Radiological Parameters for the Detection of Pulmonary Hypertension in Severe Aortic Valve Stenosis and Their Influence on Mortality: Does Sex Matter?

Background: Echocardiography has long been established as the primary noninvasive method for diagnosing pulmonary hypertension (PH) prior to transcatheter aortic valve replacement (TAVR) in patients with severe aortic valve stenosis (AS). In recent years, radiological methods for diagnosing PH have been investigated. Measurements such as the computed tomography angiography (CTA)-derived pulmonary artery (PA) diameter and PA diameter/body surface area (PA/BSA) have shown promising results regarding their diagnostic strength. However, it has yet to be determined if a patient's sex has any impact on the effectiveness of these diagnostic measurements. Methods: In all, 271 patients (51.3% male, mean age 82.6 ± 4.8 years) with severe AS undergoing TAVR were separated into male and female groups. The cut-off values for the diagnosis of PH were calculated for the CTA-derived PA diameter and PA/BSA based on different systolic pulmonal artery pressure values (40-45-50 mmHg). Patients were then subclassified according to measurements above or below these PA diameters and PA/BSA cut-off values. A PA diameter ≥29.5 mm and PA/BSA ≥ 15.7 mm/m2 qualified for PH. The 1-5 year survival rate in these cohorts was further analyzed. Results: Patients with a PA diameter ≥29.5 mm showed a significantly higher 1 year mortality rate (p = 0.014). This observation could only be confirmed for the male sex (p = 0.018) and not for the female sex (p = 0.492). As for the PA/BSA, in patients over the cut-off value, no significant increase in mortality was noted in the overall cohort. However, the male patients showed increased 3 year (p = 0.048) and 5 year mortality rates (p = 0.033). Conclusions: The CTA-obtained PA diameter and PA/BSA are both useful in the diagnosis of PH and mortality risk stratification in patients with severe AS undergoing TAVR, especially in males. Male patients with PA ≥ 29.5 mm or PA/BSA ≥ 15.7 mm/m2 seem to be at a higher risk of death during follow-up after undergoing TAVR. In females, no such correlation was observed.

Sustainable and cost-effective MAS DNP-NMR at 30 K with cryogenic sample exchange.

We report here instrumental developments to achieve sustainable, cost-effective cryogenic Helium sample spinning in order to conduct dynamic nuclear polarisation (DNP) and solid-state NMR (ssNMR) at ultra-low temperatures (<30 K). More specifically, we describe an efficient closed-loop helium system composed of a powerful heat exchanger (95% efficient), a single cryocooler, and a single helium compressor to power the sample spinning and cooling. The system is integrated with a newly designed triple-channel NMR probe that minimizes thermal losses without compromising the radio frequency (RF) performance and spinning stability (±0.05%). The probe is equipped with an innovative cryogenic sample exchange system that allows swapping samples in minutes without introducing impurities in the closeloop system. We report that significant gain in sensitivity can be obtained at 30-40 K on large micro-crystalline molecules with unfavorable relaxation timescales, making them difficult or impossible to polarize at 100 K. We also report rotor-synchronized 2D experiments to demonstrate the stability of the system.

Chemical and biological differences between original and mimetic pentosan polysulfates.

Pentosan polysulfate sodium (PPS) is a semi-synthetic, heparin-like polysaccharide with manifold therapeutic actions. It is approved for treatment of bladder pain syndrome / interstitial cystitis in humans and treatment of musculoskeletal diseases in animals. PPS is produced by a complex procedure using beech wood as starting material. It consists of a mixture of sulfated glucuronoxylans, whose structural composition cannot be fully characterized by physicochemical analysis. The question arises whether PPS follow-on products are identical with the original and thus meet the requirement for generic drug application. The aim of this study was to investigate whether commercially available PPS products differ in physicochemical characteristics and biological effects from the original. Ten PPS preparations from different manufactures were analyzed using orthogonal analytical techniques including, inter alia, size exclusion chromatography with triple detection, nuclear magnetic resonance spectroscopy, and high-resolution mid-infrared spectroscopy in aqueous solution with chemometric evaluation. For functional analysis, we measured the plasma kallikrein generation in human plasma and FXII activation. The study revealed significant structural and biological differences between PPS from different sources. Therefore, follow-on products cannot be considered identical but at best similar to original PPS. However, their similar efficacy and safety have still to be proven by comprehensive studies.

