Improvement In Left Ventricular Function Research Articles

Extracellular vesicle-mediated VEGF-A mRNA delivery rescues ischaemic injury with low immunogenicity.

Lackluster results from recently completed gene therapy clinical trials of VEGF-A delivered by viral vectors have heightened the need to develop alternative delivery strategies. This study aims to demonstrate the pre-clinical efficacy and safety of extracellular vesicles (EVs) loaded with VEGF-A mRNA for the treatment of ischaemic vascular disease. After encapsulation of full-length VEGF-A mRNA into fibroblast-derived EVs via cellular nanoporation (CNP), collected VEGF-A EVs were delivered into mouse models of ischaemic injury. Target tissue delivery was verified by in situ analysis of protein and gene expression. Functional rescue was confirmed by in vivo imaging and histology. The safety of single and serial delivery was demonstrated using immune-based assays. VEGF-A EVs were generated with high mRNA content using a CNP methodology. VEGF-A EV administration demonstrated expression of exogenous VEGF-A mRNA by in situ RNA hybridization and elevated protein expression by western blot, microscopy, and enzyme-linked immunosorbent assay. Mice treated with human VEGF-A EVs after femoral or coronary artery ligation exhibited heightened neovascularization in ischaemic tissues with increased arterial perfusion and improvement in left ventricular function, respectively. Serial delivery of VEGF-EVs in injured skin showed improved wound healing with repeat administration. Importantly, as compared with adeno-associated viral and lipid nanoparticle VEGF-A gene therapy modalities, murine VEGF-A EV delivery did not trigger innate or adaptive immune responses at the injection site or systemically. This study demonstrated that VEGF-A EV therapy offers efficient, dose-dependent VEGF-A protein formation with low immunogenicity, resulting in new vessel formation in murine models of ischaemic vascular disease.

Left ventricular function improvement during angiotensin receptor-neprilysin inhibitor treatment in a cohort of HFrEF/HFmrEF patients.

Heart failure (HF) patients may lack improvement of left ventricular (LV) ejection fraction (LVEF) despite optimal HF medication comprising an angiotensin receptor-neprilysin inhibitor (ARNI). Therefore, we aimed to identify key predictors for LV functional enhancement and prognostic reverse cardiac remodelling in HF patients on ARNI treatment. We retrospectively analysed 294 consecutive patients with HF with reduced (HFrEF) or mildly reduced (HFmrEF) ejection fraction in our 'EnTruth' patient registry. LVEF was determined by echocardiography at initiation of ARNI and at 12months of follow-up. We assessed the predictive value of clinically relevant patient-, HF- and treatment-related parameters in regard to changes in LVEF and all-cause mortality using medoid clustering and the XGBoost machine learning algorithm. Cluster analysis integrating clinically relevant patient characteristics unveiled four characteristic sub-phenotypes of patients with HFrEF and HFmrEF, respectively. Distinct clusters exhibit a strong (P<0.05) therapeutic response to ARNI treatment and enhanced LV function. Key patient criteria, such as duration and aetiology of HF, renal function and de novo ARNI treatment, were significantly (P<0.05) associated with change of LVEF and independently predicted cardiac remodelling. By training various machine learning models on relevant clinical parameters, stratification of LVEF improvement by XGBoost resulted in a high prediction accuracy. The stratification of patients with HFrEF [area under the receiver operating characteristic curve (AUC)=0.77] and HFmrEF (AUC=0.70) led to an increased diagnostic accuracy of LVEF improvement in the validation cohort. Using machine learning, the likelihood of cardiac remodelling following ARNI treatment, as indicated by our newly established EnTruth score, was directly associated with absolute LVEF improvement in both HFrEF (r=0.51, P<0.0001) and HFmrEF (r=0.42, P=0.001). Ultimately, patients with HFrEF and a high EnTruth score have a lower risk of all-cause mortality (P<0.05 in survival analysis). Recognition of essential clinical factors by integrating machine learning and cluster analyses may help to identify HF patients benefiting from improvement of LVEF following ARNI treatment. Early identification of those patients with a high response to ARNI treatment may allow a more refined selection of patients benefiting from an early escalation of HF treatment or interventional therapy.

Sacubitril/valsartan on right ventricular-pulmonary artery coupling and albumin-bilirubin score in heart failure in Chinese patients with reduced ejection fraction

ObjectiveImpaired right ventricular (RV)-pulmonary arterial (PA) coupling, calculated by measuring the tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP), can be used as an early indicator of right ventricular dysfunction (RVD) in patients with heart failure with a reduced ejection fraction (HFrEF). Patients suffering from HFrEF experience improvements in left ventricular (LV) function through the administration of sacubitril/valsartan therapy. In addition, the albumin-bilirubin (ALBI) score was associated with the fluid overload status and adverse clinical outcomes in patients with heart failure. This study aimed to assess whether angiotensin receptor-neprilysin inhibitor (ARNI) affects the TAPSE /PASP in patients with HFrEF, and whether there is a correlation between changes in the ALBI score and ARNI treatment.MethodsA retrospective observational study was conducted on 305 patients with HFrEF and RVD who were hospitalized between June 2020 and December 2021. One year after treatment, laboratory test results, ALBI score, transthoracic echocardiography (TTE), New York Heart Association classification, Minnesota Living with Heart Failure Questionnaire scores and changes in relevant variables were reevaluated.ResultsCompared to before sacubitril/valsartan treatment, the ALBI was found to be significantly reduced after one year of follow-up (-2.42 ± 0.37 vs. -2.51 ± 0.32, p < 0.001). Additionally, A significant improvement was demonstrated in the following echocardiography parameters assessing RV function after 1 year of treatment with sacubitril/valsartan: TAPSE (15 ± 1 vs. 18 ± 2 mm, p < 0.001), PASP (45 ± 8 vs. 40 ± 9 mmHg, p < 0.001), pulmonary artery diastolic pressure (PADP) (22 ± 4 vs. 19 ± 4 mmHg, p < 0.001), RV-PA coupling (0.35 ± 0.08 vs. 0.48 ± 0.12, p < 0.001), and RV s’(8.7 ± 2.2 vs. 9.5 ± 2.6 cm/s, p < 0.001). Multivariate analysis showed that the improvement of RV-PA coupling was associated with baseline PASP (r: -0.45, p < 0.001) and PADP (r: -0.45, p < 0.001).ConclusionsSacubitril/valsartan improves RV-PA conjugation in patients with RVD and HFrEF, and has a positive impact on the ALBI score by improving liver function in patients with HFrEF.

