Citations

ABSTRACT Introduction Cardiogenic shock (CS) carries high morbidity and mortality. However, evidence for mechanical circulatory support (MCS) in non‐ischemic CS remains limited, as prior trials have focused on infarct‐related shock. Methods We performed a retrospective cross‐sectional study using the Nationwide Inpatient Sample (2017–2019), identifying hospitalizations with a principal diagnosis of CS and excluding acute myocardial infarction. Patients were categorized into mutually exclusive groups: no MCS, intra‐aortic balloon pump (IABP) only, Impella only, or extracorporeal membrane oxygenation (ECMO) only. Primary outcomes were in‐hospital mortality, length of stay (LOS), and total hospital cost. Survey‐weighted multivariable models adjusted for demographics, hospital characteristics, and comorbidity burden using Elixhauser and Charlson indices. Results Among 104 045 hospitalizations, 6040 received MCS. IABP was most common, followed by Impella and ECMO. Among patients receiving a single MCS strategy, overall in‐hospital mortality was 29.5%., with lower mortality in the IABP group (19.9%) compared with Impella (37.4%) and ECMO (44.3%). After adjustment, IABP was associated with lower observed in‐hospital mortality versus no MCS (aOR 0.58, 95% CI 0.53–0.64; p < 0.01), whereas Impella and ECMO showed increased aOR. IABP and ECMO were associated with longer LOS, while Impella was not. All MCS strategies were associated with higher costs, with ECMO showing the greatest increase (cost ratio 3.30, 95% CI 3.12–3.50). Conclusion In non‐ischemic CS, MCS strategies demonstrate distinct profiles of mortality and resource utilization. IABP was associated with lower observed in‐hospital mortality, whereas all MCS were linked to higher costs, highlighting heterogeneity in outcomes and the need for further research.

ABSTRACT Background Optimal management of direct oral anticoagulants (DOAC) prior to implantation of cardiac implantable electronic devices (CIED) remains controversial. Objective To determine whether a strategy of minimal interruption of DOAC before cardiac CIED implantation is associated with improved clinical outcomes compared to uninterrupted DOAC use. Methods The electronic clinical records of 310 patients who were on DOAC and underwent CIED implantation were evaluated. The patients were separated into 2 groups: patients in Group 1 had minimal DOAC interruption (DOAC held < 24 h before procedure), while patients in Group 2 continued DOAC before procedure. Resumption of DOAC in both groups was on the same day of the procedure or the next morning at the operator's discretion. Clinically significant pocket hematoma and thromboembolic events were compared. Results Among the 310 patients, 71 (22.9%) of them had DOAC held < 24 h before procedure, while DOAC was continued without interruption in 239 (77.1%) in the periprocedural period. Clinically significant pocket hematomas were found in 1 patient (1.4%) in the DOAC interrupted group and 24 (10.0%) in the DOAC continuous group ( p = 0.046). Low thromboembolic events were observed in both groups: 0 in the minimally interrupted group and 1 (0.4%) in the un‐interrupted group ( p > 0.05). Conclusion The bleeding risk in our cohort of patients who underwent CIED implantation with the uninterrupted DOAC approach is higher than previously reported in the literature. A minimally interrupted approach appears to mitigate this risk without significantly increasing the risk of thromboembolism.

Background: We have previously reported that Sorbs2 (sorbin and SH3 domain 2) knockout mice have significant cardiac structural and electrical remodeling, including atrial enlargement and fibrosis. The mechanisms of such changes were unknown. Hypothesis: We hypothesized that loss of Sorbs2 in cardiac fibroblasts promotes profibrotic signaling pathways and alters the balance between matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) resulting in excessive collagen deposition in the atria. Methods: We used Sorbs2 global knockout ( Sorbs2 KO) mice and age-matched wild-type (WT) controls at 4 to 5 months of age. Left atrial fibrosis was quantitated by Masson's trichrome staining in serial sections. Scratch wound healing assays and transwell migration assays were performed in isolated Sorbs2 KO and WT atrial fibroblasts. Protein expression was determined by Western blots. Interleukin-6 (IL-6) production in cultured fibroblast supernatants was measured by ELISA. Results: Sorbs2 KO mice showed significant increase in atrial diameter (16.6 ± 1.5 mm vs 12.0 ± 1.1 mm in WT; n=3, p < 0.05) and atrial fibrosis (fraction of fibrotic areas: 18.6± 2.9 % vs. 7.6 ± 0.9 % in WT; p < 0.01). Collagen 1 and collagen 3 protein levels in Sorbs2 KO mouse atria were 1.8-fold and 1.7-fold higher than those of WT respectively. Sorbs2 KO atrial fibroblasts showed impaired function with significantly reduced migration and slower scratch-wound closure (migration area after 24h: 18.5 ± 3.8 % vs 70.1 ± 6.7 % in WT; n=6, p < 0.01).Moreover, transforming growth factor β1 (TGF-β1), α-smooth muscle actin, and periostin expression levels were significantly reduced in isolated fibroblasts and atrial myocardia from Sorbs2 KO mice, suggesting that fibrosis is not caused by TGF-b1-dependent mechanisms or from myofibroblast transformation. Analysis of ECM proteins showed significant downregulation of MMP1 and MMP3 but upregulation of TIMP1, while TIMP3 was unchanged. Consistent with a pro-inflammatory phenotype, Sorbs2 KO atrial fibroblasts secreted higher IL-6 levels at baseline (3303± 463 pg/mL vs. 2075 ± 731 pg/mL in WT; n=6, p < 0.01) and with LPS stimulation (7791 ± 604 pg/mL vs. 5588 ± 763 pg/mL in WT; n=6, p < 0.01). Conclusion: Sorbs2 deficiency is associated with abnormal atrial fibroblast function showing impaired migration and scratch wound healing, as well as increased IL-6 production and imbalanced MMP/TIMP. These changes result in collagen accumulation and enhanced fibrosis.

