Effect of Encapsulated Purple Garlic Oil on Microvascular Function and the Components of Metabolic Syndrome: A Randomized Placebo-Controlled Study-The ENDOTALLIUM Study.

Endothelial dysfunction (ED) is associated with progressive changes contributing to clinical complications related to macro- and microvascular diseases. Garlic (Allium sativum L.) and its organosulfur components have been related to beneficial cardiovascular effects and could improve endothelial function. The ENDOTALLIUM Study aimed to evaluate the effect of the regular consumption of encapsulated purple garlic oil on microvascular function, endothelial-related biomarkers, and the components of metabolic syndrome (MetS) in untreated subjects with cardiometabolic alterations. Fifty-two individuals with at least one MetS component were randomized (1:1) in a single-center, single-blind, placebo-controlled, parallel-group study. The participants received encapsulated purple garlic oil (n = 27) or placebo (n = 25) for five weeks. Skin microvascular peak flow during post-occlusive reactive hyperemia significantly increased in the purple garlic oil group compared to the placebo group (between-group difference [95%CI]: 15.4 [1.5 to 29.4] PU; p = 0.031). Likewise, hs-CRP levels decreased in the purple garlic group compared to the control group (-1.3 [-2.5 to -0.0] mg/L; p = 0.049). Furthermore, we observed a significant reduction in the mean number of MetS components in the purple garlic group after five weeks (1.7 ± 0.9 vs. 1.3 ± 1.1, p = 0.021). In summary, regular consumption of encapsulated purple garlic oil significantly improved microvascular function, subclinical inflammatory status, and the overall MetS profile in a population with cardiometabolic alterations.

A new variant (c.1A>G) in LDLRAP1 causing autosomal recessive hypercholesterolemia: Characterization of the defect and response to PCSK9 inhibition.

BACKGROUND AND AIMS: Autosomal recessive hypercholesterolemia (ARH) is a rare disorder caused by mutations in LDLRAP1, which impairs internalization of hepatic LDL receptor (LDLR). ARH patients respond relatively well to statins or the combination of statins and Ezetimibe, but scarce and variable data on treatment with PCSK9 inhibitors is available. We aimed to identify and characterize the defect in a hypercholesterolemic patient with premature cardiovascular disease and determine the response to lipid-lowering treatment. METHODS AND RESULTS: Gene sequencing revealed a homozygous c.1A > G:p.? variant in LDLRAP1. Primary lymphocytes were isolated from the ARH patient, one control and two LDLR-defective subjects, one LDLR:p.(Cys352Ser) heterozygote and one LDLR:p.(Asn825Lys) homozygote. The patient had undetectable full-length ARH protein by Western blotting, but expressed a lower-than-normal molecular weight peptide. LDLR activity was measured by flow cytometry, which showed that LDL binding and uptake were reduced in lymphocytes from the ARH patient as compared to control lymphocytes, but were slightly higher than in those from the LDLR:p.(Cys352Ser) heterozygote. Despite the analogous internalization defect predicted in ARH and homozygous LDLR:p.(Asn825Lys) lymphocytes, LDL uptake was higher in the former than in the latter. LDL-cholesterol levels were markedly reduced by the successive therapy with Atorvastatin and Atorvastatin plus Ezetimibe, and the addition of Evolocumab biweekly decreased LDL-cholesterol by a further 39%. CONCLUSIONS: The LDLRAP1:c.1A > G variant is associated with the appearance of an N-terminal truncated ARH protein and to reduced, although still significant, LDLR activity in lymphocytes. Residual LDLR activity may be relevant for the substantial response of the patient to Evolocumab.

Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation.