Impact of pacing mode and different echocardiographic parameters on cardiac output (PADIAC).

Introduction: The extent of the hemodynamic benefit from AV-synchronous pacing in patients with sinus rhythm and AV block is not completely understood. Thus, we systematically investigated the association of an array of echocardiographic and epidemiological parameters with the change in cardiac output depending on the stimulation mode (AV-synchronous or AV-asynchronous pacing). Methods: Patients in sinus rhythm after previous dual chamber pacemaker implantation underwent a thorough basic echocardiographic assessment of diastolic and systolic left ventricular function, and atrial function (26 echo parameters, including novel speckle tracking strain measurements). Then, stroke volume was measured with AV-synchronous (DDD) and AV-asynchronous (VVI) pacing. Each patient represented their own control, and the sequence of stroke volume measurements was randomized. Results: In this prospective single-center study (NCT04068233, registration August 22nd 2019), we recruited 40 individuals. The stroke volume was higher in all patients when applying AV-synchronous DDD pacing [median increase 12.8 ml (16.9%), P < 0.001]. No echo parameter under investigation was associated with the extent of stroke volume increase in a linear regression model. Of all epidemiological variables, a history of acute myocardial infarction (AMI) was associated with an attenuated stroke volume gain in a univariate and a multivariate regression model that adjusted for confounders. A- and S-wave velocities were reduced in the AMI group. Discussion: In our cohort of patients, each subject benefited from AV-synchronous DDD pacing. No single echo parameter could predict the amount of stroke volume increase. The beneficial effect of AV-synchronous pacing on stroke volume was attenuated after prior acute myocardial infarction.ClinicalTrials.gov identifier (NCT number): NCT04068233.

The Presence of Ascending Aortic Dilatation in Patients Undergoing Transcatheter Aortic Valve Replacement Is Negatively Correlated with the Presence of Diabetes Mellitus and Does Not Impair Post-Procedural Outcomes.

Both relevant aortic valve stenosis (AS) and aortic valve insufficiency significantly contribute to structural changes in the ascending aorta (AA) and thus to its dilatation. In patients with severe AS undergoing transcatheter aortic valve replacement (TAVR), survival data regarding aortic changes and laboratory biomarker analyses are scarce. METHODS: A total of 179 patients with severe AS and an available computed tomography were included in this retrospective study. AA was measured, and dilatation was defined as a diameter ≥ 40 mm. Thirty-two patients had dilatation of the AA. A further 32 patients from the present population with a normal AA were matched to the aortic dilatation group with respect to gender, age, body mass index and body surface area, and the resulting study groups were compared with each other. In addition to echocardiographic and clinical characteristics, the expression of cardiovascular biomarkers such as brain natriuretic peptide (BNP), soluble suppression of tumorigenicity-2 (sST2), growth/differentiation of factor-15 (GDF-15), heart-type fatty-acid binding protein (H-FABP), insulin-like growth factor binding protein 2 (IGF-BP2) and soluble urokinase-type plasminogen activator receptor (suPAR) was analyzed. Kaplan-Meier curves for short- and long-term survival were obtained, and Pearson's and Spearman's correlations were calculated to identify the predictors between the diameter of the AA and clinical parameters. RESULTS: A total of 19% of the total cohort had dilatation of the AA. The study group with an AA diameter ≥ 40 mm showed a significantly low comorbidity with respect to diabetes mellitus in contrast to the comparison cohort with an AA diameter < 40 mm (p = 0.010). This result continued in the correlation analyses performed, as the presence of diabetes mellitus correlated negatively not only with the diameter of the AA (r = -0.404; p = 0.001) but also with the presence of aortic dilatation (r = -0.320; p = 0.010). In addition, the presence of AA dilatation after TAVR was shown to have no differences in terms of patient survival at 1, 3 and 5 years. There were no relevant differences in the cardiovascular biomarkers studied between the patients with dilated and normal AAs. CONCLUSION: The presence of AA dilatation before successful TAVR was not associated with a survival disadvantage at the respective follow-up intervals of 1, 3 and 5 years. Diabetes mellitus in general seemed to have a protective effect against the development of AA dilatation or aneurysm in patients with severe AS.

NT-pro-BNP as a Predictor for Recurrence of Atrial Fibrillation after Primary Cryoballoon Pulmonary Vein Isolation.

