Urinary vanin-1 as a novel biomarker for survival in peripheral artery disease.

BACKGROUND: Chronic kidney disease is associated with increased rates of incidence, morbidity, and mortality in lower-extremity peripheral artery disease (PAD). No specific marker for a functional risk assessment of kidney disease in PAD is known, especially at the early stages. Thus, we speculated that urinary vanin-1 (uVNN1), a marker of oxidative stress even in early kidney injury, could further stratify outcome assessment in patients with PAD. METHODS: Patients with stable PAD (n = 304) of the Vienna medical cohort were followed up for up to 10 years and the outcome was assessed by central death database queries. uVNN1 was measured by enzyme-linked immunosorbent assay (ELISA) at study inclusion and normalized to urinary creatinine (uVNN1/Cr). During the observation time (9.3, 7.0-9.8 years), 104 patients died, 54.8% of which were due to cardiovascular causes. RESULTS: uVNN1/Cr was associated with a urine albumin-creatinine ratio (UACR) (R = 0.166, p = 0.004) but not with an estimated glomerular filtration rate (R = 0.102, p = 0.077). Levels of uVNN1/Cr did not differ between asymptomatic and symptomatic PAD (p = 0.406). Kaplan-Meier curves showed a clear-cut association with higher all-cause (log-rank p = 0.034) and cardiovascular mortality (log-rank p = 0.032) with higher uVNN1/Cr levels. Similarly, significant associations for all-cause (hazard ratio [HR] 1.34, 95% CI [1.08-1.67], p = 0.009) and cardiovascular mortality (HR 1.45, 95% CI [1.06-1.99], p = 0.020) could be seen in multivariable Cox regression models. CONCLUSIONS: uVNN1/Cr showed an independent association with both all-cause and cardiovascular mortality in patients with PAD and was associated with early kidney disease. Thus, uVNN1 could be a useful marker for risk stratification of kidney disease in PAD.

A RAND/UCLA-Modified VAS Study on Telemedicine, Telehealth, and Virtual Care in Daily Clinical Practice of Vascular Medicine.

Background: Telemedicine is increasingly used in several fields of healthcare, including vascular medicine. This study aimed to investigate the views of experts and propose clinical practice recommendations on the possible applications of telemedicine in vascular medicine. Methods: A clinical guidance group proposed a set of 67 clinical practice recommendations based on the synthesis of current evidence and expert opinion. The Telemedicine Vascular Medicine Working Group included 32 experts from Europe evaluating the appropriateness of each clinical practice recommendation based on published RAND/UCLA methodology in two rounds. Results: In the first round, 60.9% of clinical practice recommendations were rated as appropriate, 35.9% as uncertain, and 3.1% as inappropriate. The strongest agreement (a median value of 10) was reached on statements regarding the usefulness of telemedicine during the 2019 coronavirus disease (COVID-19) pandemic, its usefulness for geographical areas that are difficult to access, and the superiority of video calls compared to phone calls only. The lowest degree of agreement (a median value of 2) was reported on statements regarding the utility of telemedicine being limited to the COVID-19 pandemic and regarding the applicability of teleconsultation in the diagnosis and management of abdominal aortic aneurysm. In the second round, 11 statements were re-evaluated to reduce variability. Conclusions: This study highlights the levels of agreement and the points that raise concern on the use of telemedicine in vascular medicine. It emphasizes the need for further clarification on various issues, including infrastructure, logistics, and legislation.

Serum Trefoil Factor-3 Predicts Survival in Peripheral Artery Disease.

