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.

Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism.

Siponimod, a next-generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism, and excretion (ADME) of a single 10-mg oral dose of [14C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine, and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (area under the concentration-time curve), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 hours) and moderate distribution (Vz/F: 291 l). Siponimod was mainly cleared through biotransformation, predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 hours. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical pharmacokinetic studies, a long-lived nonpolar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. We further conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. The selective inhibitor and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other cytochrome P450 enzymes.

Insight in genome-wide association of metabolite quantitative traits by exome sequence analyses.

Metabolite quantitative traits carry great promise for epidemiological studies, and their genetic background has been addressed using Genome-Wide Association Studies (GWAS). Thus far, the role of less common variants has not been exhaustively studied. Here, we set out a GWAS for metabolite quantitative traits in serum, followed by exome sequence analysis to zoom in on putative causal variants in the associated genes. 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy experiments yielded successful quantification of 42 unique metabolites in 2,482 individuals from The Erasmus Rucphen Family (ERF) study. Heritability of metabolites were estimated by SOLAR. GWAS was performed by linear mixed models, using HapMap imputations. Based on physical vicinity and pathway analyses, candidate genes were screened for coding region variation using exome sequence data. Heritability estimates for metabolites ranged between 10% and 52%. GWAS replicated three known loci in the metabolome wide significance: CPS1 with glycine (P-value  = 1.27×10-32), PRODH with proline (P-value  = 1.11×10-19), SLC16A9 with carnitine level (P-value  = 4.81×10-14) and uncovered a novel association between DMGDH and dimethyl-glycine (P-value  = 1.65×10-19) level. In addition, we found three novel, suggestively significant loci: TNP1 with pyruvate (P-value  = 1.26×10-8), KCNJ16 with 3-hydroxybutyrate (P-value  = 1.65×10-8) and 2p12 locus with valine (P-value  = 3.49×10-8). Exome sequence analysis identified potentially causal coding and regulatory variants located in the genes CPS1, KCNJ2 and PRODH, and revealed allelic heterogeneity for CPS1 and PRODH. Combined GWAS and exome analyses of metabolites detected by high-resolution 1H-NMR is a robust approach to uncover metabolite quantitative trait loci (mQTL), and the likely causative variants in these loci. It is anticipated that insight in the genetics of intermediate phenotypes will provide additional insight into the genetics of complex traits.

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.

Impact of High-Intensity-NIV on the heart in stable COPD: a randomised cross-over pilot study.

BACKGROUND: Although high-intensity non-invasive ventilation has been shown to improve outcomes in stable COPD, it may adversely affect cardiac performance. Therefore, the aims of the present pilot study were to compare cardiac and pulmonary effects of 6 weeks of low-intensity non-invasive ventilation and 6 weeks of high-intensity non-invasive ventilation in stable COPD patients. METHODS: In a randomised crossover pilot feasibility study, the change in cardiac output after 6 weeks of each NIV mode compared to baseline was assessed with echocardiography in 14 severe stable COPD patients. Furthermore, CO during NIV, gas exchange, lung function, and health-related quality of life were investigated. RESULTS: Three patients dropped out: two deteriorated on low-intensity non-invasive ventilation, and one presented with decompensated heart failure while on high-intensity non-invasive ventilation. Eleven patients were included in the analysis. In general, cardiac output and NTproBNP did not change, although individual effects were noticed, depending on the pressures applied and/or the co-existence of heart failure. High-intensity non-invasive ventilation tended to be more effective in improving gas exchange, but both modes improved lung function and the health-related quality of life. CONCLUSIONS: Long-term non-invasive ventilation with adequate pressure to improve gas exchange and health-related quality of life did not have an overall adverse effect on cardiac performance. Nevertheless, in patients with pre-existing heart failure, the application of very high inspiratory pressures might reduce cardiac output. TRIAL REGISTRATION: The trial was registered in the Deutsches Register Klinischer Studien (DRKS-ID: DRKS00007977 ).

Interconversion Rates between Conformational States as Rationale for the Membrane Permeability of Cyclosporines.

