Association of liver fibrosis-4 index with adverse outcomes in hypertrophic cardiomyopathy patients.

AIMS: The fibrosis-4 index (FIB-4) is a non-invasive tool to assess fibrosis risk in chronic liver disease. We aimed to explore the relationship between the FIB-4 index and long-term major adverse cardiovascular events (MACE) in HCM patients. METHODS AND RESULTS: Consecutive patients diagnosed with HCM were included. Patients were divided into two groups using a defined cutoff value established through a ROC analysis for predicting MACE (FIB-4 ≥ 2.37 and FIB-4 < 2.37). The final analysis comprised 187 HCM patients (34.8% females, 66.49 ± 11.43 years of age), with 47 (25.1%) in the FIB-4 ≥ 2.37 group and 140 (74.9%) in the FIB-4 < 2.37 group. Among these, 147 (78.6%) individuals had complete follow-up data. Patients with FIB-4 ≥ 2.37 demonstrated a higher prevalence of co-morbidities such as atrial fibrillation (27.7% vs. 7.9%; P < 0.001), heart failure (55.3% vs. 24.3%; P < 0.001), elevated NT-proBNP levels (3.03 ± 4.74 vs. 0.66 ± 1.08; P < 0.001), and lower LVEF (58.51 ± 7.86 vs. 61.84 ± 5.04; P = 0.001). Over a median of 41 (IQR 16-63) months follow-up, MACE occurred in 49 (33.3%), with a significantly higher incidence in the FIB-4 ≥ 2.37 group (58.8% vs. 25.7%, P < 0.001). Cardiac death rates were also elevated in the FIB-4 ≥ 2.37 group (20.6% vs. 2.7%, P = 0.001). Cox regression analysis revealed an independent association between FIB-4 ≥ 2.37 and a higher risk of MACE (adjusted HR: 1.919, 95% CI 1.015-3.630; P = 0.045) and cardiac death (adjusted HR: 9.518, 95% CI 1.718-52.732; P = 0.010). Furthermore, the FIB-4 index shows positive correlations with left atrium diameter (r = 0.229; P = 0.003), septal thickness (r = 0.231; P = 0.002), posterior wall thickness (r = 0.235; P = 0.001), and NT-proBNP (r = 0.271; P < 0.001). Conversely, a negative correlation was observed between the FIB-4 index and left ventricular ejection fraction (r = -0.185; P = 0.011). CONCLUSION: Elevated FIB-4 index, indicative of liver fibrosis, is independently associated with an increased risk of long-term MACE in HCM patients. This emphasizes the potential influence of liver function abnormalities on HCM prognosis, underscoring the need for comprehensive risk assessment in clinical management.

Triglyceride-glucose index is associated with myocardial ischemia and poor prognosis in patients with ischemia and no obstructive coronary artery disease.

BACKGROUND: Ischemia and no obstructive coronary artery disease (INOCA) is increasingly recognized and associated with poor outcomes. The triglyceride-glucose (TyG) index is a reliable alternative measure of insulin resistance significantly linked to cardiovascular disease and adverse prognosis. We investigated the association between the TyG index and myocardial ischemia and the prognosis in INOCA patients. METHODS: INOCA patients who underwent both coronary angiography and myocardial perfusion imaging (MPI) were included consecutively. All participants were divided into three groups according to TyG tertiles (T1, T2, and T3). Abnormal MPI for myocardial ischemia in individual coronary territories was defined as summed stress score (SSS) ≥ 4 and summed difference score (SDS) ≥ 2. SSS refers to the sum of all defects in the stress images, and SDS is the difference of the sum of all defects between the rest images and stress images. All patients were followed up for major adverse cardiac events (MACE). RESULTS: Among 332 INOCA patients, 113 (34.0%) had abnormal MPI. Patients with higher TyG index had a higher rate of abnormal MPI (25.5% vs. 32.4% vs. 44.1%; p = 0.012). Multivariate logistic analysis showed that a high TyG index was significantly correlated with abnormal MPI in INOCA patients (OR, 1.901; 95% CI, 1.045-3.458; P = 0.035). During the median 35 months of follow-up, 83 (25%) MACE were recorded, and a higher incidence of MACE was observed in the T3 group (T3 vs. T2 vs. T1: 36.9% vs. 21.6% vs. 16.4%, respectively; p = 0.001). In multivariate Cox regression analysis, the T3 group was significantly associated with the risk of MACE compared to the T1 group (HR, 2.338; 95% CI 1.253-4.364, P = 0.008). CONCLUSION: This study indicates for the first time that the TyG index is significantly associated with myocardial ischemia and poor prognosis among INOCA patients.

Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect.

BACKGROUND: The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding the functional dynamics and resistance mechanisms of TKIs is essential for advancing the treatment of NSCLC. METHODS: This study assessed the effects of short-term and long-term TKI treatments on the TME in NSCLC, particularly targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. We analyzed changes in immune cell composition, cytokine profiles, and key proteins involved in immune evasion, such as laminin subunit γ-2 (LAMC2). We also explored the use of aspirin as an adjunct therapy to modulate the TME and counteract TKI resistance. RESULTS: Short-term TKI treatment enhanced T cell-mediated tumor clearance, reduced immunosuppressive M2 macrophage infiltration, and downregulated LAMC2 expression. Conversely, long-term TKI treatment fostered an immunosuppressive TME, contributing to drug resistance and promoting immune escape. Differential responses were observed among various oncogenic mutations, with ALK-targeted therapies eliciting a stronger antitumor immune response compared with EGFR-targeted therapies. Notably, we found that aspirin has potential in overcoming TKI resistance by modulating the TME and enhancing T cell-mediated tumor clearance. CONCLUSIONS: These findings offer new insights into the dynamics of TKI-induced changes in the TME, improving our understanding of NSCLC challenges. The study underscores the critical role of the TME in TKI resistance and suggests that adjunct therapies, like aspirin, may provide new strategies to enhance TKI efficacy and overcome resistance.

Is systemic inflammation a missing link between cardiometabolic index with mortality? Evidence from a large population-based study.

BACKGROUND: This study sought to elucidate the associations of cardiometabolic index (CMI), as a metabolism-related index, with all-cause and cardiovascular mortality among the older population. Utilizing data from the National Health and Nutrition Examination Survey (NHANES), we further explored the potential mediating effect of inflammation within these associations. METHODS: A cohort of 3029 participants aged over 65 years old, spanning six NHANES cycles from 2005 to 2016, was enrolled and assessed. The primary endpoints of the study included all-cause mortality and cardiovascular mortality utilizing data from National Center for Health Statistics (NCHS). Cox regression model and subgroup analysis were conducted to assess the associations of CMI with all-cause and cardiovascular mortality. The mediating effect of inflammation-related indicators including leukocyte, neutrophil, lymphocyte, systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR) were evaluated to investigate the potential mechanism of the associations between CMI and mortality through mediation package in R 4.2.2. RESULTS: The mean CMI among the enrolled participants was 0.74±0.66, with an average age of 73.28±5.50 years. After an average follow-up period of 89.20 months, there were 1,015 instances of all-cause deaths and 348 cardiovascular deaths documented. In the multivariable-adjusted model, CMI was positively related to all-cause mortality (Hazard Ratio (HR)=1.11, 95% CI=1.01-1.21). Mediation analysis indicated that leukocytes and neutrophils mediated 6.6% and 13.9% of the association of CMI with all-cause mortality. CONCLUSION: Elevated CMI is positively associated with all-cause mortality in the older adults. The association appeared to be partially mediated through inflammatory pathways, indicating that CMI may serve as a valuable indicator for poor prognosis among the older population.

Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer.

In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5 µM) significantly enhanced the anti-tumor efficacy of osimertinib (1 µM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg-1·d-1) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg-1·d-1) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.

The correlation of atherogenic index of plasma with non-obstructive CAD and unfavorable prognosis among patients diagnosed with MINOCA.

