Search

Hypertrophic cardiomyopathy (HCM) is a complex myocardial disorder with no well-established disease-modifying therapy so far. Our study aimed to investigate how autophagy, oxidative stress, inflammation, stress signalling pathways, and apoptosis are hallmark of HCM and their contribution to the cardiac dysfunction. Demembranated cardiomyocytes from patients with HCM display increased titin-based stiffness (Fpassive), which was corrected upon antioxidant treatment. Titin as a main determinant of Fpassive was S-glutathionylated and highly ubiquitinated in HCM patients. This was associated with a shift in the balance of reduced and oxidized forms of glutathione (GSH and GSSG, respectively). Both heat shock proteins (HSP27 and α-s crystalline) were upregulated and S-glutathionylated in HCM. Administration of HSPs in vitro significantly reduced HCM cardiomyocyte stiffness. High levels of the phosphorylated monomeric superoxide anion-generating endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO) bioavailability, decreased soluble guanylyl cyclase (sGC) activity, and high levels of 3-nitrotyrosine were observed in HCM. Many regulators of signal transduction pathways that are involved in autophagy, apoptosis, cardiac contractility, and growth including the mitogen-activated protein kinase (MAPK), protein kinase B (AKT), glycogen synthase kinase 3s (GSK-3s), mammalian target of rapamycin (mTOR), forkhead box O transcription factor (FOXO), c-Jun N-terminal protein kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) were modified in HCM. The apoptotic factors cathepsin, procaspase 3, procaspase 9 and caspase 12, but not caspase 9, were elevated in HCM hearts and associated with increased proinflammatory cytokines (Interleukin 6 (IL-6), interleukin 18 (IL-18), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), the Toll-like receptors 2 (TLR2) and the Toll-like receptors 4 (TLR4)) and oxidative stress (3-nitrotyrosine and hydrogen peroxide (H2O2)). Here we reveal stress signalling and impaired PQS as potential mechanisms underlying the HCM phenotype. Our data suggest that reducing oxidative stress can be a viable therapeutic approach to attenuating the severity of cardiac dysfunction in heart failure and potentially in HCM and prevent its progression.

BACKGROUND/OBJECTIVES Platelet-activating factor receptor (PAFR) activation controls adipose tissue (AT) expansion in animal models. Our objective was twofold: (i) to check whether PAFR signaling is involved in human obesity and (ii) investigate the PAF pathway role in hematopoietic or non-hematopoietic cells to control adipocyte size. MATERIALS/SUBJECTS AND METHODS Clinical parameters and adipose tissue gene expression were evaluated in subjects with obesity. Bone marrow (BM) transplantation from wild-type (WT) or PAFR-/- mice was performed to obtain chimeric PAFR-deficient mice predominantly in hematopoietic or non-hematopoietic-derived cells. A high carbohydrate diet (HC) was used to induce AT remodeling and evaluate in which cell compartment PAFR signaling modulates it. Also, 3T3-L1 cells were treated with PAF to evaluate fat accumulation and the expression of genes related to it. RESULTS PAFR expression in omental AT from humans with obesity was negatively correlated to different corpulence parameters and more expressed in the stromal vascular fraction than adipocytes. Total PAFR-/- increased adiposity compared with WT independent of diet-induced obesity. Differently, WT mice receiving PAFR-/--BM exhibited similar adiposity gain as WT chimeras. PAFR-/- mice receiving WT-BM showed comparable augmentation in adiposity as total PAFR-/- mice, demonstrating that PAFR signaling modulates adipose tissue expansion through non-hematopoietic cells. Indeed, the PAF treatment in 3T3-L1 adipocytes reduced fat accumulation and expression of adipogenic genes. CONCLUSIONS Therefore, decreased PAFR signaling may favor an AT accumulation in humans and animal models. Importantly, PAFR signaling, mainly in non-hematopoietic cells, especially in adipocytes, appears to play a significant role in regulating diet-induced AT expansion.

Background Thrombi and spontaneous echo contrast (SEC) in the left atrial appendage (LAA) are associated with thromboembolic events and poor prognosis. There are very few data on long-term outcome, especially with the use of direct acting anticoagulants (DOAC). Methods In this retrospective study, all transoesophageal echocardiographies performed at a tertiary care university hospital from 2015 to 2020 were analyzed. All patients with thrombus or SEC in the LAA were included. Medical history, laboratory, echocardiographic parameters and medication at discharge were documented. The primary endpoint of the study was a composite endpoint (all-cause mortality, non-fatal stroke or transient ischaemic attack [TIA], non-fatal systemic embolization, non-fatal major bleeding and non-fatal myocardial infarction). Results Of a total of 4062 transoesophageal echocardiographies, thrombi were detected in 51 patients (1.2%) and SEC in 251 patients (6.2%). These patients formed the final study cohort (n = 302). During a mean follow-up period of 956 ± 663 days, 87 patients (29%) suffered the primary point. The following baseline characteristics predicted the primary endpoint: age, haemoglobin, a previous coronary artery bypass grafting, dialysis and choice of anticoagulation. Prescription of apixaban at discharge was associated with lower rate of adverse events (hazard ratio 0.564, confidence interval 0.331–0.960; p = 0.035) while prescription of dabigatran was associated with higher rate of adverse events (hazard ratio 3.091, confidence interval 1.506–6.347; p = 0.002). Conclusion Even in the DOAC era, the occurrence of thrombus or SEC in the LAA is associated with a high rate of MACCE. Our study suggests that the choice of DOAC therapy may have an impact on long-term survival. Graphic abstract

