Risultati per: Probiotici: in vivo vs in vitro

Circulation, Volume 146, Issue Suppl_1, Page A9874-A9874, November 8, 2022. Introduction:Global longitudinal strain (GLS) by two-dimensional (2D) transthoracic echocardiography (TTE) is a robust index for identifying early left ventricular (LV) myocardial dysfunction. Positron emission tomography (PET) myocardial perfusion imaging (MPI) is widely used in the assessment of ischemic heart disease (IHD) but has not been used for strain analysis.Hypothesis:Longitudinal, radial, and circumferential myocardial strain measures at rest and at pharmacologic stress by Rb-82 ECG-gated PET MPI are correlated to those measured by resting 2D TTE.Methods:We developed a novel PET MPI method to track the LV myocardium throughout the cardiac cycle processed in the Emory Cardiac Toolbox, to measure LV strain from longitudinal, radial, and circumferential direction at regadenoson-stress and at rest. We retrospectively identified 80 patients who underwent Rb-82 PET MPI and also had TTE with strain analysis within 3 months. The agreement between LV strain and LVEF derived from PET MPI and resting TTE was assessed with Bland-Altman analysis, Pearson’s correlation, and the concordance correlation coefficient (CCC).Results:PET MPI derived measurements of longitudinal (Figure 1A-1B: Bland-Altman analysis; 1C-1D: Pearson’s correlations), circumferential (Figure 1E-1F: Pearson’s correlations) and radial (Figure 1G-1H: Pearson’s correlations) strain measures at rest and stress were strongly correlated to resting TTE derived GLS (p

Circulation, Volume 146, Issue Suppl_1, Page A15525-A15525, November 8, 2022. Introduction:Surgical/ablation treatment for atrial arrhythmias such as anatomic sinoatrial node (SAN) tachycardia and atrial fibrillation either target or preserve the SAN. However, defining SAN is challenging because clinical electrophysiological (EP) mapping can visualize only exits of SAN activation as early activation sites (EAS) and not the leading pacemaker (LP) within the 3D intramural SAN.Methods:High resolution (300-900μm2) including epi/endocardial (Epi/Endo) dual sided near infrared optical mapping (NIOM) was conducted on coronary perfused explanted human atria (n=26, 19-69 y.o.). SAN was defined by optical action potential morphologies as the region of slow diastolic depolarization (slow upstroke) preceding atrial excitation. Serial histology and contrast enhanced MRI (CE-MRI, 100μm3resolution) were used to define the 3D fibrotic structure of the SAN pacemaker complex.Results:During sinus rhythm (SR) (83±22 bpm), the LP was primarily located in the SAN center. Electrical impulses exit from SAN to atria through 1-2 sinoatrial conduction pathways (SACP), leading to discrete EAS along crista terminalis (CT), preferentially from lateral superior/middle SACPs. The distance between SAN LP and EAS varied from 3.5-23 mm. Heterogeneous atrial wall thickness, fibrosis content and myofiber orientation along the SAN and CT (5-15mm thick) regions led to complex intramural conduction from SAN LP to EAS and substantial Epi-Endo activation dyssynchrony.Conclusions:EAS visualized on both Epi/Endo mapping mainly distributed along thick CT, but not on the surface projection of SAN, due to intramural fiber orientation of preferential SACPs. The higher fibrotic content in the human SAN than CT detected by CE-MRI, integrated with EP mapping can be helpful to accurately define SAN structure and pathways for reentrant SAN arrhythmias ablations.

