Vascular Diseases in Women: Do Women Suffer from Them Differently?

According to the World Health Organization, cardiovascular disease (CVD) is the leading cause of death among women worldwide, yet its magnitude is often underestimated. Biological and gender differences affect health, diagnosis, and healthcare in numerous ways. The lack of sex and gender awareness in health research and healthcare is an ongoing issue that affects not only research but also treatment and outcomes. The importance of recognizing the impacts of both sex and gender on health and of knowing the differences between the two in healthcare is beginning to gain ground. There is more appreciation of the roles that biological differences (sex) and sociocultural power structures (gender) have, and both sex and gender affect health behavior, the development of diseases, their diagnosis, management, and the long-term effects of an illness. An important issue is the knowledge and awareness of women about vascular diseases. The risk of cardiovascular events is drastically underestimated by women themselves, as well as by those around them. The purpose of this review is to draw attention to improving the medical care and treatment of women with vascular diseases.

Diagnostic criteria for Buerger's disease: International Consensus of VAS - European Independent Foundation in Angiology/Vascular Medicine.

Buerger's disease (BD) remains a debilitating condition and early diagnosis is paramount for its effective management. Despite many published diagnostic criteria for BD, selective criteria have been utilized in different vascular centers to manage patients with BD worldwide. A recent international Delphi Consensus Study on the diagnostic criteria of BD showed that none of these published diagnostic criteria have been universally accepted as a gold standard. Apart from the presence of smoking, these published diagnostic criteria have distinct differences between them, rendering the direct comparison of patient outcomes difficult. Hence, the expert committees from the Working Group of the VAS-European Independent Foundation in Angiology/Vascular Medicine critically reviewed the findings from the Delphi study and provided practical recommendations on the diagnostic criteria for BD, facilitating its universal use. We recommend that the 'definitive' diagnosis of BD must require the presence of three features (history of smoking, typical angiographic features and typical histopathological features) and the use of a combination of major and minor criteria for the 'suspected' diagnosis of BD. The major criterion is the history of active tobacco smoking. The five minor criteria are disease onset at age less than 45 years, ischemic involvement of the lower limbs, ischemic involvement of one or both of the upper limbs, thrombophlebitis migrans and red-blue shade of purple discoloration on edematous toes or fingers. We recommend that a 'suspected' diagnosis of BD is confirmed in the presence of a major criterion plus four or more minor criteria. In the absence of the major criterion or in cases of fewer than four minor criteria, imaging and laboratory data could facilitate the diagnosis. Validation studies on the use of these major and minor criteria are underway.

The Influence of Antioxidants on Oxidative Stress-Induced Vascular Aging in Obesity.

Obesity is a worldwide trend that is growing in incidence very fast. Adipose tissue dysfunction caused by obesity is associated with the generation of oxidative stress. Obesity-induced oxidative stress and inflammation play a key role in the pathogenesis of vascular diseases. Vascular aging is one of the main pathogenesis mechanisms. The aim of this study is to review the effect of antioxidants on vascular aging caused by oxidative stress in obesity. In order to achieve this aim, this paper is designed to review obesity-caused adipose tissue remodeling, vascular aging generated by high levels of oxidative stress, and the effects of antioxidants on obesity, redox balance, and vascular aging. It seems that vascular diseases in obese individuals are complex networks of pathological mechanisms. In order to develop a proper therapeutic tool, first, there is a need for a better understanding of interactions between obesity, oxidative stress, and aging. Based on these interactions, this review suggests different lines of strategies that include change in lifestyle to prevent and control obesity, strategies for adipose tissue remodelling, oxidant-antioxidant balance, inflammation suppression, and strategies against vascular aging. Some antioxidants support different lines of these strategies, making them appropriate for complex conditions such as oxidative stress-induced vascular diseases in obese individuals.

The Potential Role of Antioxidants in the Treatment of Peripheral Arterial Disease: A Systematic Review.