NT-pro-BNP is produced in the cardiac atria and ventricles in response to increased wall stress. It may be a marker of both AF disease progression and co-morbidities that affect success after pulmonary vein isolation (PVI). This single-center retrospective study analyzed the association between pre-procedural NT-pro-BNP serum levels and the long-term outcome after a first-ever PVI in cryo-technique. Patients were followed by searching the hospital information system and conducting structured telephone interviews. Treatment failure was defined as any relapse of atrial fibrillation (AF) occurring 90 days after the index PVI at the earliest. Kaplan−Meier survival curves and Cox proportional hazards models were computed to assess the impact of NT-pro-BNP on AF recurrence. Following 374 patients over a median of 3.8 years (range: 0.25−9.4 years), baseline NT-pro-BNP was associated with the combined endpoint in univariate analysis (HR 1.04 per 100 pg/mL increase, 95% CI: 1.02−1.07, p < 0.001). Results were virtually unchanged in the multivariate model or if the data were log-transformed. Intraprocedural left atrial pressure correlated positively with log NT-pro-BNP. NT-pro-BNP was associated with AF relapse during a long-term follow-up after first-ever cryo-PVI in our cohort of patients with predominantly normal left ventricular function. This lab parameter is easy to obtain and has significant potential to guide treatment decisions.

On the authenticity of Beethoven's skull fragments from the estate of Prof. Dr. Romeo Seligmann.

On the occasion of the reburial of Beethoven's mortal remains in 1863, skull fragments are said to have come into the possession of Prof. Dr. Seligmann, who was present at that time and had conducted scientific investigations. These fragments were inherited in his family and are currently housed in the USA. Their authenticity is doubted by some scientists. On the basis of a plaster cast of Beethoven's skull kept in the Natural History Museum, Fool's Tower, in Vienna, the exact topographical position of these skull fragments could be reconstructed and it could be shown that there is no indication that the fragments did not originate from Beethoven's skull.

Comparability between Computed Tomography Morphological Vascular Parameters and Echocardiography for the Assessment of Pulmonary Hypertension in Patients with Severe Aortic Valve Stenosis-Results of a Multi-Center Study.

Background: Computed tomography (CT) of the aorta and cardiac vessels, which is performed in patients with severe aortic valve stenosis (AS) before transcatheter aortic valve replacement (TAVR), offers the possibility of non-invasive detection of pulmonary hypertension (PH), for example, by determining the diameter of the main pulmonary artery (PA), the right pulmonary artery (RPA) or the left pulmonary artery (LPA). An improvement of the significance of these radiological parameters is often achieved by indexing to the body surface area (BSA). The aim of this study was to compare different echocardiographic systolic pulmonary artery pressure (sPAP) values with radiological data in order to define potential clinical cut-off values for the presence or absence of PH. Methods: A total of 138 patients with severe AS undergoing TAVR underwent pre-interventional transthoracic echocardiography with determination of sPAP values and performance of CT angiography (CTA) of the aorta and femoral arteries. Radiologically, the PA, RPA, LPA, and ascending aorta (AA) diameters were obtained. Vascular diameters were not only indexed to BSA but also ratios were created with AA diameter (for example PA/AA-ratio). From these CT-derived vascular parameters, AUROC curves were obtained regarding the prediction of different sPAP values (sPAP 40−45−50 mmHg) and finally correlation analyses were calculated. Results: The best AUROC and correlation analyses were generally obtained at an sPAP ≥ 40 mmHg. When considering diameters alone, the PA diameter was superior to the RPA and LPA. Indexing to BSA generally increased the diagnostic quality of the parameters, and finally, in a synopsis of all results, PA/BSA had the best AUC 0.741 (95% CI 0.646−0. 836; p < 0.001; YI 0.39; sensitivity 0.87; specificity 0.52) and Spearman's correlation coefficient (r = 0.408; p < 0.001) at an sPAP of ≥40 mmHg. Conclusions: Features related to pulmonary hypertension are fast and easily measurable on pre-TAVR CT and offer great potential regarding non-invasive detection of pulmonary hypertension in patients with severe AS and can support the echocardiographic diagnosis. In this study, the diameter of the main pulmonary artery with the additionally determined ratios were superior to the values of the right and left pulmonary artery. Additional indexing to body surface area and thus further individualization of the parameters with respect to height and weight can further improve the diagnostic quality.

CT-Diagnosed Sarcopenia and Cardiovascular Biomarkers in Patients Undergoing Transcatheter Aortic Valve Replacement: Is It Possible to Predict Muscle Loss Based on Laboratory Tests?-A Multicentric Retrospective Analysis.