BACKGROUND: The atherogenic index of plasma (AIP) is linked to lipid metabolism and has shown considerable prognostic value in cardiovascular disorders. However, its role in myocardial infarction with non-obstructive coronary arteries (MINOCA) has not been investigated. We assessed the relationship between AIP, the severity of coronary stenosis, and prognosis in MINOCA. METHODS: We included consecutive patients who were diagnosed with MINOCA. AIP was calculated using the base 10 logarithm of the ratio between the levels of TG and HDL-C. The patients were divided into four groups based on their AIP quartiles: Q1 (AIP<-0.145), Q2 (AIP≥-0.145and≤0.049), Q3 (AIP>0.049and≤0.253), and Q4 (AIP>0.253). All patients underwent follow-up for MACE. RESULTS: The final analysis included 421 patients, with 188 having normal coronaries (0 stenosis) and 233 exhibiting non-obstructive coronary artery disease (CAD) (<50 % stenosis). In the multivariate logistic analysis, highest AIP (Q4) group was significantly associated with increased risk of non-obstructive CAD in MINOCA (OR,1.994;95 % CI:1.075-3.698; P = 0.029). During the follow-up period, MACE occurred in 22.8 % of MINOCA patients. Q4 group exhibited a significantly higher rate of MACE (P = 0.021). Furthermore, when both AIP and coronary stenosis status were considered, the results revealed individuals in the Q4 group with non-obstructive CAD had the highest risk of MACE (log-rank P = 0.027). The adjusted Cox analysis indicated that the Q4 group was associated with a 2.052-fold increase in the HR of MACE. CONCLUSION: AIP exhibits a notable association with the incidence of MACE in MINOCA patients and serves as a substantial marker for non-obstructive CAD in this patient group.

Stress hyperglycemia ratio as a prognostic indicator for long-term adverse outcomes in heart failure with preserved ejection fraction.

BACKGROUND: Recent studies highlighted that stress hyperglycemia ratio (SHR) is a potential predictor for future risk in heart failure (HF) patients. However, its implications specifically in HF with preserved ejection fraction (HFpEF) are not yet fully elucidated. We aimed to investigate the association between SHR and long-term clinical outcomes in HFpEF patients. METHODS: HFpEF patients enrolled between 2015 and 2023, were followed (mean 41 months) for a composite outcome of all-cause, cardiovascular mortality, and HF rehospitalization. SHR was established as the ratio of acute-chronic glycemia from admission blood glucose and glycated hemoglobin. The optimal cut-off for SHR to predict outcomes based on event prediction was determined through ROC analysis, and the cutoff was identified at 0.99. The effect of SHR on adverse risk was examined through the Cox hazards and Kaplan-Meier survival methods. A Pearson correlation analysis was conducted to assess the relationship between SHR and the severity of HF, as indicated by N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Furthermore, the incremental prognostic value of SHR was further assessed by the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI). RESULTS: Among the 400 enrolled patients, 190 individuals (47.5%) encountered composite events over the 41-month follow-up period. SHR was significantly elevated in patients with events compared with those without (p < 0.001). All patients were stratified into high SHR (n = 124) and low SHR (n = 276) groups based on the SHR cutoff. The high SHR group had a significantly higher incidence of adverse events than the low SHR group (log-rank; p < 0.001). Additional analysis indicated a poorer prognosis in patients with low left ventricular EF (LVEF) levels (50 < LVEF < 60) and high SHR (SHR > 0.99) in comparison to the other groups (log-rank p < 0.001). In adjusted analysis, after accounting for age, sex, diabetes, and NT-proBNP, elevated SHR remained independently predictive of adverse outcomes (adjusted HR: 2.34, 95% CI 1.49-3.67; p < 0.001). Furthermore, adding SHR to a model with MAGGIC score provided an incremental improvement in predicting adverse events. Additionally, SHR displayed a slight correlation with NT-proBNP. CONCLUSION: Elevated SHR was independently associated with an increased risk for composite events of all-cause, cardiovascular mortality, and HF readmission than those with lower SHR. SHR is a valuable tool for predicting and stratifying long-term adverse risks among HFpEF patients.

Screening and verifying the mutations in the LDLR and APOB genes in a Chinese family with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. The primary objective of this study was to identify the major pathogenic mutations in a Chinese family with FH. METHODS: Whole-genome sequencing (WGS) was used to identify variants of FH-related genes, including low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). Bioinformatics software was used to predict signal peptides, transmembrane structures, and spatial construction information of the mutated sequences. Western blotting was performed on the mutant protein to determine the presence of the major structural domains of the LDLR. The PCSK9 and APOB genes were screened and analyzed. Moreover, the proband and his brother were treated with a PCSK9 inhibitor for 1 year, and the effect of the treatment on lipid levels was assessed. RESULTS: WGS revealed two potentially pathogenic mutations in the LDLR gene. One was a novel mutation, c.497delinsGGATCCCCCAGCTGCATCCCCCAG (p. Ala166fs), and the other was a known pathogenic mutation, c.2054C>T (p. Pro685Leu). Bioinformatics prediction and in vitro experiments revealed that the novel mutation could not be expressed on the cell membrane. Numerous gene variants were identified in the APOB gene that may have a significant impact on the family members with FH. Thus, it is suggested that the severe manifestation of FH in the proband primarily resulted from the cumulative genetic effects of variants in both LDLR and APOB. However, a subsequent study indicated that treatment with a PCSK9 inhibitor (Evolocumab) did not significantly reduce the blood lipid levels in the proband or his brother. CONCLUSIONS: The cumulative effect of LDLR and APOB variants was the primary cause of elevated blood lipid levels in this family. However, PCSK9 inhibitor therapy did not appear to be beneficial for the proband. This study emphasizes the importance of genetic testing in determining the most suitable treatment options for patients with FH.