The prevalence of aortic valve stenosis is increasing due to the continuously growing geriatric population. Data on procedural success and mortality of very old patients are sparse, raising the question of when this population may be deemed as "too old even for transcatheter aortic valve replacement (TAVR)." We, therefore, sought to evaluate the influence of age on outcome after TAVR and the impact of direct implantation.The data of 394 consecutive patients undergoing TF-TAVR were analyzed. Patients were divided into four age groups: ≤75 (group 1, n = 28), 76-80 (group 2, n = 107), 81-85 (group 3, n = 148), and85 (group 4, n = 111) years. Direct implantation was performed when possible according to current recommendations. Survival was evaluated by Kaplan-Meier analysis.Mortality at 30 days and 1 year was not significantly different between the four age groups (3.6 vs. 6.7 vs. 5.4 vs. 2.7% and 7.6 vs. 17 vs. 14.5 vs. 13%m respectively, log-rank p = 0.59). Direct implantation without balloon aortic valvuloplasty was more frequently performed on patients aged85 vs. ≤85 years (33.3 vs. 14.1%, p 0.001). the incidence of procedural complications frequently associated with advanced age (stroke, vascular complications) was not significantly increased in group 4.Outcome after TF-TAVR is comparable among different age cohorts, even in very old patients. Direct implantation simplifies the procedure and could therefore play a role in reducing the incidence of peri-interventional complications in patients of advanced age.HINTERGRUND: Die Prävalenz der Aortenklappenstenose steigt durch eine kontinuierlich wachsende geriatrische Bevölkerung. Daten über prozeduralen Erfolg sowie Mortalität von sehr alten Patienten sind gering, sodass sich die Frage stellt, wann diese Population „als bereits zu alt“ für einen Transkatheter-Aortenklappenersatz (TAVR) anzusehen wäre. Ziel dieser Studie war es, den Einfluss der direkten Implantation auf die Ergebnisse nach transfemoraler (TF-)TAVR bei Patienten in fortgeschrittenem Alter zu evaluieren.Dazu wurden die Daten von 394 konsekutiven Patienten nach TF-TAVR ermittelt. Die Patienten wurden in 4 Altersgruppen eingeteilt: ≤75 Jahre (Gruppe 1, n = 28), 76–80 Jahre (Gruppe 2, n = 107), 81–85 Jahre (Gruppe 3, n = 148) und85 Jahre (Gruppe 4, n = 111). Sofern es die aktuellen Empfehlungen erlaubten, wurde eine direkte Implantation durchgeführt. Das Überleben wurde mittels Kaplan–Meier-Analyse evaluiert.Zwischen den 4 Altersgruppen waren keine signifikanten Unterschiede der Mortalität nach 30 Tagen und nach einem Jahr zu verzeichnen (entsprechend 3,6 vs. 6,7 vs. 5,4 vs. 2,7 % und 7,6 vs. 17 vs. 14,5 vs. 13 %; p = 0,59 für Log-Rank-Test). Eine direkte Implantation ohne Ballonvalvuloplastie wurde bei Patienten85 Jahre häufiger durchgeführt als ≤85 Jahre (33,3 vs. 14,1 %; p 0,001). Die Inzidenz von häufig mit fortgeschrittenem Patientenalter assoziierten prozeduralen Komplikationen (Schlaganfall, vaskuläre Komplikationen) war in der Gruppe 4 nicht signifikant erhöht.In verschiedenen Alterskollektiven zeigen sich vergleichbare Ergebnisse nach TF-TAVR, dies gilt sogar für Patienten sehr hohen Alters. Die direkte Implantation kann die Prozedur vereinfachen und zu einer konsekutiven Reduktion der Inzidenz von periprozeduralen Komplikationen bei Patienten mit fortgeschrittenem Alter führen.

The complex physiological signal transduction networks that respond to the dual challenges of inflammatory and oxidative stress are major factors that promote the development of cardiovascular pathologies. These signaling networks contribute to the development of age-related diseases, suggesting crosstalk between the development of aging and cardiovascular disease. Inhibition and/or attenuation of these signaling networks also delays the onset of disease. Therefore, a concept of targeting the signaling networks that are involved in inflammation and oxidative stress may represent a novel treatment paradigm for many types of heart disease. In this review, we discuss the molecular mechanisms associated with the physiological responses to inflammation and oxidative stress especially in heart failure with preserved ejection fraction and emphasize the nature of the crosstalk of these signaling processes as well as possible therapeutic implications for cardiovascular medicine.

Background A certain degree of prosthesis oversizing is recommended for the SAPIEN 3 (S3; Edwards Lifesciences Corp., Irvine, California, United States) to ensure device success. We aimed to investigate midterm outcomes in patients who received oversized (OS) S3 valve after transapical–transcatheter aortic valve replacement (TA-TAVR). Methods Out of 122 patients with aortic stenosis who underwent TA-TAVR using S3 at our institution, 42 received OS prosthesis. We used computed tomography (CT) derived effective diameter to assess oversizing. We defined oversizing if the labeled diameter of the selected valve for implantation was ≥2 mm bigger than the effective annulus diameter calculated by the annulus area. We conducted a midterm follow-up and compared the OS cohort with the non-OS (nOS) cohort. Results The study groups showed similar risk score and age (STS [Society of Thoracic Surgery] score: 5.4 ± 3; mean age: 80.7 ± 5.7). The 30-day mortality was 7.1% in OS versus 2.4% in nOS. The 30-day all-stroke was 2.4% in OS versus 0% in nOS. The 1- and 3-year all-cause mortality were 28.5 and 42.8% in OS versus 21.9 and 26.8% in nOS, respectively. Midterm freedom from death and from cardiocerebral events was similar in both groups. Moderate/severe paravalvular leakage occurred in 0% in OS versus 5.4% in nOS. The postdilation rate was 7.1% in OS versus 15.3% in nOS. The rate of new permanent pacemaker implantation (PPI) was 15.7% in OS versus 9.3% in nOS. The STS score was detected as an independent predictor of mortality. Conclusion Oversizing reduces the risk of device failure and intraprocedural postdilation but increases the risk of PPI. Early and midterm morbidity and mortality after OS and nOS with S3 are comparable.

BACKGROUND Two fully automated oscillometric devices have become available for the noninvasive assessment of central aortic blood pressure (BP). They tend, however, to underestimate SBP. It has been proposed that calibration by mean/diastolic instead of systolic/diastolic brachial BP may reduce this bias. The present work compares the accuracy of these two calibrations in the Mobil-O-Graph. METHODS Post-hoc analysis of the largest validation study on noninvasive assessment of central BP so far. Data on both calibration approaches were available in 159 patients without atrial fibrillation, who underwent simultaneous invasive and noninvasive assessment of central BP. Noninvasive BP measurements were conducted using the SphygmoCor XCEL (calibration by systolic/diastolic brachial BP only) and the Mobil-O-Graph (calibration by both systolic/diastolic and mean/diastolic brachial BP). RESULTS Measurements of both devices and both calibration methods revealed highly significant correlations for systolic and diastolic central BP with invasively assessed BP (P

Key points The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism. The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly-bound myosin cross-bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca2+ /calmodulin-dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2), maximizing the recruitment of available strongly-bound myosin cross-bridges. Short-lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation. Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise. Abstract The present study investigated whether oxidative stress and Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKOCaMKII ). In snap-frozen WT hearts, force-pCa relationship, H2 O2 generation, CaMKII oxidation and phosphorylation of myofilament and Ca2+ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H2 O2 generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKOCaMKII -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca2+ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca2+ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca2+ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds.

