Maternal vascular indices at 36 weeks' gestation in the prediction of preeclampsia.

BACKGROUND: Epidemiological studies have shown that women with preeclampsia (PE) are at increased long term cardiovascular risk. This risk might be associated with accelerated vascular ageing process but data on vascular abnormalities in women with PE are scarce. OBJECTIVE: This study aimed to identify the most discriminatory maternal vascular index in the prediction of PE at 35 to 37 weeks' gestation and to examine the performance of screening for PE by combinations of maternal risk factors and biophysical and biochemical markers at 35 to 37 weeks' gestation. STUDY DESIGN: This was a prospective observational nonintervention study in women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices, and hemodynamic parameters obtained by a noninvasive operator-independent device (pulse wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressures, total peripheral resistance, and fetal heart rate), mean arterial pressure, uterine artery pulsatility index, and serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1. The performance of screening for delivery with PE at any time and at <3 weeks from assessment using a combination of maternal risk factors and various combinations of biomarkers was determined. RESULTS: The study population consisted of 6746 women with singleton pregnancies, including 176 women (2.6%) who subsequently developed PE. There were 3 main findings. First, in women who developed PE, compared with those who did not, there were higher central systolic and diastolic blood pressures, pulse wave velocity, peripheral vascular resistance, and augmentation index. Second, the most discriminatory indices were systolic and diastolic blood pressures and pulse wave velocity, with poor prediction from the other indices. However, the performance of screening by a combination of maternal risk factors plus mean arterial pressure was at least as high as that of a combination of maternal risk factors plus central systolic and diastolic blood pressures; consequently, in screening for PE, pulse wave velocity, mean arterial pressure, uterine artery pulsatility index, placental growth factor, and soluble fms-like tyrosine kinase-1 were used. Third, in screening for both PE within 3 weeks and PE at any time from assessment, the detection rate at a false-positive rate of 10% of a biophysical test consisting of maternal risk factors plus mean arterial pressure, uterine artery pulsatility index, and pulse wave velocity (PE within 3 weeks: 85.2%; 95% confidence interval, 75.6%-92.1%; PE at any time: 69.9%; 95% confidence interval, 62.5%-76.6%) was not significantly different from a biochemical test using the competing risks model to combine maternal risk factors with placental growth factor and soluble fms-like tyrosine kinase-1 (PE within 3 weeks: 80.2%; 95% confidence interval, 69.9%-88.3%; PE at any time: 64.2%; 95% confidence interval, 56.6%-71.3%), and they were both superior to screening by low placental growth factor concentration (PE within 3 weeks: 53.1%; 95% confidence interval, 41.7%-64.3%; PE at any time: 44.3; 95% confidence interval, 36.8%-52.0%) or high soluble fms-like tyrosine kinase-1-to-placental growth factor concentration ratio (PE within 3 weeks: 65.4%; 95% confidence interval, 54.0%-75.7%; PE at any time: 53.4%; 95% confidence interval, 45.8%-60.9%). CONCLUSION: First, increased maternal arterial stiffness preceded the clinical onset of PE. Second, maternal pulse wave velocity at 35 to 37 weeks' gestation in combination with mean arterial pressure and uterine artery pulsatility index provided effective prediction of subsequent development of preeclampsia.

Maternal Cardiac Function at Midgestation and Development of Preeclampsia.

BACKGROUND: Preeclampsia (PE) is an independent risk factor for adverse maternal cardiovascular outcomes. The role of maternal cardiac function in the pathophysiology of PE remains unclear. OBJECTIVES: This study sought to describe differences in cardiac function at midgestation between women who develop PE and those with uncomplicated pregnancy and to establish whether routine cardiac assessment at midgestation can improve performance of screening for PE achieved by established biomarkers. METHODS: Mean arterial pressure was measured, medical history was obtained, and left ventricular (LV) systolic and diastolic functions were assessed using standard echocardiography and speckle tracking imaging. Uterine artery pulsatility index and serum placental growth factor and soluble fms-like tyrosine kinase-1 were measured. RESULTS: In 4,795 pregnancies, 126 (2.6%) developed PE. Following multivariable analysis, peripheral vascular resistance was significantly higher and LV global longitudinal systolic strain, ejection fraction, cardiac output, and left atrial area were mildly lower in women who developed PE compared to those who did not. There was a weak association between maternal cardiovascular indices and biomarkers of placental perfusion and function. Cardiac indices did not improve the performance of screening for PE on top of maternal risk factors, mean arterial pressure, and biomarkers of placental perfusion and function. CONCLUSION: Women who develop PE have an increase in peripheral vascular resistance and a mild reduction in LV functional cardiac indices long before PE development. However, cardiac indices do not improve the performance of screening for PE; thus, their routine clinical use is not advocated.

