Objectives. Transcriptomics of atrial fibrillation (AFib) in the setting of chronic primary mitral regurgitation (MR) remains to be characterized. We aimed to compare the gene expression profiles of patients with degenerative MR in AFib and sinus rhythm (SR) for a clearer picture of AFib pathophysiology. Methods. After transcriptomic analysis and bioinformatics ( ), differentially expressed genes were defined using 1.5-fold change as the threshold. Additionally, independent datasets from GEO were included as meta-analyses. Results. QRT-PCR analysis confirmed that AFib persistence was associated with increased expression molecular changes underlying a transition to heart failure (NPPB, ; ANGPTL2, ; IGFBP2, ), structural remodeling including changes in the extracellular matrix and cellular stress response (COLQ, ; COMP, ; DHRS9, ; CHGB, ), and cellular stress response (DNAJA4, ). Furthermore, AFib persistence was associated with decreased expression of the targets of structural remodeling (BMP7, ) and electrical remodeling (CACNB2, ; MCOLN3, ) in both left and right atrial samples. The transmission electron microscopic analysis confirmed ultrastructural atrial remodeling and autophagy in human AFib atrial samples. Conclusions. Atrial cardiomyocyte remodeling in persistent AFib is closely linked to alterations in gene expression profiles compared to SR in patients with primary MR. Study findings may lead to novel therapeutic targets. This trial is registered with ClinicalTrials.gov identifier: NCT00970034.

Summary: Aims: This study investigates the expression patterns of BCL2 (B‐cell CLL/lymphoma2) family of proteins and the extent of vascular smooth muscle cell (VSMC) apoptosis in thoracic aortic aneurysms (TAA), type‐A aortic dissections (TAD), and nondilated ascending aortic samples. Methods: Aortic wall specimens were obtained from patients undergoing surgical repair for TAA (n = 24), TAD (n = 20), and normal aortic tissues from organ donors (n = 6). The expression pattern of BCL2, BCL2L1 (BCL2‐like1), BAK1 (BCL2‐antagonist/killer1), and BAX (BCL2‐associated X protein) proteins was investigated by immunohistochemistry. Furthermore, colocalization of alpha smooth muscle actin (ACTA2) and caspase3 (CASP3) in aortic VSMCs was analyzed by double‐immunofluorescence staining. Onset of DNA fragmentation was measured by TUNEL assay. Results: Apoptotic index was significantly increased in both TAD group (31.3 ± 17.2, P < 0.001) and TAA group (21.1 ± 12.7, P = 0.001) relative to control aortas (2.0 ± 1.2). Anti‐CASP3 and ACTA2 double‐immunostaining confirmed apoptosis in VSMCs in TAA and TAD groups but not in controls. Proapoptotic BAX expression was significantly elevated in VSMCs of TAA patients, compared with that of controls (OR = 20; P = 0.02; 95% CI, 16–250). In contrast, antiapoptotic BCL2L1 expression was higher in controls compared with that of TAA group (OR = 11.2; P = 0.049; 95% CI, 1.0–123.9). Furthermore, BAX/BCL2 ratio was significantly increased in both TAA (1.2 ± 0.7, P < 0.001) and TAD (0.6 ± 0.4, P = 0.05) groups relative to controls (0.2 ± 0.1, P < 0.001). Conclusions: Apoptotic VSMC depletion in human TAA/TAD is associated with disturbance of the balance between proapoptotic and antiapoptotic members of the BCL2 family proteins, which may have a role in the pathogenesis of vascular remodelling in aortic disease. In light of the future studies, targeting apoptotic pathways in TAA and TAD pathogenesis may provide therapeutic benefits to patients by slowing down the progression and even possibly preventing the TAD.