Peripheral arterial disease (PAD) has a worldwide prevalence and is a significant cause of cardiovascular morbidity and mortality. Due to its high prevalence and higher rates of ischemic cardiovascular and lower-extremity events, its treatment is essential. Increased levels of oxidative stress cause disease. This review aimed to evaluate different studies of antioxidant treatments for PAD patients. A systematic search for relevant studies was performed on the PubMed, SCOPUS, and ScienceDirect databases, and 18 studies fulfilled the inclusion criteria. In total, 16.6% of the studies used natural antioxidants, and 83.3% used synthetic antioxidants. The reviewed studies show that natural antioxidants were completely effective in treating PAD, and synthetic antioxidants showed effective results in only 53% of the studies. A less-than-optimal pro-oxidant-antioxidant balance does not improve the symptoms of PAD. In conclusion, antioxidants in their natural forms are more effective for PAD patients, and ensuring the optimal pro-oxidant-antioxidant balance is an effective method for managing treatment with antioxidants.

Secondary Infertility: A Neglected Aspect of Buerger's Disease.

Background: During the gathering of demographic data for the biobank on Buerger's Disease (BD), we found that, after the clinical manifestation of BD, the patients usually became infertile, and the age of their last child was compatible with the time of disease diagnosis. The aim of this study was to evaluate the underlying cause of secondary infertility in BD patients. Methods: Anti-sperm antibodies (ASA), testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in the sera of 39 male BD patients were measured and compared with 39 age-matched Caucasian male controls. Results: Six patients declared that they suffered from impotency. The ASA level was positive in 25.6% of the patients and 2.4% of the controls (p= 0.003, CC= 6.96). The mean levels of testosterone in the patients and controls were 393.12±32.9 ng/dl and 354.37±30.9 ng/dl, respectively. The mean levels of LH in the patients and controls were 0.88±0.12 mIU/r and 0.85±0.1 mIU/r, respectively. The mean levels of FSH in the patients and controls were 4.1± 0.35 mIU/r and 3.56±0.33 mIU/r, respectively. No significant difference in the serum levels of testosterone, LH, or FSH was found between the patients and controls (p> 0.05). The spermograms of three ASA-negative patients demonstrated impaired sperm motility. Discussion: Anti-sperm antibodies, disturbed genital circulation, autonomic dysfunction and sperm motility may be responsible for secondary infertility in Buerger's Disease.

An International Delphi Consensus on Diagnostic Criteria for Buerger's Disease.

BACKGROUND: Buerger's disease (BD) remains a debilitating condition. Despite multiple published diagnostic criteria for BD, none is universally accepted as a gold standard. METHODS: We conducted a 2-round modified Delphi consensus study to establish a consensus on the diagnostic. The questionnaire included statements from several commonly used diagnostic criteria for BD. Qualitative and quantitative analysis methods were performed. An agreement level of 70% was applied. RESULTS: Twenty nine experts from 18 countries participated in this study. Overall, 75 statements were circulated in Round 1. Of these, 28% of statements were accepted. Following comments, 21 statements were recirculated in Round 2 and 90% were accepted. Although more than 90% of the experts did not agree that the diagnosis of BD can be based only on clinical manifestation, none of the nonclinical manifestations of BD were agreed as a part of the diagnostic criteria. There was an agreement that a history of tobacco consumption in any form, not necessarily confined to the current use, should be a part of the diagnostic criteria of BD. The history of thrombophlebitis migrans, even if not present at presentation, was accepted as a clue for BD diagnosis. It was also agreed that discoloration of the toes or fingers could be included in the diagnostic criteria of BD. Experts agreed that histology results could differentiate BD from atherosclerosis obliterans and other types of vasculitis. The presence of corkscrew collaterals on imaging and burning pain reached the agreement at the first round but not at the second. There was no consensus regarding age cut-off, the requirement of normal lipid profile, and normal blood glucose for BD diagnosis. CONCLUSIONS: The present study demonstrated discrepancies in the various published diagnostic criteria for BD and their selective utilization in routine clinical practice worldwide. We propose that all published diagnostic criteria for BD be re-evaluated for harmonization and universal use.

Recent Updates and Advances in Winiwarter-Buerger Disease (Thromboangiitis Obliterans): Biomolecular Mechanisms, Diagnostics and Clinical Consequences.