Outcome and Impact of Associated Left-Sided Cardiac Lesions in Coarctation of the Aorta Diagnosed During Fetal Life.

Significant effort has been put into the optimization of the antenatal diagnosis of coarctation of the aorta (CoA). However, although left-sided cardiac lesions are known to cluster, the necessity to intervene postnatally for other left-sided cardiac lesions has not been reported in a cohort of fetuses with suspected CoA. We report a study of all 89 fetuses with antenatally suspected and postnatally confirmed diagnosis of CoA who underwent CoA repair as the primary procedure at a single tertiary congenital heart disease center over 10 years (January 1, 2010, to December 31, 2019). Almost 1 in 5 patients (18%) had to undergo surgery and/or transcatheter intervention on additional left-sided cardiac lesions (14%) and/or reintervention on the aortic arch (12%) during follow-up to median age of 2.85 years. Freedom from intervention at 5 years was 78% (95% confidence interval [CI] 67 to 88%) if reintervention on CoA was excluded, and 72% (95% CI 60 to 82%) if this was included. Five-year survival was 95% (95% CI 90 to 100%). Furthermore, 20% of affected infants had genetic (10%) and/or extracardiac (16%) abnormalities. Our study highlights the need for comprehensive antenatal counseling, including the prognosis of primary repair of CoA and the potential development of additional left-sided cardiac lesions, which may be difficult to diagnose prenatally even in expert hands or impossible to diagnose because of the physiology of the fetal circulation.

A Bayesian meta-analysis on early tobacco exposure and vascular health: From childhood to early adulthood.

BACKGROUND: Smoking has been consistently associated with increased cardiovascular risk in adults. Although exposure to tobacco products often starts in early life, evidence for the possible adverse effects on the cardiovascular system of the young is scarce. We sought to derive pooled estimates of smoking effects on indices of early vascular damage in children and adolescents. DESIGN AND METHODS: We performed a systematic review and meta-analysis of clinical studies involving young individuals up to 21 years old that provided data on smoking exposure (active or passive) and flow-mediated dilatation, carotid to femoral pulse wave velocity and maximum carotid intima-media thickness. We employed three distinct methodologies of random-effects data synthesis, including the Sidik-Jonkman estimator, the Hartung and Knapp correction and a Bayesian method with a well-informed prior on the level of between-study variance. RESULTS: In 12 studies and 5279 individuals in total, smoking exposure was related to deterioration in all three outcomes (mean adjusted flow-mediated dilatation decrease: -0.77%, 95% confidence interval -1.38--0.15, mean adjusted pulse wave velocity increase: 0.1 m/s, 95% confidence interval 0.02-0.17 and mean adjusted carotid intima-media thickness increase: 0.35 mm, 95% confidence interval 0.16-0.55, for the Sidik-Jonkman estimator). No difference was established between active and passive smoking on associations with arterial damage. CONCLUSIONS: Exposure to tobacco products is associated with subclinical vascular damage early in life, even from childhood. Public health initiatives should target these very young age groups to prevent early smoking exposure and associated arterial damage and its sequelae.

Maternal Cardiac Assessment at 35 to 37 Weeks Improves Prediction of Development of Preeclampsia.

