Improvement In Left Ventricular Function Research Articles

The prolyl-hydroxylase inhibitior Roxadustat upregulates HIF-1alpha and is associated with improved cardiac repair after myocardial infarction in mice

Abstract Introduction Activation of the CXCL12/CXCR4-axis is known to aid myocardial repair by attraction of reparative CXCR4+ cells through ischemia triggered hypoxia-inducible factor-1α (HIF-1α) activation of CXCL12 (1). To prolongate upregulation of CXCL12 we aimed to stabilize HIF-1α by administration of Roxadustat, the only prolyl hydroxylase inhibitor (PHI) clinically approved by the EMA with the purpose to augment myocardial remodelling and improve LV function. Methods To analyse the effects of HIF-1α mediated CXCL12 upregulation in vivo (BM & heart), optimal doses (50mg/kg i.p., every 72h) of the PHI Roxadusat (FG-4592) were administered to Bl6/J mice. CXCL12 and CXCR4 expression was analysed in-vitro in human umbilical vascular endothelial cells (HUVEC) after administration of FG-4592 (20µM to 1000µM) at different time points (1 to 24 hrs). Western Blots were performed and effects on HIF-1α -signalling were quantified by densitometry. We induced MI in BL6/J mice at the age of 8-10 weeks by LAD-ligation. Two groups (n=10) were treated with Roxadustat or saline for 28 days before assessment of cardiac function by echocardiography and evaluation by histology. Two other groups of n=5 mice were treated with Roxadustat or saline for one week and analysed regarding apoptotic-index by automated cell count in DAPI & Tunel stained sections. Results We were able to show a significant upregulation of HIF-1α after exposure of 50-500 μM Roxadustat for 4-24 hours in-vitro (HUVEC) and in-vivo (murine BL6/J hearts). Moreover, administration of 500 µM Roxadustat induced marked activation of CXCR4 and CXCL12, respectively. Infarct size (19.07%±7.86 vs. 24.14%±12,05; n= 10/8; p = 0.297), as well as LV-wall thickness in the infarcted myocardium (788.27µm±240.10 vs. 651.40µm±231.47; n=10/8; p = 0.240) revealed no significant differences 28 days after MI. Automated cell counting in the borderzone revealed a lowered apoptotic-index of Roxadustat treated animals (3.7%±1.1 vs. 6.3%±2.3; p = 0.071). Echocardiographic analyses showed a significantly preserved ejection fraction (EF) (46.1%±6.0 vs. 30.5%±9.3; n=10/9; p<0.001), reduced diastolic (4.18±0.32 vs. 4.77±0.40; p=0.002) and systolic (3.23±0.31 vs. 3.95±0.43; p<0.001) LV diameters in Roxadustat treated mice 28 days after MI compared to saline treated controls. Conclusion The clinically approved PHI Roxadustat revealed increased expression of HIF-1α associated with upregulation of CXCR4 and CXCL12. Administration of Roxadustat after MI revealed attenuated infarct remodelling and functional improvement showing its potential in ischemic heart disease.

QRS width variation as a marker of prognosis after CRT implantation: getting slimmer is getting better

Abstract Introduction Cardiac resynchronization therapy (CRT) is a major therapeutic tool in the management of patients with systolic heart failure. However, controversy remains regarding who will most benefit from this device. The aim of the present study was to evaluate the impact of QRS duration on echocardiographic response and clinical outcomes. Methods We conducted a retrospective, observational, single-center study of patients submitted to CRT implantation. Only patients with electro and echocardiographic data on baseline and follow-up were included. CRT response was defined as an improvement of LVEF >10% or LVESV>5%. CRT superresponse was defined as an improvement of LVEF above the population 4th quartile (18%). Impact of QRS variables on CRT response was evaluated with ROC curve analysis. Clinical outcomes were defined as hospitalizations due to heart failure and all-cause mortality. Impact of QRS on clinical endpoints, response and superresponse was evaluated with survival analysis. Results From a total of 654 pts a total of 245 fulfilled the inclusion criteria. (57,3%% female, mean age). Most of the pts had a non-ischemic etiology (61,5%) and atrial fibrillation was present in 29.4%. The QRS characteristics were the following, baseline: 162+21ms, follow-up 159+28ms, mean QRS variation: 3+29ms. CRT response occurred in 69% of the pts and superresponse in 26%. QRS variation is the best predictor of CRT response (AUC =0,66, 95%CI 0,58-0,74, p<0,001). Interestingly, a QRS reduction above 8ms presented the best accuracy (S:70%;E:57%) for response to CRT. On multivariate analysis, after adjustment for gender, atrial fibrillation and cardiopathy etiology, only a QRS reduction above 8ms (p 0.028, HR 1.974 CI (1.075-3.623) and lower baseline LVEF (p = 0.02, 95% CI 0.943 (0.909-0.979) were significant independent predictors of CRT superresponse. Additionally, a QRS reduction higher than 8ms was a protective factor for long-term clinical outcomes during follow-up (p<0.001 HR (2,445) 1,553 a 3,849) – fig.1. Conclusion In pts with implanted CRT a reduction in QRS width, as small as 8ms, its a marker of improved LV function and a better clinical prognosis.

