Reactive oxygen species, such as superoxide and hydrogen peroxide, are generated in all cells by mitochondrial and enzymatic sources. Left unchecked, these reactive species can cause oxidative damage ...to DNA, proteins, and membrane lipids. Glutathione peroxidase-1 (GPx-1) is an intracellular antioxidant enzyme that enzymatically reduces hydrogen peroxide to water to limit its harmful effects. Certain reactive oxygen species, such as hydrogen peroxide, are also essential for growth factor-mediated signal transduction, mitochondrial function, and maintenance of normal thiol redox-balance. Thus, by limiting hydrogen peroxide accumulation, GPx-1 also modulates these processes. This review explores the molecular mechanisms involved in regulating the expression and function of GPx-1, with an emphasis on the role of GPx-1 in modulating cellular oxidant stress and redox-mediated responses. As a selenocysteine-containing enzyme, GPx-1 expression is subject to unique forms of regulation involving the trace mineral selenium and selenocysteine incorporation during translation. In addition, GPx-1 has been implicated in the development and prevention of many common and complex diseases, including cancer and cardiovascular disease. This review discusses the role of GPx-1 in these diseases and speculates on potential future therapies to harness the beneficial effects of this ubiquitous antioxidant enzyme.
The transcatheter mitral valve interventions (TRAMI) registry was established in order to assess safety and efficacy of catheter-based mitral valve interventional techniques in Germany, and ...prospectively enrolled 828 MitraClip patients (median age 76 years, median log. EuroSCORE I 20.0%) between August 2010 and July 2013. We present the 1-year outcome in this MitraClip cohort-which is the largest published to date.
Seven forty-nine patients (90.5%) were available for 1-year follow-up and included in the following analyses. Mortality, major adverse cardiovascular event rates, and New York Heart Association (NYHA) classes were recorded. Predictors of 1-year mortality were identified by multivariate analysis using a Cox regression model with stepwise forward selection. The 1-year mortality was 20.3%. At 1 year, 63.3% of TRAMI patients pertained to NYHA functional classes I or II (compared with 11.0% at baseline), and self-rated health status (on EuroQuol visual analogue scale) also improved significantly by 10 points. Importantly, a significant proportion of patients regained the complete independence in self-care after MitraClip implantation (independence in 74.0 vs. 58.6% at baseline, P = 0.005). Predictors of 1-year mortality were NYHA class IV (hazard ratio, HR 1.62, P = 0.02), anaemia (HR 2.44, P = 0.02), previous aortic valve intervention (HR 2.12, P = 0.002), serum creatinine ≥1.5 mg/dL (HR 1.77, P = 0.002), peripheral artery disease (HR 2.12, P = 0.0003), left ventricular ejection fraction <30% (HR 1.58, P = 0.01), severe tricuspid regurgitation (HR 1.84, P = 0.003), and procedural failure (defined as operator-reported failure, conversion to surgery, failure of clip placement, or residual post-procedural severe mitral regurgitation) (HR 4.36, P < 0.0001).
Treatment of significant MR with MitraClip resulted in significant clinical improvements in a high proportion of TRAMI patients after 12 months. In the TRAMI cohort, the failure of procedural success exhibited the highest hazard ratio concerning the prediction of 1-year mortality.
Objectives Early identification of myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation. Background The aim of the current ...investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to cardiac troponin in early evaluation of patients with suspected myocardial infarction. Methods Between January 2007 and July 2008, patients with suspected acute coronary syndrome were consecutively enrolled in this multicenter study. Copeptin, troponin T (TnT), myoglobin, and creatine kinase-myocardial band were determined at admission and after 3 and 6 h. Results Of 1,386 (66.4% male) enrolled patients, 299 (21.6%) had the discharge diagnosis of acute myocardial infarction, 184 (13.3%) presented with unstable angina, and in 903 (65.2%) an acute coronary syndrome could be excluded. Combined measurement of copeptin and TnT on admission improved the c-statistic from 0.84 for TnT alone to 0.93 in the overall population and from 0.77 to 0.9 in patients presenting within 3 h after chest pain onset (CPO) (p < 0.001). In this group the combination of copeptin with a conventional TnT provided a negative predictive value of 92.4%. Conclusions In triage of chest pain patients, determination of copeptin in addition to troponin improves diagnostic performance, especially early after CPO. Combined determination of troponin and copeptin provides a remarkable negative predictive value virtually independent of CPO time and therefore aids in early and safe rule-out of myocardial infarction.
Mitral regurgitation (MR) is the most common valvular disease. With a rising incidence in older age, the prevalence of relevant comorbidities inevitably increases. Considering the constantly aging ...population with high surgical risk, transcatheter therapy of MR is gaining increasing importance. Interventional therapy of either primary or secondary MR represents an alternative to pure drug or surgical therapy. With mitral valve transcatheter edge-to-edge repair, a well-established treatment has evolved in the past two decades. In addition, direct or indirect annuloplasty and ultimately transcatheter mitral valve implantation further expand the armamentarium. The current broad spectrum of interventional therapy options allows for patient-oriented therapy individually targeting different MR pathologies. This review discusses the current landscape of transcatheter therapies for relevant MR.
This report relates the authors' ongoing experience with percutaneous left ventricular (LV) unloading by using a transaortic LV assist device in combination with venoarterial extracorporeal membrane ...oxygenation (VA-ECMO) and provides an in-depth analysis of the hemodynamic benefit of this approach.
VA-ECMO is increasingly used in cases of severe cardiogenic shock. However, increase in afterload with subsequent LV overload is a major drawback of VA-ECMO.
