treatment in cardiovascular prevention is also warranted. Seeking for atheromatous sites is needed as they determine prognosis. Evidence of the benefit of medical treatment to slow AAA growth is still lacking. In practice, it is recommended to prescribe statins and angiotensin converting enzyme inhibitor to prevent cardiovascular events. These preventive measures are as well necessary to improve postoperative prognosis and must be continued after surgical repair. A vascular medical and surgical cooperation is primordial to enhance comprehensive management of patients with AAA.

Optimal Time for Pharmacological Treatment of Abdominal Aortic Aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA), if left untreated, poses the main risks of progressive expansion, rupture, and hemorrhage, leading to death. Large AAA with a risk of rupture is usually treated by graft replacement or endovascular aneurysm repair. Nonsurgical treatment is not an alternative for large AAA, but is potentially beneficial for small AAA which usually requires a watchful waiting approach with medication. OBJECTIVE: We introduce current clinical research regarding the pharmacological treatment of small AAA and assess the optimal time for starting the treatment. RESULTS: Data from current clinical researches on pharmacological treatment of AAA investigating the efficacy of pharmacological treatment to limit AAA growth were presented and introduced the medicines currently evaluated by randomized controlled trials for their efficacy for AAA. CONCLUSION: The optimal time to administer pharmacological treatment for AAA is during the stage wherein its diameter is still small. To detect early small-diameter AAA, screening tests are mandatory in high-risk patients. For pharmacological treatment, the drug that shows acceptable results in clinical tests and is the most effective for the patient's condition should be carefully selected. Lifestyle changes should also accompany pharmacological treatment.

Anesthetic management of cesarean delivery in parturients with ruptured sinus of Valsalva aneurysm: CARE-compliant 2 case reports and literature review.

RATIONALE: Ruptured sinus of Valsalva aneurysm is rare and dangerous in parturients. Few cases of ruptured SVA in pregnancy are reported, and the anesthetic management for cesarean delivery has scarcely been described. PATIENT CONCERNS: A parturient at 37-week gestation complained of a sore throat and cough that started 3 days before admission, followed 1 day later by fever, dizziness, breathlessness, and palpitation on exertion. Case two at 36-week gestation complained of a 1-day history of bloating in the lower abdomen. DIAGNOSES: Full term and preterm parturients with ruptured sinus of Valsalva aneurysm. INTERVENTIONS: Cesarean deliveries were performed with incremental epidural anesthesia technique under invasive monitoring. Surgical correction of the ruptured sinus of Valsalva aneurysms and ventricular septal defect were performed uneventfully 13 days and 7 days postpartum, respectively, for the 2 cases. OUTCOMES: No complications were observed in the intra- or postoperative period for both mothers and babies. LESSONS: We reviewed the pertinent literature and reached the following conclusions: use of a multidisciplinary team to guide anesthetic management is helpful and necessary; and both general anesthesia and incremental epidural anesthesia can be safely used in parturients with ruptured sinus of Valsalva aneurysm.

Ruptured penetrating ulcer of the ascending aorta with pulmonary artery compression.

Pulmonary artery involvement has been reported in various degrees of complicated dissection of the ascending aorta. The prognosis remains poor without high-risk surgical intervention, but conservative management can be considered in high-risk cases. We report a case of nonoperative management of an octogenarian who presented with a contained rupture of his proximal ascending aorta, likely from a penetrating atherosclerotic ulcer. It was complicated by extrinsic compression of the pulmonary trunk and transient pulmonary hypertension without features of acute right heart failure. He remained alive at the one-year follow-up.

Nutrition therapy for the critically ill surgical patient with aortic aneurysmal rupture: defining and improving current practice.

