Apolipoproteins C-I, C-II, C-III and E have been associated with risk of arterial thrombotic diseases. We investigated whether these apolipoproteins have prothrombotic properties and are associated ...with risk of venous thromboembolism (VTE).
A total of 127 VTE patients and 299 controls were randomly selected from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study (1999-2004), in the Netherlands. The apolipoproteins were quantified using mass spectrometry (LC/MS/MS), and their levels were analyzed as continuous variable (per SD increase).
In controls, increases in levels of apolipoproteins were associated with increases in levels of vitamin K-dependent factors, factor XI, antithrombin and clot lysis time. Additionally, increasing apolipoproteins C-III and E levels were associated with higher factor VIII and von Willebrand factor levels. Levels of C-reactive protein were not associated with any apolipoprotein. The age- and sex-adjusted odds ratios of apolipoproteins E, C-III, CII and CI to the risk of venous thrombosis were 1.21 (95% CI, 0.98-1.49), 1.19 (95% CI, 0.99-1.44), 1.24 (95% CI, 0.95-1.61) and 1.06 (95% CI, 0.87-1.30) per SD increase, respectively. These odds ratios did not attenuate after adjustments for statin use, estrogen use, BMI, alcohol use, and self-reported diabetes.
Levels of apolipoproteins C-I, C-II, C-III and E are associated with those of several coagulation factors. However, whether these apolipoproteins are also associated with an increased risk of VTE remains to be established.
Apelin, a potent vasodilator and angiogenic factor, may be a novel therapeutic agent in neonatal chronic lung disease, including bronchopulmonary dysplasia.
To determine the beneficial effect of ...apelin in neonatal rats with hyperoxia-induced lung injury, a model for premature infants with bronchopulmonary dysplasia.
The cardiopulmonary effects of apelin treatment (62 μg/kg/d) were studied in neonatal rats by exposure to 100% oxygen, using two treatment strategies: early concurrent treatment during continuous exposure to hyperoxia for 10 days and late treatment and recovery in which treatment was started on Day 6 after hyperoxic injury for 9 days and continued during the 9-day recovery period. We investigated in both models the role of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in apelin treatment by specific inhibition of the nitric oxide synthase activity with N(ω)-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg/d).
Parameters investigated include survival, lung and heart histopathology, pulmonary fibrin deposition and inflammation, alveolar vascular leakage, lung cGMP levels, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue. Prophylactic treatment with apelin improved alveolarization and angiogenesis, increased lung cGMP levels, and reduced pulmonary fibrin deposition, inflammation, septum thickness, arteriolar wall thickness, and right ventricular hypertrophy. These beneficial effects were completely absent in the presence of L-NAME. In the injury-recovery model apelin also improved alveolarization and angiogenesis, reduced arteriolar wall thickness, and attenuated right ventricular hypertrophy.
Apelin reduces pulmonary inflammation, fibrin deposition, and right ventricular hypertrophy, and partially restores alveolarization in rat pups with neonatal hyperoxic lung injury via a nitric oxide synthase-dependent mechanism.
Nitric oxide (NO) produced in the heart by nitric oxide synthase (NOS) is a highly reactive signaling molecule and an important modulator of myocardial function. NOS catalyzes the conversion of
l
...-arginine to
l
-citrulline and NO but under particular circumstances reactive oxygen species (ROS) can be formed instead of NO (uncoupling). In the heart, three NOS isoforms are present: neuronal NOS (nNOS, NOS1) and endothelial NOS (eNOS, NOS3) are constitutively present enzymes in distinct subcellular locations within cardiomyocytes, whereas inducible NOS (iNOS, NOS2) is absent in the healthy heart, but its expression is induced by pro-inflammatory mediators. In the tissue, NO has two main effects: (i) NO stimulates the activity of guanylate cyclase, leading to cGMP generation and activation of protein kinase G, and (ii) NO nitrosylates tyrosine and thiol-groups of cysteine in proteins. Upon nitrosylation, proteins may change their properties. Changes in (i) NOS expression and activity, (ii) subcellular compartmentation of NOS activity, and (iii) the occurrence of uncoupling may lead to multiple NO-induced effects, some of which being particularly evident during myocardial overload as occurs during aortic constriction and myocardial infarction. Many of these NO-induced effects are considered to be cardioprotective but particularly if NOS becomes uncoupled, formation of ROS in combination with a low NO bioavailability predisposes for cardiac damage.
Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD), a chronic lung disease in very preterm infants who were ...mechanically ventilated for respiratory distress syndrome.
Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50-150 mg/kg body weight/day; injected subcutaneously) and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue.
Prophylactic treatment with an optimal dose of sildenafil (2 x 50 mg/kg/day) significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH).
Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary inflammatory response, fibrin deposition and RVH, and stimulates alveolarization. Initiation of sildenafil treatment after hyperoxic lung injury and continued during room air recovery improves alveolarization and restores pulmonary angiogenesis and RVH in experimental BPD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Serum troponin within the normal range is an emerging predictor of cardiovascular mortality. We aimed to determine how rapidly high‐sensitivity troponin‐I (hs‐cTnI) levels are lowered by statin ...therapy in patients with stable cardiovascular disease. In the RADAR substudy, patients were randomized to atorvastatin 20 mg/day (n = 39) or rosuvastatin 10 mg/day (n = 39) and up‐titrated at 6‐week intervals to 80 mg of atorvastatin or 40 mg of rosuvastatin. Hs‐cTnI concentrations were measured at baseline and at 6 and 18 weeks of follow‐up. Statin treatment resulted in a mean change of serum hs‐cTnI of –8.2% (P = 0.010) after 6 weeks and –12.3% (P = 0.001) after 18 weeks. After 18 weeks, hs‐cTnI levels were lowered by 21.8% with atorvastatin and by 4.1% with rosuvastatin (P = 0.001 and P = 0.133, respectively). During statin therapy, serum hs‐cTnI levels decreased rapidly within weeks of treatment, suggesting an effect beyond long‐term atherosclerosis regression. Mechanisms that mediate this effect require further study.
The clinical use of advanced imaging modalities for early determination of infarct size and prognosis is limited. As a specific indicator of myocardial necrosis, cardiac troponin T (cTnT) can be used ...as a surrogate measure for this purpose. The present study sought to investigate the use of peak and serial 6-hour fixed-time high-sensitive (hs) cTnT for estimation of infarct size, left ventricular (LV) function, and prognosis in consecutive patients with ST-segment elevation myocardial infarction. The infarct size was expressed as the 48-hour cumulative creatine kinase release. LV function at 3 months was assessed using the echocardiographic wall motion score index and LV ejection fraction using radionuclide ventriculography. Adverse outcomes, comprising all-cause death, implantable cardioverter-defibrillator implantation, or hospitalization for heart failure, were recorded at 1 year of follow-up. In 188 patients, the peak and all fixed-time values correlated significantly with the 48-hour cumulative creatine kinase release, wall motion score index, and LV ejection fraction. The hs-cTnT value at 24 hours demonstrated the greatest correlation (r = 0.86, r = 0.47, and r = −0.59, respectively; p <0.001 for all). In the multivariate regression models adjusted for the clinical parameters, almost all were independently associated with the 48-hour cumulative creatine kinase release, wall motion score index, and LV ejection fraction, with the hs-cTnT value at 24 hours having the largest effect. Moreover, all cTnT values independently predicted adverse outcomes, again, with the hs-cTnT value at 24 hours showing the largest influence (hazard ratio 3.77, 95% confidence interval 2.12 to 6.73, p <0.001). In conclusion, not only peak, but all fixed-time hs-cTnT values were associated with infarct size, LV function at 3 months, and adverse outcomes 1 year after ST-segment elevation myocardial infarction. The value 24 hours after the onset of symptoms had the closest associations with all outcomes. Therefore, serial sampling for a peak value might be redundant.
