Present and future of drug therapy in hypertension: an overview.

Purpose: High blood pressure (HBP) is the leading cause of mortality and years of disability, and its prevalence is increasing. Therefore, diagnosis and effective treatment of HBP is one of the main goals to prevent and reduce its complications, and pharmacological treatment is the cornerstone of hypertension management.Materials and Methods: The gradual introduction of different drug families has led to the development of new molecules that have improved efficacy and reduced adverse effects. Results: Current drugs include a large number that target key mechanisms of blood pressure regulation as well as those that contribute to hypertension-induced organ damage. Recently, new antihypertensive drugs have been introduced that not only aim to lower blood pressure but also provide additional protection against organ damage and metabolic disorders. Some of them were introduced for specific indications other than hypertension and other are based in a pharmacogenomic approach. Other routes of administration, such subcutaneous injection, are also being explored to improve protection and compliance.Conclusions: The main characteristics of each class of antihypertensive drug are summarised.

Diabetogenic Action of Statins: Mechanisms.

PURPOSE OF REVIEW: Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the diabetogenic effect of statins. RECENT FINDINGS: Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired ß-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus. The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.

Increased thioredoxin levels are related to insulin resistance in familial combined hyperlipidaemia.

BACKGROUND: Thioredoxins (TRX) are major cellular protein disulphide reductases that are critical for redox regulation. Oxidative stress and inflammation play promoting roles in the genesis and progression of atherosclerosis, but until now scarce data are available considering the influence of TRX activity in familial combined hyperlipidaemia (FCH). Since FCH is associated with high risk of cardiovascular disease, the objective of the present study was to assess oxidative stress status in FCH patients, and evaluate the influence of insulin resistance (IR). MATERIALS AND METHODS: A cohort of 35 control subjects and 35 non-related FCH patients were included, all of them nondiabetic, normotensive and nonsmokers. We measured lipid profile, glucose and insulin levels in plasma, and markers of oxidative stress and inflammation such as oxidized glutathione (GSSG), reduced glutathione (GSH) and TRX. RESULTS: Familial combined hyperlipidaemia subjects showed significantly higher levels of GSSG, GSSG/GSH ratio and TRX than controls. In addition, FCH individuals with IR showed the worst profile of oxidative stress status compared to controls and FCH patients without IR (P < 0·01). TRX levels correlated with higher insulin resistance. CONCLUSION: Familial combined hyperlipidaemia patients showed increased TRX levels. TRX was positively correlated with IR. These data could partially explain the increased risk of cardiovascular events in primary dyslipidemic patients.

Variable patterns of obesity and cardiometabolic phenotypes and their association with lifestyle factors in the Di@bet.es study.

BACKGROUND AND AIM: Prevalence rates of "metabolically healthy obese" (MHO) subjects vary depending on the criteria used. This study examined the prevalence and characteristics of MHO subjects and metabolically abnormal normal-weight subjects and compared the findings with the NHANES 1999-2004 study. The aims of the present study were, first, to determine the prevalence rates of MHO and MNHNO subjects using the same criteria as those of the National Health and Nutrition Examination Survey (NHANES) (1999-2004) study, and second to compare the prevalence and correlates of obese subjects who are resistant to the development of adiposity-associated cardiometabolic abnormalities (CA) and normal-weight individuals who display cardiometabolic risk factor clustering between the Spanish and the US populations. METHODS AND RESULTS: Di@bet.es study is a national, cross-sectional population-based survey of 5728 adults conducted in 2009-2010. Clinical, metabolic, sociodemographic, and anthropometric data and information about lifestyle habits, such as physical activity, smoking habit, alcohol intake and food consumption, were collected. Subjects were classified according to their body mass index (BMI) (normal-weight, <25 kg/m(2); overweight, 25-29.9 kg/m(2); and obese, >30 kg/m(2)). CA included elevated blood pressure; elevated levels of triglycerides, fasting glucose, and high-sensitivity C-reactive protein (hs-CRP); and elevated homeostasis model assessment of insulin resistance (HOMA-IR) value and low high-density lipoprotein cholesterol (HDL-c) level. Two phenotypes were defined: metabolically healthy phenotype (0-1 CA) and metabolically abnormal phenotype (≥2 CA). The prevalence of metabolically abnormal normal-weight phenotype was slightly lower in the Spanish population (6.5% vs. 8.1%). The prevalence of metabolically healthy overweight and MHO subjects was 20.9% and 7.0%, respectively, while in NHANES study it was 17.9% and 9.7%, respectively. Cigarette smoking was associated with CA in each phenotype, while moderate physical activity and moderate alcohol intake were associated with being metabolically healthy. Olive oil intake was negatively associated with the prevalence of CA. CONCLUSIONS: Smoking, physical activity level, and alcohol intake contribute to the explanation of the prevalence of CA in the Spanish population, as in the US population. However in Spain, olive oil intake contributes significantly to the explanation of the variance in the prevalence of CA.

