Cardiovascular Drugs and Therapy最新文献

Background: Cardiac fibroblasts (CFs) are numerically a highly abundant cell type in the heart and are responsible for the homeostasis of the extracellular matrix (ECM) in the myocardium under normal conditions. Upon cardiac stress, these cells become activated and transdifferentiate into myofibroblasts (MyCFs), which are characterized by their increased capacity to proliferate, migrate, and secrete ECM components and bioactive molecules. The trans-differentiation of CFs is induced by several factors like angiotensin II (Ang II) and transforming growth factor-ß (TGF-ß and is crucial in cardiac remodeling. In recent years, signal mechanisms playing a role in MyCFs behavior have been intensively investigated, including the role of the universal second messenger calcium (Ca²⁺).

Aims and scope: Here, we review the current knowledge on Ca²⁺ handling and Ca²⁺-dependent signal transduction in cardiac (myo)fibroblasts, with a focus on the mechanisms leading to intracellular Ca²⁺ release and Ca²⁺ entry from the extracellular space, which is involved in the generation of Ca²⁺ transients and regulation of Ca²⁺ oscillation. Moreover, the activation of Ca²⁺-induced signal transduction involving different kinases and the phosphatase calcineurin in CFs is described.

Purpose: Totally thoracoscopic and beating-heart techniques used in tricuspid valve surgery (TTC-TVS) show favorable outcomes. Transcatheter tricuspid valve replacement (TTVR) is an increasingly utilized alternative for patients with tricuspid regurgitation (TR) at high surgical risk. The purpose of this study was to compare TTVR with TTC-TVS to examine the outcomes of these two different management protocols for patients with symptomatic severe TR.

Methods: A total of 116 patients with symptomatic severe TR were retrospectively collected and divided into the TTVR (n = 38) and the TTC-TVS (n = 78) groups. The primary end points included 2-year all-cause mortality and the combined endpoint (all-cause mortality and hospitalizations for heart failure).

Results: At a median follow-up of 630 (IQR 450-720) days, the similar freedom from 2-year all-cause mortality (85.2% vs. 70.8%; log-rank P = 0.13) and different freedom from combined endpoint (75.3% vs. 49.8%; log-rank P = 0.0049) were followed in TTVR and TTC-TVS. After stratification by TRI-SCORE, TTVR subgroups showed significant difference in combined endpoint, and both also showed significant difference compared to the corresponding TTC-TVS subgroups (all log-rank P < 0.05). In multivariate Cox regression analysis, TRI-SCORE ≥ 6 was independently correlated with all-cause mortality (HR 3.913, 95% CI 1.481-10.337; P = 0.006) and combined endpoint (HR 4.070, 95% CI 1.924-8.608; P < 0.001).

Conclusions: TTVR may offer greater benefit compared to TTC-TVS for sicker patients with severe TR. However, this observation should be interpreted within a specific clinical context emphasizing the importance of early intervention.

Purpose: Physicians can be supported by electronic clinical decision support systems (CDSS) for drug-drug interaction (DDI) management of DDIs between direct oral anticoagulants (DOACs) and CYP3 A4/P-glycoprotein (P-gp) inhibitors and inducers, to prevent adverse drug events (ADEs).

Methods: A retrospective cohort study was performed studying DDI alerts for DOAC-CYP3 A4/P-gp influencing drug combination prescriptions in patients admitted to a tertiary care hospital. Patient-, DDI-, and ADE-related data were analyzed to explore CDSS performance and real-world DDI management. A multidisciplinary panel conducted an ADE analysis using the Drug Interaction Probability Scale.