Fehlfunktionen bei implantierten Schrittmacher- und Defibrillatorsystemen konnen alle Bauteile des Gerats betreffen (Batterie, Kondensator, „central processing unit“ (CPU), Konnektor, Lotstellen, Elektroden). Die daraus entstehenden Probleme konnen sich als inadaquate Therapie, eine unterbleibende Therapie trotz Notwendigkeit einer Stimulation oder Schockabgabe bei aufgetretener ventrikularer Tachyarrhythmie oder als eine ineffektive Therapieabgabe manifestieren. Die hohe Anzahl von implantierten Schrittmacher- und Defibrillatorsystemen, die gestiegene Lebenserwartung sowie der technische Fortschritt der kardialen Device-Therapie konfrontiert den nachsorgenden Arzt mit zunehmend komplexeren Problemen im Follow-up. Neben der Kenntnis der basalen Funktion dieser Gerate wird ein strukturiertes Vorgehen gefordert, um Fehlfunktionen rechtzeitig zu erkennen und zu behandeln. In dieser Ubersicht werden haufige Fehlfunktionen von Schrittmachern und Defibrillatoren dargestellt, auf einzelne Probleme hingewiesen und Losungsansatze sowie Therapieoptionen gezeigt.

Background Interventional closure of the left atrial appendage (LAA) is an alternative option to stroke prophylaxis, particularly in multimorbid patients with a high risk of bleeding under oral anticoagulation. Due to the multiple comorbidities, the prognosis of patients is reduced, and the clinical benefit of the procedure is therefore questionable in the individual patient. Hypothesis The present study aims to identify independent preprocedural risk factors to improve risk stratification in these highly selected patients. Methods This study consecutively included 128 patients who received an interventional LAA occlusion with Amplatzer device (St Jude Medical, St Paul, Minnesota). The preinterventional risk assessment was performed with the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) II. The primary endpoint was all‐cause mortality. Secondary endpoints were thromboembolic events and severe bleeding. Results During a follow‐up of 781 ± 498 days the primary endpoint (all‐cause mortality) was reached in 35 patients (27%). The only independent predictor of mid‐term mortality was a logistic EuroSCORE II > 2% (Hazard risk [HR] 4.55, confidence interval [CI] 1.599‐12.966, P = .005). In our study, 33 patients (26%) suffered from end‐stage renal disease which was not associated with increased mortality (P = .371), increased thromboembolic events (P = .475), or severe bleeding (P = .613). Conclusions In patients undergoing interventional LAA occlusion, preprocedural assessment of logistic EuroSCORE II provide independent prognostic information. This parameter might help to improve risk stratification in these highly selected patients. In contrast, terminal renal failure was not associated with a significantly worse outcome.

The German Maintenance Study (GERMAIN) was designed to evaluate the impact of lenalidomide maintenance after induction therapy with bortezomib, melphalan and prednisolone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (MM) patients. Due to poor accrual and high dropout rate, only 85 patients (planned 286) entered the trial and 40 (planned 200) were randomized to lenalidomide maintenance (n = 19) vs. observation (n = 21). The primary endpoint, improved progression-free survival, was not met (p = 0.3572). After a median follow-up of 12.9 months, median progression-free survival in the lenalidomide arm was 14.4 months and 11.4 months with placebo. The hazard ratio 0.621 (95% confidence interval: [0.224, 1.725]) was about the same as expected (0.625). However, with only 40 patients randomized, the actual power to detect a difference was 11%. Of patients receiving at least one dose of induction, 54% were frail according to a modified International Myeloma Working Group frailty score. Discontinuations were high during induction (47%), and affected mainly frail patients (54%). Despite a higher rate of adverse events in the lenalidomide arm (p = 0.0061), only 2 patients discontinued lenalidomide due to toxicity. A frailty assessment with appropriate dose modification for induction therapy should be mandatory for all elderly non-transplant-eligible myeloma patients.

Background: The angiotensin receptor-neprilysin inhibitor (ARNI) decreases cardiovascular mortality in patients with chronic heart failure with a reduced ejection fraction (HFrEF). Data regarding the impact of ARNI on the outcome in HFrEF patients according to heart failure etiology are limited. Methods and results: One hundred twenty-one consecutive patients with HFrEF from the years 2016 to 2017 were included at the Medical Centre Mannheim Heidelberg University and treated with ARNI according to the current guidelines. Left ventricular ejection fraction (LVEF) was numerically improved during the treatment with ARNI in both patient groups, that with ischemic cardiomyopathy (n = 61) (ICMP), and that with non-ischemic cardiomyopathy (n = 60) (NICMP), p = 0.25. Consistent with this data, the NT-proBNP decreased in both groups, more commonly in the NICMP patient group. In addition, the glomerular filtration rate (GFR) and creatinine changed before and after the treatment with ARNI in both groups. In a one-year follow-up, the rate of ventricular tachyarrhythmias (ventricular tachycardia and ventricular fibrillation) tended to be higher in the ICMP group compared with the NICMP group (ICMP 38.71% vs. NICMP 17.24%, p = 0.07). The rate of one-year all-cause mortality was similar in both groups (ICMP 6.5% vs. NICMP 6.6%, log-rank = 0.9947). Conclusions: This study shows that, although the treatment with ARNI improves the LVEF in ICMP and NICMP patients, the risk of ventricular tachyarrhythmias remains higher in ICMP patients in comparison with NICMP patients. Renal function is improved in the NICMP group after the treatment. Long-term mortality is similar over a one-year follow-up.

BACKGROUND Optimization of cardiac resynchronization therapy (CRT) is often time-consuming and therefore underused in a clinical setting. Novel device-based algorithms aiming to simplify optimization include a dynamic atrioventricular delay (AVD) algorithm (SyncAV, Abbott) and multipoint pacing (MPP, Abbott). This study examines the acute effect of SyncAV and MPP on electrical synchrony in patients with newly and chronically implanted CRT devices. METHODS Patients with SyncAV and MPP enabled devices were prospectively enrolled during implant or scheduled follow-up. Blinded 12-lead electrocardiographic acute measurements of QRS duration (QRSd) were performed for intrinsic QRSd (Intrinsic), bi-ventricular pacing (BiV), MPP, BiV with SyncAV at default offset 50 ms (BiVSyncAVdef ), BiV with SyncAV at patient-specific optimised offset (BiVSyncAVopt ), MPP with SyncAV at default offset 50 ms (MPPSyncAVdef ), and MPP with SyncAV at patient-specific optimised offset (MPPSyncAVopt ). RESULTS Thirty-three patients were enrolled. QRSd for Intrinsic, BiV, MPP, BiVSyncAVdef , BiVSyncAVopt , MPPSyncAVdef , MPPSyncAVopt were 160.4 ± 20.6 ms, 141.0 ± 20.5 ms, 130.2 ± 17.2 ms, 121.7 ± 20.9 ms, 117.0 ± 19.0 ms, 121.2 ± 17.1 ms, 108.7 ± 16.5 ms respectively. MPPSyncAVopt led to greatest reduction of QRSd relative to Intrinsic (-31.6 ± 11.1%; p

