Genetically Triggered Aortic Disease Outcomes: On the Long Road to Personalized Medicine

Sex differences in the clinical presentation, diagnosis, and treatment outcomes of cardiac disease have long been recognized. Since the mid-1980s, the total number of deaths from cardiovascular disease has been higher for women than for men. A greater proportion of women (52%) than men (42%) with myocardial infarction die of sudden cardiac death before reaching the hospital, perhaps in part because women tend to have nonspecific prodromal symptoms rather than chest pain and these symptoms are not recognized as being cardiac in origin.1 Even after acute myocardial infarction, women are 46% less likely to undergo coronary angiography than men, despite accounting for confounders.2 Two-thirds of women who suffer a myocardial infarction never completely recover,3,4 and those who do survive have a 2-fold recurrence of myocardial infarction and mortality during the first year compared with their male counterparts.5 Article p 26 Women with stable angina have higher in-hospital mortality rates6 and worse outcomes after coronary interventions, both percutaneous and surgical. Following percutaneous coronary interventions women have higher rates of short- and long-term mortality, cardiac events, and the need for emergency coronary artery bypass grafting. This may relate to the comparatively smaller coronary artery size of women,7 although this is unproven.8 Higher mortality and complication rates of coronary artery bypass grafting also occur, with women obtaining less functional relief, more frequent hospital readmissions, and lower functional gains than their male counterparts.9 Whether some of these sex disparities relate to an autoimmune precursor for atherosclerotic disease remains speculative. Sex-specific differences in C-reactive protein, as an inflammatory marker, are consistent with the 10-fold increased frequency of inflammatory-mediated autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and thyroiditis in women compared with men.4,10 Recent studies report atherosclerotic plaque in both the carotid and coronary arteries …

Background Gender-related biases in outcomes after thoracic aortic surgery are an important factor to consider in the prevention of potential complications related to aortic diseases and in the analysis of surgical results. Methods The aim of this study is to provide an up-to-date review of gender-related differences in the epidemiology, specific risk factors, outcome, and screening and prevention programmes in aortic aneurysms. Results Female patients affected by aortic disease still have worse outcomes and higher early and late mortality than men. It is difficult to plan new specific strategies to improve outcomes in women undergoing major aortic surgery, given that the true explanations for their poorer outcomes are as yet not clearly identified. Some authors recommend further investigation of hormonal or molecular explanations for the sex differences in aortic disease. Others stress the need for quality improvement projects to quantify the preoperative risk in high-risk populations using non-invasive tests such as cardiopulmonary exercise testing. Conclusions The treatment of patients classified as high risk could thus be optimised before surgery becomes necessary by means of numerous strategies, such as the administration of high-dose statin therapy, antiplatelet treatment, optimal control of hypertension, lifestyle improvement with smoking cessation, weight loss and careful control of diabetes. Future efforts are needed to understand better the gender differences in the diagnosis, management and outcome of aortic aneurysm disease, and for appropriate and modern management of female patients.

