Development Of Peripheral Arterial Disease Research Articles

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Peripheral artery disease is a considered as one of the major macrovascular complications in diabetes mellitus type 2. It is chronic arteriosclerotic illness that mainly affects the lower limbs and is presented as narrowed or blocked blood vessels. The prevalence increases with the age, it affects 15-20% of persons older than 70 years age, 10-15% of the general population. Smoking and high cholesterol levels increase the risk for PAD progression in large blood vessels such as legs, while diabetes increases the risk for PAD in small blood vessels such as the feet. Critical ischemia, its most severe form can lead to limb amputation and the patient’s death, and even its asymptomatic forms are associated with a high risk of cardiovascular morbidity and mortality. Approximately more than half of all patients are asymptomatic and preventive therapy reduces the risk of complications and death, so it’s important to recognize the subclinical forms in time and to control risk factors of disease. The risk factors that can be modified are tobacco use, hypertension, hyperlipidemia, diabetes mellitus, obesity and some of them cannot be modified such as age, sex or family medical history. Diabetes mellitus type 2 is considered as the most important risk factor for development of peripheral artery disease. The experts suggest that is necessary to establish an HBA1C therapeutic target below 8% in patient with DM and PAD.

Mitochondrial DNA damage in human skeletal muscle tissue correlates with peripheral artery disease development and progression

Mitochondrial DNA damage in human skeletal muscle tissue correlates with peripheral artery disease development and progression

Peripheral artery disease patients with chronic kidney disease have lower muscle strength and mitochondrial function compared to those with normal kidney function

Introduction: Chronic kidney disease is a significant risk factor for both the development of peripheral artery disease (PAD) and major adverse limb events. However, little is known about how the coalescence of these two conditions impacts limb muscle pathophysiology. The objective of the current study was to determine the impact of CKD on skeletal muscle strength and mitochondrial health in patients with and without PAD. Methods: A cross-sectional prospective study design was employed to assess plantar flexor muscle strength, muscle fiber cross-sectional area (CSA), and mitochondrial health in four groups of patients (61 males and 29 females): PAD only (Toe brachial index, TBI<0.5 and eGFR>60 mL/min), CKD only (TBI>0.75 and eGFR:15-45 mL/min), PAD with CKD (TBI<0.5 and eGFR:15-45 mL/min), and adult controls without PAD and CKD (TBI>0.75 and eGFR>60 mL/min). Results: Plantar flexor muscle strength was lowest in PAD patients with CKD compared to adult controls ( P<0.0001), PAD only ( P=0.001), and CKD only ( P=0.003). No differences in the mean muscle fiber CSA were detected. The percentage of COX+ fibers was significantly lower in PAD patients with CKD compared to adult controls ( P=0.03). High resolution respirometry analysis of mitochondrial oxidative phosphorylation (OXPHOS) function demonstrated that CKD has a significant negative impact on muscle bioenergetics. PAD patients with CKD had lower OXPHOS function than adult controls ( P=0.0016) and PAD patients without CKD ( P=0.0015). Notably, CKD patients without PAD also had lower OXPHOS function than adult controls ( P=0.0054) and PAD patients without CKD ( P=0.005). Conclusion: The current results demonstrate a profound negative impact of CKD on the associated myopathy of PAD patients. This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (T.E.R.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pathological Changes in the Gastrocnemius Muscle throughout Hind Limb Ischemia Modeling in Rats.

We present a two-stage model for the study of chronic hind limb ischemia in rats. In the area of ischemia, sclerotic changes with atrophic rhabdomyocytes and reduced vascularization were revealed. CD31 expression in the endothelium increased proportionally to the number of vessels in the ischemic zone, and at the same time, focal expression of βIII-tubulin was detected in the newly formed nerve fibers. These histological features are equivalent to the development of peripheral arterial disease in humans, which allows using our model in the search for new therapeutic strategies.

Different Impact of Metabolic Syndrome on the Risk of Incidence of the Peripheral Artery Disease and the Venous Thromboembolism: A Nationwide Longitudinal Cohort Study in South Korea.