Thromboangiitis obliterans (TAO) or Buerger's disease is a segmental inflammatory, thrombotic occlusive peripheral vascular disease with unknown aetiology that usually involves the medium and small-sized vessels of young male smokers. Due to its unknown aetiology and similarities with atherosclerosis and vasculitis, TAO diagnosis is still challenging. We aimed to review the status of biomolecular and laboratory para-clinical markers in TAO compared to atherosclerosis and vasculitis. We reported that, although some biomarkers might be common in TAO, atherosclerosis, and vasculitis, each disease occurs through a different pathway and, to our knowledge, there is no specific and definitive marker for differentiating TAO from atherosclerosis or vasculitis. Our review highlighted that pro-inflammatory and cell-mediated immunity cytokines, IL-33, HMGB1, neopterin, MMPs, ICAM1, complement components, fibrinogen, oxidative stress, NO levels, eNOS polymorphism, adrenalin and noradrenalin, lead, cadmium, and homocysteine are common markers. Nitric oxide, MPV, TLRs, MDA, ox-LDL, sST2, antioxidant system, autoantibodies, and type of infection are differential markers, whereas platelet and leukocyte count, haemoglobin, lipid profile, CRP, ESR, FBS, creatinine, d-dimer, hypercoagulation activity, as well as protein C and S are controversial markers. Finally, our study proposed diagnostic panels for laboratory differential diagnosis to be considered at first and in more advanced stages.

Milestones in thromboangiitis obliterans: a position paper of the VAS-European independent foundation in angiology/vascular medicine.

Even today thromboangiitis obliterans has disease features that remain misunderstood or underappreciated. The epidemiology, etiology and pathophysiology of the disease are still unclear. Biomarkers and disease activity markers are lacking, thus clinical assessment is difficult. We are still struggling to establish unique diagnostic, staging and treatment criteria. This is an academic-collaborative effort to describe the pathophysiology, the clinical manifestations, the diagnostic approach, and the challenges of management of patients with TAO. A systematic search for relevant studies dating from 1900 to the end of 2020 was performed on the PubMed, SCOPUS, and Science Direct databases. Given the intriguing nature of presentation of TAO, its management, to some extent is not only different in different regions of the world but also varies within the same region. Following this project, we discovered ambiguity, overlap and lack of clear-cut criteria for management of TAO. An international group of experts however came to one conclusion. They all agree that management of TAO needs a call for action for a renewed global look with multi-center studies, to update the geographical distribution of the disease and to establish a unique set of diagnostic criteria and a consensus-based guideline for best treatment based on current evidence.

Game theory applications in host-microbe interactions toward disease manifestation: Mycobacterium tuberculosis infection as an example.

OBJECTIVES: Game theory describes the interactions between two players and the pay-off from winning, losing, or compromising. In the present study, Mycobacterium tuberculosis (Mtb)-host interactions were used as an example for the application of game theory to describe and predict the different outcomes of Mtb-infection and introducing target molecules for use in protection or therapy. MATERIALS AND METHODS: The gene expression for eight main markers (CCR1, CCR2, IDO, Tbet, TGFß, iNOS, MMP3, MMP9) of host response and three Mtb virulence factors (Ag85B, CFP-10, ESAT-6) were assessed in broncho-alveolar lavage of TB+ and TB- patients. RESULTS: The players' strategies in the "Nash equilibrium", showed that Ag85B is the main virulence factor for Mtb in active phase, and also the most immunogenic factor, if the host can respond by high expression of T-bet and iNOS toward a Th1 response. In this situation, Mtb can express high levels of ESAT-6 and CFP10 and change the game to the latency, in which host responses by medium expression of T-bet and iNOS and medium level of TGF-ß and IDO. Consistently, the IDO expression was 134-times higher in TB+s than the TB-s,and the T-bet expression,~200-times higher in the TB-s than the TB+s. Furthermore, Mtb-Ag85B had a strong positive association with CCR2, T-bet and iNOS, but had a negative correlation with IDO. CONCLUSION: Ag85B and maybe ESAT6 (without its suppressive C-terminal) should be considered for making subunit vaccines. And, preventing IDO formation in dendritic cells might be a novel target for immunotherapy of tuberculosis, to reduce the pressure of immune-suppression on Th1 responses.

