Adipose tissue n-3/n-6 fatty acids ratios versus n-3 fatty acids fractions as predictors of myocardial infarction.

BACKGROUND: Tissue levels of n-3 polyunsaturated fatty acids (PUFAs) have been inversely related with risk of myocardial infarction (MI). Whether ratios of n-3 to n-6 PUFAs, reflecting both dietary intake of n-3 PUFAs and competing n-6 PUFAs, are better predictors of future MI than n-3 PUFA fractions is unclear. We aimed at investigating whether such ratios in adipose tissue better predict MI than n-3 PUFA fractions. METHODS: Subcutaneous adipose tissue biopsies were obtained in a random sample (n = 3,500) of the Diet, Cancer and Health cohort (n = 57,053). Adipose tissue content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), arachidonic acid (AA) and linoleic acid was determined using gas chromatography. Fractions of selected n-3 PUFAs and n-3/n-6 PUFA ratios were correlated to the 15-year occurrence of MI in a case-cohort design. RESULTS: A total of 2,406 participants experienced an MI during follow-up. Adipose tissue total marine n-3 PUFAs, EPA+DHA, EPA, EPA/AA, DHA/AA and (EPA + DPA + DHA)/AA were all inversely associated with risk of incident MI. Evaluating the predictive power (Harrel's C-index) of the selected metrics, fractions of marine n-3 PUFAs and ratios of EPA/AA, DHA/AA, (EPA + DHA)/AA and (EPA + DPA + DHA)/AA all refined risk prediction over age and sex alone. At multivariable analyses, however, the above ratios were the only metrics providing additional risk prediction. Differences in ratios were related to differences in food intake. CONCLUSIONS: Both adipose tissue n-3 PUFAs fractions and ratios of n-3 PUFAs/AA were associated with a lower occurrence of MI, but ratios provided superior risk prediction. Dietary strategies affecting n-3/n-6 PUFA ratios should be further investigated for prediction of MI with dietary interventions at the population level and in intervention studies.

Analysis of the Anti-Inflammatory and Anti-Osteoarthritic Potential of Flonat Fast®, a Combination of Harpagophytum Procumbens DC. ex Meisn., Boswellia Serrata Roxb., Curcuma longa L., Bromelain and Escin (Aesculus hippocastanum), Evaluated in In Vitro Models of Inflammation Relevant to Osteoarthritis.

Osteoarthritis (OA) is a joint disease characterized by inflammation of the synovium, angiogenesis, cartilage degradation, and osteophyte formation. Harpagophytum Procumbens DC. ex Meisn., Boswellia Serrata Roxb., Curcuma longa L., Bromelain and Escin (Aesculus hippocastanum) are plants which extracts, together to Bromelain and Escin (Aesculus hippocastanum) are traditionally used in OA. However, their mechanistic role remains unclear. We aimed to investigate whether these bioactives alone or in combination (as in Flonat Fast®) can suppress TNF-α-induced inflammation, angiogenesis, and osteophyte formation using two cell models involved in OA: endothelial cells and monocytes. Each plant extract was evaluated for its polyphenol content, antioxidant activity, and toxicity. In endothelial cells and monocytes, expression of genes involved in OA was assessed, functional assays for inflammation and angiogenesis were performed, and impairment of reactive oxygen species production (ROS) was evaluated. Exposure of cells to the bioactives alone and in combination before cytokine stimulation resulted in differential counterregulation of several gene and protein expressions, including those for cyclooxygenases-2, metalloproteinase-9, transforming growth factor ß1, and bone morphogenic protein-2. We demonstrated that these bioactives modulated monocyte adhesion to endothelial cells as well as cell migration and endothelial angiogenesis. Consistent with radical scavenging activity in the cell-free system, the bioactives curbed TNF-α-stimulated intracellular ROS production. We confirmed the potential anti-inflammatory and antiangiogenic effects of the combination of Harpagophytum procumbens, Boswellia, Curcuma, Bromelain, and Escin and provided new mechanistic evidence for their use in OA. However, further clinical studies are needed to evaluate the true clinical utility of these bioactives as supportive, preventive, and therapeutic agents.

