Stress echocardiography for left ventricular diastolic dysfunction detection in patients with non-severe chronic obstructive pulmonary disease: a cross-sectional study

Aim To assess whether the simultaneous performance of exercise stress echocardiography and cardio-pulmonary testing (ESE-CPET) may facilitate the timely diagnosis of subclinical left ventricular diastolic dysfunction (LVDD) in patients with non-severe chronic obstructive pulmonary disease (COPD), preserved left ventricular systolic function, and exertional dyspnea or exercise intolerance. Methods This cross-sectional study, conducted between May 2017 and April 2018, involved 104 non-severe COPD patients with exertional dyspnea and preserved ejection fraction who underwent echocardiography before CPET and 1-2 minutes after peak exercise. Based on the peak E/e’ ratio, patients were divided into the group with stressinduced LVDD – E/e’>15 and the group without stress-induced LVDD. We assessed the association between LVDD and the following CPET variables: minute ventilation, peak oxygen uptake (VO2), ventilatory efficiency, heart rate reserve, and blood pressure.Results During ESE-CPET, stress-induced LVDD occurred in 67/104 patients (64%). These patients had lower work load, peak VO2, O2 pulse, and minute ventilation (VE), and higher VE/VCO2 slope than patients without stress-induced LVDD (35.18 ± 10.4 vs 37.01 ± 11.11, P < 0.05). None of the CPET variables correlated with E/e’. Conclusion Combined ESE-CPET may distinguish masked LVDD in patients with non-severe COPD with exertional dyspnea and preserved left ventricular systolic function. None of the CPET variables was a predictor for subclinical LVDD

Influence of transcrystalline layer on finite element mesoscale modeling of polyamide 6 based single polymer laminate composites

This study presents a novel approach for finite element modeling of the elastic behavior of a plain-woven reinforced single polymer laminate composites (WSPC) based on polyamide 6 (PA6). These composites are produced via compression molding of PA6 woven textile structures that are powder-coated by anionic PA6 microparticles. Morphological and structural analysis complemented by electron microscopy, image processing and X-ray diffraction suggest the presence of transcrystalline layer (TCL) at the matrix-reinforcement interface. Having in mid this experimental fact, a novel procedure is developed for finite level discretization of TCL in the representative volume element (RVE) during tensile straining. The procedure correlates the material properties with the overall load applied, thus adequately modelling the tensile behavior of the WSPC based on the constituent materials. The stress field along the elements of the RVE model is studied while the tensile loads were applied in two principal directions. A good agreement between the real mechanical behavior and that calculated based on the model was demonstrated.IPC and 2C2T gratefully acknowledge the support of the project TSSiPRO-NORTE-01-0145-FEDER-000015 funded by the regional operational program NORTE 2020, under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund. The authors affiliated to 2C2T acknowledge also partial funding from FCT - Fundação para a Ciência e a Tecnologia within the projects POCI- 01-0145-FEDER-007136 and UID/CTM/00264. S.D. Tohidi thanks to FCT for the PhD Grant SFRH/BD/94759/2013. N. Dourado acknowledges FCT for the financial support through the projects UID/EEA/04436/2013 and POCI-01-0145-FEDER-006941. M. Rezazadeh acknowledges the support provided by FEDER and FCT funds through project POCI-01-0145-FEDER-029485. N.Q. Quyền thanks for the financial support of FCT through the project PESTUID/CTM/00264. A. Zille also acknowledges the FCT Investigator Research contract IF/00071/2015. S. Hesseler and T. Gries gratefully acknowledge the financial support of German Science Foundation (DFG) through the project RE1057/41. Z. Z. Denchev and N. V. Dencheva acknowledge the support by National Funds through FCT, project UID/CTM/50025/2019. N. Dencheva is also grateful for the financial support of FCT in the frames of the strategic project UID/CTM/50025/2013 and the personal program-contract CTTI-51/18-IP