Background: Voltage-gated Nav1.5 channel, encoded by SCN5A , is essential for initiation and propagation of action potentials (AP) in atria. Nav1.5 channelopathy is strongly associated with arrhythmogenesis, including atrial fibrillation. Sorbin and SH3 domain-containing protein 2 (Sorbs2), encoded by SORBS2 , is an important cytoskeletal protein for maintaining atrial structural and electrical integrity. However, the specific mechanisms through which Sorbs2 modulates Nav1.5 function in atria is unknown. Hypothesis: Sorbs2 modulates atrial Nav1.5 expression and function through direct protein-protein interaction. Methods: We created the cardiac-specific Sorbs2 knockout ( c-Sorbs2 KO) mice. We determined the mechanisms by which Sorbs2 regulates Nav1.5 channel expression and function by performing electrophysiological experiments using atrial cells and tissues from control and c-Sorbs2 KO mice, in conjunction with molecular biological studies and in silico analysis. Results: c-Sorbs2 KO mice at 8-10 months showed marked left atrial (LA) enlargement, and ECG showed significantly prolonged P-R durations. Compared to wild-type controls, intracellular recordings in LA tissues isolated from c-Sorbs2 KO mice showed reduced AP amplitude, decreased upstroke velocity, prolonged AP duration at 90% repolarization and effective refractory period, spontaneous atrial tachycardias and triggered activity. Patch-clamp recordings in freshly isolated atrial cardiomyocytes showed a significantly reduced peak sodium current density in c-Sorbs2 KO mice (-12.0 ± 1.6 pA/pF at -45 mV, n = 10), compared to controls (-21.3 ± 4.0 pA/pF at -45 mV, n = 12, p < 0.05). Also, the steady-state activation and inactivation curves of Nav1.5 channel were rightward shifted in c-Sorbs2 KO atrial cardiomyocytes. Molecular docking analysis showed that the Sorbs2 SH3 domain interacts directly with the voltage-sensing domain of Nav1.5. Co-immunoprecipitation assays confirmed the physical interactions between Nav1.5 and the C-terminal SH3 domain of Sorbs2. Furthermore, results from membrane biotinylation study demonstrated that deletion of the SH3 domains of Sorbs2 significantly reduced Nav1.5 surface expression in HEK293 cells. Sorbs2 interacts directly with Nav1.5 through its SH3 domain, playing a key role in regulating Nav1.5 channel gating kinetics and surface expression in atrial cardiomyocytes. Loss of Sorbs2 results in Nav1.5 channelopathy and contributes to atrial electrical remodeling.

Background: Cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3 ) and Sorbin and SH3 domain-containing protein 2 (Sorbs2, encoded by SORBS2 ) are critical sarcomeric components that maintain cardiac structure and function. MYBPC3 and SORBS2 are linked to hypertrophic and dilated cardiomyopathies. But the relationship between Sorbs2 and cMyBP-C regulation, and their roles in the pathogenesis of atrial fibrotic cardiomyopathy (AFCM), remains unclear. Hypothesis: Sorbs2 acts as a cytoskeletal and RNA-binding protein that regulates cMyBP-C expression in atrial myocardium. Methods: We created the cardiac-specific Sorbs2 knockout ( c-Sorbs2 KO mice. We used next-generation RNA sequencing, molecular biology techniques, and in silico analysis to study how Sorbs2 regulates cMyBP-C expression in the atria of c-Sorbs2 KO mice. Results: Compared to age-matched wild-type (WT) mice at 8-9 months of age, the c-Sorbs2 KO male exhibited significant left atrial (LA) enlargement (diameter: 2.41±0.11 mm vs 1.82 ± 0.05 mm in WT; n = 8; p < 0.001) and severe atrial fibrosis (fibrotic area: 12.29±1.73 vs 2.83 ± 0.41% in WT; p < 0.001), accompanied by marked reductions in both mRNA and protein levels of cMyBP-C in LA. In vitro knock-down of Sorbs2 by 60% via shRNA led to an 86.3% decrease in cMyBP-C protein levels, while a 3-fold Sorbs2 overexpression via adenoviral transduction resulted in a 1.4-fold increase in cMyBP-C protein levels in HL-1 cells . cMyBP-C mRNAs were identified in the ribonucleoprotein complexes immunoprecipitated with anti-Sorbs2 antibodies from cardiomyocyte lysates. Loss of Sorbs2 significantly reduced the half-life of cMyBP-C mRNA (from 2.1 hrs in WT to 1.2 hrs in KO). Co-immunoprecipitation with truncated Sorbs2 constructs showed that the C-terminal SH3 domains of Sorbs2, but not the N-terminal SoHo domain, interacted with cMyBP-C protein. Molecular docking and modeling showed hydrophobic interactions and hydrogen bonds between residues H906 and G907 in the SH3 domain of Sorbs2 and residue A954, P955 and T957 in the SH3-binding motif (949-MA P GA P VT-957) of cMyBP-C with a weighted score of -1036 using ClusPro online service. Conclusions: Sorbs2 regulates cMyBP-C expression through direct interaction with both cMyBP-C mRNA and protein. Loss of Sorbs2 results in reduced cMyBP-C expression, atrial fibrosis, and chamber enlargement, revealing a novel Sorbs2/cMyBP-C axis underlying AFCM pathogenesis.