Circulation, Volume 146, Issue Suppl_1, Page A13062-A13062, November 8, 2022. Background:Non-ischemic diabetic heart disease (NiDHD) is characterised by diastolic dysfunction and decreased or preserved systolic function, eventually resulting in heart failure. The fundamental mechanisms leading to NiDHD are still not known. microRNAs (miRNAs) plays a significant role in the development of NiDHD.Objective:To investigate the pathological role of cardiomyocyte enriched pro-apoptotic miR-320 in the development of NiDHD and to determine if therapeutic knockdown of miR-320 can restore impaired cardiac function and angiogenesis in the diabetic heart.Methods and Results:Cardiac tissue were collected from type-2 diabetic individuals undergoing cardiac surgery showed marked upregulation of miR-320, which was associated with downregulation of its direct target pro-survival insulin growth factor-1 (IGF-1) and anti-apoptotic protein Bcl-2. Analysis of cardiac tissue samples collected from type 2 diabetic mice (BKS.Cg-m+/+Leprdb/J) every 4wks, from 8 to 32wks of age showed activation of miR-320 and downregulation of IGF-1 at the later stages of diabetes. To determine if therapeutic knockdown of miR-320 is beneficial, high glucose cultured adult cardiomyocytes were treated with either locked nucleic acid (LNA) anti-precursor (pre)-miR-320 or scrambled (Scr) sequence. Results showed that LNA-anti-pre-320 significantly restored IGF-1 expression and reduced apoptotic cells death (3.1±05 in Scr vs 1.3±0.6 in LNA-anti-pre-320, P

Circulation, Volume 146, Issue Suppl_1, Page A13915-A13915, November 8, 2022. BACKGROUND:Differentiation of wide QRS complex tachycardias (WCTs) into ventricular tachycardia (VT) and supraventricular wide QRS tachycardia (SWCT) through 12-lead electrocardiogram (ECG) interpretation is one of the most critical yet challenging tasks in clinical practice. Recent research highlights novel automated methods that successfully diagnose WCTs. We sought to directly compare the diagnostic efficacy of these novel automated WCT differentiation methods (i.e., WCT Formula, VT Prediction Model, and WCT Formula II) to traditional ECG interpretation approaches (i.e., Brugada and Vereckei aVR algorithms).METHODS:A collection of paired WCT and baselined ECGs were retrospectively analyzed. Next, an electrophysiologist blindly and prospectively applied the Brugada and Vereckei aVR algorithms. Separately, computerized measurements were used to apply the three automated WCT differentiation methods. The diagnostic performance of each method was then evaluated.RESULTS:213 WCTs (111 VT and 102 SWCT) from 105 patients were analyzed. The WCT Formula demonstrated superior overall accuracy (84.7% vs. 64.8%), specificity (86.2% vs. 35.3%), positive predictive value (PPV) (85.7% vs. 60.7%), and positive (+) likelihood ratio (LR) (6.06 vs. 1.42) compared to Vereckei aVR algorithm. Similarly, the WCT Formula attained higher specificity (86.2% vs. 61.8%), PPV (85.7% vs. 71.9%), and (+) LR (6.06 vs. 2.36) than the Brugada algorithm. The WCT Formula II demonstrated superior overall accuracy (89.2% vs. 64.8%), specificity (84.3 % vs. 35.3%), PPV (86.7% vs. 60.7%), and positive (+) LR (5.97 vs.1.42) compared to Vereckei aVR algorithm as well as higher specificity (84.3 % vs. 61.8 %), PPV (86.7% vs. 71.9%), and (+) LR (5.97 vs. 2.36) than the Brugada algorithm. The VT prediction model yielded superior specificity (79.4% vs. 35.3%), PPV (79.8 vs. 60.7%) and (+) LR (3.63 vs.1.42) compared to the Vereckei aVR algorithm but did not demonstrate superior diagnostic performance to the Brugada algorithm.CONCLUSIONS:Novel automated WCT differentiation methods achieved similar or superior diagnostic performance metrics compared to traditional ECG interpretation approaches.

Circulation, Volume 146, Issue Suppl_1, Page A11239-A11239, November 8, 2022. Introduction:Gender disparities in the utilization of catheter-directed thrombolytic (CDT) therapy vs. systemic thrombolytic (ST) therapy in patients with acute pulmonary embolism (PE) have not been studied before.Methods:Using the National Inpatient Sample database from 2012 to 2018, we identified all adult patients with acute PE who received any thrombolytic therapy. The primary outcome was the utilization of CDT vs. ST therapy in females compared to males. The secondary outcome was the mortality in females compared to males in all patients of acute PE who received any thrombolytic therapy.Results:We identified 45,950 patients who received CDT or ST therapy. The mean age was 59.7 years in females vs. 59 in males (p-value – .03). Males were more likely to have saddle PE (33% vs. 29%, p-value < .01) and less likely to have vasopressor use (3% vs. 5%, p-value < .01). Baseline characteristics are shown inTable 1.Females were less likely to have CDT vs. ST therapy on adjusted analysis (AOR - 0.85, p-value < .01), as shown inTable 2.Females also had 27% higher in-hospital mortality than males in the entire cohort who received any thrombolytic therapy even after adjustment for age, race, comorbidities, and hospital factors (AOR - 1.27, p-value < .01). CDT was associated with a 58% lower risk of in-hospital mortality than systemic thrombolytic therapy in the adjusted model (AOR - 0.42, p-value < .01).Conclusion:Gender disparities exist in the utilization of CDT in patients of acute PE who receive thrombolytic therapy, with lower utilization in females than males, despite significantly reduced in-hospital mortality associated with CDT vs. ST therapy.