Transcriptional regulation of vascular smooth muscle cell proliferation, differentiation and senescence: Novel targets for therapy.

Vascular smooth muscle cells (SMC) possess a unique cytoplasticity, regulated by transcriptional, translational and phenotypic transformation in response to a diverse range of extrinsic and intrinsic pathogenic factors. The mature, differentiated SMC phenotype is physiologically typified transcriptionally by expression of genes encoding "contractile" proteins, such as SMα-actin (ACTA2), SM-MHC (myosin-11) and SM22α (transgelin). When exposed to various pathological conditions (e.g., pro-atherogenic risk factors, hypertension), SMC undergo phenotypic modulation, a bioprocess enabling SMC to de-differentiate in immature stages or trans-differentiate into other cell phenotypes. As recent studies suggest, the process of SMC phenotypic transformation involves five distinct states characterized by different patterns of cell growth, differentiation, migration, matrix protein expression and declined contractility. These changes are mediated via the action of several transcriptional regulators, including myocardin and serum response factor. Conversely, other factors, including Kruppel-like factor 4 and nuclear factor-κB, can inhibit SMC differentiation and growth arrest, while factors such as yin yang-1, can promote SMC differentiation whilst inhibiting proliferation. This article reviews recent advances in our understanding of regulatory mechanisms governing SMC phenotypic modulation. We propose the concept that transcription factors mediating this switching are important biomarkers and potential pharmacological targets for therapeutic intervention in cardiovascular disease.

Coffee Bioactive N-Methylpyridinium Attenuates Tumor Necrosis Factor (TNF)-α-Mediated Insulin Resistance and Inflammation in Human Adipocytes.

Although coffee consumption has been historically associated with negative health outcomes, recent evidence suggests a lower risk of metabolic syndrome, obesity and diabetes among regular coffee drinkers. Among the plethora of minor organic compounds assessed as potential mediators of coffee health benefits, trigonelline and its pyrolysis product N-methylpyridinium (NMP) were preliminary shown to promote glucose uptake and exert anti-adipogenic properties. Against this background, we aimed at characterizing the effects of trigonelline and NMP in inflamed and dysfunctional human adipocytes. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with NMP or, for comparison, trigonelline, for 5 h before stimulation with tumor necrosis factor (TNF)-α. NMP at concentrations as low as 1 µmol/L reduced the stimulated expression of several pro-inflammatory mediators, including C-C Motif chemokine ligand (CCL)-2, C-X-C Motif chemokine ligand (CXCL)-10, and intercellular adhesion Molecule (ICAM)-1, but left the induction of prostaglandin G/H synthase (PTGS)2, interleukin (IL)-1ß, and colony stimulating factor (CSF)1 unaffected. Furthermore, NMP restored the downregulated expression of adiponectin (ADIPOQ). These effects were functionally associated with downregulation of the adhesion of monocytes to inflamed adipocytes. Under the same conditions, NMP also reversed the TNF-α-mediated suppression of insulin-stimulated Ser473 Akt phosphorylation and attenuated the induction of TNF-α-stimulated lipolysis restoring cell fat content. In an attempt to preliminarily explore the underlying mechanisms of its action, we show that NMP restores the expression of the master regulator of adipocyte differentiation peroxisome proliferator-activated receptor (PPAR)γ and downregulates activation of the pro-inflammatory mitogen-activated protein jun N-terminal kinase (JNK). In conclusion, NMP reduces adipose dysfunction in pro-inflammatory activated adipocytes. These data suggest that bioactive NMP in coffee may improve the inflammatory and dysmetabolic milieu associated with obesity.

[Iron and stable ischemic heart disease - lessons from heart failure]. / Ferro e cardiopatia ischemica stabile ­ lezioni dallo scompenso cardiaco.

