Improvement In Cardiac Function Research Articles

Evaluating the Efficacy of Interventional Approaches for Cardiac Arrhythmias in Acute Myocardial Infarction

Objective: To assess the effectiveness of interventional treatments for cardiac arrhythmias in acute myocardial infarction (AMI). Methods: Eighty AMI patients admitted between August 2022 and August 2023 were selected and randomly assigned into groups using the random number table method. The control group (n = 40) received conventional thrombolytic treatment, while the observation group (n = 40) underwent percutaneous coronary intervention (PCI). Clinical effects were compared between the two groups. Results: Before treatment, there were no significant differences in heart rate indicators, cardiac function indicators, and physiological indicators between the two groups (P > 0.05). After treatment, the observation group showed significantly improved heart rate indicators, cardiac function indicators, and physiological indicators compared to the control group (P < 0.05). The adverse reaction rates in the observation group were lower than in the control group (P < 0.05). Conclusion: PCI treatment demonstrated significant improvements in heart rate, cardiac function, and physiological indicators among AMI patients, leading to a reduced incidence of adverse reactions such as arrhythmia. The overall effect is deemed significant.

CPA toxicity screening of cryoprotective solutions in rat hearts

In clinical practice, donor hearts are transported on ice prior to transplant and discarded if cold ischemia time exceeds ∼5 h. Methods to extend these preservation times are critically needed, and ideally, this storage time would extend indefinitely, enabling improved donor-to-patient matching, organ utilization, and immune tolerance induction protocols. Previously, we demonstrated successful vitrification and rewarming of whole rat hearts without ice formation by perfusion-loading a cryoprotective agent (CPA) solution prior to vitrification. However, these hearts did not recover any beating even in controls with CPA loading/unloading alone, which points to the chemical toxicity of the cryoprotective solution (VS55 in Euro-Collins carrier solution) as the likely culprit. To address this, we compared the toxicity of another established CPA cocktail (VEG) to VS55 using ex situ rat heart perfusion. The CPA exposure time was 150 min, and the normothermic assessment time was 60 min. Using Celsior as the carrier, we observed partial recovery of function (atria-only beating) for both VS55 and VEG. Upon further analysis, we found that the VEG CPA cocktail resulted in 50 % lower LDH release than VS55 (N = 4, p = 0.017), suggesting VEG has lower toxicity than VS55. Celsior was a better carrier solution than alternatives such as UW, as CPA + Celsior-treated hearts spent less time in cardiac arrest (N = 4, p = 0.029). While we showed substantial improvement in cardiac function after exposure to vitrifiable concentrations of CPA by improving both the CPA and carrier solution formulation, further improvements will be required before we achieve healthy cryopreserved organs for transplant.

Lack of cardiac benefit after intramyocardial or intravenous injection of mesenchymal stem cell-derived extracellular vesicles supports the need for optimized cardiac delivery.

To determine the differences in improvement in cardiac function by intramyocardial (IM) vs. intravenous (IV) injection of human bone mesenchymal stem cell-derived extracellular vesicles (HBMSC-EV) after acute MI. FVB mice underwent acute MI via left anterior descending coronary artery ligation and subsequent injection of: (1) IM saline control; (2) IM HBMSC-EV; (3) IV saline control; and (4) IV HBMSC-EV. Cardiac function was evaluated with weekly postoperative echocardiography. On postoperative day 28, the mice were euthanized, and the heart, lungs, liver, spleen, and kidneys were harvested. Given previous studies showing HBMSC-EV hepatic uptake after IV injection, the liver was evaluated for changes in inflammation, fibrosis, and proliferation. On postoperative day 28, there were no significant differences in left ventricular ejection fraction (P = 0.6151), fractional shortening (P = 0.1135), or anterior border zone fibrosis (P = 0.6333) in any of the experimental groups. Interestingly, there was a strong trend demonstrating improvement in infarct size on fibrosis staining, which did not reach significance (P = 0.05620). There were no differences in hepatic inflammation, fibrosis, and proliferation. Although there was a trend in the improvement in infarct size, a single-dose administration of neither IM nor IV injection of HBMSC-EV resulted in significant improvement in post-MI cardiac function. A major limitation of this study is the lack of trials determining the optimal dose of HBMSC-EV needed in this model. However, the current study demonstrates that future studies are required to either optimize administration or bioengineer HBMSC-EV with cardiac-homing properties.