Results: Out of 15,201 triggered CDS alerts, 166 individual alerts were included. Primary indication for DOAC therapy was atrial fibrillation (86.1%). The most involved DOAC was dabigatran (63%). DDI exposure was median 3 days (IQR = 2-7 days). CYP3 A4/P-gp inhibitor DDIs were most prevalent (n = 121), with amiodarone being most prevalently prescribed (71%). Inducers were mainly antiepileptic drugs (n = 31). Thirty-four CDS alerts (20%) were actively shown to the physician upon prescribing (acceptance rate 50%). Eighteen ADEs were identified (11%, 14 bleeding; 4 thromboembolic events), 15 having a possible and 3 a probable probability of being DDI associated.

Conclusion: Despite a low number of observed, potentially associated ADEs, CDSS for DDI management aids physicians to optimize DOAC treatment as the described DDIs can cause significant patient harm. Increased ADE monitoring and larger real-world studies are needed to refine CDS tools and further optimize patient safety.

Purpose: There is an urgent unmet need for new pharmacologic approaches that promote re-muscularization and repair following myocardial infarction (MI). We previously reported that genetic depletion of the acetyltransferase Tip60 after MI in a mouse model activates the CM cell-cycle, reduces scarring, and restores cardiac function, and that these beneficial effects are mimicked by the Tip60-selective inhibitor TH1834. Here, we investigated whether the FDA-approved anti-microbial agent pentamidine, a Tip60 inhibitor from which TH1834 is derived, also protects from the damaging effects of MI.

Methods: Adult (10-14 weeks old) C57Bl/6 mice were subjected to permanent left coronary artery ligation to induce MI. Subsequently, echocardiography, electrocardiography, cardiac staining, and molecular analyses were performed to monitor the effects of treatment with pentamidine on cardiac injury and function.

Results: We report that transient systemic administration of pentamidine on days 3-16 post-MI at a daily dose of 3 mg/kg efficiently improved cardiac function for up to ten months. This was accompanied by improved survival, diminished scarring, and increased activation of cell-cycle markers in CMs located in the infarct border zone in the absence of hypertrophy. Histological assessments suggested that post-MI treatment with pentamidine reduced site-specific acetylation of the minor histone variant H2A.Z at lysines K4 and K7 in CMs, indicative of the dedifferentiation process which must occur prior to CM proliferation. Treating mice with pentamidine post-MI produced no prominent electrophysiological changes.

Conclusions: These findings support the translational potential of pentamidine for treatment of MI, and provide evidence that functional improvement is mediated, in part, by CM renewal due to inhibition of the acetyltransferase activity of Tip60.

Background: Neutrophil extracellular traps (NETs) play a crucial role in the pathogenesis of acute myocardial infarction (AMI), but the role of high-mobility group box 1 (HMGB1), a key target of the cell migration family, remains unclear.

Methods: This study investigated the HMGB1-CXCR4/CXCL12 -NETs pathway in ST-segment elevation myocardial infarction (STEMI) patients and a murine myocardial infarction (MI) model, with a focus on mechanisms associated with injury and aging.

Results: Peripheral blood analysis in 29 STEMI patients revealed elevated HMGB1 and myeloperoxidase (MPO) levels compared to controls. In C57BL/6J mice subjected to permanent left anterior descending (LAD) ligation, the CXCR4/CXCL12 axis was significantly upregulated in infarcted hearts, correlating with impaired ventricular function. Deoxyribonuclease (DNase) I or glycyrrhizic acid (a HMGB1 inhibitor) attenuated NETs formation and CXCR4/CXCL12 activation. Histological, echocardiographic, and transcriptomic analyses revealed that HMGB1 promotes NETs formation, exacerbating cardiac inflammation and fibrosis. Flow cytometry of murine blood demonstrated altered CD62L/CD11b expression, suggesting age-like immunophenotypic shifts in post-MI inflammation.

Conclusion: These findings delineate a pivotal HMGB1-CXCR4/CXCL12-NETs axis in AMI pathology, driving cardiac injury through inflammation and fibrosis, with implications for cellular aging/senescence. Targeting this pathway presents a promising therapeutic strategy for mitigating ischemia-related damage.