A case of recurring perioperative circulatory arrest: mind the autonomic nervous system.

We report the case of an elderly woman who developed recurring episodes of unexplained cardiocirculatory arrest. The index event appeared during surgery to fix a fracture of the ankle and consisted of bradypnea, hypotension and asystole, coherent with a Bezold-Jarisch-like cardioprotective reflex. Classical signs of acute myocardial infarction were absent. Yet, occlusion of the right coronary artery (RCA) was observed and successfully revascularized, whereupon circulatory arrests vanished. We discuss several differential diagnoses. Unexplainable circulatory failure, with sinus bradycardia and arterial hypotension, despite lack of ECG signs of ischemia or significant troponin levels, suggest the action of cardioprotective reflexes of the autonomic nervous system. Coronary artery disease is a common source. Attention to cardioprotective reflexes should be taken in the case of unexplained cardiac arrest without overt reasons. We recommend performing coronary angiography to exclude significant coronary stenosis.

Absorption, Distribution, Metabolism, and Excretion of Capmatinib (INC280) in Healthy Male Volunteers and In Vitro Aldehyde Oxidase Phenotyping of the Major Metabolite.

Capmatinib (INC280), a highly selective and potent inhibitor of the MET receptor tyrosine kinase, has demonstrated clinically meaningful efficacy and a manageable safety profile in patients with advanced non-small-cell lung cancer harboring MET exon 14-skipping mutations. We investigated the absorption, distribution, metabolism, and excretion of capmatinib in six healthy male volunteers after a single peroral dose of 600 mg 14C-labeled capmatinib. The mass balance, blood and plasma radioactivity, and plasma capmatinib concentrations were determined along with metabolite profiles in plasma, urine, and feces. The metabolite structures were elucidated using mass spectrometry and comparing with reference compounds. The parent compound accounted for most of the radioactivity in plasma (42.9% ± 2.9%). The extent of oral absorption was estimated to be 49.6%; the Cmax of capmatinib in plasma was reached at 2 hours (median time to reach Cmax). The apparent mean elimination half-life of capmatinib in plasma was 7.84 hours. Apparent distribution volume of capmatinib during the terminal phase was moderate-to-high (geometric mean 473 l). Metabolic reactions involved lactam formation, hydroxylation, N-dealkylation, formation of a carboxylic acid, hydrogenation, N-oxygenation, glucuronidation, and combinations thereof. M16, the most abundant metabolite in plasma, urine, and feces was formed by lactam formation. Absorbed capmatinib was eliminated mainly by metabolism and subsequent biliary/fecal and renal excretion. Excretion of radioactivity was complete after 7 days. CYP phenotyping demonstrated that CYP3A was the major cytochrome P450 enzyme subfamily involved in hepatic microsomal metabolism, and in vitro studies in hepatic cytosol indicated that M16 formation was mainly catalyzed by aldehyde oxidase. SIGNIFICANCE STATEMENT: The absorption, distribution, metabolism, and excretion of capmatinib revealed that capmatinib had substantial systemic availability after oral administration. It was also extensively metabolized and largely distributed to the peripheral tissue. Mean elimination half-life was 7.84 hours. The most abundant metabolite, M16, was formed by imidazo-triazinone formation catalyzed by cytosolic aldehyde oxidase. Correlation analysis, specific inhibition, and recombinant enzymes phenotyping demonstrated that CYP3A is the major enzyme subfamily involved in the hepatic microsomal metabolism of [14C]capmatinib.

Kendomycin Cytotoxicity against Bacterial, Fungal, and Mammalian Cells Is Due to Cation Chelation.

Kendomycin is a small-molecule natural product that has gained significant attention due to reported cytotoxicity against pathogenic bacteria and fungi as well as a number of cancer cell lines. Despite significant biomedical interest and attempts to reveal its mechanism of action, the cellular target of kendomycin remains disputed. Herein it is shown that kendomycin induces cellular responses indicative of cation stress comparable to the effects of established iron chelators. Furthermore, addition of excess iron and copper attenuated kendomycin cytotoxicity in bacteria, yeast, and mammalian cells. Finally, NMR analysis demonstrated a direct interaction with cations, corroborating a close link between the observed kendomycin polypharmacology across different species and modulation of iron and/or copper levels.

