A Modified Surgical Ventricular Reconstruction in Post-infarction Mice Persistently Alleviates Heart Failure and Improves Cardiac Regeneration

Objectives: Large ventricular aneurysm secondary to myocardial infarction (MI) results in severe heart failure (HF) and limits the effectiveness of regeneration therapy, which can be improved by surgical ventricular reconstruction (SVR). However, the conventional SVR procedures do not yield optimal long-term outcome in post-MI rodents. We hypothesized that a modified SVR procedure without aggressive purse string suture would persistently alleviate HF and improve cardiac regeneration in post-MI mice.Methods: Adult male C57 mice were subjected to MI or sham surgery. Four weeks later, mice with MI underwent SVR or 2nd open-chest operation alone. SVR was performed by plicating the aneurysm with a single diagonal linear suture from the upper left ventricle (LV) to the right side of the apex. Cardiac remodeling, heart function and myocardial regeneration were evaluated.Results: Three weeks after SVR, the scar area, LV volume, and heart weight/body weight ratio were significantly smaller, while LV ejection fraction, the maximum rising and descending rates of LV pressure, LV contractility and global myocardial strain were significantly higher in SVR group than in SVR-control group. The inhibitory effects of SVR on LV remodeling and HF persisted for at least eight-week. SVR group exhibited improved cardiac regeneration, as reflected by more Ki67-, Aurora B- and PH3-positive cardiomyocytes and a higher vessel density around the plication area of the infarcted LV.Conclusions: SVR with a single linear suture results in a significant and sustained reduction in LV volume and improvement in both LV systolic and diastolic function as well as cardiac regeneration.

Ubiquinol-cytochrome c reductase core protein 1 contributes to cardiac tolerance to acute exhaustive exercise

Ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) is an indispensable component of mitochondrial complex III. It plays a key role in cardioprotection and maintaining mitochondrion function. However, the exact role of UQCRC1 in maintaining cardiac function has not been reported by in vivo models. Also, the exact biological functions of UQCRC1 are far from fully understood. UQCRC1+/− mice had decreased both mRNA and protein expression of UQCRC1 in the left ventricular myocardia, and these mice had reduced tolerance to acute exhaustive exercise including decreased time and distance with higher apoptosis rate, higher expression level of cleaved CASPASE 3, and higher ratio of cleaved PARP1 to full-length PARP1. Moreover, UQCRC1 knockdown led to increased LV interventricular septal thicknesses both at systole and diastole, as well as decreased LV volume both at end-systole and end-diastole. Finally, UQCRC1 gene disruption resulted in mitochondrial vacuolation, fibril disarrangement, and more severe morphological and structural changes in mitochondria after acute exhaustive exercise. In conclusion, UQCRC1 contributes to cardiac tolerance to acute exhaustive exercise in mice, and it may be an essential component of complex III, playing a crucial role in maintaining cardiac functions.

Dyssynchronous cardiomyopathy in patients with WPW syndrome and its reversibility after RFA of accessory pathway