Right ventricular subclinical dysfunction in high-burden idiopathic outflow tract premature ventricular contraction population.

The relationship between premature ventricular contractions (PVC) and right ventricular (RV) function is not widely known. Left ventricular (LV) dysfunction due to PVC is known as PVC-induced cardiomyopathy (PIC) and suppressing the PVC substrate would improve LV function. The effect of PVC ablation on changes in RV function in patients with subtle RV subclinical dysfunction remains unknown. Understanding the alterations in RV function parameters after PVC ablation. Basic and speckle-tracking echocardiography has been performed on 42 individuals with symptomatic idiopathic outflow tract PVC before and 1 month after a successful ablation. At the baseline of the study, there were 26 patients with RV subclinical dysfunction and 16 patients without RV dysfunction. Patients with RV subclinical dysfunction exhibited significantly higher PVC burden and QRS complex duration than those with normal RV function (p < 0.05). A PVC burden ≥ 21% (OR 9.11, 1.54-53.87, p = 0.015) and a QRS complex duration ≥ 138 ms (OR 5.74, 1.07-30.90, p = 0.042) were independently associated with RV subclinical dysfunction. In both groups, measurements of RV subclinical function before and after ablation, specifically by free wall longitudinal strain (FWLS) and global longitudinal strain (GLS), demonstrated significant changes. These improvements were more pronounced in the group with RV dysfunction (FWLS 9.7 ± 4.0, p < 0.001; GLS 7.5 ± 4.2, p < 0.001). Lower initial FWLS and GLS before ablation emerged as significant parameters in the multivariate analysis for the improvement of RV function post-ablation. Patients with RV subclinical dysfunction had higher PVC burden and wider QRS duration. Patients with idiopathic outflow tract PVC with RV subclinical dysfunction may experience improvements in RV function after successful PVC ablation.

Left Ventricular Hypertrabeculation (LVHT) in Athletes: A Negligible Finding?

Left ventricular hypertrabeculation (LVHT) used to be a rare phenotypic trait. With advances in diagnostic imaging techniques, LVHT is being recognised in an increasing number of people. The scientific data show the possibility of the overdiagnosis of this cardiomyopathy in a population of people who have very high levels of physical activity. We describe the case of a young athlete with no medical history, who presented with syncope during a marathon running race. Initial evaluation showed elevated troponin I; transthoracic echocardiography showed a trabeculated ventricle and subsequent cardiac magnetic resonance (CMR) revealed left ventricular hypertrabeculation (LVHT). During subsequent evaluation by tilt table testing, vasovagal syncope was identified as the likely aetiology of the syncope. The patient was advised to cease sports and stimulants like caffeine use. At the 29-month follow-up, CMR showed the normalisation of the non-compacted to compacted myocardial ratio and an improvement in left ventricular function, with no further syncopal episodes reported. This is an example of the physiological hypertrabeculation of the LV apex in a recreational endurance athlete, with the normalisation of the non-compacted to compacted myocardial layer ratio after detraining. Physiological hypertrabeculation, a benign component of exercise-induced cardiac remodelling, must be differentiated from non-compaction cardiomyopathy and other pathologies causing syncope. This case underscores the importance of distinguishing physiological hypertrabeculation from pathological LVHT in athletes, highlighting that exercise-induced cardiac remodelling can normalise with detraining.

Deep Septal Pacing for Pacemaker-Induced Cardiomyopathy.

Right ventricular (RV) pacing can impair left ventricular function and cause heart failure, known as pacing-induced cardiomyopathy (PICM). Upgrade to cardiac resynchronization (CRT) is its usual treatment; recently left bundle branch area pacing (LBBAP) has emerged as a potential alternative. Deep septal pacing (DSP), a simplified alternative to LBBAP, is still able to achieve narrower paced QRS than during conventional RV pacing. The aim of this study was to assess the effect of DSP in a cohort of patients with PICM. Consecutive patients diagnosed with PICM were included. The aim was to upgrade patients to DSP. The procedure was considered successful if a paced QRS duration ≤140ms was obtained, in the absence of a terminal R wave in V1. Twelve patients were included. The mean baseline LVEF was 33% (SD 4%), and the mean percentage of RV pacing was 99% (SD 1%). All patients had symptomatic heart failure. The mean paced QRS duration was 172ms (SD 14ms) with RV pacing, and 130ms (SD 7ms) with DSP (mean difference 42ms, p<0.001). At 6 months, the mean LVEF after the upgrade was 46% (SD 9%), significantly superior to LVEF with RV pacing (p = 0.001), a mean improvement of 13% (SD 10%). All patients except one experienced an improvement in LVEF of at least 5%. Our data suggest that DSP may be an effective and simpler alternative to biventricular or LBBAP in patients with PICM. Narrower paced QRS complexes can be achieved, which may lead to an improvement in left ventricular function.