Feasibility study on cardiac resynchronization in the treatment of heart failure by single left bundle branch pacing

To examine the feasibility of single left bundle branch pacing for cardiac resynchronization therapy (CRT) by carrying out a frequency adaptive atrioventricular delay (RAAVD) algorithm and automatic optimization of the single left bundle branch pacing atrioventricular interval (AVI) based on the right atrioventricular interval (RAS–RVS). Thirty-six patients with CRT class Ia indications according to the European Society of Cardiology 2016 guidelines and implanted with RAAVD functional three-chamber pacemakers were prospectively enrolled in this study. Patients were divided into a single left bundle branch pacing group (n = 21) and a standard biventricular pacing group (n = 15). The optimization of the two groups was performed under standard cardiac colour Doppler ultrasound, followed by the comparison of the QRS width, cardiac function improvement, and echocardiography indicators. The ratio of AVI to the right atrial-right ventricular interval (RAS–RVS) after single LV pacing optimization was defined as the single left bundle branch pacing coefficient (LUBBPε). In comparison to the BVP, the QRS was significantly narrowed (P = 0.017), accompanied by a significantly increased proportion of patients with NYHA class I and II, as well as the 6MWT. Compared with standard biventricular pacing, LVEDD was significantly shortened (P = 0.045), accompanied by significantly improved LAD, AVVTI, EA distance/RR, IVMD, and TS-SD after the operation. RAS–RVS was 156 ± 33 ms, the optimized AVI was 102 ± 10 ms, and LUBBPε was calculated to be 0.66 ± 0.06. Depending on the LUBBPε, a three-chamber pacemaker with a single left bundle branch pacing system was developed based on RAS–RVS-optimized AVI automatically. A three-chamber pacemaker with single left bundle branch pacing can achieve CRT based on RAS–RVS, reaching the optimal AVI of 66% of RAS–RVS.

Berberine inhibits NLRP3 inflammasome activation by regulating mTOR/mtROS axis to alleviate diabetic cardiomyopathy

Diabetes cardiomyopathy (DCM) refers to myocardial dysfunction and disorganization resulting from diabetes. In this study, we investigated the effects of berberine on cardiac function in male db/db mice with metformin as a positive control. After treatment for 8 weeks, significant improvements in cardiac function and a reduction in collagen deposition were observed in db/db mice. Furthermore, inflammation and pyroptosis were seen to decrease in these mice, as evidenced by decreased expressions of p-mTOR, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), IL-1β, IL-18, caspase-1, and gasdermin D (GSDMD). In vitro experiments on H9C2 cells showed that glucose exposure at 33 mmol/L induced pyroptosis, whereas berberine treatment reduced the expression of p-mTOR and NLRP3 inflammasome components. Moreover, berberine treatment was seen to inhibit the generation of mitochondrial reactive oxygen species (mtROS) and effectively improve cell damage in high glucose-induced H9C2 cells. The mTOR inhibitor, Torin-1, showed a therapeutic effect similar to that of berberine, by reducing the expression of NLRP3 inflammasome components and inhibiting mtROS generation. However, the activation of mTOR by MHY1485 partially nullified berberine's protective effects during high glucose stress. Collectively, our study reveals the mechanism that berberine regulates the mTOR/mtROS axis to inhibit pyroptosis induced by NLRP3 inflammasome activation, thereby alleviating DCM.

Blockade of Inflammatory Markers Attenuates Cardiac Remodeling and Fibrosis in Rats with Supravalvular Aortic Stenosis.

Since cardiac inflammation has been considered an important mechanism involved in heart failure, an anti-inflammatory treatment could control cardiac inflammation and mitigate the worsening of cardiac remodeling. This study evaluated the effects of dexamethasone (DEX) and ramipril treatment on inflammation and cardiac fibrosis in an experimental model of heart failure induced by supravalvular aortic stenosis. Wistar rats (21d) were submitted to an aortic stenosis (AS) protocol. After 21 weeks, an echocardiogram and a maximal exercise test were performed, and after 24 weeks, rats were treated with DEX, ramipril or saline for 14d. The left ventricle (LV) was removed for histological and inflammatory marker analyses. The AS group showed exercise intolerance (-32% vs. Sham), higher relative wall thickness (+63%), collagen deposition and capillary rarefaction, followed by cardiac disfunction. Both treatments were effective in reducing cardiac inflammation, but only DEX attenuated the increased relative wall thickness (-17%) and only ramipril reduced LV fibrosis. In conclusion, both DEX and ramipril decreased cardiac inflammatory markers, which probably contributed to the reduced cardiac fibrosis and relative wall thickness; however, treated AS rats did not show any improvement in cardiac function. Despite the complex pharmacological treatment of heart failure, treatment with an anti-inflammatory could delay the patient's poor prognosis.

Myocardial infarct size for predicting improvements in cardiac function in patients with ischemic cardiomyopathy following coronary artery bypass grafting.