Association between the atherogenic index of plasma and adverse long-term prognosis in patients diagnosed with chronic coronary syndrome.

BACKGROUND: The Atherogenic Index of Plasma (AIP) is a newly identified biomarker associated with lipid metabolism, demonstrating significant prognostic capabilities in individuals diagnosed with cardiovascular disease. However, its impact within the context of chronic coronary syndromes (CCS) remains unexplored. Thus, the present investigation sought to examine the potential association between AIP levels and long-term clinical outcomes in patients diagnosed with CCS. METHODS: A total of 404 patients diagnosed with CCS and who underwent coronary angiography were included in this study. The AIP index was calculated as log (triglycerides / high-density lipoprotein-cholesterol). The patients were categorized into four groups based on their AIP values: Q1 (< -0.064), Q2 (-0.064 to 0.130), Q3 (0.130 to 0.328), and Q4 (> 0.328). The occurrence of major adverse cardiovascular events (MACE) was monitored during the follow-up period for all patients. Cox regression analysis and Kaplan-Meier curve analysis were employed to examine the relationship between AIP and MACE. Furthermore, ROC analysis was utilized to determine the optimal cut-off value of AIP for predicting clinical MACE. RESULTS: During the median 35 months of follow-up, a total of 88 patients experienced MACE. Notably, the group of patients with higher AIP values (Q4 group) exhibited a significantly higher incidence of MACE compared to those with lower AIP values (Q1, Q2, and Q3 groups) (31.7% vs. 16.8%, 15.7%, and 23.0% respectively; P = 0.023). The Kaplan-Meier curves illustrated those patients in the Q4 group had the highest risk of MACE relative to patients in the other groups (log-rank P = 0.014). Furthermore, the multivariate Cox regression analysis demonstrated that individuals in the Q4 group had a 7.892-fold increased risk of MACE compared to those in the Q1 group (adjusted HR, 7.892; 95% CI 1.818-34.269; P = 0.006). Additionally, the ROC curve analysis revealed an optimal AIP cut-off value of 0.24 for predicting clinical MACE in patients with CCS. CONCLUSION: Our data indicate, for the first time, that AIP is independently associated with poor long-term prognosis in patients suffering from CCS. The optimal AIP cut-off value for predicting clinical MACE among CCS patients was 0.24.

Coronary microvascular dysfunction and myocardial infarction with non-obstructive coronary arteries: Where do we stand?

In the past decade, scientific and clinical research has provided a translational perspective on myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA). MINOCA is characterized by clinical documentation of an acute MI but angiography shows no significant coronary artery obstruction (stenosis <50%). The prevalence of MINOCA is estimated to range from approximately 6 to 10% among MI patients, and those with this condition have a poor prognosis, experiencing high rates of mortality, rehospitalization, and socioeconomic burden. MINOCA represents a major unmet need in cardiovascular medicine, with uncertain clinical management. It is a complex condition that can be caused by various factors, including atherosclerosis, plaque rupture, coronary vasospasm, and microvascular dysfunction. Effective management of MINOCA depends on identifying the underlying mechanism of the infarction, thus a systematic diagnostic approach is recommended. Contemporary data shows that a significant number of patients exhibit structural and functional abnormalities in coronary microcirculation, which is referred to as coronary microvascular dysfunction (CMD). CMD plays a crucial role in patients with signs and symptoms of myocardial ischemia and non-obstructive coronary artery stenosis, including MINOCA. Furthermore, conducting a thorough evaluation of coronary function can have significant prognostic and therapeutic implications, since personalized patient management strategies based on this assessment have been shown to improve symptoms and prognosis. Therefore, an accurate and timely diagnosis of CMD is essential for effective patient management, which can be achieved through various invasive and non-invasive methods. This review will discuss the pathophysiological understanding, current diagnostic techniques, and management strategies of patients with MINOCA and CMD.

