Treatment-related adverse events of immune checkpoint inhibitors in clinical trials: a systematic review and meta-analysis.

Aim: This study comprehensively assesses the incidence and profiles of treatment-related adverse events (trAEs) of immune checkpoint inhibitor (ICI)-based therapies across cancer at various sites. Methods: We systematically searched the PubMed, Embase, and Cochrane databases for trials investigating ICI-based therapies published between their inception and August 2023. Results: In total, 147 studies involving 45,855 patients met the inclusion criteria. Among them, patients treated with ICIs reported 39.8% and 14.9% of all-grade and grade ≥3 immune-related adverse events (irAEs), respectively. The most common all-grade irAEs were dermatological and gastrointestinal issues, diarrhea, and pruritus, whereas patients who received ICIs showed most common grade ≥3 irAEs, including gastrointestinal events, diarrhea, increased aspartate aminotransferase and alanine transaminase levels, and hepatic and dermatological events. The overall trAE incidence in patients treated with ICIs was 83.2% for all-grade trAEs and 38.2% for grade ≥3 trAEs. TrAE incidence was highest for patients treated with cytotoxic T lymphocyte antigen-4 inhibitors for all-grade and grade ≥3 trAEs, with incidences of 86.4% and 39.2%, respectively. ICIs combined with targeted therapy showed the highest all-grade and grade ≥3 trAEs, with incidences of 96.3% and 59.4%, respectively. The most common all-grade trAEs were anemia, decrease in white blood cell count, decrease in neutrophil count, nausea, fatigue, diarrhea, and alopecia; patients who received ICIs presented relatively high incidences of grade ≥3 trAEs. Conclusion: This study provided comprehensive data regarding irAEs and trAEs in patients receiving ICIs. These results should be applied in clinical practice to provide an essential reference for safety profiles of ICIs. Systematic review registration: INPLASY platform, identifier INPLASY202380119.

Significance of QRS scoring system in left ventricular function recovery after acute myocardial infarction.

AIMS: The Selvester scoring system has been derived from ECG parameters for estimating infarct size. However, there is still a lack of evidence for Selvester score as an alternative to cardiac magnetic resonance (CMR) myocardial injury makers for risk stratification and prediction of left ventricular function (LVF) recovery among patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: This multicentre observational study enrolled 328 STEMI patients (88.4% men, 57.3 ± 10.6 years of age) undergoing CMR examination 1 week post-reperfusion therapy. Patients with baseline left ventricular ejection fraction (LVEF) < 50% underwent a follow-up CMR 6 months later, categorized into baseline normal LVF (ejection fraction [EF] ≥ 50% at baseline, n = 155); recovered LVF (EF < 50% at baseline and ≥50% after 6 months, n = 69); and reduced LVF (EF < 50% at baseline and after 6 months, n = 104). The median follow-up was 4 (3-4) years for all patients, with 61 patients experiencing major adverse cardiovascular event (MACEs). Patients with reduced LVF had a higher risk of MACEs than those with baseline normal LVF (P = 0.01), while the recovered LVF group had no significant difference (P > 0.05). A Selvester score >10 doubled the risk of MACEs in patients with systolic dysfunction (1.91 [1.02 to 3.58], P = 0.04). Additionally, Selvester score, baseline LVEF, transmural infarction, and peak CK-MB were independent predictors of recovered LVF, with Selvester score providing incremental predictive value to peak CK-MB in predicting recovered LVF (∆AUC = 0.07, P < 0.05). CONCLUSIONS: The Selvester score improves risk stratification among STEMI patients beyond LVEF and provide independent and incremental information to clinical parameters in predicting recovered LVF.

Non-Contrast Cine Cardiac Magnetic Resonance Derived-Radiomics for the Prediction of Left Ventricular Adverse Remodeling in Patients With ST-Segment Elevation Myocardial Infarction.