Iron is an essential element for cardiomyocyte viability and contractility. Systemic iron deficiency, even without anemia, is reflected by iron deficiency in cardiomyocytes. As in other cells, there is here a complex, local and autonomous regulation of iron metabolism, based on two molecular systems: the hepcidin/ferroportin/transferrin receptor-1 axis; and the iron regulatory proteins-1,2 system. These molecular pathways allow cardiomyocytes to react to changes in serum iron availability. In mice, dietary manipulations of serum iron availability or cardio-specific deletions and mutations of regulatory genes for intracellular iron metabolism have clarified some aspects of the causal relationship between cardiomyocyte iron deficiency and the development of severe heart failure, prevented by intravenous iron treatment even without the occurrence of iron deficiency (sideropenic) anemia. The deleterious effects of iron deficiency and hypoxia on gene expression of the main regulators of intracellular iron and oxygen metabolism and on cardiac function are very similar in heart failure and in chronic stable ischemic heart disease, and conjure towards cardiomyocyte injury. We here hypothesize that in non-anemic patients with stable ischemic heart disease a chronic or acute serum iron deficiency can amplify the chronic activation of the cardiomyocyte hypoxia-inducible factor-1α. As a consequence, cardiac adaptative responses to chronic hypoxia/ischemia are significantly impaired, and cardiac dysfunction exacerbated. We hypothesize that, in such patients, iron replacement through forced iron supplementation may replete cardiomyocyte iron deficiency and improve ischemic heart disease. This hypothesis requires further experimental studies, but also, and already now, specific clinical trials.

The Non-Vitamin K Antagonist Oral Anticoagulants in Heart Disease: Section V-Special Situations.

Non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban and rivaroxaban, which inhibit factor Xa. In large clinical trials comparing the NOACs with the vitamin K antagonist (VKA) warfarin, dabigatran, apixaban, rivaroxaban and edoxaban were at least as effective for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but were associated with less intracranial bleeding. In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. Consequently, the NOACs are now replacing VKAs for these indications, and their use is increasing. Although, as a class, the NOACs have a favourable benefit-risk profile compared with VKAs, choosing among them is complicated because they have not been compared in head-to-head trials. Therefore, selection depends on the results of the individual trials, renal function, the potential for drug-drug interactions and preference for once- or twice-daily dosing. In addition, several 'special situations' were not adequately studied in the dedicated clinical trials. For these situations, knowledge of the unique pharmacological features of the various NOACs and judicious cross-trial comparison can help inform prescription choices. The purpose of this position article is therefore to help clinicians choose the right anticoagulant for the right patient at the right dose by reviewing a variety of special situations not widely studied in clinical trials.

The acute impact of high-dose lipid-lowering treatment on endothelial progenitor cells in patients with coronary artery disease-The REMEDY-EPC early substudy.

RATIONALE AND OBJECTIVE: Endothelial progenitor cells (EPCs) play a role in vascular repair, while circulating endothelial cells (CECs) are biomarkers of vascular damage and regeneration. Statins may promote EPC/CEC mobilization in the peripheral blood. We evaluated whether pre-procedural exposure to different lipid-lowering drugs (statins±ezetimibe) can acutely increase levels/activity of EPCs/CECs in patients with stable coronary artery disease (CAD). METHODS: In a planned sub-analysis of the Rosuvastatin For REduction Of Myocardial DamagE During Coronary AngioplastY (REMEDY) trial, 38 patients with stable CAD on chronic low-dose statin therapy were randomized, in a double-blind, placebo-controlled design, into 4 groups before PCI: i. placebo (n = 11); ii. atorvastatin (80 mg+40 mg, n = 9); iii. rosuvastatin (40 mg twice, n = 9); and iv. rosuvastatin (5 mg) and ezetimibe (10 mg) twice, (n = 9). At baseline and 24 h after treatment-before PCI-, patients underwent blinded analyses of EPCs [colony forming units-endothelial cells (CFU-ECs), endothelial colony-forming cells (ECFCs) and tubulization activity] and CECs in peripheral blood. RESULTS: We found no significant treatment effects on parameters investigated such as number of CECs [Median (IQR): i. 0(0), ii. 4.5(27), iii. 1.9(2.3), iv. 1.9(2.3)], CFU-ECs [Median (IQR): i. 27(11), ii. 19(31), iii. 47(36), iv. 30(98)], and ECFCs [Median (IQR): i. 86(84), ii. 7(84), iii. 8/(42.5), iv. 5(2)], as well as tubulization activity [total tubuli (well), Median (IQR): i. 19(7), ii. 5(4), iii. 25(13), iv. 15(24)]. CONCLUSIONS: In this study, we found no evidence of acute changes in levels or activity of EPCs and CECs after high-dose lipid-lowering therapy in stable CAD patients.

Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease.

BACKGROUND: Valvular heart disease (VHD) and atrial fibrillation (AF) often coexist. Phase III trials comparing non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin excluded patients with moderate/severe mitral stenosis or mechanical heart valves, but variably included patients with other VHD and valve surgeries. OBJECTIVES: This study aimed to determine relative safety and efficacy of NOACs in patients with VHD. METHODS: We performed a meta-analysis of the 4 phase III AF trials of the currently available NOACs versus warfarin in patients with coexisting VHD to assess pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for stroke/systemic embolic events (SSEE), major bleeding, intracranial hemorrhage (ICH), and all-cause death. RESULTS: Compared with warfarin, the rate of SSEE in patients treated with higher-dose NOACs was lower and consistent among 13,585 patients with (RR: 0.70; 95% CI: 0.58 to 0.86) or 58,098 without VHD (RR: 0.84; 95% CI: 0.75 to 0.95; interaction p = 0.13). Major bleeding in patients on higher-dose NOACs versus warfarin was similar and consistent among patients with (RR: 0.93; 95% CI: 0.68 to 1.27) or without VHD (RR: 0.85; 95% CI: 0.70 to 1.02; interaction p = 0.63 for VHD/no-VHD difference). Intracranial hemorrhage was lower with higher-dose NOACs than with warfarin irrespective of VHD (RR: 0.47; 95% CI: 0.24 to 0.93, and 0.49; 95% CI: 0.41 to 059, respectively; interaction p = 0.91). No protective effect of higher-dose NOACs in preventing all-cause death seemed to be present in patients with VHD versus without VHD (RR:1.01; 95% CI: 0.90 to 1.14 vs. RR: 0.88; 95% CI: 0.82 to 0.94, respectively; interaction p = 0.03). CONCLUSIONS: High-dose NOACs provide overall efficacy and safety similar in AF patients with or without VHD.

Polypill: quo vadis?

Cardiovascular disease (CVD) is still the leading cause of death worldwide. The overall growth of this epidemic during the last decade is largely because of the increasing incidence of CVD in low and middle-income countries, where inadequate health policies, poor availability, and lack of affordable medications, as well as poor patient adherence to treatment all limit the efficacy of cardiovascular prevention strategies. Complementary to a promotion of healthy lifestyles, a fixed dose combination or a 'polypill,' containing two or more drugs addressed at controlling various risk factors, might reduce costs and improve patient accessibility and adherence to treatment. As of now, several clinical trials have shown that combination pills are well tolerated and decrease risk factors for CVD, with a projected improvement of end points by as much as 60-70% by reducing blood pressure and low-density lipoprotein cholesterol. However, uncertainty remains about changes of hard end points, long-term adherence, cost-effectiveness and the 'medicalization' of asymptomatic individuals who account for a large percentage of the world population. Because cardiovascular risk increases significantly for patients aged more than 50 years, it has been proposed to use a polypill to treat specifically all such patients. However, approach to be neither practical nor cost-effective, because it involves a large number of patients at low risk. Some investigators have suggested to incorporate the Coronary Artery Calcium Score with the Framingham Risk Score to identify a suitable target population of patients benefitting most from the polypill. Trials in progress will shed light on several issues currently debated and unresolved.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants After Cardioversion for Nonvalvular Atrial Fibrillation.