Introduction In some cases accessory pathway-mediated ventricular preexcitation can be associated with electro-mechanical dyssynchrony and, consequently, with dyssynchrony-related dilated cardiomyopathy, even in the absence of supraventricular tachycardia (SVT). Sometimes rapid progression of ventricular dysfunction developed in such patients after birth. Methods and materials 8 patients with asymptomatic WPW and dyssynchronous cardiomyopathy were examined in our Institute from 2017 till 2019. Four patients of the group were observed in other clinics with dilated cardiomyopathy (DCM) and prescribed appropriate therapy without significant clinical effect. The absence of complaints of heartbeat and episodes of tachycardia at the scheduled Holter monitoring allowed eliminating incessant tachycardia as a possible cause of cardiomyopathy. After radiofrequency ablation (RFA) all patients were performed ECG to assess QRS duration, Holter monitoring, echocardiography (Echo) for assessment of heart chamber volume and left ventricle (LV) contractile function and Speckle tracking – Echo with LV longitudinal strain assessment. The average age of the patients was 9.5 years (from 2 to 14 years). 6 children had heart failure (NYHA Class II). Results According to Echo all patients had widened QRS complex. Dilatation and enlargement of LV volume were marked in 6 pts. According to Echo7 patients had decrease of LV contractile function. According to Speckle tracking – Echo all patients had intraventricular dyssynchrony, decrease of longitudinal strain indices. At intracardiac electrophysiology study right-sided accessory pathways was diagnosed in all patients, successful RFA was performed. Preexitation relapsed, and the repeated RFA was performed in 2 pts. Complications caused by RFA were not marked. After RFA all patients showed a regular normalization of QRS duration. At the 5th day after RFA Echo was performed to all patients. The patients with initially decreased LV ejection fraction had it increased. The patients with initial dilatation and LV volume enlargement had normalization of the given indices. According to Speckle tracking – Echo normalization of global and regional myocardial function, LV longitudinal strain, disappearance of intraventricular and interventricular dyssynchrony were marked in all patients. The index of longitudinal strain was 17,0±0,64% before RFA, after RFA - 23,75±0,92% (p=0,ehab724.035946). Conclusion As a result of RFA of accessory pathways electromechanical resynchronization causes LV demodeling and restoration of its contractile ability. The presented clinical examples are an additional indication for RFA of accessory pathways even in the absence of SVT in patients regardless of age. FUNDunding Acknowledgement Type of funding sources: None.

Automated non-invasive pressure-volume loop analysis of cardiac aging in a large cohort of healthy community dwellers

Background/Introduction Pressure-volume loops (PVloops) provide a wealth of information on cardiac function that is not readily available from cardiac imaging alone. Methods To estimate left ventricular (LV) PVloops non-invasively have been available, but have so far not been used to interrogate ventricular function in large patient cohorts, due to the complexity of estimating PVloops. A new method was recently validated that construct PVloops non-invasively from cine cardiac magnetic resonance (CMR), based on the time-varying elastance model [1]. At the same time, we have validated a framework for automated, quality controlled analysis of cine CMR in large cohorts of patients/subjects [2]. Combining these two methods could automated PVloop estimation, enabling analysis of ventricular pressure-volume relationships in large study populations. Purpose Evaluate if CMR-based non-invasive PVloops can be used to interrogate the impact of cardiac ageing on LV function occurring in a large population of healthy community dwellers. Methods Non-invasive PVloops were calculated from a full cardiac cycle LV volume curve and brachial blood pressure data using a recently validated method based on the time-varying elastance model [1], in 7,650 healthy community dwellers from the UKBiobank population study. The LV volume curve was automatically obtained using our state-of-the-art, quality controlled deep learning (DL) based cine CMR analysis framework [2]. External Work, pressure-volume-area (PVA), end-systolic pressure (Pes), ventricular elastance (Ees, an estimate of contractility) and arterial elastance (Ea) and energy per ejected volume (EEV: PVA/ stroke volume) were calculated from the PVloops. We performed univariate regression between PVloop parameters and age. We also calculated the additional impact of cardiovascular risk-factors in a multivariate analysis. Results See results in table 1. With age, LV volumes fall (p<0.001) in healthy subjects, while systolic blood pressure and Pes increases (both p<0.001). As a result of the higher afterload, PVA (p=0.894) and EW (p=0.499) do not significantly change with age despite a lower SV. Arterial elastance (Ea) increased, and so did contractility, as measured by Ees (p<0.001). Due to all these changes, EEV increased with age (p<0.001). In multivariate analysis, cardiovascular risk factors hypercholesterolemia and hypertension negatively impacted Pes, PVA, Ees and EEV. Diabetes and smoking habits did not. Conclusion Non-invasive CMR-based PVloop analyses capture the impact of known changes occurring during cardiac ageing on cardiac work, contractility and energetic expenditure. Obtaining PVloops automatically using our AI analysis system in this large cohort of healthy subjects allows to formulate reference for assessment of cardiac disease. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The authors acknowledge financial support (support) the National Institute for Health Research (NIHR) Cardiovascular MedTech Co-operative (previously existing as the Cardiovascular Healthcare Technology Co-operative 2012 - 2017) award to the Guy's and St Thomas' NHS Foundation Trust, in partnership with King's College London and the NIHR comprehensive Biomedical Research Centre of the Guy's & St Thomas' NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health Univariate regression analysis Example of estimated PV loop