Limited data is available between metabolic syndrome (MetS) and the development of peripheral arterial disease (PAD) or venous thromboembolism (VTE) in the Asian population. We investigated the incidence of PAD and VTE according to the prevalence of MetS and evaluated the impact of individual components in MetS on the development of PAD and VTE using Korean national data. Data obtained from national health screening examinations of the Korean National Health Insurance Service from January 1, to December 31, 2009. In total, 9,927,538 participants, 7,830,602 participants were included in this study and the incidence rate of PAD and VTE was investigated retrospectively during a 7-year follow-up. Using the National Cholesterol Education Program Adult Treatment Panel III criteria, patients were placed into one of three groups depending on MetS component numbers: 0 (normal), 1-2 (Pre-MetS), or 3-5 (MetS). The incidence rates of PAD and VTE in MetS were 2.25% and 0.71%, respectively. After multivariable adjustment, the risk of PAD was significantly associated with MetS (hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.42-1.49), the risk of VTE was not associated with MetS (HR 1.01, 95% CI 0.96-1.05). When subgroup analyses were conducted according to MetS components, elevated fasting glucose (HR 1.26, 95% CI 1.23-1.27), abdominal obesity (HR 1.15, 95% CI 1.12-1.17), and elevated blood pressure (HR 1.13, 95% CI 1.12-1.15) were the most related to PAD. Abdominal obesity (HR 1.104, 95% CI 1.064-1.146) was associated with an increased risk of VTE. MetS was significantly associated with an increased incidence rate of PAD among the general Korean population. On the other hand, MetS was not associated with the VTE incidence rate. Of the MetS components, only abdominal obesity was a significant predictor of VTE.

Ortalama Trombosit Hacmi/Trombosit Sayısı (MPV/PLT Oranı ile Periferik Arter Hastalığı Arasındaki İlişki

Background/Aim: In our study, we aimed to evaluate the effect of mean platelet volume/platelet count ratio on the development of peripheral artery disease (PAD) by comparing it with the control group. Material and Methods: A total of 115 patients with peripheral artery disease as a result of lower extremity color Doppler ultrasonography examination in our hospital were included in the study as the patient group and 100 individuals without peripheral artery disease as the control group. Results: History of coronary artery disease (p<0.001), diabetes mellitus (p=0.009), hypertension (p<0.001) and smoking history (p<0.001) were significantly higher in the PAD group than in the control group. Serum glucose (121.27±25.66 vs. 104.81±34.77; p<0.001), MPV levels (9.99±0.79 vs. 9.04±0.7; p<0.001) and MPV/PLT ratio (0.041±0.07 vs. 0.037±0.006, p< 0.001) were found to be significantly higher in the PAD group than in the control group. Serum HDL levels (45.03±11.5 vs. 48.67±12.52 p=0.026) were significantly lower in the PAD group than in the control group. In multivariate analysis, age, MPV and MPV/PLT ratio were determined as independent predictors for peripheral arterial disease. Conclusion: In our study, we found that MPV and MPV/PLT ratio were independent predictors of peripheral artery disease.

Outcomes of the V-Healthy education and awareness program that empowers high school students to understand and diagnose vascular disease risk factors