Abstract 11320: Sonothrombolysis Leads to Early Improvement of Left Ventricular Function in Acute Coronary Syndromes

Introduction: Acute coronary syndromes (ACS) are among the main causes of death worldwide. Despite important advances in revascularization strategies, there are a considerable number of patients who neither have access to these therapies, or, if so, may experience the no-reflow phenomenon. In STEMI, sonothrombolysis has been shown to restore patency of coronary vessels, especially in the microcirculation, leading to better left ventricular (LV) function recovery, hence emerging as a new adjuvant treatment to reperfusion. Hypothesis: Sonothrombolysis would improve the LV function in ACS. Aim: Compare ejection fraction (EF) and global longitudinal strain (GLS) in patients with ACS randomized to receive sonothrombolysis (therapy group-TG) or conventional treatment (control group-CG). Methods: Patients were randomized from two major clinical trials (NCT04732091 and NCT02410330 - HUBBLE databank). The therapy consists of high-energy intermittent ultrasound pulses associated with ultrasound-enhancing agent infusion (Definity® - Lantheus), initiated immediately after patient admission and continued after PCI or applied only after PCI for a total of 50 minutes. EF and GLS were measured off-line (TomTec Imaging System). Images were acquired immediately post Therapy/PCI or PCI only and 48/72 hours after the patient's inclusion. Comparisons were made using Student t-test, Chi-square test, and Fisher's exact test when indicated. Results: 120 patients were included (CG=60: 51 STEMI, 1 thrombolyzed STEMI, and 8 NSTEMI; TG=60: 53 STEMI, 1 thrombolyzed STEMI e 6 NSTEMI). Demographic characteristics were similar between groups, except for a tendency of higher number of diabetic patients in TG (43% vs. 25%, p=0.054). EF and GLS were similar between TG and CG immediately post-treatment (Therapy/PCI or PCI only) (47±12 vs. 45±11, p=0.393 and 13.2±4.1 vs. 12.5±3.3, p=0.325, respectively). However, after 48/72 hours, patients who received Therapy/PCI had similar values of EF despite higher GLS (49±10 vs. 46±11, p=0.126 and 13.5±3.8 vs. 11.8±3.1, p=0.010, respectively). Conclusions: Preliminary data shows that Sonothrombolysis associated with PCI could be an effective adjuvant treatment for ACS, contributing to the early improvement of LV function.

Abstract 18918: Outcomes of Patients With Transcatheter Aortic Valve Replacement (TAVR) and Cardiac Resynchronization Therapy (CRT): A Retrospective Analysis

Introduction: Many patients with TAVR have a pre-existing reduced LVEF <35% and left bundle branch block (LBBB) requiring CRT-D for potential improvement in LV function and secondary prevention of sudden death. Few studies have examined patient outcomes in this specific subpopulation. The aim of our study was to see if this patient population had worse outcomes compared to patients with TAVR without CRT-D. Hypothesis: We hypothesized that patients undergoing CRT would have better outcomes. Methods: Patients aged >18 years with TAVR and CRT versus TAVR alone were identified from the United States National Inpatient Sample (2015-2020). ICD 9 and 10 codes were utilized and multivariate regression analysis was used to estimate the odds ratios of in-hospital mortality, average length of stay (LOS), and hospital charges (TOTHC), after adjusting for age, gender, race, insurance, and hospital demographics (type, size, region, and teaching status). Propensity matching was performed using the Kernel method. Weighted analysis utilizing Stata 17 MP was performed. Results: This study identified approximately 324,563 patients with TAVR, of which 2,613 patients had CRT. The analysis revealed mortality (OR: 2.59, p<0.025, CI: 1.13-5.94), length of stay (LOS) (+5.69 days, p<0.0001, CI: 4.44-6.95), and TOTHC ($165,520, p<0.0001, CI: 134,551-196,489) were increased for patients with TAVR and CRT compared to patients with only TAVR. Secondary analysis is described in Table 1. Conclusions: Our study revealed that patients with TAVR and CRT had worse outcomes including increased mortality, LOS, and TOTHC. Despite CRT, this patient subpopulation had worse outcomes compared to those with only a TAVR. We suspect that these patients either have a poor functional status at baseline or CRT may not have as much benefit for patients with TAVR. Further studies are required to further evaluate this patient population.