BACKGROUND: Patients with severe aortic valve stenosis (AS) often present with heart failure and sarcopenia. Sarcopenia, described as progressive degradation of skeletal muscle mass, has frequently been implicated as a cause of increased mortality, prolonged hospitalization and generalized poor outcome after transcatheter aortic valve replacement (TAVR). At present, sarcopenia is defined by the European Working Group on Sarcopenia in Older People (EWGSOP) based on clinical examination criteria and radiological imaging. The aim of the present study was to compare patients with Computed Tomography (CT)-diagnosed sarcopenia with regard to the expression of cardiovascular biomarkers in order to obtain additional, laboratory-chemical information. METHODS: A total of 179 patients with severe AS were included in this retrospective study. Sarcopenia was determined via CT by measurement of the psoas muscle area (PMA), which was indexed to body surface area (PMAi). According to previous studies, the lowest tertile was defined as sarcopenic. Patients with (59/179) and without sarcopenia (120/179) in the overall cohort were compared by gender-specific cut-offs with regard to the expression of cardiovascular biomarkers such as brain natriuretic peptide (BNP), soluble suppression of tumorigenicity-2 (sST2), growth/differentiation of factor-15 (GDF-15), heart-type fatty-acid binding protein (H-FABP), insulin like growth factor binding protein 2 (IGF-BP2) and soluble urokinase-type plasminogen activator receptor (suPAR). Additionally, binary logistic regression analyses were calculated to detect possible predictors of the presence of sarcopenia. RESULTS: No statistical differences regarding one-year survival could be detected between sarcopenic and non-sarcopenic patients in survival curves (log rank test p = 0.179). In the entire cohort, only BNP and hemoglobin (HB) showed a statistically significant difference, with only HB emerging as a relevant predictor for the presence of sarcopenia after binary logistic regression analysis (p = 0.015). No relevant difference in biomarker expression could be found in the male cohort. Regarding the female cohort, statistically significant differences were found in BNP, HB and hematocrit (HK). In binary logistic regression, however, none of the investigated criteria could be related to sarcopenia. CONCLUSION: Regardless of gender, patients with imaging-based muscle degradation did not demonstrate significantly different cardiovascular biomarker expression compared to those without it.

Empagliflozin in acute myocardial infarction: the EMMY trial.

AIMS: Sodium-glucose co-transporter 2 inhibition reduces the risk of hospitalization for heart failure and for death in patients with symptomatic heart failure. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking. METHODS AND RESULTS: In this academic, multicentre, double-blind trial, patients (n = 476) with acute myocardial infarction accompanied by a large creatine kinase elevation (>800 IU/L) were randomly assigned to empagliflozin 10 mg or matching placebo once daily within 72 h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. Baseline median (interquartile range) NT-proBNP was 1294 (757-2246) pg/mL. NT-proBNP reduction was significantly greater in the empagliflozin group, compared with placebo, being 15% lower [95% confidence interval (CI) -4.4% to -23.6%] after adjusting for baseline NT-proBNP, sex, and diabetes status (P = 0.026). Absolute left-ventricular ejection fraction improvement was significantly greater (1.5%, 95% CI 0.2-2.9%, P = 0.029), mean E/e' reduction was 6.8% (95% CI 1.3-11.3%, P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5 mL (95% CI 3.4-11.5 mL, P = 0.0003) and 9.7 mL (95% CI 3.7-15.7 mL, P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for heart failure (three in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups. CONCLUSION: In patients with a recent myocardial infarction, empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 weeks, accompanied by a significant improvement in echocardiographic functional and structural parameters. CLINICALTRIALS.GOV REGISTRATION: NCT03087773.

Main pulmonary artery diameter in combination with cardiovascular biomarkers. New possibilities to identify pulmonary hypertension in patients with severe aortic valve stenosis?