Consecutive patients were treated with a transaortic LV assist device in addition to VA-ECMO for cardiogenic shock. The primary endpoint was 30-day all-cause mortality. Additional endpoints included weaning from VA-ECMO and safety endpoints.
Between September 2013 and January 2018, 106 patients were treated with percutaneous LV unloading, using a transaortic LV assist device in combination with VA-ECMO. Successful weaning from VA-ECMO support was achieved in 51.9% of all patients. In the overall cohort, survival at day 30 was 35.8%, which was higher than predicted by the SAVE score (20%) or by the SAPS-II score (6.9%). Right heart catheterization indicated a marked decrease of PCWP after addition of the device to VA-ECMO.
The strategy of percutaneous LV unloading using a transaortic LV assist device in combination with VA-ECMO improved outcome in an all-comers cohort compared to established risk scores. A prospective, randomized study is needed to further investigate this approach.
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Aims
We sought to evaluate the impact of pulmonary hypertension on outcomes following MitraClip therapy.
Methods and results
The 643 patients in the TRAnscatheter Mitral valve Interventions (TRAMI) ...registry were divided into three groups according to echocardiographically graded systolic pulmonary artery pressure (sPAP) (Group 1: patients with sPAP of ≤36 mmHg; Group 2: patients with sPAP of 37–50 mmHg; Group 3: patients with sPAP of >50 mmHg) and followed for 1 year. Recent cardiac decompensation, aortic valve disease and tricuspid valve insufficiency were observed more frequently in patients with higher sPAP. Furthermore, logEuroSCORE, Society of Thoracic Surgeons score and age were higher with rising sPAP values. No differences were observed in mitral regurgitation (MR) severity, co‐morbidities or clinical findings (New York Heart Association class, 6‐min walking distance). Reduction to MR of grade 1 or lower was achieved more often in patients with lower sPAP levels (P = 0.01). In Groups 2 and 3, sPAP was reduced significantly. Major adverse cardiac or cardiovascular events (MACCEs) occurring in hospital (death, myocardial infarction, stroke; <4% in each group), as well as 30‐day rates of MACCEs (6.1% in Group 1, 11.9% in Group 2, 12.4% in Group 3) and rehospitalization (18.9% in Group 1, 24.8% in Group 2, 24.8% in Group 3) did not differ significantly. At 1 year, differences in rates of mortality and MACCEs (20.3% in Group 1, 33.1% in Group 2, 34.7% in Group 3; P < 0.01) were significant. Both Groups 2 hazard ratio (HR) 1.81, P = 0.0122 and 3 (HR 1.85, P = 0.0092) were independently predictive of death. Rehospitalization rates did not differ during follow‐up.
Conclusions
Despite higher mortality in patients with elevated sPAP, these data suggest the safety, feasibility and benefit of MitraClip therapy even in advanced stages of disease. An early approach might prevent the progress of pulmonary hypertension and improve outcomes.
Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial ...infarction.
In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission.
For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve AUC, 0.96), as compared with the troponin T assay (AUC, 0.85) and traditional myocardial necrosis markers. With the use of the sensitive troponin I assay (cutoff value, 0.04 ng per milliliter) on admission, the clinical sensitivity was 90.7%, and the specificity was 90.2%. The diagnostic accuracy was virtually identical in baseline and serial samples, regardless of the time of chest-pain onset. In patients presenting within 3 hours after chest-pain onset, a single sensitive troponin I assay had a negative predictive value of 84.1% and a positive predictive value of 86.7%; these findings predicted a 30% rise in the troponin I level within 6 hours. A troponin I level of more than 0.04 ng per milliliter was independently associated with an increased risk of an adverse outcome at 30 days (hazard ratio, 1.96; 95% confidence interval, 1.27 to 3.05; P=0.003).
The use of a sensitive assay for troponin I improves early diagnosis of acute myocardial infarction and risk stratification, regardless of the time of chest-pain onset.
Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits ...and have a critical role in physiological and disease processes.
To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself.
This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.
Recently, we demonstrated that gene ablation of mitochondrial manganese superoxide dismutase and aldehyde dehydrogenase-2 markedly contributed to age-related vascular dysfunction and mitochondrial ...oxidative stress. The present study has sought to investigate the extent of vascular dysfunction and oxidant formation in glutathione peroxidase-1-deficient (GPx-1(-/-)) mice during the aging process with special emphasis on dysregulation (uncoupling) of the endothelial NO synthase. GPx-1(-/-) mice on a C57 black 6 (C57BL/6) background at 2, 6, and 12 months of age were used. Vascular function was significantly impaired in 12-month-old GPx-1(-/-) -mice as compared with age-matched controls. Oxidant formation, detected by 3-nitrotyrosine staining and dihydroethidine-based fluorescence microtopography, was increased in the aged GPx-1(-/-) mice. Aging per se caused a substantial protein kinase C- and protein tyrosine kinase-dependent phosphorylation as well as S-glutathionylation of endothelial NO synthase associated with uncoupling, a phenomenon that was more pronounced in aged GPx-1(-/-) mice. GPx-1 ablation increased adhesion of leukocytes to cultured endothelial cells and CD68 and F4/80 staining in cardiac tissue. Aged GPx-1(-/-) mice displayed increased oxidant formation as compared with their wild-type littermates, triggering redox-signaling pathways associated with endothelial NO synthase dysfunction and uncoupling. Thus, our data demonstrate that aging leads to decreased NO bioavailability because of endothelial NO synthase dysfunction and uncoupling of the enzyme leading to endothelial dysfunction, vascular remodeling, and promotion of adhesion and infiltration of leukocytes into cardiovascular tissue, all of which was more prominent in aged GPx-1(-/-) mice.
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