Abstract 13851: CAR-T Cells: A Potential Novel Strategy for Mitigating Fibrosis in Duchenne Muscular Dystrophy

Introduction: Chimeric Antigen T (CAR)-T cells have proven effective preclinically for mitigating cardiac fibrosis in hypertensive cardiomyopathy. Hypothesis: We assessed whether this approach could be applied to Duchenne Muscular Dystrophy (DMD) by targeting Fibroblast Activating Protein (FAP)-expressing activated fibroblasts in cardiac and skeletal muscle fibrosis. Methods: A protocol for the lymphodepletion conditioning of mice was developed to optimize the dosing of cyclophosphamide. Next, immune-magnetically selected T cells were retrovirally transduced to target FAP (FAP-CAR) and quality-controlled by co-culture killing assays using FAP-expressing HEK target cells. Finally, lymphodepleted D2. mdx mice were intravenously injected with 10 7 FAP-CAR T cells (n=9) or 10 7 GFP-T cells (n=9) or Bovine Serum Albumin (BSA, n=8). Cardiac and skeletal muscle end points were assessed 2 and 5 weeks after treatment. Results: In vitro , the engineered CAR-T cells expressed activation markers (CD69, PD-1) and released large amounts of granzyme, perforin and interferon γ upon exposure to FAP-expressing target cells. One IP injection of cyclophosphamide (3mg) 4 days before treatment was safe and induced a lymphodepletion which enabled robust in vivo expansion of FAP-CAR T cell assessed by flow cytometry in lymphoid organs and blood: 10 5 , 2.10 6 and 10 7 detected CAR-T cells at day 3, 5 and 7 post-injections, respectively. This was paralleled by a more than a 2-fold decrease in endogenous FAP expression in skeletal muscles, as assessed by PCR at day 5 post-injections, and measurable FAP-CAR levels in the spleen compared with GFP-T cell controls. In vivo , FAP-CAR T cells significantly improved LV function with an EF change from baseline (Mean±SEM) of 33.1% ± 6.7% in FAP-CAR vs. 3.7% ± 6.4% and -9.6% ± 7.9% in GFP-T and BSA ( p <0.037 and p <0.005, respectively) at 2 weeks. The benefit was maintained at 5 weeks post-treatment. Several markers of fibrosis, particularly collagens 1 and 3, were also down-regulated in heart and muscles. Conclusions: FAP-CAR-T cells might represent a new therapeutic option for mitigating fibrosis in DMD, likely in conjunction with approaches aimed at addressing the root cause of the disease through a re-expression of a functional dystrophin.

Switch to gliflozins and biventricular function improvement in patients with chronic heart failure and diabetes mellitus.

SGLT2 inhibitors have been shown to reduce hospitalisation in patients with chronic heart failure (CHF). The cardioprotective mechanisms of gliflozins however have not been fully elucidated. The aim of this study was therefore to evaluate the effect of SGLT2 inhibitors on right and left ventricular function in patients with diabetes and HF. Seventy-eight patients with diabetes and CHF were enroled in the study and followed up; 38 started treatment with SGLT2i, while the remaining 40 continued their previous antidiabetic therapy. All patients underwent conventional, TDI and strain echocardiography in an ambulatory setting, at the beginning and after 3 months of therapy with SGLT2i. After 3 months of therapy with SGLT2i, echocardiographic parameters assessing both left and right ventricular dimensions and function were found as significantly improved in patients switching to SGLT2i than control group: LVEF (45 ± 9% vs. 40 ± 8%, p < 0.001), LVEDD (54 ± 6.5 vs. 56 ± 6.5 mm, p < 0.01), GLS (-13 ± 4% vs. -10 ± 3%, p < 0.001), TAPSE (21 ± 3 vs. 19 ± 3 mm, p < 0.001), RV S' (12.9 ± 2.5 vs 11.0 ± 1.9 cm/sec, p < 0.001)and PAsP (24 ± 8 vs. 31 ± 9 mmHg, p < 0.001). Also mitral (1.0 ± 0.5 vs. 1.3 ± 0.5, p < 0.01) and tricuspid regurgitation (1.0 ± 0.5 vs. 1.3 ± 0.5, p < 0.01) improved after SGLT2i therapy. Changes were not statistically significant in patients not treated with SGLT2i (p n.s. in all cases). In a real-world scenario, treatment with SGLT2i in patients with CHF and diabetes is associated with an improvement in both left and right ventricular function assessed at echocardiography. These data may explain potential anti-remodelling effects of gliflozins.