Comparison of 19F NMR and 14C Measurements for the Assessment of ADME of BYL719 (Alpelisib) in Humans.

The human mass balance study is the definitive study for the assessment of absorption, distribution, metabolism, and excretion (ADME) properties of a new chemical entity in humans. Traditionally this has been carried out by the administration of radiolabeled drug substances, typically 14C or occasionally 3H, as detection methods for these isotopes allow the absolute quantification of drug-related material (DRM) in blood, plasma, and excreta. Coupled with the use of analytical techniques such as liquid chromatography-mass spectrometry, a picture of the metabolic fate of a compound can be elucidated. In this study, we demonstrate the capabilities of 19F nuclear magnetic resonance (NMR) spectroscopy, applied as an alternative to radiolabeling, for the determination of mass balance and for metabolite profiling of an orally administered fluorinated drug. To demonstrate the capabilities of NMR, the study was conducted on remaining samples from a 14C human mass balance study conducted on Alpelisib (BYL719), a compound in late stage development at Novartis for the treatment of solid tumors. Quantitative 14C data were used to cross-validate the data obtained by NMR. The data show that, using 19F NMR, comparable data can be obtained for key human ADME endpoints including mass balance, total DRM determination in plasma and metabolite profiling and identification in plasma and excreta. Potential scenarios where NMR could be employed as an alternative to radiolabeling for the conduct of an early human ADME study are discussed.

Pneumocystis jirovecii-induced chronic interstitial lung disease in Waldenström's macroglobulinemia.

Infections with Pneumocystis jirovecii can result in asymptomatic colonization or induce life threatening clinical symptoms. However, there appears to be a 'gray area' between colonization and severe pneumonia that remains underestimated so far. We describe a case with chronic interstitial lung disease and chronic cough that was attributed to P. jirovecii. The patient's history of chronic cough, although very likely being fostered by the underlying Waldenström's macroglobulinemia and interstitial lung disease, was most likely caused by P. jirovecii infection. This gives raise to the hypothesis that P. jirovecii infections do not necessarily induce life threatening pneumonia. Consequently, serial testing is required in eligible patients with positive PCR results in order to discriminate between colonization, 'gray zone' infection, and beginning pneumonia.

Is it time to rebalance the case mix? A portfolio analysis of direct catheterization laboratory costs over a 5-year period.

BACKGROUND: Cardiac catheterization laboratories (CLL) have continued to function as profit centers for hospitals. Due to a high percentage of material and labor costs, they are natural targets for process improvement. Our study applied a contribution margin (CBM) concept to evaluate costs and cost dynamics over a 5-year period. METHODS: We retrospectively analyzed all procedures performed at a tertiary heart center between 2007 and 2011. Total variable costs, including labor time, material, and maintenance-expenses, were allocated at a global as well as a procedural level. CBM and CBM ratios were calculated by integration of individual DRG revenues. RESULTS: Annual case volume increased from 1288 to 1545. In parallel, overall profitability improved as indicated by a 2% increase in CBM ratio and a higher CBM generated per hour of CLL working time (4325 vs. 5892 €, p < 0.001). Coronary angiography generated higher average CBMs per hour than coronary or electrophysiological interventions (5831 vs. 3458 vs. 1495 €; p < 0.001). The latter are characterized by relatively high per case material expenditures. On a procedural level, DRG-specific trends as a steady improvement of examination time or an increase in material costs were detectable. CONCLUSIONS: The CBM concept allows a comprehensive analysis of CLL costs and cost dynamics. From a health service providers view, its range of application includes global profitability analysis, portfolio evaluation, and a detailed cost analysis of specific service lines. From a healthcare payers perspective, it may help to monitor hospital activities and to provide a solid data basis in cases where inappropriate developments are suspected. The calculation principle is simple which may increase user acceptance and thus the motivation of team members.

Impact of Cryoballoon Ablation in Hypertrophic Cardiomyopathy-related Heart Failure due to Paroxysmal Atrial Fibrillation. A Comparative Case Series.