A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1

Coenzyme A (CoA) is a key cellular metabolite which participates in diverse metabolic pathways, regulation of gene expression and the antioxidant defense mechanism. Human NME1 (hNME1), which is a moonlighting protein, was identified as a major CoA-binding protein. Biochemical studies showed that hNME1 is regulated by CoA through both covalent and non-covalent binding, which leads to a decrease in the hNME1 nucleoside diphosphate kinase (NDPK) activity. In this study, we expanded the knowledge on previous findings by focusing on the non-covalent mode of CoA binding to the hNME1. With X-ray crystallography, we solved the CoA bound structure of hNME1 (hNME1-CoA) and determined the stabilization interactions CoA forms within the nucleotide-binding site of hNME1. A hydrophobic patch stabilizing the CoA adenine ring, while salt bridges and hydrogen bonds stabilizing the phosphate groups of CoA were observed. With molecular dynamics studies, we extended our structural analysis by characterizing the hNME1-CoA structure and elucidating possible orientations of the pantetheine tail, which is absent in the X-ray structure due to its flexibility. Crystallographic studies suggested the involvement of arginine 58 and threonine 94 in mediating specific interactions with CoA. Site-directed mutagenesis and CoA-based affinity purifications showed that arginine 58 mutation to glutamate (R58E) and threonine 94 mutation to aspartate (T94D) prevent hNME1 from binding to CoA. Overall, our results reveal a unique mode by which hNME1 binds CoA, which differs significantly from that of ADP binding: the α- and β-phosphates of CoA are oriented away from the nucleotide-binding site, while 3′-phosphate faces catalytic histidine 118 (H118). The interactions formed by the CoA adenine ring and phosphate groups contribute to the specific mode of CoA binding to hNME1

Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

Background: We evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Methods and Results: Plasma Lp‐PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA2 activity levels and outcomes. At baseline, the median Lp‐PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA2 activity. There were no associations between on‐treatment Lp‐PLA2 activity or changes of Lp‐PLA2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA2 activity or changes in Lp‐PLA2 activity levels and the effects of darapladib on outcomes. Conclusions: Although high Lp‐PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA2 activity

Impairment of coronary flow and left ventricular function in patients with slow coronary flow phenomenon and other types of microvascular angina

Цел: Цел на проучването е определяне на степена на нарушение на коронарния кръвоток във връзка с използвани анти-исхемични медикаменти и индекси за левокамерна функция. Материал и методи: Нарушенията на коронарния кръвток са характеризирани при 70 пациенти с коронарни стенози Резултати: Устновяваме значимо по-ниски скорости на движение на левокамерната стена в диастола (Е’L и E’s) и по-високо преднатоварване (Е/Е‘) при феномена на бавен коронарен кръвоток (SCFP) спрямо болните с микроваскуларна ангина и нормален коронарен кръвоток, и тези с левокамерна хипертрофия при хипертонична болест (SFLVH). При сравнение на болните с SFLVH и SCFP се наблюдава удължено време на децелерация на ранния трансмитрален кръвоток (ДТ), повишена скорост на късния трансмитрален кръвоток (А вълна) и тенденция за по-изразено нарушение на коронарния кръвоток. Липсват различия в камерната функция и коронарния кръвоток в зависимост от приема на β-блокер като монотерапия или при комбинрането му с блокер на калциевите канали или нитрат. Извод: При болни с микроваскуларна аингина, приемащи антиангинозни медикаменти се наблюдва по-бавна камерна релаксация в случаите с левокамерна хипертрофия спрямо пациентите с SCFP и тези с нормален коронарен кръвоток.  Purpose: We aimed at assessing the impairment in coronary flow and left ventricular function in patients without obstructive coronary disease on anti-ischemic treatment admitted with diagnosis unstable angina. Material and methods: The epicardial coronary flow was evaluated in 71 patients with unstable angina in absence of coronary stenosis >50% applying the methods the corrected TIMI frame count and systolic arrest of coronary flow at coronary angiography. The abnormalities in the diastolic function were assessed by echocardiography using PW-Doppler of the diastolic mitral flow and tissue Doppler imaging. Results:  The early diastolic velocity of interventricular septum (E’sept) and left ventricular free wall (E’ lat) were reduced in the SFLVH group compared to SCFP and the patients with normal coronary flow. Significant difference was found in between the patients with SFLVH and SCFP regarding DT and A-wave velocity in sub-analysis. The epicardial coronary flow of the patients with SFLVH was as tendency impaired compared to SCFP. The therapy with β- blocker alone or combined with calcium channel blocker or nitrate did not influence either cardiac function or coronary flow in this analysis. Conclusion:  Slower left ventricular relaxation is typical for the patients with microvascular angina and left ventricular hypertrophy associated with hypertension on treatment compared to SCFP and patients with normal coronary flow