Circulation, Volume 146, Issue Suppl_1, Page A10487-A10487, November 8, 2022. Introduction:PH is a disorder characterized by remodeling of the pulmonary vasculature which causes increased pulmonary vascular resistance and ultimately right ventricular (RV) failure leading to death. MetS is a recognized risk factor for PH, particularly in patients suffering from PH associated with left-sided heart failure (WHO Group 2 PH) for which there are no approved therapies.Activins and growth differentiation factors (GDFs) are implicated in both PH pathology as well as body composition and metabolism by genetic disease association, preclinical, translational, and clinical evidence.HS135 is a rationally designed first-in-class activin-receptor (ActR)-based fusion protein that addresses both vascular remodeling and MetS in PH without affecting hematological parameters; hematological effects limit the dosing of other ActR-based agents.Methods:HS135’s ability to counteract vascular remodeling and heart failure in PH was assessed using a rat monocrotaline (MCT) model: a single dose of 60 mg/kg MCT was administered on Day 0 followed by 4 weeks of twice weekly treatment with either HS135 (1, 4, or 16 mg/kg) or vehicle. PH efficacy was assessed at end of study by echocardiography and histological readouts. HS135’s ability to improve body composition and metabolism was assessed in wild type mice by administering HS135 (1, 3, 10, 20, or 50 mg/kg) or vehicle twice weekly for 3 weeks. The effect of HS135 on hematological parameters was assessed by whole blood cell count in non-human primates (NHPs) 2 weeks following a single administration of HS135 at 3 or 30 mg/kg.Results:HS135 at 3 or 30 mg/kg did not lead to changes in hematological parameters in NHPs. Compared to vehicle, HS135 was effective at counteracting the MCT-induced PH phenotype in rats as evidenced by significant reductions in Fulton index and improved echocardiography parameters. In wild type mice, HS135 led to significant improvements in body composition.Conclusions:Contrary to other ActR-based therapies, HS135 did not lead to increases in hematocrit which would limit its dosing. HS135 was efficacious at treating PH while simultaneously improving body composition in preclinical models. Clinical trials with HS135 are expected to commence within 2023.

Circulation, Volume 146, Issue Suppl_1, Page A11854-A11854, November 8, 2022. Introduction:In the SPRINT trial, intensive blood pressure control reduced all-cause mortality and major adverse cardiovascular events in individuals at high risk for cardiovascular events. However, it is unclear whether individuals with polyvascular disease, compared to individuals without established atherosclerosis, similarly benefit from intensive blood pressure control.Methods:We performed a post-hoc analysis of the SPRINT trial to determine the efficacy of intensive versus standard blood pressure control on the primary composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death); and secondary outcomes (cardiovascular death, myocardial infarction). Individuals were stratified by severity of atherosclerosis: no known atherosclerotic disease (Framingham Risk Score > 15%), subclinical atherosclerosis, symptomatic single-bed atherosclerosis, and symptomatic polyvascular atherosclerosis. Uni- and multivariable Cox regression models were used to compute the crude and adjusted hazard ratios. Interaction between intensive vs standard blood pressure control and atherosclerotic burden was evaluated.Results:In the SPRINT trial, 6,837 individuals had elevated Framingham Risk Score, 128 had subclinical atherosclerosis, 1,207 had symptomatic single-bed atherosclerosis, and 254 had symptomatic polyvascular disease. There was graded increase in risk of primary composite outcome and secondary outcomes with more atherosclerotic burden, even when controlling for differences in baseline characteristics (Figure). There was no interaction among groups between treatment assignment and primary or secondary outcomes.Conclusions:This post-hoc analysis of SPRINT trial demonstrates a higher risk of adverse in patients with escalating atherosclerotic burden. Individuals derive benefit from intensive blood pressure control regardless of burden of atherosclerosis.

