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Key Points Infective endocarditis (IE) is a major challenge for clinicians and a considerable burden for health-care systems In high-income countries over the past 5 decades, patients have been contracting IE at an increasingly old age, and the incidence of health-care-associated staphylococcal IE has risen An improved understanding of the mechanisms of vegetation formation, growth, and embolization will help to combat microbial resistance IE after transfemoral aortic valve implantation in elderly patients can be aggravated by immunosenescence Many factors that increase mortality in patients with IE have been identified, which will help to optimize treatment Mortality risk increases substantially when patients with IE develop septic shock Infection of the endocardium or prosthetic surfaces in the heart, if ineffectively treated, is associated with severe complications and a high mortality. In this Review, Karl Werdan and colleagues summarize the pathogen–host interactions and mechanisms of increased risk in patients with infective endocarditis, including immunosenescence in elderly patients, and the transition from local infection to systemic sepsis and shock. Patients with infective endocarditis (IE) form a heterogeneous group, ranging from those who are successfully treated with no adverse events, to those with severe complications and a high mortality. In this Review, we highlight pathogen–host interactions and the mechanisms underlying various risk factors for patients with IE. A temporal trend in the pattern of IE has been observed in high-income countries within the past 5 decades, with patients contracting IE at an increasingly old age, and a growing incidence of health-care-associated staphylococcal IE. Consequently, prevention strategies should no longer focus on prophylaxis of streptococcal bacteraemia during dental procedures, but instead encourage a more-general approach to reduce the incidence of health-care-associated IE. Much knowledge has been gained about the mechanisms of vegetation formation, growth, and embolization on damaged or inflamed cardiac valves, and on cardiac devices. Improved understanding of these mechanisms will help to combat the increasing problem of antimicrobial resistance. Two mechanisms of IE should increasingly be the focus of future research: the role of immunosenescence in elderly patients with IE, particularly after transcatheter aortic valve implantation, and the mechanisms that trigger septic shock, a condition that leads to a substantial increase in the risk of death in patients with IE.

In this trial, patients with acute MI and cardiogenic shock who were expected to undergo coronary revascularization were randomly assigned to receive or not to receive intraaortic balloon support. Balloon support had no effect on 30-day mortality. The rate of death among patients with cardiogenic shock complicating acute myocardial infarction is high even when the patients undergo early revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). 1 – 4 Intraaortic balloon counterpulsation is the most widely used form of mechanical hemodynamic support in this clinical setting. 5 In U.S. and European guidelines, the use of an intraaortic balloon in the treatment of cardiogenic shock is given a class IB and class IC recommendation, respectively. 6 – 8 However, evidence is based mainly on registry data, and there is a lack of adequately powered randomized trials. A meta-analysis that . . .

In current international guidelines the recommendation for intra-aortic balloon pump (IABP) use has been downgraded in cardiogenic shock complicating acute myocardial infarction on the basis of registry data. In the largest randomised trial (IABP-SHOCK II), IABP support did not reduce 30 day mortality compared with control. However, previous trials in cardiogenic shock showed a mortality benefit only at extended follow-up. The present analysis therefore reports 6 and 12 month results. The IABP-SHOCK II trial was a randomised, open-label, multicentre trial. Patients with cardiogenic shock complicating acute myocardial infarction who were undergoing early revascularisation and optimum medical therapy were randomly assigned (1:1) to IABP versus control via a central web-based system. The primary efficacy endpoint was 30 day all-cause mortality, but 6 and 12 month follow-up was done in addition to quality-of-life assessment for all survivors with the Euroqol-5D questionnaire. A masked central committee adjudicated clinical outcomes. Patients and investigators were not masked to treatment allocation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00491036. Between June 16, 2009, and March 3, 2012, 600 patients were assigned to IABP (n=301) or control (n=299). Of 595 patients completing 12 month follow-up, 155 (52%) of 299 patients in the IABP group and 152 (51%) of 296 patients in the control group had died (relative risk [RR] 1·01, 95% CI 0·86–1·18, p=0·91). There were no significant differences in reinfarction (RR 2·60, 95% CI 0·95–7·10, p=0·05), recurrent revascularisation (0·91, 0·58–1·41, p=0·77), or stroke (1·50, 0·25–8·84, p=1·00). For survivors, quality-of-life measures including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression did not differ significantly between study groups. In patients undergoing early revascularisation for myocardial infarction complicated by cardiogenic shock, IABP did not reduce 12 month all-cause mortality. German Research Foundation; German Heart Research Foundation; German Cardiac Society; Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte; University of Leipzig—Heart Centre; Maquet Cardiopulmonary; Teleflex Medical.