Atrial fibrillation (AF) is a major cause of cardiovascular morbidity and mortality. To early detect and to avoid AF-related complications, several cardiac imaging modalities and approaches aim to quantify the severity of the underlying atrial cardiomyopathy (i.e., the extent of atrial remodeling). However, most established cardiac imaging modalities just incorporate single components of atrial remodeling and do not reflect the complete multifactorial process, which may contribute to their limited predictive value. Echocardiography-derived PA-TDI duration is a sophisticated echocardiographic parameter to assess total atrial conduction time and directly reflects both electrical and structural changes to the atria. Therefore, PA-TDI duration provides a more comprehensive quantification of the extent of atrial remodeling than other imaging modalities. In this article we review the role of PA-TDI duration as a marker of atrial remodeling and summarize the available data on PA-TDI duration to identify patients at risk for AF, as well as to guide AF management. Moreover, we discuss how to assess PA-TDI duration and provide recommendations on the implementation of PA-TDI duration into routine clinical care. Graphic abstract

Background: A considerable amount of evidence has shown that acute cardiovascular diseases exhibit specific temporal patterns in their onset.Aim: This study was performed to determine if takotsubo syndrome (TTS) shows chronobiological variations with short and long-term impacts on adverse events.Design: Our institutional database constituted a collective of 114 consecutive TTS patients between 2003 and 2015.Methods: Patients were divided into groups defined by the onset of TTS as per time of the day, day of the week, month and quarter of year.Results: TTS events were most common afternoon and least common in the night, indicating a wave-like pattern (p = 0.001) of manifestation. The occurrence of TTS events was similar among days of the week and weeks of the month. TTS patients diagnosed in the month of November and subsequently in the fourth quarter showed a significantly longer QTc interval. These patients also revealed a significantly lower event-free-survival over a 1-year follow-up. In a multivariate Cox regression analysis, TTS events occurring in the fourth quarter of year (HR 6.8, 95%CI: 1.3–35.9; p = 0.02) proved to be an independent predictor of lower event-free-survival.Conclusions: TTS seems to exhibit temporal preference in its onset, but nevertheless this possibly coincidental result needs to be analyzed in a large multicenter registry.

Standard heart failure (HF) therapies have failed to improve cardiac function or survival in HF patients with right ventricular (RV) dysfunction suggesting a divergence in the molecular mechanisms of RV vs. left ventricular (LV) failure. Here we aimed to investigate interventricular differences in sarcomeric regulation and function in experimental myocardial infarction (MI)-induced HF with reduced LV ejection fraction (HFrEF). MI was induced by LAD ligation in Sprague–Dawley male rats. Sham-operated animals served as controls. Eight weeks after intervention, post-ischemic HFrEF and Sham animals were euthanized. Heart tissue samples were deep-frozen stored (n = 3–5 heart/group) for ELISA, kinase activity assays, passive stiffness and Ca2+-sensitivity measurements on isolated cardiomyocytes, phospho-specific Western blot, and PAGE of contractile proteins, as well as for collagen gene expressions. Markers of oxidative stress and inflammation showed interventricular differences in post-ischemic rats: TGF-β1, lipid peroxidation, and 3-nitrotyrosine levels were higher in the LV than RV, while hydrogen peroxide, VCAM-1, TNFα, and TGF-β1 were increased in both ventricles. In addition, nitric oxide (NO) level was significantly decreased, while FN-1 level was significantly increased only in the LV, but both were unchanged in RV. CaMKII activity showed an 81.6% increase in the LV, in contrast to a 38.6% decrease in the RV of HFrEF rats. Cardiomyocyte passive stiffness was higher in the HFrEF compared to the Sham group as evident from significantly steeper Fpassive vs. sarcomere length relationships. In vitro treatment with CaMKIIδ, however, restored cardiomyocyte passive stiffness only in the HFrEF RV, but had no effect in the HFrEF LV. PKG activity was lower in both ventricles in the HFrEF compared to the Sham group. In vitro PKG administration decreased HFrEF cardiomyocyte passive stiffness, however, the effect was more pronounced in the HFrEF LV than HFrEF RV. In line with this, we observed distinct changes of titin site-specific phosphorylation in the RV vs. LV of post-ischemic rats, which may explain divergent cardiomyocyte stiffness modulation observed. Finally, Ca2+-sensitivity of RV cardiomyocytes was unchanged, while LV cardiomyocytes showed increased Ca2+-sensitivity in the HFrEF group. This could be explained by decreased Ser-282 phosphorylation of cMyBP-C by 44.5% in the RV, but without any alteration in the LV, while Ser-23/24 phosphorylation of cTnI was decreased in both ventricles in the HFrEF vs. the Sham group. Our data pointed to distinct signaling pathways-mediated phosphorylations of sarcomeric proteins for the RV and LV of the post-ischemic failing rat heart. These results implicate divergent responses for oxidative stress and open a new avenue in targeting the RV independently of the LV.

Multipoint pacing [Multipoint™ Pacing (MPP), Abbott] via a single left ventricular lead (Quartet™ LV lead, Abbott) improves acute left ventricular (LV) function and response to cardiac resynchronization therapy (CRT). Aim of this study was to examine additional benefits in terms of LV reverse remodeling and CRT response by activating MPP in responders and non-responders to conventional biventricular pacing (CONV). 43 consecutive patients receiving CRT (Quadra Assura MP™, Abbott) received LV dP/dtmax optimized CONV programming for 6 months. MPP programming with large anatomical electrode separation (> 30 mm) and basal LV1 pacing location was activated afterwards. Echocardiographic and clinical parameters were obtained at baseline, 6- and 12-month follow-up (FU). The response was defined as an improvement of LVESV ≥ 15% and super-response as improvement ≥ 30% relative to baseline. 41 patients completed FU (one died of non-cardiac cause and one was lost to FU) and after 6 months CONV, 26 patients (63%) were classified as CRT responders. With MPP, the response rate increased to 90% (p

