LIM kinase 2 activates cardiac fibroblasts and exacerbates postinfarction left ventricular remodeling via crosstalk between the canonical and non-canonical Wnt pathways.

Ischemic heart failure rates rise despite decreased acute myocardial infarction (MI) mortality. Excessive myofibroblast activation post-MI leads to adverse remodeling. LIM kinases (LIMK1 and LIMK2) regulate cytoskeleton homeostasis and are pro-fibrotic markers in atrial fibrillation. However, their roles and mechanisms in postinfarction fibrosis and ventricular remodeling remain unclear. This study found that the expression of LIMKs elevated in the border zone (BZ) in mice MI models. LIMK1/2 double knockout (DKO) restrained pathological remodeling and reduced mortality by suppressing myofibroblast activation. By using adeno-associated virus (AAV) with a periostin promoter to overexpress LIMK1 or LIMK2, this study found that myofibroblast-specific LIMK2 overexpression diminished these effects in DKO mice, while LIMK1 did not. LIMK2 kinase activity was critical for myofibroblast proliferation by using AAV overexpressing mutant LIMK2 lack of kinase activity. According to phosphoproteome analysis, functional rescue experiments, co-immunoprecipitation, and protein-protein docking, LIMK2 led to the phosphorylation of ß-catenin at Ser 552. LIMK2 nuclear translocation also played a role in myofibroblast proliferation after MI with the help of AAV overexpressing mutant LIMK2 without nuclear location signal. Chromatin immunoprecipitation sequencing identified that LIMK2 bound to Lrp6 promoter region in TGF-ß treated cardiac fibroblasts, positively regulating Wnt signaling via Wnt receptor internalization. This study demonstrated that LIMK2 promoted myofibroblast proliferation and adverse cardiac remodeling after MI, by enhancing phospho-ß-catenin (Ser552) and Lrp6 signaling. This suggested that LIMK2 could be a target for the treatment of postinfarction injury.

Prognostic value of fibrosis-5 index combined with C-reactive protein in patients with acute decompensated heart failure.

BACKGROUND: Fibrosis-5 (FIB-5) index is a marker of liver fibrosis and has been shown to have a good prognostic value for patients with acute heart failure (AHF), and C-reactive protein (CRP) has inflammatory properties and predicts adverse prognosis in patients with HF. However, the long-term prognostic value of FIB-5 index combined with CRP in patients with acute decompensated HF (ADHF) is yet unclear. METHODS: This retrospective study included 1153 patients with ADHF hospitalized from January 2018 to May 2022.The FIB-5 index was calculated as (albumin [g/L]×0.3 + PLT count [109/L]×0.05)-(ALP [U/L]×0.014 + AST to ALT ratio×6 + 14). Patients were stratified into the following four groups according to the median value of FIB-5 index (=-2.11) and CRP (= 4.5): Group 1 had a high FIB-5 index (FIB-5 index >-2.11) and a low CRP (CRP ≤ 4.5); Group 2 had both low FIB-5 index and low CRP; Group 3 had both high FIB-5 index and high CRP; Group 4 had a low FIB-5 index (FIB-5 index ≤-2.11) and a high CRP (CRP > 4.5). The endpoint was major adverse cardiac and cerebral events (MACCEs). Multivariate Cox analysis was used to evaluate the association of the combination with the development of MACCEs. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analysis were used to compare the accuracy of the combination with a single prognostic factor for predicting the risk of MACCEs. RESULTS: During the mean follow-up period of 584 ± 12 days, 488 (42.3%) patients had MACCEs. Kaplan-Meier analysis revealed that the incidence of MACCEs was different in the four groups (P < 0.001). After adjusting for the confounding factors, the hazard ratio (HR) for MACCEs in Group 4 (low FIB-5 index + high CRP) was the highest (Model 1, HR = 2.04, 95%CI 1.58-2.65, P < 0.001; Model 2, HR = 1.67, 95%CI 1.28-2.18, P < 0.001; Model 3, HR = 1.66, 95%CI: 1.27-2.17, P < 0.001). Additionally, the combination of FIB-5 index and CRP enabled more accurate prediction of MACCEs than FIB-5 index alone (NRI, 0.314,95%CI 0.199-0.429; P < 0.001; IDI, 0.023; 95% CI 0.015-0.032; P < 0.001). CONCLUSIONS: In patients with ADHF, the combination of the FIB-5 index and CRP may be useful in risk stratification in the future.