Trefoil factor 3 (TFF3) has been studied in processes leading to atherosclerosis. Data are scarce in manifest disease and missing in peripheral artery disease (PAD). This study aims to elucidate TFF3 with disease stages, degrees of atherosclerosis, and outcomes. TFF3 was measured in serum in 364 PAD patients without critical limb ischemia and mild to moderate chronic kidney disease (CKD). Mortality data were retrieved from the Austrian central death registry (median observation 9.6 years). Survival analyses were performed using Cox regression and the Kaplan-Meier method. A negative association between ankle-brachial index and TFF3 (P < .001) was observed, while levels were similar in asymptomatic and symptomatic PAD. TFF3 increased with history of cardiovascular and cerebrovascular disease (P < .001). TTF3 was associated with the estimated glomerular filtration rate (R = -0.617, P < .001) and urinary albumin-creatinine ratio (R = 0.229, P < .001). One SD increase in TFF3 showed a worsening in all-cause mortality (hazard ratio 1.68, CI 1.37-2.05) which persisted after multiple adjustment for cardiovascular risk, inflammatory, and angiogenetic markers (hazard ratio 1.35, CI 1.01-1.81). This study is the first to link TFF3 with both disease markers and outcomes in PAD. TFF3 demonstrated associations with renal function, PAD severity measured by ankle-brachial index, and additional atherosclerotic burden in PAD.

Hyperparathyroidism and Peripheral Arterial Disease.

Primary hyperparathyroidism (PHPT) is presented in various forms, including classic PHPT, characterised by increased parathyroid hormone (PTH) secretion, normohormonal PHPT, and normocalcaemic PHPT. Secondary hyperparathyroidism is characterised by increased PTH secretion triggered by factors such as vitamin D deficiency and kidney failure. This review aims to discuss the involvement of hyperparathyroidism (HPT) in atherosclerosis, including peripheral arterial disease (PAD). The increased level of PTH is involved in developing subclinical and overt vascular diseases, encompassing endothelial dysfunction, vascular stiffness, hypertension, and coronary and peripheral arterial diseases. It has been consistently associated with an augmented risk of cardiovascular morbidity and mortality, independent of classical risk factors for atherosclerosis. Chronic hypercalcemia associated with increased levels of PTH contributes to the development of calcification of vessel walls and atherosclerotic plaques. Vascular calcification can occur in the intima or media of the arterial wall and is associated with stiffness of peripheral arteries, which the formation of atherosclerotic plaques and narrowing of the vessel lumen can follow. For treating hyperparathyroidism, particularly SHPT, calcimimetics, novel phosphorus binders and novel vitamin D receptor activators are used. However, they are ineffective in severe PHPT. Therefore, parathyroidectomy remains the primary therapeutic option of PHPT.

Thyroid Disorders and Peripheral Arterial Disease.

Hypothyroidism and hyperthyroidism, both overt and subclinical, are associated with increased risk of cardiovascular morbidity and mortality. The association between thyroid-stimulating hormone levels and cardiovascular risk has been demonstrated in large epidemiological studies and meta-analyses and is now considered a U-shaped curve. Several pathophysiological mechanisms linking thyroid and cardiovascular disease are known; however, specific clinical complications of peripheral arterial disease as endpoints of clinical trials have not been adequately investigated. The potential mechanisms linking hypothyroidism and peripheral arterial disease are endothelial dysfunction, blood pressure changes, dyslipidemia, and low-grade systemic inflammation. The potential mechanisms linking hyperthyroidism and peripheral arterial disease are hyperdynamic circulation, elevated systolic blood pressure, hypercoagulability, and possibly increased arterial inflammation.

The Effect of Menopause and Menopausal Hormone Therapy on the Risk of Peripheral Artery Disease.

Peripheral artery disease (PAD), defined as lower extremity arterial disease, constitutes an underestimated aspect of the menopause-associated risk of atherosclerotic cardiovascular disease (ASCVD). Accumulation of ASCVD risk factors, such as atherogenic dyslipidaemia, diabetes, and arterial hypertension, after the transition to menopause may contribute to atherosclerotic plaque formation in peripheral arteries. However, inconsistency exists among studies as to whether transition to menopause increases the risk of PAD, although early menopause (<45 years) or premature ovarian insufficiency may accelerate peripheral atherosclerotic plaque formation. Menopausal hormone therapy may decrease the risk of PAD if administered early (i.e., within the first 5-6 years after last menstruation), whereas it has no effect in women with established ASCVD.

Cardiometabolic Risk, Peripheral Arterial Disease and Cardiovascular Events in Polycystic Ovary Syndrome: Time to Implement Systematic Screening and Update the Management.