In persons with dyslipidemia, a high residual risk of cardiovascular disease remains despite lipid lowering therapy. Current cardiovascular risk prediction mainly focuses on low-density lipoprotein ...cholesterol (LDL-c) levels, neglecting other contributing risk factors. Moreover, the efficacy of LDL-c lowering by statins resulting in reduced cardiovascular risk is only partially effective. Secondly, from a metrological viewpoint LDL-c falls short as a reliable measurand. Both direct and calculated LDL-c tests produce inaccurate test results at the low end under aggressive lipid lowering therapy. As LDL-c tests underperform both clinically and metrologically, there is an urging need for molecularly defined biomarkers. Over the years, apolipoproteins have emerged as promising biomarkers in the context of cardiovascular disease as they are the functional workhorses in lipid metabolism. Among these, apolipoprotein B (ApoB), present on all atherogenic lipoprotein particles, has demonstrated to clinically outperform LDL-c. Other apolipoproteins, such as Apo(a) - the characteristic apolipoprotein of the emerging risk factor lipoprotein(a) -, and ApoC-III - an inhibitor of triglyceride-rich lipoprotein clearance -, have attracted attention as well. To support personalized medicine, we need to move to molecularly defined risk markers, like the apolipoproteins. Molecularly defined diagnosis and molecularly targeted therapy require molecularly measured biomarkers. This review provides a summary of the scientific validity and (patho)physiological role of nine serum apolipoproteins, Apo(a), ApoB, ApoC-I, ApoC-II, ApoC-III, ApoE and its phenotypes, ApoA-I, ApoA-II, and ApoA-IV, in lipid metabolism, their association with cardiovascular disease, and their potential as cardiovascular risk markers when measured in a multiplex apolipoprotein panel.
Abstract Background In chronic heart failure (CHF), persistent autonomic derangement and neurohumoral activation cause structural end-organ damage, decrease exercise capacity, and reduce quality of ...life. Beneficial effects of pharmacotherapy and of exercise training in CHF have been documented at various functional and structural levels. However, pharmacologic treatment can not yet reduce autonomic derangement and neurohumoral activation in CHF to a minimum. Various studies suggest that exercise training is effective in this respect. Methods and Results After reviewing the available evidence we conclude that exercise training increases baroreflex sensitivity and heart rate variability, and reduces sympathetic outflow, plasma levels of catecholamines, angiotensin II, vasopressin, and brain natriuretic peptides at rest. Conclusions Exercise training has direct and reflex sympathoinhibitory beneficial effects in CHF. The mechanism by which exercise training normalizes autonomic derangement and neurohumoral activation is to elucidate for further development of CHF-related training programs aimed at maximizing efficacy while minimizing workload.
Introduction
The current way to assess the risk of cardiovascular disease (CVD) is to measure conventional lipid and lipoprotein cholesterol fractions. Despite the success of statin treatment, ...residual cardiovascular risk remains high. Therefore, the value of extensive serum apolipoprotein (apo) profiling to assess the risk of ST-segment elevation myocardial infarction (STEMI) and of major adverse cardiac events (MACE) in patients with STEMI was investigated in a case–control design.
Methods and results
Serum apo levels were measured using liquid chromatography and mass spectrometry in 299 healthy individuals and 220 patients with STEMI. First, the association of apo profiles in baseline samples with risk of STEMI was examined, and second, the association of apo profiles at baseline with risk of recurrent MACE in patients with STEMI in a longitudinal study design was studied. High baseline (> 1.25 g/L) apoA1 levels were associated with a decreased risk of STEMI odds ratio (OR) 0.17; 95% CI 0.11–0.26, whereas high apoB (> 1.00 g/L) levels (OR 2.17; 95% CI 1.40–3.36) and apoB/apoA1 ratio (OR per 1 SD (OR/SD): 2.16; 95% CI 1.76–2.65) were associated with an increased risk. Very-low-density-lipoprotein (VLDL)-associated apos gave conflicting results. Neither conventional lipid levels nor apo levels were associated with MACE in the STEMI group.
Conclusion
In conclusion, apoA1, apoB, and apoB/apoA1 were strongly associated with risk of STEMI. No clear relation between VLDL-associated apos and the risk of STEMI was found. Neither baseline serum apos nor lipids predicted MACE in statin-treated patients during long-term follow-up after a first STEMI.
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