Preeclampsia at term accounts for half of maternal deaths from hypertensive disorders. We aimed to assess differences in maternal cardiac indices at 35+0 to 36+6 weeks' gestation between women who subsequently developed preeclampsia at term compared with those with uncomplicated pregnancy and to evaluate whether cardiac indices offer incremental prognostic value to the available screening algorithm for preeclampsia. We recruited 1602 women with singleton pregnancies who attended for a routine hospital visit at 35+0 to 36+6 weeks' gestation between April and November 2018. We recorded maternal characteristics and preeclampsia-risk-score derived from a competing risks model and measured cardiac indices. Preeclampsia developed in 3.12% (50/1602) of participants. Women with preeclampsia, compared with those without, had increased mean arterial pressure (97.6, SD, 5.53 versus 87.9, SD, 6.82 mm Hg), systemic vascular resistance (1500, interquartile range, 1393-1831 versus 1400, interquartile range, 1202-1630 PRU) and preeclampsia-risk-score (23.4, interquartile range, 9.13-40 versus 0.9, interquartile range, 0.32-3.25). Multivariable analysis demonstrated independent association between the incidence of preeclampsia and E/e' (hazard ratio, 1.19/unit [95% CI, 1.03-1.37]; P=0.018) as well as left ventricular mass indexed for body surface area (hazard ratio, 1.03/[g·m2] [95% CI, 1.003-1.051]; P=0.029). Women with E/e' ≥7.3 and left ventricular mass indexed for body surface area ≥63.2 g/m2 had an increased risk for developing preeclampsia, despite low preeclampsia-risk-score <5% (hazard ratio, 20.1 [95% CI, 10.5-38.7], P<0.001). Increased left ventricular mass and E/e' offer incremental information to available scoring systems and better stratify women at risk of developing preeclampsia at term.

Placental function and fetal weight are associated with maternal hemodynamic indices in uncomplicated pregnancies at 35-37 weeks of gestation.

BACKGROUND: Over the years, there has been an increasing interest in the assessment of maternal hemodynamic responses during pregnancy. With the use of both noninvasive devices and/or maternal echocardiography, it has been shown that mothers who have pregnancy complications have altered hemodynamics compared with those who have uncomplicated pregnancies. It also has been suggested that preexisting maternal cardiac changes might drive the development of complications in pregnancy that are associated with impaired placentation. To understand, however, this potential link in complicated pregnancies, it is important to clarify whether placental function is associated with maternal cardiac functional indices in normal pregnancies. OBJECTIVE: To determine whether placental function, perfusion, and fetal weight are associated with maternal cardiac hemodynamic responses at 35-36 weeks of gestation in normal pregnancies. STUDY DESIGN: Prospective screening of women attending Kings' College Hospital for routine hospital visit at 35-37 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure, uterine artery pulsatility index, sonographic estimated fetal weight, and serum placental growth factor and soluble fms-like tyrosine kinase 1. We also performed maternal echocardiogram to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function, including global longitudinal systolic function and left ventricular mass indexed to body surface area. RESULTS: We studied 1386 women. Maternal characteristics were associated with both maternal hemodynamics and functional and structural indices. Uterine artery pulsatility index was associated with left ventricular mass (P=.03) and global longitudinal systolic function (P=.017). There were significant nonlinear associations between placental growth factor and cardiac output and peripheral vascular resistance (P<.001 for both) and between soluble fms-like tyrosine kinase 1 and peripheral vascular resistance (P=.018). Estimated fetal weight was associated with maternal cardiac output (mean increase=0.186, 95% confidence interval, 0.133-0.238, P<.001) and peripheral vascular resistance (mean decrease=-0.164, 95% confidence interval, -0.217 to -0.111, P<.001). No association was noted between placental and fetal parameters and maternal cardiac functional and structural indices. In multivariable analysis, placental growth factor remained strongly associated with maternal cardiac output and peripheral vascular resistance (P=.002 for both) over and above maternal characteristics and estimated fetal weight. Estimated fetal weight was associated with left ventricular mass (0.102, 95% confidence interval, 0.044-0.162, P=.001). CONCLUSION: The results of this study suggest a strong link between maternal hemodynamic responses and fetoplacental needs across the whole spectrum in normal pregnancies. These findings would also indicate that to diagnose maternal cardiac dysfunction in pregnancies complicated by impaired placentation a more extensive echocardiographic assessment might be needed rather than relying on hemodynamics which are strongly associated with fetoplacental indices.

Reactive Vasodilation Predicts Mortality in Primary Systemic Light-Chain Amyloidosis.

