Role and Mechanism of Lamellar Derived Growth Factor /AKT Pathway in Ventricular Remodeling Induced by Pressure Overload.

This study aimed to investigate the role and underlying mechanisms of the platelet-derived growth factor (PDGF)/protein kinase B (AKT) signaling pathway in pressure overload-induced ventricular remodeling. Ventricular remodeling, a critical pathological process in heart failure, is commonly triggered by pressure overload. While PDGF is known to promote cell proliferation and growth, the AKT pathway is crucial for cell growth, survival, and metabolism. However, the specific role of the PDGF/AKT pathway in pressure overload-induced ventricular remodeling remains unclear. Thus, this study aimed to elucidate the precise mechanisms of PDGF/AKT involvement in this process using animal models and cell experiments. 45 female C57BL/6 mice were utilized, randomly divided into three groups: model group (M group, n = 15), control group (C group, n = 15), and experimental group (E group, n = 15). M group mice underwent thoracotomy without aortic constriction (AC). C group mice received phosphate-buffered saline (PBS) and dimethyl sulfoxide (DMSO) treatment following AC surgery. E group mice were treated with the PDGF receptor inhibitor AG1296 and PBS solution after AC surgery. Additionally, 293 T cells were categorized into three groups: PDGF shRNA transfected group (downregulating PDGF expression, D group), PDGF overexpression group (B group), and control group (NV group). Left ventricular end-systolic volume (LVESV) and ejection fraction (FS) of the mice were measured via echocardiography. Western blot analysis was conducted to assess the expression levels of p-AKT and t-AKT in myocardial tissues. Furthermore, myocardial cell area was measured using hematoxylin and eosin (HE) staining and image analysis software. The LVESV in the C group was significantly higher than in the M and E groups (48.32 ± 3.08 mL vs. 18.24 ± 3.19 mL and 25.44 ± 3.12 mL, P < 0.05). The FS in the C group was significantly lower compared to the M and E groups (21.18 ± 2.99% vs. 42.45 ± 3.02% and 26.89 ± 2.54%, P < 0.05). Western blot analysis revealed that p-AKT and t-AKT levels were significantly elevated in the C group and PDGF overexpression group (B group) compared to the M and PDGF shRNA groups (D group) (P < 0.05). HE staining showed a significant increase in myocardial cell cross-sectional area in the C and D groups, with the most pronounced enlargement in the D group (P < 0.05). PDGF facilitates pressure overload-induced ventricular remodeling and myocardial fibrosis. Inhibition of the PDGF/AKT signaling pathway effectively mitigates myocardial cell hypertrophy and ventricular remodeling. These findings offer novel potential targets and therapeutic strategies for the treatment of pressure overload-related heart failure.

Validating real-time three-dimensional echocardiography against cardiac magnetic resonance, for the determination of ventricular mass, volume and ejection fraction: a meta-analysis.

INTRODUCTION: Real-time three-dimensional echocardiography (RT3DE) is currently being developed to overcome the challenges of two-dimensional echocardiography, as it is a much cheaper alternative to the gold standard imaging method, cardiac magnetic resonance (CMR). The aim of this meta-analysis is to validate RT3DE by comparing it to CMR, to ascertain whether it is a practical imaging method for routine clinical use. METHODS: A systematic review and meta-analysis method was used to synthesise the evidence and studies published between 2000 and 2021 were searched using a PRISMA approach. Study outcomes included left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), left ventricular mass (LVM), right ventricular end-systolic volume (RVESV), right ventricular end-diastolic volume (RVEDV) and right ventricular ejection fraction (RVEF). Subgroup analysis included study quality (high, moderate), disease outcomes (disease, healthy and disease), age group (50 years old and under, over 50 years), imaging plane (biplane, multiplane) and publication year (2010 and earlier, after 2010) to determine whether they explained the heterogeneity and significant difference results generated on RT3DE compared to CMR. RESULTS: The pooled mean differences for were - 5.064 (95% CI - 10.132, 0.004, p > 0.05), 4.654 (95% CI - 4.947, 14.255, p > 0.05), - 0.783 (95% CI - 5.630, 4.065, p > 0.05, - 0.200 (95% CI - 1.215, 0.815, p > 0.05) for LVEF, LVM, RVESV and RVEF, respectively. We found no significant difference between RT3DE and CMR for these variables. Although, there was a significant difference between RT3DE and CMR for LVESV, LVEDV and RVEDV where RT3DE reports a lower value. Subgroup analysis indicated a significant difference between RT3DE and CMR for studies with participants with an average age of over 50 years but no significant difference for those under 50. In addition, a significant difference between RT3DE and CMR was found in studies using only participants with cardiovascular diseases but not in those using a combination of diseased and healthy participants. Furthermore, for the variables LVESV and LVEDV, the multiplane method shows no significant difference between RT3DE and CMR, as opposed to the biplane showing a significant difference. This potentially indicates that increased age, the presence of cardiovascular disease and the biplane analysis method decrease its concordance with CMR. CONCLUSION: This meta-analysis indicates promising results for the use of RT3DE, with limited difference to CMR. Although in some cases, RT3DE appears to underestimate volume, ejection fraction and mass when compared to CMR. Further research is required in terms of imaging method and technology to validate RT3DE for routine clinical use.