BACKGROUND: Echocardiography is currently the noninvasive method of choice to screen patients with severe aortic valve stenosis (AS) for pulmonary hypertension (PH) by estimating systolic pulmonary artery pressure (sPAP). However, radiological options are also available by determining the main pulmonary artery (MPA) diameter in the setting of CT angiography. The aim of the present study was to compare cardiovascular biomarkers with the MPA diameter to allow other ways of detecting PH in patients with severe AS. METHODS: 194 patients with severe AS undergoing transcatheter aortic valve replacement (TAVR) were included in this study and were divided into two groups based on the CT-angiographically determined MPA diameter. In accordance with ESC guidelines, a cut-off value of 29 mm was determined in this study, with the absence of PH defined by an MPA diameter < 29 mm (n = 79/194) and the presence of PH defined by an MPA diameter ≥ 29 mm (115/194). Immediately before interventional aortic valve replacement, blood samples were drawn from the subjects and relevant cardiovascular biomarkers such as BNP, cTnI, GDF-15, H-FABP, IGF-BP2 and suPAR were assessed. RESULTS: Patients with an MPA diameter ≥ 29 mm had significantly higher BNP (p = 0.004), cTnI (p = 0.039) and HFABP (p = 0.015) plasma levels, whereas GDF-15 (p = 0.140), IGF-BP2 ( p = 0.088) and suPAR (p = 0.140) showed no significant differences. In addition, cut-off values were calculated to predict an MPA diameter ≥ 29 mm. Significant results were shown with 1634.00 pg/ml for BNP (p = 0.004), with 16.50 pg/ml for cTnI (p = 0.039) and with 1.16 ng/ml for H-FABP (p = 0.016). In a combined biomarker analysis, the 2-way combination of BNP and IGF-BP2 (AUC 0.671; 95%CI 0.538 - 0.805; p = 0.023) and the 3-way combination of BNP, H-FABP and IGF-BP2 (AUC 0.685; 95%CI 0.551 - 0.818; p = 0.015) showed the best results. Biomarker follow-up at 3 and 12 months after TAVR did not require additional information gain. Regarding 1-year survival, no significant difference could be detected between patients with an MPA diameter < 29 mm compared to patients with ≥ 29 mm (log-rank test: p = 0.262). CONCLUSIONS: The MPA diameter remains a controversial parameter for the detection of PH in patients with severe AS. Standing on its own, this non-invasive parameter may not be precise enough to detect PH accurately. Combining this parameter with several biomarkers did not provide significant additional information.

Pentosan Polysulfate Inhibits Attachment and Infection by SARS-CoV-2 In Vitro: Insights into Structural Requirements for Binding.

Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS-CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side effect. One alternative, with structural similarities to heparin, is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated, and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective in inhibiting cell infection than low-molecular-weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.

Delayed Total Atrioventricular Block After Transcatheter Aortic Valve Replacement Assessed by Implantable Loop Recorders.

OBJECTIVES: The aims of this study were to evaluate the rate and time course of delayed total atrioventricular block (DT-AVB) after transcatheter aortic valve replacement (TAVR) using continuous electrocardiographic monitoring by implantable loop recorders and to identify potential predictors. BACKGROUND: DT-AVB has been defined as onset more than 2 days after TAVR or after hospital discharge and is reported in 10% to 15% of patients at 30-day follow-up. To date, there is no standardized diagnostic and therapeutic algorithm to manage TAVR patients at risk for DT-AVB. METHODS: Consecutive patients undergoing TAVR and simultaneous electrophysiologic testing without persistent or recurrent total atrioventricular block within 48 hours after the procedure underwent loop recorder implantation for full disclosure of atrioventricular conduction during 12-month follow-up. RESULTS: DT-AVB occurred in 7 of 59 patients (11.9%), with onset between 2 days and 3 months after the procedure. Both prolongation of the PQ interval between baseline and day 2 after TAVR (OR: 1.04; 95% CI: 1.01-1.09); P = 0.032) and prolongation of the HV interval during the procedure (OR: 1.07; 95% CI: 1.02-1.14; P = 0.015) significantly predicted the onset of DT-AVB. CONCLUSIONS: TAVR was associated with a considerable rate of DT-AVB of nearly 12% in this series. Prolongation of the PQ interval between baseline and day 2 and intraprocedural prolongation of the HV interval were significant predictors of DT-AVB.

Tumor necrosis factor alpha-an underestimated risk predictor in patients undergoing transcatheter aortic valve replacement (TAVR)?

