L-Arginine Ameliorates High-Fat Diet-Induced Atherosclerosis by Downregulating miR-221.

OBJECTIVES: Atherosclerosis (AS) is a severe disease in which the inside of an artery narrows because of plaque formation, leading to endothelial injury in the patients. Although it has been found that endothelial nitric oxide synthase (eNOS), which produces a low concentration of NO, is necessary for endothelial function and integrity, the regulatory mechanisms of eNOS expression against the pathogenesis and development of AS are unclear. Evidence has indicated that diet supplementation with L-arginine could reduce the size of the endothelial injury lesions in AS patients. In addition, nonencoding microRNAs (miRNAs) were found to be a promising tool that regulates the expression of eNOS in human endothelial cells. DESIGN: The aim of this research was to explore the role of L-arginine in the development of AS and the mechanisms by which miR-221 influences the possible signaling pathways in endothelial cells during AS. RESULTS: The results suggested that L-arginine could prevent oxidized low-density lipoprotein-induced apoptosis in endothelial cells, which is associated with the downregulation of miR-221. Similar results were also observed in rat AS models. CONCLUSION: This research could provide potential therapies for the treatment of AS.

Intraoperative Arterial Biopsy in Incident Hemodialysis Patients: Differences Observed.

INTRODUCTION: Arterial calcification (AC) is a common complication in chronic kidney disease (CKD) patients that starts to develop before these patients need renal replacement therapy. In these patients, calcification can involve tunica intima or tunica media. This study has looked for the prevalence, severity, and distribution of arterial wall calcification in incident hemodialysis patients through intraoperative arterial biopsy obtained during creation of arteriovenous vascular access for hemodialysis. METHODOLOGY: One hundred and seventy-two stage 5 CKD adults (98 male and 74 female) were included. Beside histopathology of the obtained arterial samples, all these cases were tested for serum calcium (Ca), phosphorus (P), alkaline phosphatase, uric acid, parathormone (PTH), fibroblast growth factor 23 (FGF23), and 25 hydroxy vitamin D. RESULTS: Eighty six (50%) of the cases had AC (group I); 29 (17%) as intimal (subgroup Ii), 36 (21%) as medial (subgroup Im), while 21 (12%) had both intimal and medial calcification (subgroup Iim). Eighty-six patients (50%) were devoid of calcification (group II). Apart from the significantly higher serum level of PTH in group I, statistical analysis failed to disclose significant difference in any of the other studied parameters between the 2 groups. On the other hand, there were significant differences in serum P, Ca × P product, serum PTH, and FGF23 between patients according to intensity of calcification. CONCLUSION: Half of incident hemodialysis CKD patients have developed AC mainly in tunica media. Discrepancy in serum P can have an impact on calcification intensity.

Puerarin protects against endothelial dysfunction and end-organ damage in Ang II-induced hypertension.

Puerarin, a major isoflavonoid compound from Chinese herb Kudzu roots, has been widely used for the treatment of hypertensive and cardiovascular diseases in China. Here, we investigated puerarin's beneficial effects on the cardiovascular system in angiotensin (Ang) II-induced hypertensive rats. Sprague-Dawley rats were treated with Ang II for 5 days or with puerarin for 10 days followed by Ang II and puerarin for 5 days. Endothelium-dependent relaxation (EDR) to acetylcholine was determined using an organ chamber bath. Ang II increased the systolic blood pressure (SBP: 178 ± 5 mmHg vs. 112 ± 3 mmHg in control, p < 0.05), aortic (30%, p < 0.05), and left ventricular (LV) weight (23%); puerarin reduced SBP (160 ± 2 mmHg, p < 0.05), aortic, and left ventricular weight in Ang II-infused rats. Puerarin also reduced aortic medial thickness and myocardial cell surface area in Ang II-infused rats. Compared with control rats, Ang II infused rats exhibited an impaired EDR with reduction in the protein expression of phosphor-eNOS at Ser 1177 and an increase in the expression of gp91phox (85%), p22phox (113%), transforming growth factor ß1 (145%) and vascular cell adhesion molecule 1 (82%). Puerarin improved EDR and reversed the changes in Ang II-induced protein expression of above molecules. Our results demonstrate that in Ang II-induced hypertensive rats, puerarin protects against endothelial dysfunction and end organ damage with a mild reduction in SBP, and that the cardiovascular beneficial effects of puerarin may be in part attributed to its anti-oxidant and upregulation of phosphor-eNOS.