Cardiovascular prevention in diabetes mellitus. Is it appropriate to speak of moderate or intermediate risk? / Prevención cardiovascular en la diabetes mellitus. ¿Es adecuado hablar de riesgo moderado o intermedio?

Diabetes, especially type 2, is considered a risk situation for atherosclerotic cardiovascular disease (ASCVD). Subjects with diabetes type 2 have a mortality rate due to ASCVD 3 times higher than that found in the general population, attributed to hyperglycemia and the frequent association of other cardiovascular risk factors, such as atherogenic dyslipidemia. Numerous scientific societies have established a risk classification for ASCVD in diabetes based on 3 degrees (moderate, high and very high). The objectives of dyslipidemia control are clearly defined and accepted, and vary depending on the previously established cardiovascular risk. In moderate or intermediate risk, the guidelines propose a less intensive intervention, maintaining LDL-C levels<100mg/dL and NO-HDL-C levels<130mg/dL, and waiting 10 years until reaching the high-risk category to initiate more intensive treatment. However, during the decade of follow-up recommended in the guidelines, cholesterol deposition in the arterial wall increases, facilitating the development of an unstable and inflammatory atheromatous plaque, and the development of ASCVD. Alternatively, diabetes could be considered from the outset to be a high-risk situation and the goal should be LDL-C<70mg/dL. Furthermore, maintaining LDL-C levels<70mg/dL contributes to reducing and stabilizing atheromatous plaque, avoiding or reducing mortality episodes due to ASCVD during those years of diabetes evolution. Should we maintain the proposed objectives in subjects with diabetes and moderate risk for a decade until reaching the high cardiovascular risk phase or, on the contrary, should we adopt a more intensive stance from the beginning seeking to reduce cardiovascular risk in the majority of patients with diabetes? Is it better to wait or prevent with effective therapeutic measures from the first moment?

Factors affecting levels of urinary albumin excretion in the general population of Spain: the Di@bet.es study.