Cyclic peptides have regained interest as potential inhibitors of challenging targets but have often a low bioavailability. The natural product cyclosporine A (CsA) is the textbook exception. Despite its size and polar backbone, it is able to passively cross membranes. This ability is hypothesized to be due to a conformational change from the low-energy conformation in water to a "congruent" conformation that is populated both in water and inside the membrane. Here, we use a combination of NMR measurements and kinetic models based on molecular dynamics simulations to rationalize the difference in the membrane permeability of cyclosporine E (CsE) and CsA. The structure of CsE differs only in a backbone methylation, but its membrane permeability is one order of magnitude lower. The most striking difference is found in the interconversion rates between the conformational states favored in water and in chloroform, which are up to one order of magnitude slower for CsE compared to CsA.

Effect of patient's age on the profitability of inpatient cardiac catheterization: a contribution margin analysis of frequently performed procedures over a 5-year period.

BACKGROUND: Due to a continuing age shift in the German society hospital providers are concerned about the additional costs associated with the treatment of elderly patients. It is not clear if cardiac catheterization in aged patients leads to higher resource utilization and if DRG-revenues do compensate for this factor. METHODS: Procedure-related and administrative data of all patients who underwent cardiac catheterization at a tertiary heart center between 2007 and 2011 were collected and analyzed. Then a profitability analysis was performed by comparing the case related variable costs with the Diagnosis-related group (DRG) per case revenues. A particular emphasis was placed on a comparative analysis of identical clusters of procedures. RESULTS: The most frequently performed catheterization procedure (n = 1800) was associated with significantly higher material expenditure in very old patients (178 ± 48 €) than in old (171 ± 28; p = 0.001) and young patients (172 ± 39; p = 0.046). Furthermore, radiation time and the length of hospital stay were increased in very old patients (3.5 ± 3.8 min and 6.2 ± 4.8 days) compared to old (2.7 ± 2.8 min and 4.6 ± 3.8 days; p < 0.001) and young patients (2.5 ± 2.5 min and 4.5 ± 3.9 days; p < 0.001). Due to higher DRG revenues very old patients achieved higher absolute contribution margins (2065 ± 1033 €) than old (1804 ± 1902 €; p < 0.001) and young patients (1771 ± 902 €; p < 0.001). However, the contribution margins per day were significantly smaller (440 ± 226 €) than those in old (488 ± 234 €; p = 0.001) and young patients (484 ± 206 €; p = 0.001). CONCLUSIONS: Catheterization of very old patients is related to lower contribution margins per day despite higher material and time expenditures. Since efforts to reduce the length of hospital stay of these patients are limited, this may result in a competitive disadvantage of hospitals which are more affected by the demographic change.

Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States.

The membrane permeability of cyclic peptides and peptidomimetics, which are generally larger and more complex than typical drug molecules, is likely strongly influenced by the conformational behavior of these compounds in polar and apolar environments. The size and complexity of peptides often limit their bioavailability, but there are known examples of peptide natural products such as cyclosporin A (CsA) that can cross cell membranes by passive diffusion. CsA is an undecapeptide with seven methylated backbone amides. Its crystal structure shows a "closed" twisted ß-pleated sheet conformation with four intramolecular hydrogen bonds that is also observed in NMR measurements of CsA in chloroform. When binding to its target cyclophilin, on the other hand, CsA adopts an "open" conformation without intramolecular hydrogen bonds. In this study, we attempted to sample the complete conformational space of CsA in chloroform and in water by molecular dynamics simulations in order to better understand its conformational behavior in these two environments and to rationalize the good membrane permeability of CsA observed experimentally. From 10 µs molecular dynamics simulations in each solvent, Markov state models were constructed to characterize the metastable conformational states. The model in chloroform is compared to nuclear Overhauser effect NMR spectroscopy data reported in this study and taken from the literature. The conformational landscapes in the two solvents show significant overlap but also clearly distinct features.

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.

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.

Ethanol contamination of cerebrospinal fluid during standardized sampling and its effect on (1)H-NMR metabolomics.