Xanthine oxidoreductase (XOR) catalyzes the final two reactions that lead to uric acid formation. XOR is a complex molibdoflavoenzyme present in two different functional forms: dehydrogenase and xantine oxidase (XO). XO is a critical source of reactive oxygen species (ROS) that contribute to vascular inflammation. Under normal physiological conditions, it is mainly found in the dehydrogenase form, while in inflammatory situations, posttranslational modification converts the dehydrogenase form into XO. These inflammatory conditions lead to an increase in XO levels and thus an increased ROS generation by the enzymatic process, finally resulting in alterations in vascular function. It has also been shown that XO secondarily leads to peroxynitrite formation. Peroxynitrite is one of the most powerful ROS that is produced by the reaction of nitric oxide and superoxide radicals, and is considered to be a marker for reactive nitrogen species, accompanied by oxidative stress. Febuxostat is a novel nonpurine XO-specific inhibitor for treating hyperuricemia. As febuxostat inhibits both oxidized and reduced forms of the enzyme, it inhibits the ROS formation and the inflammation promoted by oxidative stress. The administration of febuxostat has also reduced nitro-oxidative stress. XO serum levels are significantly increased in various pathological states such as inflammation, ischemia-reperfusion or aging and that XO-derived ROS formation is involved in oxidative damage. Thus, it may be possible that the inhibition of this enzymatic pathway by febuxostat would be beneficial for the vascular inflammation. In animal models, febuxostat treatment has already demonstrated anti-inflammatory effects, together with the reduction in XO activity. However, the role of febuxostat in humans requires further investigation.

Poor response to antiplatelet drugs. An important issue in drug-eluting stents.

Platelet aggregation activity is the cornerstone of the pathogenesis of atherothrombosis and plays a main role in the appearance of major adverse cardiac events (MACE). This aspect has become even more important nowadays due to the use of drug-eluting stents (DES), where a proper platelet inhibition is required. Dual antiplatelet therapy with aspirin and clopidogrel in patients undergoing percutaneous coronary intervention (PCI) has widely demonstrated its beneficial effect in reducing MACE compared with aspirin alone. These benefits had also been established in short and long term treatment in patients with coronary artery disease managed with a conservative strategy. However, despite dual antiplatelet therapy an important number of patients experience new MACE related to an incomplete platelet inhibition that can be caused by the interaction of different mechanisms, not fully known at the moment. Several clinical studies suggested the significant variability in individual patient response to antiplatelet drugs to be due to the use of different laboratory tests. Moreover, other studies associated the low responsiveness status with an increased risk of recurrent cardiovascular events. Notably, resistance or reduced response to antiplatelet therapy with aspirin and clopidogrel is a clinically relevant entity that needs to be taken into account in order to perform a proper and individualized treatment strategy. Recent antiplatelet drugs such as prasugrel and ticagrelor have appeared to be an attractive option for patients with resistance or low response to traditional therapy. In this article we review aspirin and clopidogrel resistance as a clinical entity, the different mechanisms that could be linked to treatment failure, its relation with special situations and future perspectives in this area.

Pseudoxanthoma elasticum: case report with arterial stiffness evaluated by a research cardiovascular profiling system.

Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder characterized by calcification of elastic tissue, affecting the skin, the eyes and vascular system. The aim of our study was to specify the cardiovascular changes in a case of pseudoxanthoma elasticum by a non-invasive haemodynamic evaluation. We present a 50-year-old woman with a clinical diagnosis of pseudoxanthoma elasticum. Except for hypertension, treated over the past four years, there was no other modifiable cardiovascular risk factor. The patient had a familiar history of early cardiovascular death. In the physical examination, typical skin lesions were present and also an angioid streak of the retina. The patient and a control group were evaluated by the CR-2000 Research Cardiovascular Profiling System. A lower elasticity in large arteries (p = 0.006), a higher cardiac output (p = 0.006) and a higher total vascular impedance (p = 0.006) were observed with respect to the control group. There was no difference comparing this value with an elderly control group. We suggest that patients with PXE present vascular changes comparable with elderly patients and that these differences can not be explained by hypertension.

[Lights and shades in the application of new guidelines for the management of type 2 diabetes mellitus. Practical advice about combined therapy and insulin therapy]. / Luces y sombras en la aplicación de las nuevas guías para el tratamiento de la diabetes mellitus tipo 2. Consejos prácticos sobre el tratamiento combinado y la insulinoterapia.