The present study was undertaken to examine the prevalence of urinary ACR (albumin/creatinine ratio) >30 mg/g and the associated clinical and environmental factors in a representative sample of the population of Spain. Di@bet.es study is a national, cross-sectional population-based survey conducted in 2009-2010. Clinical, metabolic, socio-demographic, anthropometric data and information about lifestyle habit were collected. Those subjects without KDM (known diabetes mellitus) were given an OGTT (oral glucose tolerance test). Albumin and creatinine were measured in a urinary sample and ACR was calculated. The population prevalence of ACR >30 mg/g was 7.65% (adjusted for sex and age). The prevalence of ACR >30 mg/g increased with age (P<0.001). Subjects with carbohydrate metabolism disorders had a greater prevalence of ACR >30 mg/g but after being adjusted for age, sex and hypertension, was significant only in those subjects with UKDM (unknown diabetes mellitus) {OR (odd ratio), 2.07 [95% CI (confidence interval), 1.38-3.09]; P<0.001] and KDM [OR, 3.55 (95% CI, 2.63-4.80); P<0.001]. Prevalence of ACR >30 mg/g was associated with hypertension [OR, 1.48 (95% CI, 1.12-1.95); P=0.001], HOMA-IR (homoeostasis model assessment of insulin resistance) [OR, 1.47 (95% CI, 1.13-1.92); P≤0.01], metabolic syndrome [OR, 2.17 (95% CI, 1.72-2.72); P<0.001], smoking [OR, 1.40 (95% CI, 1.06-1.83); P≤0.05], physical activity [OR, 0.68 (95% CI, 0.54-0.88); P≤0.01] and consumption of fish [OR, 0.38 (95% CI, 0.18-0.78); P≤0.01]. This is the first study that reports the prevalence of ACR >30 mg/g in the Spanish population. The association between clinical variables and other potentially modifiable environmental variables contribute jointly, and sometimes interactively, to the explanation of prevalence of ACR >30 mg/g. Many of these risk factors are susceptible to intervention.

A simulation model to estimate 10-year risk of coronary heart disease events in patients with schizophrenia spectrum disorders treated with second-generation antipsychotic drugs.

BACKGROUND: The risk for cardiovascular (CV) events has been shown to be considerably higher among schizophrenia patients than the general population. OBJECTIVE: The aim of this study was to describe a general stochastic simulation model for the treatment of schizophrenia related to CV-associated risks of second-generation antipsychotics (SGAs). METHODS: A model to simulate the expected 10-year incidence of all types of coronary heart disease (CHD) events in patients treated with SGAs was developed from the Cardiovascular, Lipid and Metabolic Outcomes Research in Schizophrenia (CLAMORS) study to reproduce baseline conditions. The CHD event risk was estimated through a locally adjusted Framingham risk function using the expected mean change in the CV risk factors from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. RESULTS: The 10-year CHD event rate after treatment with SGAs was 0.181, 0.179, 0.176, and 0.172 for olanzapine, quetiapine, risperidone, and ziprasidone, respectively. Relative risk was calculated relative to no treatment, and values were as follows: olanzapine, 1.03 ± 1.05 (95% CI, 0.74 to 1.42), quetiapine, 1.02 ± 1.05 (95% CI, 0.74 to 1.41), risperidone, 1.00 ± 0.99 (95% CI, 0.73 to 1.36), and ziprasidone, 0.97 ± 0.95 (95% CI, 0.72 to 1.31). There were approximately 25,269 CHD events over a 10-year period in schizophrenia patients treated with olanzapine, 25,157 events with quetiapine, 24,883 with risperidone, and 24,514 events with ziprasidone. CONCLUSIONS: The estimated outcomes suggest that each SGA shows a different level of CV event risk, with ziprasidone showing the lowest rate without any association for increased risk of CHD.

Plant sterols and cardiovascular disease: a systematic review and meta-analysis.

The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols (sitosterol, campesterol) and cardiovascular disease (CVD). We systematically searched the databases MEDLINE, EMBASE, and COCHRANE for studies published between January 1950 and April 2010 that reported either risk ratios (RR) of CVD in relation to serum sterol concentrations (either absolute or expressed as ratios relative to total cholesterol) or serum sterol concentrations in CVD cases and controls separately. We conducted two meta-analyses, one based on RR of CVD contrasting the upper vs. the lower third of the sterol distribution, and another based on standardized mean differences between CVD cases and controls. Summary estimates were derived by fixed and random effects meta-analysis techniques. We identified 17 studies using different designs (four case-control, five nested case-control, three cohort, five cross-sectional) involving 11 182 participants. Eight studies reported RR of CVD and 15 studies reported serum concentrations in CVD cases and controls. Funnel plots showed evidence for publication bias indicating small unpublished studies with non-significant findings. Neither of our meta-analyses suggested any relationship between serum concentrations of sitosterol and campesterol (both absolute concentrations and ratios to cholesterol) and risk of CVD. Our systematic review and meta-analysis did not reveal any evidence of an association between serum concentrations of plant sterols and risk of CVD.