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder in women of reproductive age. It presents with gynaecologic, metabolic, and psychologic manifestations. The dominant drivers of pathophysiology are hyperandrogenism and insulin resistance. Both conditions are related to cardiometabolic risk factors, such as obesity, hypertension, dyslipidaemia, hyperglycaemia, type 2 and gestational diabetes, nonalcoholic fatty liver disease and obstructive sleep apnoea. Women with PCOS of reproductive age consistently demonstrated an elevated risk of subclinical atherosclerosis, as indicated by different measurement methods, while findings for menopausal age groups exhibited mixed results. Translation of subclinical atherosclerosis into the increased incidence of peripheral arterial disease and major cardiovascular (CV) events is less clear. Although several expert groups have advised screening, the CV risk assessment and prevention of CV events are frequently underdiagnosed and overlooked aspects of the management of PCOS. A combination of lifestyle management and pharmacotherapy, including the promising new era of anti-obesity medicine, can lead to improvements in cardiometabolic health.

Testosterone and Peripheral Arterial Disease.

Testosterone levels in men begin declining in the early years of adulthood, with a 1-2% reduction/year. Low testosterone levels in men are associated with obesity, metabolic syndrome, diabetes mellitus, dyslipidaemia, hypertension and increased cardiovascular mortality. However, observational studies of testosterone levels in males and their relationship with peripheral arterial disease (PAD) have yielded mixed results; only some cohorts show a clear association with low free testosterone levels. This discrepancy may, in part, be due to methodological issues with estimating free testosterone but also to different effects of testosterone on the vessel wall and metabolism. While testosterone improves glycaemic control, has anti-obesity effects and induces vasodilation, it also stimulates platelet aggregation and increases the haematocrit. Androgen deprivation treatment for advanced prostate cancer may be associated with elevated cardiovascular risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.

Involvement of APOE in Incidence of Revascularization in Patients Affected by Peripheral Arterial Disease: A Prospective Study from Southern Italy.

INTRODUCTION: Atherosclerosis is a complex multifactorial disease and apolipoprotein E (APOE) polymorphism has been associated with cardiovascular events. The APOE gene, located on chromosome 19q13.2, has an important role in lipid metabolism, in particular on circulating cholesterol levels, implying further pleiotropic effects; from its polymorphism are derived three alleles (ε2, ε3 and ε4), which induce different phenotypes, while its impact on carotid and femoral atherosclerosis is still controversial. OBJECTIVES: The aim of the study is to investigate the relationship between APOE genotypes and peripheral revascularization in a cohort of patients affected by advanced peripheral arterial disease (PAD) at a prolonged follow-up. MATERIALS AND METHODS: Some 332 patients (259 males and 73 females; mean age 70.86 ± 7.95 years) with severe PAD were enrolled in a longitudinal study, with a 90.75 ± 32.25 month follow-up, assessing major adverse cardiovascular events (MACE). RESULTS: As compared with ε3/ε3, in ε4 patients we observed a significant higher incidence of carotid (13.2% vs. 5.6%; HR = 2.485, 95% CI 1.062-5.814; p = 0.036) and lower limb (11.8% vs. 4.3%; HR = 2.765, 95% CI 1.091-7.008; p = 0.032) revascularizations and, accordingly, a higher incidence of total peripheral revascularizations (13.5% vs. 9.5%; HR = 2.705, 95% CI 1.420-5.151; p = 0.002). HR remained statistically significant even when adjusted for classic cardiovascular risk factors. CONCLUSIONS: In our observational study, we confirm that the ε4 allele is associated with higher total peripheral revascularization in patients with advanced atherosclerotic vascular disease at prolonged follow-up.

The importance of socio-economic determinants of health in the care of patients with peripheral artery disease: A narrative review from VAS.

