Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke. Methods: We performed genome-wide association studies (GWAS) for subsequent major adverse cardiovascular events (MACE) (Ncases=51,929, Ncntrl=39,980) and subsequent arterial ischemic stroke (AIS) Ncases=45,120, Ncntrl=46,789) after first incident stroke within the Million Veteran Program and UK Biobank. We then used genetic variants associated with proteins (pQTLs) to determine the effect of 1,463 plasma protein abundances on subsequent MACE using Mendelian randomization (MR). Results: Two variants were significantly associated with subsequent cardiovascular events: rs76472767 (OR=0.75, 95% CI = 0.64-0.85, p= 3.69×10-08) with subsequent AIS and rs13294166 (OR=1.52, 95% CI = 1.37-1.67, p=3.77×10-08) with subsequent MACE. Using MR, we identified 2 proteins with an effect on subsequent MACE after a stroke: CCL27 (effect OR= 0.77, 95% CI = 0.66-0.88, adj. p=0.05), and TNFRSF14 (effect OR=1.42, 95% CI = 1.24-1.60, adj. p=0.006). These proteins are not associated with incident AIS and are implicated to have a role in inflammation. Conclusions: We found evidence that two proteins with little effect on incident stroke appear to influence subsequent MACE after incident AIS. These associations suggest that inflammation is a contributing factor to subsequent MACE outcomes after incident AIS and highlights potential novel targets.

PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL-C and CVD risk. OBJECTIVES: Primary To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention. SEARCH METHODS: We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017. SELECTION CRITERIA: All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables. MAIN RESULTS: We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used  an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of -2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD -1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD -2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence). Compared to active treatment the alirocumab effects, for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was -1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence). Compared to placebo the evolocumab, for CVD, the RD was -2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was -1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than -1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence).  Compared to active treatment, the evolocumab effects, for any CVD event RD was less than -1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke.  AUTHORS' CONCLUSIONS: The evidence for the clinical endpoint effects of  evolocumab and alirocumab were graded as high. There is a strong evidence base to prescribe PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials.  The evidence base of PCSK9 inhibitors compared with active treatment is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies. Related, most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal. Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.

Plasma protein patterns as comprehensive indicators of health.

Proteins are effector molecules that mediate the functions of genes1,2 and modulate comorbidities3-10, behaviors and drug treatments11. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning12-16 coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.

Investigating the importance of the local food environment for fruit and vegetable intake in older men and women in 20 UK towns: a cross-sectional analysis of two national cohorts using novel methods.

BACKGROUND: Local neighbourhood environments can influence dietary behavior. There is limited evidence focused on older people who are likely to have greater dependence on local areas and may suffer functional limitations that amplify any neighbourhood impact. METHODS: Using multi-level ordinal regression analysis we investigated the association between multiple dimensions of neighbourhood food environments (captured by fine-detail, foot-based environmental audits and secondary data) and self-reported frequency of fruit and vegetable intake. The study was a cross-sectional analysis nested within two nationally representative cohorts in the UK: the British Regional Heart Study and the British Women's Heart and Health Study. Main exposures of interest were density of food retail outlets selling fruits and vegetables, the density of fast food outlets and a novel measure of diversity of the food retail environment. RESULTS: A total of 1124 men and 883 women, aged 69 - 92 years, living in 20 British towns were included in the analysis. There was strong evidence of an association between area income deprivation and fruit and vegetable consumption, with study members in the most deprived areas estimated to have 27% (95% CI: 7, 42) lower odds of being in a higher fruit and vegetable consumption category relative to those in the least deprived areas. We found no consistent evidence for an association between fruit and vegetable consumption and a range of other food environment domains, including density of shops selling fruits and vegetables, density of premises selling fast food, the area food retail diversity, area walkability, transport accessibility, or the local food marketing environment. For example, individuals living in areas with greatest fruit and vegetable outlet density had 2% (95% CI: -22, 21) lower odds of being in a higher fruit and vegetable consumption category relative to those in areas with no shops. CONCLUSIONS: Although small effect sizes in environment-diet relationships cannot be discounted, this study suggests that older people are less influenced by physical characteristics of neighbourhood food environments than is suggested in the literature. The association between area income deprivation and diet may be capturing an important social aspect of neighbourhoods that influence food intake in older adults and warrants further research.

Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene.