Maternal exposure to diets containing flaxseed flour or flaxseed oil during pregnancy and lactation protects the aortic remodeling in adult male offspring of diabetic rat dams.

BACKGROUND: Diabetes during pregnancy is associated with cardiovascular complications in the fetus and extends into adulthood. Therapeutic applications of flaxseed have been studied in cardiovascular disorders, because its oilseed is the best plant source of omega-3 fatty acid, which is currently considered by researchers to be an essential protective against cardiovascular disease. The aim of this study was to evaluate the influence of flaxseed flour and oil on cardiovascular biochemical parameters and the histoarchitecture of the aorta in adult rats which were offspring of diabetic mothers. RESULTS: At 100 days of age in offspring it was observed that maternal consumption of a high-fat diet containing flaxseed oil (FOG) and flaxseed flour (FFG) did not affect the serum concentration of monocyte chemoattractant protein-1, vascular endothelial growth factor, cholesterol, triglycerides, high-density-, low-density- or very-low-density-lipoprotein cholesterol. However, the thickness of the intima media layer of the aorta was significantly smaller in FOG and FFG groups; the lumen area was similar among the groups; and a higher percentage of elastic fiber was found in FOG and FFG groups. CONCLUSION: These data suggest that the use of both flaxseed flour and its oil reduces the remodeling of the aorta; however; it has not been possible to modify the cardiovascular biochemical parameters.

Anti-atherosclerotic effect of geniposidic acid in a rabbit model and related cellular mechanisms.

CONTEXT: Geniposidic acid, one of the main active ingredients in Gardenia jasminoides J. Ellis (Rubiaceae), may also possess important pharmacological activities for cardiovascular disorders similar to other derivatives, such as geniposide. OBJECTIVE: To evaluate its anti-atherosclerosis (anti-AS) effect, the related pharmacological activities and possible cellular mechanisms were studied. MATERIALS AND METHODS: Thirty rabbits were randomly divided into normal control group, model control group, and geniposidic acid subgroups. In the AS model, its effects on the intima/media thickness ratio and aortic morphology were observed. In the study of primary cultured endothelial cells (ECs) and human umbilical artery smooth muscle cells (HUASMCs), its activities on both ECs and HUASMCs proliferation, HUASMCs' migration were also studied. RESULTS: Compared with the model control group, the plaque area, intima/media thickness ratio, and intimal foam cells number in geniposidic acid (80, 160, and 240 mg/kg) subgroups were significantly improved (p < 0.05). By HE staining, the activities of geniposidic acid on relieving ECs shedding and improving aortic morphology disorders were also demonstrated. From the results of CCK-8 testing, only 100 µg/ml geniposidic acid performed significant inhibition on SMC proliferation. The relative IC50 of geniposidic acid on SMC inhibition was 87.73 µg/ml. Geniposide acid also showed promotion effect on ECs proliferation, and the related ED50 of geniposidic acid was 86.05 µg/ml. Besides, only 50 and 100 µg/ml geniposidic acid showed obvious inhibition on SMC migration from the upper chamber (p < 0.05). DISCUSSION AND CONCLUSION: The effects of geniposidic acid on protecting vascular endothelium and reversing plaque formation in an atherosclerotic model were demonstrated.

Ectopic calcification in diabetic vascular disease.

INTRODUCTION: Cardiovascular diseases represent over one-half of all deaths in both type 1 and type 2 diabetes mellitus. In diabetic patients, vascular calcifications are more frequently observed than in people without diabetes. In particular, elevated degrees of coronary artery and valvular calcifications are reported in populations with diabetes. AREAS COVERED: We will present and discuss findings from clinical and basic science studies that investigate the pathophysiological processes leading to exaggerated arterial/valve calcification in diabetic patients. We will also illustrate the likely effects of the current therapies on vascular calcification progression in diabetic patients. A special focus will be dedicated to the contribution of resident/circulating calcifying cells to the calcific processes observed under diabetic conditions. EXPERT OPINION: Interest in the topic of ectopic calcification in diabetic vascular disease is expanding and more knowledge is adding on its mechanisms and consequences. Importantly, new therapeutic targets are emerging, implying possible future chances to modulate vascular calcification for cardiovascular protection.