Total 25-Hydroxyvitamin D Is an Independent Marker of Left Ventricular Ejection Fraction in Heart Failure with Reduced and Mildly Reduced Ejection Fraction.

Vitamin D emerged as an important prognostic biomarker in heart failure (HF), with currently highly debated therapeutic implications. Several trials on vitamin D supplementation in HF showed improvements in left ventricular (LV) remodeling and function and health-related quality of life (HRQoL), which did not translate into mid- to long-term beneficial effects regarding physical performance and mortality. We addressed total 25-hydroxyvitamin D (25(OH)D), serum albumin, and uric acid (UA) levels, focusing mainly on vitamin D deficiency, as potential markers of LV systolic dysfunction in HF with reduced and mildly reduced ejection fraction (HFrEF, HFmrEF). Seventy patients with LVEF < 50% were comprehensively evaluated using ECG, echocardiography, lung ultrasound (LUS), blood sampling, and the six-minute walk test (6MWT). HRQoL was also assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Statistically significant positive correlations were found between LVEF, 25(OH)D, serum UA, and albumin, respectively (p = 0.008, p = 0.009, and p = 0.001). Serum UA (7.4 ± 2.4 vs. 5.7 ± 2.1, p = 0.005), NT-proBNP levels (1090.4 (675.2-2664.9) vs. 759.0 (260.3-1474.8), p = 0.034), and MLHFQ scores (21.0 (14.0-47.0) vs. 14.5 (4.5-25.5), p = 0.012) were significantly higher, whereas 25(OH)D concentrations (17.6 (15.1-28.2) vs. 22.7 (19.5-33.8), p = 0.010) were lower in subjects with severely reduced LVEF. Also, 25(OH)D was independently associated with LVEF in univariate and multiple regression analysis, maintaining its significance even after adjusting for confounders such as age, NT-proBNP, the presence of chronic coronary syndrome, hypertension, and anemia. According to our current findings, 25(OH)D is closely associated with LVEF, further supporting the need to establish correct vitamin D supplementation schemes and dietary interventions in HF. The changes in LVEF, 25(OH)D, serum UA, and albumin levels in HFrEF and HFmrEF indicate a similar pathophysiological background.

Viability and Outcomes With Revascularization or Medical Therapy in Ischemic Ventricular Dysfunction