BACKGROUND AND AIMS: Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects. RESULTS: The ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∼14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C (p = 0.004), and higher risk of coronary heart disease (CHD) (p = 0.04). The SNP is in modest linkage disequilibrium (r2 > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p = 1.36 × 10-05). CONCLUSIONS: Both rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering.

Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.

Variants of ADRA2A are associated with fasting glucose, blood pressure, body mass index and type 2 diabetes risk: meta-analysis of four prospective studies.

AIMS/HYPOTHESIS: We quantified the effect of ADRA2A (encoding α-2 adrenergic receptor) variants on metabolic traits and type 2 diabetes risk, as reported in four studies. METHODS: Genotype data for ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 were analysed in >17,000 individuals (1,307 type 2 diabetes cases) with regard to metabolic traits and type 2 diabetes risk. Two studies (n = 9,437), genotyped using the Human Cardiovascular Disease BeadChip, provided 12 additional ADRA2A SNPs. RESULTS: Rs553668 was associated with per allele effects on fasting glucose (0.03 mmol/l, p = 0.016) and type 2 diabetes risk (OR 1.17, 95% CI 1.04-1.31; p = 0.01). No significant association was observed with rs10885122. Of the 12 SNPs, several showed associations with metabolic traits. Overall, after variable selection, rs553668 was associated with type 2 diabetes risk (OR 1.38, 95% CI 1.09-1.73; p = 0.007). rs553668 (per allele difference 0.036 mmol/l, 95% CI 0.008-0.065) and rs17186196 (per allele difference 0.066 mmol/l, 95% CI 0.017-0.115) were independently associated with fasting glucose, and rs17186196 with fasting insulin and HOMA of insulin resistance (4.3%, 95% CI 0.6-8.1 and 4.9%, 95% CI 1.0-9.0, respectively, per allele). Per-allele effects of rs491589 on systolic and diastolic blood pressure were 1.19 mmHg (95% CI 0.43-1.95) and 0.61 mmHg (95% CI 0.11-1.10), respectively, and those of rs36022820 on BMI 0.58 kg/m(2) (95% CI 0.15-1.02). CONCLUSIONS/INTERPRETATION: Multiple ADRA2A SNPs are associated with metabolic traits, blood pressure and type 2 diabetes risk. The α-2 adrenergic receptor should be revisited as a therapeutic target for reduction of the adverse consequences of metabolic trait disorders and type 2 diabetes.

The Latin American Consortium of Studies in Obesity (LASO).

Current, high-quality data are needed to evaluate the health impact of the epidemic of obesity in Latin America. The Latin American Consortium of Studies of Obesity (LASO) has been established, with the objectives of (i) Accurately estimating the prevalence of obesity and its distribution by sociodemographic characteristics; (ii) Identifying ethnic, socioeconomic and behavioural determinants of obesity; (iii) Estimating the association between various anthropometric indicators or obesity and major cardiovascular risk factors and (iv) Quantifying the validity of standard definitions of the various indexes of obesity in Latin American population. To achieve these objectives, LASO makes use of individual data from existing studies. To date, the LASO consortium includes data from 11 studies from eight countries (Argentina, Chile, Colombia, Costa Rica, Dominican Republic, Peru, Puerto Rico and Venezuela), including a total of 32,462 subjects. This article describes the overall organization of LASO, the individual studies involved and the overall strategy for data analysis. LASO will foster the development of collaborative obesity research among Latin American investigators. More important, results from LASO will be instrumental to inform health policies aiming to curtail the epidemic of obesity in the region.

Interethnic differences in the accuracy of anthropometric indicators of obesity in screening for high risk of coronary heart disease.