The Acute Effect of Hot Water Immersion on Cardiac Function in Individuals with Cervical Spinal Cord Injury.

Background/Objectives: Thermotherapy is expected to assist in the prevention of arteriosclerosis and cardiovascular disease in individuals with spinal cord injuries. This study aimed to investigate the impact and underlying mechanisms of whole-body heat stress on cardiac function in patients with cervical spinal cord injury (CSCI) and healthy controls using head-out hot water immersion (HHWI). Methods: Eight male patients with complete motor CSCI and nine healthy controls were recruited. Participants were immersed for 60 min in water set at 2 °C above the resting esophageal temperature. Esophageal temperature, heart rate, and arterial pressure were monitored throughout the experiment. Before and after HHWI, echocardiography was used to measure indices of left ventricular diastolic capacity (E, E', and A), left atrial contractility (A and A'), and left ventricular contractility [S' and isovolumic acceleration (IVA)]. Results: Both groups exhibited an increase in body temperature and heart rate, while blood pressure remained stable. In the control group, there was a significant increase in E (67.0 ± 22.6 to 89.1 ± 13.6), E' (9.5 ± 3.8 to 15.1 ± 4.1), A (50.0 ± 15.2 to 75.8 ± 18.2), A' (8.1 ± 1.6 to 14.8 ± 5.9), S' (8.7 ± 1.4 to 15.1 ± 4.5) and isovolumic acceleration (IVA) (104.2 ± 14.7 to 151.1 ± 20.6). In the CSCI group, only A (49.5 ± 9.9 to 56.9 ± 10.9) and IVA (94.4 ± 27.2 to 134.7 ± 27.7) showed a significant change. Conclusions: In the control group, heat stress increased left atrial contractility, left ventricular dilatation, and left ventricular contractility, while in patients with CSCI, left atrial contractility and left ventricular contractility improved, but there was no improvement in left ventricular diastolic function. This discrepancy in the impact of HHWI on cardiac function suggests that the sympathetic nervous system predominantly influences left ventricular dilatation during whole-body heat stress. However, other factors may also contribute to left atrial and ventricular contractility.

The Metabolically Resistant Apelin-17 Analogue LIT01-196 Reduces Cardiac Dysfunction and Remodelling in Heart Failure After Myocardial Infarction.

To protect patients after myocardial infarction (MI) and preserve cardiac function, the development of new therapeutics remains an important issue. Apelin, a neuro-vasoactive peptide, increases aqueous diuresis and cardiac contractility while reducing vascular resistance. However, its invivo half-life is very short. We therefore developed a metabolically resistant apelin-17 analogue, LIT01-196 and investigated its effects on cardiac function and remodelling in a murine MI model. The selectivity of LIT01-196 toward the apelin receptor was checked invitro. Its invivo half-life was assessed in male Swiss mice using radioimmunoassay. After permanent coronary artery ligation to induce MI, mice received subcutaneous administration of LIT01-196 (MI+ LIT01-196, 9 mg/kg/d) or saline (MI+ vehicle) for 4 weeks. Left ventricular (LV) function was assessed using echocardiography and Millar (Houston, TX) catheter, vascular density using immunofluorescence, and cardiac fibrosis using Sirius red staining. Real-time quantitative PCR was used to measure mRNA expression of heart failure (HF) fibrosis biomarkers and sarco/endoplasmic reticulum Ca2+-ATPase-2. The invivo half-life of LIT01-196, a specific and selective apelin receptor agonist, was 2.5 hours. MI+ LIT01-196 showed significantly improved LV function, reduced HF biomarkers, and enhanced cardiac contractility and sarco/endoplasmic reticulum Ca2+-ATPase-2 expression compared with MI+ vehicle. LIT01-196 treatment almost doubled cardiac vascular density and maintained LV wall thickness post MI. It also significantly reduced cardiac fibrosis and fibrosis biomarkers, without decreasing arterial blood pressure. Chronic LIT01-196 treatment post MI improves LV function without decreasing blood pressure, increases cardiac vascular density, and reduces cardiac remodelling. This suggests that apelin receptor activation by LIT01-196 might constitute an original pharmacological approach for HF treatment after MI.

Characterization of Myocardial Recovery in Patients With Tachycardiomyopathy.