This study used late gadolinium enhancement-cardiac magnetic resonance (LGE-CMR) to assess myocardial infarct size, with the data being employed to predict whether patients with ischemic cardiomyopathy (ICM) would experience improvements in left ventricular function at 6 months following coronary artery bypass grafting (CABG). The data of patients with ICM with left ventricular ejection fraction (LVEF) ≤40% who underwent CABG were retrospectively analyzed. All patients underwent preoperative LGE-CMR imaging. Echocardiography results from 6 months post-CABG were used to assess improvements in LVEF, with improvement being defined as ΔLVEF ≥5%. The value of myocardial infarction segments and infarct size as predictors of improved cardiac function following CABG was analyzed. Of the included patients, 66.7% (52/78) exhibited improved cardiac function at 6 months post-CABG. LGE-CMR imaging data revealed that compared to improved group, the improved group had significantly more myocardial infarct segments [improved group: median 1.0, interquartile range (IQR) 0-3; nonimproved group: median 4.0, IQR 3.0-6.0; P<0.001] and significantly greater myocardial infarct size (improved group: 22.4%±8.2%; nonimproved group: 34.7%±5.9%; P<0.001). The area under the receive operating characteristic curve values for myocardial infarct size in predicting cardiac function improvement were significantly higher than those of myocardial infarct segments (0.88 vs. 0.81; P=0.041). The respective sensitivity and specificity values for using a myocardial infarct size cutoff of 26.4% in differentiating between these 2 patient groups were 92.3% and 71.2%, respectively. According to logistic regression analysis, myocardial infarct size was an independent predictor of nonimprovement in cardiac function [odds ratio (OR) =1.244; 95% confidence interval (CI): 1.114-1.389; P<0.001]. A median 1.6-year follow-up interval (range, 0.5-4.1 years) revealed that the incidences of major adverse cerebrovascular events and cardiovascular events were significantly higher in the nonimproved group (5.8% vs. 26.9%; P<0.001), with these individuals having a higher New York Heart Association grading than patients with improved cardiac function (P=0.019). Myocardial infarct size can be measured to reliably predict improvements in cardiac function in patients with ICM following CABG. These results can guide clinicians in their efforts to identify those patients most likely to achieve positive outcomes following CABG.

Predictors of short-term survival in cardiac valvular surgery patients with intra-aortic balloon pump implantation.

Intro-aortic balloon pump (IABP) is widely used in cardiac surgery patients nowadays. This study aimed to analyze the predictor of short-term survival in cardiac valvular surgery patients with intra-aortic balloon pump implantation. This was a retrospective study and a total of 102 cardiac valvular surgery patients who received intra-aortic balloon pump implantation were consecutively included. We retrospectively collected the baseline characteristics and short-term outcomes. Baseline characteristics were compared between survivors with non-survivors, and logistic regression was performed to identify predictors for short-term mortality. Among all the patients, there were 71 (69.6%) patients successfully weaned from IABP and survived to discharge, the other 31 (30.4%) patients failed to wean from IABP and died within the first 30days after surgery. When compared with non-survivors, survivors had a higher proportion of males (62% vs 32.3%, p = 0.006), a lower rate of Atrial fibrillation (38% vs 62%, p < 0.03). After IABP implantation, vasoactive drug use was significantly lower in survivors compared with non-survivors, and survivors showed significant improvements in cardiac function and urine volume. Univariate and multivariate logistic regression analysis indicated that atrial fibrillation and combined use of continuous renal replacement therapy (CRRT) were significant independent predictors for short-term mortality. Timely implantation of IABP can improve patients' cardiac and renal function and reduce the dosage of vasoactive drugs. Atrial fibrillation and combined use of CRRT are independent predictors for short-term mortality in patients who underwent cardiac valvular surgery with IABP implantation.

The association between levosimendan and mortality in patients with sepsis or septic shock: a systematic review and meta-analysis.

Levosimendan is increasingly being used in patients with sepsis or septic shock because of its potential to improve organ function and reduce mortality. We aimed to determine if levosimendan can reduce mortality in patients with sepsis or septic shock via meta-analysis. We comprehensively searched the PubMed, Embase, Web of Science, and Cochrane Library databases from inception through 1 October 2022. Literature evaluating the efficacy of levosimendan in patients with sepsis or septic shock was included. Two reviewers extracted data and assessed study quality. A meta-analysis was performed to calculate an odds ratio (OR), 95% confidence intervals (CI), and P -values for 28-day mortality (primary outcome). Secondary outcomes included changes in indexes reflecting cardiac function before and after treatment, changes in serum lactate levels in the first 24 h of treatment, and the mean SOFA score during the study period. Safety outcomes included rates of tachyarrhythmias and total adverse reactions encountered with levosimendan. Eleven randomized controlled trials were identified, encompassing a total of 1044 patients. After using levosimendan, there was no statistical difference between groups for 28-day mortality (34.9% and 36.2%; OR: 0.93; 95% CI [0.72-1.2]; P = 0.57; I 2 = 0%; trial sequential analysis-adjusted CI [0.6-1.42]) and sequential organ failure assessment (SOFA) score, and more adverse reactions seemed to occur in the levosimendan group, although the septic shock patient's heart function and serum lactate level improved. There was no association between the use of levosimendan and 28-day mortality and SOFA scores in patients with septic shock, though there was statistically significant improvement in cardiac function and serum lactate.

Catheter ablation of typical atrial flutter improves cardiac chamber size and function.