IntroductionV-Healthy (Center for Vascular Awareness Inc, Latham NY) is a grassroots vascular health education and awareness campaign that educates high school students about the importance of the vascular disease risks they face today and its impact decades later, and empowers health care professionals and schoolteachers to lead vascular health education in their communities. This study evaluates the impact of the V-Healthy initiative in empowering and educating adolescents about the implications of vascular disease risk factors and in creating a blueprint for a community outreach program that focuses on vascular health and disease education and awareness. MethodsThe V-Healthy program is an initiative that connects community vascular health care professionals and educators with high school students, for a day of vascular health education. The V-Healthy program curriculum is provided in two distinct stages. Stage I consists of didactic vascular health education and takes place in the classroom for the duration of one class period (40-50 minutes). The class period is divided into four sessions including a PowerPoint presentation to teach the impact of vascular disease risk factors (hypertension, diabetes, hyperlipidemia, smoking/vaping, and genetics) on the development of peripheral arterial disease, venous disease, aortic disease, and stroke, and three hands-on sessions that introduce students to vascular innovation and technology, vascular patients, and the diagnosis of a vascular disease risk factor such as hypertension. Stage I concludes with a student questionnaire aimed to gauge students’ retention of the material and attitude toward the program. Stage II offers students (with parental consent) the opportunity to participate in the “Diagnosing Hypertension” study. Students were provided automated blood pressure monitors and taught to measure blood pressure in their parents daily for 1 week. Findings are recorded in designated blood pressure logs, which are then categorized using the 2018 American Heart Association blood pressure categorization system: normal (<120/<80), elevated (120-129/<80), stage I (130-139/80-89), or stage II (≥140/≥90). No identifiable student or guardian information is collected. ResultsOver 3 years, more than 12,000 students participated in the V-Healthy program and 5120 students completed student surveys, which indicated that 97% improved their understanding of vascular health, >93% could identify vascular disease risk factors, 84% wanted to educate their families, and 76% wanted more vascular health education. A total of 1064 students participated in the “Diagnosing Hypertension” study and diagnosed hypertension in 73% of their parents: 34% for stage I hypertension and 39% for stage II hypertension. Over a 3-year period of this study, the number of schools participating increased 20-fold (from 1 to 20), the number of volunteer vascular health professionals and schoolteachers increased 13-fold (from 16 to 210), and our ability to connect with and impact high school students grew 15-fold (from 800 to over 12,000). ConclusionsV-Healthy is the first program to connect over 12,000 students to vascular health professionals in their communities to empower them to diagnose and understand vascular disease risk factors and their implications on the development of vascular disease. Furthermore, the V-Healthy program has displayed substantial growth over a 3-year period in impacting high school students and vascular health care professionals, and has the potential to be used as a blueprint for community-based vascular health education and awareness initiatives.

Metabolic Syndrome and Risk of Peripheral Arterial Disease: A Systematic Review and Meta-Analysis.

This systematic review aimed to evaluate metabolic syndrome as a risk factor for the development of peripheral arterial disease (PAD). We searched in four databases: (1) PubMed, (2) Web of Science, (3) Scopus, and (4) Embase until March 2021. We included cohort studies that evaluated the risk of PAD in patients with and without metabolic syndrome. Study selection, data extraction, and risk of bias analysis were performed independently by 2 authors. We used a random-effects model to conduct a meta-analysis of effect measures [hazard ratio (HR), risk ratio (RR), and odds ratio (OR)]. Individual analyses were performed according to the diagnostic criterion used for metabolic syndrome. We included 7 cohort studies with a total of 43 824 participants. Most of the studies were performed in the general adult population. The metabolic syndrome and PAD diagnostic criteria used in the individual studies were heterogeneous. Almost all studies using RR found an association between metabolic syndrome and the development of PAD (RR: 1.31; confidence interval 95%: 1.03-1.59; I 2 : 15.6%). On the other hand, almost all the studies that used HR found no association between the two variables. All studies had a low risk of bias. In conclusion, available evidence on the association between metabolic syndrome and the risk of developing PAD is inconsistent. However, given the high prevalence of risk factors that patients with metabolic syndrome have, testing to rule out PAD could be recommended. Future studies should analyze each component of the metabolic syndrome separately and according to the severity of PAD.

SS31 Ameliorates Oxidative Stress via the Restoration of Autophagic Flux to Protect Aged Mice From Hind Limb Ischemia.

BackgroundOxidative stress and impaired autophagic flux play important roles in the development of peripheral artery disease (PAD). SS31 is considered an important antioxidant peptide and autophagy regulator. We aimed to investigate the role of SS31 in PAD myopathy and its possible mechanism both in vivo and in vitro.MethodsA hind limb ischemia (HLI) model was established with old C57BL/6 (14-month-old) mice. Mice in the SS31 group were intraperitoneally injected with SS31 (3 mg/kg) for 4 weeks. We examined skeletal muscle function and histomorphology, autophagy-related protein levels and reactive oxygen species (ROS) content. For the in vitro experiments, after C2C12 myotubes were treated with CoCl2, SS31, and chloroquine (CQ) or rapamycin (RAPA), we measured ROS content, autophagy-related protein levels and antioxidant enzyme expression.ResultsSS31 treatment effectively enhanced the recovery of skeletal muscle function, alleviated skeletal muscle injury and suppressed mitochondrial ROS production in ischemic limbs. SS31 reduced apoptosis and oxidative stress, and SS31 restored impaired autophagic flux by inhibiting the AKT-mTOR pathway. In vitro studies showed that SS31 restored autophagic flux and improved oxidative stress in C2C12 cells. Moreover, phosphorylated AKT (p-AKT) and phosphorylated mTOR (p-mTOR) levels were reduced.ConclusionThese experiments indicated that SS31 can inhibit oxidative stress by restoring autophagic flux to reverse hypoxia-induced injury in vivo and in vitro.