BACKGROUND: Systemic inflammation has been identified as a major cardiovascular risk factor in patients undergoing transcatheter aortic valve replacement (TAVR), yet currently, it is not adequately portrayed in scores for pre-interventional risk assessment. The aim of this study was to investigate the predictive ability of TNF-α in TAVR. METHODS: A total of 431 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were drawn prior to intervention, 24 h post-intervention, 4, 5, and 7 days post-intervention, and 1, 3, and 6 months post-TAVR. RESULTS: In a univariate Cox proportional hazard analysis, plasma concentrations of TNF-α after 24 h and after 5 days were associated with mortality after 12 months (after 24 h: HR 1.002 (1.000-1.004), p = 0.028; after 5d: HR 1.003 (1.001-1.005), p = 0.013). This association remained significant even after correction for confounders in a multivariate Cox regression analysis. Additionally, cut-offs were calculated. Patients above the cut-off for TNF-α after 5d had a significantly worse 12-month mortality than patients below the cut-off (18.8% vs. 2.8%, p = 0.046). CONCLUSION: Plasma levels of TNF-α after 24 h and 5 days were independently associated with 12-month mortality in patients undergoing TAVR. Thus, TNF-α could represent a novel biomarker for enhanced risk stratification in these patients.

Remote ischemic preconditioning does not induce activation of Akt and STAT5 in the rat heart.

Remote ischemic preconditioning (RIPC) is hypothesized to be a promising cardioprotective strategy to protect hearts against ischemia and reperfusion (I/R) injury; however, the current understanding of the underlying signal transduction pathways involved remains unclear. It has been previously demonstrated that protein kinase B/AKT, which is a crucial protein of the reperfusion injury salvage kinases pathway, and STAT5, which is a member of the survivor activating factor enhancement pathway, serve a pivotal role in cardioprotection. However, whether and at what time-points (TPs) RIPC leads to the activation of AKT and STAT5 in a rat model of RIPC and I/R injury remains to be determined. The present study hypothesized that RIPC may induce the phosphorylation of AKT and/or STAT5 immediately following RIPC and/or at a later TP with or without subsequent I/R. In the first set of experiments (part A), male Wistar rats were randomized into 2 groups (n=6 per group): The first group underwent RIPC via a hind limb tourniquet (4x5 min I/R episodes), while the second group received the respective sham treatment. In the second set of experiments (part B), the rats were randomized into 4 groups (n=6 per group) that either underwent RIPC or sham treatment prior to 35 min of ischemia by occlusion of the left anterior descending coronary artery followed by 120 min reperfusion or a respective sham treatment. At the end of the experiments, the heart tissue was isolated in order to analyze the phosphorylation levels of AKT and STAT5. The results revealed that RIPC did not induce the immediate or late phosphorylation of AKT or STAT5. In addition, following I/R, the activation of AKT and STAT5 was not modulated by RIPC. In conclusion, the findings of the present study suggested that RIPC-induced cardioprotection may not be mediated by the activation of AKT or STAT5 at the investigated TPs.

Beethoven's death-the result of medical malpractice?

Two different strands of hair taken from Beethoven's head after his death were examined for heavy metals using scanning electron microscopy (SEM) and laser ablation-ICP-MS (inductively coupled plasma-mass spectroscopy). The results revealed the presence of small lead particles on the surface of Beethoven's hairs and fluctuating lead levels in hair medulla along the length of the hair due to alternating lead exposure, with an average lead exposure of 100 times the normal value. The time-line attached to the peaks of these fluctuating values correlate with the pneumonia treatment and the paracenteses performed, including the subsequent treatment of the procedure wounds. While the administration of lead-containing drugs and treatments had been proven to resolve the pneumonia, it had simultaneously caused massive liver failure, accelerated by pre-existing cirrhosis. The question as to whether Beethoven's death was a case of malpractice can only be answered from a forensic point of view ex ante, since the state of the medical knowledge of the time has to be taken into account.

Cardiac Computed Tomography-Derived Left Atrial Volume Index as a Predictor of Long-Term Success of Cryo-Ablation in Patients With Atrial Fibrillation.