Aims The value of platelet function testing (PFT) in predicting clinical outcomes and guiding P2Y12-inhibitor treatment is uncertain. In a pre-specified sub-study of the TROPICAL-ACS trial, we assessed ischaemic and bleeding risks according to high platelet reactivity (HPR) and low platelet reactivity (LPR) to ADP in patients receiving uniform prasugrel vs. PFT-guided clopidogrel or prasugrel. Methods and results Acute coronary syndrome patients with PFT done 14 days after hospital discharge were included with prior randomization to uniform prasugrel for 12 months (control group, no treatment modification) vs. early de-escalation from prasugrel to clopidogrel and PFT-guided maintenance treatment (HPR: switch-back to prasugrel, non-HPR: clopidogrel). The composite ischaemic endpoint included cardiovascular death, myocardial infarction, or stroke, while key safety outcome was Bleeding Academic Research Consortium (BARC) 2–5 bleeding, from PFT until 12 months. We identified 2527 patients with PFT results available: 1266 were randomized to the guided and 1261 to the control group. Before treatment adjustment, HPR was more prevalent in the guided group (40% vs. 15%), while LPR was more common in control patients (27% vs. 11%). Compared to control patients without HPR on prasugrel (n = 1073), similar outcomes were observed in guided patients kept on clopidogrel [n = 755, hazard ratio (HR): 1.06 (0.57–1.95), P = 0.86] and also in patients with HPR on clopidogrel switched to prasugrel [n = 511, HR: 0.96 (0.47–1.96), P = 0.91]. In contrast, HPR on prasugrel was associated with a higher risk for ischaemic events in control patients [n = 188, HR: 2.16 (1.01–4.65), P = 0.049]. Low platelet reactivity was an independent predictor of bleeding [HR: 1.74 (1.18–2.56), P = 0.005], without interaction (P int = 0.76) between study groups. Conclusion Based on this substudy of a randomized trial, selecting prasugrel or clopidogrel based on PFT resulted in similar ischaemic outcomes as uniform prasugrel therapy without HPR. Although infrequent, HPR on prasugrel was associated with increased risk of ischaemic events. Low platelet reactivity was a strong and independent predictor of bleeding both on prasugrel and clopidogrel.

In the synthesis of chiral molecules, the incorporation of enantioselective enzymatic conversions within the synthetic route often presents a useful approach. For the substitution of a chemical step with an enzymatic reaction, however, the complete synthetic route leading to and from this reaction needs to be considered carefully. An integrated approach, taking the possibilities and challenges of both types of conversions into account, can give access to chemo-enzymatic processes with great potential for effective synthesis strategies. We here report on the synthesis of enantiopure flurbiprofen using arylmalonate decarboxylase (AMDase, EC 4.1.1.76) in a chemo-enzymatic approach. Interestingly, practical considerations required shifting the enzymatic step to an earlier position in the synthetic route than previously anticipated. Engineered enzyme variants made it possible to obtain both (R)- and (S)-enantiomers of the target compound in excellent optical purity (>99%ee). The presented results underline that enzymes are most useful when they fit in a synthetic route, and that the optimization of biocatalytic steps and the planning of synthetic routes should be an integrated process.

Controversy exists about the pathophysiology of different hemodynamic subgroups of AS. In particular, the mechanism of the paradoxical low-flow, low-gradient (PLFLG) AS with preserved ejection fraction (EF) is unclear. A total of 41 patients with severe, symptomatic AS were divided into the following 4 subgroups based on the echocardiographically determined hemodynamics: (1) normal-flow, high-gradient (NFHG) AS; (2) low-flow, high-gradient AS; (3) paradoxical low-flow, low-gradient (PLFLG) AS with preserved EF and (4) low-flow, low-gradient (LFLG) AS with reduced EF. As part of the comprehensive invasive examinations, the analyses of the PV loops were performed with the IntraCardiac Analyzer (CD-Leycom, The Netherlands). PLFLG was characterized by small left ventricular volumes as well as a decreased cardiac index, a decreased systolic contractility and a lower stroke work, than the conventional NFHG AS. Alterations in effective arterial elastance (2.36 ± 0.67 mmHg/ml in NFHG versus 3.01 ± 0.79 mmHg/ml in PLFLG, p = 0.036) and end-systolic elastance (3.72 ± 1.84 mmHg/ml in NFHG versus 5.53 ± 2.3 mmHg/ml in PLFLG, p = 0.040) indicated impaired vascular function and increased chamber stiffness. The present study suggests that the hemodynamics of PLFLG AS can be explained by two mechanisms: (1) stiffness of the small left ventricle with reduced contractility, and (2) increased afterload due to the impairment of vascular function. Both mechanisms have similarities to those of heart failure with preserved EF. This type of remodeling may explain the poor prognosis of PLFLG AS.

Background: Intensity-modulated radiotherapy (IMRT) is the standard of care in chemoradiotherapy (CRT) for anal cancer. Until now, only a limited number of studies have analyzed the results with VMAT (volumetric modulated arc therapy). We conducted a retrospective study on patients treated at our institution. Patients and Methods: We included patients who received curative CRT for anal cancer. We compared VMAT-treated and 3DCRT (3D conformal radiotherapy)-treated patients. We analyzed toxicities (acute: CTCAE criteria, late: LENT/SOMA criteria), treatment compliance, overall survival, cancer-specific survival (CSS), distant control (DC), and locoregional control. Results: A total of 149 patients (3DCRT: n = 87, VMAT: n = 62) were included. The median follow-up was longer in 3DCRT-treated patients (3DCRT: 61.3 months, VMAT: 39.1 months, p &lt, 0.05). VMAT-treated patients had more G3 tumors (3DCRT: 12/87 (13.8%), VMAT: 18/62 (29.0%), p &lt, 0.001). VMAT reduced acute toxicities ≥grade 3 (3DCRT: n = 48/87 (55.2%), VMAT: n = 11/62 (17.7%), p &lt, 0.001). VMAT improved treatment compliance (less interruptions/delays) (3DCRT: 37/87, 42.5%, VMAT: 4/62, 6.5%, 0.001), provided a shorter median overall treatment time (3DCRT: 41 days, VMAT: 38 days, p = 0.02), and gave a higher median absolute 5-fluorouracil dose (3DCRT: 13,700 mg, VMAT: 14,400 mg, p = 0.001). Finally, we found improved CSS (p = 0.02, 3DCRT: 81.9% at 3 years, VMAT: 94.1% at 3 years) and DC (p = 0.01, 3DCRT: 89.4% at 3 years, VMAT: 100.0% at 3 years) with VMAT. Summary: Our study is the first to demonstrate improved treatment compliance and outcomes with VMAT for anal cancer. Previous studies have indicated that organs at risk sparing might be more improved with the use of VMAT vs. with conventional IMRT. Future studies should address whether these advantages lead to a further reduction in CRT-associated morbidity.