AORTIC INVOLVEMENT IN TAKAYASU ARTERITIS: A NATIONAL INPATIENT SAMPLE ANALYSIS

To summarize the experience of endovascular repairing aortic arch disease hybrid with supra-arch debranching procedures. It was a retrospective study. From January 2002 to December 2014, 42 high risk patients with aortic arch disease were treated by supra-arch debranching hybrid with subsequent endovascular repair in the First Affiliated Hospital of Sun Yat-sen University. There were 39 male and 3 female patients with a mean age of (53±13) years (ranging from 34 to 80 years). Of the 42 patients, 7 were thoracic aortic aneurysm, 20 were Stanford type B aortic dissection and 15 were Stanford type A aortic dissection. After the supra-aortic debranching technique, simultaneous (n=16) or staged (n=26, mean interval (7±3) days) endovascular repair were performed. Fisher exact test was used to compare the in-hospital mortality of ascending aorta based debranching and non-ascending aorta based debranching. Technical success rate was 81.0% (34/42). The overall 30-day complication rate was 31.0% (13/42), including 3 cerebral stroke (7.1%), 8 endoleak (19.0%, including 6 type I endoleak and 2 type II endoleak), 1 circulatory failure, 1 aorto-tracheal fistula. The 30-day mortality was 9.5% (4/42), 2 died of cerebral stroke, 1 died of circulatory failure, 1 died of aorto-tracheal fistula. The in-hospital mortality of ascending aorta based debranching group was obviously higher than that of the non-ascending aorta based debranching group (4/16 vs. 0, P=0.02). The median time of follow-up was 64.8 (2 to 156.9) months. CT scanning was performed at 1, 3 months after surgery and annually thereafter. The overall survival rate was 76.6%. During the follow-up period, there was 4 deaths, and 2 of them were aortic artery related (5.3%). There were 4 de novo complications during the follow-up period, 1 stroke attributed to bypass occlusion was cured by medical treatment, 2 pseudoaneurysm was successfully treated with open surgery, 1 stent-graft induced new distal entry tear was successfully treated with a tapered stent-graft, there was no new endoleak during follow up period, 3 type I endoleak disappeared spontaneously, and 1 type II endoleak disappeared after secondary intervention. Endovascular repair of aortic arch disease hybrid with supra-arch debranching procedure is low invasive with favorable long-term outcomes. It is suitable for high risk patients of poor general condition with little tolerance to aortic arch replacement. The in-hospital mortality is higher in the ascending aorta based debranching group than in the non-ascending aorta based debranching group. Stroke is a critical fatal complication and should be attached attention.

Data on female patients with atherosclerotic peripheral arterial disease (PAD) are scarce, and limited primarily to the elderly population with multilevel disease. In this longitudinal observational study we compare female patients below 60 years of age with isolated lesions at the aortic bifurcation or focal superficial femoral artery disease. Analysis is based on consecutive series of 43 female patients with PAD limited to the aortoiliac bifurcation (n = 28, group I) or an isolated femoral segment at the adductor channel (n = 15, group II) seen in a tertiary referral center between 1998 and 2000. The first assessment provided baseline data, with follow up data obtained at this study. Traditional risk factors, carotid artery disease and clinical outcome (mortality, cardiovascular events, vascular re-intervention rate, PAD progression) were evaluated over an interval of 5 (2 to 8) years. Female patients with aortic disease [group I] were younger (51.8 +/- 7.7 vs. 56.7 +/- 7.6 years in group II; p = 0.048), presented a more masculine phenotype, and smoked significantly more often (82% vs. 40%; p = 0.007). Arterial hypertension and diabetes mellitus were more common in group II, though it missed statistical significance (p = 0.068 and p = 0.085). Cardiovascular and limb outcome were comparable in both groups of female patients, while carotid artery disease was more severe in group I (i.e., carotid plaques in 71 vs. 53%). Our data support previous findings that cigarette smoking is a stronger risk factor for aortic disease as compared to femoral disease in younger female patients, with the strongest effect of smoking on a localized region of the aortic bifurcation.

Dilatation of the thoracic or abdominal aorta can progress to dissection or rupture with significant associated morbidity and mortality. Aortic disease remains a treatable contributor to mortality in the US and its burden is likely underestimated. Recent clinical studies have uncovered sex and gender distinctions in the epidemiology, pathophysiology, and outcomes of aortic disease. Despite this, there has been little progress in the application of these findings to clinical practice. Improved understanding of the sex-specific mechanisms of aortic disease may inform personalized indications for elective repair and thus reduce the morbidity of aortic catastrophe. The objective of this review is to summarize known clinical and biological sex differences in both thoracic and abdominal aortic disease and highlight promising areas for future investigation.

Aortic diseases, such as aortic dissection and aortic rupture, often lead to catastrophic complications, significantly increasing morbidity and mortality. Population-based screening for early detection in asymptomatic individuals is not feasible due to high costs and practical challenges. However, recent advancements in four dimensions (4D) Flow magnetic resonance imaging (MRI) offer a comprehensive tool for evaluating hemodynamic changes within the aortic lumen. This technology allows for the quantification and visualization of flow patterns and the calculation of advanced hemodynamic parameters, such as wall shear stress (WSS). WSS is crucial in the development, risk stratification, and surgical outcomes of aortic diseases and their complications, enabling noninvasive and quantitative screening of high-risk populations. This review explores the current status and limitations of 4D flow MRI-derived WSS imaging for aortic disease.