Interaction between the left ventricular ejection fraction and left ventricular strain and its relationship with coronary stenosis.

BACKGROUND: Coronary artery stenosis (CAS) is the most common type of heart disease and the leading cause of death in both men and women globally. CAS occurs when the arteries that supply blood to the heart muscle harden and become narrower due to plaque buildup - cholesterol and other material - on their inner walls. As a result, the heart muscle cannot receive the blood or oxygen it needs. Most heart attacks happen when a blood clot suddenly cuts off the hearts' blood supply, causing permanent heart damage. AIM: To analyze the relationship between the left ventricular ejection fraction (LVEF), left ventricular strain (LVS), and coronary stenosis. METHODS: A total of 190 participants were enrolled in this trail. The control group comprised 93 healthy individuals, and observation group comprised 97 patients with coronary heart disease who were hospitalized between July 2020 and September 2021. Coronary lesions were assessed using the Gensini score, and the LVEF and LVS were measured using magnetic resonance imaging (MRI). The interaction between the LVEF and LVS was examined using a linear regression model. The relationship between LVEF and coronary stenosis was examined using Spearman's correlation. RESULTS: The LVEF of the observation group was lower than that of the control group. The left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) of the observation group were significantly higher than those of the control group (P < 0.05). The longitudinal and circumferential strains (LS, CS) of the observation group were significantly higher than those of the control group; however, the radial strain (RS) of the observation group was significantly lower than that of the control group (P < 0.05). LVS, LS, and CS were significantly negatively correlated with the LVEF, and RS was positively correlated with the LVEF. There were significant differences in the LVEF, LVESV, and LVEDV of patients with different Gensini scores; the LVEF significantly decreased and the LVESV and LVEDV increased with increasing Gensini scores (P < 0.05). In the observation group, the LVEF was negatively correlated and the LVESV and LVEDV were positively correlated with coronary stenosis (P < 0.05). CONCLUSION: The LVEF measured using MRI is significantly linearly correlated with LVS and negatively correlated with coronary stenosis.

Prospective multiparametric CMR characterization and MicroRNA profiling of anthracycline cardiotoxicity: A pilot translational study.