Plasma homocysteine levels are independently associated with the severity of peripheral polyneuropathy in type 2 diabetic subjects.

Peripheral polyneuropathy (PN) is a frequent complication of diabetes. However, mechanisms underlying the development of PN are multifactorial and not well understood. Our aim was to examine the association of plasma homocysteine (Hcy) with the prevalence and grade of peripheral PN in patients with type 2 diabetes (T2DM). We studied a cohort of 196 subjects with T2DM classified according to the grade of PN (Neuropathy Disability Score, NDS). Subjects with the highest grade of PN were older and had significantly increased levels of creatinine, microalbuminuria, HbA1c, and plasma Hcy compared to the other two groups. The differences in plasma Hcy values were maintained after correcting for confounding factors. Plasma Hcy, HbA1c, duration of diabetes, and age were predictors of the grade of PN. In conclusion, for each increase of 1 µmol in plasma Hcy there was a 23% increase of the risk of diabetic PN evaluated by NDS. Moreover, the grade of PN was predicted by plasma Hcy and HbA1c values, age and duration of diabetes. Further prospective studies should be conducted to confirm the association of plasma Hcy levels with the grade of PN in subjects with T2DM.

Different impacts of cardiovascular risk factors on oxidative stress.

The objective of the study was to evaluate oxidative stress (OS) status in subjects with different cardiovascular risk factors. With this in mind, we have studied three models of high cardiovascular risk: hypertension (HT) with and without metabolic syndrome, familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) with and without insulin resistance. Oxidative stress markers (oxidized/reduced glutathione ratio, 8-oxo-deoxyguanosine and malondialdehide) together with the activity of antioxidant enzyme triad (superoxide dismutase, catalase, glutathione peroxidase) and activation of both pro-oxidant enzyme (NAPDH oxidase components) and AGTR1 genes, as well as antioxidant enzyme genes (CuZn-SOD, CAT, GPX1, GSR, GSS and TXN) were measured in mononuclear cells of controls (n = 20) and patients (n = 90) by assessing mRNA levels. Activity of some of these antioxidant enzymes was also tested. An increase in OS and pro-oxidant gene mRNA values was observed in patients compared to controls. The hypertensive group showed not only the highest OS values, but also the highest pro-oxidant activation compared to those observed in the other groups. In addition, in HT a significantly reduced antioxidant activity and mRNA induction of antioxidant genes were found when compared to controls and the other groups. In FH and FCH, the activation of pro-oxidant enzymes was also higher and antioxidant ones lower than in the control group, although it did not reach the values obtained in hypertensives. The thioredoxin system was more activated in patients as compared to controls, and the highest levels were in hypertensives. The increased oxidative status in the presence of cardiovascular risk factors is a consequence of both the activation of pro-oxidant mechanisms and the reduction of the antioxidant ones. The altered response of the main cytoplasmic antioxidant systems largely contributes to OS despite the apparent attempt of the thioredoxin system to control it.

Arteriosclerosis and other diseases in heads of government and its consequences for the population. / Arteriosclerosis y otras enfermedades en líderes políticos y sus consecuencias para la población.

Heads of government with cerebrovascular arteriosclerosis and other diseases in key historical moments have led to decisions that have marked the destiny of countries not always in a beneficial direction. Severe diseases in political leaders in power have often been hidden from citizens with the collaboration of personal physicians. The confidentiality of the patient-doctor relationship in special political circumstances should be reexamined and subjected to debate. Legal provisions to ensure total transparency of medical information about the health of heads of government should be implemented. Transparency ensures the trust of citizens.

[Global therapy of diabetic dyslipidemia: benefits and new therapeutic approaches]. / Tratamiento integral de la dislipidemia diabética: beneficios y nuevas alternativas terapéuticas.

