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.

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.

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.

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.

[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.

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.

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.

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.

Late aortic silver graft re-infection due to Streptococcus milleri group (Streptococcus anginosus). Case report and literature review / Reinfección tardía de prótesis aórtica de plata debida a grupo Streptococcus milleri (Streptococcus anginosus). Reporte de caso y revisión de la literatura

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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.

Aneurysmal disease: thoracic aorta.

Thoracic aortic aneurysms are clinically significant for their high mortality risk in the face of rupture. This article reviews the natural history and pathophysiology of thoracic and thoracoabdominal aortic aneurysms, discusses the evaluation of these patients, and details the treatment options. Specifically discussed are treatment advances arising from the development of endovascular technology.

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.

Doxycycline does not influence established abdominal aortic aneurysms in angiotensin II-infused mice.

BACKGROUND: There is no proven medical approach to attenuating expansion and rupture of abdominal aortic aneurysms (AAAs). One approach that is currently being investigated is the use of doxycycline. Despite being primarily used as an antimicrobial drug, doxycycline has been proposed to function in reducing AAA expansion. Doxycycline is effective in reducing the formation in the most commonly used mouse models of AAAs when administered prior to the initiation of the disease. The purpose of the current study was to determine the effects of doxycycline on established AAAs when it was administered at a dose that produces therapeutic serum concentrations. METHODS AND RESULTS: LDL receptor -/- male mice fed a saturated-fat supplemented diet were infused with AngII (1,000 ng/kg/min) via mini-osmotic pumps for 28 days. Upon verification of AAA formation by noninvasive high frequency ultrasonography, mice were stratified based on aortic lumen diameters, and continuously infused with AngII while also administered either vehicle or doxycycline (100 mg/kg/day) in drinking water for 56 days. Administration of doxycycline led to serum drug concentrations of 2.3 ± 0.6 µg/ml. Doxycycline administration had no effect on serum cholesterol concentrations and systolic blood pressures. Doxycycline administration did not prevent progressive aortic dilation as determined by temporal measurements of lumen dimensions using high frequency ultrasound. This lack of effect on AAA regression and progression was confirmed at the termination of the study by ex vivo measurements of maximal width of suprarenal aortas and AAA volumes. Also, doxycycline did not reduce AAA rupture. Medial and adventitial remodeling was not overtly changed by doxycycline as determined by immunostaining and histological staining. CONCLUSIONS: Doxycycline administration did not influence AngII-induced AAA progression and aortic rupture when administered to mice with established AAAs.

The use of heparin in patients with ruptured abdominal aortic aneurysms.

The use of systemic heparin in patients with ruptured abdominal aortic aneurysms (rAAAs) remains a contentious issue with no clear guidelines. This review reports the current understanding, at a molecular and clinical level, of the possible benefits and risks of heparin in emergency aneurysm repair (both open and endovascular). MEDLINE, EMBASE, AMED, SCOPUS, CINAHL and Cochrane Library were searched for all articles containing the keywords 'rupture', 'abdominal', 'aneurysm' and 'heparin'. Current experience, indications and outcomes were analyzed. Articles were searched for both endovascular and open repair of AAAs. A total of eight studies were included for analysis in the systematic review. Of these, only one paper focused specifically on heparin use in open repair of ruptures and suggested a benefit. Of the remaining seven, two were self-reporting retrospective studies assessing individual surgeons' practice, one was a case report and the remaining four included mention of heparin use but with no outcome data. The evidence available suggests that a pro-coagulable state exists in rAAAs. This may be responsible for the morbidity and mortality postprocedure, which arises predominantly from multiple organ failure and cardiac compromise rather than outright hemorrhage. This diathesis may respond well to heparin administration, suggesting that heparin administration in ruptured aneurysms is appropriate.

Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: treatment with folic acid.

It has been shown that endothelial NO synthase (eNOS) uncoupling occurs in hypertension and atherosclerosis. However, its causal role in vascular pathogenesis has not been characterized previously. Here, we challenged eNOS preuncoupled hyperphenylalaninemia (hph)-1 mice (deficient in eNOS cofactor tetrahydrobiopterin biosynthetic enzyme GTPCHI) with angiotensin II (Ang II; 0.7 mg/kg per day, 14 days). Both wild-type and hph-1 groups developed hypertension similarly up to day 6 to 7. Thereafter, ≈14% of Ang II-infused (0.7 mg/kg per day) hph-1 mice (n=72) started to die suddenly of ruptured abdominal aortic aneurysm (AAA). Among the survivors, 65% developed AAA, resulting in a total morbidity rate of 79%. In contrast, none of the Ang II-infused wild-type mice died or developed AAA. Ang II progressively deteriorated eNOS uncoupling in hph-1 mice while augmenting tetrahydrobiopterin and nitric oxide (NO(·)) deficiencies. The abundance of the tetrahydrobiopterin salvage enzyme dihydrofolate reductase in the endothelium was decreased in hph-1 mice and further diminished by Ang II infusion. Intriguingly, restoration of dihydrofolate reductase expression by oral administration of folic acid or overexpression of dihydrofolate reductase completely prevented AAA formation in Ang II-infused hph-1 mice while attenuating progressive uncoupling of eNOS. Folic acid also attenuated vascular remodeling and inflammation characterized by medial elastin breakdown and augmented matrix metalloproteinase 2 activity and activation of matrix metalloproteinase 9, as well as macrophage infiltration. In conclusion, these data innovatively suggest a causal role of eNOS uncoupling/tetrahydrobiopterin deficiency in AAA formation. Therefore, oral folic acid administration, endothelium-targeted dihydrofolate reductase gene therapy, and perhaps other countermeasures directed against eNOS uncoupling could be used as new therapeutics for AAA.

In vivo feasibility case study for evaluating abdominal aortic aneurysm tissue properties and rupture potential using acoustic radiation force impulse imaging.

An abdominal aortic aneurysm (AAA) is defined as a permanent and irreversible localized dilatation of the abdominal aorta. A reliable, non-invasive method to assess the wall mechanics of an aneurysm may provide additional information regarding their susceptibility to rupture. Acoustic radiation force impulse (ARFI) imaging is a phenomenon associated with the propagation of acoustic waves in attenuating media. This study was a preliminary evaluation to explore the feasibility of using ARFI imaging to examine an AAA in vivo. A previously diagnosed in vivo aneurysm case study was imaged to demonstrate the viability of excitation of the abdominal aorta using ARFI imaging. Ex vivo experiments were used to assess an artificially induced aneurysm to establish its development and whether ARFI was able to capture the mechanical changes during artificial aneurysm formation. A combination of in vivo and ex vivo results demonstrated a proposed hypothesis of estimation of the tissue's stiffness properties. The study details a method for non-invasive rupture potential prediction of AAAs using patient-specific moduli to generate a physiological stiffness rupture potential index (PSRPI) of the AAA. Clinical feasibility of ARFI imaging as an additional surgical tool to interrogate AAAs was verified and methods to utilize this data as a diagnostic tool was demonstrated with the PSRPI.