Rationale: Cardiac involvement and hypotension dominate the prognosis of light-chain amyloidosis (AL). Evidence suggests that there is also peripheral vascular involvement in AL but its prognostic significance is unknown. Objective: To evaluate vascular dysfunction in patients with AL as a potential future area of intervention, we assessed the prognostic utility of flow-mediated dilatation (FMD), a marker of vascular reactivity, which is augmented under conditions of hypotension and autonomic dysfunction. Methods and Results: We prospectively evaluated 115 newly diagnosed untreated AL patients in whom FMD was measured. FMD in AL patients was significantly higher than age-, sex- and risk factors-matched controls (4.0% versus 2.32%; P=0.006) and comparable with control groups at lower cardiovascular risk (P>0.1). Amyloidosis patients presented increased plasma and exhaled markers of the NO pathway while their FMD significantly correlated with augmented sustained vasodilatation after sympathetic stimulation. Increased FMD (≥4.5%) was associated with early mortality (hazard ratio, 4.36; 95% CI, 1.41-13.5; P=0.010) and worse survival (hazard ratio, 2.11; 95% CI, 1.17-3.82; P=0.013), even after adjustment for Mayo stage, nerve involvement and low systolic blood pressure. This finding was confirmed in a temporal validation AL cohort (n=55; hazard ratio, 4.2; 95% CI, 1.45-12.3; P=0.008). FMD provided significant reclassification value over the best prognostic model (continuous Net Reclassification Index, 0.61; P=0.001). Finally, better hematologic response was associated with lower posttreatment FMD. Conclusions: FMD is relatively increased in AL and independently associated with inferior survival with substantial reclassification value. Reactive vasodilation merits further investigation as a novel risk biomarker in AL.Visual Overview: An online visual overview is available for this article.

Postnatal Outcome Following Prenatal Diagnosis of Discordant Atrioventricular and Ventriculoarterial Connections.

Discordant atrioventricular and ventriculoarterial connection(s) (DAVVAC) are a rare group of congenital heart lesions. DAVVAC can be isolated or associated with a variety of other cardiac abnormalities. Previous studies examining the outcome of prenatally diagnosed DAVVAC have described only fetal and early postnatal outcome in small cohorts. We aimed to describe the medium-term outcome of these fetuses. Cases were identified by searching the fetal cardiac databases of two centers. Follow-up data were collected from the electronic patient records. We identified 98 fetuses with DAVVAC. 39 pregnancies were terminated and 51 resulted in a liveborn infant. Postnatal data were available for 43 patients. The median length of follow-up was 9.5 years (range 36 days to 22.7 years). The overall 5-year survival of the cohort was 80% (95% confidence interval 74-86%), no deaths were seen after this period. Associated cardiac lesions had a significant effect on both survival and surgery-free survival. Isolated DAVVAC and DAVVAC with pulmonary stenosis ± ventricular septal defect had a low mortality (89% and 100% 5-year survival, respectively). Poorer survival was seen in the group with Ebstein's anomaly of the tricuspid valve, and other complex cardiac abnormalities. Antenatal tricuspid regurgitation had a significant negative impact on postnatal survival. In conclusion, the short- and medium-term outlook for fetuses with isolated DAVVAC, and those with DAVVAC and pulmonary stenosis are good. Antenatal risk factors for postnatal mortality include Ebstein's anomaly of the tricuspid valve, especially if associated with tricuspid regurgitation, and the presence of complex associated lesions.

Early vascular damage from smoking and alcohol in teenage years: the ALSPAC study.

Aims: To determine the impact of smoking and alcohol exposure during adolescence on arterial stiffness at 17 years. Methods and results: Smoking and alcohol use were assessed by questionnaires at 13, 15, and 17 years in 1266 participants (425 males and 841 females) from the ALSPAC study. Smoking status (smokers and non-smoker) and intensity ('high' ≥100, 'moderate' 20-99, and 'low or never' <20 cigarettes in lifetime) were ascertained. Participants were classified by frequency (low or high) and intensity of drinking [light (LI <2), medium (MI 3-9), and heavy (HI >10 drinks on a typical drinking day)]. Carotid to femoral pulse wave velocity (PWV) was assessed at 17 years [mean ± standard deviation and/or mean difference (95% confidence intervals)]. Current smokers had higher PWV compared with non-smokers (P = 0.003). Higher smoking exposure was associated with higher PWV compared with non-smokers [5.81 ± 0.725 vs. 5.71 ± 0.677 m/s, mean adjusted difference 0.211 (0.087-0.334) m/s, P = 0.001]. Participants who stopped smoking had similar PWV to never smokers (P = 0.160). High-intensity drinkers had increased PWV [HI 5.85 ± 0.8 vs. LI 5.67 ± 0.604 m/s, mean adjusted difference 0.266 (0.055-0.476) m/s, P = 0.013]. There was an additive effect of smoking intensity and alcohol intensity, so that 'high' smokers who were also HI drinkers had higher PWV compared with never-smokers and LI drinkers [mean adjusted increase 0.603 (0.229-0.978) m/s, P = 0.002]. Conclusion: Smoking exposure even at low levels and intensity of alcohol use were associated individually and together with increased arterial stiffness. Public health strategies need to prevent adoption of these habits in adolescence to preserve or restore arterial health.

