Impact of the completeness of revascularization and high bleeding risk status in acute coronary syndrome patients with multi-vessel disease: A retrospective analysis.

Objectives: To investigate the long-term mortality of acute coronary syndrome (ACS) patients with multivessel disease according to the level of completeness of revascularization (CR) and high-bleeding risk (HBR) status. Design Setting and Participants: This retrospective study collected the data of ACS patients with multivessel disease who underwent percutaneous coronary intervention between May 2018 and February 2019. Complete to reasonable revascularization (CR) was defined by the residual Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery score (RSS) of 0 to ≤8. The HBR was defined by the PRECISE-DAPT score ≥25. Main Outcome Measures: The all-cause death at 36 months according to the CR and HBR status. Results: A total of 209 patients with 743 lesions were included in the analysis. The median follow-up was 3.6 years. Patients with CR had lower event rates than ICR (4.5 vs. 11.5 per 100 patient-year, HR 0.39, 95% CI 0.22-0.70), p = 0.002). Similar observations were noted when compared between non-HBR and HBR (3.9 vs. 11.1 per 100 patient-year, HR 0.35, 95% CI 0.18-0.64, p < 0.001). Kaplan-Meier analysis revealed that all-cause death was highest among those in the ICR/HBR (40.5%) followed by ICR/non-HBR (28.6%), CR/non-HBR (28.3%) and the lowest among the CR/HBR group (7.1%), log-rank p = <0.001. No significant interaction was observed between the two factors regarding all-cause death (p = 0.10 for interaction). Conclusions: In ACS patients with MVD, the achievement of CR was associated with reducing mortality rates and consistency irrespective of the HBR status. (Trial Registration: TCTR20211222003).

Alterations of senescence-associated markers in patients with non-syndromic cleft lip and palate.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial anomalies. Abnormal Alu methylation in DNA of the pregnant mother may influence the abnormal development of the child. This study aimed to examine Alu methylation and cellular senescence in NSCL/P patients and their mothers as well as the correlation with the severity of NSCL/P. A total of 39 patients with NSCL/P and 33 mothers were enrolled. Of these patients, 6 were cleft lip only (CLO), 9 were cleft palate only (CPO), and 24 were cleft lip and palate (CLP). Alu methylation and senescence markers were determined in the white blood cells of NSCL/P patients, their mothers, and in the lip and palatal tissues of patients at the time of cheiloplasty and palatoplasty. Total Alu methylation was not significantly different between groups. However, a decrease in Alu hypermethylation, increased partial Alu methylation, RAGE, and p16 expression were shown in CLP, the most severe cleft type. Alu methylation in tissues did not differ between groups. In mothers, an increase in Alu methylation was observed only in the CLP. Therefore, the pathogenesis of NSCL/P may be related to Alu methylation of the mother promoting loss of Alu methylation and subsequently senescence in the children.

Mechanistic insights into Lipocalin-2 in ischemic stroke and hemorrhagic brain injury: Integrating animal and clinical studies.

Brain injuries, including strokes and traumatic brain injuries (TBI), are a major global health concern, contributing significantly to both mortality and long-term disability. Recent research has identified lipocalin-2 (LCN2), a glycoprotein secreted by various brain cells, as a key factor in influencing brain injury outcomes. Evidence from animal and clinical studies firmly establishes the pivotal role of LCN2 in driving the inflammatory responses triggered by damage to brain tissue. Furthermore, increased LCN2 promotes cellular differentiation, blood-brain barrier breakdown, and decreases cell viability. Interventions with LCN2 inhibitors attenuated brain injury through a reduction in the inflammation process and enhanced cellular viability. Potential mechanisms of LCN2 involve several pathways including the Janus kinase-2 (JAK2)-signal transducers and the transcription-3 (STAT3) signaling, hypoxia-inducible factor 1-alpha (HIF-1α)-LCN2-vascular endothelial growth factor alpha (VEGFα), and the PKR-like ER kinase (PERK) pathways. LCN2 itself interacts with diverse inflammatory cytokines in TBI and intracranial hemorrhage (ICH), resulting in disruption of the blood-brain barrier, increased programmed cell death, and an imbalance in iron homeostasis. Clinical studies have also shown that increased LCN2 level can act as a prognostic biomarker of outcomes following brain injuries. Therefore, this review aims to comprehensively evaluate the role and underlying mechanisms of LCN2 in brain injuries, including stroke and TBI, and explore potential therapeutic interventions targeting LCN2 in these conditions.