Diabetic dyslipidemia, characterized by the lipid triad (elevated plasma triglycerides, low HDL cholesterol and predominance of small, dense LDL particles), is a significant contributor to the elevated cardiovascular risk of type 2 diabetic patients. Statin monotherapy has shown, in different prospective trials, significant reductions in cardiovascular events and mortality. However, the residual risk in these subjects remains elevated, probably due to the incomplete control of diabetic dyslipidemia. In this review we discuss the global therapeutic approach, underlying the need of combining statins with agents that more effective in reducing triglycerides and elevating HDL cholesterol, even in subjects whose LDL cholesterol values are at target. Available data supports that such combinations contribute to normalize the lipid profile with possible beneficial effects on the cardiovascular risk. Ongoing clinical trials, using different combinations and focusing on cardiovascular morbidity and mortality are also discussed. In our opinion, the future treatment of diabetic dyslipidemia will include the combination of statins and other hypolipidemic agents.

Chronic kidney disease as a cardiovascular risk factor.

: Chronic kidney disease (CKD) is a public health threat with impact in cardiovascular risk. All forms of cardiovascular disease and mortality are more common in CKD. Treatment of cardiovascular risk factors, hypertension, dyslipidemia and diabetes is essential for cardiovascular and kidney protection. CKD is a marker of high or very high cardiovascular risk and its presence require early treatment and specific goals. Lifestyle is a pivotal factor, stopping smoking, reducing weight in the overweight or obese, starting regular physical exercise and healthy dietary pattern are recommended. Office BP should be lowered towards 130/80 mmHg or even lower if tolerated with sodium restriction and single pill combination, including angiotensin system blocker. Out-of-office BP monitoring, mainly 24-h assessment, is recommended. Diabetes requires treatment from the moment of diagnosis, but prediabetes benefits with lifestyle changes and metformin in patients stage 2 and 3a. iSGLT2 and GLP-1RA are initially recommended in T2D patients with high or very high cardiovascular risk. Concerning dyslipidemia, for patients in stage 4, LDL-C 55 mg/dl or less (1.4 mmol/l) and an LDL-C reduction of 50% or less from baseline is recommended. In stage 3, LDL-C goal is 70 mg/dl or less (1.8 mmol/l) and an LDL-C. reduction of at least 50% from baseline. Statins are the lipid-lowering therapy of choice with or without ezetimibe. Higher doses of statins are required as GFR declines. Available evidence suggests that combined PCSK9 inhibitors with maximally tolerated dose of statins may have an emerging role in treatment of dyslipidemia in CKD patients.

Cost-effectiveness of intensive atorvastatin therapy in secondary cardiovascular prevention in the United Kingdom, Spain, and Germany, based on the Treating to New Targets study.

The Treating to New Targets (TNT) clinical trial found that intensive 80 mg atorvastatin (A80) treatment reduced cardiovascular events by 22% when compared to 10 mg atorvastatin (A10) treatment. We evaluated the cost-effectiveness of intensive A80 vs A10 treatment in the United Kingdom (UK), Spain, and Germany. A lifetime Markov model was developed to predict cardiovascular disease-related events, costs, survival, and quality-adjusted life-years (QALYs). Treatment-specific event probabilities were estimated from the TNT clinical trial. Post-event survival, health-related quality of life, and country-specific medical-care costs were estimated using published sources. Intensive treatment with A80 increased both the per-patient QALYs and corresponding costs of care, when compared to the A10 treatment, in all three countries. The incremental cost per QALY gained was 9,500, 21,000, and 15,000 in the UK, Spain, and Germany, respectively. Intensive A80 treatment is estimated to be cost-effective when compared to A10 treatment in secondary cardiovascular prevention.

Respiratory chain polymorphisms and obesity in the Spanish population, a cross-sectional study.