Efficacy and Safety of mesenchymal stem cell therapy in patients with acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials

Background and Objectives: The adjuvant treatment of stem cell therapy for acute myocardial infarction (AMI) has been studied in multiple clinical trials, but many questions remain to be addressed, such as efficacy, safety, identification of the optimal cell type, tractable route of delivery, transplant dosage, and transplant timing. The current meta-analysis aimed to explore the issues of mesenchymal stem cells (MSCs) transplantation in patients with AMI based on published randomized controlled trials (RCTs) and guide the design of subsequent clinical trials of MSCs therapy for AMI. Methods: The Cochrane Library, PubMed, EMBASE databases were searched for relevant clinical trials from January 1, 2000, to January 23, 2021. Results from RCTs involving MSCs transplantation for the treatment of AMI were identified. According to the Cochrane systematic review method, the literature quality, including studies, was evaluated and valid data was extracted. RevMan 5.3 and Stata 15.1 software were used for Meta-analysis. Results: After a literature search and detailed evaluation, 9 randomized controlled trials enrolling 460 patients were included in the quantitative analysis. Pooled analyses indicated that MSCs therapy was associated with a significantly greater improvement in overall left ventricular ejection fraction (LVEF), and the effect was maintained for up to 24 months. No significant difference in favor of MSCs treatment in left ventricular (LV) volume and in the risk of rehospitalization as a result of heart failure (HF) was noted, compared with the controls. For transplantation dose, the LVEF of patients accepting a MSCs dose of 107-108 cells was significantly increased by 2.62% (95% CI 1.54 to 3.70; P < 0.00001; I2 =0%), but this increase was insignificant in the subgroup that accepted an MSCs dose of < 107 cells (1.65% in LVEF, 95% CI, 0.03 to 3.27; P =0.05; I2 =75%) or >108 cells (4.65% in LVEF, 95% CI, -4.55 to 13.48; P =0.32; I2 =95%), compared with the controls. For transplantation timing, a significant improvement of LVEF of 3.18% was achieved in the group of patients accepting a MSCs infusion within 2 to 14 days Percutaneous coronary intervention (PCI) (95% CI, 2.89 to 3.47; P <0.00001; I2 = 0). There was no association between MSCs therapy and major adverse events. Conclusion: Results from our systematic review suggest that MSCs therapy for patients with AMI appears to be safe and might induce a significant increase in LVEF with a limited impact on LV volume and rehospitalization caused by HF. The effect was maintained for up to 24 months. MSCs dose of 107-108 cells was more likely to achieve better clinical endpoints than <107 or >108 cells. The optimal time window for cell transplantation might be within 2-14 days after PCI. This meta-analysis was registered with PROSPERO, number CRD 42021241104.

Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling

While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Global GPR55−/− and wildtype (WT) mice were basally characterized or assigned to 1, 3 or 28 days permanent MI and subsequently analysed via pro-inflammatory and pro-hypertrophic parameters. GPR55−/− deficiency was basally associated with bradycardia, increased diastolic LV volume and sarcomere length and a subtle inflammatory phenotype. While infarct size and myeloid cell infiltration were unaffected by GPR55 depletion, acute cardiac chemokine production was prolonged post-MI. Concurrently, GPR55−/− hearts exhibited a premature expansion of pro-reparative and phagocytic macrophages paralleled by early up-regulation of extracellular matrix (ECM) factors 3 days post-MI, which could be mimicked by sole haematopoietic GPR55 depletion. Moreover, global GPR55 deficiency mitigated MI-induced foetal gene re-programming and cardiomyocyte hypertrophy, culminating in aggravated LV dilatation and infarct expansion. GPR55 regulates cardiac homeostasis and ischaemia responses by maintaining adequate LV filling and modulating three crucial processes post-MI: wound healing kinetics, cardiomyocyte hypertrophy and maladaptive remodelling.