Lentil-based diets attenuate hypertension and large-artery remodelling in spontaneously hypertensive rats.

Hypertension is a major risk factor for CVD, the leading cause of mortality worldwide. The prevalence of hypertension is expected to continue increasing, and current pharmacological treatments cannot alleviate all the associated problems. Pulse crops have been touted as a general health food and are now being studied for their possible effects on several disease states including hypertension, obesity and diabetes. In the present study, 15-week-old spontaneously hypertensive rats (SHR) were fed diets containing 30% w/w beans, peas, lentils, chickpeas, or mixed pulses or a pulse-free control diet for 4 weeks. Normotensive Wistar-Kyoto (WKY) rats were placed on a control diet. Pulse wave velocity (PWV) was measured weekly, while blood pressure (BP) was measured at baseline and week 4. Fasting serum obtained in week 4 of the study was analysed for circulating lipids. A histological analysis was carried out on aortic sections to determine vascular geometry. Of all the pulse varieties studied, lentils were found to be able to attenuate the rise in BP in the SHR model (P< 0·05). Lentils were able to decrease the media:lumen ratio and media width of the aorta. The total cholesterol (TC), LDL-cholesterol (LDL-C) and HDL-cholesterol levels of rats fed the pulse-based diets were found to be lower when compared with those of the WKY rat and SHR controls (P< 0·05). Although all pulses reduced circulating TC and LDL-C levels in the SHR, only lentils significantly reduced the rise in BP and large-artery remodelling in the SHR, but had no effect on PWV. These results indicate that the effects of lentils on arterial remodelling and BP in the SHR are independent of circulating LDL-C levels.

High phosphate feeding induced arterial medial calcification in uremic rats: roles of Lanthanum carbonate on protecting vasculature.

AIMS: High cardiovascular mortality in patients with end-stage renal disease is closely associated with arterial medial calcification (AMC) caused by hyperphosphatemia, the mechanism of which associated hormones (FGF-23, klotho) and osteochondrogenic events is unclear. We examined the effect of Lanthanum carbonate on AMC via regulating the abnormalities in phosphorus metabolism of uremic rats. MAIN METHODS: 45 healthy SD rats were randomly divided into 3 groups: Normal group (n=15), CRF group (n=15), CRF diet supplemented with 2% La (n=15). AMC in great arteries were evaluated by VonKossa. Osteochondrogenic specific genes were analyzed by Immunohistochemistry and qRT-PCR. Serum FGF-23 and klotho levels were detected by ELISA kit. KEY FINDINGS: Serum phosphate was markedly increased in CRF group (6.94 ± 0.97 mmol/L) and 2%La group (5.12 ± 0.84 mmol/L) at week 4, while the latter became hypophosphatemic (2.92 ± 0.73 mmol/L vs CRF group, p<0.01) at week 10. Inhibitory effect of 2%La on development of AMC was reflected by downregulated Runx2, Osterix, BSP, Osteocalcin and collagenII and a reduction of FGF-23 at week 4(vs CRF group, p<0.01) but not week 10. SIGNIFICANCE: Beneficial effects of Lanthanum carbonate on progression of AMC in CRF could be mainly due to the decreased phosphate retention and FGF-23 in early stage and likewise a reduction of bone-associated proteins via osteochondrogenic pathway. Lanthanum carbonate has no effect on soluble klotho and serum FGF-23 in late stage of CRF.

Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension.

Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is effective in the treatment of monocrotaline-induced PH in the rodent.

Insulin resistance induces medial artery calcification in fructose-fed rats.