The degree and time course of improvement in left ventricular (LV) function with treatment in patients with tachycardiomyopathy (TCMP) is highly variable. This study aims to clinically characterize the recovery of TCMP based on the extent and course of improvement in LV function and identify predictors of complete myocardial recovery. In this prospective, single-center, observational study, patients with suspected TCMP who underwent successful tachyarrhythmia termination/control were included. Clinical and echocardiographic assessment of LV function was done at baseline, within 1 h after tachyarrhythmia termination, 24 h later, and at 12 weeks follow-up. Ninety-nine patients were enrolled in the study. Six patients had immediate normalization of LV ejection fraction (LVEF) with reversion to sinus rhythm and were labeled as "pseudo-TCMP"; the remaining 93 patients were included in the analysis. Based on complete versus partial normalization of LVEF at 12-week follow-up, 50 patients (53.8%) were labeled as completely recovered TCMP and 43 (46.2%) as partially recovered TCMP respectively. Causative arrhythmias included atrial fibrillation (38%), focal atrial tachycardia (28%), atrial flutter (22%), ventricular arrhythmias (11%), and orthodromic re-entrant tachycardia (2%). The LVEF at presentation was 0.25 ± 0.05 which improved to 0.36 ± 0.11 within 1 h after tachycardia termination (p < 0.0001), 0.41 ± 0.14 24 h later (p = 0.009) and to 0.52 ± 0.12 at 12 weeks follow-up (p < 0.0001). Male gender was the only differentiating statistically significant variable between completely recovered and partially recovered TCMP, 24 (48%) versus 30 (69.7%) respectively (p = 0.0339). Nearly half of the TCMP patients have complete recovery of LV function at 12 weeks follow-up, while the other half have a partial recovery only. There was no robust predictor of complete myocardial recovery.

Subclinical cardiac dysfunction detected by speckle-tracking echocardiography in patients with liver cirrhosis undergoing liver transplantation

BackgroundCirrhosis is associated with chronic cardiovascular dysfunction termed cirrhotic cardiomyopathy (CCM), characterized by myocardial hypertrophy and diastolic dysfunction. Detecting early cardiac changes is crucial, especially in patients undergoing liver transplantation. Objective: This study aims to evaluate left ventricular systolic function in cirrhotic patients undergoing liver transplantation using speckle-tracking echocardiography.MethodsA prospective observational study was conducted involving 54 cirrhotic patients who underwent liver transplantation, along with 28 age- and sex-matched healthy controls. Echocardiography, including conventional and two-dimensional speckle tracking echocardiography (2D-STE), was performed at baseline and one-month post-transplantation.ResultsThe mean age in the cirrhotic group was 52.2 ± 12.7 years, with no significant difference compared to the control group. Viral hepatitis was the predominant etiology of cirrhosis (68.6%). Conventional echocardiography did not reveal significant differences between groups in LV ejection fraction [62% (56–69) vs. 59% (56–62); p = 0.830]. However, in cirrhotic patients, 2D-STE demonstrated significantly lower LV global longitudinal strain (LV-GLS) [17.5 (15.5–19.1) vs 19.0 (18.0–19.7), p = 0.006]. Post-transplantation, conventional echocardiography indices remained unchanged, while 2D-STE showed remarkable improvement in LV function, with increased LV-GLS compared to pre-transplantation value.Conclusions2D-STE is a valuable tool for detecting and monitoring left ventricular systolic dysfunction in liver cirrhosis patients, particularly following transplantation. While conventional echocardiography may not detect subtle changes, 2D-STE reveals improvements in LV function post-transplantation, emphasizing its role in assessing cirrhotic cardiomyopathy.

Safety and therapeutic potential of allogeneic adipose-derived stem cell spray transplantation in ischemic cardiomyopathy: a phase I clinical trial

BackgroundIschemic cardiomyopathy, characterized by coronary artery atherosclerosis, impairs the myocardial tissue. Coronary artery bypass grafting (CABG) is commonly used to revascularize affected areas and improve patient survival rates; however, it can fail to enhance cardiac function. Impaired capillary blood flow may obstruct functional recovery, prompting interest in treatments, such as angiogenic factor administration. Adipose-derived stem cells (ADSCs), which are known for immune evasion, have shown the potential to construct capillary networks and improve myocardial function. This clinical trial aimed to evaluate the safety and efficacy of ADSC spray therapy combined with CABG.MethodsThis single-center, randomized, double-blind study involved patients with ischemic cardiomyopathy who were scheduled for CABG and who had a left ventricular ejection fraction ≤ 40%. The participants were randomized to receive CABG as well as ADSC spray therapy or placebo. The primary endpoints were safety, changes in late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) volumes, and feasibility. The secondary endpoints included left ventricular function, exercise tolerance, and heart failure symptoms.ResultsSeven patients were enrolled; of them, six were randomized to receive ADSC therapy (n = 3) or placebo (n = 3). The procedure was successfully completed with minimal adverse events. One patient in the ADSC group developed pleural effusion that was resolved with drainage. The LGE-MRI volumes decreased in the ADSC group but remained unchanged in the placebo group. Improvements in left ventricular function and exercise tolerance were noted in the ADSC group, with heart failure symptoms improving to New York Heart Association class I. In contrast, the placebo group showed no significant changes, with one patient experiencing worsening symptoms.ConclusionsADSC spray therapy combined with CABG demonstrated safety and efficacy at enhancing cardiac function. ADSC likely contributes to capillary network reconstruction, thereby augmenting the benefits of CABG. Future phase II and III trials are warranted to confirm its therapeutic efficacy and long-term outcomes. This novel approach represents a significant advancement in the treatment of ischemic cardiomyopathy and offers a viable strategy for improving myocardial function and patient prognosis.Trial registration This study was registered with the Japan Registry of Clinical Trials (jRCT2053190103) and ClinicalTrials.gov (NCT04695522)Graphical

Echocardiographic Evaluation in Cardiac Resynchronization Therapy: A Single Center Experience.