OBJECTIVE: To investigate the predictive value of radiomics features based on cardiac magnetic resonance (CMR) cine images for left ventricular adverse remodeling (LVAR) after acute ST-segment elevation myocardial infarction (STEMI). MATERIALS AND METHODS: We conducted a retrospective, single-center, cohort study involving 244 patients (random-split into 170 and 74 for training and testing, respectively) having an acute STEMI (88.5% males, 57.0 ± 10.3 years of age) who underwent CMR examination at one week and six months after percutaneous coronary intervention. LVAR was defined as a 20% increase in left ventricular end-diastolic volume 6 months after acute STEMI. Radiomics features were extracted from the one-week CMR cine images using the least absolute shrinkage and selection operator regression (LASSO) analysis. The predictive performance of the selected features was evaluated using receiver operating characteristic curve analysis and the area under the curve (AUC). RESULTS: Nine radiomics features with non-zero coefficients were included in the LASSO regression of the radiomics score (RAD score). Infarct size (odds ratio [OR]: 1.04 (1.00-1.07); P = 0.031) and RAD score (OR: 3.43 (2.34-5.28); P < 0.001) were independent predictors of LVAR. The RAD score predicted LVAR, with an AUC (95% confidence interval [CI]) of 0.82 (0.75-0.89) in the training set and 0.75 (0.62-0.89) in the testing set. Combining the RAD score with infarct size yielded favorable performance in predicting LVAR, with an AUC of 0.84 (0.72-0.95). Moreover, the addition of the RAD score to the left ventricular ejection fraction (LVEF) significantly increased the AUC from 0.68 (0.52-0.84) to 0.82 (0.70-0.93) (P = 0.018), which was also comparable to the prediction provided by the combined microvascular obstruction, infarct size, and LVEF with an AUC of 0.79 (0.65-0.94) (P = 0.727). CONCLUSION: Radiomics analysis using non-contrast cine CMR can predict LVAR after STEMI independently and incrementally to LVEF and may provide an alternative to traditional CMR parameters.

Cardiac magnetic resonance for the early prediction of reverse left ventricular remodeling in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: To evaluate the changes in cardiac magnetic resonance (CMR) characteristics and investigate the predictors of reverse left ventricular remodeling (r-LVR) in ST-segment elevation myocardial infarction (STEMI) patients. MATERIALS AND METHODS: Eighty-six STEMI patients (median 56 years) were retrospectively studied. The patients were divided into r-LVR and without r-LVR groups. CMR analysis included LV volume, infarct characteristics, and global and regional myocardial function. The strain and displacement were assessed by CMR-feature tracking. The predictors of r-LVR were analyzed by the logistic regression method. RESULTS: There were 37 patients in the r-LVR group and 49 patients in the without r-LVR group. At initial CMR, there was no difference in LV volume and global cardiac function between the two groups. However, the infarct zone radial and longitudinal displacements were higher in the r-LVR group (p < 0.05, respectively). At the second CMR, the r-LVR group showed higher LVEF, lower LV volume, and total enhanced mass (all p < 0.05). The infarct zone radial and circumferential strains and radial displacement were higher in the r-LVR group (all p < 0.05). The r-LVR group had better recovery of myocardial injury and function. Of note, microvascular obstruction (MVO) mass (odds ratio: 0.779 (0.613-0.989), p = 0.041) and infarct zone peak longitudinal displacement (PLD) (odds ratio: 1.448 (1.044-2.008), p = 0.026) were independent predictors of r-LVR. CONCLUSIONS: At initial CMR, there were no differences in global cardiac function between the two groups, but infarct zone displacements were higher in the r-LVR group. The r-LVR group had better recovery of cardiac function. In addition, MVO mass and infarct zone PLD were independent predictors of r-LVR. CLINICAL RELEVANCE STATEMENT: Our study assessed changes in cardiac structure, function, and tissue characteristics after STEMI by CMR, investigated the best predictors of r-LVR in STEMI patients, and laid the foundation for the development of new parameter-guided treatment strategies for STEMI patients. KEY POINTS: • At initial CMR, the reverse left ventricular remodeling (r-LVR) group had less myocardial damage and higher infarct zone displacement, but there were no differences in global function between the two groups. • Both groups showed recovery of myocardial injury and cardiac function over time, but the r-LVR group had less enhanced mass and better cardiac function compared to the without r-LVR group at the second CMR. • Microvascular obstruction mass and infarct zone peak longitudinal displacement by cardiac magnetic resonance feature-tracking were significant predictors of r-LVR in STEMI patients.