IDF21-0196 Study of peripheral arterial disease among type 2 diabetes mellitus patients

Background: Diabetes is a complex chronic metabolic disorder, characterized by persistent hyperglycemia because of lack of insulin secretion, insulin resistance, or both. Peripheral arterial disease (PAD) is one of the major recognised diabetic macro vascular complications. It is a marker of generalised systemic atherosclerosis and is closely associated with symptomatic coronary and cerebrovascular disease, hence significant morbidity and mortality. Aim: To study the various risk factors contributing to development of peripheral arterial disease in adult type2 diabetic patients and vasculopathy profile. Method: This was a retrospective analytical descriptive study conducted at internal medicine department on 13 months. Forty-seven type 2 diabetic patients were included. All patients underwent a detailed history which included age, gender, smoking intake, history of diabetes mellitus with duration and treatment. Biochemical characteristics were studied. Diagnosis of PAD was made by using color Doppler ultrasound. The statistical analysis was carried out using Epi-Info7. Results: The study was conducted on 47type2 diabetic patients with a mean age of 66±10 years with male predominance (77%) compared to females (23%). Mean duration of diabetes mellitus was15±9 years. Majority of patients were on insulin (n=22;46.81%). Eleven patients (23.40%) were on combined insulin and OHA. and ten were on oral hypoglycemic agents (OHA) (21.28%). Sixteen (34%) patients were cigarette smokers. Regarding hypertension status, 24 (51.06%) patients were hypertensive. Metabolic syndrome was prevalent in twenty patients, with mean of BMI 25±5 kg/m2. PAD was prevalent in 38(80.85%) patients. Of these, there were 27(57.45%) obliterating arteriopathy of the lower limbs,20(42.55 %) had mediacalcinosis, 10 (21.28 %) had acute arterial occlusion, 8 (17.02%) stenosis, and 2(4.26 %) arterial thrombosis. The prevalence of neuropathy was 46.81% (n=22) and diabetic foot was present in all patients (n=47) of patients. Regarding biochemical parameters: mean of fasting blood glucose was 1.73±0.76g/l, mean of post prandial blood glucose 2.45±0.77g/l, mean of HBA1C 9±3%, mean of HDLc 0.32±0.14 g/l, mean of triglycerides1.56±1.29g/l, mean of creatinine clearance according MDRD equation was 69±41 ml/min/1.73m2, mean of protein C reactive in this population was 88±80mg/l. Discussion: The increasing burden of diabetes is considered as one of the greatest global public health problem of our time. Diabetic patients with PAD are at high risk of increased morbidity and mortality from cardiovascular diseases and a high rate of lower extremity amputation. Various risk factors like age, gender persistant hyperglycemia, increased glycated hemoglobin, smoking and hypertension, and dyslipidaemia are associated with an increased risk of peripheral artery disease. This study documents a high prevalence of PAD among adult type2 diabetic patients. This strongly calls for aggressive screening for PAD be emphasised.

Midlife Cardiorespiratory Fitness and the Development of Peripheral Artery Disease in Later Life.