Hypertension in Coarctation of the Aorta: Challenges in Diagnosis in Children.

Evidence indicates that patients with coarctation of the aorta (COA) suffer from increased cardiovascular morbidity and mortality in later life despite successful repair of COA in childhood. Systolic arterial hypertension is common, presenting in up to one-third of patients, and is regarded as the main driver of premature cardiovascular events in this group of patients. In this review, we discuss the prevalence and pathophysiology of hypertension in children following successful COA repair with no residual arch obstruction. The challenges in accurate blood pressure assessment at this early phase are considered and non-invasive measures of central blood pressure are discussed. Although the pathways for investigations in adults are well defined, we highlight the need to address the issues of cardiovascular surveillance in children and describe techniques which can provide complementary information for cardiovascular assessment in this group of patients such that timely treatment can occur.

Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC).

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is an autosomal-dominant disease with frequency of 1/500 to 1/250 that leads to premature coronary heart disease. New approaches to identify FH mutation-carriers early are needed to prevent premature cardiac deaths. In a cross-sectional study of the Avon Longitudinal Study of Parents and Children (ALSPAC), we evaluated the biochemical thresholds for FH screening in childhood, and modelled a two-stage biochemical and sequencing screening strategy for FH detection. METHODS: From 5083 ALSPAC children with cholesterol measurement at age nine years, FH genetic diagnosis was performed in 1512 individuals, using whole-genome or targeted sequencing of known FH-causing genes. Detection rate (DR) and false-positive rate (FPR) for proposed screening thresholds (total-cholesterol > 1.53, or LDL-C > 1.84 multiples of the median (MoM)) were assessed. RESULTS: Six of 1512 sequenced individuals had an FH-causing mutation of whom five had LDL-C > 1.84 MoM, giving a verification-bias corrected DR of 62.5% (95% CI: 25-92), with a FPR of 0.2% (95% CI: 0.1-0.4). The DR for the TC cut-point of 1.53 MoM was 25% (95% CI: 3.2-65.1) with a FPR of 0.4% (95% CI: 0.2-0.6). We estimated 13 of an expected 20 FH mutation carriers (and 13 of the 20 parental carriers) could be detected for every 10,000 children screened, with false-positives reliably excluded by addition of a next generation sequencing step in biochemical screen-positive samples. CONCLUSIONS: Proposed cholesterol thresholds for childhood FH screening were less accurate than previously estimated. A sequential strategy of biochemical screening followed by targeted sequencing of FH genes in screen-positive children may help mitigate the higher than previously estimated FPR and reduce wasted screening of unaffected parents.

Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased cardiovascular risk. Recent studies suggest that high-density lipoprotein (HDL) may lose its protective vascular phenotype in inflammatory conditions. However, the effects of common anti-inflammatory treatments on HDL function are not yet known. METHODS: We compared the function of HDL in 18 patients with RA and 18 matched healthy controls. Subsequently, patients were randomised to (methotrexate+infliximab (M+I) (5 mg/kg)) or methotrexate+placebo (M+P) infusions for 54 weeks. At week 54 and thereafter, all patients received infliximab therapy until completion of the trial (110 weeks), enabling assessment of the impact of 1 year of infliximab therapy in all patients. HDL functional properties were assessed at baseline, 54 weeks and 110 weeks by measuring the impact on endothelial nitric oxide (NO) bioavailability and superoxide production (SO), paraoxonase activity (PON-1) and cholesterol efflux. RESULTS: All HDL vascular assays were impaired in patients compared with controls. After 54 weeks, NO in response to HDL was significantly greater in patients who received M+I compared with those who received M+P. Endothelial SO in response to HDL was reduced in both groups, but PON-1 and cholesterol efflux remained unchanged. All vascular measures improved compared with baseline after ≥1 infliximab therapy in the analysis at 110 weeks. No significant trend was noted for cholesterol efflux. CONCLUSIONS: HDL function can be improved with anti-inflammatory treatment in patients with RA. The M+I combination was superior to the M+P alone, suggesting that the tumour necrosis factor-α pathway may have a role in HDL vascular properties.