OBJECTIVE: To study the association of genes involved in the mitochondrial respiratory chain (MRC) pathway with body mass index (BMI) and obesity risk. DESIGN: This work studies three cross-sectional populations from Spain, representing three provinces: HORTEGA (Valladolid, Northwest/Centre), SEGOVIA (Segovia, Northwest/centre) and PIZARRA (Malaga,South). SETTING: Forty-eight single nucleotide polymorphisms (SNPs) from MRC genes were selected and genotyped by SNPlex method. Association studies with BMI and obesity risk were performed for each population. These associations were then verified by analysis of the studied population as a whole (3731 samples). PARTICIPANTS: A total of 3731 Caucasian individuals: 1502 samples from HORTEGA, 988 from PIZARRA and 1241 from SEGOVIA. RESULTS: rs4600063 (SDHC), rs11205591 (NDUFS5) and rs10891319 (SDHD) SNPs were associated with BMI and obesity risk (p values for BMI were 0.04, 0.0011 and 0.0004, respectively, and for obesity risk, 0.0072, 0.039 and 0.0038). However, associations between rs4600063 and BMI and between these three SNPs and obesity risk are not significant if Bonferroni correction is considered. In addition, rs11205591 and rs10891319 polymorphisms showed an additive interaction with BMI and obesity risk. CONCLUSIONS: Several polymorphisms from genes coding MRC proteins may be involved in BMI variability and could be related to the risk to become obese in the Spanish general population.

A new PCSK9 gene promoter variant affects gene expression and causes autosomal dominant hypercholesterolemia.

CONTEXT: Autosomal dominant hypercholesterolemia (ADH) is a genetic disorder characterized by increased low-density lipoprotein (LDL)-cholesterol levels, leading to high risk of premature cardiovascular disease. More than 900 mutations in LDL receptor, six in APOB and 10 in PCSK9 have been identified as a cause of the disease in different populations. All known mutations in PCSK9 causing hypercholesterolemia produce an increase in the enzymatic activity of this protease. Up to now, there are data about the implication of PCSK9 in ADH in a low number of populations, not including a Spanish population. OBJECTIVE: The objective of the study was to study the prevalence of PCSK9 mutations in ADH Spanish population. PARTICIPANTS: We screened PCSK9 gene in 42 independent ADH patients in whom mutations in LDL receptor and APOB genes had been excluded. RESULTS: None of the known mutations causing ADH was detected in our sample, but we found two variations in the promoter region that could cause ADH, c.-288G>A and c.-332C>A (each in one proband). The analysis of the effect of these two variations on the transcription activity of the PCSK9 promoter showed that c.-288G>A did not modify the transcription, whereas c.-332C>A variant caused a 2.5-fold increase when compared with the wild-type sequence, either with or without lovastatin. CONCLUSIONS: PCSK9 is a rare cause of ADH in Spanish population and, up to what we know, none of the previously described mutations has been detected. We have identified a new mutation that could cause ADH by increasing the transcription of PCSK9.

Concordance of standard and modified NCEP ATP III criteria for identification of metabolic syndrome in outpatients with schizophrenia treated with antipsychotics: a corollary from the CLAMORS study.

OBJECTIVE: To analyze the concordance between standard and modified NCEP-ATP-III criteria for identification of metabolic syndrome (MS) in outpatients with schizophrenia. METHOD: We used the sample from a cross-sectional study carried out to ascertain the prevalence of MS in schizophrenia. Kappa agreement and the symmetry Kendall's tau-b coefficients were calculated in a post-hoc analysis, a long with McNemar test and logistic regression models. RESULTS: The study enrolled 1,452 consecutive outpatients. MS was found in 24.6% (95%CI: 22.4%-26.8%) using the standard criteria and in 25.5% (23.2%-27.7%) using the modified criteria. Agreement was high; kappa 0.81 (p<0.0001) and tau-b 0.81 (p<0.0001), with a McNemar value of 0.2325. Kappa coefficients varied between 1.0 and 0.76 in subgroups according to sex, age-group, severity of disease, and duration of therapy. CONCLUSIONS: MS in outpatients with schizophrenia may be assessed by either the standard or the modified NCEP ATP III criteria without losing reliability.

