Inflammatory Markers and Incident Heart Failure Risk in Older Adults: The Health, Aging, and Body Composition Study

Background: Inflammation is associated with heart failure (HF) risk factors and also directly affects myocardial function. However, the association between inflammation and HF risk in older adults has not been adequately evaluated. Methods: The association of baseline serum concentrations of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF- ), and C-reactive protein (CRP) with incident HF was assessed with Cox proportional hazards models among 2610 older persons without prevalent HF enrolled in the Health, Aging, and Body Composition (Health ABC) Study (age, 73.6±2.9 years; 48.3% men; 59.6% white). Results: Median (interquartile range) baseline concentrations of IL-6, TNF- , and CRP were 1.80 (1.23, 2.76) pg/mL, 3.14 (2.41, 4.06) pg/mL, and 1.64 (0.99, 3.04) µg/mL, respectively. On follow-up (median, 9.4 years), 311 participants (11.9%) developed HF. In models controlling for clinical predictors of HF and incident coronary heart disease, doubling of IL-6, TNF- , and CRP concentrations was associated with 34% (95% CI, 18 -52%; P<.001), 33% (95% CI, 9 - 63%; P=.006), and 13% (95% CI, 3-24%; P=.01) increase in HF risk, respectively. In models including all 3 markers, IL-6 and TNF- , but not CRP, remained significant. Findings were similar across sex and race. Post-HF ejection fraction (EF) was available in 239 (76.8%) cases. When only cases with preserved EF were considered (n=105), IL-6 (HR per doubling, 1.57; 95% CI, 1.28 -1.94; P<.001), TNF- (HR per doubling, 1.59; 95% CI, 1.12-2.26; P=.01), and CRP (HR per doubling, 1.23; 95% CI, 1.05-1.44; P=.01) were all associated with HF risk in adjusted models. In contrast, when only cases with reduced EF (n=134) were considered, only IL-6 attained marginal significance in adjusted models (HR per doubling, 1.20; 95% CI, 0.99 -1.46; P=.06). Participants with 2 or 3 markers above median had pronounced HF risk in adjusted models (HR, 1.66; 95% CI, 1.12-2.46; P=.01; and HR, 1.76; 95% CI, 1.16 -2.65; P=.007, respectively). Addition of IL-6 to the clinical Health ABC HF model improved discrimination (C index from 0.717 to 0.734; P=.001) and fit (decreased Bayes information criterion by 17.8; P<.001). Conclusions: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.

Improved prediction of coronary heart disease with markers of atherosclerosis and of inflammation in older adults?

Background: Several markers of atherosclerosis and of inflammation have been shown to predict coronary heart disease (CHD) individually. However, the utility of markers of atherosclerosis and of inflammation on prediction of CHD over traditional risk factors has not been well established, especially in the elderly. Methods: We studied 2202 men and women, aged 70-79, without baseline cardiovascular disease over 6-year follow-up to assess the risk of incident CHD associated with baseline noninvasive measures of atherosclerosis (ankle-arm index [AAI], aortic pulse wave velocity [aPWV]) and inflammatory markers (interleukin-6 [IL-6], C-reactive protein [CRP], tumor necrosis factor-a [TNF-a]). CHD events were studied as either nonfatal myocardial infarction or coronary death ("hard" events), and "hard" events plus hospitalization for angina, or the need for coronary-revascularization procedures (total CHD events). Results: During the 6-year follow-up, 283 participants had CHD events (including 136 "hard" events). IL-6, TNF-a and AAI independently predicted CHD events above Framingham Risk Score (FRS) with hazard ratios [HR] for the highest as compared with the lowest quartile for IL-6 of 1.95 (95%CI: 1.38-2.75, p for trend <0.001), TNF-a of 1.45 (95%CI: 1.04-2.02, p for trend 0.03), of 1.66 (95%CI: 1.19-2.31) for AAI 0.9, as compared to AAI 1.01-1.30. CRP and aPWV were not independently associated with CHD events. Results were similar for "hard" CHD events. Addition of IL-6 and AAI to traditional cardiovascular risk factors yielded the greatest improvement in the prediction of CHD; C-index for "hard"/total CHD events increased from 0.62/0.62 for traditional risk factors to 0.64/0.64 for IL-6 addition, 0.65/0.63 for AAI, and 0.66/0.64 for IL-6 combined with AAI. Being in the highest quartile of IL-6 combined with an AAI 0.90 or >1.40 yielded an HR of 2.51 (1.50-4.19) and 4.55 (1.65-12.50) above FRS, respectively. With use of CHD risk categories, risk prediction at 5 years was more accurate in models that included IL-6, AAI or both, with 8.0, 8.3 and 12.1% correctly reclassified, respectively. Conclusions: Among older adults, markers of atherosclerosis and of inflammation, particularly IL-6 and AAI, are independently associated with CHD. However, these markers only modestly improve cardiovascular risk prediction beyond traditional risk factors.