Twenty-year trajectories of alcohol consumption during midlife and atherosclerotic thickening in early old age: findings from two British population cohort studies.

BACKGROUND: Epidemiological evidence indicates a protective effect of light-moderate drinking on cardiovascular disease and an increased risk for heavier drinking. Nevertheless, the effect of alcohol on atherosclerotic changes in vessel walls is disputed. Most previous studies have only looked at the cross-sectional relationship between alcohol and carotid intima media thickness (cIMT) - a surrogate marker of atherosclerosis. Single measurements of alcohol assume that alcohol exposure is stable and ignore the possible cumulative effects of harm, leading to possibly incorrect inferences. METHODS: Data were retrieved from two UK population based cohort studies: the Whitehall II cohort of civil servants and the MRC National Survey of Health and Development (combined sample size of 5403 men and women). Twenty year-drinking trajectories during midlife were linked to measures of cIMT when participants were in early old age, and adjusted for age, sex, socioeconomic position, ethnicity and smoking. RESULTS: Those who consistently drank heavily had an increased cIMT compared to stable moderate drinkers (pooled difference in cIMT 0.021 mm; 95 % CI 0.002 to 0.039), after adjustment for covariates. This was not detected in cross-sectional analyses. Former drinkers also had an increased cIMT compared to moderate drinkers (pooled difference in cIMT 0.021; 95 % CI 0.005 to 0.037). There were no appreciable differences in cIMT between non-drinkers and consistent moderate drinkers. CONCLUSION: The drinking habits among adults during midlife affect the atherosclerotic process and sustained heavy drinking is associated with an increased cIMT compared to stable moderate drinkers. This finding was not seen when only using cross-sectional analyses, thus highlighting the importance of taking a life course approach. There was no evidence of a favourable atherosclerotic profile from stable moderate drinking compared to stable non-drinking.

Targeting myocardial metabolism for the treatment of stable angina.

The goals of pharmacological treatment of stable angina pectoris are to improve quality of life by reducing the severity and/or frequency of symptoms and also the long-term prognosis. Patients with coronary artery disease have viable but dysfunctional myocardium. The metabolism of the ischemic myocardium is characterized by a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Targeting myocardial metabolism as a pharmacologic approach for chronic angina is based on the concept that metabolic adaptive mechanisms during ischemia resemble fetal energy metabolism by shifting substrate use towards glucose metabolism. Potential pharmacologic approaches should target i) the suppression of lipolysis and the plasma fatty acid levels and subsequent uptake and oxidation by the heart, ii) direct inhibition of the enzymes of fatty acid beta-oxidation, iii) inhibition of carnitine palmitoyl transferase- I (CPT-1). Currently, there are no approved medications directly targeting myocardial metabolism. However, in the last two years a number of medications indirectly targeting cardiac metabolism have been tested in small clinical trials, and some of them appear to be promising potential therapies for stable angina. This review summarizes the main aspects of myocardial metabolism and focuses on the therapeutic approaches that could offer clinical benefit in patients with stable angina.

Combined effects of atorvastatin and metformin on glucose-induced variations of inflammatory process in patients with diabetes mellitus.

