MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis.

Triple negative breast cancer (TNBC) cells have a high demand for oxygen and glucose to fuel their growth and spread, shaping the tumor microenvironment (TME) that can lead to a weakened immune system by hypoxia and increased risk of metastasis. To disrupt this vicious circle and improve cancer therapeutic efficacy, a strategy is proposed with the synergy of ferroptosis, immunosuppression reversal and disulfidptosis. An intelligent nanomedicine GOx-IA@HMON@IO is successfully developed to realize this strategy. The Fe release behaviors indicate the glutathione (GSH)-responsive degradation of HMON. The results of titanium sulfate assay, electron spin resonance (ESR) spectra, 5,5'-Dithiobis-(2-nitrobenzoic acid (DTNB) assay and T1 -weighted magnetic resonance imaging (MRI) demonstrate the mechanism of the intelligent iron atom (IA)-based cascade reactions for GOx-IA@HMON@IO, generating robust reactive oxygen species (ROS). The results on cells and mice reinforce the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis triggered by the GOx-IA@HMON@IO with the following steps: 1) GSH peroxidase 4 (GPX4) depletion by disulfidptosis; 2) IA-based cascade reactions; 3) tumor hypoxia reversal; 4) immunosuppression reversal; 5) GPX4 depletion by immunotherapy. Based on the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis, the intelligent nanomedicine GOx-IA@HMON@IO can be used for MRI-guided tumor therapy with excellent biocompatibility and safety.

Long-term and short-term cardiovascular disease mortality among patients of 21 non-metastatic cancers.

INTRODUCTION: Previous studies on cardiovascular disease (CVD) death risk in cancer patients mostly focused on overall cancer, age subgroups and single cancers. OBJECTIVES: To assess the CVD death risk in non-metastatic cancer patients at 21 cancer sites. METHODS: A total of 1,672,561 non-metastatic cancer patients from Surveillance, Epidemiology, and End Results (SEER) datebase (1975-2018) were included in this population-based study, with a median follow-up of 12·7 years. The risk of CVD deaths was assessed using proportions, competing-risk regression, absolute excess risks (AERs), and standardized mortality ratios (SMRs). RESULTS: In patients with localized cancers, the proportion of CVD death and cumulative mortality from CVD in the high-competing risk group (14 of 21 unique cancers) surpassed that of primary neoplasm after cancer diagnosis. The SMRs and AERs of CVD were found higher in patients with non-metastatic cancer than the general US population (SMR 1·96 [95 %CI, 1·95-1·97]-19·85[95 %CI, 16·69-23·44]; AER 5·77-210·48), heart disease (SMR 1·94[95 %CI, 1·93-1·95]-19·25[95 %CI, 15·76-23·29]; AER 4·36-159·10) and cerebrovascular disease (SMR 2·05[95 %CI, 2·02-2·08]-24·71[95 %CI, 16·28-35·96]; AER 1·01-37·44) deaths. In the high-competing risk group, CVD-related SMR in patients with localized stage cancer increased with survival time but followed a reverse-dipper pattern in the low-competing risk group (7 of 21 cancers). The high-competing risk group had higher CVD-related death risks than the low-competing risk group. CONCLUSION: The CVD death risk in patients with non-metastatic cancer varied by cancer stage, site and survival time. The risk of CVD mortality is higher in 14 out of 21 localized cancers (high-competing cancers). Targeted strategies for CVD management in non-metastatic cancer patients are needed.

Different heart failure phenotypes of valvular heart disease: the role of mitochondrial dysfunction.

Valvular heart disease (VHD)-related heart failure (HF) is a special subtype of HF with an increasingly concerned heterogeneity in pathophysiology, clinical phenotypes, and outcomes. The mechanism of VHD-related HF involves not only mechanical damage to the valve itself but also valve lesions caused by myocardial ischemia. The interactions between them will lead to the occurrence and development of VHD-related HF subtypes. Due to the spatial (combination of different valvular lesions) and temporal effects (sequence of valvular lesions) of valvular damages, it can make the patient's condition more complicated and also make the physicians deal with a dilemma when deciding on a treatment plan. This indicates that there is still lack of deep understanding on the pathogenic mechanism of VHD-related HF subtypes. On the other hand, mitochondrial dysfunction (MitD) is not only associated with the development of numerous cardiac diseases such as atherosclerosis, hypertension, diabetes, and HF but also occurs in VHD. However, the role of MitD in VHD-related HF is still not fully recognized. In this comprehensive review, we aim to discuss the current findings and challenges of different valvular damages derived from HF subtypes as well as the role of MitD in VHD-related HF subtypes.