Purpose This study aimed to concisely describe the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to extracorporeal membrane oxygenation (ECMO). Methods Narrative review based on a systematic analysis of the medical literature, national and international guidelines, and expert opinion. Results The use of venovenous ECMO (VV-ECMO) is increasing in the most severe forms of acute lung injury. In patients with cardiogenic shock, short-term veno-arterial ECMO (VA-ECMO) provides both pulmonary and circulatory support. Technological improvements and recently published studies suggest that ECMO is able to improve patients’ outcomes. There are, however, many uncertainties regarding the real benefits of this technique both in hemodynamic and respiratory failure, the territorial organization to deliver ECMO, the indications and the use of concomitant treatments. Conclusions Although there have been considerable advances regarding the use of ECMO in critically ill patients, the risk/benefit ratio remains underinvestigated. ECMO indications, organization of ECMO delivery, and use of adjuvant therapeutics need also to be explored. Ongoing and future studies may be able to resolve these issues.

BackgroundReports about the influence of the COVID-19 pandemic on the number of hospital admissions and in-hospital mortality during the first wave between March and May 2020 showed conflicting results and are limited by single-center or limited regional multicenter datasets. Aim of this analysis covering all German federal states was the comprehensive description of hospital admissions and in-hospital mortality during the first wave of the COVID-19 pandemic.Methods and resultsWe conducted an observational study on hospital routine data (§21 KHEntgG) and included patients with the main diagnosis of acute myocardial infarction (ICD 21 and ICD 22). A total of 159 hospitals included 36,329 patients in the database, with 12,497 patients admitted with ST-elevation myocardial infarction (STEMI) and 23,832 admitted with non-ST-elevation myocardial infarction (NSTEMI). There was a significant reduction in the number of patients admitted with STEMI (3748 in 2020, 4263 in 2019 and 4486 in 2018; p < 0.01) and NSTEMI (6957 in 2020, 8437 in 2019 and 8438 in 2020; p < 0.01). These reductions were different between the Federal states of Germany. Percutaneous coronary intervention was performed more often in 2020 than in 2019 (odds ratio 1.13, 95% confidence interval [CI] 1.06–1.21) and 2018 (odds ratio 1.20, 95% CI 1.12–1.29) in NSTEMI and more often than in 2018 (odds ratio 1.26, 95% CI 1.10–1.43) in STEMI. The in-hospital mortality did not differ between the years for STEMI and NSTEMI, respectively.ConclusionsIn this large representative sample size of hospitals in Germany, we observed significantly fewer admissions for NSTEMI and STEMI during the first COVID-19 wave, while quality of in-hospital care and in-hospital mortality were not affected.Admissions for STEMI and NSTEMI during the months March to May over 3 years and corresponding in-hospital mortality for patients with STEMI and NSTEMI in 159 German hospitals. (p-value for admissions 2020 versus 2019 and 2018: < 0.01; p-value for mortality: n.s.)

Monocytes and macrophages contribute to pathogenesis of various inflammatory diseases, including auto-inflammatory diseases, cancer, sepsis, or atherosclerosis. They do so by production of cytokines, the central regulators of inflammation. Isoprenylation of small G-proteins is involved in regulation of production of some cytokines. Statins possibly affect isoprenylation-dependent cytokine production of monocytes and macrophages differentially. Thus, we compared statin-dependent cytokine production of lipopolysaccharide (LPS)-stimulated freshly isolated human monocytes and macrophages derived from monocytes by overnight differentiation. Stimulated monocytes readily produced tumor necrosis factor-α, interleukin-6, and interleukin-1β. Statins did not alter cytokine production of LPS-stimulated monocytes. In contrast, monocyte-derived macrophages prepared in the absence of statin lost the capacity to produce cytokines, whereas macrophages prepared in the presence of statin still produced cytokines. The cells expressed indistinguishable nuclear factor-kB activity, suggesting involvement of separate, statin-dependent regulation pathways. The presence of statin was necessary during the differentiation phase of the macrophages, indicating that retainment-of-function rather than costimulation was involved. Reconstitution with mevalonic acid, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate blocked the retainment effect, whereas reconstitution of cholesterol synthesis by squalene did not. Inhibition of geranylgeranylation by GGTI-298, but not inhibition of farnesylation or cholesterol synthesis, mimicked the retainment effect of the statin. Inhibition of Rac1 activation by the Rac1/TIAM1-inhibitor NSC23766 or by Rac1-siRNA (small interfering RNA) blocked the retainment effect. Consistent with this finding, macrophages differentiated in the presence of statin expressed enhanced Rac1-GTP-levels. In line with the above hypothesis that monocytes and macrophages are differentially regulated by statins, the CD14/CD16-, merTK-, CX 3 CR1-, or CD163-expression (M2-macrophage-related) correlated inversely to the cytokine production. Thus, monocytes and macrophages display differential Rac1-geranylgeranylation-dependent functional capacities, that is, statins sway monocytes and macrophages differentially.

Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti‐inflammatory capacities, in addition to their lipid‐lowering effects. We investigated the anti‐inflammatory effect of statins in the cytokine‐mediated‐interaction‐model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis‐related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over‐additive) IL‐6 (interleukin‐6) production as measured in ELISA. Recombinant IL‐1, tumour necrosis factor‐α and IL‐6 mediated the synergistic IL‐6 production. The standard anti‐inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL‐6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL‐6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL‐6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL‐6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL‐6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti‐inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine‐mediated innate inflammatory pathways in the vessel wall.