Introduction Heart failure develops as a result of dysfunction in the cardiac muscle, which impairs the heart's ability to pump blood effectively. For this reason, many studies have shown that cardiac resynchronization therapy (CRT) has significantly reduced symptoms and improved cardiac function in patients with heart failure. Echocardiography is crucial in assessing CRT response, as it helps differentiate between patients who benefit from CRT and those who do not by evaluating key parameters like left ventricular ejection fraction (LVEF), a critical parameter in determining CRT eligibility. However, few studies focus specifically on the effectiveness of echocardiography for assessing CRT response, with existing research limited by a lack of standardized protocols and inadequate predictive tools. Accordingly, this study aims to assess the role of echocardiography in evaluating the efficacy of CRT in patients with heart failure at King Faisal Cardiac Center. Methodology This was a retrospective analytical cohort study that included all adult patients diagnosed with heart failure and underwent CRT between January 2017 and December 2021 at King Faisal Cardiac Center, King Abdulaziz Medical City, Jeddah, Saudi Arabia. Data were obtained from the Cardiac Non-invasive Lab, which was selected for its essential diagnostic tools for comprehensive echocardiographic evaluation of CRT efficacy. Study subjects were over 18 years old, diagnosed with heart failure with reduced ejection fraction (LVEF <35%), underwent CRT, and had echocardiograms at baseline and at least six months post-therapy. The collected data were retrieved from electronic medical records (BestCare; ezCaretech Co., Ltd,Seoul, South Korea), including relevant demographics and echocardiographic parameters such as end-systolic volume (ESV), end-diastolic volume (EDV), and ejection fraction (EF). Statistical analysis, paired t-tests,and Shapiro-Wilk test to assess data normality were conducted to evaluate pre- and post-CRT changes, with significance set at P<0.05. Results A total of 53 heart failure patients met the inclusion and exclusion criteria. The results of the study indicate statistically significant differences in the mean EF before and after CRT increased from 29.09±6.52% to 33.3±10.69% (p-value=0.0014). The mean ESV decreased from 114.46±60.63 mL to 97.13±65.89 mL, demonstrating a clinically significant improvement (p=0.056), and the mean EDVdecreased from 157.08±64.67 mL to 138.87±78.07 mL (p = 0.0158). Furthermore, the EF increased by 14.47%, and the ESV decreased by 15.14% after CRT.These findings indicate improvement in left ventricular function following CRT. Conclusion The study demonstrates significant improvements in echocardiographic parameters based on echocardiogram findings, particularly the outcomes of EF and ESV after CRT in patients with heart failure with reduced ejection fraction.These findings highlight the potential of CRT as an effective therapy and aid in detecting responders to treatment. Nevertheless, the study is limited by a relatively small sample size, exclusion of comorbidities, and short follow-up period. Therefore, further longitudinal studies with larger cohorts and consideration of comorbidities are recommended.

Abstract 4138380: Cardiac protection of hiPSC-CMs loaded chitosan cardiac patch in myocardial infarcted swine

Background: The low grafting rate of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) following direct injection into the myocardium limits the efficacy of cardiac repair after myocardial infarction (MI). Chitosan-based scaffolds have emerged as functional biomaterials for designing delivery systems in cardiac therapies. This study aimed to enhance the potency of cardiac repair using a hiPSC-CMs loaded chitosan cardiac muscle patch (hCCMP). Methods: The patches were fabricated using chitosan. Characterization of the chitosan patches involved assessing their swelling rate and porosity. The biocompatibility of the hCCMP was analyzed through scanning electron microscopy (SEM) and the CCK8 assay. 16 Yorkshire swine (15-20 kg, 45-50 days of age) were randomly divided into 4 groups (n=4 per group): Sham, MI without further intervention, MI with an empty patch (without hiPSC-CMs), and MI with hCCMP implantation. One and four weeks post-MI, heart function, Infarction size, myocardial perfusion and metabolism were evaluated via cardiac PET-MRI. Engraftment was assessed through human cardiac troponin T staining. Histological analysis including left ventricular anterior wall thickness, cardiac remodeling, angiogenesis, arterialization, and apoptosis in the infarct border area were analyzed using immunofluorescence. Results: SEM showed that the chitosan patch had regular pore size and good 3D structure; porosity was about (96.7±0.37)%. On day3, the patch swelling rate was about (715±64.55)%. SEM, CCK8 assay showed a normal cells growth in the chitosan patch. The hiPSC-CMs grafted well with chitosan patch delivery systems and was associated with significantly improvement in LV function, infarction size, angiogenesis and cardiomyocyte apoptosis in pigs 4 weeks after MI. Conclusions: The 3D chitosan cardiac patch with hiPSC-CMs loaded can enhance the potency of cardiac repair in pigs after MI and present a novel and promising therapic strategy.

Mitral regurgitation improvement following left bundle branch pacing versus right ventricular septum pacing: a dedication to postoperative amelioration of mitral regurgitation