Cardiovascular toxicities by calcineurin inhibitors: Cellular mechanisms behind clinical manifestations.

Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in vitro and in vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR-377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial-dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin-independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.

Premature Ventricular Contraction-Induced Cardiomyopathy: Contemporary Evidence from Risk Stratification, Pathophysiology, and Management.

Premature ventricular complexes (PVCs) are commonly encountered problems in clinical settings. The range of symptoms can be from asymptomatic to palpitations, fatigue, or heart failure symptoms. A higher burden of PVCs is a risk factor for development of PVC-induced cardiomyopathy (PIC). Rhythm evaluation by 12-lead ECG and an ambulatory monitoring device are essential. Currently, several imaging modalities, such as echocardiography and cardiac magnetic resonance imaging, are utilized to evaluate the underlying structure that may be related to PIC. Beta blockers and antiarrhythmic drugs are typically part of the initial management strategy. If these fail, catheter ablation of PVCs is typically the next step. The purpose of this article is to summarize the current evidence/knowledge about PIC.

An Increase in Vascular Stiffness Is Positively Associated With Mitochondrial Bioenergetics Impairment of Peripheral Blood Mononuclear Cells in the Older Adults.

The cardio-ankle vascular index (CAVI) is a noninvasive parameter reflecting vascular stiffness. CAVI correlates with the burden of atherosclerosis and future cardiovascular events. Mitochondria of peripheral blood mononuclear cells (PBMCs) have been identified as a noninvasive source for assessing systemic mitochondrial bioenergetics. This study aimed to investigate the relationship between CAVI values and mitochondrial bioenergetics of PBMCs in the older adults.. This cross-sectional study enrolled participants from the Electricity Generating Authority of Thailand between 2017 and 2018. A total of 1 640 participants with an ankle-brachial index greater than 0.9 were included in this study. All participants were stratified into 3 groups based on their CAVI values as high (CAVI ≥ 9), moderate (9 > CAVI ≥ 8), and low (CAVI < 8), in which each group comprised 702, 507, and 431 participants, respectively. The extracellular flux analyzer was used to measure mitochondrial respiration of isolated PBMCs. The mean age of the participants was 67.9 years, and 69.6% of them were male. After adjusted with potential confounders including age, sex, smoking status, body mass index, diabetes, dyslipidemia, hypertension, and creatinine clearance, participants with high CAVI values were independently associated with impaired mitochondrial bioenergetics, including decreased basal respiration, maximal respiration, and spare respiratory capacity, as well as increased mitochondrial reactive oxygen species. This study demonstrated that CAVI measurement reflects the underlying impairment of cellular mitochondrial bioenergetics in PBMCs. Further longitudinal studies are necessary to establish both a causal relationship between CAVI measurement and underlying cellular dysfunction.

Current evidence regarding the cellular mechanisms associated with cancer progression due to cardiovascular diseases.

Several large cohort studies in cardiovascular disease (CVD) patients have shown an increased incidence of cancer. Previous studies in a myocardial infarction (MI) mouse model reported increased colon, breast, and lung cancer growth. The potential mechanisms could be due to secreted cardiokines and micro-RNAs from pathological hearts and immune cell reprogramming. A study in a MI-induced heart failure (HF) mouse demonstrated an increase in cardiac expression of SerpinA3, resulting in an enhanced proliferation of colon cancer cells. In MI-induced HF mice with lung cancer, the attenuation of tumor sensitivity to ferroptosis via the secretion of miR-22-3p from cardiomyocytes was demonstrated. In MI mice with breast cancer, immune cell reprogramming toward the immunosuppressive state was shown. However, a study in mice with renal cancer reported no impact of MI on tumor growth. In addition to MI, cardiac hypertrophy was shown to promote the growth of breast and lung cancer. The cardiokine potentially involved, periostin, was increased in the cardiac tissue and serum of a cardiac hypertrophy model, and was reported to increase breast cancer cell proliferation. Since the concept that CVD could influence the initiation and progression of several types of cancer is quite new and challenging regarding future therapeutic and preventive strategies, further studies are needed to elucidate the potential underlying mechanisms which will enable more effective risk stratification and development of potential therapeutic interventions to prevent cancer in CVD patients.