Hypertension-Driven Regulatory T-Cell Perturbations Accelerate Myocardial Ischemia-Reperfusion Injury.

BACKGROUND: Patients with a history of hypertension have elevated inflammation and a worse prognosis after acute myocardial infarction (AMI). Regulatory T cells (Tregs) are reported to lose their immunosuppressive capacity under pathological conditions. However, whether hypertension leads to Treg dysfunction, thus accelerating myocardial ischemia-reperfusion injury, is still unknown. METHODS: Studies were performed in hypertensive rats and mice with myocardial ischemia-reperfusion injury. The frequencies and phenotypes of Tregs were analyzed by flow cytometry and immunohistochemistry. Reconstruction Treg experiments were performed to evaluate the effect of Tregs on ischemia-reperfusion injury. Patients with AMI were enrolled to assess circulating Tregs, inflammatory cytokines, and cardiac function. RESULTS: In this study, we found that hypertension leads to proinflammatory Th1 (T helper 1 cell)-like Treg subsets with compromised suppressive capacity. Reconstruction Treg experiments identified that dysfunctional Tregs induced by hypertension play a pathogenic role in the progression of myocardial ischemia-reperfusion injury. In particular, we identified HDAC6 (histone deacetylase 6) as a central regulator in the perturbed Tregs. Clinical studies revealed that the hypertension-induced reduction in circulating Tregs strongly correlated with the higher occurrence rate of microvascular obstruction in AMI patients with hypertension. CONCLUSIONS: Our study provided promising clues to explain the poor prognosis of hypertensive AMI patients due to alterations in Tregs. Targeting disturbed Tregs may be a new strategy to treat AMI patients with hypertension.

Infusion of two-dose mesenchymal stem cells is more effective than a single dose in a dilated cardiomyopathy rat model by upregulating indoleamine 2,3-dioxygenase expression.

BACKGROUND AND AIMS: The therapeutic efficacy of single-dose mesenchymal stromal cell (MSC) therapy for heart failure (HF) remains inconsistent. This study aimed to investigate whether infusion with two-dose human umbilical cord MSC (hUCMSCs) could be therapeutically superior to single-dose therapy in a rat model of dilated cardiomyopathy (DCM) and explored the underlying mechanisms. METHODS: Male Sprague-Dawley rats were intraperitoneally injected with doxorubicin (DOX) to establish a DCM model and randomized to intravenously receive single-dose or two-dose hUCMSCs at an interval of 14 days. Their left ventricular (LV) systolic and diastolic functions were analyzed by echocardiography. The percentages of Th1, Th2, Th17, and Treg cells in the heart, spleen, lymph nodes, and peripheral blood and the levels of serum cytokines in individual rats were analyzed by flow cytometry and cytometric bead assay, respectively. The degrees of cardiac fibrosis and cardiomyocyte apoptosis were examined by histology. The importance of indoleamine 2,3-dioxygenase (IDO), an activator of Treg differentiation, in the therapeutic effect of hUCMSCs on inflammation and heart function of rats was determined after induction of IDO over-expression (IDO-OE) using IFN-γ (1 ng/ml) and TNF-α (10 ng/ml) stimulation or silencing (IDO-KD) using small interfering RNA (siRNA) technology. RESULTS: Compared with the single dose, two-dose hUCMSCs were more effective in improving LV performance, attenuating cardiac dilation, reducing cardiomyocyte apoptosis and cardiac fibrosis. Two-dose hUCMSC therapy significantly increased Treg number in the heart and peripheral blood, accompanied by increased cardiac IDO expression. Compared with the control hUCMSCs, IDO-OE hUCMSCs significantly enhanced Treg and Th2 cell responses and decreased systemic Th17 cell responses and Th1 cell numbers in the mediastinal lymph nodes. Treatment with IDO-OE hUCMSCs significantly improved LV remodeling and dysfunction. However, treatment with IDO-KD hUCMSCs had opposite effects in rats. CONCLUSIONS: Administration of two-dose hUCMSCs has better therapeutic effects than single-dose therapy for inhibiting myocardial inflammation to improve LV function in DCM rats. These effects are associated with upregulating IDO expression and its systemic anti-inflammatory activities.

Colchicine Ameliorates Dilated Cardiomyopathy Via SIRT2-Mediated Suppression of NLRP3 Inflammasome Activation.