The treatment with sacubitril/valsartan in patients suffering from chronic heart failure with reduced ejection fraction increases left ventricular ejection fraction and decreases the risk of sudden cardiac death. We conducted a retrospective analysis regarding the impact of age differences on the treatment outcome of sacubitril/valsartan in patients with chronic heart failure with reduced ejection fraction. Patients were defined as adults if ≤65 years (n = 51) and older if65 years of age (n = 76). The incidence of ventricular arrhythmias at 1-year follow-up was comparable in both groups (30.8 vs 26.5%; p = 0.71). The mortality rate in adult patients is significantly lower as compared with older patients (2 vs 14.5%; log-rank = 0.04). Older patients may suffer remarkably more side effects than adult patients (21.1 vs 11.8%; p = 0.03).Lay abstract Many patients still die from heart failure (HF). Better drugs for this condition were developed over the past 20 years. The drug combination sacubitril/valsartan improves heart function and might lower the risk of sudden cardiac death from a fast heart rate (ventricular arrythmia). More research is needed on the effect of sacubitril/valsartan on older patients with HF. We wanted to see how sacubitril/valsartan affects older patients with HF. Seventy-six patients above 65 years of age were compared with 51 patients below 65 years. A year later, the number of ventricular arrhythmias was similar in both groups. Side effects were more common in older patients. At 2 years, there were more deaths in the older group. In summary, side effects of sacubitril/valsartan could be an obstacle to treating older patients. Finding better concepts to treat older patients with a weak heart remains necessary.

Autologous stem cell transplantation (ASCT) conditioned with melphalan 200 mg/m2 (Mel200) is standard of care for young multiple myeloma (MM) patients. Lower doses of melphalan (MelRed) have been used to reduce toxicity, although data regarding their efficacy are not concordant. We retrospectively evaluated 313 MM patients receiving ASCT at Jena University Hospital between 2003 and 2017. Patients receiving MelRed were on average older (p < 0.001), had a worse renal function (p < 0.001) and more comorbidities (p < 0.001). No differences were seen in treatment response before ASCT between the two groups, whilst after ASCT the rate of at least very good partial responses (VGPR) was significantly higher for patients receiving Mel200 (93% vs. 76%, p < 0.001). PFS (39 vs. 20 months, p < 0.001) and OS (103 vs. 59 months, p = 0.001) were longer with Mel200. Toxicities were comparable in the two groups. After adjusting for age and clinical characteristics using the propensity score, for VGPR before and after ASCT and for double ASCT strategy in a Cox regression analysis, Mel200 was still associated with a lower risk of disease progression (HR = 0.40, 95% CI = 0.40–0.96) and of death (HR = 0.61, 95% CI = 0.35–1.07). Our results confirm that Mel200 is still the standard of care for ASCT eligible myeloma patients.

CA extern - Weitere Nicht-UDE-Autoren sind nicht genannt. Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiology

Metabolic syndrome is a primary risk factor for the development of heart failure. In patients with metabolic syndrome, the etiology of cardiovascular disease is complex and may involve coronary disease, arterial hypertension, left ventricular hypertrophy, diastolic dysfunction, endothelial dysfunction, cardiomyocyte dysfunction, coronary microvascular disease, and autonomic dysfunction. The pathogenesis of metabolic syndrome is also multifactorial and is associated with a range of systemic abnormalities, including insulin resistance, diabetes, obesity, dyslipidemia, hyperglycemia, hypertension, oxidative stress, and inflammation. At the molecular level, the impact of metabolic syndrome on gene expression patterns has been investigated in various tissue types, and altered gene expression patterns were found in insulin-sensitive tissues such as liver, skeletal muscle, adipose tissue, and pancreatic β-cells. Nevertheless, the transcriptome in the heart is still poorly understood. This review will highlight the mechanisms driving cardiac dysfunction, with a focus on cardiac transcriptomic remodeling in metabolic syndrome and its impact on cardiac function.

The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase-4 (DPP-4) levels, we investigated whether the clinically approved DPP-4 inhibitor linagliptin reduces left ventricular stiffness in MetS-induced cardiac disease. Sixteen-week-old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin-supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (Fpassive ). The reduced Fpassive was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP-4 directly cleaved titin in vitro, resulting in an increased Fpassive , which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4-mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS-induced early diastolic dysfunction in human. ispartof: Journal Of Cellular And Molecular Medicine vol:25 issue:2 ispartof: location:England status: Published online

Background. Previous research reported adverse clinical outcomes in association with systemic inflammation (SI) after transcatheter aortic valve replacement (TAVR). However, data characterizing the impact of SI, as reflected by postprocedural routine inflammatory parameters (pRIP), on clinical outcome of patients undergoing TAVR are sparse. Objectives. In light of this, the present work aimed to analyze incidence and clinical significance of pRIP after transapical (TA) and transfemoral (TF)-TAVR. Methods and Results. Data of 81 high-risk consecutive patients undergoing TAVR in our center from 2017 to 2018 were analyzed in a retrospective manner. 40 out of 81 patients (49, 4%) were treated via TF access (group A) and 41 patients via TA access (group B). Incidence, cause, and amplitude of pRIP were analyzed in relation to pre- and peri-interventional data. Assessment of outcomes was conducted according to the valve academic research consortium (VARC-2). Postprocedural C-reactive protein (pCRP) and leucocytes (pL) were significantly increased in patients undergoing TA-TAVR (group B) vs. TF-TAVR (group A; 12.1 ± 9.7 vs. 22.1 ± 7.9 mg/dl, p p = 0.002); however, there was no significant difference regarding incidence of postprocedural fever (pF) ≥38.0°C (12.5% vs. 22%, p = 0.37). Furthermore, we observed a vast (though insignificant) trend towards a longer fever duration in group B vs. group A (9.9 ± 14.9 vs. 3.2 ± 5.9 hours, p = 0.06). Further analysis identified pCRP >30 mg/dl (hazard ratio (HR) 3.15, confidence interval (CI) 1.22–8.14, p = 0.018) and European System for Cardiac Operative Risk Evaluation (logistic EuroSCORE I (ES)) >20% (HR 2.95, CI 1.17–7.47, p = 0.02) as predictors of mortality; in this context, we also discovered a marginally significant trend for pL > 14/nl (HR 2.44, CI 0.97–6.14, p = 0.05). Multivariate analysis by use of the fisher`s exact test revealed a significant association between pCRP >30 mg/dl and ES >20% ( p 30 mg/dl, ES>20%, and pL > 14/nl are hallmark of adverse prognosis and require further investigation.

Described as the ‘single largest unmet need in cardiovascular medicine’, heart failure with preserved ejection fraction (HFpEF) remains an untreatable disease currently representing 65% of new heart failure diagnoses. HFpEF is more frequent among women and associates with a poor prognosis and unsustainable healthcare costs. Moreover, the variability in HFpEF phenotypes amplifies complexity and difficulties in the approach. In this perspective, unveiling novel molecular targets is imperative. Epigenetic modifications—defined as changes of DNA, histones, and non-coding RNAs (ncRNAs)—represent a molecular framework through which the environment modulates gene expression. Epigenetic signals acquired over the lifetime lead to chromatin remodelling and affect transcriptional programmes underlying oxidative stress, inflammation, dysmetabolism, and maladaptive left ventricular remodelling, all conditions predisposing to HFpEF. The strong involvement of epigenetic signalling in this setting makes the epigenetic information relevant for diagnostic and therapeutic purposes in patients with HFpEF. The recent advances in high-throughput sequencing, computational epigenetics, and machine learning have enabled the identification of reliable epigenetic biomarkers in cardiovascular patients. Contrary to genetic tools, epigenetic biomarkers mirror the contribution of environmental cues and lifestyle changes and their reversible nature offers a promising opportunity to monitor disease states. The growing understanding of chromatin and ncRNAs biology has led to the development of several Food and Drug Administration approved ‘epidrugs’ (chromatin modifiers, mimics, anti-miRs) able to prevent transcriptional alterations underpinning left ventricular remodelling and HFpEF. In the present review, we discuss the importance of clinical epigenetics as a new tool to be employed for a personalized management of HFpEF.