Circulation, Volume 146, Issue Suppl_1, Page A11913-A11913, November 8, 2022. Introduction:Imaging the coronary microcirculation in the beating heart is challenging due to motion artifact from cardiac contraction and respiration, which limits the application of high-resolution microscopy techniques. In the brain and other tissues with less motion artifact, optical coherence tomography angiography (OCTA) has been successfully used in rodents to create label-free maps of blood flow down to the capillary level. We hypothesized that advanced cardiac and respiratory gating together with high-speed optical coherence tomography can be used to implement OCTA of the capillary microcirculationin vivoin the mouse heart.Methods:C57BL/6 mice (n=30) were imaged through a sternotomy while anesthetized and ventilated. OCTA was performed using a custom tissue stabilizer and a Thorlabs TEL 321 Spectral Domain OCT system, which was synchronized to physiologic signals using custom hardware and software and cardiac pacing protocols. The system had an optical center wavelength of 1300 nm and produced axial (depth) and lateral resolutions of 4.2 μm and 13 μm, respectively. Angiograms were created from the difference between two consecutive images acquired during diastole, and a volumetric three-dimensional scan was acquired over multiple cardiac cycles. Images were analyzed in MATLAB and ImageJ to produce projection angiograms of the coronary microcirculation.Results:OCTA with cardiac and respiratory gating can produce high-resolution angiograms of the coronary microcirculation without exogenous contrast agents. OCTA has improved imaging depth and field of view compared to conventional confocal microscopy, and can produce widefield coronary angiograms (Fig. 1A) while maintaining the ability to visualize individual capillaries (Fig. 1B).Conclusion:In vivoOCTA can image the coronary microcirculation in the heart and will provide a powerful new tool for investigating coronary microvascular dysfunction in mouse models of heart disease.

Circulation, Volume 146, Issue Suppl_1, Page A9809-A9809, November 8, 2022. Introduction:Patients with left ventricular assist device (LVAD) often develop aortic insufficiency (AI) requiring an intervention on the aortic valve. We sought to analyze the outcomes of patients with a history of LVAD who underwent either transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR).Methods:The Nationwide Readmission Database (NRD) was used to extract relevant patient information from January 1, 2016, to December 31, 2018. The NRD is a nationally representative sample of all-payer discharges from U.S. non-federal hospitals. The primary outcome of interest was in-hospital mortality. Secondary outcomes included length of stay, inpatient outcomes, costs, and 30-day all-cause readmissions. Complex samples multivariable logistic and linear regression models were used to determine the association of procedure type with outcomes.Results:Among 148 hospitalizations with a history of LVAD, 87 underwent TAVR, and 61 underwent SAVR. The inpatient mortality in SAVR group was numerically higher compared to the TAVR cohort, however, it did not reach statistical significance. The use of invasive mechanical ventilation, cardiogenic shock, bleeding, and vascular complications were higher in the SAVR cohort compared to the TAVR cohort. The mean length of stay (in days) and costs were higher in the SAVR cohort compared to the TAVR cohort. The 30-day all-cause readmission rate was numerically higher in the SAVR group, however, it was not statistically significant (Table 1).Conclusions:TAVR in patients with LVAD is a viable treatment option for AI and potentially leads to better inpatient mortality and inpatient outcomes compared to patients who undergo SAVR.