Association between the triglyceride-glucose index and the presence and prognosis of coronary microvascular dysfunction in patients with chronic coronary syndrome.

BACKGROUND: Coronary microvascular dysfunction (CMD) is a strong determinant of prognosis in patients with chronic coronary syndrome (CCS). The triglyceride-glucose index (TyG index), an alternative method to evaluate insulin resistance, is positively correlated with the incidence and adverse outcomes of cardiovascular diseases. However, the relationship between the TyG index and the presence and prognosis of CMD in CCS patients has not been investigated. Therefore, we aimed to evaluate the association between the TyG index and the presence and clinical outcomes of CMD among CCS patients. METHODS: CCS patients who underwent coronary angiography between June 2015 to June 2019 were included. The TyG index was calculated as Ln[fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2]. Coronary angiography­derived index of microvascular resistance (caIMR) was used to measure microvascular function, and CMD was defined as caIMR ≥ 25U. Patients with CMD were divided into three groups (T1, T2, and T3 groups) according to TyG tertiles. The primary endpoint was major adverse cardiac event (MACE). RESULTS: Of 430 CCS patients, 221 patients had CMD. CMD patients had significantly higher TyG index than those without CMD. Sixty-three MACE was recorded during the follow-up duration among CMD patients, and the incidence rate of MACE was higher in the T3 group compared to T1/T2 groups (39.2% vs. 20.5% vs. 25.7%; P = 0.035). Multivariable logistic regression analysis showed that the TyG index was an independent predictor of CMD (OR, 1.436; 95% CI, 1.014-2.034; P = 0.042). Compared to the T1 group, the T3 group strongly correlated with the risk of MACE in CMD patients even after adjusting for additional confounding risk factors (HR, 2.132; 95%CI, 1.066-4.261; P = 0.032). CONCLUSION: TyG index is significantly associated with the risk of CMD, and it is an independent predictor of MACE among CMD patients with CCS. This study suggests that the TyG index has important clinical significance for the early prevention and risk stratification of CMD.

Prognostic Significance of Coronary Microvascular Dysfunction in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The prognostic impact of coronary microvascular dysfunction (CMD) has been scarcely addressed in heart failure with preserved ejection fraction (HFpEF). This study investigated the prevalence and prognostic significance of CMD as measured by a novel pressure wire-free coronary angiography-derived index of microcirculatory resistance (caIMR) on clinical outcomes. METHODS: Patients diagnosed with HFpEF from 2019 to 2021 were enrolled retrospectively. caIMR was used to quantify microvascular function, and patients were categorised into 2 groups based on their caIMR. The primary end points were composite of all-cause death and heart failure rehospitalisation. RESULTS: Of 137 HFpEF patients, CMD (defined as caIMR ≥ 25) was present in 88 patients (64.2%). Forty-five patients (32.8%) experienced composite events during a mean follow-up of 15 months. Compared with patients with caIMR < 25, those with caIMR ≥ 25 had a notably higher incidence of composite events (16.3% vs 42.0%; P = 0.002). On survival analysis, patients with caIMR ≥ 25 demonstrated a worse prognosis than those with caIMR < 25 for composite events (P = 0.006). Patients with caIMR ≥ 25 in multiple coronary arteries showed a trend to worse outcome than those with caIMR ≥ 25 in a single coronary artery (log-rank P = 0.056). In adjusted analysis, caIMR ≥ 25 was independently predictive of adverse outcomes (adjusted hazard ratio 2.93, 95% confidence interval [CI] 1.28-6.70; P = 0.010). caIMR displayed a significant predictive power for adverse event prediction (area under the receiver operating characteristic curve 0.767, 95% CI 0.677-0.858; P < 0.001). CONCLUSIONS: CMD is highly prevalent and is an independent predictor of adverse outcomes in HFpEF patients. Assessment of CMD may identify high-risk patients early for intensified treatment and risk-factor management.

Association of stress hyperglycemia ratio and poor long-term prognosis in patients with myocardial infarction with non-obstructive coronary arteries.