In the Revascularization for Ischemic Ventricular Dysfunction (REVIVED-BCIS2) trial, percutaneous coronary intervention (PCI) did not improve outcomes for patients with ischemic left ventricular dysfunction. Whether myocardial viability testing had prognostic utility for these patients or identified a subpopulation who may benefit from PCI remained unclear. To determine the effect of the extent of viable and nonviable myocardium on the effectiveness of PCI, prognosis, and improvement in left ventricular function. Prospective open-label randomized clinical trial recruiting between August 28, 2013, and March 19, 2020, with a median follow-up of 3.4 years (IQR, 2.3-5.0 years). A total of 40 secondary and tertiary care centers in the United Kingdom were included. Of 700 randomly assigned patients, 610 with left ventricular ejection fraction less than or equal to 35%, extensive coronary artery disease, and evidence of viability in at least 4 myocardial segments that were dysfunctional at rest and who underwent blinded core laboratory viability characterization were included. Data analysis was conducted from March 31, 2022, to May 1, 2023. Percutaneous coronary intervention in addition to optimal medical therapy. Blinded core laboratory analysis was performed of cardiac magnetic resonance imaging scans and dobutamine stress echocardiograms to quantify the extent of viable and nonviable myocardium, expressed as an absolute percentage of left ventricular mass. The primary outcome of this subgroup analysis was the composite of all-cause death or hospitalization for heart failure. Secondary outcomes were all-cause death, cardiovascular death, hospitalization for heart failure, and improved left ventricular function at 6 months. The mean (SD) age of the participants was 69.3 (9.0) years. In the PCI group, 258 (87%) were male, and in the optimal medical therapy group, 277 (88%) were male. The primary outcome occurred in 107 of 295 participants assigned to PCI and 114 of 315 participants assigned to optimal medical therapy alone. There was no interaction between the extent of viable or nonviable myocardium and the effect of PCI on the primary or any secondary outcome. Across the study population, the extent of viable myocardium was not associated with the primary outcome (hazard ratio per 10% increase, 0.98; 95% CI, 0.93-1.04) or any secondary outcome. The extent of nonviable myocardium was associated with the primary outcome (hazard ratio, 1.07; 95% CI, 1.00-1.15), all-cause death, cardiovascular death, and improvement in left ventricular function. This study found that viability testing does not identify patients with ischemic cardiomyopathy who benefit from PCI. The extent of nonviable myocardium, but not the extent of viable myocardium, is associated with event-free survival and likelihood of improvement of left ventricular function. ClinicalTrials.gov Identifier: NCT01920048.

Improvement in Left and Right Ventricular Function after Introduction of SGLT2 Inhibitors in Heart Failure Outpatients with Reduced Ejection Fraction.

Type 2 sodium-glucose cotransporter inhibitors (SGLT2i) are among the main therapeutic options for patients with chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate the effects of SGLT2i on the echocardiographic parameters of left (LV) and right (RV) ventricular function among outpatients with a long history of HFrEF, in optimized therapy. We evaluated consecutive patients affected by HFrEF in whom the SGLT2i therapy was prescribed. Following a baseline evaluation (T0), in which SGLT2i was prescribed, patients were re-evaluated at 3 (T3), 6 (T6), and 12 (T12) months. We considered 60 patients for the analysis with a median history of HFrEF of more than seven years in optimal medical and electrical therapy. After SGLT2i therapy, LV ejection fraction and LV global longitudinal strain improved from baseline at T3, T6, and T12. Analogously, RV global and free wall longitudinal strain improved at T3 and T6. Our study shows that the addition of SGLT2i to the optimized therapy for HFrEF was associated with a significant improvement in both LV and RV function, thus highlighting a possible mechanism responsible for the benefit obtained with this class of drugs.

Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression

Immune cell infiltration in response to myocyte death regulates extracellular matrix remodeling and scar formation after myocardial infarction (MI). Caspase-recruitment domain family member 9 (CARD9) acts as an adapter that mediates the transduction of pro-inflammatory signaling cascades in innate immunity; however, its role in cardiac injury and repair post-MI remains unclear. We found that Card9 was one of the most upregulated Card genes in the ischemic myocardium of mice. CARD9 expression increased considerably 1 day post-MI and declined by day 7 post-MI. Moreover, CARD9 was mainly expressed in F4/80-positive macrophages. Card9 knockout (KO) led to left ventricular function improvement and infarct scar size reduction in mice 28 days post-MI. Additionally, Card9 KO suppressed cardiomyocyte apoptosis in the border region and attenuated matrix metalloproteinase (MMP) expression. RNA sequencing revealed that Card9 KO significantly suppressed lipocalin 2 (Lcn2) expression post-MI. Both LCN2 and the receptor solute carrier family 22 member 17 (SL22A17) were detected in macrophages. Subsequently, we demonstrated that Card9 overexpression increased LCN2 expression, while Card9 KO inhibited necrotic cell-induced LCN2 upregulation in macrophages, likely through NF-κB. Lcn2 KO showed beneficial effects post-MI, and recombinant LCN2 diminished the protective effects of Card9 KO in vivo. Lcn2 KO reduced MMP9 post-MI, and Lcn2 overexpression increased Mmp9 expression in macrophages. Slc22a17 knockdown in macrophages reduced MMP9 release with recombinant LCN2 treatment. In conclusion, our results demonstrate that macrophage CARD9 mediates the deterioration of cardiac function and adverse remodeling post-MI via LCN2.