Socio-economic determinants of health (SDoH) include various nonmedical factors in the socio-economic sphere with a potentially significant impact on health outcomes. Their effects manifest through several mediators/moderators (behavioral characteristics, physical environment, psychosocial circumstances, access to care, and biological factors). Various critical covariates (age, gender/sex, race/ethnicity, culture/acculturation, and disability status) also interact. Analyzing the effects of these factors is challenging due to their enormous complexity. Although the significance of SDoH for cardiovascular diseases is well documented, research regarding their impact on peripheral artery disease (PAD) occurrence and care is less well documented. This narrative review explores to what extent SDoH are multifaceted in PAD and how they are associated with its occurrence and care. Additionally, methodological issues that may hamper this effort are addressed. Finally, the most important question, whether this association may contribute to reasonable interventions aimed at SDoH, is analyzed. This endeavor requires attention to the social context, a whole systems approach, multilevel-thinking, and a broader alliance that reaches out to more stakeholders outside the medical sphere. More research is needed to justify the power in this concept to improve PAD-related outcomes like lower extremity amputations. At the present time, some evidence, reasonable consideration, and intuitive reasoning support the implementation of various interventions in SDoH in this field.

NT-proBNP as a surrogate for unknown heart failure and its predictive power for peripheral artery disease outcome and phenotype.

Patients with peripheral artery disease (PAD) are at high risk of excess mortality despite major improvements in multimodal pharmacotherapy for cardiovascular disease. However, little is known about co-prevalences and implications for the combination of heart failure (HF) and PAD. Thus, NT-proBNP as a suggested surrogate for HF was evaluated in symptomatic PAD regarding long-term mortality. After approval by the institutional ethics committee a total of 1028 patients with PAD, both with intermittent claudication or critical limb ischemia were included after admission for endovascular repair and were followed up for a median of 4.6 years. Survival information was obtained from central death database queries. During the observation period a total of 336 patients died (calculated annual death rate of 7.1%). NT-proBNP (per one standard deviation increase) was highly associated with outcome in the general cohort in crude (HR 1.86, 95%CI 1.73-2.01) and multivariable-adjusted Cox-regression analyses with all-cause mortality (HR 1.71, 95%CI 1.56-1.89) and CV mortality (HR 1.86, 95% CI 1.55-2.15). Similar HR's were found in patients with previously documented HF (HR 1.90, 95% CI 1.54-2.38) and without (HR 1.88, 95%CI 1.72-2.05). NT-proBNP levels were independently associated with below-the-knee lesions or multisite target lesions (OR 1.14, 95% CI 1.01-1.30). Our data indicate that increasing NT-proBNP levels are independently associated with long-term mortality in symptomatic PAD patients irrespective of a previously documented HF diagnosis. HF might thus be highly underreported in PAD, especially in patients with the need for below-the-knee revascularization.

[Individualising antihypertensive therapy in patients with diabetes. A guideline by the Austrian Diabetes Association (update 2023)]. / Individualisierung der antihypertensiven Therapie bei Patient:innen mit Diabetes mellitus. Leitlinie der Österreichischen Diabetes Gesellschaft (Update 2023).

Hypertension is one of the most important comorbidities of diabetes, contributing significantly to death and leading to macrovascular and microvascular complications. When assessing the medical priorities for patients with diabetes, treating hypertension should be a primary consideration. In the present review practical approaches to hypertension in diabetes, including individualized targets for preventing specific complications are discussed according to current evidence and guidelines. Blood pressure values of about 130/80 mm Hg are associated with the best outcome; most importantly, at least blood pressure values < 140/90 mm Hg should be achieved in most patients. Angiotensin converting enzyme inhibitors or angiotensin receptor blockers should be preferred in patients with diabetes, especially in those who also have albuminuria or coronary artery disease. Most patients with diabetes require combination therapy to achieve blood pressure goals; agents with proven cardiovascular benefit should be used (including, besides angiotensin converting enzyme inhibitors and alternatively angiotensin receptor blockers, dihydropyridin-calcium antagonists and thiazide diuretics), preferable in single-pill combinations. Once the target is achieved, antihypertensive drugs should be continued. Newer antidiabetic medications such as SGLT-2-inhibitors or GLP1-receptor agonists have also antihypertensive effects.

Secondary calciprotein particle size is associated with patient mortality in peripheral artery disease.