Cavo-tricuspid isthmus (CTI) dependent atrial flutter (AFL) is one of the most common atrial arrhythmias involving the right atrium (RA) for which radiofrequency catheter ablation has been widely used as a therapy of choice. However, there is limited data on the effect of this intervention on cardiac size and function. A retrospective study was conducted on 468 patients who underwent ablation for CTI dependent typical AFL at a single institution between 2010 and 2019. After excluding patients with congenital or rheumatic heart disease, heart transplant recipients, or those without baseline echocardiogram, a total of 130 patients were included in the analysis. Echocardiographic data were analyzed at baseline before ablation, and at early follow-up within 1-year postablation. Follow-up echocardiographic data was available for 55 patients. Of the 55 patients with CTI-AFL, the mean age was 64.2 ± 14.8 years old with 14.5% (n = 8) female. The average left ventricular ejection fraction (LVEF) significantly improved on follow-up echo (40.2 ± 16.9 to 50.4 ± 14.9%, p < .0001), of which 50% of patients had an improvement in LVEF of at least 10%. There was a significant reduction in left atrial volume index (82.74 ± 28.5 to 72.96 ± 28 mL/m2 , p = .008) and RA volume index (70.62 ± 25.6 to 64.15 ± 31 mL/m2 , p = .046), and a significant improvement in left atrial reservoir strain (13.04 ± 6.8 to 19.10 ± 7.7, p < .0001). Patients who underwent CTI dependent AFL ablation showed an improvement in cardiac size and function at follow-up evaluation. While long-term results are still unknown, these findings indicate that restoration of sinus rhythm in patients with typical AFL is associated with improvement in atrial size and left ventricular function.

Sleeve Gastrectomy Provides Cardioprotection from Oxidative Stress In Vitro Due to Reduction of Circulating Myeloperoxidase.

Bariatric surgery, including sleeve gastrectomy (SG), improves systolic and diastolic function, which is independent of weight loss in rodent models. The cause of weight loss-independent improvements in cardiac function are unknown but may originate from the gastrointestinal tract. In this study, we investigated whether a circulating blood factor is a mechanism for acute cardioprotection after SG by testing the utility of rodent SG plasma to reduce metabolic stress in vitro. For the initial experiment, obese male Zucker rats underwent SG, ad lib sham, or pair-fed sham surgeries (n = six SG, n = eight SH, n = eight PF). For all other studies, a second group of Zucker rats underwent SG or ad lib sham surgeries (n = eight SH, n = six SG). Six weeks following surgery, plasma was collected from each group, both in the fasting and post-prandial (pp) state. This plasma was then pooled per surgical group and nutrient state and tested in multiple in vitro cell culture and extra-cellular assays to determine the effect of SG on myotubular metabolic stress compared to the sham surgeries. Post-prandial SG plasma (ppSG), but not fasting SG, pp, or fasting sham plasma, reduced the metabolic stress of the H9c2 cells as measured by lactate dehydrogenase (LDH) release (p < 0.01). Unlike SG, weight reduction through pair-feeding did not prevent H9c2 metabolic stress. The PpSG plasma had the slowest rate of extracellular hydrogen peroxide consumption and peroxidatic activity compared to the pp sham, fasting SG, and fasting sham groups. Redox testing of plasma with aminiobenzoic acid hydrazide and edaravone suggested a pattern supporting myeloperoxidase (MPO), or other peroxidases, as the primary component responsible for reduced metabolic stress with ppSG plasma. The PpSG plasma contained 35% less circulating MPO protein as compared to the pp sham and fasting SG plasma. The plasma from an MPO global knockout rat also prevented metabolic stress of the H9c2 cells, compared to the significant increase in LDH release from the plasma of the WT controls (p < 0.01). The MPO global knockout plasma also had a rate of extracellular hydrogen peroxide consumption and peroxidatic activity comparable to the ppSG plasma. These studies suggest that one of the weight loss-independent mechanisms by which SG improves myocellular function could be a reduced pro-oxidative environment due to lower circulating levels of MPO. It appears that the gastrointestinal tract is of critical importance to these findings, as the MPO levels were only lowered after enteral, nutrient stimulation in the SG rats. If this surgical effect is confirmed in humans, SG may be a unique surgical treatment for multiple diseases with a pathogenesis of inflammation and oxidative damage, including obesity-associated heart failure with preserved ejection fraction.

Effects of recombinant human brain natriuretic peptide combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure.