The IL-33/sST2 Axis in Thromboangiitis Obliterans.

BACKGROUND: Until recently, it remains unknown whether thromboangiitis obliterans (TAO) is a type of systemic vasculitis. A high level of IL-33 and its soluble decoy receptor sST2 in the acute phase of systemic vasculitis has been demonstrated. METHODS: The serum level of IL-33 and sST2 in 50 TAO patients, 20 age- and smoking habit-matched controls and 19 age-matched non-smoker controls was evaluated. RESULTS: The mean level of IL-33 in TAO, smokers and non-smokers was 370.2±61.7ng/mL,132.14±2.6ng/mL and 11.3±0.38ng/mL, respectively. The IL-33 was significantly higher in the TAO than in either control groups (p < 0.001). The IL-33 in the acute phase of TAO was significantly higher than in the patients in the quiescent phase of the disease (p = 0.019). Also, IL-33 in the patients with gangrene was significantly higher than in the patients with non-healing ulcers (p = 0.021). The sST2 in the TAO patients was 49.3±5.58ng/mL, and in smoker and non-smoker controls, it was 45.3±6.3ng/mL and 4.11±0.17ng/mL, respectively. No significant difference was found between the patients and smoker control groups (p = 0.87). The mean ratio of IL-33/sST2 was 27.89±10.44 in the TAO group and, in smokers and non-smokers, it was 2.85±0.48 and 2.84±0.14, respectively. A significantly high level of IL-33/sST2 ratio was observed in TAO patients in both the active and quiescent phases of the disease in comparison to both control groups (p<0.001). CONCLUSION: The regulation pattern of IL-33/sST2 was different in TAO in comparison to autoimmune vasculitis.

The Imbalance among Oxidative Biomarkers and Antioxidant Defense Systems in Thromboangiitis Obliterans (Winiwarter-Buerger Disease).

(1) Background: Thromboangiitis obliterans or Winiwarter-Buerger disease (WBD), is an inflammatory, thrombotic occlusive, peripheral vascular disease, usually occurring in young smokers. The pathophysiological mechanisms underlying the disease are not clearly understood. The aim of this study is to investigate the imbalance between oxidants and antioxidants occurring in these patients. (2) Patients and Methods: In this cross-sectional study, 22 male patients with WBD and 20 healthy male smoking habit matched control group were included. To evaluate the possible sources of oxidative stress, the antioxidant biomarkers, and the markers of lipid peroxidation and protein oxidation, serum samples were analyzed for total oxidative status (TOS), total antioxidant capacity (TAC), myeloperoxidase (MPO), coenzyme Q10 (CoQ10), superoxide dismutase (SOD), glutathione reductase (GR), malondialdehyde (MDA), and protein carbonyl (PC) activity and/or content. (3) Results: The circulating levels of TOS, TAC, and CoQ10 were significantly higher in WBD patients, with respect to healthy smokers as controls. No significant difference was found among the serum level of PC, total cholesterol, MPO, and GR activity in WBD patients and healthy smoker controls. The activity of SOD and the mean serum level of MDA were significantly lower in WBD patients, with respect to healthy smoker controls. (4) Conclusion: Considerably high levels of oxidative stress were detected in WBD patients, which were greater than the antioxidant capacity. The low level of MDA may be associated with the enzymatic degradation of lipid peroxidation products. High levels of CoQ10 and low levels of SOD may be related to a harmful oxidative cooperation, leading to the vasoconstriction of WBD, representing a promising tool to discern possible different clinical risks of this poorly understood peripheral occlusive disease.

Unexpected inflammation in the sympathetic ganglia in thromboangiitis obliterans: more likely sterile or infectious induced inflammation?