BACKGROUND AND AIMS: Secondary calciprotein particles (CPP-II) induce inflammation and contribute to vascular calcification. CPP-II size is associated with vascular calcification in patients with chronic kidney disease (CKD) and all-cause mortality in hemodialysis patients. Here, we investigate for the first time a possible role of CPP-II size in patients with peripheral artery disease (PAD) without severe CKD. METHODS: We measured the hydrodynamic radius (Rh) of CPP-II by using dynamic light scattering in a cohort of 281 PAD patients. Mortality was evaluated over a period of ten years by central death registry queries. 35% of patients died during the observation period (median of 8.8 (6.2-9.0) years). Cox-regression analyses were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) and to allow for multivariable adjustment. RESULTS: The mean CPP-II size was 188 (162-218) nm. Older patients, patients with reduced kidney function, and those with media sclerosis had larger CPP-II (p < 0.001, p = 0.008, and p = 0.043, retrospectively). There was no association between CPP-II size and overall atherosclerotic disease burden (p = 0.551). CPP-II size was independently significantly associated with all-cause (HR 1.33 (CI 1.01-1.74), p = 0.039) and cardiovascular mortality (HR 1.52 (CI 1.05-2.20), p = 0.026) in multivariable regression analyses. CONCLUSIONS: Large CPP-II size is associated with mortality in PAD patients and might be a new feasible biomarker for the presence of media sclerosis in this patient population.

Lipoprotein (a) and long-term outcome in patients with peripheral artery disease undergoing revascularization.

BACKGROUND AND AIMS: Despite low LDL-C goals, the residual risk for further cardiovascular (CV) events in patients with peripheral artery disease (PAD) remains high. Lipoprotein (a) (Lp(a)) is a known risk factor for PAD incidence, but little is known regarding the outcome in patients with symptomatic PAD. Thus, this study investigates Lp(a) and CV mortality in PAD after endovascular repair. METHODS: A total of 1222 patients with PAD in two cohorts according to Lp(a) assay in nmol/L (n = 964, Lip-LEAD-A) or mg/dl (n = 258, Lip-LEAD-B) were followed up for 4.3 (IQR 3.0-5.6) or 7.6 (IQR 3.2-8.1) years. Lp(a) was measured before endovascular repair for either intermittent claudication (IC) or critical limb ischemia (CLI). Outcome information was obtained from the federal death registry. RESULTS: In Lip-LEAD-A, 141 CV-deaths occurred (annual calculated CV-death rate 3.4%), whereas 64 CV-deaths were registered in Lip-LEAD-B (annual calculated CV-death rate 3.3%). After adjustment for traditional CV risk factors Lp(a) was neither associated with outcome in Lip-LEAD-A (highest tertile HR 1.47, 95%CI [0.96-2.24]) nor in Lip-LEAD-B (highest tertile HR 1.34 [0.70-2.58]). Subanalyses for IC (HR 1.37 [0.74-2.55]; HR 1.10 [0.44-2.80], CLI (HR 1.55 [0.86-2.80], HR 3.01 [0.99-9.10]), or concomitant coronary artery disease (CAD; HR 1.34 [0.71-2.54]; HR 1.21 [0.46-3.17]) failed to show a significant association between Lp(a) and CV-mortality. CONCLUSIONS: In this large-scale cohort of symptomatic PAD no association of elevated Lp(a) with CV mortality was found over a median observation period of 5 years. Thus, an even longer study including asymptomatic patients is warranted.

High-Density Lipoprotein Particle Subclasses in Statin-Treated Patients with Peripheral Artery Disease Predict Long-Term Survival.