This study examined the effects of recombinant human brain natriuretic peptide (rhBNP) combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure (HF). This retrospective study included 90 patients with severe HF who were treated at our hospital between January 2019 and August 2021. Patients treated with tolvaptan tablets were assigned to the control group, and those treated with rhBNP combined with tolvaptan were assigned to the observation group. Efficacy, cardiac function, levels of inflammatory factors, renal function, 6 minutes walking test, Minnesota Living with Heart Failure Questionnaire score, and adverse reactions were assessed. The curative effect (97.78% vs 77.78%) and improvement in cardiac function were greater in the observation group than in the control group (P < .05). Decreased levels of inflammatory factors were seen in both groups after treatment, and the levels of tumor necrosis factor-α, interleukin-33, and intercellular adhesion factor-1 in the observation group were lower than those in the control group (P < .05). The 6 minutes walking test was higher and the Minnesota Living with Heart Failure Questionnaire score was lower in the observation group compared with the control group (P < .05). The incidence of adverse reactions such as dry mouth, nausea, polyuria, hypotension, and headache in the observation group was lower than that in the control group (P < .05). In conclusion, for patients with severe HF, rhBNP combined with tolvaptan can improve cardiac function, alleviate symptoms of dyspnea, protect renal function, and reduce serum inflammatory factor levels when compared with tolvaptan alone.

Adssl1-mediated purine synthesis modulates cardiomyocyte proliferation and heart regeneration

Abstract Introduction The enhancement of pre-exist cardiomyocyte proliferation has been proved to be an effective treatment of myocardial infarction(MI) (1-2). Purine bases from the de novo purine synthesis (DNPS) pathways is the critical source of nucleotide synthesis for proliferative cell (3). The muscle specific isoform of adenylosuccinate synthase (Adssl1) catalyses the last step of DNPS pathway (4). Patients with Adssl1 mutation develop cardiomyopathy at 13-15 years (5). Nevertheless, its role and mechanism in cardiomyocyte cell-cycle re-entry and heart regeneration remain unknown. Purpose To explore the effect and underlying mechanism of Adssl1 and its mediated DNPS pathway in cardiomyocyte proliferation and heart regeneration. Methods We used qRT-PCR, Western blot and Immunofluorescence to assess the expression of Adssl1 during heart developement and heart regeneration after apical resection (AR) operation. Using newly generated loss- and gain-of-function genetic tools to investigate the role of Adssl1 in cardiac regeneration after AR or MI operation. Transcriptomic RNA sequencing (RNA-Seq) and liquid chromatography-tandem mass spectrometry (LC/MS) allowed us to determine the metabolism of Adssl1 in modulating cardiomyocyte proliferation. Results Here, we found that Adssl1 was increased during heart regeneration. Depletion of Adssl1 in neonatal hearts significantly inhibited purine synthesis pathway and attenuated heart regenerative capacity after AR operation. Cardiomyocyte-specific overexpression of Adssl1 extended postnatal regenerative window and induced a robust cell-cycle re-entry after MI, leading to a decrease in fibrosis scar size and improvement of cardiac function. Adssl1 caused accumulation of Inosine, which could promote the cardiac repair in mice. Mechanistically, we demonstrated that Adssl1 significantly involved in modulating mTORC1/S6K pathway. Conclusion Collectively, our study elucidates the role of Adssl1 in modulating cardiac proliferation and heart regeneration through activating mTORC1/S6K pathway after MI. Notably, Inosine has the potential to be employed as an effective agent in regulating cardiac proliferation and myocardial repair.Heart regeneration

Physical capacity determines physical and mental health in patients with chronic heart failure - a case control study

Abstract Background Chronic heart failure (CHF) is associated with reduced quality of life (QoL), but underlying mechanisms are incompletely understood. In this study we aimed to assess determinants of both physical and mental functioning in patients with and without chronic heart failure and investigated the impact of physical capacity (PC). Methods This is a cross-sectional analysis conducted in two cohorts using a case-control design. Both, the case cohort (RoC-HF, n=205) and the control cohort (BioPersMed, n=1022) were prospective, single center cohort studies. The case cohort included patients with diagnosed CHF with a current left ventricular ejection fraction (LVEF) &amp;lt;50%, while the control cohort included apparently healthy individuals with at least one cardiovascular risk factor. Laboratory parameters, transthoracic echocardiography, PC (Biopersmed: 6-minute walking distance [6MWD]; RoC-HF: 4-meter gait speed [4MGS]), and SF-36 health survey parameters as the main read-out of this study, were available in all participants. Results Cases and controls were matched by age, sex and body mass index yielding a study sample of 188 vs. 188 individuals. Medians with interquartile range of NT-proBNP and LVEF were 985 (325 – 2183) pg/dl and 37 (30 – 44) % in cases, and 72 (33 - 118) pg/dl and 64 (60 – 68) % in controls. Cases had lower levels than controls regarding all eight QoL aspects of the SF-36 HS (Figure 1). Both within the case and the control cohort, measures of heart failure severity (LVEF, NT-proBNP, TAPSE) were not or only marginally associated with SF-36 HS scales. PC parameters correlated significantly with physical component summary score (PCS) both within cases and controls, and with mental component summary score (MCS) only in cases (Figure 2). Multivariate linear regression analyses with adjustment for age, sex, eGFR, LVEF, NT-proBNP and TAPSE were conducted in each cohort, respectively. Within cases, 4MGS, but not LVEF, NT-proBNP and TAPSE, was significantly associated with MCS (adjusted beta 0.228, P=0.011) and PCS (beta = 0.318, P&amp;lt;0.001). Within controls, 6MWD was significantly associated with PCS (beta = 0.332, P&amp;lt;0.001), but not with MCS (beta = -0.62, P=0.472). Conclusion In patients with CHF, impairment of both physical and mental functioning is determined by physical capacity, but not by measures of cardiac function and congestion. By contrast, only physical functioning, but not mental functioning, can be explained by PC in healthy controls. Given the increasing relevance of QoL as a patient-oriented outcome in CHF, assessment and improvement of PC should be considered essential aspects in CHF care, besides biomarker-guided improvements in cardiac function and congestion. Whether targeting PC, for instance by medical and device therapies, translates into better physical and mental well-being in CHF should be specifically addressed in randomized controlled trials.