Excessive daytime sleepiness, morning tiredness and major adverse cardiovascular events in patients with chronic coronary syndrome

Background Sleep-related breathing disorders (SRBDs), particularly obstructive sleep apnoea, are associated with increased cardiovascular (CV) risk. However, it is not known whether individual questions used for SRBD screening are associated with major adverse CV events (MACE) and death specifically in patients with chronic coronary syndrome (CCS). Methods Symptoms associated with SRBD were assessed by a baseline questionnaire in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. The patients reported the frequency (never/rarely, sometimes, often and always) of: 1) loud snoring; 2) more than one awakening/night; 3) morning tiredness (MT); 4) excessive daytime sleepiness (EDS); or 5) gasping, choking or apnoea when asleep. In adjusted Cox regression models, associations between the frequency of SRBD symptoms and CV outcomes were assessed with never/rarely as reference. Results During a median follow-up time of 3.7 years, 1,588 MACE events (541 CV deaths, 749 nonfatal myocardial infarctions [MI] and 298 nonfatal strokes) occurred. EDS was associated (hazard ratio [HR], 95% confidence interval [CI]) with increased risk of MACE (sometimes 1.14 [1.01-1.29], often 1.19 [1.01-1.40] and always 1.43 [1.15-1.78]), MI (always 1.61 [1.17-2.20]) and all-cause death (often 1.26 [1.05-1.52] and always 1.71 [1.35-2.15]). MT was associated with higher risk of MACE (often 1.23 [1.04-1.45] and always 1.46 [1.18-1.81]), MI (always 1.61 [1.22-2.14]) and all-cause death (always 1.54 [1.20-1.98]). The other SRBD-related questions were not consistently associated with worse outcomes. Conclusions In patients with CCS, gradually higher levels of EDS and MT were independently associated with increased risk of MACE, including mortality

Excessive daytime sleepiness, morning tiredness, and prognostic biomarkers in patients with chronic coronary syndrome

Background Sleep-related breathing disorders (SRBD) are related to cardiovascular outcomes in patients with chronic coronary syndrome (CCS). Whether SRBD-related symptoms are associated with prognostic biomarkers in patients with CCS is not established. Methods Associations between frequency (never/rarely, sometimes, often, always) of self-reported SRBD-related symptoms (excessive daytime sleepiness [EDS]; morning tiredness [MT]; loud snoring; multiple awakenings/night; gasping, choking, or apnea when asleep) and levels of biomarkers related to cardiovascular prognosis (high-sensitivity C-reactive protein [hs-CRP], interleukin 6 [IL-6], high-sensitivity cardiac troponin T [hs-cTnT], N-terminal pro B-type natriuretic peptide [NT-proBNP], cystatin C, growth differentiation factor 15 [GDF-15] and lipoprotein-associated phospholipase A2 activity) were assessed at baseline in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. Cross-sectional associations were assessed by adjusted linear regression models testing for trends with the never/rarely category serving as reference. Results EDS was associated (geometric mean ratio, 95% confidence interval) with increased levels of IL-6 (often 1.07 [1.03–1.10], always 1.15 [1.10–1.21]), GDF-15 (often 1.03 [1.01–1.06], always 1.07 [1.03–1.11]), NT-proBNP (always 1.22 [1.12–1.33]), and hs-cTnT (always 1.07 [1.01–1.12]). MT was associated with increased levels of IL-6 (often 1.05 [1.01–1.09], always 1.09 [1.04–1.15]), and GDF-15 (always 1.06 [1.03–1.10]). All symptoms were to some degree associated with higher levels of hs-CRP and loud snoring was also associated with decreased levels of NT-proBNP and hs-cTnT. Conclusions In patients with CCS, stepwise increased frequency of SRBD-related symptoms, such as EDS and MT, were associated with gradually higher levels of IL-6 and GDF-15, each reflecting distinct pathophysiological pathways