Osteogenic differentiation of vascular smooth muscle cells (VSMCs) results in medial artery calcification, which is common in diabetes, but the pathogenesis is poorly understood. We aimed to explore the pathophysiological roles of insulin resistance (IR) on medial artery calcification in rats with 10% fructose in drinking water. After 12 weeks of fructose feeding, rats showed severe IR, with increased levels of fasting blood glucose, serum insulin and oral glucose tolerance test (OGTT). Fructose-fed rats showed aortic calcification, increased aortic calcium deposition and irregular elastic fibers in the medial layer of the vessel wall. Moreover, plasma phosphorus concentration, calcium × phosphorus product and alkaline phosphatase (ALP) activity, and aortic calcium content and ALP activity were significantly increased. Fructose feeding increased mRNA levels of osteopontin, type III sodium-dependent phosphate co-transporter, bone morphogenetic protein-2 and the key transcription factor core binding factor alpha 1 in aortic tissue and downregulated mRNA levels of osteoprotegerin and matrix γ-carboxyglutamic acid protein. Fructose feeding decreased protein levels of smooth-muscle lineage markers and induced severe lipid peroxidation injury. IR induced by high fructose feeding could evoke osteogenic transdifferentiation of VSMCs and promote vascular calcification.

Predictors of anterior and posterior wall carotid intima media thickness progression in men and women at moderate risk of coronary heart disease.

BACKGROUND: The rate of carotid intima media thickness (CIMT) progression has been widely used in clinical trials as a surrogate marker for subclinical atherosclerosis. OBJECTIVE: The aim of this study was to investigate relationships between coronary heart disease (CHD) risk markers and progression of CIMT in patients at moderate CHD risk. METHODS: Participants included men (45-75 years) and women (55-74 years) in the control arm of a clinical trial. All had at least one major CHD risk factor and baseline posterior wall CIMT 0.7-2.0 mm, without significant stenosis. Posterior (n = 134) and anterior wall (in a subset, n = 72) CIMT were assessed with B-mode ultrasound at baseline and 12 and ∼18 months. Fasting lipoprotein lipid, apolipoprotein (Apo), inflammatory, and oxidative stress markers were evaluated. RESULTS: Baseline CIMT was inversely associated (P < .001) with CIMT progression. After adjustment for baseline CIMT, significant predictors of anterior wall CIMT progression in linear regression analyses included glucose (P = .044), high-density lipoprotein cholesterol (HDL-C, inverse, P = .006), triglycerides (TG, P = .006), and ratios of total cholesterol (TC)/HDL-C (P = .013), TG/HDL-C (P = .005), and Apo B/HDL-C (P = .021). Posterior wall CIMT progressed on average, whereas anterior wall CIMT regressed (0.0078 vs -0.0164 mm/year, P = .014). Significant baseline CIMT-adjusted predictors of posterior wall CIMT progression included TC (P = .028), low-density lipoprotein-C (P = .035), non-HDL-C (P = .004), TG (P = .016), Apo B (P = .005), and ratios of TC/HDL-C (P < .001), TG/HDL-C (P = .015), Apo B/Apo AI (P = .012) and Apo B/HDL-C (P = .004). CONCLUSION: The strongest predictors for CIMT progression in anterior and posterior walls were lower baseline CIMT, increased TG, and elevated ratios, including TC/HDL-C, TG/HDL-C and Apo B/HDL-C.

Effect of 3 y of folic acid supplementation on the progression of carotid intima-media thickness and carotid arterial stiffness in older adults.

BACKGROUND: Observational studies have shown that low folate and elevated homocysteine concentrations are risk factors for vascular disease in the general population. Randomized controlled trials in vascular patients have failed to show that folic acid reduces the risk of recurrent vascular disease, whereas such trials are lacking in the general population. OBJECTIVE: The objective was to determine whether folic acid supplementation reduces the progression of atherosclerosis as measured by common carotid intima-media thickness (CIMT)-a validated marker of atherosclerosis and predictor of vascular disease risk. DESIGN: A randomized, double-blind, placebo-controlled study in 819 men and postmenopausal women aged 50-70 y, free-living in the Netherlands, and with a total homocysteine concentration ≥13 µmol/L at screening was conducted. Participants received either 800 µg folic acid or placebo daily for 3 y. Rate of change in CIMT and arterial distensibility were the primary and secondary outcomes, respectively. RESULTS: Compared with placebo, serum folate increased by 577% and plasma total homocysteine concentrations decreased by 26% after 3 y of folic acid supplementation. The mean (±SE) rate of change in CIMT was 1.9 ± 0.9 µm/y in the folic acid arm and 1.3 ± 0.8 µm/y in the placebo arm (mean difference: 0.7 µm/y; 95% CI: -1.8, 3.1 µm/y; P = 0.59). No difference was observed (P = 0.23) between the rates of change in distensibility in the folic acid arm (-0.53 ± 0.06 × 10(-3) kPa(-1)) and in the placebo arm (-0.62 ± 0.06 × 10(-3) kPa(-1)). CONCLUSION: Despite a considerable increase in folate concentrations and a reduction in total homocysteine concentrations, 3-y folic acid supplementation did not slow down atherosclerotic progression or arterial stiffening. This trial was registered at clinicaltrials.gov as NCT00110604.