Effect of Vigileo/FloTrac System-Guided Aggressive Hydration in Acute Myocardial Infarction Patients to Prevent Contrast-Induced Nephropathy After Urgent Percutaneous Coronary Intervention.

Tailored hydration strategies appear to provide an effective solution for preventing contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI). The Vigileo/FloTrac system could predict the patients' fluid responsiveness and tolerance to hydration. This prospective multicenter, randomized controlled, open-label study evaluated the efficacy of aggressive hydration guided by the Vigileo/FloTrac system for CIN prevention in patients with acute myocardial infarction (AMI). This trial enrolled patients with AMI undergoing urgent PCI, and these patients were randomized (1:1) to receive either aggressive hydration guided by Vigileo/FloTrac system (intervention group) or general hydration (control group). Patients with AMI in the intervention group received a loading dose of saline, and the hydration speed was adjusted according to the change of Vigileo/FloTrac index. The primary end point is CIN, which was defined as a >25% or >0.5 mg/100 ml increase in serum creatinine compared with baseline during the first 72 hours after urgent PCI. This trial was registered in ClinicalTrials.gov (NCT04382313). A total of 344 patients with AMI were enrolled and randomized in our trial, and the baseline characteristics, including risk factors of CIN, of the Vigileo/FloTrac-guided hydration group (n = 173) and control group (n = 171) were well balanced (all p >0.05). The total hydration volume in Vigileo/FloTrac-guided hydration group was significantly much more than control group (1,910 ± 600 vs 440 ± 90 ml, p <0.001). The incidence of CIN in the Vigileo/FloTrac-guided hydration group was significantly decreased than that in the control group (12.1% [21/173] vs 22.2% [38/171], p = 0.013). There was not significantly different in the incidence of acute heart failure after PCI (9.2% [16/173] vs 7.6% [13/171], p = 0.583). The incidence of main adverse cardiovascular events in the Vigileo/FloTrac-guided hydration group was lower than that in the control group but without statistically difference (30 events [17.3%] vs 38 events [22.2%], p = 0.256). In conclusion, Vigileo/FloTrac system-guided aggressive hydration could effectively decrease the risk of CIN for patients with AMI undergoing urgent PCI and avoid attack of acute heart failure at the same time.

Early Trimetazidine Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST Segment Elevation Myocardial Infarction Reduces Myocardial Infarction Size.

PURPOSE: Trimetazidine, a metabolic agent with anti-ischemic effects, was reported to reduce reperfusion injury in animal models. In this randomized double-blind placebo-controlled trial, we investigated the effects of trimetazidine on the reduction of infarction size in patients undergoing revascularization for ST segment elevation myocardial infarction (STEMI). METHODS: Patients with STEMI randomly received trimetazidine (n = 87) or placebo (n = 86) before primary percutaneous coronary intervention (PCI), and subsequently received oral trimetazidine or placebo for 12 months after reperfusion. The predefined primary endpoint was infarction size on cardiac magnetic resonance (CMR) performed at 7 days after primary PCI. The trial was registered on www. CLINICALTRIALS: gov (registration number: NCT02826616). RESULTS: The clinical characteristics of the patients in both groups were well-matched at baseline. At 7 days after primary PCI, the percentage and absolute infarction size in the trimetazidine group were significantly smaller than those in the control group (22% ± 12% [n = 74] vs. 27% ± 13% [n = 74], p = 0.011 and 28 ± 18 g [n = 74] vs. 35 ± 19 g [n = 74], p = 0.022, respectively), and the incidence of myocardial microvascular obstruction (MVO) measured by CMR was significantly reduced in the trimetazidine group (29.7% [22/74] vs. 52.7% [39/74], p = 0.005). The myocardial salvage index (MSI) measured by CMR was significantly higher in the trimetazidine group (48% ± 20% vs. 39% ± 20%, p = 0.008). The incidence of readmission due to aggravated heart failure did not differ significantly between the trimetazidine group and the control group (8.0% vs. 14.0%, p = 0.234). CONCLUSIONS: In patients with STEMI undergoing primary PCI, early trimetazidine before reperfusion reduced myocardial infarction size and MVO, and improved MSI.