Circulation, Volume 146, Issue Suppl_1, Page A15300-A15300, November 8, 2022. Introduction:Higher doses of the glucagon-like peptide-1 agonist (GLP-1RA) semaglutide and, more recently, the GIP and GLP-1RA tirzepatide demonstrated a significant reduction in body weight in patients with Type 2 Diabetes Mellitus (T2DM). However, their comparative value for money for this indication is unclear.Hypothesis:Tirzepatide provides better value for money than semaglutide in facilitating weight loss.Methods:We calculated the cost needed to treat (CNT) to achieve a one percent reduction in body weight using high-dose tirzepatide (15mg) versus semaglutide (2.4mg). The body weight reductions were extracted from published results of SURMOUNT-1 and STEP 1 trials, respectively. We performed a scenario analysis to mitigate the primary differences between the two studies’ populations (Table 1). Drug costs were based on US GoodRx prices as of June 2022.Results:Using tirzepatide resulted in weight loss of 17.8% (95% CI: 16.3%-19.3%) compared to 12.4% (95% CI: 11.5%-13.4%) for semaglutide. The total annual cost of therapy with tirzepatide was estimated at $17,554 compared with $22,899 for semaglutide. Accordingly, the CNT per one percent of body weight reduction with tirzepatide is estimated at $987 (95% CI:$910-$1,077) compared to $1,847 (95% CI: $1,708-$1,991) with semaglutide. Scenario analysis confirmed these findings.Conclusions:Tirzepatide provides better value for money than semaglutide for weight reduction at high doses.

Circulation, Volume 146, Issue Suppl_1, Page A212-A212, November 8, 2022. Targeted Temperature Management (TTM) following shockable out-of-hospital cardiac arrest (OHCA) has been recommended. The effect of different targeted temperatures on the human metabolome has not been compared. Elevated levels of metabolites from the Krebs cycle have recently been associated with a poor outcome in OHCA patients. Similarly, decreased levels of the amino acids valine and leucine have been linked with a poor outcome in septic shock patients.Method:From a single center in the randomized clinical TTM trial, we analyzed blood samples from resuscitated unconscious OHCA patients at two timepoints (hospital arrival and 48 hours later) using ultra-performance liquid mass-spectrometry. Patients were randomized to either 33°C or 36°C hypothermia for the first 28 hours. Sixty-one metabolites of the ~3000 compounds detected were prespecified for quantification and analyzed in the current study. Differences (95% CI) in metabolite concentrations from a constrained linear mixed model are reported, and p-values from the interaction term timepoint x TTM arm.Results:Of the 146 patients, 70 (48 %) were randomized to TTM 33°C. The baseline characteristics (age, gender, shockable rhythm, time to return of spontaneous circulation) and outcome (180 days mortality) were similar in the TTM groups. After 48 hours, approx. 24 hours from the cessation of TTM, fourteen metabolites differed significantly between the two groups. Among these, lactate acid (190 μM (74-305 μM),p

Circulation, Volume 146, Issue Suppl_1, Page A13063-A13063, November 8, 2022. Calcific aortic valve disease (CAVD) is the most common age-related heart valve disease, with no medical therapy to halt progression. Age is associated with the enrichment of somatic mutations in hematopoietic stem cells leading to clonal hematopoiesis (CH). CH mutations promote inflammation, occur in more than 30% of patients with severe CAVD and CAVD patients harboring CH mutations have a worse prognosis. Single-cell RNA-sequencing of immune cells (n=127120 cells) of CAVD patients with CH-mutations showed strong proinflammatory and M1-like macrophage gene signatures (CD38, CXCL10) along with genes associated with calcification (S100A9, RUNX2, Oncostatin M=OSM) suggesting that CH might be causally involved in CAVD. Indeed, silencing of TET2 or DNMT3A in macrophages in vitro induce the prototypic osteoblastic transcription factor RUNX2 and paracrine acting genes such as OSM and S100A9, which can promote vascular calcification. Secreted factors from TET2 or DNMT3A-silenced macrophages induced osteoblastic differentiation as demonstrated by elevated calcium deposition and genes involved in the RUNX2 signaling pathway (COL1A2, ALP), which could be ablated by silencing of OSM in CH-macrophages. Atheroprone Ldlr-/-mice receiving TET2-/-bone marrow transplants mice showed increased total calcified area along (1.49-fold) with increased numbers of calcification deposits (2.33-fold) as evidenced by von Kossa staining. Increased myeloid derived OSM and S100A9 was found in the valves of TET2-/-BMT mice with S100A9 strongly co-occurring with OSM. This study provides insights into the development of incident CAVD for patients with CH mutations and therefore yields plausible interventions for nearly one third of CAVD cases to slow or stop disease progression.