Hypotensive, hypolipidemic, and vascular protective effects of Morus alba L. in rats fed an atherogenic diet.

Morus alba L. has been used in traditional Chinese medicine and almost all parts of this plant are useful in cardiovascular, liver and spleen disorders. The present study was designed to investigate the inhibitory effect of a water extract from Morus alba L. (WMA) on vascular dysfunction in rat models fed a high fat and high cholesterol diet. Male rats were fed an atherogenic diet consisting of food with 7.5% cocoa butter and 1.25% cholesterol, with or without 100 or 200 mg/day/kg WMA, for 14 weeks. Chronic treatment with low (100 mg/kg/day) or high (200 mg/day/kg) doses of WMA markedly attenuated hypertension and the impairments of acetylcholine-induced relaxation of aortic rings in rats fed an atherogenic diet. WMA reduced intima/media thickness in rats fed an atherogenic diet. WMA improved plasma levels of triglyceride (TG) and augmented plasma levels of high-density lipoprotein (HDL) and plasma low-density lipoprotein (LDL), but did not affect blood glucose levels. Interestingly, WMA suppressed increased cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) expression in the aorta. Taken together, these results suggested that Morus alba L. could improve an atherogenic diet-induced hypertension, hyperlipidemia, and vascular dysfunction through inhibition of cell adhesion molecules expression and induction of vascular relaxation.

Histopathological findings in varicose veins following bipolar radiofrequency-induced thermotherapy--results of an ex vivo experiment.

OBJECTIVE: To describe the histopathological changes of the vein wall caused by bipolar radiofrequency-induced thermotherapy (RFITT), and to examine influence of power and application time on the histopathological changes. MATERIAL AND METHODS: Twenty vein specimens atraumatically extracted near the saphenofemoral junction were treated by RFITT ex vivo. RFITT was applied with fixed (2 seconds) and varied (up to an impedance of 400 Ω) application time and increasing power (5, 10, 15, 20, 25 W). Specimens were processed histologically. RESULTS: RFITT induced coagulation of collagen bundles, shrinking of muscles, splitting and necrosis of the vein wall. Circumferential necrosis of intima and media was reached by a power of 20-25 W and an application time up to an impedance of 400 Ω. Only heterogeneous necrosis of intima and media in parts of the vessel was reached by lower power with long application time. CONCLUSION: A homogeneous necrosis of the circumferential vein wall needs high power and sufficient application time.

[Effect of compound Danshen Dripping Pill on carotid arterial intima-media in patients with type 2 diabetes mellitus].

OBJECTIVE: To investigate the effect of compound Danshen Dripping Pill (DSP) on carotid arterial intima-media thickness (IMT) in patients with type 2 diabetes mellitus (T2DM). METHODS: One hundred and thirty T2DM patients were assigned to four groups, 32 in the Group A, the control group treated with blood glucose (BG) and blood pressure (BP) controlling; 32 in the Group B, with BG, BP and blood lipid (BL) controlling, 32 in Group C with BG, BP, BL controlling and vitamin E administration, and 34 in Group D with BG, BP, BL controlling and DSP administration. Patients in Group D were subdivided by Chinese medicine syndrome differentiation into four types, 8 of Yin-deficiency with flourishing heat type (YDFH), 5 of both qi-yin deficient type (BQYD), 8 of both yin-yang deficient type (BYYD) and 13 of blood-stasis and qi-stagnant type (BSQS). Fasting blood glucose (FBG), BP and BL in patients were observed periodically, and IMT in them were measured by ultrasonography before treatment, as well as at the end of the 1st, 3rd, and 5th year of treatment to dynamically observe the changes of IMT and condition of plaque formation, and analyze the relation between them with FBG, BP and BL. RESULTS: The 5-year follow-up was performed in 105 patients. In the observation period, level of total cholesterol (TC) showed a decreasing trend and level of high density cholesterol (HDL-C) showed an increasing trend in all the 4 groups, the improvements in Group C and D were slightly better than those in Group B, while significantly superior to those in Group A; the changes of FBG and glycosylated hemoglobin (HbAlc) were insignificant in the 4 groups. IMT and numbers of atheroma plaque increased gradually in all groups in the observation period, however, the changes in Group D were lesser than those in other groups, showing significant difference (P < 0.01). It was showed that the increasing of cervical carotid IMT in T2DM patients was correlated with levels of HbAlc, HDL-C, LDL-C, triglyceride and TC, especially in Group D. CONCLUSION: DSP might delay the occurrence and development of diabetic macro-vascular disease.