Machine learning-based prediction of infarct size in patients with ST-segment elevation myocardial infarction: A multi-center study.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) is the gold standard for measuring infarct size (IS). However, this method is expensive and requires a specially trained technologist to administer. We therefore sought to quantify the IS using machine learning (ML) based analysis on clinical features, which is a convenient and cost-effective alternative to CMR. METHODS AND RESULTS: We included 315 STEMI patients with CMR examined one week after morbidity in final analysis. After feature selection by XGBoost on fifty-six clinical features, we used five ML algorithms (random forest (RF), light gradient boosting decision machine, deep forest, deep neural network, and stacking) to predict IS with 26 (selected by XGBoost with information gain greater than average level of 56 features) and the top 10 features, during which 5-fold cross-validation were used to train and optimize models. We then evaluated the value of actual and ML-IS for the prediction of adverse remodeling. Our finding indicates that MLs outperform the linear regression in predicting IS. Specifically, the RF with five predictors identified by the exhaustive method performed better than linear regression (LR) with 10 indicators (R2 of RF: 0.8; LR: 0). The finding also shows that both actual and ML-IS were independently associated with adverse remodeling. ML-IS ≥ 21% was associated with a twofold increase in the risk of LV remodeling (P < 0.01) compared with patients with reference IS (1st tertile). CONCLUSION: ML-based methods can predict IS with widely available clinical features, which provide a proof-of-concept tool to quantitatively assess acute phase IS.

Effects of Nicorandil Administration on Infarct Size in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: The CHANGE Trial.

Background Nicorandil was reported to improve microvascular dysfunction and reduce reperfusion injury when administered before primary percutaneous coronary intervention. In this multicenter, prospective, randomized, double-blind clinical trial (CHANGE [Effects of Nicorandil Administration on Infarct Size in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention]), we investigated the effects of nicorandil administration on infarct size in patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention. Methods and Results A total of 238 patients with ST-segment-elevation myocardial infarction were randomized to receive intravenous nicorandil (n=120) or placebo (n=118) before reperfusion. Patients in the nicorandil group received a 6-mg intravenous bolus of nicorandil followed by continuous infusion at a rate of 6 mg/h. Patients in the placebo group received the same dose of placebo. The predefined primary end point was infarct size on cardiac magnetic resonance (CMR) imaging performed at 5 to 7 days and 6 months after reperfusion. CMR imaging was performed in 201 patients (84%). Infarct size on CMR imaging at 5 to 7 days after reperfusion was significantly smaller in the nicorandil group compared with the placebo (control) group (26.5±17.1 g versus 32.4±19.3 g; P=0.022), and the effect remained significant on long-term CMR imaging at 6 months after reperfusion (19.5±14.4 g versus 25.7±15.4 g; P=0.008). The incidence of no-reflow/slow-flow phenomenon during primary percutaneous coronary intervention was much lower in the nicorandil group (9.2% [11/120] versus 26.3% [31/118]; P=0.001), and thus, complete ST-segment resolution was more frequently observed in the nicorandil group (90.8% [109/120] versus 78.0% [92/118]; P=0.006). Left ventricular ejection fraction on CMR imaging was significantly higher in the nicorandil group than in the placebo group at both 5 to 7 days (47.0±10.2% versus 43.3±10.0%; P=0.011) and 6 months (50.1±9.7% versus 46.4±8.5%; P=0.009) after reperfusion. Conclusions In the present trial, administration of nicorandil before primary percutaneous coronary intervention led to improved myocardial perfusion grade, increased left ventricular ejection fraction, and reduced myocardial infarct size in patients with ST-segment-elevation myocardial infarction. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03445728.