Eight-year follow-up of cardiosphere-derived cell transplantation in patients with single ventricle congenital heart disease

Abstract Background Although transcoronary infusion of cardiosphere-derived cells (CDCs) in patients with single ventricles provides short-term improvement in cardiac function, the long-term efficacy is still unknown. Purpose: We tested the hypothesis that CDC infusion is associated with improved long-term clinical outcome in patients with single ventricles and heart failure. Methods: Patients were enrolled in the TICAP phase 1 (Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single Ventricle Physiology) and PERSEUS phase 2 (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) trials between January 5, 2011, and January 30, 2015. The inclusion criteria were that patients were aged &amp;lt;6 years who were diagnosed with single ventricle lesions undergoing stage 2 (bidirectional Glenn: BDG) or stage 3 (total cavopulmonary connection: TCPC) palliation. Ventricular ejection fraction should be &amp;lt;60% during the initial screening through the final enrollment. Medical records of patients with single ventricles were obtained and analyzed as a control group who were eligible but were treated by staged palliation alone. We evaluated the effectiveness of CDCs using an integrated cohort study in 93 patients with single ventricles, including 41 patients who received CDC infusion and 52 controls. Results: At the time of this study, 36 patients with CDC infusion and 42 controls were alive without cardiac transplantation, with mean follow-up of 9.7±1.2 years. Survival rate did not differ between the 2 groups (log-rank P = 0.351), whereas overall patients treated by CDCs had lower incidents of late failure defined as late death, protein-losing enteropathy, plastic bronchitis, BDG or TCPC take down, disqualified TCPC candidate, Ross classification 3 or 4, or rehospitalization for heart failure (P = 0.048) compared with controls. Adverse events defined as unplanned cardiac operation, arrhythmia, thromboembolic events, cerebral hemorrhage, or tumor formation (P = 0.057) and unplanned catheter intervention (P = 0.094) did not differ between 2 groups. Conclusions: Intracoronary delivery of CDCs in patients with single ventricles did not improve all-cause mortality rate but significantly reduced the incidence of late failure at 8 years of follow-up.

Treatment with empagliflozin improves cardiac function in infarcted animals associated with increased baroreflex sensitivity

Abstract Background Several clinical and experimental studies have shown an improvement in cardiac function in infarcted patients and animals (diabetic or not) when treated with empagliflozin, as well as an improvement in outcomes in patients with heart failure with reduced ejection fraction or with preserved ejection fraction. Hypothesis: Treatment with empagliflozin for 14 days (10 mg/kg) improves cardiac function in infarcted rats, secondary to increased baroreflex sensitivity. Methods Wistar rats were divided into 2 groups: AMI - acute myocardial infarction (n=8) and AMI+EMPA - acute myocardial infarction + Empagliflozin (n=8). The animals in both groups were anesthetized and submitted to thoracotomy and ligature of the left coronary artery. The animals in the AMI+EMPA group received daily, through oral gavage, 10 mg/kg of empagliflozin, for 14 days. After this period, an echocardiographic examination was performed, followed by cannulation of the femoral vein and artery, to assess hemodynamic parameters and baroreflex activity. The results were evaluated for normality. Data were compared by Student's t tests. And the relationship between the parameters was tested by Pearson's correlation. Results are presented as mean and standard deviation. Results In the echocardiographic evaluation, an improvement in diastolic function indexes was observed in the AMI+EMPA group in relation to the AMI group: E'/A' ratio (1.584 ± 0.437 vs 0.589 ± 0.129), E/E' ratio (14.11 ± 3.946 vs 29.92 ± 6.878) and systolic function: SF (29.30% ± 7.974 vs 19.20% ± 2.445), EF (53.86% ± 11.78 vs 37.91% ± 4.212), FAC (39.31% ± 7.135 vs 23.51 ± 3.940). There was a reduction in mean blood pressure in the AMI+EMPA group (102.4 mmHg ± 6,408) compared to the AMI group (110.7 mmHg ± 8,514) and in diastolic blood pressure (84.4 mmHg ± 3.889 vs 92.8 mmHg ± 7.664). In the assessment of baroreflex sensitivity, an improvement in tachy and bradycardic indexes was observed in the treated animals: tachycardic index (5.021 bpm/mmHg ± 0.346 vs 3.214 bpm/mmHg ± 0.418) and bradycardic index (1.569 bpm/mmHg ± 0.148 vs 0.73 bpm/ mmHg ± 0.046). In addition, the systolic function expressed by the FAC was positively associated with the reflex tachycardic index (p: 0.008; r: 0.616) and to the E'/A' ratio (p: 0.025; r: 0.576) and negatively with PAD (p: 0.040; r: -0.503). Conclusion Treatment with Empagliflozin in infarcted rats was able to improve left ventricular systolic and diastolic function associated with improved performance of arterial baroreceptors.

