297 Echocardiographic biventricular coupling index to predict pre-capillary pulmonary hypertension

Aims Pulmonary hypertension (PH) affects millions of people worldwide. Right heart catheterization (RHC) is the gold standard to correctly classify the subtype of PH. Biventricular coupling index (BCI) is a new echocardiographic index defined as the ratio between non-invasive right ventricular stroke work index (RVSWI) and E/E′ ratio. Due to his comprehensive functional characterization of the right heart physiology, we hypothesized it might correctly identify pre-capillary PH. Methods and results BCI was derived in a cohort of 334 patients from the University Hospital of Trieste (Italy) and Karolinska University Hospital (Sweden) who underwent transthoracic echocardiography and RHC for all indications (<6 h between the exams). The accuracy of BCI to identify pre-capillary PH was high in the derivation cohort (AUC: 0.82, P < 0.001, CI: 0.78–0.88). Subsequently BCI was tested in a large validation cohort of 1349 patients with available transthoracic echocardiography and RHC from the Fondazione Toscana G. Monasterio of Pisa (Italy). Among patients with PH, BCI showed a high accuracy to correctly identify pre-capillary PH (AUC = 0.91, 95% CI: 0.89–0.93, P < 0.001), with an optimal cut-off of 1.9 providing a sensitivity of 82% and a specificity of 89%, PPV 77%, and a NPV 92%. BCI outperformed previous indexes, such as the D’Alto score (Z coefficient 3.56, difference between areas 0.05 95% CI: 0.02–0.07, P < 0.001) and the echocardiographic Pulmonary to Left Atrial Ratio (ePLAR) index (Z coefficient 2.88, difference between areas 0.02 95% CI: 0.01–0.04, P < 0.004). Conclusions BCI is a new non-invasive index based on standard echocardiographic parameters that allows, with high accuracy, the identification of patients with pre-capillary PH, outperforming previously proposed indexes. Routine use of BCI index could be implemented in the screening work-up of pre-capillary PH.

EFFECT OF AMMONIUM PYRROLIDINE DITHIOCARBAMBATE ON THE FORMATION OF RACTIVE OXYGEN AND NITROGEN SPECIES IN LIVER OF RATS KEPT ON CARBOHYDRATE-LIPID DIET AND EXPOSED TO ROUND-THE-CLOCK LIGHTING

This aim of the experiment performed on 21 white rats is to clear up the effect of the nuclear factor kappa B (NF-kappa B) inhibitor on the production of reactive oxygen and nitrogen species in the liver of animals kept on carbohydrate-lipid diet and exposed to round-the-clock lighting. The study has demonstrated the administration of ammonium pyrrolidine diothiocarbamate (76 mg/kg three times a week, starting on the 30th day of the experiment) under the conditions of high-calorie carbohydrate-lipid diet (60 days) and exposure of the test animals to round-the-clock light (1500 lux for the last 30 days of the experiment) reduces the production of superoxide anion radical in the liver tissues by NADPH- and NADH-dependent electron transport chains by 45.2% and 43.5%. The production of this radical by leukocytes by NADPH oxidase was 41.6% lower than in the comparison group. The activity of NO-synthase (total and its inducible isoenzyme) decreased by 34.4 and 29.8%, the activity of the constitutive isoform increased threefold. The coupling index of the latter elevated by 5.16 times that indicates the restoration of the coupling state of this isoenzyme. The decrease in the generation of superoxide anion radical and nitric oxide was accompanied by lowering in the peroxynitrites concentration by 36.4%. We can conclude that the administration of ammonium pyrrolidine dithiocarbamate, an NF-kappa B inhibitor, during the metabolic syndrome simulated in rats by round-the-clock lightening exposure and diet rich in carbohydrates and fats is an effective means to restrict the production of reactive oxygen species.

Dynamic Allostery Highlights the Evolutionary Differences between the CoV-1 and CoV-2 Main Proteases

ABSTRACTThe SARS-CoV-2 coronavirus has become one of the most immediate and widely-studied systems since its identification and subsequent global outbreak from 2019-2020. In an effort to understand the biophysical changes as a result of mutations, the mechanics of multiple different proteins within the SARS-CoV-2 virus have been studied and compared with SARS-CoV-1. Focusing on the main protease (mPro), we first explored the long range dynamic-relationship, particularly in cross-chain dynamics, using the Dynamic Coupling Index (DCI) to investigate the dynamic coupling between the catalytic site residues and the rest of the protein, both inter and intra chain for the CoV-1 and CoV-2 mPro. We found that there is significant cross-chain coupling between these active sites and distal residues in the CoV-2 mPro but it was missing in CoV-1. The enhanced long distance interactions, particularly between the two chains, suggest subsequently enhanced cooperativity for CoV-2. A further comparative analysis of the dynamic flexibility using the Dynamic Flexibility Index (DFI) between the CoV-1 and CoV-2 mPros shows that the inhibitor binding near active sites induces change in flexibility to a distal region of the protein, opposite in behavior between the two systems; this region becomes more flexible upon inhibitor binding in CoV-1 while it becomes less flexible in the CoV-2 mPro. Upon inspection, we show that, on average, the dynamic flexibility of the sites substituted from CoV-1 to CoV-2 changes significantly less than the average calculated across all residues within the structure, indicating that the differences in behaviors between the two systems is likely the result of allosteric influence, where the new substitutions in COV-2 induce flexibility and dynamical changes elsewhere in the structure.SIGNIFICANCEHere we have conducted a comparative analysis between the SARS-CoV-1 and SARS-CoV-2 mPro systems to shed mechanistic insight on the biophysical changes associated with the mutations between these two enzymes. Our work shows that the CoV-2 mPro system exhibits enhanced cross-chain communication between catalytic site residues and the rest of the structure. Further, both dynamic coupling and dynamic flexibility analyses indicates that, largely, the dynamic changes as evaluated by DCI and DFI occur at sites other than the mutation sites themselves, indicating that the functional differences between these two proteins are a result of dynamic allostery