Impact of apical and mid-ventricular transmural infarcts in patients with acute myocardial infarction determined by using late gadolinium enhancement combined with feature tracking magnetic resonance.

Background: To analyze the relationship between left ventricular (LV) myocardial strain and transmurality of myocardial infarction at three circular sections (basal, mid-ventricular, apical) by a combined analysis of cardiac magnetic resonance feature tracking (CMR-FT) and late gadolinium enhancement (LGE) information in a cohort of ST-elevation acute myocardial infarction (STEMI) patients after primary percutaneous coronary intervention (PPCI). Methods: In all, 136 patients with STEMI who underwent PPCI within 12 hours of symptom onset were included. CMR-FT and LGE-MRI were performed 5±2 days after PCI for measuring regional and global myocardial strain indexes and transmural extent. Multivariate regression analysis and Kaplan-Meier survival analysis were performed. Results: Regional radial and circumferential strain decreased with increasing transmurality of myocardial infarction irrespective of basal, mid-ventricular, or apical segments. Segmental longitudinal strain was significantly decreased in the transmural infarcted segments only at the apical and mid-ventricular levels. A significant correlation was found between the number of transmural infarcts and global strain parameters in the apical and mid-ventricular portions. Transmural infarcted segments in apical + mid-ventricular portions >2 was related to an increased risk of cardiac events in patients with STEMI following PPCI than those ≤2. GLS was found to be an independent predictor of cardiac events in these patients. Conclusions: The number of transmural infarcted segments in apical + mid-ventricular portions affects LV global function and prognosis. Global longitudinal strain (GLS) is a significant predictor of adverse events after PPCI for STEMI. Morphologic and functional data fused to study complex pathophysiologic processes of LV early after STEMI may help in risk stratification of patients.

Mitophagy alleviates ischemia/reperfusion-induced microvascular damage through improving mitochondrial quality control.

The coronary arteries mainly function to perfuse the myocardium. When coronary artery resistance increases, myocardial perfusion decreases and myocardial remodeling occurs. Mitochondrial damage has been regarded as the primary cause of microvascular dysfunction. In the present study, we explored the effects of mitophagy activation on microvascular damage. Hypoxia/reoxygenation injury induced mitochondrial oxidative stress, thereby promoting mitochondrial dysfunction in endothelial cells. Mitochondrial impairment induced apoptosis, reducing the viability and proliferation of endothelial cells. However, supplementation with the mitophagy inducer urolithin A (UA) preserved mitochondrial function by reducing mitochondrial oxidative stress and stabilizing the mitochondrial membrane potential in endothelial cells. UA also sustained the viability and improved the proliferative capacity of endothelial cells by suppressing apoptotic factors and upregulating cyclins D and E. In addition, UA inhibited mitochondrial fission and restored mitochondrial fusion, which reduced the proportion of fragmented mitochondria within endothelial cells. UA enhanced mitochondrial biogenesis in endothelial cells by upregulating sirtuin 3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These results suggested that activation of mitophagy may reduce hypoxia/reoxygenation-induced cardiac microvascular damage by improving mitochondrial quality control and increasing cell viability and proliferation.

Novel Insights Into the Role of Mitochondria-Derived Peptides in Myocardial Infarction.

Mitochondria-derived peptides (MDPs) are a new class of bioactive peptides encoded by small open reading frames (sORFs) within known mitochondrial DNA (mtDNA) genes. MDPs may affect the expression of nuclear genes and play cytoprotective roles against chronic and age-related diseases by maintaining mitochondrial function and cell viability in the face of metabolic stress and cytotoxic insults. In this review, we summarize clinical and experimental findings indicating that MDPs act as local and systemic regulators of glucose homeostasis, immune and inflammatory responses, mitochondrial function, and adaptive stress responses, and focus on evidence supporting the protective effects of MDPs against myocardial infarction. These insights into MDPs actions suggest their potential in the treatment of cardiovascular diseases and should encourage further research in this field.

Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets.