INTRODUCTION: The aim of this study was to determine if the inflammation of the sympathetic ganglia (SG) in thromboangiitis obliterans (TAO) is induced by an infectious pathogen inside or if it is a reactive sterile inflammation. METHODS: For the purpose of this study, the gene expression of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), toll-like receptor 9 (TLR9), and the receptor for advanced glycation end-products (RAGE) were evaluated on the complementary DNA (cDNA) of the SG tissues of 24 TAO patients and two controls with hyperhidrosis by real-time polymerase chain reaction (PCR) and analysed by the Pfaffl method. RESULTS: The gene expression of HMGB1 and TLR9 increased by about 25- and 2-fold changes in the SG of the TAO patients, respectively. However, there was no change in the gene expression of TLR4 or RAGE. CONCLUSION: It appears that the inflammation in the SG of TAO patients is more likely a sterile inflammation, and its trigger may be mitochondrial DNA (mtDNA). Cadmium in cigarettes could be responsible for the induction of mtDNA release to the cell cytoplasm. In addition, the high expression of HMGB1 may play a role in the pathogenesis of TAO and may be responsible for both clinical manifestation of the disease and the imaging findings. Moreover, HMGB1 may be a target for treatment protocols for TAO. Further studies are highly recommended.

Evaluation of Non-Viral Surrogate Markers as Predictive Indicators for Monitoring Progression of Human Immunodeficiency Virus Infection: An Eight-Year Analysis in a Regional Center.

Suitable methods for clinical monitoring of HIV-infected patients are crucial in resource-poor settings. Demographic data, clinical staging, and laboratory findings for 112 asymptomatic subjects positive for HIV were assessed at the first admission and the last visit from 2002 to 2010. Cox regression analysis showed hemoglobin (Hb) (HR = 0.643, P = 0.021) to be a predictive indicator for disease progression, while CD4, CD8, and platelet counts showed low HRs, despite having significant probability values. Hb and total lymphocyte count (TLC) rapidly declined from stage II to III (10.9 and 29.6%, respectively). Reduced CD4 and platelet counts and Hb during stage I were associated with disease progression, and TLC was correlated with CD4 counts at the last follow-up (P < 0.001). However, WHO TLC cutoff of 1,200 cell/mm(3) had 26.1% sensitivity and 98.6% specificity. ROC curve analysis suggested that a TLC cutoff of 1,800 cell/mm(3) was more reliable in this region. Statistical analysis and data mining findings showed that Hb and TLC, and their rapid decline from stage II to III, in addition to reduced platelet count, could be valuable markers for a surrogate algorithm for monitoring of HIV-infected subjects and starting anti-viral therapy in the absence of sophisticated detection assays.

Association of the five gene related endothelial cell dysfunction polymorphisms with Buerger's disease development.

BACKGROUND: The aim of this study was to evaluate the impact of the polymorphisms of four genes related to vascular endothelium dysfunction on the development and outcome of Buerger's disease (BD). The genes studied were eNOS-786 T>C, eNOS894 G>T, ET-1 8000 T>C, PAI-1 4G/5G and ACE I/D. METHODS: Polymerase chain reaction and restriction fragment analysis were used to detect eNOS-786 T>C, eNOS894 G>T, ET-1 8000 T>C, PAI-1(4G/5G) and ACE(I/D) polymorphisms in 36 BD patients and 36 healthy individuals matched for race, age and gender. A decision tree for predicting BD was drawn using Rapidminer 5.3 software. RESULTS: The frequency of eNOS-T786C alleles was significantly different between the BD group and the healthy controls (P<0.001, OR:6.1). The frequency of PAI-1(4G/5G) alleles was significantly different between the BD group and the healthy controls (P=0.005, OR:4.9). The frequency of eNOS G894T alleles was not statistically different between BD and the healthy controls (P=0.09). No significant difference between allele frequency of ACE(I/D) was found (P=0.07). There was, also, no significant difference between the allele frequency of ET-1 8000 T>C (P=0.1). In logistic regression analysis, the C allele for eNOS-786 and 4G/4G for PAI-1 were significant for predicting BD. According to the decision tree, the proportion of the current gene-polymorphisms likely to develop BD was calculated as maximum 27.7%. CONCLUSIONS: It seems that eNOS-T786C, PAI-1(4G/5G) are important polymorphisms in developing BD. However, the decision tree might give confidence to the families of BD patients that if they maintain a healthy lifestyle, they may not develop BD.