Background Dilated cardiomyopathy remains a leading cause of heart failure worldwide. Immune inflammation response is recognized as a significant player in the progression of heart failure; however, immunomodulatory strategies remain a long-term challenge. Colchicine, a potent anti-inflammatory drug, has many benefits in ischemic cardiovascular events, but its role in nonischemic heart failure remains unclear. Methods and Results Doxorubicin administration was used to establish a murine dilated cardiomyopathy model, and colchicine or saline was orally given. At the end point, cardiac function and fibrosis were measured to investigate the effects of colchicine. Inflammatory cytokine levels, neutrophil recruitment, and NLRP3 (NOD-like receptor protein 3) inflammasome activation were detected to evaluate the inflammatory response. Furthermore, to examine the downstream target of colchicine, SIRT2 (Sirtuin 2) was pharmacologically inhibited in vitro; thus, changes in the NLRP3 inflammasome were detected by immunoblotting. These results showed that murine cardiac function was significantly improved and fibrosis was significantly alleviated after colchicine treatment. Moreover, the infiltration of neutrophils and the levels of inflammatory cytokines in the failing myocardium were both decreased by colchicine treatment. Mechanistically, colchicine upregulated the expression of SIRT2, leading to the inactivation of the NLRP3 inflammasome in an NLRP3 deacetylated manner. Conversely, the inhibition of SIRT2 attenuated the suppressive effect of colchicine on NLRP3 inflammasome activation. Conclusions This study indicated that colchicine could be a promising therapeutic candidate for dilated cardiomyopathy and other nonischemic heart failure associated with the inflammatory response.

Renal Denervation Attenuates Adverse Remodeling and Intramyocardial Inflammation in Acute Myocardial Infarction With Ischemia-Reperfusion Injury.

Background: Inhibition of sympathetic activity and renin-angiotensin system with renal denervation (RDN) was proved to be effective in managing refractory hypertension, and improving left ventricular (LV) performance in chronic heart failure. The inhibition of sustained sympathetic activation prevents or delays the development of cardiac fibrosis and dysfunction that occurs after myocardial infarction and ischemia-reperfusion (I/R) injury. The translational efficiency of RDN remains to be defined in preclinical animal studies. Objectives: This study investigated the therapeutic role of RDN in adverse remodeling and intramyocardial inflammation in myocardial ischemia-reperfusion (MI/R) injury. Methods: Herein, 15 minipigs were subjected to 90-min percutaneous occlusion of the left anterior descending artery followed by reperfusion. Eight animals received simultaneous RDN using catheter-based radiofrequency ablation (MI/R-RDN). Cardiac function and infarct volume were measured in vivo, followed by histological and biochemical analyses. Results: The infarct volume in I/R-RDN pigs reduced at 30 days postreperfusion, compared to I/R-Sham animals. The levels of catecholamine and cytokines in the serum, kidney cortex, the border, and infarcted regions of the heart were significantly reduced in I/R-RDN group. Moreover, the gene expression of collagen and the protein expression of adrenergic receptor beta 1 in heart were also decreased in I/R-RDN mice. Additionally, RDN therapy alleviated myocardial oxidative stress. Conclusion: RDN is an effective therapeutic strategy for counteracting postreperfusion myocardial injury and dysfunction, and the application of RDN holds promising prospects in clinical practice.

Percutaneous intravenous catheter forceps biopsy in right atrial mass: two case reports and literature review.

BACKGROUND: Primary malignant tumors of the heart are rare. Although preoperative histological diagnosis is difficult, it has paramount value in therapeutic strategy development and prognostic estimation. Herein, we reported 2 cases of intracardiac tumors. CASES PRESENTATION: Both patients presented to the hospital with heart-related symptoms. Echocardiography showed massive masses in the atrium and positron emission tomography-computed tomography (PET/CT) revealed hypermetabolism and invasiveness. One patient cannot take surgery due to extensive metastasis and poor condition. The other patient was primarily diagnosed with lymphoma, and surgery was not recommended. They successfully underwent intravenous atrial biopsy, and histological samples confirmed intimal sarcoma and diffuse large B cell lymphoma. Based on immunohistochemical and molecular assessments, targeted chemotherapy was administered, resulting in clinical and imaging remission at discharge. CONCLUSIONS: Percutaneous intravenous catheter biopsy as a safe invasive test provides an accurate pathological diagnosis after imaging evaluation, and offers a therapeutic direction. Nonmalignant masses and some chemo-radiosensitive malignant tumors in the atrium could have good prognosis after targeted therapy.