BACKGROUND: Statin treatment improves survival in patients with atherosclerosis, but their effect on the glucose-induced variations of inflammatory markers, is unknown. We examined the effect of combined therapy with atorvastatin and metformin on glucose-induced variations of inflammatory molecules in patients with newly diagnosed diabetes mellitus type 2 (DM). METHODS: Thirty five subjects with newly diagnosed DM were randomized to receive metformin 850 mg/d (M, n=17) or metformin 850 mg/d+atorvastatin 10mg (n=18). All subjects underwent glucose loading (75 g oral glucose) at baseline and after 12 weeks of treatment. Blood samples were obtained at baseline and 3h post-loading, while serum tumor necrosis factor alpha (TNF-α) levels were determined at baseline and at 3h. RESULTS: Serum TNF-α remained unchanged in metformin at baseline (1.36±0.18 to 1.47±0.21 pg/ml p=NS) and after treatment (1.44±0.71 to 1.31±0.17 pg/ml, p=NS), while it was reduced in metformin+atorvastatin (2.3±0.3 to 2.0±0.4 pg/ml, p=NS at baseline and 1.80±0.2 to 1.65±0.2 pg/ml, p=0.03 after treatment). CONCLUSIONS: Interestingly, the combination of metformin and atorvastatin partly prevents the glucose-loading induced elevation of glucose levels (at 1 h), suggesting a better response to glucose intake than monotherapy with metformin. In addition, combined treatment with atorvastatin and metformin reduces the post-glucose loading levels of TNF-α compared to metformin monotherapy.

Role of NADPH oxidase in endothelial ischemia/reperfusion injury in humans.

BACKGROUND: Reactive oxygen species have been implicated in the pathogenesis of ischemia/reperfusion (IR) injury. Recent studies suggest that NADPH oxidase may be a source of ROS during IR. Using an in vivo model of endothelial IR injury in the arm, we compared the response to IR in healthy volunteers with that in patients with chronic granulomatous disease. These patients have a molecular lesion in a subunit of NADPH oxidase that renders the enzyme inactive. METHODS AND RESULTS: Flow-mediated dilatation was used to assess endothelial function in patients with X-linked (NOX2) or autosomal (p47) chronic granulomatous disease. IR injury was induced by 20 minutes of upper limb ischemia followed by reperfusion. Flow-mediated dilatation was determined before IR and after 20 minutes of reperfusion. The response to IR in chronic granulomatous disease patients was compared with that in age- and sex-matched healthy control subjects. Flow-mediated dilatation was expressed as mean and compared statistically with mixed linear models. IR caused a significant reduction in flow-mediated dilatation in control subjects (-5.1%; 95% confidence interval, 6.3 to 3.%; P<0.001; n=11). IR had no effect on endothelial function in NOX2-chronic granulomatous disease patients (-0.9; 95% confidence interval, -2.1 to 0.3; P=0.12; n=11). Similarly, IR-induced reduction in flow-mediated dilatation was not observed in p47-chronic granulomatous disease patients (-1.5%; 95% confidence interval, -3.1 to 0.2; P=0.08; n=6) in contrast to healthy control subjects (-6.5%; 95% confidence interval, -8.2 to -4.9%; P<0.001; n=6). CONCLUSIONS: These data indicate, for the first time in humans in vivo, that reactive oxygen species produced by NADPH oxidase are determinants of endothelial function after IR injury in humans. These findings have implications for the design of strategies to limit clinical IR injury.

Comparative effects of rosuvastatin and allopurinol on circulating levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (HF) are characterized by alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) levels. However, the impact of hypolipidemic and antioxidant treatment in MMPs and TIMPs is unknown. In the present study, we sought to compare the effects of statins and xanthine oxidase inhibitors on circulating levels of MMPs and TIMPs in patients with chronic HF. METHODS: Forty-two clinically stable patients with mild to moderate HF were randomized to receive rosuvastatin 10 mg or allopurinol 300 mg daily and followed up for 1 month. Serum levels of MMP-2, -9, TIMP-1, and -2 were measured before and after treatment. RESULTS: Levels of MMP-2 and -9 were significantly decreased in the rosuvastatin group (from 251±52 ng/ml and 400±206 ng/ml to 215±47 ng/ml and 309±166 ng/ml, p<0.001 and p<0.05 respectively), but not in the allopurinol group. In the rosuvastatin group, TIMP-2 levels were significantly increased (from 85±17 ng/ml to 93±16 ng/ml, p<0.05), while TIMP-1 remained unchanged. In the allopurinol group, no significant changes were observed regarding the levels of TIMPs. CONCLUSIONS: Short-term rosuvastatin but not allopurinol administration decreases MMP-2 and -9 and increases TIMP-2 levels.