BackgroundData are sparse on the prospective associations between physical activity and incidence of lower extremity peripheral artery disease (PAD).Methods and ResultsLinking participant data from the CCLS (Cooper Center Longitudinal Study) to Medicare claims files, we studied 19 023 participants with objectively measured midlife cardiorespiratory fitness through maximal effort on the Balke protocol who survived to receive Medicare coverage between 1999 and 2009. The study aimed to determine the association between midlife cardiorespiratory fitness and incident PAD with proportional hazards intensity models, adjusted for age, sex, body mass index, and other covariates, to PAD failure time data. During 121 288 person‐years of Medicare follow‐up, we observed 805 PAD‐related hospitalizations/procedures among 19 023 participants (21% women, median age 50 years). Lower midlife fitness was associated with a higher rate of incident PAD in patients aged 65 years and older (low fit [quintile 1]: 11.4, moderate fit [quintile 2 to 3]: 7.8, and high fit [quintile 4 to 5]: 5.7 per 1000 person years). After multivariable adjustment for common predictors of incident PAD such as age, body mass index, hypertension, and diabetes, these findings persisted. Lower risk for PAD per greater metabolic equivalent task of fitness was observed (hazard ratio [HR], 0.93 [95% CI, 0.90–0.97]; P<0.001). Among a subset of patients with an additional fitness assessment, each 1 metabolic equivalent task increase from baseline fitness was associated with decreased risk of incident PAD (HR, 0.90 [95% CI, 0.82–0.99]; P=0.03).ConclusionsCardiorespiratory fitness in healthy, middle‐aged adults is associated with lower risk of incident PAD in later life, independent of other predictors of incident PAD.

The Association Between Socioeconomic Factors and Incident Peripheral Artery Disease in the Chronic Renal Insufficiency Cohort (CRIC)

BackgroundThe association between socioeconomic factors and development of peripheral artery disease (PAD) has not been as well characterized compared to other cardiovascular diseases. We sought to define how annual income, sex, race, and education level are associated with newly diagnosed PAD in a well-characterized, diverse set of adults with CKD. MethodsThe Chronic Renal Insufficiency Cohort Study (CRIC) is a multicenter, prospective cohort study designed to examine risk factors for progression of CKD and cardiovascular disease. Demographic and clinical data including ankle brachial index (ABI) and interventions were collected at baseline, as well as yearly during follow-up visits. Annual income was categorized as: <$25,000, $25,000–50,000, $50,000–100,000, or above $100,000. We excluded those with pre-existing PAD, defined as enrollment ABI of <0.9 or >1.4, or missing income data. Cox proportional hazards regression was used to estimate the risk for incident PAD during CRIC enrollment, defined as a drop in ABI to <0.90 or a confirmed PAD intervention, including revascularization or amputation. ResultsA total of 3,313 patients met inclusion criteria, the mean age was 58.7 years, 56% were male, and 42% were Black. Over a median follow-up of 10.1 years, 639 participants (19%) were newly diagnosed with PAD. After adjusting for cardiovascular risk factors, all lower levels of annual household income were associated with increased incidence of PAD (income <$25,000 HR 1.7, 95% CI 1.1–2.4, P = 0.008; income $25,000–50,000 HR 1.5, 95% CI 1.1–2.3, P = 0.009; income $50,000–100,000 HR 1.6, 95% CI 1.2–2.4, P = 0.004), relative to a baseline annual income of >$100,000 (overall P-value = 0.02). In the multivariable model, there was no association between education level and PAD incidence (P = 0.80). Black race (HR 1.2, 95% CI 1.0–1.5, P = 0.023) and female sex (HR 1.7, 95% CI 1.4–2.0, P < 0.001) were independently associated with PAD incidence. Multiple imputation analysis provided similar results. ConclusionsIn the CRIC, a multi-center cohort of prospectively followed CKD patients undergoing yearly CVD surveillance, lower annual household income, female sex, and Black race were significantly associated with the PAD incidence. In contrast, level of education was not independently associated with incident PAD.

