Simulation of bempedoic acid and ezetimibe in the lipid-lowering treatment pathway in Austria using the contemporary SANTORINI cohort of high and very high risk patients.

OBJECTIVE: The low-density lipoprotein cholesterol goals in the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidaemia guidelines necessitate greater use of combination therapies. We describe a real-world cohort of patients in Austria and simulate the addition of oral bempedoic acid and ezetimibe to estimate the proportion of patients reaching goals. METHODS: Patients at high or very high cardiovascular risk on lipid-lowering treatments (excluding proprotein convertase subtilisin/kexin type 9 inhibitors) from the Austrian cohort of the observational SANTORINI study were included using specific criteria. For patients not at their risk-based goals at baseline, addition of ezetimibe (if not already received) and subsequently bempedoic acid was simulated using a Monte Carlo simulation. RESULTS: A cohort of patients (N = 144) with a mean low-density lipoprotein cholesterol of 76.4 mg/dL, with 94% (n = 135) on statins and 24% (n = 35) on ezetimibe monotherapy or in combination, were used in the simulation. Only 36% of patients were at goal (n = 52). Sequential simulation of ezetimibe (where applicable) and bempedoic acid increased the proportion of patients at goal to 69% (n = 100), with a decrease in the mean low-density lipoprotein cholesterol from 76.4 mg/dL at baseline to 57.7 mg/dL overall. CONCLUSIONS: The SANTORINI real-world data in Austria suggest that a proportion of high and very high-risk patients remain below the guideline-recommended low-density lipoprotein cholesterol goals. Optimising use of oral ezetimibe and bempedoic acid after statins in the lipid-lowering pathway could result in substantially more patients attaining low-density lipoprotein cholesterol goals, likely with additional health benefits.

Simvastatin reduces serum level of vascular endothelial growth factor in hypercholesterolemic patients.

Vascular endothelial growth factor plays a pivotal role in the progression of atherosclerotic lesions and causes instability of atherosclerotic plaques by inducing neoangiogenesis inside the current plaque. The pro-inflammatory cytokine interleukin (IL-) 6 induces vascular endothelial growth factor in smooth muscle cells (SMC). HMG-CoA reductase inhibitors (statins), display beside their lipid-lowering potency various pleiotropic effects. Such pleiotropic effects include improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques. In this study we investigate the influence of statin treatment on the serum levels of VEGF in hypercholesterolemic patients. One hundred and seven hypercholesterolemic patients were treated with 20 (n = 52) or 40 mg (n = 55) simvastatin daily. Six weeks of treatment resulted in a significant decrease of VEGF from 1017.1 +/- 297.8 pg/mL at baseline to 543.5 +/- 317.4 pg/mL after 6 weeks (-47.7%) and to 211.8 +/- 155.3 pg/mL after 6 months (-79.7%; all P < 0.001). IL-6 induced the expression of vascular endothelial growth factor in human SMC as analyzed by rt-PCR and flow cytometry. Statins decreased the stimulatory effect of IL-6 on mRNA and protein levels. This effect could be inhibited by co-incubation with mevalonate acid. This study contributes in understanding the pleiotropic effects of statins particularly with regard to their use in treatment and prevention of cardiovascular disease.

Insulin, C-peptide, and restenosis after femoral artery balloon angioplasty in type II diabetic and nondiabetic patients.

PURPOSE: Endogenous and exogenous insulin is suggested to stimulate hypertrophic wound-healing responses and therefore may promote neointimal hyperplasia and restenosis after balloon angioplasty. The ratio of C-peptide to insulin reflects endogenous insulin secretion. In diabetic patients with insulin substitution, lower ratios display a higher proportion of exogenous insulin. The association and interaction of insulin and C-peptide with restenosis after percutaneous transluminal angioplasty (PTA) was investigated in type II diabetic and nondiabetic patients. MATERIALS AND METHODS: The study group included 76 patients (median age, 68 years; interquartile range [IQR], 58-74 years; 55 men [72%]; 31 patients [41%] with type II diabetes) with intermittent claudication (n = 49; 64%) or critical limb ischemia (n = 27; 36%) who underwent primary successful femoral PTA. C-peptide and insulin levels were measured at baseline, and patients were followed to determine restenosis (> or =50%) at 12 months by color-coded duplex sonography. RESULTS: Restenosis was found in 34 patients (45%) at 12 months. Patients with restenosis had higher insulin levels (median, 21.3 microU/mL IQR, 11.3-35.5 microU/mL) and a lower C-peptide/insulin ratio (median, 16; IQR, 10-21) compared with patients without restenosis (median insulin level, 11.6 microU/mL; IQR, 9.1-22.0 microU/mL [P = .008]; median ratio, 19 [IQR, 17-25], P = .039). In nondiabetic patients, insulin levels were significantly associated with restenosis (P = .046), whereas the ratio of C-peptide to insulin showed no association with restenosis. In patients with type II diabetes (n = 31; 41%), in contrast, the C-peptide/insulin ratio was associated with restenosis (P = .047), whereas insulin levels showed no significant association with restenosis (P = .14). CONCLUSIONS: Insulin levels and the C-peptide/insulin ratio were associated with restenosis after femoral PTA. Exogenous and endogenous insulin may play a role in the pathogenesis of recurrent lumen loss after balloon angioplasty.