Heart failure is often accompanied by titin-dependent myocardial stiffness. Phosphorylation of titin by cGMP-dependent protein kinase I (PKGI) increases cardiomyocyte distensibility. The upstream pathways stimulating PKGI-mediated titin phosphorylation are unclear. We studied whether C-type natriuretic peptide (CNP), via its guanylyl cyclase-B (GC-B) receptor and cGMP/PKGI signaling, modulates titin-based ventricular compliance. To dissect GC-B–mediated effects of endogenous CNP in cardiomyocytes, we generated mice with cardiomyocyte-restricted GC-B deletion (CM GC-B–KO mice). The impact on heart morphology and function, myocyte passive tension, and titin isoform expression and phosphorylation was studied at baseline and after increased afterload induced by transverse aortic constriction (TAC). Pressure overload increased left ventricular endothelial CNP expression, with an early peak after 3 days. Concomitantly, titin phosphorylation at Ser4080, the site phosphorylated by PKGI, was augmented. Notably, in CM GC-B–KO mice this titin response was abolished. TAC-induced hypertrophy and fibrosis were not different between genotypes. However, the KO mice presented mild systolic and diastolic dysfunction together with myocyte stiffness, which were not observed in control littermates. In vitro, recombinant PKGI rescued reduced titin-Ser4080 phosphorylation and reverted passive stiffness of GC-B–deficient cardiomyocytes. CNP-induced activation of GC-B/cGMP/PKGI signaling in cardiomyocytes provides a protecting regulatory circuit preventing titin-based myocyte stiffening during early phases of pressure overload., C-type natriuretic peptide via GC-B/cGMP/PKGI signalling in cardiomyocytes attenuates titin-based cardiomyocyte stiffening during early phases of pressure-overload.

BACKGROUND Several reports have described Takotsubo syndrome (TTS) secondary to thyrotoxicosis. A complex interaction of central and peripheral catecholamines with thyroid homeostasis has been suggested. In this study, we analysed sequential thyroid hormone profiles during the acute phase of TTS. METHODS Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at predefined time points in 32 patients presenting with TTS or acute coronary syndrome (ACS, n = 16 in each group) in a 2-year period in two German university hospitals. Data were compared to age- and sex-matched controls (10 samples, each of 16 subjects), and an unsupervised machine learning (ML) algorithm identified patterns in the hormone signature. Subjects with thyroid disease and patients receiving amiodarone were excluded from follow-up. RESULTS Among patients with TTS, FT4 concentrations were significantly higher when compared to controls or ACS. Four subjects (25%) suffered from subclinical or overt thyrotoxicosis. Two additional patients developed subclinical or overt thyrotoxicosis during stay in hospital. In four subjects (25%), FT4 concentrations were increased, despite nonsuppressed TSH concentration, representing an elevated set point of thyroid homeostasis. The thyroid hormone profile was normal in only six patients (38%) presenting with TTS. CONCLUSION Abnormal thyroid function is frequent in patients with TTS. Primary hyperthyroidism and an elevated set point of thyroid homeostasis are common in TTS, suggesting a stress-dependent endocrine response or type 2 thyroid allostasis. Thyroid function may be a worthwhile target in treating or preventing TTS.

Background and aims Oral anticoagulation is effective for stroke prevention in atrial fibrillation (AF). However, strokes may still occur in high-risk individuals. We conducted a prospective trial to assess the association between adipocytokine serum levels and surrogate parameters for thromboembolic events. Methods and results In this cross-sectional multicenter trial, we enrolled 189 patients with AF who were on oral anticoagulation. The primary endpoint was defined as either the presence of spontaneous echo contrast (SEC), a left atrial appendage (LAA), or a left atrial (LA) thrombus on transesophageal echocardiography. We investigated the association of adipocytokine serum levels with the combined endpoint using logistic regression analysis. Forty-eight individuals (25%) were assigned to group 1 (G1) due to the occurrence of at least one of the components of the combined endpoint (41 [21.7%] SEC, 3 [1.6%] LA thrombus, 13 [6.9%] LAA thrombus), whereas the remaining patients formed group 2 (G2). The BMI, logarithmized (loge) leptin (G1: 2.0 ± 1.3 μg/ml, G2: 2.0 ± 1.1 μg/ml, p = 0.746) and visfatin serum levels (G1: 3.4 ± 0.3 ng/ml, G2: 3.4 ± 0.5 ng/ml, p = 0.900) did not significantly differ between the groups. Conversely, logarithmized adiponectin (G1: 3.3 ± 0.6 ng/ml, G2: 3.1 ± 0.7 ng/ml, p = 0.036) and resistin levels (G1: 1.8 ± 0.5 ng/ml, G2: 1.6 ± 0.5 ng/ml, p = 0.009) were higher in patients with the primary endpoint. Multivariate logistic regression analysis using a score that combined the individual adiponectin and resistin values in each patient corroborated this association. Conclusions Our results suggest that adiponectin and resistin may act as potential biomarkers to identify individuals with AF who are at high thromboembolic risk.

Background Beside their role in the diagnosis of heart failure in symptomatic patients with dyspnea, natriuretic peptides have been suggested to improve risk prediction of cardiac events and mortality in asymptomatic cohorts. We aimed to evaluate the prognostic value of NT-proBNP for cardiovascular and all-cause mortality above traditional risk factors in a prospective cohort study of unselected elderly patients in a representative primary care setting. Methods We followed 6382 patients of the getABI-study for 7 years. Associations of NT-proBNP levels (≤125; 125–300; >300pg/ml for all) with all-cause and cardiovascular mortality were assessed using cox regression analysis. Results The incidence of all-cause and cardiovascular mortality was higher in subjects with higher levels of NT-proBNP (all-cause mortality/cardiovascular mortality: 35.4%/6% for NT-proBNP > 300 pg/ml; 16.2%/40% for NT-proBNP 125–300 pg/ml vs. 11.4%/4% for NT-proBNP ≤ 125 pg/ml. Participants with a NT-proBNP levels > 300pg/ml had increased incidence of hard endpoint (hazard ratio (HR) (95% confidence interval (CI)): 3.62 (3.15–4.17) for all-cause mortality, and 6.38 (4.84–8.41) for cardiovascular mortality). These associations remained after adjustment for traditional risk factors and cardiac medications and diseases (HR = 2.64 (2.26–3.08) for all-cause mortality, and HR = 3.93 (2.90–5.32) for cardiovascular mortality). Conclusion Our results show strong associations of higher NT-proBNP levels with cardiovascular and all-cause mortality in an unselected, large population of elderly patients in the primary care setting independent of traditional risk factors indicating that NT-proBNP can help identifying subjects at high risk for cardiac events.