Vagus nerve stimulation and acetylcholinesterase inhibitor donepezil provide cardioprotection against trastuzumab-induced cardiotoxicity in rats by attenuating mitochondrial dysfunction

Trastuzumab (Trz) is a targeted anticancer drug for human epidermal growth factor receptor 2 (HER2)-positive tumors, as Trz-induced cardiotoxicity (TIC) is commonly observed in Trz-treated patients. Since cardiac autonomic modulation with electrical vagus nerve stimulation (VNS) and acetylcholinesterase (AChE) inhibitors exerts cardioprotection against various heart diseases, the comparative effects of electrical VNS and an AChE inhibitor (donepezil) on cardiac and mitochondrial functions and programmed cell death pathways in TIC are not known. VNS devices were implanted in thirty-two male Wistar rats and were divided into 4 groups: (i) Control-Sham (CSham), (ii) Trz-Sham (TSham), (iii) Trz-VNS (TVNS), and (iv) Trz-donepezil (TDPZ). Rats in the Trz-treated groups were intraperitoneally injected with Trz (4 mg/kg/day) for 7 days, while CSham rats were injected with NSS. VNS devices were activated in the TVNS rats during the 7-day Trz treatment, but not in the sham rats. Rats in the TDPZ group received donepezil orally (5 mg/kg/day) for 7 days. At the end, left ventricular (LV) function and heart rate variability were evaluated, and heart tissue was collected for biochemical and histological analysis. Trz rats showed LV dysfunction and cardiac sympathovagal imbalance. In addition, mitochondrial function and dynamics were impaired in TIC rats. Trz also increased cardiomyocyte death by inducing apoptosis, pyroptosis, and ferroptosis. Electrical VNS and donepezil had similar efficacy in alleviating cardiac mitochondrial dysfunction, dynamic imbalances, and cardiomyocyte death, leading to improved LV function. These findings suggested that parasympathetic activation via either VNS or an AChE inhibitor could be a promising therapeutic intervention against TIC.

Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction

Background and AimsThe triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD.MethodsThe relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice.ResultsIn sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity.ConclusionElevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis.Graphical

Cardiac CT in CRT as a Singular Imaging Modality for Diagnosis and Patient-Tailored Management.

Between 30-40% of patients with cardiac resynchronization therapy (CRT) do not show an improvement in left ventricular (LV) function. It is generally known that patient selection, LV lead implantation location, and device timing optimization are the three main factors that determine CRT response. Research has shown that image-guided CRT placement, which takes into account both anatomical and functional cardiac properties, positively affects the CRT response rate. In current clinical practice, a multimodality imaging approach comprised of echocardiography, cardiac magnetic resonance imaging, or nuclear medicine imaging is used to capture these features. However, with cardiac computed tomography (CT), one has an all-in-one acquisition method for both patient selection and the division of a patient-tailored, image-guided CRT placement strategy. This review discusses the applicability of CT in CRT patient identification, selection, and guided placement, offering insights into potential advancements in optimizing CRT outcomes.

Cardiac Magnetic Resonance, Electromechanical Activation, Kidney Function, and Natriuretic Peptides in Cardiac Resynchronization Therapy Upgrades.

As the mechanism for worse prognosis after cardiac resynchronization therapy (CRT) upgrades in heart failure patients with RVP dependence (RVP-HF) has clinical implications for patient selection and CRT implementation approaches, this study's objective was to evaluate prognostic implications of cardiac magnetic resonance (CMR) findings and clinical factors in 102 HF patients (23.5% female, median age 66.5 years old, median follow-up 4.8 years) with and without RVP dependence undergoing upgrade and de novo CRT implants. Compared with other CRT groups, RVP-HF patients had decreased survival (p = 0.02), more anterior late-activated LV pacing sites (p = 0.002) by CMR, more atrial fibrillation (p = 0.0006), and higher creatinine (0.002). CMR activation timing at the LV pacing site predicted post-CRT LV functional improvement (p < 0.05), and mechanical activation onset < 34 ms by CMR at the LVP site was associated with decreased post-CRT survival in a model with higher pre-CRT creatinine and B-type natriuretic peptide (AUC 0.89; p < 0.0001); however, only the higher pre-CRT creatinine partially mediated (37%) the decreased survival in RVP-HF patients. In conclusion, RVP-HF had a distinct CMR phenotype, which has important implications for the selection of LV pacing sites in CRT upgrades, and only chronic kidney disease mediated the decreased survival after CRT in RVP-HF.