BACKGROUND: Cut points for defining obesity have been derived from mortality data among Whites from Europe and the United States and their accuracy to screen for high risk of coronary heart disease (CHD) in other ethnic groups has been questioned. OBJECTIVE: To compare the accuracy and to define ethnic and gender-specific optimal cut points for body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) when they are used in screening for high risk of CHD in the Latin-American and the US populations. METHODS: We estimated the accuracy and optimal cut points for BMI, WC and WHR to screen for CHD risk in Latin Americans (n=18 976), non-Hispanic Whites (Whites; n=8956), non-Hispanic Blacks (Blacks; n=5205) and Hispanics (n=5803). High risk of CHD was defined as a 10-year risk > or =20% (Framingham equation). The area under the receiver operator characteristic curve (AUC) and the misclassification-cost term were used to assess accuracy and to identify optimal cut points. RESULTS: WHR had the highest AUC in all ethnic groups (from 0.75 to 0.82) and BMI had the lowest (from 0.50 to 0.59). Optimal cut point for BMI was similar across ethnic/gender groups (27 kg/m(2)). In women, cut points for WC (94 cm) and WHR (0.91) were consistent by ethnicity. In men, cut points for WC and WHR varied significantly with ethnicity: from 91 cm in Latin Americans to 102 cm in Whites, and from 0.94 in Latin Americans to 0.99 in Hispanics, respectively. CONCLUSION: WHR is the most accurate anthropometric indicator to screen for high risk of CHD, whereas BMI is almost uninformative. The same BMI cut point should be used in all men and women. Unique cut points for WC and WHR should be used in all women, but ethnic-specific cut points seem warranted among men.

Non-communicable diseases in low- and middle-income countries: context, determinants and health policy.

The rise of non-communicable diseases and their impact in low- and middle-income countries has gained increased attention in recent years. However, the explanation for this rise is mostly an extrapolation from the history of high-income countries whose experience differed from the development processes affecting today's low- and middle-income countries. This review appraises these differences in context to gain a better understanding of the epidemic of non-communicable diseases in low- and middle-income countries. Theories of developmental and degenerative determinants of non-communicable diseases are discussed to provide strong evidence for a causally informed approach to prevention. Health policies for non-communicable diseases are considered in terms of interventions to reduce population risk and individual susceptibility and the research needs for low- and middle-income countries are discussed. Finally, the need for health system reform to strengthen primary care is highlighted as a major policy to reduce the toll of this rising epidemic.

C-reactive protein and coronary heart disease: a critical review.

Modestly elevated baseline concentrations of C-reactive protein (CRP), the classical acute phase protein, are associated with the long-term risk of coronary heart disease in general populations, whilst the major acute phase response of CRP following myocardial infarction is associated with death and cardiac complications. The pathogenic and clinical significance of these associations is controversial. Here we critically review the evidence and describe large-scale epidemiological studies, novel experiments and possible specific therapies which will rigorously inform the debate. We distinguish between the potential pathogenicity of high acute phase circulating CRP concentrations in individuals with substantial tissue damage and modest but persistent increases in baseline values in generally healthy subjects.

Colombian study to assess the use of noninvasive determination of the endothelium-mediated vasodilation (CANDEV) II: does location of the occlusion device affects the accuracy of the diagnosis?

Endothelial dysfunction (ED), which is often evaluated by flow-mediated vasodilation (FMV) in the brachial artery, has been postulated as a predictor of cardiac events. Although the upper and forearm location of the occlusion device have been used for FMV evaluation, currently there is no consensus whether they provide the same information. The main goal of this study was to evaluate if both techniques have the same accuracy to differentiate subjects with and without cardiovascular risk factors (CRFs). A cross-sectional study in 124 subjects was performed. The volunteers were divided in two groups: 62 subjects (20 women and 42 men) with at least one CRF and 62 (20 women and 42 men) healthy subjects without CRFs. FMV measurements using the cuff in the upper arm and forearm with intervals of 30 min were taken. In all subjects, %FMV with the cuff located in the upper arm was 10.13 +/- 4.5 and 9.8 +/- 4.1 with the cuff located below the elbow. In healthy subjects without CRFs the %FMV in the upper arm was 12.19 +/- 4.0 versus 12.31 +/- 3.4 in the upper forearm, in CRF subjects it was 8.08 +/- 4.0 vs 7.29 +/- 3.2., respectively. FMV was not affected by the location of the cuff in maintaining the test ability and accuracy to differentiate subjects with and without CRFs.

Tau gene and Parkinson's disease: a case-control study and meta-analysis.

OBJECTIVE: To investigate whether the tau H1 haplotype is a genetic risk factor in Parkinson's disease and to report a meta-analysis on all previously published data METHODS: and results: In a sample of 580 patients with Parkinson's disease and 513 controls there was an increased risk of Parkinson's disease for both the tau H1 haplotype (p

Endothelial dysfunction, angiotensin-converting enzyme inhibitors and calcium antagonists.

