Transplantation of Mesenchymal Stem Cells for Prevention of Acute Myocardial Infarction Induced Heart Failure: Study Protocol of a Phase III Randomized Clinical Trial (Prevent-TAHA8)

BackgroundResults from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF.MethodsThis single-blinded, randomized, multicenter trial aims to establish whether the intracoronary infusion of umbilical cord-derived Wharton’s jelly MSCs (WJ-MSCs) helps prevent HF development after AMI. The study will enroll 360 patients 3 to 7 days following AMI. Only patients aged below 65 years with impaired LV function (LVEF < 40%) will be included. They will be randomized (2:1 ratio) to either receive standard care or a single intracoronary infusion of 107 WJ-MSCs. The primary outcome of this study is the assessment of HF development during long-term follow-up (3 years).DiscussionData will be collected until Nov 2024. Thereafter, the analysis will be conducted. Results are expected to be ready by Dec 2024. We will prepare and submit the related manuscript in accordance with the SPIRIT guidelines. This study will help determine whether or not the infusion of intracoronary WJ-MSCs in patients with AMI will reduce the incidence of AMI-induced HF.Trial RegistrationClinicalTrials.gov, NCT05043610, Registered 14 September 2021 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05043610

Short-term melatonin supplementation decreases oxidative stress but does not affect left ventricular structure and function in myxomatous mitral valve degenerative dogs

Background Cardiac wall stress and high oxidative stress are often found in cases of myxomatous mitral valve degenerative (MMVD) disease and can lead to myocardial injuries and cardiac dysfunction. Melatonin, an antioxidant, has been shown to exert cardioprotection in laboratory animal models. However, its effect on metabolic parameters and left ventricular (LV) adaptation in MMVD dogs has rarely been investigated. This clinical trial hypothesized that a melatonin supplement for 4 weeks would improve metabolic parameters, LV structure (diameters and wall thickness), and LV function in MMVD dogs. Blood profiles, echocardiograms, and oxidative stress levels were obtained from 18 dogs with MMVD stage B2 and C at baseline and after prescribed Melatonin (2 mg/kg) for 4 weeks. Eleven dogs with MMVD stage B2 and C, which received a placebo, were evaluated as a control group. Results In this clinical trial, the baseline plasma malondialdehyde (MDA) was no different between the treatment and placebo groups. The post-treatment plasma MDA levels (4.50 ± 0.63 mg/mL) in the treatment group was significantly decreased after 4 weeks of melatonin supplementation compared to pre-treatment levels (7.51 ± 1.11 mg/mL) (P = 0.038). However, blood profiles and LV structure and function investigated using echocardiography were found not to different between pre-and post-treatment in each group. No adverse effects were observed following melatonin supplementation. Conclusions This clinical trial demonstrated that a melatonin supplement for 4 weeks can attenuate oxidative stress levels in MMVD dogs, especially in MMVD stage C, but does not result in LV structural changes or LV function in MMVD dogs of either stage B2 or stage C.

Influence of Heart Rate on Left and Right Ventricular Longitudinal Strain in Patients with Chronic Heart Failure

Over the past years, a number of studies have demonstrated the relevance of strain assessed by two-dimensional speckle tracking echocardiography (STE) in evaluating ventricular function. The aim of this study was to analyze changes in left (LV) and right ventricular (RV) longitudinal strain associated with variations of heart rate (HR) in participants with and without chronic heart failure (CHF). We enrolled 45 patients, 38 of these diagnosed with CHF and carrying an implantable cardioverter defibrillator, and seven patients with pacemakers and without CHF. The frequency of atrial stimulation was increased to 90 beats/min and an echocardiogram was performed at each increase of 10 beats/min. Global LV and RV longitudinal strain (LVGLS and RVGLS, respectively) and RV free wall longitudinal strain (RVfwLS) were calculated at each HR. When analyzed as continuous variables, significant reductions in LVGLS were detected at higher HRs, whereas improvements in both RVGLS and RVfwLS were observed. Patients with a worsening of LVGLS (76% overall) were more likely to present lower baseline LV function. Only a few patients (18% for RVGLS and 16% for RVfwLS) exhibited HR-related deteriorations of RV strain measures, which was associated with lower levels of baseline RV function and higher pulmonary systolic pressures. Finally, 21 (47%) and 25 (56%) participants responded with improvements in RVGLS and RVfwLS, respectively. Our findings revealed heterogeneous RV and LV responses to increases in HR. These findings might ultimately be used to optimize cardiac functionality in patients diagnosed with CHF.