Long-term impact of angiotensin receptor-neprilysin inhibitor based on short-term treatment response in heart failure.

The long-term effect of angiotensin receptor-neprilysin inhibitor (ARNI) remains uncertain in patients who have experienced improvements in left ventricular (LV) systolic function or significant LV reverse remodelling following a certain period of treatment. It is also unclear how ARNI performs in patients who have not shown these improvements. This study aimed to assess the impact of prolonged ARNI use compared with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with and without significant treatment response after 1year of heart failure (HF) treatment. The present study enrolled patients with HF with reduced ejection fraction (HFrEF) who were treated with either ARNI or ACEIs/ARBs within 1year of undergoing index echocardiography. After 1year of treatment, patients were reclassified into the following groups: (i) patients with HF with improved ejection fraction and persistent HFrEF and (ii) patients with and without LV reverse remodelling based on the follow-up echocardiography. The effect of ARNI versus that of ACEIs/ARBs in each group was assessed from the time of categorizing into new groups using the composite event of all-cause mortality and HF hospitalization. A total of 671 patients with HFrEF (age, 66.4±14.1years; males, 66.8%) were included, and 133 (19.8%) composite events of death and rehospitalization for HF were observed during the follow-up (median follow-up, 44 [interquartile range, 34-51] months). ARNI had a significantly lower event rate than ACEIs/ARBs in patients with HF with improved ejection fraction (7.0% vs. 30.4%, P=0.020) and those with persistent HFrEF (17.6% vs. 49.7%, P<0.001). Irrespective of whether patients exhibited LV reverse remodelling (15.8% vs. 31.1%, P=0.001) or not (15.0% vs. 54.9%, P<0.001), ARNIs were associated with a significantly lower event rate than ACEIs/ARBs. Regardless of significant treatment response measured by either LVEF or LV reverse remodelling after 1year of treatment, the extended utilization of ARNI demonstrated a more favourable prognosis than that of ACEIs/ARBs in patients with HFrEF.

Acetylcholinesterase inhibition protects against trastuzumab-induced cardiotoxicity through reducing multiple programmed cell death pathways

BackgroundTrastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases. However, it remains unknown whether donepezil exerts anti-cardiotoxic effects in rats with TIC. We hypothesized that donepezil reduces mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death, leading to improved left ventricular (LV) function in rats with TIC.MethodsMale Wistar rats were randomly assigned to be Control or Trz groups (Trz 4 mg/kg/day, 7 days, I.P.). Rats in Trz groups were assigned to be co-treated with either drinking water (Trz group) or donepezil 5 mg/kg/day (Trz + DPZ group) via oral gavage for 7 days. Cardiac function, heart rate variability (HRV), and biochemical parameters were evaluated.ResultsTrz-treated rats had impaired LV function, HRV, mitochondrial function, and increased inflammation and oxidative stress, leading to apoptosis, ferroptosis, and pyroptosis. Donepezil co-treatment effectively decreased those adverse effects of TIC, resulting in improved LV function. An in vitro study revealed that the cytoprotective effects of donepezil were abolished by a muscarinic acetylcholine receptor (mAChR) antagonist.ConclusionsDonepezil exerted cardioprotection against TIC via attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, leading to improved LV function through mAChR activation. This suggests that donepezil could be a novel intervention strategy in TIC.

Noninvasive Electrical Mapping Compared with the Paced QRS Complex for Optimizing CRT Programmed Settings and Predicting Multidimensional Response

The aim was to test the hypothesis that left ventricular (LV) and right ventricular (RV) activation from body surface electrical mapping (CardioInsight 252-electrode vest, Medtronic) identifies optimal cardiac resynchronization therapy (CRT) pacing strategies and outcomes in 30 patients. The LV80, RV80, and BIV80 were defined as the times to 80% LV, RV, or biventricular electrical activation. Smaller differences in the LV80 and RV80 (|LV80-RV80|) with synchronized LV pacing predicted better LV function post-CRT (p = 0.0004) than the LV-paced QRS duration (p = 0.32). Likewise, a lower RV80 was associated with a better pre-CRT RV ejection fraction by CMR (r = − 0.40, p = 0.04) and predicted post-CRT improvements in myocardial oxygen uptake (p = 0.01) better than the biventricular-paced QRS (p = 0.38), while a lower LV80 with BIV pacing predicted lower post-CRT B-type natriuretic peptide (BNP) (p = 0.02). RV pacing improved LV function with smaller |LV80-RV80| (p = 0.009). In conclusion, 3-D electrical mapping predicted favorable post-CRT outcomes and informed effective pacing strategies.Graphical

Trans-aortic Valvular Ejection Fraction for Monitoring Recovery of Patients with Ventricular Systolic Heart Failure.