BACKGROUND: Stress hyperglycemia ratio (SHR) is a novel biomarker of true acute hyperglycemia condition and is associated with a worse prognosis in patients with myocardial infarction (MI). However, the effects of SHR in the setting of MI with non-obstructive coronary arteries (MINOCA) have not been investigated. This study aimed to explore the association between SHR and long-term clinical outcomes among MINOCA patients. METHODS: A total of 410 MINOCA patients were included in the final analysis of this study. The patients were divided into three groups based on the SHR tertiles: [SHR1 group (SHR ≤ 0.73), (n = 143); SHR2 group (SHR 0.73-0.84), n = 131; and SHR3 group (SHR ≥ 0.84), n = 136]. Follow-up for major adverse cardiovascular events (MACE) was conducted on all patients. Cox regression and Kaplan-Meier curve analysis were used to evaluate the relationship between SHR and MACE. The receiver operating curve (ROC) analysis was applied to obtain the optimal cut-off value of SHR for predicting clinical MACE. RESULTS: A total of 92 patients developed MACE during the mean 34 months of follow-up. A significant increase in MACE was observed in the SHR3 group compared to the SHR1 and SHR2 groups (35.3% vs. 15.4% and 16.8%, respectively; P < 0.001). The Kaplan-Meier curves demonstrate that SHR3 patients had the highest MACE risk compared to SHR1 and SHR2 patients (log-rank P < 0.001). In addition, when both SHR tertiles and diabetes status were considered, those with SHR3 and diabetes had the highest hazard of MACE (log-rank P < 0.001). Multivariate Cox regression analysis showed that the SHR3 is associated with a 2.465-fold increase in the risk of MACE (adjusted HR, 2.465; 95% CI 1.461-4.159, P = 0.001). The ROC curve analysis showed that the optimal SHR cut-off value for predicting clinical MACE among MINOCA was 0.86. CONCLUSION: Our data indicates, for the first time, that SHR is independently associated with poor long-term prognosis in patients suffering from MINOCA. The optimal SHR cut-off value for predicting clinical MACE among MINOCA patients was 0.86. These findings suggest that SHR may play a potential role in the cardiovascular risk stratification of the MINOCA population.

Effect of nonobstructive coronary stenosis on coronary microvascular dysfunction and long-term outcomes in patients with INOCA.

BACKGROUND: Ischemic pain with no-obstructive coronary artery (INOCA) is clinically significant and defined by nonobstructive coronary stenosis <50%. Coronary microvascular dysfunction (CMD) is a relevant cause associated with adverse outcomes. OBJECTIVES: Investigated the effect of no-stenosis (0% stenosis) and non-obstructive (0% < stenosis < 50%) on the prognostic impact of CMD in INOCA. METHOD: A retrospective study assessed the coronary microvascular function in 151 INOCA patients who underwent invasive angiography by the coronary angiography-derived index of microcirculation-resistance (caIMR). CZT-SPECT was performed to evaluate myocardial perfusion imaging (MPI) abnormalities. Chi-square test/Fisher exact test, Student t-test, Kaplan-Meier curve, and Uni-multivariable Cox proportional models were used for analysis. Clinical outcomes were major adverse cardiovascular events (MACE) during a median follow-up of 35 months. RESULT: No-stenosis was present in 71 (47%) INOCA patients, and 80 (53%) were with nonobstructive. CMD (caIMR ≥ 25) was more prevalent in patients with no-stenosis than nonobstructive (76.1% vs. 48.8%, p = .001), along with abnormal MPI (39.4% vs. 22.5%, p = .024). The MACE rates were not different between no-stenosis and nonobstructive stenosis. CMD showed an increased risk of MACE for all INOCA. No-stenosis with CMD had the worst prognosis. Cox regression analysis identified CMD and abnormal MPI as predictors of MACE in all INOCA and patients with no-stenosis. However, no-stenosis and nonobstructive stenosis were not predictors of MACE in INOCA. CONCLUSION: CMD was more frequently present in INOCA with no-stenosis. However, there was no difference in long-term clinical outcomes between no-stenosis and nonobstructive stenosis. CMD could independently predict poor outcomes in INOCA, particularly in patients with no-stenosis.

Prognostic implication of coronary slow flow assessed by cTFC in patients with myocardial infarction with Non-obstructive coronary arteries.