Long-term risks of cardiovascular death in a population-based cohort of 1,141,675 older patients with cancer.

BACKGROUND: previous studies have focused on the risk of cardiovascular disease (CVD)-related death in individual cancers, adolescents or all cancers. OBJECTIVE: to evaluate the risk of CVD-related death in older patients with cancer. METHODS: older patients with cancer (over 65 years) of 16 cancers diagnosed between 1975 and 2018 were screened out from the Surveillance, Epidemiology and End Results program. The proportion of deaths, competing risk regression models, standardized mortality ratios (SMRs) and absolute excess risks (AERs) were used to assess the risk of CVD-related death. RESULTS: this study included 1,141,675 older patients (median follow-up: 13.5 years). Of the 16 individual cancers, the risk of CVD death exceeded primary neoplasm death in older patients with cancers of the breast, endometrium, vulva, prostate gland, penis and melanoma of the skin over time (high competing risk group). Compared to the general older population, older patients with cancer had higher SMR and AER of CVD-related death (SMR: 1.58-4.23; AER: 21.16-365.89), heart disease-related death (SMR: 1.14-4.16; AER: 16.29-301.68) and cerebrovascular disease-related death (SMR: 1.11-4.66; AER: 3.02-72.43), with the SMR trend varying with CVD-related death competing risk classifications. The risk of CVD-related death in the high-competing risk group was higher than in the low-competing risk group. CONCLUSIONS: for older patients with cancer, six of 16 individual cancers, including breast, endometrium, vulva, prostate gland, penis and melanoma of the skin was at high risk of CVD-related death. Management for long-term cardiovascular risk in older patients with cancer is needed.

Association of KATP Variants With CMD and RAP in CAD Patients With Increased Serum Lipoprotein(a) Levels.

CONTEXT: Refractory angina pectoris (RAP) is a specific subtype of coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] and its induced coronary microvascular dysfunction (CMD) play an important role in pathogenesis of RAP, but its metabolism was mostly genetically determined. The adenosine triphosphate (ATP)-sensitive potassium channel (KATP) is involved in lipid metabolism and microvascular homeostasis and becomes a promising target for the management of Lp(a) and its related RAP. OBJECTIVE: To investigate associations of KATP variants with hyperlipoprotein(a)emia, CMD, and RAP in patients with CAD. DESIGN, PATIENTS, SETTINGS: A total of 1148 newly diagnosed patients with CAD were prospectively selected and divided into control (Lp(a) < 180 mg/dL) and case (Lp(a) ≥ 180 mg/dL, hyperlipoprotein(a)emia) group. METHODS: 9 KATP variants were genotyped by MassARRAY system. The expression profile of exosome-derived microRNAs (exo-miRs) was identified by next-generation sequencing, and the expression levels of differentially expressed exo-miRs were evaluated by quantitative RT-PCR in verification cohort. RESULTS: Three KATP variants were associated with increased risk of hyperlipoprotein(a)emia in patients with CAD as follows: rs2285676 (AA + GA genotype, adjusted odds ratio [OR] = 1.44; 95% CI, 1.10-1.88; P = 0.008), rs1799858 (CC genotype, adjusted OR = 1.33; 95% CI, 1.03-1.73; P = 0.030), and rs141294036 (CC genotype, adjusted OR = 1.43; 95% CI, 1.10-1.87; P = 0.008). Only rs141294036 was associated with increased risk of CMD (CC genotype, adjusted OR = 1.62; 95% CI, 1.23-2.13; P = 0.001), and further with increased RAP risk (CC genotype, adjusted hazard ratio = 2.05; 95% CI, 1.22-3.43; P = 0.007) after median follow-up of 50.6 months. Between the 2 genotypes of rs141294036, 152 exo-miRs were significantly differentially expressed, but only 10 exo-miRs (miR-7110-3p, miR-548az-5p, miR-214-3p, let-7i-5p, miR-218-5p, miR-128-3p, miR-378i, miR-625-3p, miR-128-1-5p, and miR-3187-3p) were further confirmed in patients with RAP with hyperlipoprotein(a)emia and CMD. CONCLUSION: KATP rs141294036 may serve a potential genetic marker for hyperlipoprotein(a)emia, CMD, and RAP in patients with CAD.