Abstract Background Mitral regurgitation (MR) is correlated with left ventricular (LV) remodeling and LV function in patients. Left bundle branch pacing (LBBP) exhibits a significant decline in MR in left bundle branch block (LBBB) and cardiomyopathy patients. This research aims to evaluate the influence of LBBP on MR in comparison to right ventricular septal pacing (RVSP) in patients with atrioventricular block (AVB) or sick sinus syndrome (SSS). Methods Sixty consecutive patients with SSS or AVB were enrolled if they underwent pacemaker implantation via LBBP or RVSP. Patients with a history of mitral valve surgery were excluded. Echocardiogram parameters were assessed to measure MR and LV remodeling as well as LV function at baseline and follow-up. Results Thirty-six patients (60 %; mean age: 70.39 ± 14.80 years; 61.1 % male) underwent successful LBBP, and 24 patients (40 %; mean age: 71.58 ± 10.91 years; 66.7 % male) underwent RVSP. The average follow-up duration was relatively comparable between the two groups. In comparison to RVSP, LBBP demonstrated significant changes in MR area, and severity at baseline and follow-up (P&amp;lt;0.05). LBBP independently predicted MR amelioration in patients who underwent pacemaker implantation (HR=0.289, CI=0.087–0.9961; P=0.043). At follow-up, the LBBP subgroup with moderate/severe MR exhibited significantly shorter lead-TVA-dist, higher left atrium (LA) diameters, and mitral E/A ratio (P&amp;lt;0.05) compared to the none/mild MR subgroup. In LBBP with MR amelioration, LV remodeling (ΔLVEDD) was significantly enhanced compared to baseline (P=0.016). Additionally, a non-significant trend toward better improvement in LV function (ΔLVEF and ΔE/A) was observed in patients with MR amelioration. Conclusion LBBP, considered an optimal pacing technique for SSS or AVB patients, may substantially reduce MR and subsequently enhance LV remodeling and function compared to RVSP. This open, observational pilot study warrants confirmation through further investigations.Comparison between LBBP and RVSPKaplan-Meier curves for MR amelioration

Baroreflex activation therapy in heart failure patients with reduced ejection fraction: a long-term follow up

Abstract Introduction Heart failure with reduced ejection fraction (HFrEF) is a major public health concern with substantial morbidity and mortality. Overactivation of the sympathetic nervous system is a key pathophysiological process driving heart failure progression. Baroreceptor activation therapy (BAT) targets this autonomic imbalance and is a promising treatment strategy for patients with HFrEF. Current short-term studies indicate that BAT provides symptomatic relief, improvement in left ventricular function and cardiac biomarkers. However, data regarding the long-term effect of BAT on HFrEF are scarce. Purpose This study aims to assess long-term outcome in HFrEF patients who underwent BAT. Methods Patients with HFrEF who received BAT between 2014-2023 were followed until latest available follow-up. Symptom burden, echocardiography and laboratory testing were assessed before BAT implantation and in subsequent follow ups. Results 23 patients (mean age 66±10 years, 83% men) with HFrEF were included in the study. Etiology of heart failure was ischemic in 70%. The majority of patients (96%) suffered from NYHA III with a mean left ventricular ejection fraction (LVEF) of 23±8% and NTproBNP of 2463±2922pg/ml. Complication occurred in one patient during BAT implantation (4%). Mean follow-up was 3±2 (max. 7.5) years. BAT reduced NYHA classification in 12 patients (52%) after 1 year, of which 1 patient remained in ameliorated NYHA for 7.5 years. Evolution of NYHA functional class over time is shown in Figure 1. Echocardiographic evaluation revealed significant improvement in LVEF of 9±9% after 1 year (p&amp;lt;0.001) and by 11±9% after 2 years (p=0.005). In long-term a trend towards improved LVEF could be observed (Figure 2). In addition, BAT mildly reduced NTproBNP in the first 2 years (after 1 year non-significantly by -396±1006pg/ml and significantly after 2 years by -566±651pg/ml (p=0.039)). Seven patients reaching recommended replacement time underwent device exchange. Four patients deceased during observation time. Conclusion BAT resulted in a substantial reduction in NYHA classification, improvement in LVEF, and a delayed reduction in NTproBNP levels. These findings highlight the long-term efficacy and potential benefits of BAT as a therapeutic intervention for patients with HFrEF.Sankey plot of NYHA class over timeAlteration of LVEF over time

LV reverse remodeling after SAVR in patients with severe symptomatic aortic stenosis: impact on the clinical outcome

Abstract Introduction Surgical aortic valve replacement (SAVR) is the treatment of choice for young patients with severe aortic stenosis (AS) and low surgical risk. Left ventricular (LV) reverse remodeling (RR) after surgery is expected to occur. However, this is not always the case following afterload relief, and this may impact the prognosis. We aimed to assess the prognostic effect of distinct definitions of LV RR after SAVR in the long-term outcome of patients with severe AS. Methods Single-centre prospective study including patients referred for SAVR due to severe symptomatic AS, with no previous history of ischemic cardiomyopathy. Both pre- and post-operative transthoracic echocardiographic (TTE) and cardiac magnetic resonance (CMR) study (at the 3rd to 6th month after SAVR) were performed. LV RR was defined when in presence of at least one of the imaging criteria: &amp;gt;15% decrease in end-diastolic volume (EDV) by CMR; &amp;gt;15% decrease in LV indexed mass (LVM) by CMR; &amp;gt;10% decrease in geometric remodeling (LV mass/EDV ratio) by CMR; &amp;gt;10% increase in LV ejection fraction (LVEF) by CMR; &amp;gt;50% increase on global longitudinal strain (GLS) by TTE. We assess the prognostic value of RR definitions for the outcome after SAVR using Cox regression and Kaplan-Meier analysis. The primary endpoint was defined as all-cause mortality, heart failure (HF) hospitalization or worsening HF. Results We enrolled 140 patients – mean age 71±9 years-old, 49% male, predominantly high-gradient-normal flow AS (mean gradient 65±18mmHg, aortic valve area 0.7±0.2cm2, index stroke volume 47±11mL/m2) submitted to SAVR. At a mean follow-up (FUP) of 34±12 months, 23 (16%) patients met the primary endpoint: 4% (5 patients) died immediately after surgery; three patients died at the FUP (overall mortality rate of 6%). 12 patients (9%) were admitted for HF and 7 (5%) had at least one episode of worsening HF. 118 patients had complete pre and post-surgery imaging study (mean FUP: 36±10 months): 103 patients (87%) had at least one RR parameter (Table 1). Post-operative RR was not independently associated with the clinical outcome (Figure 1A). LVM was the sole independent predictor of the outcome at univariate analysis (Figure 1B–F). Conclusions LV RR after SAVR is highly prevalent in a cohort of patients with classical severe symptomatic AS. However, only LVM regression independently predicts the clinical outcome after surgery. This may stand the greater importance of structural reverse remodeling, rather than LV functional improvement, after pressure overload relief.