Circulation, Volume 146, Issue Suppl_1, Page A11098-A11098, November 8, 2022. Introduction:Severity of end-organ dysfunction correlates with outcomes in acute myocardial infarction-related cardiogenic shock (AMI-CS). The epidemiology of end-organ dysfunction in heart failure-related cardiogenic shock (HF-CS) has not been well described.Methods:Cardiac intensive care unit (CICU) admissions with CS in the Critical Care Cardiology Trials Network Registry (2017-2021) were identified and categorized as AMI-CS and HF-CS (de novoor acute-on-chronic HF). Admissions for each CS sub-type were characterized as having respiratory, kidney, liver, and/or neurologic dysfunction using definitions adapted from the Sequential Organ Failure Assessment score (Fig A). Outcomes were assessed by burden of non-cardiac organ dysfunction: no end-organ dysfunction (NEOD), single system end-organ dysfunction (SEOD), or multi-system end-organ dysfunction (MEOD).Results:A total of 2,911 CS admissions from 35 CICUs were identified, most of which were for HF-CS (71%, N = 2,068). The proportions of patients with NEOD, SEOD, and MEOD were 25%, 36%, 39% for HF-CS vs. 16%, 35%, 49% for AMI-CS (p

Circulation, Volume 146, Issue Suppl_1, Page A12521-A12521, November 8, 2022. Introduction:Constitutively an anticoagulant surface, endothelial cells (ECs) switch to support coagulation following pathogenic stimuli, contributing to cardiovascular disease. To promote thrombosis, coagulation proteins must assemble on a membrane surface containing the anionic phospholipid phosphatidylserine (PS). PS is asymmetrically distributed on the inner leaflet of the plasma membrane but is rapidly externalized to the outer leaflet by calcium-activated phospholipid “scramblases”, such as TMEM16F. How phospholipid externalization on ECs supports coagulation and thrombosis has not been investigated.Hypothesis:We proposed that pharmacologic inhibition of TMEM16 phospholipid scramblases inhibits EC procoagulant activity and protects against thrombosis.Methods and Results:siRNA silencing of TMEM16F, and its closest paralog, TMEM16E, inhibited factor Xa generation and thrombin generation on the EC surface (60% and 90%, respectively,p< 0.0001), equivalent to the PS-binding protein lactadherin (100 nM). Two unrelated compounds with TMEM16 inhibitory activity, benzbromarone and CaCCinh-A01 (30 μM), prevented calcium-induced PS externalization on ECs, as determined by flow cytometry and immunofluorescence microscopy. These drugs did not inhibit intracellular calcium flux, suggesting they block the PS externalization activity of TMEM16. Benzbromarone and CaCCinh-A01 inhibited factor Xa generation on the EC surface in a dose-dependent manner (IC503.2 μM and 2.0 μM, respectively). Thrombosis was evaluated using a laser injury model in the mouse cremasteric arteriole coupled with intravital microscopy to measure accumulation of fluorescently-labeled platelets and fibrin. Benzbromarone (5 mg/kg) inhibited platelet accumulation (p< 0.05) and fibrin formation (p< 0.01). Benzbromarone did not increase bleeding time in a tail-clip hemostasis assay.Conclusions:Activated ECs contribute anionic phospholipid to support coagulation, a process regulated by TMEM16 phospholipid scramblases. TMEM16 inhibition with benzbromarone protects from experimental thrombosis without resulting in excess bleeding. Benzbromarone is used worldwide to treat gout and could be repurposed for anti-thrombotic properties.

Electroconvulsive therapy was superior, but outcomes with ketamine were better than expected for this difficult-to-treat population.

To the Editor The emergence of delayed-enhancement magnetic resonance imaging (MRI) has set the stage for advancements in visualization and quantification of left atrial fibrosis. Among patients with atrial fibrillation (AF) undergoing catheter ablation, the DECAAF I trial showed an association between the extent of atrial fibrosis and the likelihood of arrhythmia recurrence. Consequently, atrial fibrotic burden gained clinical importance and became a potential target to improve procedural outcomes.