Анализ гиполипидемической терапии у больных артериальной гипертензией

Артериальная гипертензия (АГ) и нарушения липидного обмена являются одними из главных причин неблагоприятного сердечно-сосудистого прогноза, каждая из которых способствует развитию и прогрессированию заболеваний, связанных с атеросклерозом. У многих пациентов эти факторы риска присутствуют вместе. В статье на основании клинического случая обоснована необходимость назначения статинов больному с артериальной гипертензией. Приведены клинический случай наблюдения и лечения АГ у 47-летнего пациента с дислипидемией на разных временных этапах с последующим анализом современной информации о комбинации статинов и антигипертензивных средств — сартанов в процессе ведения пациентов высокого кардиоваскулярного риска. После нескольких лет эффективного антигипертензивного лечения артериальное давление больного стабилизировалось на целевых уровнях. Он бросил курить, нормализовал массу тела. Осталась асимптомная дислипидемия, которую он медикаментозно не контролировал. Во время предпоследнего визита у пациента был обнаружен неокклюзивный атеросклероз сосудов нижних конечностей, протекающий асимптомно. С учетом признаков сосудистого атеросклероза пациент попадает в группу высокого кардиоваскулярного риска. Ему нужно назначить интенсивную статинотерапию. В этом случае важно выбрать наиболее эффективный и безопасный препарат и соответствующую дозу. При просмотре клинического случая комбинированного лечения нашего пациента кандесартаном (Кантаб) и аторвастатином (Толевас) следует обратить внимание на два момента, спровоцировавшие развитие периферического атеросклероза. Во-первых, к нам обратился пациент молодого возраста с симптомами гипертонии, которые считались основными для постановки диагноза и выбора терапии. В результате он и получал достаточно эффективное антигипертензивное лечение. Сопутствующая дислипидемия имела субклинический характер, и пациент самостоятельно перестал принимать статины. Высокий общий холестерин считался только фактором риска. Во-вторых, в своих медицинских рекомендациях мы руководствовались критериями оценки степени кардиоваскулярного риска у больных с АГ (Приказ МЗ Украины от 24.05.2012 № 384) и поэтому не настаивали на некоторых этапах лечения интенсивной статинотерапии, как это рекомендуется европейскими и североамериканскими рекомендациями 2017 года.

Adherence to Recommended Eating Patterns Is Associated With Lower Risk of Peripheral Arterial Disease: Results From the Women's Health Initiative.

The potential role of nutritional factors in the development of peripheral arterial disease (PAD) remains poorly understood. We evaluated multiple recommended eating patterns as reflected by predefined diet quality indices in relation to long-term risk of PAD. We included 138 506 US postmenopausal women in the Women’s Health Initiative who had no known PAD at baseline (1993–1998). Four diet quality indices, including alternate Mediterranean diet index, alternate Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension diet index, and Healthy Eating Index-2015, were derived using dietary information collected by a validated food frequency questionnaire at baseline. Incident cases of symptomatic PAD in the lower extremities were ascertained and adjudicated through March 2019 via medical record review. During a median 18.6 years of follow-up, 1036 incident PAD cases were identified. After multivariable adjustment, all diet quality scores were significantly and inversely associated with 21% (for alternate Healthy Eating Index 2010) to 34% (for Dietary Approaches to Stop Hypertension index) lower risk of PAD when comparing the highest with the lowest quartiles (all P-fortrend values ≤0.010). Among contributing food groups and nutrients, intakes of legumes, dietary fiber, and vegetable protein were associated lower risk of PAD, while intakes of unprocessed red meat, processed meat, and regular soft drinks were associated with higher risk. In a broad sample of US postmenopausal women, adhering to different recommended eating patterns is associated with lower risk of PAD. Our findings suggest that current clinical and public health strategies that recommend healthful eating patterns may also be applicable to PAD prevention. (

Triglyceride-glucose index in the development of peripheral artery disease: findings from the Atherosclerosis Risk in Communities (ARIC) Study