A variety of complex risk factors and pathological mechanisms contribute to myocardial stress, which ultimately promotes the development of cardiovascular diseases, including acute cardiac insufficiency, myocardial ischemia, myocardial infarction, high-glycemic myocardial injury, and acute alcoholic cardiotoxicity. Myocardial stress is characterized by abnormal metabolism, excessive reactive oxygen species production, an insufficient energy supply, endoplasmic reticulum stress, mitochondrial damage, and apoptosis. Mitochondria, the main organelles contributing to the energy supply of cardiomyocytes, are key determinants of cell survival and death. Mitophagy is important for cardiomyocyte function and metabolism because it removes damaged and aged mitochondria in a timely manner, thereby maintaining the proper number of normal mitochondria. In this review, we first introduce the general characteristics and regulatory mechanisms of mitophagy. We then describe the three classic mitophagy regulatory pathways and their involvement in myocardial stress. Finally, we discuss the two completely opposite effects of mitophagy on the fate of cardiomyocytes. Our summary of the molecular pathways underlying mitophagy in myocardial stress may provide therapeutic targets for myocardial protection interventions.

FEF25-75% Is a More Sensitive Measure Reflecting Airway Dysfunction in Patients with Asthma: A Comparison Study Using FEF25-75% and FEV1.

BACKGROUND: Reduced forced expiratory flow between 25% and 75% of vital capacity percent predicted (FEF25-75%) representing small airway dysfunction (SAD) was associated with asthma development and progression. OBJECTIVE: To investigate whether FEF25-75% was superior to forced expiratory volume in 1 second in predicted (FEV1%) in reflecting asthma features in adult patients. METHODS: A retrospective spirometry dataset comprising 1801 adult patients with confirmed asthma and a subgroup of 332 patients having detailed clinical data were used to explore the association of FEF25-75% and/or FEV1% with clinical features of asthma. RESULTS: Of the 1801 subjects, FEV1% and FEF25-75% ranged from 136.8% to 10.2% and 127.3% to 3.1%, respectively. FEF25-75% < 65% was present in 1,478 (82.07%) of patients. FEF25-75% was strongly correlated with matched FEV1% (r = 0.900, P < .001). FEF25-75% and FEV1% were both correlated with airway hyperresponsiveness (r = 0.436, P < .001; r = 0.367, P < .001), asthma control test score (r = 0.329, P < .001; r = 0.335, P < .001), and sputum eosinophil count (r = -0.306, P < .001; r = -0.307, P < .001). Receiver-operating characteristic curves showed that FEF25-75% had greater value in predicting severe asthma (area under the curve: 0.84 vs 0.81, P = .018), airflow obstruction (0.97 vs 0.89, P < .001), and severe bronchial hyperresponsiveness (0.74 vs 0.69, P = .012) as compared with FEV1%. Patients with SAD (FEF25-75% < 65%) in the presence of normal FEV1% exhibited higher sputum eosinophil counts and had an increased dosage of daily inhaled corticosteroids (P < .001 and P = .010) than patients with normal lung function and their FEF25-75% values correlated with sputum eosinophil count (r = -0.419, P = .015), but not FEV1%. CONCLUSION: FEF25-75% represented small airway function and was more sensitive at reflecting airway hyperresponsiveness, inflammation, and disease severity as compared with FEV1% in patients with asthma. Our data suggest further assessment of FEF25-75% in asthma management, particularly for those with SAD who present normal FEV1%.

Protective Effect of Nicorandil on Cardiac Microvascular Injury: Role of Mitochondrial Integrity.