Antithrombotic therapy in antiphospholipid syndrome with arterial thrombosis: a systematic review and network meta-analysis.

Introduction: The optimal secondary thromboprophylactic strategies for patients with antiphospholipid syndrome (APS) and arterial thrombosis remain controversial. This study aimed to evaluate the comparative efficacy and safety of various antithrombotic strategies in APS with arterial thrombosis. Methods: A comprehensive literature search was conducted using OVID MEDLINE, EMBASE, Web of Science, and the Cochrane Controlled Register of Trials (CENTRAL) from inception until 30 September 2022, with no language restrictions. The inclusion criteria for eligible studies were as follows: inclusion of APS patients with arterial thrombosis, treatment with either antiplatelet agents, warfarin, direct oral anticoagulants (DOACs), or a combination of these therapies, and reporting of recurrent thrombotic events. Results: We conducted a frequentist random-effects network meta-analysis (NMA) involving 13 studies with a total of 719 participants, comprising six randomized and seven non-randomized studies. In comparison to single antiplatelet therapy (SAPT), the combined use of antiplatelet and warfarin demonstrated a significant reduction in the risk of recurrent overall thrombosis, with a risk ratio (RR) of 0.41 (95% CI 0.20 to 0.85). Dual antiplatelet therapy (DAPT) showed a lower risk of recurrent arterial thrombosis compared to SAPT although the difference did not reach statistical significance, with an RR of 0.29 (95% CI 0.08 to 1.07). DOAC was associated with a significant increase in the risk of recurrent arterial thrombosis, with an RR of 4.06 (95% CI 1.33 to 12.40) when compared to SAPT. There was no significant difference in major bleeding among various antithrombotic strategies. Discussion: Based on this NMA, the combination of warfarin and antiplatelet therapy appears to be an effective approach in preventing recurrent overall thrombosis in APS patients with a history of arterial thrombosis. While DAPT may also show promise in preventing recurrent arterial thrombosis, further studies are needed to confirm its efficacy. Conversely, the use of DOACs was found to significantly increase the risk of recurrent arterial thrombosis.

Potential Roles of Melatonin in Doxorubicin-Induced Cardiotoxicity: From Cellular Mechanisms to Clinical Application.

Doxorubicin is a potent chemotherapeutic drug; however, its clinical application has been limited due to its cardiotoxicity. One of the major mechanisms of doxorubicin-induced cardiotoxicity is the induction of oxidative stress. Evidence from in vitro and in vivo studies demonstrates that melatonin attenuated the increase in ROS production and lipid peroxidation from doxorubicin. Melatonin has been shown to exert protective effects on mitochondria damaged by doxorubicin via attenuating the depolarization of the mitochondrial membrane, restoring ATP production, and maintaining mitochondrial biogenesis. Doxorubicin increased mitochondrial fragmentation which impaired mitochondrial function; however, these adverse effects were reversed by melatonin. Melatonin also modulated cell death pathways by suppressing apoptotic and ferroptotic cell death caused by doxorubicin. These beneficial effects of melatonin could be responsible for the attenuation of changes in ECG, left ventricular dysfunction, and hemodynamic deterioration caused by doxorubicin. Despite these potential benefits, clinical evidence regarding the impact of melatonin in reducing cardiotoxicity induced by doxorubicin is still limited. Further clinical studies are justified to evaluate the efficacy of melatonin in protecting against doxorubicin-induced cardiotoxicity. This valuable information can be used to warrant the use of melatonin in a clinical setting under this condition.

Potential roles of sodium-glucose co-transporter 2 inhibitors in attenuating cardiac arrhythmias in diabetes and heart failure.