Prevention of the renarrowing of coronary arteries using drug-eluting stents in the perioperative period: an update.

The management of patients scheduled for surgery with a coronary stent, and receiving 1 or more antiplatelet drugs, has many controversies. The premature discontinuation of antiplatelet drugs substantially increases the risk of stent thrombosis (ST), myocardial infarction, and cardiac death, and surgery under an altered platelet function could also lead to an increased risk of bleeding in the perioperative period. Because of the conflict in the recommendations, this article reviews the current antiplatelet protocols after positioning a coronary stent, the evidence of increased risk of ST associated with the withdrawal of antiplatelet drugs and increased bleeding risk associated with its maintenance, the different perioperative antiplatelet protocols when patients are scheduled for surgery or need an urgent operation, and the therapeutic options if excessive bleeding occurs.

On-pump beating heart coronary surgery for high risk patients requiring emergency multiple coronary artery bypass grafting.

BACKGROUND: Cardiopulmonary bypass (CPB) with aortic cross-clamping and cardioplegic arrest remains the method of choice for patients requiring standard myocardial revascularization. Therefore, very high-risk patients presenting with acute coronary syndrome, unstable angina, onset of cardiac decompensation and requiring emergency multiple myocardial revascularization, can have a poor outcome. The on-pump beating heart technique can reduce the mortality and the morbidity in such a selected group of patients and this report describes our clinical experience. METHODS: Out of 290 patients operated for CABG from January 2005 to January 2006, 25 (8.6%) selected high-risk patients suffering from life threatening coronary syndrome (mean age 69 +/- 7 years) and requiring emergency multiple myocardial revascularization, underwent on-pump beating heart surgery. The mean pre-operative left ventricle ejection fraction (LVEF) was 27 +/- 8%. The majority of them (88%) suffered of tri-vessel coronary disease and 6 (24%) had a left main stump disease. Nine patients (35%) were on severe cardiac failure and seven among them (28%) received a pre-operative intra-aortic balloon pump. The pre-operative EuroScore rate was equal or above 8 in 18 patients (73%). RESULTS: All patients underwent on-pump-beating heart coronary revascularization. The mean number of graft/patient was 2.9 +/- 0.6 and the internal mammary artery was used in 23 patients (92%). The mean CPB time was 84 +/- 19 minutes. Two patients died during the recovery stay in the intensive care unit, and there were no postoperative myocardial infarctions between the survivors. Eight patients suffered of transitorily renal failure and 1 patient developed a sternal wound infection. The mean hospital stay was 12 +/- 7 days. The follow-up was complete for all 23 patients survived at surgery and the mean follow-up time was 14 +/- 5 months. One patient died during the follow-up for cardiac arrest and 2 patients required an implantable cardiac defibrillator. One year after surgery they all had a standard trans-thoracic echocardiogram showing a mean LVEF rate of 36 +/- 11.8%. CONCLUSION: Standard on-pump arrested heart coronary surgery has higher mortality and morbidity in emergencies. The on-pump beating heart myocardial revascularization seems to be a valid alternative for the restricted and selected cohort of patients suffering from life threatening coronary syndrome and requiring multiple emergency CABG.

Fungal whip beats the heart.

A 24-year-old man was admitted to the hospital because of fever, cough, and dyspnea of 4 weeks’ duration. The patient gave a history of parenteral drug abuse since he was 17 years old and had been diagnosed with HIV infection 4 years before admission. A chest radiograph showed multiple alveolar infiltrates. Four blood cultures were positive for Candida albicans.

Role of the paclitaxel-eluting stent and tirofiban in patients with ST-elevation myocardial infarction undergoing postfibrinolysis angioplasty: the GRACIA-3 randomized clinical trial.