Effect of a short course of parenteral treprostinil therapy on right heart structure and function in pulmonary arterial hypertension

Abstract Background Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, leading to increased afterload and right-sided heart failure. It is important to routinely assess disease progression and treatment response, with echocardiography an increasingly recognized important component of risk assessment. Parenteral prostacyclin therapy has been shown to be associated with improvements in right-sided cardiac structure and function, which are prognostic in PAH. Purpose To describe changes in right-sided cardiac structural and functional parameters after a short course of parenteral treprostinil. Methods The EXPEDITE trial (NCT03497689) was a 16-week open-label study of WHO Functional Class (FC) II or III patients with PAH designed to assess short-term (expedited) induction therapy with parenteral treprostinil over 2-8 weeks, to facilitate transition to comparable doses of oral treprostinil. The subset of patients in the per-protocol population that had clinical and/or echocardiographic data available at both baseline (prior to initiation of parenteral treprostinil) and end of induction (2-8 weeks) were included for analysis. Changes in each parameter were analyzed using the non-parametric Wilcoxon signed-rank test. Results In the per-protocol population of EXPEDITE (n=29), the median age was 56 years, 62% were female, and 79% were white. At baseline, 52% were classified as WHO FC II and 48% WHO FC III. Patients were on either no (n=6, 21%), 1 (n=11, 38%), or 2 (n=12, 41%) background PAH therapies. The end of the parenteral treprostinil induction period occurred at Week 2 (n=1), Week 4 (n=5), or Week 8 (n=23); the median (interquartile range) parenteral treprostinil dose achieved was 23.8 (20, 39.3) ng/kg/min. Median changes from baseline to the end of the parenteral treprostinil induction period for this analysis are shown in Table 1. There were directional changes for most measures of right-sided cardiac structure and function that reflected overall improvement; two key markers of cardiac function, cardiac output and NT-proBNP significantly improved. Conclusions In this trial of expedited parenteral treprostinil induction, we saw favorable directional trends in changes in right heart structure and function that were achieved in 8 weeks or less, including some statistically-significant parameters known to have prognostic value in PAH. The relatively rapid improvements we observed in this small cohort may signal important changes in risk status, and support treatment guidelines emphasizing importance of early improvement in the first 3-6 months following treatment. Furthermore, changes in cardiac structure and function often occur before other clinically-evident indicators of disease progression, and early response to treatment has been shown to impact long-term outcomes in patients with PAH. Larger studies with short-term serial right heart imaging assessment to confirm findings are warranted.Table 1

Abstract 13241: Long-Term Clinical Outcome After Transcoronary Cardiosphere-Derived Cell Infusion in Patients With Single Ventricle Congenital Heart Disease

Introduction: Although transcoronary infusion of cardiosphere-derived cells (CDCs) in patients with single ventricles provides short-term improvement in cardiac function, the long-term efficacy is still unknown. Hypothesis: We tested the hypothesis that CDC infusion is associated with improved long-term clinical outcome in patients with single ventricles and heart failure. Methods: Patients were enrolled in the TICAP phase 1 (Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single Ventricle Physiology) and PERSEUS phase 2 (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) trials between January 5, 2011, and January 30, 2015. The inclusion criteria were that patients were aged &lt;6 years who were diagnosed with single ventricle lesions undergoing stage 2 (bidirectional Glenn) or stage 3 (total cavopulmonary connection) palliation. Medical records of patients with single ventricles were obtained and analyzed as a control group who were eligible but were treated by staged palliation alone. We evaluated the effectiveness of CDCs using an integrated cohort study in 93 patients with single ventricles, including 40 patients who received CDC infusion and 53 controls. Results: At the time of this study, 35 patients with CDC infusion and 43 controls were alive without cardiac transplantation, with mean follow-up of 10.0±1.2 years. The absolute changes in brain natriuretic peptide ( P = 0.015), atrioventricular regurgitation grade ( P = 0.018), and weight for age ( P &lt; 0.001) from baseline to last follow-up showed significant improvements in CDC-treated patients compared with controls. Survival rate did not differ between the 2 groups (log-rank P = 0.351), whereas overall patients treated by CDCs had lower incidents of late failure ( P = 0.043) and adverse events ( P = 0.036) compared with controls. Multivariate proportional hazard regression analyses showed that CDC infusion was associated with lower risks of late failure ( P = 0.003) and adverse events ( P = 0.013). Conclusions: Intracoronary delivery of CDCs in patients with single ventricles did not improve all-cause mortality rate but significantly reduced the incidence of late failure and adverse events at 8 years of follow-up.