The endothelium plays a crucial role in the pathogenesis of cardiovascular disease. Endothelial function is attenuated by the presence of different well known cardiovascular risk factors. Evaluation of endothelial vasodilator function serve as an index integrating the overall stress imposed by cardiovascular risk factors and reinforce the suggestion that endothelial dysfunction is an early marker of cardiovascular disease that precedes clinical manifestations. Angiotensin-converting enzyme inhibitors have been shown to reduce the cardiovascular mortality, an effect that could be the consequence of an improvement in the endothelial function. Recent studies have shown that a calcium antagonist might improve the endothelial function, however, there is controversy about this action and also about the potential mechanisms for the effect of a calcium antagonist in the regulation of endothelial function.

Blockade of endothelial enzymes: new therapeutic targets.

Nitric oxide (NO) is the principal vasoactive substance produced by the vascular endothelium with antitrombotic, antiatherogenic and vasodilator actions. The loss of these functions is now known as endothelial dysfunction (ED) and it has been proposed that it is the final common pathway in cardiovascular disease. At the moment there is an important body of evidence that supports the proposal that ED is a consequence of an imbalance between the free radicals, NO, superoxide (O(-)(2)) and peroxynitrate (ONOO(-)). This imbalance is the result of the actions of well known risk factors associated with an inappropriate diet and infection-inflammation. Angiotensin-converting enzyme (ACE) inhibitors are highly effective against a variety of cardiovascular disorders. Experimental and clinical studies have demonstrated a beneficial effect of ACE inhibition on endothelial function. This action is mainly due to an increase in the concentration of bradykinin, which stimulates NO production. ACE inhibitors also block the formation of angiotensin II that results in a lower production of O(-)(2). These effects lead to improve the imbalance between NO and O(-)(2) observed in cardiovascular disease. This proposal is supported by different clinical trials that have shown that the ACE inhibitors with higher affinity by the tissular ACE, such as quinapril, are the most effective in reversing ED principally by accumulating bradykinin. Recently, the HOPE study conducted in patients at a high risk of cardiovascular events, showed how ramipril, an ACE inhibitor with high affinity by tissular ACE, decreased the mortality rate due to cardiovascular disease independently of changes in blood pressure.

Lung cavitation in primary antiphospholipid syndrome.

Pulmonary complications of primary antiphospholipid syndrome are common and diverse, with thromboembolic events counting as the most frequent manifestation. We present the case of a female patient with a diagnosis of primary antiphospholipid syndrome, pulmonary thromboembolism and infarction followed by lung cavitation.

An integrated proposal to explain the epidemic of cardiovascular disease in a developing country. From socioeconomic factors to free radicals.

An increase of coronary artery disease has been observed in developing countries during the last years. Various factors may explain this accelerated increase. We propose that inappropriate diet and inadequate sanitary infrastructure may act as triggers to create an imbalance between nitric oxide (NO) and superoxide (O2-). An increase in the concentrations of oxidized LDL produces both decreased NO and increased O2- endothelial synthesis, by accumulation of asymmetrical NG-NG-dimethyl-L-arginine, the endogenous inhibitor of NO, and by activation of NAD(P)H oxidase. On the other hand, high rates of chronic infection-inflammation, due to inappropriate sanitary environment stimulate higher circulating levels of proinflammatory cytokines. These cytokines also contribute to reduced NO and increased O2- endothelial production through the same mechanisms of oxidized LDL. The net result of this imbalance is an increased generation of peroxynitrate that injures the endothelium in a proatherogenic, prothrombotic and vasoconstrictive manner.

Preeclampsia: from epidemiological observations to molecular mechanisms.

Preeclampsia is the main cause of maternal mortality and is associated with a five-fold increase in perinatal mortality in developing countries. In spite of this, the etiology of preeclampsia is unknown. The present article analyzes the contradictory results of the use of calcium supplementation in the prevention of preeclampsia, and tries to give an explanation of these results. The proposal of an integrative model to explain the clinical manifestations of preeclampsia is discussed. In this proposal we suggest that preeclampsia is caused by nutritional, environmental and genetic factors that lead to the creation of an imbalance between the free radicals nitric oxide, superoxide and peroxynitrate in the vascular endothelium. The adequate interpretation of this model would allow us to understand that the best way of preventing preeclampsia is the establishment of an adequate prenatal control system involving adequate antioxidant vitamin and mineral supplementation, adequate diagnosis and early treatment of asymptomatic urinary and vaginal infections. The role of infection in the genesis of preeclampsia needs to be studied in depth because it may involve a fundamental change in the prevention and treatment of preeclampsia.