Cardiac fibrosis as a predictor for sudden cardiac death after transcatheter aortic valve implantation.

BACKGROUND: Cardiac fibrosis plays a major pathophysiological role in any form of chronic heart disease, and high levels are associated with poor outcome. Diffuse and focal cardiac fibrosis are different subtypes, which have different pathomechanisms and prognostic implications. The total fibrosis burden in endomyocardial biopsy tissue was recently proved to play an independent prognostic role in aortic stenosis patients after transcatheter aortic valve implantation (TAVI). AIMS: Here, for the first time, we aim to assess the specific impact of different fibrosis subtypes on sudden cardiac death (SCD) as a primary reason for cardiovascular mortality after TAVI. METHODS: The fibrosis pattern was assessed histologically in the left ventricular biopsies obtained during TAVI interventions in 161 patients, who received a structured follow-up thereafter. RESULTS: Receiver operating characteristic analyses, performed 6, 12, 24 and 48 months after TAVI, showed diffuse, but not focal, fibrosis as a significant predictor for SCD at all timepoints, with the highest area under the curve at the first time point and a decrease in its SCD predictivity over time. In both multivariate Cox proportional hazards and Fine-Gray competing risk models, including both fibrosis subtypes, as well as age, sex and ejection fraction, high diffuse fibrosis remained statistically significant. Accordingly, it represents an independent SCD predictor, most importantly for the occurrence of early events. CONCLUSIONS: The burden of diffuse cardiac fibrosis plays an important and independent prognostic role regarding SCD early after TAVI. Therefore, the histological evaluation of fibrosis topography has value as a prognostic tool for TAVI patients and may help to tailor individualised approaches to optimise their postinterventional management.

Prevalence of second victims, risk factors and support strategies among young German physicians in internal medicine (SeViD-I survey).

BACKGROUND: Second victims, defined as healthcare team members being traumatised by an unanticipated clinical event or outcome, are frequent in healthcare. Evidence of this phenomenon in Germany, however, is sparse. Recently, we reported the first construction and validation of a German questionnaire. This study aimed to understand this phenomenon better in a sample of young (<= 35 years) German physicians. METHODS: The electronic questionnaire (SeViD-I survey) was administered for 6 weeks to a sample of young physicians in training for internal medicine or a subspecialty. All physicians were members of the German Society of Internal Medicine. The questionnaire had three domains - general experience, symptoms, and support strategies - comprising 46 items. Binary logistic regression models were applied to study the influence of various independent factors on the risk of becoming a second victim, the magnitude of symptoms and the time to self-perceived recovery. RESULTS: The response rate was 18% (555/3047). 65% of the participants were female, the mean age was 32 years. 59% experienced second victim incidents in their career so far and 35% during the past 12 months. Events with patient harm and unexpected patient deaths or suicides were the most frequent key incidents. 12% of the participants reported that their self-perceived time to full recovery was more than 1 year or have never recovered. Being female was a risk factor for being a second victim (odds ratio (OR) 2.5) and experiencing a high symptom load (OR 2). Working in acute care was promoting a shorter duration to self-perceived recovery (OR 0.5). Support measures with an exceptionally high approval among second victims were the possibility to discuss emotional and ethical issues, prompt debriefing/crisis intervention after the incident and a safe opportunity to contribute insights to prevent similar events in the future. CONCLUSION: The second victim phenomenon is frequent among young German physicians in internal medicine. In general, these traumatic events have a potentially high impact on physician health and the care they deliver. A better understanding of second victim traumatisations in Germany and broad implementation of effective support programs are warranted.

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

AIMS: Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes. METHODS AND RESULTS: One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson's trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01]. CONCLUSION: Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

Genotype-Phenotype Association and Impact on Outcomes following Guided De-Escalation of Anti-Platelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Genotyping Substudy.

BACKGROUND: Phenotype-guided de-escalation (PGDE) of P2Y12-inhibitor treatment with an early switch from prasugrel to clopidogrel was identified as an effective alternative treatment strategy in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). The Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Genotyping Substudy aimed to investigate whether CYP2C19 genotypes correlate with on-treatment platelet reactivity (PR) in ACS patients treated with clopidogrel or prasugrel and thus might be useful for guidance of early de-escalation of anti-platelet treatment. METHODS AND RESULTS: A total of 603 ACS consecutive patients were enrolled in four centres (23.1% of the overall TROPICAL-ACS population). Rapid genotyping (Spartan RX) for CYP2C19*2, *3 and *17 alleles was performed. Associations between PR and the primary and secondary endpoints of the TROPICAL-ACS trial and CYP2C19*2 and CYP2C19*17 carrier status were evaluated.For the PGDE group, the on-clopidogrel PR significantly differed across CYP2C19*2 (p < 0.001) and CYP2C19*17 genotypes (p = 0.05). Control group patients were not related (p = 0.90, p = 0.74) to on-prasugrel PR. For high PR versus non-high PR patients within the PGDE group, significant differences were observed for the rate of CYP2C19*2 allele carriers (43% vs. 28%, p = 0.007). CONCLUSION: CYP2C19*2 and CYP2C19*17 carrier status correlates with PR in ACS patients treated with clopidogrel and thus might be useful for pre-selecting patients who will and who may not be suitable for PGDE of anti-platelet treatment. Regarding phenotype-guided treatment, we did not observe added benefit of genotyping to predict ischaemic and bleeding risk in patients who underwent a PGDE approach. CLINICAL TRIAL REGISTRATION: URL: https//www.clinicaltrials.gov. Unique Identifier: NCT: 01959451.