Predictors of LV reverse remodeling after SAVR: insights from a prospective TTE and CMR study in patients with severe aortic stenosis

Abstract Background Left ventricular (LV) remodeling in patients with severe aortic stenosis (AS) is believed to be reversible after pressure overload relieve, as provided by both surgical (SAVR) or transcatheter aortic valve replacement. However, LV reverse remodeling (RR) is far from uniform in patients with AS and the same clinical indication for treatment. Aim To determine the prevalence and imaging predictors of LV RR after SAVR in patients with severe symptomatic AS. Methods single-center, prospective cohort study enrolling 119 patients with severe symptomatic AS (age 71±8y, 49% male; mean transaortic gradient 62±18mmHg, mean indexed aortic valve area (AVAi) 0.40±0.10 cm2/m2, mean LV ejection fraction by TTE 58±9%), with no previous history of ischemic cardiomyopathy, undergoing SAVR between 2019 and 2022. All patients underwent serial imaging assessment beyond clinical characterization (transthoracic echocardiogram – TTE, and 1.5T cardiac magnetic resonance - CMR) prior to surgery and at the 3rd to 6th month post-SAVR. Endomyocardial biopsy (EMB) for myocardial fibrosis quantification (Masson ́s Trichrome histochemistry) was performed during SAVR. LV RR was defined when in presence of at least one of the imaging criteria: &amp;gt; 15% reduction in LV end-diastolic indexed volume (LVEDV) by CMR; &amp;gt; 15% reduction in LV indexed mass (LVM) by CMR; &amp;gt; 15% reduction in LV geometric remodeling by CMR; &amp;gt;10% increase in LV ejection fraction (LVEF) either from TTE or CMR; &amp;gt; 50% increase in global longitudinal strain (GLS) at TTE. Clinical, imaging and histology derived data were compared in patients with post-SAVR LV RR and for each of the defined criteria. Results 107 patients (90%) met at least one criteria of LV RR. Morphological criteria were more prevalent than LV functional improvement after SAVR (Figure 1). In patients who met at least one criteria of LV RR, no differences were found between NT- proBNP, LV tissue characterization (by CMR) or myocardial fibrosis at EMB. Yet, those with LV RR had significantly smaller preoperative AVAi (0.4±0.9 vs 0.5±0.9 cm2/m2, p=0.007) and higher mean valvular gradients (62±18 vs 49±12 mmHg, p=0.017). Considering individual LV RR criteria, patients with higher NT-proBNP levels met LVEF and morphological (LVEDV and LVM) LV RR criteria (p=0.027, p=0.016 and p= 0.003, respectively). Patients with higher % of late gadolinium enhancement on pre-operative CMR [7.8 (IQR 2.5-11.3) vs. 1.6 (IQR 0-5.2)%, p=0.017] had significant GLS improvement after SAVR. Conclusion In a cohort of patients with classical severe, symptomatic AS, LV RR is common after SAVR, occurring in almost 9 out of every 10 patients. Both indexes of worse valve narrowing and pre-operative LV adaptation are associated with favorable RR after surgery. This underlines the benefits of a timely intervention even in patients with more advanced disease.

Comparison of pulsed field ablation versus cryoballon and radiofrequency ablation for pulmonary vein isolation in atrial fibrillation patients with heart failure

Abstract Background Pulmonary vein isolation (PVI) is the gold standard for atrial fibrillation (AF) ablation and can be achieved by a variety of technical methodes. While thermal ablation modalities (TA), such as cryoballon (CB) and radiofrequency ablation (RF) have been established as the standard approaches, PFA has been introduced as a nvel non-thermal modality showing comparable safety and procedural efficiency. Despite the high incidence of AF in heart failure (HF) patients, data comparing outcomes of HF patients undergoing PVI by either PFA or thermal ablation (RFA/CB) are limited. Purpose This study’s aim was to compare the efficacy and safety of PFA for AF ablation versus CB/RFA in HF patients. Methods Consecutive HF patients with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) ejection fraction undergoing PVI for AF by either PFA or CB/RFA at our institution were included. The primary end-point was time to death or recurrence of AF. Secondary end-points were periprocedural complications and clinical and echocardiographic parameters. Results We included 140 HF patients who underwent PVI either by PFA (PFA group, 76 patients) or thermal ablation approaches (TA group, 64 patients). Our patients had a mean age of 69 years and were predominantly male (62%). There was no significant difference in the baseline characteristics and in the type of AF between both groups (42% with ParAF, 45% with PersAF) and 13% LSPersAF). The distribution of heart failure types was similar between both groups: HFpEF (PFA: 71%, TA: 75%), HFmrEF (PFA: 21%, TA: 20%) and HFrEF (PFA: 8 %, TA: 5%). After the 365-days follow-up period we observed no significant difference for the primary end-point between both groups (HR: 0.79, 95% CI 0.35-1.78; p=0.575). In total 58% of the PFA patients and 59% of the TA group were still free from AF. While symptom improvement was documented in both groups, patients in the PFA group showed significant improvement of left atrial volume index (p = 0.014), NT-pro BNP levels (p = 0.046), and left ventricular ejection fraction (LVEF) (p = 0.005). Conclusion In this study, PFA and thermal ablation modalities showed comparable results in terms of safety and procedural efficiency in patients with heart failure. Since previous studies have shown that HF patients with AF benefit from PVI using thermal ablation modalities, our results suggest that PFA might also be a promising ablation method in this vulnerable population, inducing left atrial reverse remodeling and thereby contributing to improvement of left ventricular systolic function.