BACKGROUND: Non-vitamin K oral anticoagulants (NOACs) are proven alternatives to vitamin K antagonists (VKAs) for the prevention of thromboembolism in patients with nonvalvular atrial fibrillation. However, there are few data on the efficacy and safety of NOAC therapy after cardioversion, where the risk of thromboembolic events is heightened. METHODS: We performed a random-effects meta-analysis of patients who underwent both electrical and pharmacologic cardioversion for atrial fibrillation in the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF-TIMI 48, and X-VeRT trials. We assessed Mantel-Haenszel pooled estimates of risk ratio (RR) and 95% confidence intervals (CIs) for stroke/systemic embolism and major bleeding at ≤42 days of follow-up. RESULTS: The analysis pooled 3949 patients in whom a total of 4900 cardioversions for atrial fibrillation were performed. Compared with VKAs, NOAC therapy was associated with a similar risk of stroke/systemic embolism (RR 0.84; 95% CI, 0.34-2.04) and major bleeding (RR 1.12; 95% CI, 0.52-2.42); no significant statistical heterogeneity was found among studies (Cochrane Q P = .59, I(2) = 0% for stroke/systemic embolism; P = .47; I(2) = 0% for major bleeding). CONCLUSIONS: The short-term incidences of thromboembolic and major hemorrhagic events after cardioversion on NOACs were low and comparable to those observed on dose-adjusted VKA therapy. Non-vitamin K oral anticoagulants are a reasonable alternative to VKAs in patients undergoing cardioversion.

Oral anticoagulants in coronary heart disease (Section IV). Position paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease.

Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.

Effect of High-Dose Atorvastatin Reload on the Release of Endothelial Progenitor Cells in Patients on Long-Term Statin Treatment Who Underwent Percutaneous Coronary Intervention (from the ARMYDA-EPC Study).

Endothelial progenitor cells (EPCs) may concur to endogenous vascular repair. Previous studies have reported that statin treatment increases EPC levels. We investigated whether this occurs in patients on long-term statin treatment who underwent percutaneous coronary interventions (PCIs). In a phase A study, 53 patients (atorvastatin reload [AR] 80 mg 12 hours before + 40 mg 2 hours before PCI, n = 27; placebo [P], n = 26) were evaluated for EPC mobilization as CD45dim/CD34+/CD133+/KDR+ cell number by flow cytometry. Assays were run at randomization (12 hours before PCI, R), immediately before PCI (T0) at 8 (T8) and 24 hours (T24). In phase B study, 50 patients (AR, n = 25; P, n = 25) were evaluated for early colony formation by Hill colony forming unit (CFU) assay, with sampling at randomization and 24 hours later. In phase A, EPCs levels were similar at randomization between 2 arms (0.23% [0.14 to 0.54] of total events in AR vs 0.22% [0.04 to 0.37] in P group; p = 0.33). At PCI, EPC levels were higher in AR arm (0.42% [0.06 to 0.30] vs 0.19% [0.06 to 030]; p = 0.009). Higher EPC levels in AR group were also found at 8 and 24 hours. In phase B, EPC CFUs/well numbers at randomization were similar in the 2 arms (8 [6 to 12] in AR vs 12 [6 to 20] in P group, p = 0.109). EPC CFU/well at 24 hours became significantly higher in AR arm (17 [10 to 23] vs 5 [2 to 13], p = 0.002). In conclusion, high-dose AR before PCI in patients on long-term statin therapy promptly increases EPCs mobilization, which are capable of early colony formation and may contribute to cardioprotection.

Nutrition, food production and health - an agenda also for cardiologists.

The relationship of cardiovascular disease to food has become more complicated on a scientific level yet starkly simpler on the level of policies for producing food for planetary as well as human health. Accordingly, we argue that professional societies in medicine should take a broader view of the scientific methods necessary to understand the complex issues of nutrition and cardiovascular and other disease, and they should lend greater support to policies for agriculture and the food industry that protect ecosystems, combat climate change and promote cardiovascular health.

Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCα and PKCß1 inhibition.