Effect of tongxinluo on vasoconstriction induced by the chronic injury of the adventitia in the rat carotid artery.

OBJECTIVE: Tongxinluo (TXL) is a traditional Chinese medicine that is developed on the meridian theory of traditional Chinese medicine, with the function of alleviating the angina. The present study was undertaken to explore the molecular mechanism of TXL in treating the pectoris angina through observing the effectiveness of TXL superfine powder on the vasoconstriction and the activation of RhoA/Rho-kinase pathway induced by the injury of the adventitia. METHODS: 36 male Wistar Kyoto rats were assigned to 3 treatments (n=12): vehicle, TXL (400 mg kg(-1) day(-1)) and fasudil (15 mg kg(-1) day(-1)). After 1 week of treatment, adventitia injury was induced by positioning a silicone collar around the right carotid artery for 1 week. Blood flow and vascular reactivity to serotonin were determined 1 week after injurying, the both sides of carotids were harvested for morphometry, Western blotting analysis and RT-PCR analysis. RESULTS: Adventitia injury leaded to histological changes of vasoconstriction with the lumen cross-sectional area of 44.7% (p<0.001) decreasing and the media diameter of 62.31% (p<0.001) increasing, accompanying by the reduction of the blood flow and the increase of vascular reactivity sensitivity to serotonin. Treatment with both TXL superfine powder and fasudil can prevent the development of vasoconstriction, improve the carotid blood flow and normalize the vascular hypersensitivity to serotonin. Adventitia injuring of the rat carotid increased the expression of Rho-kinase mRNA and p-MYPT1(Thr696) protein by 1.78-fold (p<0.05) and >2-fold respectively (p<0.05). TXL reduced the expression of Rho-kinase mRNA and p-MYPT1(Thr696) protein by 54.2% (p<0.05) and 57.1% (p<0.05) respectively in collared arteries. Fasudil restrained the p-MYPT1(Thr696) protein expression by 63.8% (p<0.05) in collared arteries, did not affect the collar-induced the increase of Rho-kinase mRNA expression (p>0.05). CONCLUSIONS: Treatment with TXL, similar to that with fasudil, can effectively prevent collar-induced vasoconstriction and vascular hyperreactivity to serotonin through inhibiting the RhoA/Rho-kinase pathway.

Coffee, decaffeinated coffee, caffeine, and tea consumption in young adulthood and atherosclerosis later in life: the CARDIA study.

OBJECTIVE: To determine the association of coffee, decaffeinated coffee, caffeine, and tea consumption in young adulthood with the presence and progression of coronary artery calcified (CAC) plaque and carotid intima-media thickness later in life. METHODS AND RESULTS: The Coronary Artery Risk Development in Young Adults (CARDIA) Study is a cohort of 5115 white and black adults who were aged 18 to 30 years when they completed a baseline clinic examination from 1985 to 1986. Subsequent examinations were conducted 2, 5, 7, 10, 15, and 20 years later. After multivariable adjustment, no association was observed between average coffee, decaffeinated coffee, or caffeine consumption (years 0 and 7) and presence of CAC (score, >0 Agatston units at year 15 or 20), CAC progression (incident CAC at year 20 or increase in CAC score by ≥20 Agatston units), or high carotid intima-media thickness (>80th percentile, year 20). However, tea consumption displayed a nonsignificant trend for an inverse association with CAC (P=0.08 for trend) and an inverse association with CAC progression (P=0.04 for trend) but no association with high carotid intima-media thickness (P>0.20 for trend). Stratification of the coffee analyses by sex, race, or smoking yielded similar nonsignificant patterns. CONCLUSIONS: We observed no substantial association between coffee or caffeine intake and coronary and carotid atherosclerosis. However, our results suggested an inverse association between tea and CAC but not carotid atherosclerosis.