BackgroundIt remains unclear whether triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, is prospectively associated with incident peripheral arterial disease (PAD).MethodsWe included 12,320 Atherosclerosis Risk in Communities Study participants (aged 54.3 ± 5.7 years) free of a history of PAD at baseline (visit 1: 1987–1989). The TyG index was determined using ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2), and measured at 5 visits between 1987 and 2013. Incident PAD was defined as the first hospitalization with PAD diagnosis or a new onset of measured ABI < 0.90 during follow-up visits. We quantified the association of both baseline and trajectories of TyG index with incident PAD using Cox regression and logistic regression analysis, respectively.ResultsOver a median follow-up of 23 years, 1300 participants developed PAD. After adjustment for traditional PAD risk factors, each 1-SD (0.58) increase in TyG index was associated with an 11.9% higher risk of incident PAD [hazard ratio, 1.119 (95% CI, 1.049–1.195)]. Results were similar when individuals were categorized by TyG index quartiles [hazard ratio, 1.239 (95% CI, 1.028–1.492); comparing extreme quartiles]. Four distinct trajectories of stable TyG indexes at various levels along the follow-up duration were identified [low (22.2%), moderate (43.2%), high (27.5%), and very high (7.1%) trajectory groups]. Compared with those with a TyG index trajectory at a low level, those participants with TyG index trajectories at high and very high levels had an even greater risk of future incident PAD [odds ratio (95%CI): 1.404 (1.132–1.740) and 1.742 (1.294–2.344), respectively] after multivariate adjustments for traditional PAD risk factors.ConclusionsHigher TyG index is independently associated with an increased risk of incident PAD. Long-term trajectories of TyG index help identify individuals at a higher risk of PAD who deserve specific preventive and therapeutic approaches.Trial registration: Clinical trial registration number: The ARIC trial was registered at clinicaltrials.gov as NCT00005131.

Successful Peripheral Vascular Intervention in Patients with High-risk Comorbidities or Lesion Characteristics.

Certain comorbidities and lesion characteristics are associated with increased risk for procedural complications, limb events, and cardiovascular events following peripheral vascular intervention (PVI) in patients with peripheral arterial disease (PAD). The purpose of this review is to provide an overview of high-risk modifiable and unmodifiable patient characteristics and its relative impact on clinical outcomes such as amputation risk and mortality. Furthermore, general approaches to potentially mitigating these risks through pre-intervention planning and use of modern devices and techniques are discussed. Diabetes, tobacco use, and older age remain strong risk factors for the development of peripheral arterial disease. Recent data highlight the significant risk of polyvascular disease on major limb and cardiac events in advanced PAD, and ongoing studies are assessing this risk specifically after PVI. Challenging lesion characteristics such as calcified disease and chronic total occlusions can be successfully treated with PVI by utilizing novel devices (e.g., intravascular lithotripsy, re-entry devices) and techniques (e.g., subintimal arterial "flossing" with antegrade-retrograde intervention). Understanding high-risk patient comorbidities and lesion characteristics will improve our ability to counsel and manage patients with advanced PAD. Continued device innovation and novel techniques will aid in procedural planning for successful interventions to improve clinical outcomes.

Cigarette Smoking, miR-27b Downregulation, and Peripheral Artery Disease: Insights into the Mechanisms of Smoking Toxicity.

Cigarette smoking is a risk factor for the development of peripheral artery disease (PAD), although the proatherosclerotic mediators of cigarette smoking are not entirely known. We explored whether circulating microRNAs (miRNAs) are dysregulated in cigarette smokers and associated with the presence of PAD. Ninety-four participants were recruited, including 58 individuals without and 36 with PAD, 51 never smokers, 28 prior smokers, and 15 active smokers. The relative expression of six circulating miRNAs with distinct biological roles (miR-21, miR-27b, miR-29a, miR-126, miR-146, and miR-218) was assessed. Cigarette smoking was associated with the presence of PAD in multivariate analysis. Active smokers, but not prior smokers, presented miR-27b downregulation and higher leukocyte, neutrophil, and lymphocyte counts; miR-27b expression levels were independently associated with active smoking. Considering the metabolic and/or inflammatory abnormalities induced by cigarette smoking, miR-27b was independently associated with the presence of PAD and downregulated in patients with more extensive PAD. In conclusion, the atheroprotective miR-27b was downregulated in active smokers, but not in prior smokers, and miR-27b expression was independently associated with the presence of PAD. These unreported data suggest that the proatherogenic properties of cigarette smoking are mediated by a downregulation of miR-27b, which may be attenuated by smoking cessation.

Intake of marine n-3 polyunsaturated fatty acids and the risk of incident peripheral artery disease.