A major shortcoming of postischemic therapy for myocardial infarction is the no-reflow phenomenon due to impaired cardiac microvascular function including microcirculatory barrier function, loss of endothelial activity, local inflammatory cell accumulation, and increased oxidative stress. Consequently, inadequate reperfusion of the microcirculation causes secondary ischemia, aggravating the myocardial reperfusion injury. ATP-sensitive potassium ion (KATP) channels regulate the coronary blood flow and protect cardiomyocytes from ischemia-reperfusion injury. Studies in animal models of myocardial ischemia-reperfusion have illustrated that the opening of mitochondrial KATP (mito-KATP) channels alleviates endothelial dysfunction and reduces myocardial necrosis. By contrast, blocking mito-KATP channels aggravates microvascular necrosis and no-reflow phenomenon following ischemia-reperfusion injury. Nicorandil, as an antianginal drug, has been used for ischemic preconditioning (IPC) due to its mito-KATP channel-opening effect, thereby limiting infarct size and subsequent severe ischemic insult. In this review, we analyze the protective actions of nicorandil against microcirculation reperfusion injury with a focus on improving mitochondrial integrity. In addition, we discuss the function of mitochondria in the pathogenesis of myocardial ischemia.

Effects of nicorandil on myocardial infarct size in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: study design and protocol for the randomized controlled trial.

Previous studies have shown that nicorandil has a protective effect on cardiomyocytes. However, there is no study to investigate whether perioperative intravenous nicorandil can further reduce the myocardial infarct size in patients with ST-segment elevation myocardial infarction (STEMI) compared to the current standard of percutaneous coronary intervention (PCI) regimen. The CHANGE (China-Admini stration of Nicorandil Group) study is a multicenter, prospective, randomized, double-blind and parallel-controlled clinical study of STEMI patients undergoing primary PCI in China, aiming to evaluate the efficacy and safety of intravenous nicorandil in ameliorating the myocar dial infarct size in STEMI patients undergoing primary PCI and provide evidence-based support for myocardial protection strategies of STEMI patients.

Screening for Susceptibility-Related Factors and Biomarkers of Xianling Gubao Capsule-Induced Liver Injury.

Although increasing reports from the literature on herbal-related hepatotoxicity, the identification of susceptibility-related factors and biomarkers remains challenging due to idiosyncratic drug-induced liver injury (IDILI). As a well-known Chinese medicine prescription, Xianling Gubao Capsule (XLGB) has attracted great attention due to reports of potential liver toxicity. But the mechanism behind it is difficult to determine. In this paper, we found that XLGB-induced liver injury belongs to IDILI through the analysis of clinical liver injury cases. In toxicological experiment assessment, co-exposure to XLGB and non-toxic dose of lipopolysaccharide (LPS) could cause evident liver injury as manifested by significantly increased plasma alanine aminotransferase activity and obvious liver histological damage. However, it failed to induce observable liver injury in normal rats, suggesting that mild immune stress may be a susceptibility factor for XLGB-induced idiosyncratic liver injury. Furthermore, plasma cytokines were determined and 15 cytokines (such as IL-1ß, IFN-γ, and MIP-2α etc) were acquired by receiver operating characteristic (ROC) curves analysis. The expression of these 15 cytokines in LPS group was significantly up-regulated in contrast to the normal group. Meanwhile, the metabolomics profile showed that mild immune stress caused metabolic reprogramming, including sphingolipid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. 8 potential biomarkers (such as sphinganine, glycerophosphoethanolamine, and phenylalanine etc.) were identified by correlation analysis. Therefore, these results suggested that intracellular metabolism and immune changes induced by mild immune stress may be important susceptibility mechanisms for XLGB IDILI.

Prevention of contrast-induced nephropathy by adequate hydration combined with isosorbide dinitrate for patients with renal insufficiency and congestive heart failure.

BACKGROUND: Adequate hydration remains the mainstay of contrast-induced nephropathy prevention, and nitrates could reduce cardiac preload. HYPOTHESIS: This study aimed to explore the adequate hydration with nitrates for patients with chronic kidney disease (CKD) and congestive heart failure (CHF) to reduce the risk of contrast-induced nephropathy (CIN) and at the same time avoid the acute heart failure. METHODS: Three hundred and ninty-four consecutive patients with CKD and CHF undergoing coronary procedures were randomized to either adequate hydration with nitrates (n = 196) or to routine hydration (control group; n = 198). The adequate hydration group received continuous intravenous infusion of isosorbide dinitrate combined with intravenous infusion of isotonic saline at a rate of 1.5 mL/kg/h during perioperative period. The definition of CIN was a 25% or 0.5 mg/dL rise in serum creatinine over baseline. This trial is registered with www.clinicaltrials.gov, number NCT02718521. RESULTS: Baseline characteristics were well-matched between the two groups. CIN occurred less frequently in adequate hydration group than the control group (12.8% vs 21.2%; P = 0.018). The incidence of acute heart failure did not differ between the two groups (8 [4.08%] vs 6[3.03%]; P = 0.599). Cumulative major adverse events (death, myocardial infarction, stoke, hospitalization for acute heart failure) during the 90-day follow-up were lower in the adequate hydration with nitrates group (P = 0.002). CONCLUSIONS: Adequate hydration with nitrates can safely and effectively reduce the risk of CIN in patients with CKD and CHF.