[Work and Training Conditions of Young German Physicians in Internal Medicine - Results of a Second Nationwide Survey by Young Internists from the German Society of Internal Medicine and the German Professional Association of Internists.] / Arbeits- und Weiterbildungsbedingungen deutscher Assistenzärztinnen und -ärzte in internistischer Weiterbildung: eine zweite bundesweite Befragung durch die Nachwuchsgruppen von DGIM und BDI.

BACKGROUND: Medical specialty training is the basis for career development of young internists and it is vital for the delivery of high-quality medical care. In 2014 the young internists of two professional bodies in Germany conducted a survey among their young members and described major factors influencing training and working conditions. We present the results of a follow-up survey to describe changes of these factors over time. An additional focus is set on the difficulties of balancing medical career and family. METHODS: In the end of 2016 we conducted an online-based survey of all members in training of the German Society of Internal Medicine (DGIM) and the Professional Association of German Internists (BDI). The questionnaire used in the 2014 survey was modified and items investigating the balance between career and family were added. RESULTS: A total of 1587 questionnaires were returned and analysed. Mayor findings did not change over time. Psychosocial strain remains very high among medical trainees in internal medicine. A structured training curriculum and meaningful feedback are associated with lower psychosocial strain and higher work satisfaction. Internists - and here especially women - with children experience the daily balance of medical career and family as extremely challenging. CONCLUSION: These results demonstrate that there is still a serious need for adjusting training and working conditions of young internists in Germany. Especially the role and increasing importance of female physicians has to be recognized by enabling a successful integration of medical career and family.

Low-flow/low-gradient aortic stenosis-Still a diagnostic and therapeutic challenge.

Aortic stenosis (AS) is the most frequently observed valvular heart disease. During the symptomatic stage, the rate of death increases dramatically, so that a precise diagnostic approach is taken to guide therapeutic options. Of patients with severe AS, 30% to 50% present with low-flow/low-gradient AS (LF/LGAS) status. This review focuses on LF/LGAS and the best diagnostic and therapeutic management in either classic LF/LGAS with reduced left ventricular ejection fraction (LVEF) or paradoxical LF/LGAS with preserved LVEF. Current literature demonstrates that in classic LF/LGAS it is crucial to rule out a pseudo-severe AS, because reduced LVEF may result in an incomplete opening of the valve. This can be done by low-dose dobutamine stress echocardiography. Classic LF/LGAS has poor clinical outcomes when managed conservatively; therefore, surgical or interventional aortic valve replacement should be performed. In paradoxical LF/LGAS, the LVEF is preserved (>50%), but impaired filling of the concentric hypertrophied ventricle leads to reduced stroke volume. Therefore, diagnostic and therapeutic decisions in paradoxical LF/LGAS are even more challenging. It is a heterogeneous disease entity, and it is crucial to rule out any diagnostic errors because numerous potential confounders might lead to misdiagnosis. As in classic stenosis, pseudo-severe stenosis must be ruled out as well. Evaluation via multidetector computed tomography or transesophageal echocardiography can help to evaluate the morphologic alterations of the valve (eg, calcification). Further studies are necessary to understand this disease entity and to evaluate the optimal diagnostic and therapeutic approach for these patients.

Cigarette smoke exposure during pregnancy alters fetomaternal cell trafficking leading to retention of microchimeric cells in the maternal lung.

Cigarette smoke exposure causes chronic oxidative lung damage. During pregnancy, fetal microchimeric cells traffic to the mother. Their numbers are increased at the site of acute injury. We hypothesized that milder chronic diffuse smoke injury would attract fetal cells to maternal lungs. We used a green-fluorescent-protein (GFP) mouse model to study the effects of cigarette smoke exposure on fetomaternal cell trafficking. Wild-type female mice were exposed to cigarette smoke for about 4 weeks and bred with homozygote GFP males. Cigarette smoke exposure continued until lungs were harvested and analyzed. Exposure to cigarette smoke led to macrophage accumulation in the maternal lung and significantly lower fetal weights. Cigarette smoke exposure influenced fetomaternal cell trafficking. It was associated with retention of GFP-positive fetal cells in the maternal lung and a significant reduction of fetal cells in maternal livers at gestational day 18, when fetomaternal cell trafficking peaks in the mouse model. Cells quickly clear postpartum, leaving only a few, difficult to detect, persisting microchimeric cells behind. In our study, we confirmed the postpartum clearance of cells in the maternal lungs, with no significant difference in both groups. We conclude that in the mouse model, cigarette smoke exposure during pregnancy leads to a retention of fetal microchimeric cells in the maternal lung, the site of injury. Further studies will be needed to elucidate the effect of cigarette smoke exposure on the phenotypic characteristics and function of these fetal microchimeric cells, and confirm its course in cigarette smoke exposure in humans.