Standardization of body fluid sampling, processing and storage procedures is pivotal to ensure data quality in metabolomics studies. Yet, despite strict adherence to standard sampling guidelines, we detected variable levels of ethanol in the (1)H-NMR spectra of human cerebrospinal fluid (CSF) samples (range 9.2 × 10(-3)-10.0 mM). The presence of ethanol in all samples and the wide range of concentrations clearly indicated contamination of the samples of some sort, which affected the (1)H-NMR spectra quality and the interpretation. To determine where in the sampling protocol the ethanol contamination occurs, we performed a CSF sampling protocol simulation with 0.9 % NaCl (saline) instead of CSF and detected ethanol in all simulation samples. Ethanol diffusion through air during sampling and preparation stages appeared the only logical explanation. With a bench study, we showed that ethanol easily diffuses into ex vivo CSF samples via air transmission. Ethanol originated from routinely used skin disinfectants containing ethanol and from laboratory procedures. Ethanol affected the CSF sample matrix at concentrations above ~9.4 mM and obscured a significant part of the (1)H-NMR spectrum. CSF sample preparation for (1)H-NMR-based metabolomics analyses should therefore be carried out in a well-ventilated atmosphere with laminar flow, and use of ethanol should be avoided.

A metabolomic profile is associated with the risk of incident coronary heart disease.

BACKGROUND: Metabolomics, defined as the comprehensive identification and quantification of low-molecular-weight metabolites to be found in a biological sample, has been put forward as a potential tool for classifying individuals according to their risk of coronary heart disease (CHD). Here, we investigated whether a single-point blood measurement of the metabolome is associated with and predictive for the risk of CHD. METHODS AND RESULTS: We obtained proton nuclear magnetic resonance spectra in 79 cases who developed CHD during follow-up (median 8.1 years) and in 565 randomly selected individuals. In these spectra, 100 signals representing 36 metabolites were identified. Applying least absolute shrinkage and selection operator regression, we defined a weighted metabolite score consisting of 13 proton nuclear magnetic resonance signals that optimally predicted CHD. This metabolite score, including signals representing a lipid fraction, glucose, valine, ornithine, glutamate, creatinine, glycoproteins, citrate, and 1.5-anhydrosorbitol, was associated with the incidence of CHD independent of traditional risk factors (TRFs) (hazard ratio 1.50, 95% CI 1.12-2.01). Predictive performance of this metabolite score on its own was moderate (C-index 0.75, 95% CI 0.70-0.80), but after adding age and sex, the C-index was only modestly lower than that of TRFs (C-index 0.81, 95% CI 0.77-0.85 and C-index 0.82, 95% CI 0.78-0.87, respectively). The metabolite score was also associated with prevalent CHD independent of TRFs (odds ratio 1.59, 95% CI 1.19-2.13). CONCLUSION: A metabolite score derived from a single-point metabolome measurement is associated with CHD, and metabolomics may be a promising tool for refining and improving the prediction of CHD.

Determinants of right ventricular muscle mass in idiopathic dilated cardiomyopathy: impact of left ventricular muscle mass and pulmonary hypertension.

INTRODUCTION: Although chronic pulmonary hypertension and right ventricular (RV) function carry important functional and prognostic implications in idiopathic dilated cardiomyopathy (IDC), little information on RV muscle mass (RVMM) and its determinants has been published. METHODS: Our study comprised thirty-five consecutive patients with IDC, left ventricular (LV) ejection fraction<40% and NYHA class≥2. Hemodynamic data and parameters on LV and RV geometry were derived from right heart catheterisation and cardiac magnetic resonance imaging. RESULTS: RVMM was normalized to body size using a common linear, body surface area based approach (RVMMI) and by an allometric index (RVMM-AI) incorporating adjustment for age, height and weight. Stepwise multiple regression analysis revealed that pulmonary artery pressure and left ventricular muscle mass were independent predictors of RVMM-AI. The interventricular mass ratio of RV and LV mass (IVRM) was closely related to RVMM (r=0.79, p<0.001) and total muscle mass (r=0.39, p<0.02). However, there was no significant relationship between LVMM and IVMR (r=0.17, p=0.32). CONCLUSION: Our data suggest that an increase in RV mass in IDC may be explained by two mechanisms: First, as a consequence of the myopathic process itself resulting in a balanced hypertrophy of both ventricles. Second, due to the chamber specific burden of pulmonary artery pressure rise, resulting in unbalanced RV hypertrophy.

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.

Segment-orientated analysis of two-dimensional strain and strain rate as assessed by velocity vector imaging in patients with acute myocardial infarction.