Metastatic patterns and prognosis of patients with primary malignant cardiac tumor.

Background: Distant metastases are independent negative prognostic factors for patients with primary malignant cardiac tumors (PMCT). This study aims to further investigate metastatic patterns and their prognostic effects in patients with PMCT. Materials and methods: This multicenter retrospective study included 218 patients with PMCT diagnosed between 2010 and 2017 from Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was utilized to identify metastatic risk factors. A Chi-square test was performed to assess the metastatic rate. Kaplan-Meier methods and Cox regression analysis were used to analyze the prognostic effects of metastatic patterns. Results: Sarcoma (p = 0.002) and tumor size¿4 cm (p = 0.006) were independent risk factors of distant metastases in patients with PMCT. Single lung metastasis (about 34%) was the most common of all metastatic patterns, and lung metastases occurred more frequently (17.9%) than bone, liver, and brain. Brain metastases had worst overall survival (OS) and cancer-specific survival (CSS) among other metastases, like lung, bone, liver, and brain (OS: HR = 3.20, 95% CI: 1.02-10.00, p = 0.046; CSS: HR = 3.53, 95% CI: 1.09-11.47, p = 0.036). Conclusion: Patients with PMCT who had sarcoma or a tumor larger than 4 cm had a higher risk of distant metastases. Lung was the most common metastatic site, and brain metastases had worst survival among others, such as lung, bone, liver, and brain. The results of this study provide insight for early detection, diagnosis, and treatment of distant metastases associated with PMCT.

Grape exosome-like nanoparticles: A potential therapeutic strategy for vascular calcification.

Vascular calcification (VC) is prevalent in hypertension, diabetes mellitus, chronic kidney disease, and aging and has been identified as an important predictor of adverse cardiovascular events. With the complicated mechanisms involved in VC, there is no effective therapy. Thus, a strategy for attenuating the development of VC is of clinical importance. Recent studies suggest that grape exosome-like nanoparticles (GENs) are involved in cell-cell communication as a means of regulating oxidative stress, inflammation, and apoptosis, which are known to modulate VC development. In this review, we discuss the roles of GENs and their potential mechanisms in the development of VC.

Long-Term Cardiovascular Mortality among 80,042 Older Patients with Bladder Cancer.

BACKGROUND: To identify the risk of death from cardiovascular disease (CVD) in older patients with bladder cancer (BC). METHODS: This population-based study included 80,042 older BC patients (≥65 years) diagnosed between 1975 and 2018, with a mean follow-up of 17.2 years. The proportion of deaths, competing risk models, standardized mortality ratio (SMR), and absolute excess risk (AER) per 10,000 person-years were applied to identify the risk of CVD-related deaths among older BC patients. RESULTS: For older patients with BC, CVD-related death was the chief cause of death, and cumulative CVD-related mortality also exceeded primary BC as the leading cause of death mostly 5-10 years after BC diagnosis, especially in localized-stage and low-grade subgroups. The risk of short- and long-term CVD-related death in older BC patients was higher than in the general older adult population (SMR = 1.30, 95% CI 1.28-1.32; AER = 105.68). The risk of sex-specific CVD-related deaths also increased compared to the general population of older adults, including heart disease, cerebrovascular diseases, hypertension without heart disease, atherosclerosis, aortic aneurysm and dissection, and other diseases of the arteries, arterioles, and capillaries. CONCLUSIONS: CVD-related death is an important competing risk among older BC patients and has surpassed primary BC as the chief cause of death, mainly 5-10 years after BC diagnosis. The risk of CVD-related death in older patients with BC was greater than in the general population. The management of older patients with BC should focus not only on the primary cancer but also on CVD-related death.

Association of marital status with cardiovascular outcome in patients with breast cancer.