Highlights • Transcatheter heart valve size selection is still challenging. • The overlap between two different prosthesis sizes for borderline annuli remains. • Undersizing but overfilling improves sizing in borderline annulus cases. • Undersizing but overfilling decreases the postprocedural THV-pressure gradient. • Prospective studies are needed considering the TAVR expansion to younger patients., Background Current recommendations for valve size selection are based on multidimensional annular measurements, yet the overlap between two different transcatheter heart valve (THV) sizes remains. We sought to evaluate whether undersizing but overfilling eliminates the gray zones of valve sizing. Methods Data of 246 consecutive patients undergoing transcatheter aortic valve replacement (TAVR) with the balloon-expandable bioprosthesis with either conventional sizing and nominal filling (group 1 (NF-TAVR), n = 154) or undersizing but overfilling under a Less Is More (LIM)-Principle (group 2 (LIM-TAVR), n = 92) were compared. Paravalvular leakage (PVL) was graded angiographically and quantitatively using invasive hemodynamics. Results Annulus rupture (AR) occurred only in group 1 (n = 3). Due to AR adequate evaluation of PVL was possible in 152 patients of group 1. More than mild PVL was found in 13 (8.6%) patients of group 1 and 1 (1.1%) patient of group 2 (p = 0.019). Postdilatation was performed in 31 (20.1%) patients of group 1 and 6 patients (6.5%) of group 2 (p = 0.003). For patients with borderline annulus size in group 1 (n = 35, 22.7%) valve size selection was left to the physiciańs choice resulting in selection of the larger prosthesis in 10 (28.6%). In group 2 all patients with borderline annulus (n = 36, 39.1%) received the smaller prosthesis (LIM-TAVR). The postprocedural mean transvalvular pressure gradient was significantly higher in the NF-TAVR-group (11.7 ± 4 vs. 10.1 ± 3.6 mmHg, p = 0.005). Conclusion LIM-TAVR eliminates the gray zones of sizing and associated PVL, can improve THV-performance, reduce incidence of annular rupture and simplify the procedure especially in borderline cases.

Background Exposure to airborne zinc oxide (ZnO) particles occurs in many industrial processes, especially in galvanizing and welding. Systemic inflammation after experimental inhalation of ZnO particles has been demonstrated previously, but little is known about the impact on the cardiovascular system, particularly on the autonomic cardiac system and the risk of arrhythmias. In this study we investigated the short-term effects of ZnO nanoparticles on heart rate variability (HRV) and repolarization in healthy adults in a concentration-dependent manner at rest and during exercise in a controlled experimental set-up. Methods Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0 and 2.0 mg/m3) for 4 h, including 2 h of cycling at low workloads. Parameters were assessed before, during, immediately after, and about 24 h after each exposure. For each subject, a total number of 46 10-min-sections from electrocardiographic records were analyzed. Various parameters of HRV and QT interval were measured. Results Overall, no statistically significant effects of controlled ZnO inhalation on HRV parameters and QT interval were observed. Additionally, a concentration-response was absent. Conclusion Inhalation of ZnO nanoparticles up to 2.0 mg/m3 for 4 h does not affect HRV and cardiac repolarization in healthy adults at the chosen time points. This study supports the view that cardiac endpoints are insensitive for the assessment of adverse effects after short-term inhalation of ZnO nanoparticles.

Background The prevalence of patients with implanted cardioverter defibrillators (ICDs) and the frequency of surgery on these patients are steadily on the rise. Guidelines recommend preoperative ICD reprogramming, although this is sometimes difficult in clinical practice. Placing a magnet on the ICD is a practical alternative and even no inactivation is possible in selected cases. Methods In this prospective observational study, we compared different perioperative ICD management strategies depending on the location of the surgery and the type of electrocautery used. Patients undergoing surgery above the umbilicus with monopolar electrocautery had their ICD therapy inactivated by reprogramming. When surgery below the navel or surgery above the navel with bipolar electrocautery was completed, ICD inactivation was performed using a magnet. No inactivation was performed on patients undergoing lower extremity surgery with bipolar electrocautery. Only ICD patients who were not pacemaker dependent were enrolled. After surgery, the ICDs were assessed regarding documented arrhythmias and parameters. Results Out of 101 patients included in this study, the ICD was preoperatively reprogrammed in 42 patients (41.6%), a magnet was used on 45 patients (44.5%), and ICDs were not deactivated at all in 14 patients (13.9%). No intraoperative electromagnetic interference was detected. Postoperative ICD analysis demonstrated no changes of preset parameters. Conclusions All three tested ICD management strategies were proved safe in this study. Keeping the location of surgery and the type of electrocautery in mind, an intraoperative magnet or even no ICD deactivation at all could be feasible alternatives in surgery on patients with ICDs.

Die Strahlenexposition im Katheterlabor ist mit signifikanten Gesundheitsrisiken verbunden. Unklar ist, ob eine Reduktion der Strahlenbelastung mit „Near-zero-fluoroscopy“-Protokollen auch bei weniger erfahreneren Untersuchern moglich ist. Es wurden konsekutive Ablationsprozeduren mit Verwendung eines 3‑D-Mapping-Systems analysiert. Hierbei wurden 3 Zeitraume betrachtet. Im ersten Zeitraum (Standard) wurde ohne Strahlenreduktionsprotokoll gearbeitet. Im zweiten Zeitraum wurde ein „Near-zero-fluoroscopy“-Protokoll eingefuhrt (Initialphase Strahlenreduktion), allerdings wurde der Grosteil der Untersuchungen von einem Experten durchgefuhrt. Im dritten Zeitraum ubernahmen zunehmend zwei weniger erfahrene Untersucher (Fellow und Anfanger) die Prozeduren als Erstuntersucher. Insgesamt wurden 290 Untersuchungen analysiert. Nach Einfuhrung des Strahlenreduktionsprotokolls wurde eine signifikante Reduktion des mittleren Flachendosisproduktes gegenuber dem Standardprotokoll beobachtet (Standard 850 ± 831,7 vs. Initialphase 197,2 ± 481,8 μGy/m2, p