ACTA2 mutations are the major cause of familial thoracic aortic aneurysms and dissections. We sought to characterize these aortic diseases in a large case series of individuals with ACTA2 mutations. Aortic disease, management, and outcome associated with the first aortic event (aortic dissection or aneurysm repair) were abstracted from the medical records of 277 individuals with 41 various ACTA2 mutations. Aortic events occurred in 48% of these individuals, with the vast majority presenting with thoracic aortic dissections (88%) associated with 25% mortality. Type A dissections were more common than type B dissections (54% versus 21%), but the median age of onset of type B dissections was significantly younger than type A dissections (27 years versus 36 years). Only 12% of aortic events were repair of ascending aortic aneurysms, which variably involved the aortic root, ascending aorta, and aortic arch. Overall, cumulative risk of an aortic event at age 85 years was 0.76 (95% confidence interval, 0.64-0.86). After adjustment for intrafamilial correlation, sex and race, mutations disrupting p.R179 and p.R258 were associated with significantly increased risk for aortic events, whereas p.R185Q and p.R118Q mutations showed significantly lower risk of aortic events compared with other mutations. ACTA2 mutations are associated with high risk of presentation with an acute aortic dissection. The lifetime risk for an aortic event is only 76%, suggesting that additional environmental or genetic factors play a role in expression of aortic disease in individuals with ACTA2 mutations.

Bovine besnoitiosis, caused by Besnoitia besnoiti , is a (re)emerging disease in Europe (Cortes et al., 2014), including Italy (Gazzonis et al., 2014; 2017). However, its economic impact is scarcely considered and generally underestimated and there are still little studied aspects concerning both the parasite and the disease. Following a natural outbreak of besnoitiosis in a dairy herd, a study was planned to characterize B. besnoiti infection in cattle through a multidisciplinary approach. Suspicious abortions and clinical cases of besnoitiosis were reported in a dairy farm (September 2017, Northern Italy) housing 216 Holstein cattle. Blood samples were collected; haematological and serological analyses (ELISA and confirmatory WB) were performed (Fernandez-Garcia et al., 2009). Histology and molecular (endpoint ITS-1 PCR (Cortes et al., 2007) and sequencing) analyses of tissues from a slaughtered cow with chronic besnoitiosis were carried out. Out of 59 ELISA-positive animals, 50 (23%) were confirmed by WB. B. besnoiti prevalence was higher in cows (41%) than in calves (12%); any heifer did not result positive. Considering haematological parameters, a significant shift in the differential leucocyte formula from lymphocyte to granulocyte was recorded in infected cows (Mean±S.D.:L=46.1±18.4,G=53.9±18.4) if compared to negative animals (Student’s T-test,p=0.012). This finding could be helpful in diagnosis, treatment and control of besnoitiosis. Histology revealed a high load of B. besnoiti tissue cysts in skin, vulva, muzzle, sclera, eyelid, respiratory tract, emphasizing the possibility of parasite transmission through direct contact among animals. B. besnoiti was confirmed by PCR in other organs (heart, liver, aorta wall, tonsil) and especially in ovary, uterus and vulva, suggesting that the infection could affect cows’ fertility. Parasite DNA was also found in masseters posing an important question for food security, even if B. besnoiti is not considered zoonotic. The study suggests that to investigate the dynamics of bovine besnoitiosis is mandatory associate clinical and laboratory tests, including the genetic characterization of the parasite and its eventual correlation with the disease outcome.

Aortic disease is the most life-threatening complication of Marfan syndrome. Over the last decades, improved medical management and surgical results of prophylactic aortic interventions on the aortic root have dramatically increased expectancy of life in Marfan syndrome patients. As a result, the number of Marfan syndrome patients requiring secondary interventions on the thoracic or thoraco-abdominal aorta due to development of aortic disease or new type B dissection, has substantially increased. In this setting, open surgical interventions represent the treatment of choice. Nevertheless, the available literature, although restricted to small case series, indicates that endovascular repair is a feasible treatment option leading to satisfactory short-term results and may provide a bridging role to definitive open reconstruction. The aim of this paper was to review surgical and endovascular outcomes of aortic disease in Marfan syndrome.