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are antidiabetic drugs that have been shown to exert cardiovascular benefits. Their benefits including a reduction of cardiovascular events and worsening heart failure have been extended to nondiabetic patients with high-risk. Although both heart failure and diabetes are known to increase risk of cardiac arrhythmias, the effects of SGLT-2 inhibitors on arrhythmia reduction and their underlying mechanisms are still not fully understood. This review aims to summarize the current available evidence ranging from basic research to clinical reports regarding the potential benefits of SGLT-2 inhibitors against cardiac arrhythmias. Previous in vitro and in vivo studies using various models including heart failure and diabetes are comprehensively summarized to examine the evidence of how SGLT-2 inhibitors affect cardiac action potential, cellular ion currents, calcium ion homeostasis, and cardiac mitochondrial function. Clinical reports investigating the association between SGLT-2 inhibitors and arrhythmias including atrial fibrillation and ventricular arrhythmias are also comprehensively summarized. Valuable information obtained from this review can be used to encourage further clinical investigations to warrant the potential use of SGLT-2 inhibitors against cardiac arrhythmias in both diabetic and heart failure settings.

A Rare Case of Central Nervous System Vasculitis in a Patient with Perinuclear Antineutrophil Cytoplasmic Antibodies-associated Interstitial Lung Disease.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic necrotizing inflammation of the small vessels. Central nervous system (CNS) ANCA-associated vasculitis is a rare manifestation of AAV. Three mechanisms of AAV affecting the CNS have been reported which include contiguous granulomatous invasion from nasal and paranasal sinuses, remote granulomatous lesions, and vasculitis of small vessels. Chronic hypertrophic pachymeningitis (CHP) is the meningeal-site involvement in AAV caused by granulomatous inflammation in the dura mater. We present a case of pachymeningitis manifested with slowly progressive cognitive dysfunction, leptomeningeal enhancement on MRI, and necrotic vessels with surrounding inflammation on biopsy. This case represents a rare development of subsequent CNS AAV in a patient with ANCA-associated interstitial lung disease treated with rituximab with a resolution of leptomeningeal enhancement on a follow-up magnetic resonance imaging (MRI).

Fragmented QRS as a predictor of in-hospital life-threatening arrhythmic complications in ST-elevation myocardial infarction patients.

BACKGROUND: Fragmented QRS (fQRS) complex is an electrocardiographic pattern that reflects the inhomogeneity of ventricular depolarization. The aims of this study were to determine the prognostic significance of fQRS for predicting in-hospital life-threatening arrhythmic complications in ST-elevation myocardial infarction (STEMI) patients, and to identify the most appropriate duration of cardiac rhythm monitoring in STEMI patients with fQRS. METHODS: Patients diagnosed with and treated for STEMI at Siriraj Hospital (Bangkok, Thailand) during 2009-2012 were enrolled. Patients were divided according to fQRS status (having or not having fQRS) at hospital admission. The primary outcome was in-hospital life-threatening arrhythmic events, including sustained ventricular tachycardia and ventricular fibrillation. Time to last life-threatening arrhythmic event from hospital admission was recorded. RESULTS: Of the 452 patients that were included, 96 patients (21.2%) had fQRS. There were significantly more life-threatening arrhythmic events in the fQRS group than in the non-fQRS group (22.9% vs. 4.5%, respectively; p < 0.001). Median (IQR) time to last life-threatening arrhythmic event from hospital admission was significantly longer in fQRS than in non-fQRS (6.58 hr [3.08-39.34] vs. 2.59 hr [1.75-5.75], respectively; p = 0.047). Multivariate analysis identified fQRS as an independent predictor of in-hospital life-threatening arrhythmic events (OR: 4.162, 95% CI: 1.669-10.384; p = 0.002). CONCLUSIONS: The presence of fQRS complex on admission ECG was found to be an independent predictor of in-hospital life-threatening arrhythmic events in STEMI patients. Since the time to last life-threatening arrhythmic event from admission was longer in fQRS than in non-fQRS, cardiac rhythm monitoring longer than 24-48 hr may be needed in patients with fQRS.