BACKGROUND: Coronary slow flow (CSF) is common and linked to worse cardiovascular events and life-threatening arrhythmias. However, the clinical implication of CSF among myocardial infarction with the non-obstructive coronary artery (MINOCA) has never been studied. We aimed to evaluate the impact of CSF on the MINOCA population. METHODS: Patients diagnosed with MINOCA were consecutively selected. The corrected TIMI frame count (cTFC) was used to evaluate the coronary flow. CSF was defined as cTFC greater than 27 frames per second (FPS) in any of the three coronary arteries. Major adverse cardiovascular events (MACE) are the primary endpoint. Cox regression analysis was used to evaluate the association between CSF and MACE. RESULTS: A total of 158 patients with MINOCA were enrolled, of which 54 (34.2%) patients had CSF. Forty incidents of MACE occurred during the median 28 months of follow-up. The MACE incidence was higher among patients who presented with CSF than the normal coronary flow patients (35.2% vs. 20.2%, p = 0.040). In the Kaplan-Meier analysis, CSF patients had significantly higher rates of MACE (log-rank P = 0.034). Multivariate Cox regression analysis showed that CSF was an independent predictor linked to an increased hazard of MACE (adjusted HR, 2.76; 95% CI, 1.34-5.67; P = 0.006). CONCLUSION: The presence of CSF is associated with a higher risk of adverse events and is an independent predictor of clinical outcomes among patients with MINOCA. This result suggests that CSF might serve as a robust tool to stratify MINOCA patients.

Prognostic value of combined coronary angiography-derived IMR and myocardial perfusion imaging by CZT SPECT in INOCA.

BACKGROUND: A significant proportion of ischemia with non-obstructive coronary artery disease (INOCA) demonstrate coronary microvascular dysfunction (CMD), a condition associated with abnormal myocardial perfusion imaging (MPI) and adverse outcomes. Coronary angiography-derived index of microvascular resistance (caIMR) is a novel non-invasive technique to assess CMD. We aimed to investigate the prognostic value of combined caIMR and MPI by CZT SPECT in INOCA patients. METHODS: Consecutive 151 patients with chest pain and < 50% coronary stenosis who underwent coronary angiography and MPI within 3 months were enrolled. caIMR was calculated by computational pressure-flow dynamics. CMD was defined as caIMR ≥ 25. The endpoint was major adverse cardiac events (MACE: cardiovascular death, nonfatal myocardial infarction, revascularization, angina-related rehospitalization, heart failure, and stroke). RESULTS: Of all INOCA patients, CMD was present in 93 (61.6%) patients. The prevalence of abnormal MPI was significantly higher in CMD compared with non-CMD patients (40.9% vs 13.8%, P < .001). CMD showed a higher risk of MACE than non-CMD patients. Patients with both CMD and abnormal MPI had the worst prognosis, followed by patients with CMD and normal MPI (log-rank P < .001). Cox regression analysis identified CMD (HR 3.121, 95%CI 1.221-7.974, P = .017) and MPI (HR 2.704, 95%CI 1.030-7.099, P = .043) as predictive of MACE. The prognostic value of INOCA patients enhanced significantly by adding CMD and MPI to the model with clinical risk factors (AUC = 0.777 vs 0.686, P = .030). CONCLUSION: caIMR-derived CMD is associated with increased risk of MACE among INOCA patients. Patients with abnormalities on both caIMR and MPI had the worse outcomes.

Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment.

Hepatitis B virus (HBV) infection is a global public health issue. Interferon-α (IFN-α) treatment has been used to treat hepatitis B for over 20 years, but fewer than 5% of Asians receiving IFN-α treatment achieve functional cure. Thus, IFN-α retreatment has been introduced to enhance antiviral function. In recent years, immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks, in-cluding both innate and adaptive immunity, triggering immune responses that control HBV replication. However, heterogeneity of the immune system to control HBV infection, particularly HBV-specific CD8+ T cell heterogeneity, has consequ-ential effects on T cell-based immunotherapy for treating HBV infection. Altogether, the host's genetic variants, negative-feedback regulators and HBV components affecting the immune system's ability to control HBV. In this study, we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-α treatment and retreatment.

Prognostic value of coronary microvascular dysfunction assessed by coronary angiography-derived index of microcirculatory resistance in diabetic patients with chronic coronary syndrome.