Patients with symptomatic, drug-refractory atrial fibrillation (AF) are frequently treated with catheter ablation. Cryo-ablation has been established as an alternative to radiofrequency ablation but long-term outcome data are still limited. This study aimed at elucidating the influence of the left atrial volume index (LAVI), derived from cardiac computed tomography (cCT) data, on the long-term outcome of ablation-naïve AF patients, after their first cryo-ablation. 415 patients (n = 290 [69.90%] male, 60.00 [IQR: 53.00 to 68.00] years old) who underwent a cCT and subsequent cryo-ablation index procedure were included in this single centre retrospective data analysis. A composite end point was defined (AF on electrocardiogram and/or electric cardioversion and/or re-do). Patients were closely followed for a year and then contacted for long-term follow-up after a median of 53.00 months (IQR: 34.50 to 73.00). Statistical analyses of the outcome and predictors of AF recurrence were conducted. In 224 patients (53.98%) no evidence of AF recurrence could be found. LAVI differed significantly between the positive and adverse (AF recurrence) outcome group (49.96 vs 56.07 ml/m2, p < 0.001). Cox regression analyses revealed cCT LAVI (HR: 1.022, 95% CI: 1.013 to 1.031, p < 0.001), BMI (HR: 1.044, 95% CI: 1.005 to 1.084, p < 0.05) and the type of AF (HR: 1.838 for nonparoxysmal AF, 95% CI: 1.214 to 2.781, p < 0.01) to be effective predictors of AF recurrence. A prognostic cCT LAVI cut-off value of 51.99 ml/m2 was calculated and must be validated in future prospective studies. In conclusion, LAVI is an accurate, yet underutilized predictor of AF recurrence after pulmonary vein isolation with cryo-energy and scores for calculating AF recurrence or progression risks might underemphasize the importance of CT-derived LAVI as a predictive factor.

Intraprocedural dynamics of cardiac conduction during transcatheter aortic valve implantation: Assessment by simultaneous electrophysiological testing.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an established treatment for patients with severe aortic stenosis and high to intermediate surgical risk. However, the proximity of the conduction system to the prosthesis landing zone bears the risk of atrioventricular conduction disorders. The underlying pathophysiology is not fully understood. OBJECTIVE: The purpose of this study was to characterize the impact of TAVI on the conduction system as assessed by simultaneous electrophysiological testing. METHODS: AH and HV intervals and QRS duration were measured using a quadripolar His catheter and surface electrocardiogram in 108 patients at baseline (BL), after balloon predilation (timepoint 1 [T1]), after implantation of the valve prosthesis (T2), and after postdilation, if deemed necessary (T3). RESULTS: Between BL and T2, significant increases of HV interval and QRS duration were observed, with a mean delta of +12.4 ms and +32.7 ms, respectively. Both balloon predilation and valve implantation had an impact on infranodal conduction. No significant increase of AH intervals was documented. The increase of QRS duration led to left bundle branch block (LBBB) in 57 patients (52.8%). Implantation depth positively correlated with QRS prolongation (ρ = 0.21, P = .042) but not with changes of AH or HV interval (ρ = -0.03, P = .762; and ρ = 0.15, P = .130, respectively). CONCLUSION: Electrophysiological testing during TAVI shows impairment of infranodal atrioventricular conduction by balloon predilation and valve implantation. This impairment is positively correlated with valve implantation depth and results in an increase of QRS duration with mainly LBBB pattern on surface electrocardiogram.

Aspiration in lethal drug abuse-a consequence of opioid intoxication.

AIMS: The primary objective of this study was to investigate whether the fatalities of opioid abuse are not only related to respiratory depression but also as a result of other side effects such as emesis, delayed gastric emptying, a reduction of the cough reflex, and impaired consciousness leading to the aspiration of gastric contents, a finding regularly observed in drug-related deaths. DESIGN: A retrospective exploratory study analyzing heroin/morphine/methadone-related deaths submitted to court-ordered autopsy. SETTING: Center for Forensic Medicine, Medical University of Vienna, Austria (2010-2015). PARTICIPANTS: Two hundred thirty-four autopsy cases were included in the study: morphine (n = 200), heroin (n = 11), and methadone (n = 23) intoxication. FINDINGS: Analyses revealed that 41.88% of all deceased showed aspiration of gastric contents with equal gender distribution (p = 0.59). Aspiration was more frequent in younger deceased (χ2 = 8.7936; p = 0.012) and in deceased with higher body mass index (BMI) (χ2 = 6.2441; p = 0.044). Blood opioid concentration was lower in deceased with signs of aspiration than in non-aspirators (p = 0.013). Toxicological evaluation revealed a high degree of concomitant substance abuse (91%)-benzodiazepines (61.6%) and/or alcohol (21.8%). CONCLUSIONS: There are lower opioid concentrations in deceased with signs of aspiration, a fact which strongly points to aspiration as alternative cause of death in opioid-related fatalities. Furthermore, this study highlights the common abuse of slow-release oral morphine in Vienna and discusses alternative medications in substitution programs (buprenorphine/naloxone or tamper-resistant slow-release oral morphine preparations), as they might reduce intravenous abuse and opioid-related deaths.