Inflammatory and thrombotic processes are associated with vascular dysfunction in children with familial hypercholesterolemia.

BACKGROUND: Evidence suggests that children with familial hypercholesterolemia (FH) have endothelial dysfunction. Inflammatory and haemostatic abnormalities are associated with advanced atherosclerosis and increased cardiovascular events. However, it is unknown whether these abnormalities present in FH children and contribute to their vascular dysfunction. METHODS AND RESULTS: We studied 38 children with FH (19 males, 19 females aged 14.8+/-0.9 years mean+/-S.E.) and 41 healthy children (controls; 22 males, 19 females aged 15.4+/-0.7 years). Endothelium-dependent reactive hyperemia (RH%) and endothelium-independent nitrate hyperemia dilatation (NH%) were measured by strain gauge plethysmography. Inflammatory and haemostatic parameters were assessed by ELISA. RH% and NH% were significantly reduced in FH compared to controls (91.3+/-9.3% vs. 120.4+/-10.6% and 53.6+/-3.8% vs. 74.5+/-7.4%, p<0.05 for both). Total cholesterol and lipoprotein (a) were increased in FH children compared to controls (282.3+/-8.8 mg/dl vs. 163.8+/-4.6 mg/dl and 11.0[4.6, 30.7]mg/dl vs. 5.24[2.63, 11.0]mg/dl median [IQR] respectively; p<0.001 for both). Intercellular cell adhesion molecule (ICAM-1) and interleukin 1 beta (IL-1 beta) serum levels were increased in FH compared to controls (p<0.05 and <0.001, respectively). Plasminogen activator inhibitor 1 (PAI-1) levels were also higher in FH children (p<0.001). Multivariate analysis revealed that reactive hyperemia was independently associated with nitrate-dependent reactive hyperemia (beta=0.597(0.199), p<0.01), PAI-1(beta=-6.78(2.65), p<0.05), log IL-1 beta (beta=-102.8 (30.2), p<0.01), age (beta=-5.06 (2.35), p<0.05) and FH status (beta=-25.2(10.6), p<0.05) (R(2) for the model: 0.63, p=0.001). CONCLUSIONS: Inflammatory and haemostatic abnormalities are present in FH children and contribute to the endothelial dysfunction observed in these children.

Differences in inflammatory and thrombotic markers between unstable angina and acute myocardial infarction.

BACKGROUND: Unstable coronary syndromes are characterised by increased inflammatory process and endothelial activation. However, the underlying mechanisms of the acute coronary syndromes are still obscure. We evaluated the differences of inflammatory and thrombotic markers, at the acute phase of unstable angina (UA) and acute myocardial infarction (AMI). METHODS: The population of the study consisted of 216 subjects: 136 patients with UA, 57 patients with AMI and 23 healthy controls. Blood samples were taken by their admission to the hospital. Inflammatory and thrombotic markers were measured by ELISA. RESULTS: Patients with UA had significantly higher levels of interleukin-6 (IL-6), soluble vascular cells adhesion molecule (sVCAM-1) and von Willebrand factor (vWF) (p<0.05 vs controls), and lower levels of antithrombin III (ATIII) (p<0.01 vs controls) and protein C (PrtC) (p<0.05 vs controls). Similarly, patients with AMI had higher levels of IL-6, sVCAM-1, vWF and tissue plasminogen activator (tPA) (p<0.01 vs controls) and lower levels of ATIII (p<0.01 vs controls) and prtC (p<005 vs controls). Patients with AMI had significantly higher levels of vWF, tPA and sVCAM-1 compared to UA patients (p<0.05). CONCLUSIONS: Patients with unstable coronary syndromes had increased levels of IL-6, sVCAM-1 and vWF as well as decreased levels of ATIII and PrtC by their admission. However, patients with AMI had higher levels of all the endothelium-derived inflammatory (e.g. sVCAM-1) of thrombotic/fibrinolytic (e.g. tPA and vWF) markers, compared to those with UA. These findings imply that patients with myocardial infarction show further increase of endothelium-derived inflammatory and thrombotic markers compared to patients with unstable angina, in response to a similar proinflammatory stimuli.