BACKGROUND: Coronary microvascular dysfunction (CMD) is common and is associated with unfavorable cardiovascular events in patients with diabetes mellitus (DM). Coronary angiography-derived index of microcirculatory resistance (caIMR) is a recently developed wire- and hyperemic agent-free method to assess CMD. We aimed to investigate the prognostic impact of CMD assessed by caIMR on clinical outcomes in patients with DM and chronic coronary syndrome (CCS). METHODS: CCS patients who underwent coronary angiography between June 2015 to May 2018 were included. Coronary microvascular function was measured by caIMR, and CMD was defined as caIMR ≥ 25U. The primary endpoint was major adverse cardiac events (MACE). Kaplan-Meier analysis and Cox proportional hazards models were used to assess the relationship between caIMR and the risk of MACE. RESULTS: Of 290 CCS patients, 102 patients had DM. Compared with non-diabetic patients, CMD (caIMR ≥ 25U) was higher among DM patients (57.8% vs. 38.3%; p = 0.001). During a mean 35 months follow-up, 40 MACE had occurred. Patients with caIMR ≥ 25 had a higher rate of MACE than patients with caIMR < 25 (20.6% vs. 8.2%, p = 0.002). Of these, the MACE rate was higher among DM patients with caIMR ≥ 25 than those with caIMR < 25 (33.9% vs. 14.0%; p = 0.022). In multivariable Cox analysis, caIMR ≥ 25 was independently associated with MACE in the DM patients but not in non-DM patients (HR, 2.760; 95% CI, 1.066-7.146; P = 0.036). CONCLUSION: CMD assessed by caIMR was common and is an independent predictor of MACE among diabetic patients with CCS. This finding potentially enables a triage of higher-risk patients to more intensive therapy.

The Antioxidative Role of Chaperone-Mediated Autophagy as a Downstream Regulator of Oxidative Stress in Human Diseases.

Chaperone-mediated autophagy (CMA) plays an important role in regulating a variety of cellular functions by selectively degrading damaged or functional proteins in the cytoplasm. One of the cellular processes in which CMA participates is the oxidative stress response. Oxidative stress regulates CMA activity, while CMA protects cells from oxidative damage by degrading oxidized proteins and preventing the accumulation of excessive reactive oxygen species (ROS). Changes in CMA activity have been found in many human diseases, and oxidative stress is also involved. Therefore, understanding the interaction mechanism of ROS and CMA will provide new targets for disease treatment. In this review, we discuss the role of CMA in combatting oxidative stress during the development of different conditions, such as aging, neurodegeneration, liver diseases, infections, pulmonary disorders, and cancers.

Prognostic impact of coronary microvascular dysfunction assessed by caIMR in overweight with chronic coronary syndrome patients.

Objective: Coronary microvascular dysfunction (CMD) may associate with adverse cardiovascular events in obese patients. Coronary angiography-derived index of microcirculatory resistance (caIMR) is proposed as a less-invasive and pressure-wire-free index to assess CMD. We aimed to investigate the impact of coronary microvascular function assessed by caIMR in patients with overweight and chronic coronary syndrome (CCS). Methods: CCS patients who underwent coronary angiography between 2015 to 2018 were included. Overweight was defined as BMI≥24.0kg/m². Impaired coronary microvascular function was defined as caIMR≥25U. The patients were classified according to BMI and caIMR. The primary endpoint was major adverse cardiac events (MACE). Kaplan-Meier and Cox regression analyses evaluated the association between caIMR and MACE. Results: Two hundred and eighty-two CCS patients were enrolled. Among these, 169 (59.93%) were overweight. Impaired coronary microvascular function was higher in overweight patients than in patients with normal weight (49.70% vs. 38.05%; P=0.035). During 35 months of follow-up, 33 MACE had occurred. Among the total CCS population, MACE was higher in patients with high caIMR than in low caIMR (18.11% vs. 6.45%, P=0.003). In subgroups analysis, MACE was higher in overweight patients with high caIMR than low caIMR (20.24% vs. 7.06%, P=0.014), while there were no significant differences in normal-weight patients. Multivariate Cox analysis demonstrated that caIMR≥25 was independently associated with MACE in overweight patients (HR, 2.87; 95% CI, 1.12-7.30; P=0.027) but not in the normal-weight patients. In addition, caIMR showed a significant predictive value for adverse outcomes in overweight patients and provided an incremental prediction when added to a prediction model with BMI. Conclusions: Impaired coronary microvascular function assessed by caIMR was common and is an independent predictor of MACE in overweight patients with CCS.