PAI-1 levels are related to insulin resistance and carotid atherosclerosis in subjects with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH) is a primary atherogenic dyslipidemia with insulin resistance and increased cardiovascular risk. Plasminogen activator inhibitor type 1 (PAI-1) and myeloperoxidase (MPO) activity are associated with proinflammatory and atherothrombotic risk. Our aim was to study the role played by PAI-1 and MPO activity in the carotid atherosclerosis prevalence in FCH subjects. 36 FCH unrelated subjects (17 women) were matched by age and body weight with 36 healthy normolipidemic subjects (19 female). Blood lipids, glucose, insulin, insulin resistance (homeostasis model assessment (HOMA)), MPO, and PAI-1 were determined in both groups. Carotid intima media thickness (IMT) was measured by the same investigator by standardized protocol. No differences in age, body mass index (BMI) or waist circumference were observed between the two groups. HOMA and PAI-1 values were higher in the FCH group, reaching statistical significance in those subjects with insulin resistance. In addition, PAI-1 values correlated significantly with metabolic syndrome components and carotid IMT. It is known that the elevated cardiovascular risk that characterizes FCH is frequently associated with insulin resistance. We have detected that two known proinflammatory and proatherothrombotic factors (MPO and PAI-1) are significantly elevated in FCH subjects with insulin resistance. These results could partly explain the high cardiovascular risk present in FCH subjects.

Correction: Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.

[This corrects the article DOI: 10.1371/journal.pone.0186196.].

Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study.

BACKGROUND: Despite the prognostic value of metabolic syndrome for predicting cardiovascular events, few trials have investigated the effects of statin therapy on cardiovascular morbidity and mortality in patients with the metabolic syndrome. Our post hoc analysis of the Treating to New Targets (TNT) study assessed whether intensive lowering of low-density lipoprotein cholesterol with high-dose atorvastatin therapy results in cardiovascular benefits for patients with both coronary heart disease and the metabolic syndrome. METHODS: The TNT study was a prospective, double blind, parallel-group trial done at 256 sites in 14 countries between April, 1998, and August, 2004, with a median follow-up of 4.9 years. 10,001 patients were enrolled aged 35-75 years with clinically evident coronary heart disease. Our analysis includes 5584 patients with metabolic syndrome based on the 2005 NCEP ATP III criteria. Patients were randomly assigned to receive either atorvastatin 10 mg per day (n=2820) or 80 mg per day (n=2764). The primary outcome measure was time to first major cardiovascular event, defined as death from coronary heart disease, non-fatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or non-fatal stroke. FINDINGS: In patients with coronary heart disease and metabolic syndrome, mean on-treatment low-density lipoprotein cholesterol concentrations at 3 months were 2.6 mmol/L (99.3 mg/dL) with atorvastatin 10 mg, and 1.9 mmol/L (72.6 mg/dL) with atorvastatin 80 mg. At a median follow-up of 4.9 years, major cardiovascular events occurred in 367 (13%) patients receiving atorvastatin 10 mg, compared with 262 (9.5%) receiving atorvastatin 80 mg (hazard ratio 0.71; 95% CI 0.61-0.84; p<0.0001). Irrespective of treatment assignment, significantly more patients with metabolic syndrome (11.3%) had a major cardiovascular event at a median of 4.9 years than those without metabolic syndrome (8.0%; hazard ratio 1.44; 95% CI 1.26-1.64; p<0.0001). This increased risk was significantly reduced by intensive therapy with atorvastatin 80 mg beyond that achieved with atorvastatin 10 mg. INTERPRETATION: These data indicate that patients with coronary heart disease and metabolic syndrome derive incremental benefit from high-dose atorvastatin therapy, irrespective of the presence of diabetes.