OBJECTIVE: Hydroxytyrosol (HT), the major olive oil antioxidant polyphenol in cardioprotective Mediterranean diets, is endowed with anti-inflammatory and anti-atherosclerotic activity. The production of cyclooxygenase (COX)-2-dependent inflammatory eicosanoids and the functionally linked release of matrix metalloproteinase (MMP)-9 by macrophages likely contribute to plaque instability leading to acute coronary events. Objective of the study was to examine the HT effects on inflammatory markers in human activated monocytes, including MMP-9 and COX-2 activity and expression and explore HT underlying mechanisms. METHODS AND RESULTS: Human peripheral blood mononuclear cells (PBMC) and U937 monocytes were treated with 1-10 µmol/L HT before activation with phorbol myristate acetate (PMA). HT blunted monocyte matrix invasive potential and reduced MMP-9 release and expression at zymography, ELISA and RT-PCR, with an IC50 = 10 µmol/L ( P< 0.05), without affecting tissue inhibitor of metalloproteinase (TIMP)-1. Moreover, HT inhibited prostaglandin (PG)E2 production and COX-2 expression, without affecting COX-1. These effects were mediated by inhibition of transcription factor nuclear factor (NF)-κB and protein kinase C (PKC)α and PKCß1 activation. CONCLUSION: HT, at nutritionally relevant concentrations, reduces MMP-9 and COX-2 induction in activated human monocytes via PKCα and PKCß1 inhibition, thus featuring novel anti-inflammatory properties. Overall, such results contribute to explaining the vascular protective effects by olive oil polyphenols in Mediterranean diets.

Refining the assessment of contrast-induced acute kidney injury: the load-to-damage relationship.

AIMS: Comparing the nephrotoxicity of individual contrast agents is challenging, as contrast-induced acute kidney injury (CI-AKI), a widely used trial endpoint, is unable to discriminate between contrast-related and contrast-unrelated causes of renal damage. We established a quantitative method to selectively evaluate the dose-dependent nephrotoxic effect of different contrast agents. METHODS: We randomized 113 patients undergoing coronary procedures to either iodixanol 320 mg/ml or iobitridol 350 mg/ml. We calculated baseline creatinine clearance (CrCl) and postprocedural change in serum creatinine. We then calculated the regression of the individual iodine load against the creatinine maximum change [load-to-damage relationship (LDR)]. We assumed that its R estimates the predictive accuracy of contrast dose-dependent effects on renal function changes, and that the slope of the LDR characterizes the intrinsic nephrotoxicity of the contrast. We also performed a semi-quantitative evaluation of procedural complexity to assess its complementary role in postprocedural AKI. RESULTS: We found significant correlations between contrast load and creatinine changes for both iobitridol (R: 0.29; P <0.0001) and iodixanol (R: 0.15; P = 0.00028). The LDR slope was, however, significantly steeper for iobitridol compared with iodixanol (19.03 ±â€Š4.02 vs. 14.50 ±â€Š4.63 Cr*CrCl/I; P <0.001) and in diabetic compared with nondiabetic patients (24.35 ±â€Š4.96 vs. 4.59 ±â€Š3.25 Cr*CrCl/I; P <0.001). Adding the procedural complexity score to the contrast load significantly increased the predictive ability of the regression model for postprocedural renal function changes (P < 0.02 for the R increase in overall population), suggesting a role for procedural complexity in postprocedural renal function damage. CONCLUSION: The LDR slope is a promising method to evaluate the specific contrast-related fraction of postprocedural AKI.

The new oral anticoagulants in atrial fibrillation: once daily or twice daily?