A high intake of marine n-3 polyunsaturated fatty acids (PUFAs) may lower the risk of coronary heart disease and ischemic stroke. The association between intake of marine n-3 PUFAs and development of peripheral artery disease (PAD), however, remains unexplored. We hypothesised that intake of marine n-3 PUFAs, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and the sum of EPA + DHA was associated with a lower risk of incident PAD. We used data from the Danish Diet, Cancer and Health cohort and investigated the associations between intake of EPA, DHA and EPA + DHA and development of PAD. Information on intake of n-3 PUFAs was obtained through a validated food frequency questionnaire. Potential PAD cases were identified through linkage to the Danish National Patient Register and subsequently, all cases were validated. Data were available from 55,248 participants and during a median of 13.6 years of follow-up, 950 cases of PAD were identified. Multivariate Cox regression analyses with adjustments for established risk factors showed no statistically significant associations between intake of EPA (p = 0.255), DHA (p = 0.071) or EPA + DHA (p = 0.168) and the rate of incident PAD. We did not confirm our hypothesis that intake of EPA, DHA or EPA + DHA was associated with a lower risk of incident PAD.

Association of Carboxyhemoglobin Levels with Peripheral Arterial Disease in Chronic Smokers Managed at Dr George Mukhari Academic Hospital.

Chronic cigarette smokers (CCS) are known to have elevated levels of carboxyhemoglobin (COHb). However, it is not known whether increased levels of COHb are associated with endothelial dysfunction (ED), and therefore the development of peripheral arterial disease (PAD). The aim of the study was to investigate the association of blood COHb and plasma nitric oxide (NO) levels, and whether it is an independent risk factor in the development of PAD among CCS at Dr George Mukhari Academic Hospital (DGMAH). A sample of 120 CCS with PAD and a convenience sample of 100 CCS without PAD were recruited into the study. Blood COHb levels were measured using the ABL 90 FLEX CO-oximeter automated spectroscopy. Plasma nitric oxide (NO) levels were measure using ELISA. Logistic regression analysis was used to investigate the association of blood COHb and plasma NO with PAD. Blood COHb levels of CCS with PAD were significantly higher than those of CCS without PAD, and the NO levels of CCS with PAD were significantly lower than those of CCS without PAD. Although both the blood COHb and plasma NO in CCS were significantly associated with PAD in bivariate logistic analysis, only plasma NO was independently associated with PAD in multivariate logistic analysis. This finding is consistent with the hypothesis that COHb is a cause of arterial damage in PAD, leading to reduced NO, and therefore reduced arterial dilation.

Trimethylamine-N-oxide Specifically Impairs Endothelium-Derived Hyperpolarizing Factor-Type Relaxation in Rat Femoral Artery.

Although substantial evidence suggests that an increase in the level of trimethylamine-N-oxide (TMAO) is associated with the risk of cardiovascular diseases, including atherosclerosis, chronic kidney diseases, and hypertension, the direct effect of TMAO on vascular endothelial function remains unclear. Therefore, we investigated the acute effects of TMAO on endothelium-dependent relaxation induced by acetylcholine (ACh) in the superior mesenteric arteries and femoral arteries of rat. In endothelium-intact preparations, it was observed that TMAO (300 µmol/L for 60 min) did not affect ACh-induced relaxation in either of the two arteries. In endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation under nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibitions by Nω-nitro-L-arginine (L-NNA) and indomethacin, respectively, TMAO specifically impairs the relaxation in femoral arteries but not in the superior mesenteric arteries. Under the inhibitory actions of NOS and as well as blockade of intermediate-conductance calcium-activated potassium channel (IKCa) (by TRAM-34) and small-conductance calcium-activated potassium channel (SKCa) (by apamin), which are putative sources of EDHF, ACh-induced relaxation was low, and there were no differences between the control and TMAO-treated groups with respect to both arteries. In femoral arteries, TMAO slightly reduces ACh-induced relaxation in the presence of indomethacin (preserved NO and EDHF signals) but does not affect ACh-induced NO-mediated relaxation under the combined presence of indomethacin, TRAM-34, and apamin. These results suggest that acute treatment with TMAO specifically impairs EDHF-mediated relaxation in the femoral arteries but not in the superior mesenteric arteries. These novel observations show that TMAO is a causative factor in the development of peripheral arterial disease.