Left Ventricular Morphology in Patients with Aortic Coarctation and Bicuspid Aortic Valve: Novel Insights from a Statistical Shape Modelling Framework

Background The functional implications of left ventricular (LV) morphological characterization in congenital heart disease (CHD) are not widely explored. This study qualitatively and quantitatively assessed LV shape associations with a) LV function and b) thoracic aortic morphology in patients with aortic coarctation (CoA) with/without bicuspid aortic valve (BAV). Methods A statistical shape modelling (SSM) framework was employed to analyse three-dimensional (3D) LV shapes from cardiac magnetic resonance (CMR) data in isolated CoA (n=25), CoA+BAV (n=30), isolated BAV (n=30), and age-matched healthy controls (n=25). Average 3D templates and deformations were computed. Correlations between shape data and CMR-derived morphometric parameters (i.e. sphericity, conicity) or global and apical strain values were assessed to elucidate possible functional implications. The relationship between LV shape features and arch architecture was also explored. Results The LV template was shorter and more spherical in CoA patient and LV sphericity was associated (p≤0.04) with lower global longitudinal, radial and circumferential strain, irrespective of the presence of aortic stenosis and/or regurgitation. Conversely, LV strain was not associated with arch architecture. Conclusions Differences in LV morphology were observed between CoA and BAV patients. Increasing LV sphericity was associated with reduced strain, independent of aortic arch architecture and functional aortic valve disease.

Assessment of global longitudinal strain by speckle tracking echocardiography in patients with severe primary mitral regurgitation

Background: In asymptomatic patients with severe primary mitral regurgitation (PMR), early detection of left ventricular (LV) dysfunction indicates the optimal timing of mitral valve surgery and predictes impaired postoperative LV function. Objectives: Evaluation long longitudinal strain by Speckle Tracking in Patients with Severe Primary Mitral Regurgitation Methods and results: 35 preoperative patients with severe PMR and 25 age-matched healthy subjects at Hanoi Heart Hospital from June 2018 to September 2019. Patients with PMR had longitudinal dysfunction by comparison with controls, although EF were similar. Mean global myocardial longitudinal strain (GLS avg) has a linear correlation with FS (r² = 0.127, p <0.05) and EF biplane (r² = 0.216, p <0.005). Conclusion: Longitudinal LV deformation assessed by speckle tracking can detect subclinical LV dysfunction and predict impaired postoperative LV function in asymptomatic patients with severe PMR.

Mitral Annular Plane Systolic Excursion (MAPSE) as a Simple Index for Assessing Left Ventricular Function: An Observational Study

Background: Mitral annular plane systolic excursion (MAPSE) has been proposed as a parameter for assessing left ventricular function. The assessment of LVF has major diagnostic and prognostic implications in patients with cardiovascular diseases. LVF is measured by Left Ventricular Ejection Fraction, however the accuracy of LVEF estimation by two dimensional echocardiography is limited especially in patients with poor image quality. Mitral annular plane systolic excursion (MAPSE) measurement predicts left ventricular function even in conditions with suboptimal echo window. Objective: To assess the correlation of MAPSE derived LVEF with LVEF measured by Modified Simpson’s method. Methods: This is a cross sectional study which included 279 patients admitted at our tertiary care hospital from December 2019 to March 2020 and the patients were divided in two groups. Group A – Patients with LVEF>= 50% and Group B – Patients with LVEF<50%. All patients underwent 2D echocardiographic examination using Modified Simpsons’ method and MAPSE measurement. The VIVID E9, VIVID T8, VIVID E95 and PHILIPS echocardiography machine was used for the non-invasive measurements. MAPSE was recorded at medial and lateral mitral annuli in the apical four-chamber approach. Results: On analysis, a cut off value for average MAPSE-S (medial mitral annuli) was 8.5 was obtained, denoting preserved LV function with sensitivity of 81.7%, specificity of 84.9%, positive predictive value of 91.6% and negative predictive value of 84.9%. The AUC for MAPSE-S was 0.822. Similarly, the cut off value of average MAPSE-L (lateral mitral annuli) was 7.5 denoting impaired LV functions with an AUC of 0.826, sensitivity of 82.8%, specificity of 72.0%, positive predictive value of 85.6% and negative predictive value of 72.0%. The AUC of 82.6% was observed for MAPSE-L. Conclusion: MAPSE reflects longitudinal myocardial shortening. MAPSE is a rapid and sensitive echocardiographic parameter for assessing normal LV function and global LV systolic dysfunction.