Low-density lipoprotein-cholesterol reduction showed a strong reduction of cardiovascular (CV) event rates in CV disease. However, the residual risk of future CV events remains high, which especially extends to peripheral arterial disease (PAD). Nuclear magnetic resonance (NMR) spectroscopy offers a novel method for analysis of the lipoprotein spectrum. This study investigates lipoprotein subclasses using NMR spectroscopy and assesses implications for long-term survival in PAD. NMR spectroscopy was performed by Nightingale Inc., in 319 patients with stable PAD and well-controlled CV risk factors. Patients were followed-up for 10 years. During that period, 123 patients (38.5%) died, of those 68 (21.3%) were defined as CV deaths. Outcome data were analyzed by the Kaplan-Meier method and multivariable Cox-regression for lipoprotein particles. Small and medium high-density lipoprotein-particles (S-HDL-P and M-HDL-P) showed a significant inverse association with all-cause mortality in Cox-regression analyses after multivariable adjustment (S-HDL-P, hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.57-0.88; M-HDL-P, HR: 0.72, 95% CI: 0.58-0.90) for each increase of one standard deviation. In contrast, cholesterol-rich X-large HDL-particles (XL-HDL-P) showed a positive association with all-cause mortality (HR: 1.51, 95% CI: 1.20-1.89). Only the association between XL-HDL-P and CV death sustained multivariable adjustment (HR: 1.49, 95% CI: 1.10-2.02), whereas associations for S-HDL-P and M-HDL-P were attenuated (HR: 0.76, 95% CI: 0.57-1.01; HR: 0.80, 95% CI: 0.60-1.06). This study shows a novel association for a beneficial role of S-HDL-P and M-HDL-P but a negative association with higher cholesterol-rich XL-HDL-P for long-term outcome in well-treated patients with PAD. Thus, these results provide evidence that NMR-measured HDL particles identify patients at high CV residual risk beyond adequate lipid-lowering therapy.

Preclinical atherosclerosis and cardiovascular events: Do we have a consensus about the role of preclinical atherosclerosis in the prediction of cardiovascular events?

Atherosclerosis has a long preclinical phase, and the risk of cardiovascular (CV) events may be high in asymptomatic subjects. Conventional risk factors provide information for the statistical probability of developing CV events, but they lack precision in asymptomatic subjects. This review aims to summarize the role of some widely publicized indicators of early atherosclerosis in predicting CV events. The earliest measurable indicator of the atherosclerotic process is endothelial dysfunction, measured by flow-mediated dilation (FMD) of the brachial artery. However, reduced FMD is a stronger predictor of future CV events in patients with existing CV disease than in apparently healthy persons. Alternatively, measurement of carotid artery intima-media thickness does not improve the predictive value of risk factor scores, while detection of asymptomatic atherosclerotic plaques in carotid or common femoral arteries by ultrasound indicates high CV risk. Coronary calcium is a robust and validated help in the estimation of vascular changes and risk, which may improve risk stratification beyond traditional risk factors with relatively low radiation exposure. Arterial stiffness of the aorta, measured as the carotid-femoral pulse wave velocity is an independent marker of CV risk at the population level, but it is not recommended as a routine procedure because of measurement difficulties. Low ankle-brachial index (ABI) indicates flow-limiting atherosclerosis in the lower limbs and indicates high CV risk, while normal ABI does not rule out advanced asymptomatic atherosclerosis. Novel circulating biomarkers are associated with the atherosclerotic process. However, because of limited specificity, their ability to improve risk classification at present remains low.

Calcification Propensity in Serum and Cardiovascular Outcome in Peripheral Artery Disease.

Peripheral artery disease (PAD) has been shown to be linked to elevated cardiovascular risk. The novel T50 test quantifies calcification propensity of serum and has been associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD) and in the general population. This study investigated the association of calcification propensity measured by the T50 test in 287 patients with PAD without severe CKD. Major cardiovascular events (MACEs) including nonfatal stroke and nonfatal myocardial infarction and all-cause death (MACE + ) were evaluated after a median follow-up of 4 years and long-term cardiovascular and all-cause mortality after a median follow-up of 8.7 years by Kaplan-Meier and Cox regression analyses. Mean T50 time was 268 ± 63 minutes in the study cohort (age 69 ± 10 years, 32% women, 47% diabetes). Low T50 values that signify high calcification propensity were significantly associated with the occurrence of MACE+ (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.55-0.94). This association sustained multivariate adjustment for cardiovascular risk factors (CVRFs), Fontaine PAD stage, and prevalent media sclerosis (HR: 0.65; CI: 0.47-0.91). Cardiovascular mortality was significantly associated with T50 after multivariate adjustment for CVRF (HR: 0.72; CI 0.53-0.99), but not all-cause mortality (HR: 0.80; CI: 0.64-1.01). In conclusion, calcification propensity associates with MACE+ and cardiovascular mortality in patients with PAD.