BACKGROUND: Our goal is to define nutrition therapy in critically ill patients after surgical repair of acute ruptured or dissecting aortic aneurysm to identify opportunities for quality improvement. METHODS: International, prospective studies in 2007-2009 and 2011 were combined. Sites provided institutional and patient characteristics including from intensive care units (ICUs) admission to ICU discharge for a maximum of 12 days. We selected patients with aortic aneurysmal rupture or acute dissection staying in the ICU for ≥ 3 days. RESULTS: There were 104 eligible patients from 72 distinct ICUs analyzed. Overall, 86.5% received artificial nutrition. There were 50.0% patients who received enteral nutrition (EN) only, 29.8% patients received a combination of EN and parenteral nutrition (PN), 6.7% patients received PN only, and 13.5% did not receive any nutrition. The mean time from admission to initiation of EN was 3.0 days (SD ± 2.4 days). The adequacy of calories from nutrition support was 46.8% (range 0%-111%) with a mean of 10.0 kcal/kg/day. Of the total of 83 patients who received EN, 53 patients (63.8%) had interruption of EN. The reasons included fasting, intolerance, patients deemed too sick for enteral feeding, and loss of enteral feeding route. For patients with gastrointestinal intolerance, 3/30 patients (10%) received small bowel feeding and 23/30 patients (76.7%) of patients received motility agents. CONCLUSION: Postoperative critically ill patients with aortic aneurysmal rupture or acute dissection are at high risk for inadequate nutrition therapy, and there may be inadequate utilization of strategies to improve nutrition uptake.

Medical management of acute traumatic rupture of the aorta.

Surgical reconstruction is the treatment for acute traumatic aortic rupture and should be accomplished immediately in most patients. In patients in whom concomitant injuries or the development of life-threatening complications preclude safe and successful aortic reconstruction, pharmacological intervention to reduce the risk of free aortic rupture may be considered. Surgical reconstruction can then be more safely performed under controlled elective circumstances.

Vascular emergencies.

This article reviews the initial assessment and emergent management of several common as well as uncommon vascular emergencies. Aortic dissection, aneurysms, and arterial occlusive disease are familiar but challenging clinical entities. Less frequently encountered conditions are also discussed including an aortic enteric fistula, mesenteric venous thrombosis, phlegmasia alba dolens, and subclavian vein thrombosis.

Ruptured mycotic salmonella aortic aneurysm treated with combined cefotaxime antibiotic and staged surgical management.

A case of salmonella infrarenal aortic aneurysm that ruptured and was treated with staged operative procedures and a highly effective antibiotic is reported and analyzed. An emergency situation with a ruptured abdominal aortic aneurysm required prompt surgical intervention with an aortobifemoral graft insertion. In the immediate postoperative period it was realized that a prosthetic graft was placed in the bed of a mycotic aneurysm. The patient had significant arteriosclerotic occlusive disease limiting the distal anastomotic site to the common femorals. Interoperatively the superficial femorals were noted to be occluded chronically. Consequently, revascularization via an extra-anatomical bypass after aortobifemoral graft removal was more complex. This was managed in a staged delayed fashion, while suppressing the infecting organism with Cefotaxime. The details of this complex situation are described within.

Nicardipine hydrochloride injectable phase IV open-label clinical trial: study on the anti-hypertensive effect and safety of nicardipine for acute aortic dissection.

We performed a multicentre, phase IV, open-label clinical trial to examine the clinical usefulness of a continuous infusion of nicardipine hydrochloride to control hypertension in 31 patients with acute aortic dissection. Target blood pressure levels were reached within 15 min in 16 patients; in 15-30 min in 10 patients; in 30-45 min in three patients; and in 45-60 min in two patients. Baseline average systolic, diastolic and mean arterial blood pressures were 147 +/- 23 mmHg, 82 +/- 18 mmHg and 104 +/- 18 mmHg, respectively, with third-day pressures significantly reduced at 119 +/- 12 mmHg, 69 +/- 9 mmHg and 86 +/- 8 mmHg. Blood pressures after discontinuation of the infusion were not significantly different from those measured on the third day of infusion and no definite adverse effects attributable to the treatment were observed. Nicardipine hydrochloride was both effective and safe at controlling blood pressure in patients with acute aortic dissection.