Reference Ranges of Left Ventricular Hemodynamic Forces in Healthy Adults: A Speckle-Tracking Echocardiographic Study

Background: The normal limits of left ventricular (LV) hemodynamic forces (HDFs) are not exactly known. The aim of this study was to explore the full spectrum of HDF parameters in healthy subjects and determine their physiologic correlates. Methods: 269 healthy subjects were enrolled (mean age: 43 ± 14 years; 123 (45.7%) men). All participants underwent an echo-Doppler examination. Tri-plane tissue tracking from apical views was used to measure 2D global endocardial longitudinal strain (GLS), circumferential strain (GCS), and LV HDFs. HDFs were normalized with LV volume and divided by specific weight. Results: LV systolic longitudinal HDFs (%) were higher in men (20.8 ± 6.5 vs. 18.9 ± 5.6, p = 0.009; 22.0 ± 6.7 vs. 19.8 ± 5.6, p = 0.004, respectively). There was a significant correlation between GCS (increased) (r = −0.240, p < 0.001) and LV longitudinal HDFs (reduced) (r = −0.155, p = 0.01) with age. In a multivariable analysis age, BSA, pulse pressure, heart rate and GCS were the only independent variables associated with LV HDFs (β coefficient = −0.232, p < 0.001; 0.149, p = 0.003; 0.186, p < 0.001; 0.396, p < 0.001; −0.328, p < 0.001; respectively). Conclusion: We report on the physiologic range of LV HDFs. Knowledge of reference values of HDFs may prompt their implementation into clinical routine and allow a more comprehensive assessment of the LV function.

Personalised reprogramming to prevent progressive pacemaker-related left ventricular dysfunction: A phase II randomised, controlled clinical trial

Background Pacemakers are widely utilised to treat bradycardia, but right ventricular (RV) pacing is associated with heightened risk of left ventricular (LV) systolic dysfunction and heart failure. We aimed to compare personalised pacemaker reprogramming to avoid RV pacing with usual care on echocardiographic and patient-orientated outcomes. Methods A prospective phase II randomised, double-blind, parallel-group trial in 100 patients with a pacemaker implanted for indications other than third degree heart block for ≥2 years. Personalised pacemaker reprogramming was guided by a published protocol. Primary outcome was change in LV ejection fraction on echocardiography after 6 months. Secondary outcomes included LV remodeling, quality of life, and battery longevity. Results Clinical and pacemaker variables were similar between groups. The mean age (SD) of participants was 76 (+/-9) years and 71% were male. Nine patients withdrew due to concurrent illness, leaving 91 patients in the intention-to-treat analysis. At 6 months, personalised programming compared to usual care, reduced RV pacing (-6.5±1.8% versus -0.21±1.7%; p<0.01), improved LV function (LV ejection fraction +3.09% [95% confidence interval (CI) 0.48 to 5.70%; p = 0.02]) and LV dimensions (LV end systolic volume indexed to body surface area -2.99mL/m2 [95% CI -5.69 to -0.29; p = 0.03]). Intervention also preserved battery longevity by approximately 5 months (+0.38 years [95% CI 0.14 to 0.62; p<0.01)) with no evidence of an effect on quality of life (+0.19, [95% CI -0.25 to 0.62; p = 0.402]). Conclusions Personalised programming in patients with pacemakers for bradycardia can improve LV function and size, extend battery longevity, and is safe and acceptable to patients. Trial registration ClinicalTrials.gov identifier: NCT03627585.

Effects of a Low‐Salt and High‐Potassium Diet on Arterial Stiffness and Left Ventricular Function in Indigenous Papuans

Background A sodium‐restricted diet represents a potential non‐pharmacological strategy for improving blood pressure, arterial stiffness, and left ventricular (LV) diastolic function. We investigated age‐related differences in LV structure and function and the relationship between LV function and central hemodynamics in an indigenous Papuan population, who maintain a traditional lifestyle, including a low‐salt and high‐potassium diet. Methods and Results We measured LV dimensions, transmitral blood flow, and mitral annular tissue velocities through echocardiography and Doppler imaging. Blood pressure and brachial‐ankle pulse wave velocity were measured using an automatic device (Omron). Central blood pressure and wave reflection parameters were estimated via oscillometry (Mobil‐O‐Graph, using European calibrations). A total of 82 native Papuans (median age, 42 years; 38 women; no blood pressure treatment) were enrolled. Age‐related difference in brachial systolic pressure was modest but significant, and brachial‐ankle pulse wave velocity significantly increased with age; however, LV mass index remained unchanged. LV ejection fraction and global longitudinal strain were preserved; mitral A‐wave velocity and average E/e´ increased; and e´ and E/A decreased with age. Brachial‐ankle pulse wave velocity and spot urine Na/K were positively and independently correlated with E/e´. Age and heart rate were inversely associated with E/A. In conclusion, LV systolic function was preserved; however, LV diastolic function decreased with age in Papuans. Moreover, age‐related arterial stiffening, but not wave reflections, was inversely related to LV diastolic function. Conclusions Our results suggest that arterial and LV stiffness may not be altered by sodium restriction. Longitudinal studies are warranted to elucidate the effects of diet on arterial and LV function.