BACKGROUND A catheter-based approach after fibrinolysis is recommended if fibrinolysis is likely to be successful in patients with acute ST-elevation myocardial infarction. We designed a 2x2 randomized, open-label, multicenter trial to evaluate the efficacy and safety of the paclitaxel-eluting stent and tirofiban administered after fibrinolysis but before catheterization to optimize the results of this reperfusion strategy. METHODS AND RESULTS We randomly assigned 436 patients with acute ST-elevation myocardial infarction to (1) bare-metal stent without tirofiban, (2) bare-metal stent with tirofiban, (3) paclitaxel-eluting stent without tirofiban, and (4) paclitaxel-eluting stent with tirofiban. All patients were initially treated with tenecteplase and enoxaparin. Tirofiban was started 120 minutes after tenecteplase in those patients randomly assigned to tirofiban. Cardiac catheterization was performed within the first 3 to 12 hours after inclusion, and stenting (randomized paclitaxel or bare stent) was applied to the culprit artery. The primary objectives were the rate of in-segment binary restenosis of paclitaxel-eluting stent compared with that of bare-metal stent and the effect of tirofiban on epicardial and myocardial flow before and after mechanical revascularization. At 12 months, in-segment binary restenosis was similar between paclitaxel-eluting stent and bare-metal stent (10.1% versus 11.3%; relative risk, 1.06; 95% confidence interval, 0.74 to 1.52; P=0.89). However, late lumen loss (0.04+/-0.055 mm versus 0.27+/-0.057 mm, P=0.003) was reduced in the paclitaxel-eluting stent group. No evidence was found of any association between the use of tirofiban and any improvement in the epicardial and myocardial perfusion. Major bleeding was observed in 6.1% of patients receiving tirofiban and in 2.7% of patients not receiving it (relative risk, 2.22; 95% confidence interval, 0.86 to 5.73; P=0.14). CONCLUSIONS This trial does not provide evidence to support the use of tirofiban after fibrinolysis to improve epicardial and myocardial perfusion. Compared with bare-metal stent, paclitaxel-eluting stent significantly reduced late loss but appeared not to reduce in-segment binary restenosis. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT00306228.

Consumption of fried foods and risk of coronary heart disease: Spanish cohort of the European Prospective Investigation into Cancer and Nutrition study.

OBJECTIVE To assess the association between consumption of fried foods and risk of coronary heart disease. DESIGN Prospective cohort study. SETTING Spanish cohort of the European Prospective Investigation into Cancer and Nutrition. PARTICIPANTS 40 757 adults aged 29-69 and free of coronary heart disease at baseline (1992-6), followed up until 2004. MAIN OUTCOME MEASURES Coronary heart disease events and vital status identified by record linkage with hospital discharge registers, population based registers of myocardial infarction, and mortality registers. RESULTS During a median follow-up of 11 years, 606 coronary heart disease events and 1135 deaths from all causes occurred. Compared with being in the first (lowest) quarter of fried food consumption, the multivariate hazard ratio of coronary heart disease in the second quarter was 1.15 (95% confidence interval 0.91 to 1.45), in the third quarter was 1.07 (0.83 to 1.38), and in the fourth quarter was 1.08 (0.82 to 1.43; P for trend 0.74). The results did not vary between those who used olive oil for frying and those who used sunflower oil. Likewise, no association was observed between fried food consumption and all cause mortality: multivariate hazard ratio for the highest versus the lowest quarter of fried food consumption was 0.93 (95% confidence interval 0.77 to 1.14; P for trend 0.98). CONCLUSION In Spain, a Mediterranean country where olive or sunflower oil is used for frying, the consumption of fried foods was not associated with coronary heart disease or with all cause mortality.

An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation.