Flow monitoring: performance characteristics of ultrasound dilution versus color Doppler ultrasound compared with fistulography.

BACKGROUND: Measurement of access blood flow is the preferred noninvasive screening test for hemodialysis arteriovenous (AV) fistula stenosis. However, performance characteristics of the 2 most frequently used ultrasound techniques compared with fistulography remain elusive. METHODS: We evaluated 59 hemodialysis patients with native forearm AV fistulae who underwent all 3 measurements in a prospective order: the ultrasound dilution technique (UDT), color Doppler ultrasonography (CDUS), and fistulography. Patients with angiographically diagnosed access stenosis underwent angioplasty and were followed up by means of monthly UDT measurements until restenosis occurred within the first 6 months. RESULTS: Both ultrasound techniques predicted access stenosis (P < 0.01). Performance was similar between both techniques, evaluated by receiver operating characteristic curves. Areas under the curve averaged 0.79 (95% confidence interval [CI], 0.66 to 0.91) for UDT and 0.80 (95% CI, 0.65 to 0.94) for CDUS. Correlation between measured UDT and CDUS blood flow rates was 0.37 (Spearman's rho, rho = 0.004). The calculated optimal cutoff value for the prediction of stenosis was 465 mL/min for the UDT and 390 mL/min for the CDUS technique. Access stenosis was diagnosed in 41 patients who subsequently underwent percutaneous angioplasty (PTA), which was successful in 34 patients. Restenosis occurred in 13 patients within the first 6 months after PTA. UDT access blood flow after PTA was significantly lower in these 13 patients compared with the other 21 patients. CONCLUSION: Our data suggest that blood flow monitoring of AV hemodialysis access by ultrasound provides a reasonable prediction of access stenosis and restenosis.

Simvastatin reduces the expression of adhesion molecules in circulating monocytes from hypercholesterolemic patients.

OBJECTIVE: The intercellular adhesion molecule-1 (ICAM-1/CD54) and its ligand, CD11a/CD18, mediate endothelial adhesion of leukocytes and their consecutive transmigration. Anti-inflammatory effects of statins are considered to be exerted in part through inhibition of leukocyte-endothelial interactions. We investigated the in vivo effects of simvastatin treatment in hypercholesterolemic patients and the influence of various statins on expression of cellular adhesion molecules in vitro. METHODS AND RESULTS: A total number of 107 hypercholesterolemic patients were treated with 20 mg (n=52) or 40 mg (n=55) of simvastatin daily. After 6 weeks of treatment, peripheral blood mononuclear cells (PBMCs) expressed lower amounts of CD54-, CD18-, and CD11a-mRNA compared with pretreatment values. Surface expression of CD54 and CD18/CD11a on CD14+-monocytes also decreased significantly in both groups of patients. Moreover, simvastatin, atorvastatin, and cerivastatin were found to downregulate tumor necrosis factor (TNF)-alpha-induced expression of CD54 and CD18/CD11a in isolated PBMCs obtained from normal donors as well as TNF-alpha-dependent expression of these CAMs in cultured human umbilical vein endothelial cells (HUVECs). Furthermore, all three statins were found to reduce the binding of PBMCs to TNF-alpha-stimulated HUVECs in vitro. CONCLUSIONS: Statin-induced inhibition of expression of CD54 and CD18/CD11a in PBMCs and HUVECs with consecutive loss of adhesive function may contribute to the anti-inflammatory effects of these drugs and some of their beneficial clinical activities.

Relation of small artery compliance and lipoprotein (a) in patients with atherosclerosis.

BACKGROUND: Lipoprotein (a) is suggested to cause endothelial dysfunction, alteration of elastic arterial properties, and decreased arterial compliance. We investigated the relation of arterial compliance and lipoprotein (a) serum [Lp(a)] levels in patients with atherosclerosis. METHODS: Prospective study included 118 consecutive patients with atherosclerosis. Noninvasive computerized pulse wave analysis was used to measure large and small artery elasticity indices in a nondiseased vessel area. Compliance parameters were correlated to Lp(a) levels. Stratified and multivariate analyses were performed to adjust for confounding factors. RESULTS: Small artery elasticity index was inversely correlated with Lp(a) serum levels (r = -0.64, P <.001). The association between Lp(a) and small artery elasticity index remained significant adjusting for age, sex, diabetes mellitus, smoking, hyperlipidemia, and lipid-lowering medication (r = -0.37, P <.0001). Lp(a) accounted for approximately 60% of the variation of small artery compliance in nondiabetic patients (n = 80) (r = -0.76, P <.0001), in diabetic patients (n = 38) no significant correlation between Lp(a) and small artery compliance was observed (r = -0.27, P =.09). No correlation was found between large artery elasticity index and Lp(a). CONCLUSIONS: Small artery compliance was negatively correlated to Lp(a) in nondiabetic patients with atherosclerosis. Increased Lp(a) serum levels might cause endothelial dysfunction measurable by decreased small artery elasticity index in these patients. Elastic properties of diabetic vessels were not directly related to Lp(a) serum levels.

Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients.

OBJECTIVE: A number of studies have shown that statins decrease morbidity and mortality in patients with cardiovascular diseases. The anti-inflammatory effects of statins have recently been implicated in the clinical benefit that can be obtained in the treatment of atherosclerosis. Little is known about the mechanisms by which statins counteract inflammation. METHODS AND RESULTS: In this study, we asked whether simvastatin can influence in vitro and in vivo production of the proinflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1. A total of 107 hypercholesterolemic patients were treated with simvastatin. As measured by ELISA, serum levels of cytokines significantly decreased after 6 weeks of treatment (P<0.05). Furthermore, simvastatin decreased the expression of IL-6, IL-8, and monocyte chemoattractant protein-1 mRNA in peripheral blood mononuclear cells. Similar results were obtained in vitro by using cultured human umbilical vein endothelial cells and peripheral blood mononuclear cells from healthy normolipemic donors. Exposure to simvastatin, atorvastatin, or cerivastatin caused downregulation of the expression of cytokine mRNA in a time- and dose-dependent manner. Furthermore, all statins tested were able to reduce the concentrations of cytokines in cellular and extracellular fractions of human umbilical vein endothelial cells (P<0.05). CONCLUSIONS: Our data show that simvastatin is anti-inflammatory through the downregulation of cytokines in the endothelium and leukocytes. These effects may explain some of the clinical benefits of these drugs in the treatment of atherosclerosis.

Femoropopliteal arteries: immediate and long-term results with a Dacron-covered stent-graft.

PURPOSE: To assess immediate and long-term outcome after femoropopliteal implantation of a Dacron-covered stent-graft in patients with peripheral arterial disease. MATERIALS AND METHODS: This prospective cohort study included 30 consecutive patients who underwent Dacron-covered stent-graft implantation because of recurrent stenosis after percutaneous transluminal angioplasty in the femoropopliteal segment. After interventional treatment, 100 mg of acetylsalicylic acid daily and oral anticoagulation therapy (therapeutic level, international normalized ratio, 2.0-3.0) were administered. Patients were followed up with ankle-brachial index measurement, color-coded duplex ultrasonography, and angiography. Primary and secondary patency rates and postintervention complications were documented as was initial technical success. Kaplan-Meier and life table analyses were used for calculation of patency rates. RESULTS: Initial technical success was achieved in all 30 patients, with significant improvement of ankle-brachial index from a preintervention mean of 0.5 +/- 0.14 (SD) to a postintervention mean of 0.8 +/- 0.17 (P <.001). Postimplantation noninfectious fever and leukocyte and C-reactive protein level elevation occurred in 12 patients (40%), and 17 patients (57%) reported persistent pain at the site of implantation for a mean of 5 days (range, 2-28 days). Early recurrent occlusion within the first 24 hours was found in five patients (17%). Within the mean follow-up period of 60 months +/- 10, restenosis occurred in 25 patients (83%). At 6, 12, 36, and 72 months, respectively, primary patency rates were 27%, 23%, 17%, 17%, and secondary patency rates were 63%, 60%, 34%, 34%. CONCLUSION: Implantation of Dacron-covered stent-grafts for treatment of femoropopliteal lesions leads to high early and late restenosis rates, with a considerable rate of complications, such as fever and pain.

Outcome of conservative medical treatment of patients with infrarenal abdominal aortic aneurysms.

OBJECTIVE: Since non-invasive diagnostic methods have become available and screening programs have become popular, abdominal aortic aneurysms are more frequently being detected at an early stage of the disease. We analyzed the course of conservatively treated patients with infrarenal abdominal aortic aneurysms (AAA), and determined independent risk factors for aneurysm expansion. METHODS: The study was designed as a retrospective-cohort study including 110 consecutive patients with AAA. Cardiovascular risk factors, comorbidities, current medication, and the findings of color coded duplex sonography and computed tomography were recorded. Ninety-two conservatively treated patients were re-investigated every 6 or 12 months (depending on an initial aneurysm size of > 45 mm or < 45 mm respectively) after initial detection by color coded duplex sonography. We performed a multivariate Cox regression analysis to determine independent predictors of diameter progression (diameter increase > or = 5 mm). RESULTS: We found AAA expansion in 46 conservatively treated patients (50%) during the median follow up period of 23 months (IQR 13 to 33), but no rupture occurred. Baseline diameter > 45 mm (HR 2.3, 95% CI 1.0 to 5.3, P = .04) and signs of aortic dissection in duplex ultrasound (HR 2.2, 1.0 to 4.6, P = .04) were independently associated with aneurysm expansion. The presence of an intraluminal thrombus showed a trend towards higher rates of disease progression (HR 2.6, 95% CI 0.9 to 7.6, P = .08). CONCLUSION: Patients with an aneurysm diameter > 45 mm or ultrasound signs of aortic dissection have an increased risk for AAA progression and need careful evaluation, optimization of risk factors and close (six-month) follow-up intervals. For patients with an aneurysm diameter below 45 mm and without additional risk factors, follow-up intervals of 12 months seem to be safe.