The modifying effect of the MTHFR genotype on the association between folic acid supplementation and pulse wave velocity: Findings from the CSPPT.

OBJECTIVE: In a subgroup analysis of the China Stroke Primary Prevention Trial, we aimed to explore the impact of folic acid supplementation on arterial stiffness and assess the modifying effect of the methylenetetrahydrofolate reductase (MTHFR) gene in Chinese patients with hypertension. METHODS: This prospective study enrolled 2529 hypertensive Chinese patients. Participants were randomized to receive treatment with either a combination of enalapril and folic acid or enalapril. Brachial-ankle pulse wave velocity (PWV) was measured by trained medical staff using PWV instruments at both baseline and exit visits, approximately 5 years after enrollment. This trial was registered with clinicaltrials.gov (NCT00794885). RESULTS: During the follow-up, change in folate was significantly and independently correlated with change in ba-PWV in study patients (ß = -1.31, P < 0.001). Individuals with CC genotype had a significantly greater PWV response to folic acid supplementation than did carriers of the T allele (ß = -2.79, P < 0.001 for CC homozygotes compared with ß = -0.56, P = 0.464 for TT homozygotes). The positive effect of folic acid on improved PWV was modified by the MTHFR genotype (P for interaction = 0.034). CONCLUSION: In a subgroup of Chinese hypertensive patients who had received 5-year antihypertensive therapy, increases in folate status were associated with higher reductions in PWV, and individuals with the CC genotype showed greatest PWV response to folic acid supplementation.

Prognostic ability of cystatin C and homocysteine plasma levels for long-term outcomes in very old acute myocardial infarction patients.

BACKGROUND AND AIMS: This study sought to evaluate the prognostic powers of combined use of cystatin C (Cys C) and homocysteine (Hcy) at predicting adverse events of patients >80 years old with acute myocardial infarction (AMI). PATIENTS AND METHODS: The analysis involved 753 patients >80 years old undergoing coronary angiography for chest pain in China from January 2006 to December 2012. Kaplan-Meier method was used for survival and major adverse cardiac events (MACE) rates. Multivariate Cox regression was performed to identify mortality predictors. Receiver operating characteristic curve analysis was performed to predict the cutoff values of Cys C and Hcy for all-cause mortality. RESULTS: The duration of follow-up was 40-116 months (median, 63 months; interquartile range, 51-74 months). The long-term survival and event-free survival rates of AMI patients were significantly lower than those of unstable angina pectoris patients (P<0.05), and were significantly different according to the tertile concentration of Cys C of AMI patients (P<0.01). Cys C and Hcy were independent risk factors for long-term all-cause mortality (odds ratio [OR] =3.72 [2.27-6.09]; OR =1.59 [1.04-2.61]) and MACE (OR =2.83 [1.82-4.40]; OR =1.09 [1.04-1.21]) of AMI patients. The predictive cutoff value of Cys C was 1.815 mg/L (82.8%, 86.4%) and that of Hcy was 15.06 µmol/L (84.4%, 83.1%) in AMI patients. Combined use of both biomarker's cutoff values further increased the sensitivity and specificity of all-cause mortality. CONCLUSION: Cys C is a strong independent predictor of long-term all-cause death and MACE in very old AMI patients. The combined use of Cys C and Hcy further improves the predictive accuracy.