Alarin alleviated cardiac fibrosis via attenuating oxidative stress in heart failure rats

The present study was to explore whether alarin could alleviate heart failure (HF) and attenuate cardia fibrosis via inhibiting oxidative stress. The fibrosis of cardiac fibroblasts (CFs) was induced by angiotensin (Ang) II. HF models were induced by ligation of the left anterior descending artery to cause ischemia myocardial infarction (MI) in Sprague–Dawley rats. Alarin (1.0 nM/kg/d) was administrated by intraperitoneal injection for 28 days. The decreases of left ventricular (LV) ejection fraction (EF), fractional shortening (FS), the maximum of the first differentiation of LV pressure (LV ± dp/dtmax) and LV systolic pressure (LVSP), and the increases of LV volume in systole (LVVS), LV volume in diastole (LVVD), LV end-systolic diameter (LVESD) and LV end-diastolic diameter (LVEDD) in MI rats were improved by alarin treatment. The increases in the expression levels of collagen I, collagen III, and transforming growth factor (TGF)-β were inhibited by alarin treatment in CFs and in the hearts of MI rats. The levels of NADPH oxidase (Nox) activity, superoxide anions and malondialdehyde (MDA) levels were increased, and the level of superoxide dismutase (SOD) activity was reduced in Ang II-treated CFs, which were reversed by alarin. Nox1 overexpression reversed the effects of alarin on attenuating the increases of collagen I, collagen III and TGF-β expression levels induced by Ang II in CFs. These results indicated that alarin improved HF and cardiac fibrosis via inhibiting oxidative stress in HF rats. Nox1 played important roles in the regulation of alarin effects on attenuating CFs fibrosis induced by Ang II.

Extended Precordial T Wave Inversions Are Associated with Right Ventricular Enlargement and Poor Prognosis in Pulmonary Hypertension

In pulmonary hypertension (PH), T wave inversions (TWI) are typically observed in precordial leads V1–V3 but can also extend further to the left-sided leads. To date, the cause and prognostic significance of this extension have not yet been assessed. Therefore, we aimed to assess the relationship between heart morphology and precordial TWI range, and the role of TWI in monitoring treatment efficacy and predicting survival. We retrospectively analyzed patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) treated in a reference pulmonary hypertension center. Patients were enrolled if they had a cardiac magnetic resonance (cMR) and 12-lead surface ECG performed at the time of assessment. They were followed from October 2008 until March 2021. We enrolled 77 patients with PAH and 56 patients with inoperable CTEPH. They were followed for a mean of 51 ± 33.5 months, and during this time 47 patients died (35.3%). Precordial TWI in V1–V6 were present in 42 (31.6%) patients, while no precordial TWI were observed only in 9 (6.8%) patients. The precordial TWI range correlated with markers of PH severity, including right ventricle to left ventricle volume RVEDVLVEDV (R = 0.76, p < 0.0001). The presence of TWI in consecutive leads from V1 to at least V5 predicted severe RV dilatation (RVEDVLVEDV ≥ 2.3) with a sensitivity of 88.9% and specificity of 84.1% (AUC of 0.90, 95% CI = 0.83–0.94, p < 0.0001). Presence of TWI from V1 to at least V5 was also a predictor of mortality in Kaplan–Meier estimation (p = 0.02). Presence of TWI from V1 to at least V5 had a specificity of 64.3%, sensitivity of 58.1%, negative predictive value of 75%, and positive predictive value of 45.5% as a mortality predictor. In patients showing a reduction in TWI range of at least one lead after treatment compared with patients without this reduction, we observed a significant improvement in RV-EDV and RV−EDVLV−EDV. We concluded that the extension of TWI to left-sided precordial leads reflects significant pathological alterations in heart geometry represented by an increase in RV/LV volume and predicts poor survival in patients with PAH and CTEPH. Additionally, we found that analysis of precordial TWI range can be used to monitor the effectiveness of hemodynamic response to treatment of pulmonary hypertension.