AIMS: Strain rate imaging techniques have been proposed for the detection of ischemic or viable myocardium in coronary artery disease, which is still a challenge in clinical cardiology. This retrospective comparative study analyzed regional left ventricular function and scaring with two-dimensional strain (2DS) in the first 4 to 10 days after acute anterior myocardial infarction (AMI). METHODS AND RESULTS: The study population consisted of 32 AMI patients with an LAD occlusion and successful reperfusion. The assessment of peak systolic 2DS and peak systolic strain rate (SR) was performed segment-oriented with the angle-independent speckle tracking algorithm Velocity Vector Imaging (VVI). The infarcted, adjacent and non-infarcted segments were revealed by late enhancement MRI (LE-MRI), which was used as reference for the comparison with 2DS. The infarcted segments showed a significant decrease of tissue velocities, 2DS and SR in comparison to the non-affected segments. CONCLUSION: 2DS and SR as assessed by VVI seem to be a suitable approach for echocardiographic quantification of global and regional myocardial function as well as a promising tool for multimodal risk stratification after anterior AMI.

Metabolic profiling of accelerated aging ERCC1 d/- mice.

Aging is a fundamental biological process for which the mechanism is still largely unknown due to its complex and multifactorial nature. Animal models allow us to simplify this complexity and to study individual factors separately. As there are many causative links between DNA repair deficiency and aging, we studied the ERCC1(d/-) mouse, which has a modified ERCC1 gene, involved in the Nucleotide Excision Repair, and as a result has a premature aging phenotype. Profiling of these mice on different levels can give an insight into the mechanisms underlying the aging phenotype. In the current study, we have performed metabolic profiling of serum and urine of these mice in comparison to wild type and in relation to aging by (1)H NMR spectroscopy. Analysis of metabolic trajectories of animals from 8 to 20 weeks suggested that wild type and ERCC1(d/-) mutants have similar age-related patterns of changes; however, the difference between genotypes becomes more prominent with age. The main differences between these two genetically diverse groups of mice were found to be associated with altered lipid and energy metabolism, transition to ketosis, and attenuated functions of the liver and kidney.

Systolic and early diastolic left ventricular velocities assessed by tissue Doppler imaging in 100 top-level handball players.

BACKGROUND AND OBJECTIVE: Echocardiographic tissue Doppler imaging (TDI) has been proposed for the differentiation of physiologic left ventricular hypertrophy and pathologic left ventricular hypertrophy in athletes. In addition, cutoff values for systolic (S'<9 cm/s) and early diastolic (E'<9 cm/s) myocardial velocities had been defined. The aim of our study was the analysis of the morphologic cardiac changes by standard echocardiography, and the myocardial velocities S' and E' by TDI in top-level handball players with respect to the predefined cutoff values. PATIENTS AND METHODS: Pulsed-wave TDI of the systolic and early diastolic velocities was performed at the lateral and septal mitral annulus (MA) in the four-chamber view in 100 athletes (100 Caucasian men; professional handball players of the first German handball league and the German national team; mean age 25.8+/-4.8 years). RESULTS: Global and regional left ventricular systolic function was normal in all athletes. They showed an eccentric hypertrophy of the left ventricle (LV), which was characterized by an increased mass of the LV (287.3+/-58.4 g), and an increased end diastolic diameter of the LV (LVEDD: 58+/-5.9 mm), but no echomorphologic signs of pathologic hypertrophy or hypertrophic cardiomyopathy. TDI showed a systolic velocity S' of the MA of 9.3+/-1.5 cm/s at the septal and 10.5+/-2.1 at the lateral MA. Ten of the 100 athletes showed a S'<9 cm/s at both sides of the MA. TDI showed an early diastolic velocity E' of the MA of 13.2+/-2.8 cm/s at the septal and of 16.6+/-3.4 cm/s at the lateral MA. None of the 100 athletes showed reduced systolic or early diastolic velocities below the proposed cutoff values (S' and E'<9 cm/s) at any sides of the MA. CONCLUSION: Our study provides further insights into systolic and diastolic function as assessed by TDI in top-level handball players. Owing to the large cohort of individuals, our findings might be helpful as reference values for the echocardiographic assessment of handball players, who are performing a moderate static and high dynamic sport.