Left atrial coupling index versus left atrial function index in heart failure with reduced ejection fraction and iron deficiency

Background Left atrial (LA) form and function has been the focus of extensive research in heart failure with reduced ejection fraction (HFrEF). The LA coupling index (LACI, see Picture 1 for definition) and the LA function Index (LAFI) have both been proposed as potent predictors of morbidity and mortality in HFrEF. Albeit promising, both parameters have drawbacks that could limit their usefulness in clinical settings - LACI can only be measured during sinus rhythm (SR), while LAFI calculation is arguably more involved. A side-by-side comparison of the two indices has not yet been performed. Purpose Investigate and compare the feasibility and efficacy of using LACI and LAFI as prognostic factors in HFrEF. Methods HFrEF patients that visited our outpatient HF clinic were invited to participate in the study. Clinical examination, 6-minute walk testing, and a full echocardiographic study were performed, the latter enabling quantification of LACI, LAFI, as well as most traditional echocardiographic predictors of HF prognosis (Picture 1). LACI and LAFI cut-offs of 6 and 25 respectively were defined in accordance with the relevant literature. Cox regression was performed to assess each parameter's correlation with risk of HF-related hospitalization and mortality over a 6-month follow-up period. Results In the end, 63 patients were included in the study (aged 69.3±9.7 years, 84% male). LACI could not be measured in 19 patients due to atrial tachycardia. The median LACI was 6.2 (8.7) while the median LAFI of the entire sample was 24.8 (44.5). LACI and LAFI correlated strongly (r=−0.813, p<0.001). Neither correlated significantly with the risk of HF-related hospitalization (Picture 1) or death in our sample (Picture 2). 6MWD was the only parameter to independently correlate with increased risk of hospitalization (HR=0.39, p<0.001) or death (HR=0.42, p=0.02). Conclusions The collinearity detected between LACI and LAFI indicate that both quantify similar aspects of left atrial (dys)function. That said, neither index had significant capability to predict hospitalization or death in our sample of HFrEF patients. Although a non-significant trend for higher LACI in patients with poorer prognosis was detected in our sample, it was also incalculable in 30% of patients, who were not in SR during echocardiography. Extended follow-up of an expanded sample size will enable more refined investigation of LACI's and LAFI's prognostic capacity. FUNDunding Acknowledgement Type of funding sources: None. Hospitalization Cox regression results LACI and LAFI survival curves

Left Atrioventricular Coupling Index to Predict Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis

Background: Although left atrial (LA) and left ventricular (LV) structural and functional parameters have independent prognostic value as predictors of heart failure (HF), the close physiological relationship between the LA and LV suggest that the assessment of LA/LV coupling could better reflect left atrioventricular dysfunction and be a better predictor of HF.Aim: We investigated the prognostic value of a left atrioventricular coupling index (LACI), measured by cardiovascular magnetic resonance (CMR), as well as change in LACI to predict incident HF in the Multi-Ethnic Study of Atherosclerosis (MESA).Materials and Methods: In the MESA, 2,250 study participants, free of clinically recognized HF and cardiovascular disease (CVD) at baseline, had LACI assessed by CMR imaging at baseline (Exam 1, 2000–2002), and 10 years later (Exam 5, 2010–2012). Left atrioventricular coupling index was defined as the ratio of LA to LV end-diastolic volumes. Univariable and multivariable Cox proportional hazard models were used to evaluate the associations of LACI and average annualized change in LACI (ΔLACI) with incident HF after adjustment for traditional MESA-HF risk factors. The incremental risk prediction was calculated using C-statistic, categorical net reclassification index (NRI) and integrative discrimination index (IDI).Results: Among the 2,250 participants (mean age 59.3 ± 9.3 years and 47.6% male participants), 50 incident HF events occurred over 6.8 ± 1.3 years after the second CMR exam. After adjustment, greater LACI and ΔLACI were independently associated with HF (adjusted HR 1.44, 95% CI [1.25–1.66] and adjusted HR 1.55, 95% CI [1.30–1.85], respectively; both p < 0.0001). Adjusted models for LACI showed significant improvement in model discrimination and reclassification compared to currently used HF risk score model for predicting HF incidence (C-statistic: 0.81 vs. 0.77; NRI = 0.411; IDI = 0.043). After adjustment, ΔLACI showed also significant improvement in model discrimination compared to the multivariable model with traditional MESA-HF risk factors for predicting incident HF (C-statistic: 0.82 vs. 0.77; NRI = 0.491; IDI = 0.058).Conclusions: In a multi-ethnic population, atrioventricular coupling (LACI), and coupling change (ΔLACI) are independently associated with incident HF. Both have incremental prognostic value for predicting HF events over traditional HF risk factors.