The CARLA study (Cardiovascular Disease, Living and Ageing in Halle) is a longitudinal population-based cohort study of the general population of the city of Halle (Saale), Germany. The primary aim of the cohort was to investigate risk factors for cardiovascular diseases based on comprehensive cardiological phenotyping of study participants and was extended to study factors associated with healthy ageing. In total, 1779 probands (812 women and 967 men, aged 45–83 years) were examined at baseline (2002–2005), with a first and second follow-up performed 4 and 8 years later. The response proportion at baseline was 64.1% and the reparticipation proportion for the first and second follow-up was 86% and 77% respectively. Sixty-four percent of the study participants were in retirement while 25% were full-or partially-employed and 11% were unemployed at the time of the baseline examination. The currently running third follow-up focuses on the assessment of physical and mental health, with an intensive 4 h examination program, including measurement of cardiovascular, neurocognitive, balance and gait parameters. The data collected in the CARLA Study resulted in answering various research questions in over 80 publications, of which two thirds were pooled analyses with other similar population-based studies. Due to the extensiveness of information on risk factors, subclinical conditions and evident diseases, the biobanking concept for the biosamples, the cohort representativeness of an elderly population, and the high level of quality assurance, the CARLA cohort offers a unique platform for further research on important indicators for healthy ageing.

Chronic heart failure (CHF) is one of the most important public health concerns in the industrialized world having increasing incidence and prevalence. Although there are several studies describing the prevalence of heart failure with reduced ejection fraction (HFREF) and heart failure with normal ejection fraction (HFNEF) in selected populations, there are few data regarding the prevalence and the determinants of symptomatic heart failure in the general population. Cross-sectional data of a population-based German sample (1,779 subjects aged 45-83 years) were analyzed to determine the prevalence and determinants of chronic SHF and HFNEF defined according to the European Society of Cardiology using symptoms, echocardiography and serum NT-proBNP. Prevalence was age-standardized to the German population as of December 31st, 2005. The overall age-standardized prevalence of symptomatic CHF was 7.7% (95%CI 6.0-9.8) for men and 9.0% (95%CI 7.0-11.5) for women. The prevalence of CHF strongly increased with age from 3.0% among 45-54- year-old subjects to 22.0% among 75-83- year-old subjects. Symptomatic HFREF could be shown in 48% (n = 78), symptomatic HFNEF in 52% (n = 85) of subjects with CHF. The age-standardized prevalence of HFREF was 3.8 % (95%CI 2.4-5.8) for women and 4.6 % (95%CI 3.6-6.3) for men. The age-standardized prevalence of HFNEF for women and men was 5.1 % (95%CI 3.8-7.0) and 3.0 % (95%CI 2.1-4.5), respectively. Persons with CHF were more likely to have hypertension (PR = 3.4; 95%CI 1.6-7.3) or to have had a previous myocardial infarction (PR = 2.5, 95%CI 1.8-3.5). The prevalence of symptomatic CHF appears high in this population compared with other studies. While more women were affected by HFNEF than men, more male subjects suffered from HFREF. The high prevalence of symptomatic CHF seems likely to be mainly due to the high prevalence of cardiovascular risk factors in this population.

Background The IABP-SHOCK-trial was a morbidity-based randomized controlled trial in patients with infarction-related cardiogenic shock (CS), which used the change of the quantified degree of multiorgan failure as determined by APACHE II score over a 4-day period as primary outcome measure. The prospective hypothesis was that adding IABP therapy to “standard care” would improve CS-triggered multi organ dysfunction syndrome (MODS). The primary endpoint showed no difference between conventionally managed cardiogenic shock patients and those with IABP support. In an inflammatory marker substudy, we analysed the prognostic value of interleukin (IL)-1β, -6, -7, -8, and -10 in patients with acute myocardial infarction complicated by cardiogenic shock. Design Inflammatory marker substudy of the prospective, randomized, controlled, open label IABP-SHOCK-trial (Clinical-Trials-gov-ID-NCT00469248). Setting and methods A single-center study was performed in a 12-bed Intensive-Care-Unit in an university hospital in which 40 consecutive patients were enrolled with an observational period of 96 h. Results The pro- and anti-inflammatory markers IL-6, -7, -8 and -10 showed a predictive power for mortality of infarct-related CS patients, while IL-1β did not discriminate. The maximal values during the observational period, in case of IL-7 the minimal value, showed the best power to predict mortality. Both, ROC and multivariate analyses confirmed these suggestions (area under the curve: IL-8, 0.80 ± 0.08; IL-6, 0.79 ± 0.08; IL-10, 0.76 ± 0.08; IL-7, 0.69 ± 0.08). Inflammatory markers were not affected by the presence of IABP support. Conclusion The inflammatory response in patients with myocardial infarction complicated by cardiogenic shock, as reflected by the inflammatory markers IL-6, IL-7, IL-8 and IL-10, demonstrates a clinically relevant prognostic contribution to clinical outcome.