RATIONALE: Lymphatic vasculature plays important roles in tissue fluid homeostasis maintenance and in the pathology of human diseases. Yet, the molecular mechanisms that control lymphatic vessel maturation remain largely unknown. OBJECTIVE: We analyzed the gene expression profiles of ex vivo isolated lymphatic endothelial cells to identify novel lymphatic vessel expressed genes and we investigated the role of semaphorin 3A (Sema3A) and neuropilin-1 (Nrp-1) in lymphatic vessel maturation and function. METHODS AND RESULTS: Lymphatic and blood vascular endothelial cells from mouse intestine were isolated using fluorescence-activated cell sorting, and transcriptional profiling was performed. We found that the axonal guidance molecules Sema3A and Sema3D were highly expressed by lymphatic vessels. Importantly, we found that the semaphorin receptor Nrp-1 is expressed on the perivascular cells of the collecting lymphatic vessels. Treatment of mice in utero (E12.5-E16.5) with an antibody that blocks Sema3A binding to Nrp-1 but not with an antibody that blocks VEGF-A binding to Nrp-1 resulted in a complex phenotype of impaired lymphatic vessel function, enhanced perivascular cell coverage, and abnormal lymphatic vessel and valve morphology. CONCLUSIONS: Together, these results reveal an unanticipated role of Sema3A-Nrp-1 signaling in the maturation of the lymphatic vascular network likely via regulating the perivascular cell coverage of the vessels thus affecting lymphatic vessel function and lymphatic valve development.

Integrating postoperative value of cardiac Troponin I for a better correlation with in-hospital outcomes after congenital heart surgery.

Objective: Cardiac Troponin-I (cTnI) is a well-recognized early postoperative marker for myocardial damage in adults and children after heart surgery. The present study was undertaken to evaluate whether the integrated value (area under the curve(AUC)) of postoperative cTnI is a better mode to predict long-term outcome than post operative cTnI maximum value, after surgery for congenital heart defects (CHD). Methods: retrospective cohort study. 279 patients (mean age 4.6 years; range 0-17 years-old, 185 males) with congenital heart defect repair on cardiopulmonary by-pass were retrieved from our database including postoperative cTnI values. Maximal post operative cTnI value, post operative cTnI AUC value at 48h and total post operative cTnI AUC value were calculated and then correlated with duration of intubation, duration of ICU stay and mortality. Results: the mean duration of mechanical ventilation was 5.1+/-7.2 days and mean duration of ICU stay was 11.0+/- 13.3 days,11 patients (3.9%) died in post operative period. When comparing survivor and deceased groups, there was a significant difference in the mean value for max cTnI (16.7+/- 21.8 vs 59.2+/-41.4 mcg/l, p+0.0001), 48h AUC cTnI (82.0+/-110.7 vs 268.8+/-497.7 mcg/l, p+0.0001) and total AUC cTnI (623.8+/-1216.7 vs 2564+/-2826.0, p+0.0001). Analyses for duration of mechanical ventilation and duration of ICU stay by linear regression demonstrated a better correlation for 48h AUC cTnI (ventilation time r+0.82, p+0.0001 and ICU stay r+0.74, p+0.0001) then total AUC cTnI (ventilation time r+0.65, p+0.0001 and ICU stay r+0.60, p+0.0001) and max cTnI (ventilation time r+0.64, p+0.0001 and ICU stay r+0.60, p+0.0001). Conclusion: Cardiac Troponin I is a specific and sensitive marker of myocardial injury after congenital heart surgery and it may predict early in-hospital outcomes. Integration of post operative value of cTnI by calculation of AUC improves prediction of early in-hospital outcomes. It probably takes into account, not only the initial surgical procedure, but probably also incorporates the occurrence of hypoxic-ischemic phenomena in the post-operative period.

A key role of TRPC channels in the regulation of electromechanical activity of the developing heart.

Aims It is well established that dysfunction of voltage-dependent ion channels results in arrhythmias and conduction disturbances in the foetal and adult heart. However, the involvement of voltage-insensitive cationic TRPC (transient receptor potential canonical) channels remains unclear. We assessed the hypothesis that TRPC channels play a crucial role in the spontaneous activity of the developing heart.Methods and results TRPC isoforms were investigated in isolated hearts obtained from 4-day-old chick embryos. Using RT-PCR, western blotting and co-immunoprecipitation, we report for the first time that TRPC1, 3, 4, 5, 6, and 7 isoforms are expressed at the mRNA and protein levels and that they can form a macromolecular complex with the alpha 1C subunit of the L-type voltage-gated calcium channel (Cav1.2) in atria and ventricle. Using ex vivo electrocardiograms, electrograms of isolated atria and ventricle and ventricular mechanograms, we found that inhibition of TRPC channels by SKF-96365 leads to negative chrono-, dromo-, and inotropic effects, prolongs the QT interval, and provokes first-and second-degree atrioventricular blocks. Pyr3, a specific antagonist of TRPC3, affected essentially atrioventricular conduction. On the other hand, specific blockade of the L-type calcium channel with nifedipine rapidly stopped ventricular contractile activity without affecting rhythmic electrical activity.Conclusions These results give new insights into the key role that TRPC channels, via interaction with the Cav1.2 channel, play in regulation of cardiac pacemaking, conduction, ventricular activity, and contractility during cardiogenesis.