Mechanisms of atrial-fibrillation-induced ventricular dysfunction and recovery in the human left ventricular myocardium

Abstract Background Atrial fibrillation (AF) frequently occurs alongside heart failure (HF). Clinical studies indicate improved left ventricular (LV) function following rhythm restoration but the underlying myocardial processes remain unclear. Purpose This study investigated effects of AF and its termination on human LV myocardium as well as potential molecular mechanisms involved in the AF-induced LV dysfunction. Methods Human LV tissue slices obtained from HF patients were long-term cultivated in-vitro. AF was simulated by tachy-arrhythmic culture pacing at 100 bpm with 30% irregularity for 7 days and contractile LV function was compared to slices undergoing sinus rhythm (SR)-simulation (60 bpm/0%). After 7 days, rhythm restoration was simulated by switching to SR-simulation. To elucidate cellular mechanisms involved in AF-induced LV dysfunction, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) were subjected to AF-simulation and examined via epifluorescence microscopy (FURA-2) and confocal microscopy (Fluo-4). Additionally, to investigate the impact of reactive oxygen species (ROS) on cardiomyocytes, iPSC-CM were subjected to treatment with the ROS-scavenger N-acetylcysteine (NAC). Results AF-simulation caused a progressive decline in systolic force of human LV myocardium (n=14 slices) with significantly reduced twitch amplitudes compared to SR-simulation (n=11). Within just 5 days of AF-termination, a significant recovery in LV function was observed, indicated by improved systolic contraction amplitudes. IPSC-CM measurements revealed a significant reduction in systolic Ca2+-transient amplitudes as well as an increased diastolic Ca2+ leak after AF-simulation (n=41) compared to SR-simulation (n=44). However, 5 days after SR-restoration, iPSC-CM exhibited no significant differences anymore, indicating a fast recovery of systolic Ca2+-cycling. We further investigated the impact of ROS on LV function and could show that Ca2+-transient amplitude was preserved after AF-simulation in iPSC-CM when treated with NAC (n=35), suggesting an interplay of ROS with the Ca2+-homeostasis of cardiomyocytes. Conclusions This study demonstrates that AF impairs LV function in human HF myocardium. However, the involved changes in contractility and cardiomyocyte Ca2+ handling are reversible upon AF termination leading to improved LV function already within few days after AF cessation. Moreover, we provided an indication for an interplay of ROS with the Ca2+ homeostasis, endorsing an AF-induced LV-dysfunction, which merits further investigation.

Spermidine attenuates left ventricular dysfunction in estrogen deprived aging rats through mitigating lipid peroxidation and mitochondrial dysfunction

Abstract Background Aging women with postmenopause are particularly susceptible to cardiovascular diseases (CVDs), which are associated with the elevation of oxidative stress and mitochondrial dysfunction. Although hormone replacement therapy (HRT) has been reported to provide cardiometabolic protection, long-term HRT could be linked to CVD consequences. A novel organic therapy with spermidine has shown promise as cardioprotection in several CVDs. However, the effects of spermidine on left ventricular (LV) function, mitochondrial function and oxidative stress in estrogen-deprived aging rats have not been investigated. Purpose To evaluate the effects of spermidine on LV function, mitochondrial function and oxidative stress in estrogen-deprived and D-galactose-induced aging rats Methods Twenty female Wistar rats were randomly assigned to the sham and the ovariectomy (OVX) along with D-galactose (150 mg/kg/day, s.c.) administration throughout the experiment for 12 weeks. OVX with D-galactose-treated rats were divided into three interventional groups: vehicle (ODV), spermidine (20 mg/kg/day, p.o., ODS), and estradiol (50 ug/kg/day, s.c., ODE) (n=5/group) for 8 weeks. The sham group received a vehicle (SVV, n=5). At the end, all rats underwent echocardiography, followed by euthanasia. The hearts were removed for measuring mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes (ΔΨm), and malondialdehyde (MDA) levels. Results Rats with OVX-induced estrogen deprivation with D-galactose-induced aging had LV impairments indicated by decreased LV ejection fraction, reduced ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E) to peak velocity flow by atrial contraction (A), and increased sympathovagal imbalance (elevated low/high frequency (LF/HF) ratio) (Fig. 1A-C). These estrogen-deprived aging rats also had an increase in cardiac tissue MDA levels, mitochondrial ROS production, and MMP depolarization (Fig. 1D-F). Both spermidine and estrogen similarly demonstrated a significant reduction in all of those detrimental effects, leading to improved LV function (Fig. 1A-F). Conclusion Spermidine exerted cardioprotection comparable to estrogen supplement through mitigating oxidative stress and mitochondrial impairments in cardiac tissue, resulting in improved LV dysfunction and cardiac autonomic balance due to estrogen deprived aging conditions in rats. These findings suggest that spermidine administration could be a promising strategy for cardioprotection in postmenopausal women with aging.