Background: Anthracycline cardiotoxicity is a significant clinical challenge. Biomarkers to improve risk stratification and identify early cardiac injury are required. Objectives: The purpose of this pilot study was to prospectively characterize anthracycline cardiotoxicity using cardiovascular magnetic resonance (CMR), echocardiography and MicroRNAs (MiRNAs), and identify baseline predictors of LVEF recovery. Methods: Twenty-four patients (age 56 range 18-75 years; 42 % female) with haematological malignancy scheduled to receive anthracycline chemotherapy (median dose 272 mg/m2 doxorubicin equivalent) were recruited and evaluated at three timepoints (baseline, completion of chemotherapy, and 6 months after completion of chemotherapy) with multiparametric 1.5 T CMR, echocardiography and circulating miRNAs sequencing. Results: Seventeen complete datasets were obtained. CMR left ventricular ejection fraction (LVEF) fell significantly between baseline and completion of chemotherapy (61 ± 3 vs 53 ± 3 %, p < 0.001), before recovering significantly at 6-month follow-up (55 ± 3 %, p = 0.018). Similar results were observed for 3D echocardiography-derived LVEF and CMR-derived longitudinal, circumferential and radial feature-tracking strain. Patients were divided into tertiles according to LVEF recovery (poor recovery, partial recovery, good recovery). CMR-derived mitral annular plane systolic excursion (MAPSE) was significantly different at baseline in patients exhibiting poor LVEF recovery (11.7 ± 1.5 mm) in comparison to partial recovery (13.7 ± 2.7 mm), and good recovery (15.7 ± 3.1 mm; p = 0.028). Furthermore, baseline miRNA-181-5p and miRNA-221-3p expression were significantly higher in this group. T2 mapping increased significantly on completion of chemotherapy compared to baseline (54.0 ± 4.6 to 57.8 ± 4.9 ms, p = 0.001), but was not predictive of LVEF recovery. No changes to LV mass, extracellular volume fraction, T1 mapping or late gadolinium enhancement were observed. Conclusions: Baseline CMR-derived MAPSE, circulating miRNA-181-5p, and miRNA-221-3p were associated with poor recovery of LVEF 6 months after completion of anthracycline chemotherapy, suggesting their potential predictive role in this context. T2 mapping increased significantly on completion of chemotherapy but was not predictive of LVEF recovery.

A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants.

This phase 1, randomized, double-blind, placebo-controlled study of aficamten (formerly CK-3773274) in healthy adults identified a pharmacologically active range of doses and exposures. At doses that were pharmacologically active (single doses of ≤50 mg or daily dosing of ≤10 mg for 14 or 17 days), aficamten appeared to be safe and well tolerated. Adverse events were generally mild and no more frequent than with placebo. Pharmacokinetic assessments showed dose proportionality over the range of single doses administered, and pharmacokinetics were not affected by administration with food or in otherwise healthy individuals with a cytochrome P450 2D6 poor metabolizer phenotype. (A Single and Multiple Ascending Dose Study of CK-3773274 in Health Adult Subjects; NCT03767855).

MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B.

Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor (Anf) and ß-myosin heavy chain (ß-Mhc) in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3' untranslated region of Atg4b mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction.

Isolated OPCABG in moderate chronic ischemic mitral regurgitation: is it a justifiable alternative approach ?

OBJECTIVE: Current evidence does not allow a consensus on the management of moderate chronic ischemic mitral regurgitation (CIMR). We compared moderate CIMR patients undergoing off-pump CABG (OPCABG) alone and CABG + MV repair for early mortality, major adverse systemic events (MASE) and mid-term functional outcomes. METHODS: 210 patients with moderate CIMR who underwent off-pump coronary artery bypass grafting (OPCABG) Group I (n = 106) or CABG + mitral valve repair (MV rep) Group II (n = 104) were followed prospectively. For comparison, patients were further sub-divided based on the product of regurgitant fraction and ejection fraction "RFEF"(Good/Bad) and MR jet direction (Central/Eccentric). The primary end point of the study was mortality and secondary end points were MASE, percentage improvements in indexed left ventricle end-systolic volume (LVESVI %), MR grade and functional outcomes of the patients. RESULTS: In-hospital and overall mortality was significantly lower in Group I (1.89% vs. 13.46%, p < 0.001 and 5.66% vs. 15.38%; p = 0.024 respectively). Group II had significantly higher MASE, ventilation time, mean ICU and hospital stay. At 36 months, LVESVI% (17.56% ± 9.12% vs. 18.81% ± 7.48%; p = 0.279), MR grade improvement (80.18% vs. 83.50%; p = 0.544), NYHA class and MLHF scores were also similar in both groups. On subgroup analysis, Good RFEF with Central jet subgroup had comparable improvement in LVESVI% and MR grade with either procedure, while Bad Eccentric subgroup showed a significantly higher improvement in LVESVI% and MR grade with CABG + MV repair. CONCLUSION: OPCABG is associated with significantly reduced mortality and MASE with comparable improvement in LVEDVI% and MR grade. CABG + MV Rep results in significant improvement in LVEDVI% and MR grade in patients with bad eccentric MR. The recommended procedures in the "Good Central" and "Bad Eccentric" subsets are CABG and CABG + Mvrepair, respectively.