BACKGROUND: Atrial fibrillation (AF) represents a turning point in hypertrophic cardiomyopathy (HCM). Pulmonary Vein Isolation (PVI) with Radiofrequency Catheter Ablation (RFCA) is accepted to be successful in restoring sinus rhythm (SR) in HCM patients. The efficacy of cryoballoon (CB) therapy in HCM patients has not been studied so far. METHODS: 166 patients with AF underwent PVI with CB technology in our single center between 1/2012 and 12/2015. To evaluate the efficacy of the CB therapy in HCM patients, we compared their clinical outcome with those in "Non-HCM" AF patients in a 3 and 6 months follow-up. RESULTS: Out of 166 AF patients (65.7% paroxysmal AF, PAF), 4 patients had HCM and PAF (young males < 50 years). During the blanking period, 26 patients (15.8%) suffered from AF recurrence (11.0% PAF), including all HCM patients. The 6 months follow up of "Non-HCM" AF patients showed acceptable results (80% stable SR), whereas the HCM patients remained AF. IN CONCLUSION: Even if the CB provides advantages, the single device cannot be recommended in HCM patients because of early AF recurrences. Anyway, because of the specific hemodynamic changes in HCM patients with AF, ablation should be sought in an early state of its occurrence, then, however, preferably with RFCA.

ECG-Guided Surveillance Technique in Cryoballoon Ablation for Paroxysmal and Persistent Atrial Fibrillation: A Strategy to Prevent From Phrenic Nerve Palsy.

AIMS: Phrenic nerve palsy (PNP) is still a cause for concern in Cryoballoon ablation (CBA) procedures. New surveillance techniques, such as invasive registration of the compound motor action potential (CMAP), have been thought to prevent the occurrence of PNP. The present study investigates the impact of CMAP surveillance via an alternative and non-invasive ECG-conduction technique during CBA. METHODS: PVI with CBA was performed in 166 patients suffering from AF. Diaphragmal contraction was monitored by abdominal hands-on observation in Observation Group I; Observation Group II was treated using additional ECG-conduction, as a means of modified CMAP surveillance method. During the ablation of the right superior and inferior pulmonary veins, the upper extremities lead I was newly adjusted between the inferior sternum and the right chest, thereby recording the maximum CMAP. The CMAP in the above-mentioned ECG leads was continuously observed in a semi-quantitative manner. RESULTS: PNP was observed in 10 (6%) patients in total. In Observation Group I, 6 out of 61 (9.8%) demonstrated PNP. In Observation Group II a significant decrease of PNP could be demonstrated (p <0,001) and occurred in 4 out of 105 patients (3.8%). While three patients from Observation Group I left the EP lap with an ongoing PNP, none of the patients in Observation Group II had persistent PNP outside of the EP lab. CONCLUSION: The present study demonstrates that additional ECG-conduction, used as modified CMAP surveillance, is an easy, effective and helpful additional safety measure to prevent PNP in CBA.

Pulmonary vein isolation in 2012: is it necessary to perform a time consuming electrophysical mapping or should we focus on rapid and safe therapies? A retrospective analysis of different ablation tools.