The new anticoagulants (NOACs) tested for prevention or treatment of venous thromboembolism (VTE), stroke prevention in atrial fibrillation (AF), and acute coronary syndromes (ACS) differ in bioavailability, metabolism, route of excretion and interaction with other drugs, but have remarkably similar pharmacokinetics, with very similar half lives. However the choice of dosing regimens in different clinical conditions has been different for the various NOACs, and has been established on the basis of widely different considerations, including the clinical setting (venous versus arterial thrombosis), the indications (prophylaxis versus treatment), the likelihood of concomitant antiplatelet drugs, and marketing opportunities; these latter were based on the knowledge that patients' compliance is generally better with once daily than with twice daily dosing. Current prevailing wisdom is that peak plasma drug concentrations are important determinants of bleeding: since a fractioning of the total daily dose into a twice daily regimen reduces peak plasma drug concentrations compared with once daily dosing, this should maximize safety. However, recent pharmacokinetic analyses of a phase II study with edoxaban in AF found that bleeding, with the same daily dosing, was less frequent with once daily dosing than with twice daily dosing, and correlated - better than other pharmacokinetic parameters - through drug concentrations. Higher rates of bleeding have been also reported with the twice daily versus once daily dosing of darexaban in a phase II study in ACS. These results may lead to a rethinking on the pathophysiology of bleeding in the setting of anticoagulation.

Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer.

Diets with high content of antioxidant polyphenols are associated with low prevalence of cardiovascular diseases and cancer. Inflammatory angiogenesis is a key pathogenic process both in cancer and atherosclerosis, and is tightly regulated by the proinflammatory enzyme cyclooxygenase (COX)-2 and the matrix degrading enzymes matrix metalloproteinases (MMPs). We studied the effects of antioxidant polyphenols from virgin olive oil (oleuropein and hydroxytyrosol) and red wine (resveratrol and quercetin) on endothelial cell angiogenic response in vitro, and explored underlying mechanisms. Cultured endothelial cells were pre-incubated with 0.1-50 µmol/L polyphenols before stimulation with phorbol myristate acetate (PMA). All tested polyphenols reduced endothelial cell tube formation on matrigel and migration in wound healing assays. The reduced angiogenesis was associated with the inhibition of PMA-induced COX-2 protein expression and prostanoid production, as well as MMP-9 protein release and gelatinolytic activity. These effects were accompanied by a significant reduction in the stimulated intracellular reactive oxygen species levels and in the activation of the redox-sensitive transcription factor nuclear factor (NF)-κB. Our findings reveal that olive oil and red wine polyphenols reduce inflammatory angiogenesis in cultured endothelial cells, through MMP-9 and COX-2 inhibition, supporting a potential protective role for dietary polyphenols in atherosclerotic vascular disease and cancer.

Genetic determinants of blood pressure responses to caffeine drinking.

BACKGROUND: The widely observed between-subject variability in cardiovascular responses to coffee may have a genetic basis. OBJECTIVE: We evaluated acute blood pressure (BP) responses to caffeine and explored whether they are influenced by candidate gene variants affecting caffeine metabolism (for cytochrome P450 1A2), adenosine metabolism (for adenosine receptor and AMP deaminase), or catecholamine receptors. METHODS: We recruited 110 healthy male habitual moderate coffee drinkers who refrained from drinking coffee on the day preceding the study. Each subject underwent ambulatory BP monitoring at 6-min intervals for 2 h. Each participant was administered, in a double-blind design, 40 mL of either a decaffeinated coffee preparation plus 3 mg caffeine/kg (caf) or the corresponding vehicle (decaf). The protocol was repeated 24 h later with the alternative preparation. Blood samples were collected for genetic and plasma caffeine and catecholamine evaluations. RESULTS: Compared with decaf, caf was associated with a mean (± SD) significant increase in systolic BP of 4 ± 12 mm Hg and in diastolic BP of 3 ± 10 mm Hg (P < 0.001 for both). Plasma caffeine and adrenaline increased after caf, but not after decaf. Of 11 gene polymorphisms analyzed, a relation was observed between the ADORA2A TT variant and the change in SBP peak and between the ADRA2B I variant and the changes in both SBP mean and peak; mean peak change in SBP; these variants were associated with increased SBP responses to caf. CONCLUSIONS: Variability in the acute BP response to coffee may be partly explained by genetic polymorphisms of the adenosine A2A receptors and α(2)-adrenergic receptors. This trial is registered at clinicaltrials.gov as NCT01330680.