Cardiac Magnetic Resonance as a diagnostic tool in arrhythmias

Funding Acknowledgements Type of funding sources: None. Introduction Etiology of cardiac arrhythmias is often difficult to determine.As the gold standard to anatomical and functional cardiac evaluation,Cardiac Magnetic Resonance(CMR)can be a fundamental technique for accurate assessment of myocardial arrhythmic substrates or for arrhythmias management. Purpose The aim of this study is to determine diagnostic and arrhythmic risk stratification impact of CMR performed in patients with suspected or confirmed arrhythmias. Methods We performed a six-years prospective study of patients with suspected or confirmed arrhythmias which evaluation with other techniques did not provide a definitive diagnosis.These patients underwent CMR for diagnostic and risk stratification assessment.We applied a protocol to evaluate both ventricles’ morphology and functional and late gadolinium enhancement (LGE) presence. Results A total of 93 patients were included,of which 66% were male, with a mean age of 45 ± 17 years old. The indications for patients with suspected or confirmed arrhythmias performing CMR evaluation were the following: 33% (n = 31) of the patients had very frequent premature ventricular complexes, 23% (n = 21) had sustained ventricular tachycardia (VT), 5%(n = 5) non-sustained VT, 17%(n = 16) suspected structural heart disease with high arrhythmic potential,10%(n = 9) unexplained recurrent syncope,9 %(n = 8) supraventricular tachycardia and 3% (n = 3) aborted sudden cardiac death. Depressed ejection fraction (EF)(&lt;50%) was present in 10% (n = 9) for LV(mean EF 38 ± 9%) and 15%(n = 14) for RV (mean EF 42 ± 7%). Dilation of LV was found in 25% of patients (n = 23, mean LV volume: 115 ± 7ml/m²), with RV dilation being present in only 1 patient, who had right ventricle arrhythmogenic dysplasia (RVAD) (RV volume: 152ml/m²). In total, 16%had interventricular septum hypertrophy (mean 15 ± 4mm/m2).We found slight anterior leaflet prolapse of mitral valve in 10% (n = 9) of the cases and mild mitral regurgitation in 15% (n = 14). Left atrium dilation was observed in 17% (n = 16) of patients (mean area of 18 ± 2cm2/m2), as right atrium was dilated in only two. In 20% of the patients, CMR contributed to establish a previously unknown diagnosis: 6% (n = 5) have hypertrophic cardiomyopathy,4%(n = 4)a myocarditis sequelae and 2%(n = 2)had RVAD. LV non-compaction,a silent myocardial infarction scar and non-ischemic dilated cardiomyopathy were diagnosed in 3%of the cases each. In 15%(n = 14)we found nonspecific variations, which deserve follow-up. On the remaining patients, CMR was considered normal. Conclusion As a high reproducible, accurate and versatile technique, CMR allowed an increase on diagnosis in 20% of the patients with suspected or confirmed arrhythmias. Consequently, it contributed to the risk stratification of our study population with suspected high arrhythmic potential when the first-line complementary exams were inconclusive.

Haematopoietic and Cardiac GPR55 Synchronize Post-myocardial Infarction Remodelling

Background and purpose: While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Methods and results: Global GPR55-/- and wildtype (WT) mice were basally characterized or assigned to 1, 3 or 28 days permanent MI and subsequently analysed via pro-inflammatory and pro-hypertrophic parameters. GPR55-/- deficiency was basally associated with bradycardia, increased diastolic LV volume and sarcomere length and a subtle inflammatory phenotype. While infarct size and myeloid cell infiltration were unaffected by GPR55 depletion, acute cardiac chemokine production was prolonged post-MI. Concurrently, GPR55-/- hearts exhibited a premature expansion of pro-reparative and phagocytic macrophages paralleled by early up regulation of extracellular matrix (ECM) factors 3 days post-MI, which could be mimicked by sole haematopoietic GPR55 depletion. Moreover, global GPR55 deficiency mitigated MI-induced foetal gene re-programming and cardiomyocyte hypertrophy, culminating in aggravated LV dilatation and infarct expansion. Conclusions: GPR55 regulates cardiac homeostasis and ischaemia responses by maintaining adequate LV filling and modulating three crucial processes post-MI: wound healing kinetics, cardiomyocyte hypertrophy and maladaptive remodelling.