Durable mechanical circulatory support in the form of left ventricular (LV) assist device (LVAD) therapy is increasingly considered in the context of the recovery of native cardiac function. Progressive improvement in LV function may facilitate LVAD explantation and a resultant reduction in device-related risk. However, ascertaining LV recovery remains a challenge. In this study, we investigated the use of trans-aortic valvular flow rate and trans-LVAD flow rate to assess native LV systolic function using a well-established lumped parameter model of the mechanically assisted LV with pre-existing systolic dysfunction. Trans-aortic valvular ejection fraction (TAVEF) was specifically found to characterize the preload-independent contractility of the LV. It demonstrated excellent sensitivity to simulated pharmacodynamic stress tests and volume infusion tests. TAVEF may prove to be useful in the ascertainment of LV recovery in LVAD-supported LVs with pre-existing LV systolic dysfunction.

Xin-Li formula attenuates heart failure induced by a combination of hyperlipidemia and myocardial infarction in rats via Treg immunomodulation and NLRP3 inflammasome inhibition.

Heart failure (HF) is a complex clinical syndrome that represents the end result of several pathophysiologic processes. Despite a dramatic evolution in diagnosis and management of HF, most patients eventually become resistant to therapy. Xin-Li Formula (XLF) is a Chinese medicine formula which shows great potential in the treatment of HF according to our previous studies. The present study was designed to investigate the effects of XLF on HF induced by a combination of hyperlipidemia and myocardial infarction (MI) in rats and reveal the underlying mechanism. A rat model of HF induced by hyperlipidemia and MI was established with intragastric administration of XLF and Perindopril. Invitro, CD4+ T cells from mouse spleen and LPS/ATP-stimulated THP-1 macrophages were employed. XLF was shown to have markedly protective effects on MI-induced HF with hyperlipidemia in rats, including improvement of left ventricular function, reduction of left ventricular fibrosis and infarct size. Moreover, XLF administration significantly increased the number of Foxp3+ Tregs, and inhibited mTOR phosphorylation and NLRP3 signaling pathway. Invitro, we found that XLF had induced Treg activation via the inhibition of mTOR phosphorylation in CD4+ T cells. Additionally, XLF inhibited NLRP3 inflammasome activation in LPS/ATP-stimulated THP-1 macrophages. Taken together, this study raises the exciting possibility that Xin-Li Formula may benefit HF patients due to its immunomodulatory and anti-inflammatory effects via Treg activation and NLRP3 inflammasome inhibition.

Introduction of SGLT2 Inhibitors and Variations in Other Disease-Modifying Drugs in Heart Failure Patients: A Single-Centre Real-World Experience.

The sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as a crucial therapeutic option for patients with chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate, in a real-world population from a single centre, the feasibility of introducing SGLT2i and their interaction with other recommended drug classes. Consecutive patients affected by chronic heart failure (CHF) were evaluated beginning in January 2022. At the baseline clinical visit, both the patient's current medication and the prescribed treatments were recorded. Over a 6- to 12-month follow-up, changes in concomitant therapy were analysed. At baseline, among 350 patients evaluated, only 17 (5%) were already taking SGLT2i: 13 with HFrEF, five with mildly reduced (HFmrEF), preserved (HFpEF) or improved (HFimpEF) ejection fraction. After the baseline assessment, SGLT2i were prescribed to 224 (64%) of the patients, including 179 (84%) with HFrEF, 27 (42%) with HFmrEF/HFimpEF, and 18 (22%) with HFpEF/HFimpEF. After follow-up, SGLT2i therapy was well tolerated and was associated with a significant increase in sacubitril/valsartan prescriptions and a decrease in diuretic use. Finally, a significant improvement in functional status and left ventricular systolic function after SGLT2i therapy was observed. In this single-centre, real-world study, SGLT2i were primarily prescribed to HFrEF patients who were already on other recommended drug classes for their treatment. Additionally, there was a noticeable enhancement in the prescribed therapy during a short-term follow-up. These findings further bolster the inclusion of this therapeutic approach in regular clinical practice.