Objective To explore the association of abdominal aortic calcification score (AACS) with cardiovascular disease (CVD) outcomes in peritoneal dialysis (PD) patients. Methods The patients who underwent regular PD at Renji Hospital between July 2011 and July 2014 were recruited and prospectively followed up until the end of the study (August 31, 2018), death, or dropout PD. Abdomen lateral X-ray was used to determine AACS for each patient at enrollment. Patients were divided into three groups based on the tertiles of AACS: non-calcified group, AACS group (AACS=0), mild-moderate calcification group AACS group (0<AACS≤4) and severe calcification group (4<AACS≤24). Cumulative incidences of cardiovascular outcomes among three groups were estimated using competing risk model and compared through Gray test. Competing risk regression model was used to evaluate the association of AACS and cardiovascular events as well as CVD mortality. Results Two hundred and ninety-two PD patients were enrolled in this study. The cohort consisted of 160 males (54.8%) with the age (57.1±15.2) years and median PD vintage 28.4 (IQR 12.0, 57.8) months, and their average AACS was 2.0 (0.0, 6.0). Order logistic regression analysis showed that older age (OR=1.081, 95%CI 1.057-1.106, P<0.001) and longer PD vintage (OR=1.012, 95%CI 1.004-1.019, P=0.003), CVD history (OR=1.919, 95%CI 1.108-3.325, P=0.020) and diabetes (OR=2.554, 95%CI 1.415-4.609, P=0.002) were independent risk factors of escalating AACS in PD patients. During the follow-up, 65 cases CVD events and 50 cases CVD-related deaths developed. Patients in the upper AACS tertile had significantly higher estimated cumulative incidences of CVD occurrence (Gray=27.81, P<0.001) and CVD mortality (Gray=20.91, P<0.001). AACS was an independent predictor of both CVD occurrence (medium AACS group vs low AACS group: SHR=2.823, 95%CI 1.333-5.970, P=0.007; high AACS group vs medium AACS group: SHR=3.063, 95%CI 1.460-6.430, P=0.003) and CVD mortality (SHR=2.590, 95%CI 1.132-5.920, P=0.024) in competing risk regression models. Conclusions Age, PD vintage, diabetes and preexisting CVD are associated with higher AACS in the present cohort. AACS can predict CVD morbidity and mortality in PD population and therefore may help with the early identification of PD patients with adverse cardiovascular outcomes. Key words: Vascular calcification; Aorta, abdominal; Peritoneal dialysis; Cardiovascular disease; Mortality

Extending the spectrum in aortopathy: stenosis to aneurysm

Chronic periaortitis (CP) is a disease characterized by a fibro-inflammatory periaortic cuff and adventitia-predominant fibrosis. CP encompasses idiopathic retroperitoneal fibrosis and inflammatory abdominal aortic aneurysm (AAA), and recent studies have documented overlap between CP and immunoglobulin G4-related disease (IgG4-RD). This study aimed to investigate clinical characteristics and treatment outcomes of patients with CP. CP patients were identified by retrospective review of 1245 patients with International Classification of Diseases 10th edition code of aortitis or aortic disease. Patients were further classified into IgG4-related and non-IgG4-related CP according to the criteria proposed by a Japanese study. A total of 61 CP patients were identified. Patients showed a male predominance (70%) with median age of 61 at diagnosis. The abdominal aorta was most commonly involved (84%), while the thoracic aorta was affected in 46% of patients. Twenty-three (38%) patients had accompanying aortic aneurysm. Approximately 60% of patients achieved remission without further relapse during the course. Ten patients were classified as IgG4-related and 25 as non-IgG4-related. There was no significant difference in clinical features and outcomes between groups, with the exception of older age and greater pancreas involvement in IgG4-related patients. We documented 61 CP patients including 10 IgG4-related cases. CP involved the abdominal aorta in most patients and the thoracic aorta in approximately 50% of patients. IgG4-related CP patients were older and had greater pancreas involvement, but disease outcomes appeared to be similar between IgG4-related and non-IgG4-related CP.

Invited Commentary

Background In pilot studies, increased vascular tortuosity is associated with adverse outcomes in children and young adults withheritable thoracic aortic disease, specifically Marfan syndrome (MFS) and Loeys Dietz syndrome (LDS). It is known that vertebral artery tortuosity is highly prevalent in older adults who do not have heritable thoracic aortic disease. We hypothesized that tortuosity increases with age in patients with aortic disease <50 years old.