The L162V polymorphism of the PPARA gene is associated with stage C of heart failure.

In human heart failure (HF) peroxisome proliferator-activated receptor alpha (PPAR alpha) is downregulated and consequently, the expression of genes involved in fatty acid oxidation repressed. The L162V (rs1800206) is a functional polymorphism of the human PPAR alpha gene (PPARA). In the present study we have investigated whether this polymorphism is associated with the development of stage C of HF.

Short-term therapy with simvastatin reduces inflammatory mediators and heart inflammation during the acute phase of experimental Chagas disease

Trypanosoma cruzi infection induces progressive cardiac inflammation that leads to fibrosis and modifications in the heart architecture and functionality. Statins, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have been studied due to their pleiotropic roles in modulating the inflammatory response. Our goal was to evaluate the effects of simvastatin on the cardiac inflammatory process using a cardiotropic strain of T. cruzi in a murine model of Chagas cardiomyopathy. C57BL/6 mice were infected with 500 trypomastigotes of the Colombian strain of T. cruzi and treated with an oral dose of simvastatin (20 mg/Kg/day) for one month and inflammatory and morphometric parameters were subsequently evaluated in the serum and in the heart, respectively. Simvastatin reduced the total cholesterol and inflammatory mediators (interferon-gamma, tumour necrosis factor-alpha, CCL2 and CCL5) in the serum and in the heart tissue at 30 days post-infection. Additionally, a proportional reduction in heart weight and inflammatory infiltration was observed. Simvastatin also reduced epimastigote proliferation in a dose-dependent manner in vitro and was able to reduce blood trypomastigotes and heart amastigote nests during the acute phase of Chagas disease in vivo. Based on these data, we conclude that simvastatin exerts a modulatory effect on the inflammatory mediators that are elicited by the Colombian strain of T. cruzi and ameliorates the heart damage that is observed in a murine model of Chagas disease.

Controls on ostracod valve geochemistry, Part 1: Variations of environmental parameters in ostracod (micro-)habitats

The variations of environmental conditions (T°, pH, δ13CDIC, [DIC], δ18O, Mg/Ca, and Sr/Ca) of ostracod habitats were examined to determine the controls of environmental parameters on the chemical and isotopic composition of ostracod valves. Results of a one-year monitoring of environmental parameters at five sites, with depths of between 2 and 70 m, in Lake Geneva indicate that in littoral to sub-littoral zones (2, 5, and 13 m), the chemical composition of bottom water varies seasonally in concert with changes in temperature and photosynthetic activity. An increase of temperature and photosynthetic activity leads to an increase in δ13C values of DIC and to precipitation of authigenic calcite, which results in a concomitant increase of Mg/Ca and Sr/Ca ratios of water. In deeper sites (33 and 70 m), the composition of bottom water remains constant throughout the year and isotopic values and trace element contents are similar to those of deep water within the lake. The chemical composition of interstitial pore water also does not reflect seasonal variations but is controlled by calcite dissolution, aerobic respiration, anaerobic respiration with reduction of sulphate and/or nitrate, and methanogenesis that may occur in the sediment pores. Relative influence of each of these factors on the pore water geochemistry depends on sediment thickness and texture, oxygen content in bottom as well as pore water. Variations of chemical compositions of the ostracod valves of this study vary according to the specific ecology of the ostracod species analysed, that is its life-cycle and its (micro-)habitat. Littoral species have compositions that are related to the seasonal variations of temperature, δ13C values of DIC, and of Mg/Ca and Sr/Ca ratios of water. In contrast, the compositions of profundal species are largely controlled by variations of pore fluids along sediment depth profiles according to the specific depth preference of the species. The control on the geochemistry of sub-littoral species is a combination of controls for the littoral and profundal species as well as the specific ecology of the species.