BACKGROUND: Pulmonary Vein Isolation (PVI) is evolving as an established treatment option in atrial fibrillation (AF). Different fluoroscopy-guided ablation devices exist either on the basis of expandable circumferential and mesh designs with mapping and ablation of pulmonary vein potentials, or of a balloon technology, a "single shot" device with a purely anatomical approach. Systematic comparisons between procedure duration (PD), fluoroscopy time (FT) and clinical outcome in using different ablation tools are lacking in the literature. METHODS: In a single center retrospective analysis, 119 PVI procedures were performed between August 2008 and March 2011 in paroxysmal AF (PAF, 59.7%) and persistent AF (persAF, 40.3%) patients with mean age of 59.4±10.3 years and history of AF since 8.1±9.7 months. The PVI procedures were evaluated by comparing PD and FT using I) the High Density Mesh Mapper (HDMM), II) the High Density Mesh Ablator (HDMA), and III) the Arctic Front® Cryoballoon. The primary endpoints were FT and PD, the secondary endpoint was procedural safety and efficacy in short- and longterm follow-up. RESULTS: The procedures performed for 119 patients (63.0 % male) included 42 PVIs with the HDMM (35.3 %), 47 with the HDMA (39.5 %) and 30 with the cryoballoon (25.2 %). Comparing the 30 first procedures in groups of 10 in the HDMM and HDMA group, PD and FT fell in the HDMM group (PD from 257.5 to 220.9 min and FT from 80.5 to 67.3 min, both p < 0.05) as well as in the HDMA group (PD from 182.9 to 147.2 min and FT from 41.02 to 29.1 min, both p < 0.05). In the cryoballoon group, there was a steep learning curve with a steady state after the first 10 procedures (PD and FT decreased significantly from 189.5 to 138.1 min and 36.9 to 27.3 min, p values 0.005 and 0.05 respectively). With respect to recurrence of AF in a 24 months follow up, the HDMM and cryoballoon group showed comparable results with ~72% of patients free of arrhythmias. None of the patients died due to severe complications, or suffered a hemodynamic relevant pericardial effusion and/or stroke. Impairment of the phrenic nerve was observed in three patients. CONCLUSION: Use of the cryoballoon technology was associated with a steep learning curve and a reduced PD and FT; the long-term outcome was similar compared with the HDMM group. The efficacy and safety of the devices but also PD and FT should be respected as the strongest indicators of the quality of ablation. Further studies with long time follow-ups will show if the time for correct mapping of the PV potentials is a price we should be willing to pay or if we should adopt a "wait-and-see" attitude referring the AF recurrence.

Metabonomic investigation of human Schistosoma mansoni infection.

Schistosomiasis is a parasitic infection that is endemic in many developing countries in the tropics and subtropics afflicting more than 207 million people primarily in rural areas. After malaria, it is the second most important parasitic infection in terms of socio-economic and public health. Investigation of the host-parasite interaction at the molecular level and identification of biomarkers of infection and infection-related morbidity would be of value for improved strategies for treatment and morbidity control. To this end, we conducted a nuclear magnetic resonance (NMR) based metabonomics study involving a well-characterized cohort of 447 individuals from a rural area in Uganda near Lake Victoria with a high prevalence of Schistosoma mansoni, a species predominantly occurring in Africa including Madagascar and parts of South America. Cohort samples were collected from individuals at five time-points, before and after (one or two times) chemotherapy with praziquantel (PZQ). Using supervised multivariate statistical analysis of the recorded one-dimensional (1D) NMR spectra, we were able to discriminate infected from uninfected individuals in two age groups (children and adults) based on differences in their urinary profiles. The potential molecular markers of S. mansoni infection were found to be primarily linked to changes in gut microflora, energy metabolism and liver function. These findings are in agreement with data from earlier studies on S. mansoni infection in experimental animals and thus provide corroborating evidence for the existence of metabolic response specific for this infection.

Primary malignant pericardial mesothelioma - a rare cause of pericardial effusion and consecutive constrictive pericarditis: a case report.

INTRODUCTION: Primary malignant pericardial mesothelioma is a very rare pericardial tumor of unknown etiology. CASE PRESENTATION: A 61-year-old Caucasian woman was admitted to our hospital complaining of exertional dyspnea due to a large pericardial effusion. Intrapericardial fluid volume declined after repeated pericardiocentesis, but the patient progressively developed a hemodynamically relevant pericardial constriction. Pericardiectomy revealed a pericardial mesothelioma. Subsequently, four cycles of chemotherapy (dosage according to recently published trials) were administered. The patient remained asymptomatic, and there was no recurrence of the tumor after three years. CONCLUSION: Pericardial mesothelioma should be considered and managed appropriately in non-responders to pericardiocentesis, and in patients who develop constrictive pericarditis late in their clinical course.

Contrast medium induced nephropathy in patients undergoing percutaneous coronary intervention for acute coronary syndrome: differences in STEMI and NSTEMI.