Type 2 diabetes is a disease with an increasing prevalence due to the ageing and sedentary lifestyle of the general population. Its associated with the risk of developing a series of chronic complications in mid/long-term. The current guidelines recommend certain therapy targets that have proven difficult to achieve due to poor compliance or because doctors do not always adhere to expert guidelines. The inability to achieve an adequate glycemic control in the course of diabetes may result in part from the typical conservative stepwise treatment approach that includes monotherapy initiated alter failure of diet and exercise, followed by a combination of oral antiglycemic agents, and ultimately insulin therapy. With respect to insulin therapy, the availability of different analogues as well as the new routes of administration (e.g., inhaled insulin) may allow the early introduction of this therapy, which may be more readily accepted by the patient.

Luces y sombras en la aplicación de las nuevas guías para el tratamiento de la diabetes mellitus tipo 2. Consejos prácticos sobre el tratamiento combinado y la insulinoterapia / Lights and shades in the application of new guidelines for the management of type 2 diabetes mellitus. Practical advice about combined therapy and insulin therapy

La diabetes mellitus tipo 2 es una enfermedad cada vez más prevalente por el sedentarismo y el envejecimiento poblacional, y está asociada, a medio-largo plazo, con el riesgo de desarrollar una serie de complicaciones crónicas. Las guías terapéuticas actuales recomiendan objetivos de tratamiento que son inalcanzables para la mayoría de los pacientes, bien por incumplimiento terapéutico o porque el médico no respeta las directrices de los expertos. La incapacidad para alcanzar los adecuados controles glucémicos al inicio del curso evolutivo de la diabetes puede deberse al clásico abordaje conservador y escalonado, que se basa en la monoterapia, tras el fracaso de la dieta y el ejercicio, seguida de tratamiento oral combinado y posterior insulinización sola o en combinación. Con respecto a la insulina, la actual disponibilidad de análogos «a la carta», así como las nuevas formas de administración como la insulina inhalada, puede permitir su introducción temprana sin el rechazo del paciente

Type 2 diabetes is a disease with an increasing prevalence due to the ageing and sedentary lifestyle of the general population. Its associated with the risk of developing a series of chronic complications in mid/long-term. The current guidelines recommend certain therapy targets that have proven difficult to achieve due to poor compliance or because doctors do not always adhere to expert guidelines. The inability to achieve an adequate glycemic control in the course of diabetes may result in part from the typical conservative stepwise treatment approach that includes monotherapy initiated alter failure of diet and exercise, followed by a combination of oral antiglycemic agents, and ultimately insulin therapy. With respect to insulin therapy, the availability of different analogues as well as the new routes of administration (e.g., inhaled insulin) may allow the early introduction of this therapy, which may be more readily accepted by the patient (AU)

Sex and body mass index specific regulation of blood pressure by CYP19A1 gene variants.

Sexual dimorphism in blood pressure (BP) regulation has been observed both in humans and experimental animals, and estrogens have been shown to contribute to this epidemiological observation. A key enzyme in determining estrogen levels is aromatase cytochrome P450. The aim of this study was to evaluate the role of the gene encoding aromatase, CYP19A1, as an independent risk factor for hypertension and its relationship with systolic and diastolic BP measures. We genotyped 2 polymorphisms within the CYP19A1 gene, IVS4 rs11575899 and 3'UTR rs10046, in 3448 individuals. In quantitative analysis, we observed significant associations between the 2 polymorphisms and BP values in women, being these associations dependent on BMI and independent of menopause status. The case-control analysis revealed that the most prominent associations were found for nonobese women in diastolic hypertension (DHT): the IVS4_22 and 3'UTR_11 are risk genotypes (OR=1.61, P=0.027 and OR=1.59, P=0.012, respectively), whereas IVS4_11 and 3'UTR_22 genotypes have a protective effect against DHT (OR=0.63, P=0.009, and OR=0.61, P=0.020, respectively). Haplotype analysis confirmed the above associations: among nonobese women the haplotype 21 is overrepresented in hypertensive women (OR=1.33, P=0.004, for DHT and OR=1.25, P=0.026, for systolic hypertension, SHT) and, conversely, the haplotype 12 protects against hypertension (OR=0.78, P=0.015 for DHT and OR=0.82, P=0.04 for SHT). Our study has shown that the CYP19A1 gene may be involved in the genetic regulation of BP in women. This effect is dependent on BMI and independent of menopause status, suggesting that this action is mainly driven by aromatase activity in fat tissue.

Resistencia a la aspirina / Aspirin resistance

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