OBJECTIVES: Patients on venoarterial or venovenous extracorporeal membrane oxygenation (ECMO) support may require venoarterial–venous (VAV-ECMO) configuration during follow-up. We report 12 cases of VAV-ECMO with significant outflow steal. METHODS: Between October 2014 and November 2016, a total of 97 patients (56.6 ± 12.0 years; 59 men/38 women; body surface area 1.84 ± 0.36 m²) were supported with venoarterial ECMO (n = 85) or venovenous ECMO (n = 12). Among the 97 patients, 12 patients (age 61.5 ± 3.5 years; 8 men/4 women; body surface area 1.8 ± 0.8 m²) required hybrid use of VAV-ECMO. Control and monitoring of flow ratios in supplying cannulae using flow sensors were performed, and occluder devices were used according to patient requirements to achieve optimum haemodynamics and oxygenation. RESULTS: Among the 85 venoarterial ECMO-supported patients, Harlequin syndrome was detected in 9 cases (10.6%) who required switching to VAV-ECMO. Among the 12 patients, 3 (25%) patients required VAV-ECMO while on venovenous ECMO support as a result of initial respiratory failure subsequently developed cardiac decompensation. Mean duration of VAV-ECMO support was 6.4 ± 1.8 days. Overall, on VAV-ECMO support, 70.0 ± 4.6% of blood flow was detected within the supplying right internal jugular vein cannula as a result of lower afterload in venous system. We partially occluded the internal jugular vein cannula and directed flow to the common femoral artery. After adjustment, 34.3 ± 7.4% flow was directed to internal jugular vein and 65.6 ± 7.4% to common femoral artery. CONCLUSIONS: Non-invasive monitoring of flow rates within the supplying cannulae of VAV-ECMO and the use of partial occlusion for venous-supplying cannula enable individualized patient management and effective weaning from VAV-ECMO.

Cell therapy for patients with ischaemic cardiomyopathy (IC) is still an open issue. We aimed to assess the long-term safety and therapeutic potency of autologous bone marrow mononuclear cell (ABMMNC) implantation into ungraftable coronary artery (UCA) territories in patients with IC. Bone marrow was aspirated from the iliac crest, and transepicardial ABMMNC implantation (n=25, 24 men, aged 57+/-7 years) as an adjunct to coronary artery bypass grafting (CABG) was performed into an area of reversible ischaemia within the territory of UCA (1.29+/-0.09 x 10(9) ABMMNCs). Control group (n=25, 23 men, aged 59+/-7 years) underwent incomplete CABG due to poor target vessel graftability. The study protocol consisted of coronary angiography, stress echocardiography, nuclear imaging and Holter monitoring at baseline and follow-up. The mean follow-up time was 988+/-423 days. There was no difference between the groups regarding postoperative complications and outcome. Overall 5-year survival for the ABMMNC group was 79+/-10%, and 71+/-12% for the controls (p=0.48). Left ventricular ejection fraction (LVEF) at baseline was 24.8+/-3.7 versus 25.9+/-3.1 in the ABMMNC group and the controls, respectively. After 6 months, mean global LVEF increased to 36.3+/-7.4 (p<0.001) versus 31.4+/-4.1 (p=0.001), respectively. A significant difference was noted in delta LVEF between the groups (p<0.001, 95% confidence interval (CI): 3.4-8.9) at 6 months, and (p=0.001, 95% CI: 2.0-7.4) at 1 year. Accordingly, perfusion scores in UCA segments detected by single-photon emission computed tomography (SPECT) improved with ABMMNC therapy to 18.0+/-24.4 from 7.1+/-25.7 (p=0.001 vs control UCA segments). Cellular therapy for IC within UCA could augment myocardial perfusion and contractility but does not improve overall survival. No adverse events were detected after cell therapy at mid-term follow-up.

Considerable information is available regarding the experimental and clinical applications of bone marrow derived stem cells (BMDSC) for regenerative medicine. Optimized stem cell delivery systems might help to maintain better stem cell viability. We have investigated whether needle diameters and flow rates through the needles cause any difference in terms of BMDSC viability.