Patterns of cardiovascular magnetic resonance inflammation in acute myocarditis from South Asia and Middle East.

Background: Cardiovascular magnetic resonance (CMR) is the test of choice for diagnosis and risk stratification of myocardial inflammation in acute viral myocarditis. The objective of this study was to assess patterns of CMR inflammation in a cohort of acute myocarditis patients from Northern Africa, Asia, and the Middle East using unsupervised machine learning. Methods: A total of 169 racially and ethnically diverse adults ( ≥ 18 years of age) with CMR confirmed acute myocarditis were studied. The primary outcome was a combined clinical endpoint of cardiac death, arrhythmia, and dilated cardiomyopathy. Machine learning was used for exploratory analysis to identify patterns of CMR inflammation. Results: Our cohort was diverse with 25% from Northern Africa, 33% from Southern Asia, and 28% from Western Asia/the Middle East. Twelve patients met the combined clinical endpoint - 3 had arrythmia, 8 had dilated cardiomyopathy, and 1 died. Patients who met the combined endpoint had increased anterior (p = 0.034) and septal (p = 0.042) late gadolinium enhancement (LGE). Multivariable logistic regression, adjusted for age, gender, and BMI, found that patients from Southern Asia (p = 0.041) and the Middle East (p = 0.043) were independently associated with lateral LGE. Unsupervised machine learning and factor analysis identified two distinct CMR patterns of inflammation, one with increased LGE and the other with increased myocardial T1/T2. Conclusions: We found that anteroseptal inflammation is associated with worsened outcomes. Using machine learning, we identified two patterns of myocardial inflammation in acute myocarditis from CMR in a racially and ethnically diverse group of patients from Southern Asia, Northern Africa, and the Middle East.

A Glimpse Into the Future of Transcatheter Interventional Heart Failure Therapies.

Chronic heart failure is one of the most debilitating chronic conditions affecting millions of people and adding a significant financial burden to health care systems worldwide. Despite the significant therapeutic advances achieved over the last decade, morbidity and mortality remain high. Multiple catheter-based interventional therapies targeting different physiological and anatomical targets are already under different stages of clinical investigation. The present paper provides a technical overview of the most relevant catheter-based interventional therapies under clinical investigation.

Left ventricular vortex analysis by high-frame rate blood speckle tracking echocardiography in healthy children and in congenital heart disease.

BACKGROUND: High-frame rate blood speckle tracking (BST) echocardiography is a new technique for the assessment of intracardiac flow. The purpose of this study was to evaluate the characteristics of left ventricular (LV) vortices in healthy children and in those with congenital heart disease (CHD). METHODS: Characteristics of LV vortices were analyses based on 4-chamber BST images from 118 healthy children (median age 6.84 years, range 0.01-17 years) and 43 children with CHD (median age 0.99 years, range 0.01-14 years). Both groups were compared after propensity matching. Multiple linear regression was used to identify factors that independently influence vortex characteristics. RESULTS: Feasibility of vortex imaging was 93.7% for healthy children and 95.6% for CHD. After propensity matching, there were no overall significant differences in vortex distance to apex, distance to interventricular septum (IVS), height, width, sphericity index, or area. However, multiple regression analysis revealed significant associations of LV morphology with vortex characteristics. Furthermore, CHD involving LV volume overload and CHD involving LV pressure overload were both associated with vortices localized closer to the IVS. CONCLUSIONS: LV vortex analysis using high-frame rate BST echocardiography is feasible in healthy children and in those with CHD. As they are associated with LV morphology and are modified in some types of CHD, vortices might yield diagnostic and prognostic value. Future studies are warranted to establish applications of vortex imaging in the clinical setting.