Abstract 12927: Impact of AAV- MYBPC3 Gene Transfer on Heart Structure and Function in Human and Mouse Models of Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a life-threatening inherited heart disease characterized by left ventricular hypertrophy and diastolic dysfunction. The most common cause of HCM is genetic variants in MYBPC3 , encoding cardiac myosin binding protein C (cMyBP-C), a sarcomeric protein with structural and regulatory roles. The majority of MYBPC3 gene variants are truncating leading to protein haploinsufficiency. Hypothesis: Transfer of a functional copy of MYBPC3 to heart muscle deficient in cMyBP-C will lead to sustained improvements in cardiac function. Aims: To determine whether BMN 293 (AAV-hMYBPC3) can restore cMyBP-C levels in the sarcomere and halt and/or reverse disease progression in non-clinical models of genetic HCM due to MYPBC3 deficiency. Methods: BMN 293 is an adeno-associated virus (AAV) vector that encodes wild-type human MYBPC3 under the control of a cardiomyocyte-selective promoter. We transduced human iPSC-derived cardiomyocytes and engineered heart tissues (EHTs) carrying a compound heterozygous truncating MYBPC3 mutation (MYBPC3 -/- ) with BMN 293 and assessed cMyBP-C levels and contractile parameters. We also systemically administered BMN 293 to MYBPC3 -/- mice and assessed cardiac distribution of human cMyBP-C by molecular and histological methods and determined its impact on left ventricular hypertrophy and function by echocardiography and other imaging techniques. Results: BMN 293 transduction of human iPSC MYBPC3 -/- cardiomyocytes and EHTs resulted in high levels of human MYBPC3 mRNA and cMyBP-C protein, correct incorporation of cMyBP-C into the sarcomere, and complete normalization of contractile kinetics. BMN 293 was well tolerated in MYBPC3 -/- mice and resulted in uniform restoration of cMyBP-C expression throughout the heart and significant correction of structural and functional cardiac abnormalities. Conclusions: A single IV infusion of BMN 293 to MYBPC3 -/- mice resulted in early and sustained reduction in left ventricular hypertrophy and durable improvements in diastolic function.

Abstract 14198: Therapy for Myocardial Ischemia-Reperfusion Injury Using Novel Allogenic Mitochondria and Associated Organelle Complex

Background: Ischemia and reperfusion (I/R) injury induces intracellular calcium overload and generation of reactive oxygen species, which trigger intracellular mitochondrial damage, resulting in cardiomyocyte apoptosis. Freshly prepared autologous mitochondria improved damaged cardiac function, however, little is known whether allogenic mitochondrial organelle complex -Q (MRC-Q) can be replenished in the heart to achieve cardioprotective effects against I/R injury. Purpose: The aim of this study was to investigate whether the exogenous administration of allergenically isolated mitochondria leads to a protective effect on the myocardium after I/R injury using a well-established murine model. Methods and Results: The MRC-Q used in the current experiments were isolated by a proprietary technology ( WO2021132735A2) . All MRC-Q was frozen and stored at -80 °C before use. First, purified GFP-labeled HUVEC-derived MRC-Q were added to a rat cardiomyocyte cell line, and observed to be uptaken in cardiomyocytes in a time-dependent manner, which was also confirmed by quantitative polymerase chain reaction detecting human mitochondria DNA in rat cardiomyocytes. In addition, we demonstrated that cell viability was improved in the MRC-Q-treated group 96 hours after hypoxia/reoxygenation (H/R). Further examinations suggested the one of mechanism on cardioprotection by incorporating MRC-Q into the cardiomyocyte to be mediated by the secretion of mitochondria-derived peptides (MDP), which could inhibit apoptosis-promoting signals in addition to anti-ROS activity of MRC-Q. Next, we examined potential cardioprotective effect of MRC-Q administration on I/R injury in a murine model. Simultaneously at reperfusion, MRC-Q were administered intramyocardially in the damaged myocardium area. Compared to the vehicle group, MRC-Q-treated group showed a reduction in infarct size with fewer apoptotic cells, a decrease in circulating cardiac enzymes, and an improvement in cardiac function 24 hours after reperfusion. Finally, a preclinical pig model also confirmed the cardioprotective effects of MRC-Q. Conclusion: Our data demonstrated that MRC-Q have a protective effect on the heart by modulating cardiac apoptosis after ischemia/reperfusion injury.