The role of ezetimibe in the prevention of cardiovascular disease: where do we stand after ARBITER 6-HALTS.

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, rapidly became one of the most widely drugs in the US following its approval by the FDA in 2002. Due to its capacity to significantly lower LDL-C with few side effects, ezetimibe has been very useful in enabling patients who were statin intolerant to reach their recommended therapeutic goal for LDL-C. In addition, ezetimibe also reduces non-HDL-C and raises HDL-C, further enhancing its effectiveness in clinical practice. A significant preponderance of evidence supports the reduction of LDL-C and non-HDL-C as the most effective therapy to prevent or reverse atherosclerotic cardiovascular disease (ASCVD). However 3 recent clinical trials, ENHANCE, SEAS, and ARBITER 6-HALTS have raised questions about the efficacy and safety of ezetimibe and have led to a re-examination of its clinical use as a drug for managing lipid risk factors to prevent or manage ASCVD. An in-depth analysis of these three trials reveals methodological deficiencies and concerns with the statistical methods used which significantly diminish their indictment of the clinical utility of ezetimibe. In contrast, The SANDS trial has confirmed the effectiveness of ezetimibe in managing both LDL-C and non-HDL-C, and also demonstrated this drug's ability to improve carotid atherosclerosis by producing regression of CIMT. One of the important conclusions of the SANDS Trail is that ezetimibe remains an effective adjunctive medication for use in patients who do not reach their LDL-C goals on statin monotherapy. However, as a significant residual risk for ASCVD remains even after aggressive goals for LDL-C and non-HDL-C are reached, current treatment strategies should emphasize managing of all cardiac risk factors and increasing HDL in addition to the attainment and maintenance of recommended goals for LDL-C and non-HDL-C. Hence, ezetimibe should be considered as an important component of broad-spectrum management of lipid risk factors with therapy that includes statins, niacin, bile acid sequestrants, fibrates and Omega 3 fatty acids in appropriate combinations in addition to therapeutic life change.

Fatty acids in serum phospholipids and carotid intima-media thickness in Spanish subjects with primary dyslipidemia.

BACKGROUND: Low rates of incident ischemic heart disease (IHD) and cardiac death occur in Spain despite a high prevalence of cardiovascular risk factors. High consumption of unsaturated fatty acid-rich foods, such as olive oil, nuts, and seafood, might underlie this paradox. OBJECTIVE: We investigated whether serum phosphatidylcholine enrichment in oleic, linoleic, alpha-linolenic, and n-3 (omega-3) long-chain polyunsaturated fatty acids (as biomarkers of olive oil, seed oil, walnut, and fish intake, respectively) relate to carotid atherosclerosis in Spanish subjects at risk of IHD. DESIGN: In a cross-sectional study, we measured fatty acid concentrations in serum phosphatidylcholine and measured carotid intima-media thickness (IMT) by using ultrasound in 451 asymptomatic subjects (261 men, 190 women; mean age: 45 y) with primary dyslipidemia. Main and secondary outcomes were mean and maximum IMT in the common carotid artery (CCA) and other carotid segments, respectively. RESULTS: Phosphatidylcholine fatty acid composition was similar to that reported for other Spanish populations. Multiple regression analyses showed that proportions of oleic and docosahexaenoic acids were inversely related to mean CCA IMT (P < 0.02, all) after adjustment for several confounders. In similar models, alpha-linolenic acid related inversely to mean and maximum internal carotid artery IMT (P < 0.05 for all). Linoleic and eicosapentaenoic acids were unrelated to IMT. CONCLUSIONS: Higher phospholipid proportions of oleic, alpha-linolenic, and docosahexaenoic acids showed inverse associations with IMT at specific carotid segments in subjects with primary dyslipidemia. High intakes of healthy fats might explain, in part, the Spanish paradox of low IHD rates in the face of a high burden of cardiovascular risk factors.