UNLABELLED: The aim of this study was to assess the incidence, clinical predictors, and outcome of patients developing contrast medium induced nephropathy (CIN) after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). BACKGROUND: CIN is associated with significant higher morbidity and mortality after coronary intervention. Recently it was shown, that patients undergoing percutaneous coronary intervention for acute myocardial infarction have a significant higher risk of developing CIN. Non-ST-elevating myocardial infarction (NSTEMI) patients (pts) might be at an even higher risk developing CIN than patients with ST-elevating myocardial infarction (STEMI), because of presenting older and more often with diabetes. METHODS: In 392 consecutive ACS patients developing myocardial infarction and therefore undergoing emergent coronary angiography between October 2004 and March 2007, we measured serum creatinine concentration (Cr) at baseline and each day of the following 3 days. Contrast medium induced nephropathy was defined as an increase in Cr > 0.5 mg/dl. ACS was defined according to the guidelines of the German Society of Cardiology. RESULTS: Overall, 392 pts were included: 203 (51.8%) with STEMI and 189 (48.2%) with NSTEMI. Patients with STEMI developed more often a cardiogenic shock (18 vs. 6%; P < 0.001) whereas patients with NSTEMI were older (67 vs. 61 years; P < 0.001) and presenting with a higher co-morbidity. Forty-five (11.5%) pts developed CIN; 22 (10.8%) in the STEMI group and 23(12.2%) in the NSTEMI group (P = 0.75). Patients developing CIN presented a more complicated clinical course and a significantly longer hospital stay (14 vs. 10 days; P < 0.001). The mortality rate was also significantly higher (16 vs. 6%; P < 0.05). CONCLUSION: This prospective study showed no differences in the incidence of developing CIN in patients undergoing PCI for STEMI or NSTEMI, but the predisposing factors, however, differed significantly. Although STEMI patients needed significantly more contrast medium for revascularisation, they did not develop CIN more often. CIN was associated with higher in-hospital complication rate and mortality. Thus, better preventive strategies according to the different predisposing factors leading to CIN are needed to reduce morbidity and mortality, especially in high risk patients.

Segmental pulmonary vein isolation in atrial fibrillation: new insights from the high density mesh mapper technique in an electrophysiologically guided approach.

OBJECTIVE: As opposed to fundamental investigations into the nature of atrial fibrillation (AF) current clinical studies of AF ablation techniques sometimes only contain sparse information about the underlying electrophysiological properties. The purpose of this prospective, pilot study was to evaluate acute therapeutic success and clinical outcome after 6 month of segmental ostial ablation (SOA) using the High Density Mesh Mapper catheter (HDMM, BARD Electrophysiology, Lowell, MA, USA) for an electrophysiological guided approach. The HDMM is a novel, single expandable basket electrode catheter for high resolution recordings at the left atrium/pulmonary vein (PV) junction. METHODS: SOA was performed by irrigated radiofrequency (RF) application around the HDMM. Entry- and exit conduction block, as well as decreased local electrode amplitude, were endpoints for short-term successful ablation. RESULTS: Seventy-two patients with highly symptomatic paroxysmal AF (PAF; 47, 65.2%), persistent AF (12, 16.7%) and permanent AF (13, 18.1%) were studied. Entrance conduction block was obtained in 93%, exit conduction block in 81% of all PV. After 6 month no PV stenosis was observed, 62 patients (86.1%) improved clinically, whereas 52 patients (72.2%) were free from arrhythmias and sinus rhythm was present favoring patients with PAF. CONCLUSIONS: In this first prospective study of PV isolation using the HDMM, our findings suggest, that this method is safe and yields good primary success rates and favourable clinical outcome at 6 month. The new technology based on high resolution recordings, offers beside good anatomical orientation a direct electrophysiological control for monitoring of bidirectional conduction block.

Impact of irrigated energy application on the right coronary artery hemodynamics: FFR measurement in patients who underwent ablation of common type atrial flutter.

OBJECTIVE: The purpose of this first in vivo study was to assess the incidence of thermal influence to the right coronary artery (RCA) during ablation of common type atrial flutter (Aflu) by measuring the fractional flow reserve (FFR) in the vessel before, under and after ablation. METHODS: In thirty three patients ablated we performed coronary angiography (CA) before and at the end of the procedure. The FFR wire was positioned in the distal, the isthmus underlying, part of the RCA. Before and after the procedure FFR measurement was done at baseline and during adenosine administration. During the whole ablation procedure FFR measurement was continuously carried on, to monitor a transient thermal impact to the RCA. RESULTS: Of the 33 patients observed, 25 males, 8 females, mean age 58 +/- 9.5 years, none with CAD, all patients, except one with unidirectional block, were successfully ablated. The FFR at rest and under medication with adenosine before and after ablation was 0.985/0.949 and 0.981/0.942, respectively (p = ns). The CA of the RCA did not reveal any morphological change. The mean FFR while ablation declined from 0.94 to 0.904 (p = ns). Twenty-six patients (78.8%) had no or moderate decrease in FFR, seven patients (21.2%) demonstrated a substantial decrease [five patients (15.2%), FFR < 0.9 and >0.75] or significant change [two patients (6.1%)], FFR < 0.75 consistent with a remarkable or significant reduction of coronary flow. CONCLUSION: Ablation of AFlu did not alter RCA morphology; simultaneous FFR measurement showed severe depression of the FFR in a few patients, consistent with impairment in myocardial perfusion.

[Disproportionate shortening of left ventricular diastolic duration in patients with dilated cardiomyopathy]. / Abnorme Verkürzung der linksventrikulären Diastolendauer unter körperlicher Belastung bei Patienten mit dilatativer Kardiomyopathie.

BACKGROUND AND PURPOSE: Cardiac performance can be characterized in terms of the relative duration of systole and diastole. In pediatric patients with dilated cardiomyopathy (DCM), a disproportionate shortening of left ventricular diastole was observed. The present study was intended to reproduce these findings in an adult patient group and to evaluate exercise-related changes of both time intervals. PATIENTS AND METHODS: Exercise radionuclide angiography was used in 61 patients with DCM NYHA (New York Heart Association) stage II-III. The phases of the cardiac cycle were derived from a radionuclide time-activity curve with high temporal resolution. The control group consisted of 26 patients referred for ventricular function assessment with radionuclide angiography before cardiotoxic cancer treatment. RESULTS: When the duration of systole was expressed as the product of systolic time and heart rate, DCM patients exhibited a significant increase in left ventricular systolic time at rest (23.9 vs. 21.5 s/min; p = 0.006) and during peak exercise (29.2 vs. 26.7 s/min; p = 0.01). The prolongation of left ventricular systole at peak exercise was evident, although the peak heart rate was significantly lower in the patient group than in the control group (118 vs. 127/min; p = 0.04). In DCM patients the diastolic time loss per beat was further quantified using a regression equation obtained from the healthy control group. A significant shortening of left ventricular diastolic time was confirmed during peak exercise. Furthermore, a progressive loss in diastolic time per beat from rest to peak exercise was noted. CONCLUSION: Cardiac cycle abnormalities of patients with DCM are characterized by a prolongation of left ventricular systole and an abnormal shortening of left ventricular diastole. The systolic-diastolic mismatch is accentuated during exercise and has the potential to impair the cardiac reserve in these patients by restricting ventricular filling and perfusion.

NMR studies of the fifth transmembrane segment of sarcoplasmic reticulum Ca2+-ATPase reveals a hinge close to the Ca2+-ligating residues.

Two recent X-ray structures have tremendously increased the understanding of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and related proteins. Both structures show the fifth transmembrane span (M5) as a single continuous alpha-helix. The inherent structural and dynamic features of this span (Lys758-Glu785) were studied in isolation in sodium dodecyl sulfate (SDS) micelles using liquid-state nuclear magnetic resonance (NMR) spectroscopy. We find that a flexible region (Ile765-Asn768) is interrupting the alpha-helix. The location of the flexible region near the Ca(2+) binding residues Asn768 and Glu771 suggests that together with a similar region in M6 it has a hinge function that may be important for cooperative Ca(2+) binding and occlusion.