Background: The influences of marital status on cardiovascular death risk in patients with breast cancer remained unclear. This study aimed to evaluate the associations of different marital status with cardiovascular death risk in patients with breast cancer. Methods: A total of 182,666 female breast cancer patients were enrolled in this study from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2014, and was divided into two groups: married (N=107,043) and unmarried (N=75,623). A 1:1 propensity score matching (PSM) was applied to reduce inter-group bias between the two groups. Competing-risks model was used to assess the associations between different marital status and cardiovascular death risk in patients with breast cancer. Results: After PSM, marital status was an independent predictor for cardiovascular death in patients with breast cancer. Unmarried condition was associated with increased cardiovascular death risk than married condition among breast cancer patients [unadjusted model: hazard ratio (HR) =2.012, 95% confidence interval (CI): 1.835-2.208, P<0.001; Model 1: HR =1.958, 95% CI: 1.785-2.148, P<0.001; Model 2: HR =1.954, 95% CI: 1.781-2.144, P<0.001; Model 3: HR =1.920, 95% CI: 1.748-2.107, P<0.001]. With the exception of separated condition (adjusted HR =0.886, 95% CI: 0.474-1.658, P=0.705), further unmarried subgroups analysis showed that the other three unmarried status were associated with increased cardiovascular death risk as follows: single (adjusted HR =1.623, 95% CI: 1.421-1.853, P<0.001), divorced (adjusted HR =1.394, 95% CI: 1.209-1.608, P<0.001), and widowed (adjusted HR =2.460, 95% CI: 2.227-2.717, P<0.001). In particularly, widowed condition showed the highest cardiovascular death risk in all 4 unmarried subgroups. Conclusions: Unmarried condition (e.g., single, divorced and widowed) was associated with elevated cardiovascular death risk compared with their married counterparts in patients with breast cancer, suggesting that more attention and humanistic care should be paid to unmarried breast cancer patients (especially the widowed patients) in the management of female breast cancer patients.

Associations of ATP-Sensitive Potassium Channel's Gene Polymorphisms With Type 2 Diabetes and Related Cardiovascular Phenotypes.

Type 2 diabetes (T2D) is characterized by increased levels of blood glucose but is increasingly recognized as a heterogeneous disease, especially its multiple discrete cardiovascular phenotypes. Genetic variations play key roles in the heterogeneity of diabetic cardiovascular phenotypes. This study investigates possible associations of ATP-sensitive potassium channel (KATP) variants with cardiovascular phenotypes among the Chinese patients with T2D. Six hundred thirty-six patients with T2D and 634 non-diabetic individuals were analyzed in the study. Nine KATP variants were determined by MassARRAY. The KATP rs2285676 (AA + GA, OR = 1.43, 95% CI: 1.13-1.81, P = 0.003), rs1799858 (CC, OR = 1.42, 95% CI: 1.12-1.78, P = 0.004), and rs141294036 (CC, OR = 1.45, 95% CI: 1.15-1.83, P = 0.002) are associated with increased T2D risk. A follow-up of at least 45.8-months (median) indicates further association between the 3 variants and risks of diabetic-related cardiovascular conditions. The associations are categorized as follows: new-onset/recurrent acute coronary syndrome (ACS) (rs2285676/AA + GA, HR = 1.37, 95% CI: 1.10-1.70, P = 0.005; rs141294036/TT + CT, HR = 1.59, 95% CI: 1.28-1.99, P < 0.001), new-onset stroke (rs1799858/CC, HR = 2.58, 95% CI: 1.22-5.43, P = 0.013; rs141294036/CC, HR = 2.30, 95% CI: 1.16-4.55, P = 0.017), new-onset of heart failure (HF) (rs1799858/TT + CT, HR = 2.78, 95% CI: 2.07-3.74, P < 0.001; rs141294036/TT + CT, HR = 1.45, 95% CI: 1.07-1.96, P = 0.015), and new-onset atrial fibrillation (AF) (rs1799858/TT + CT, HR = 2.05, 95% CI: 1.25-3.37, P = 0.004; rs141294036/CC, HR = 2.31, 95% CI: 1.40-3.82, P = 0.001). In particular, the CC genotype of rs1799858 (OR = 2.38, 95% CI: 1.11-5.10, P = 0.025) and rs141294036 (OR = 1.95, 95% CI: 1.04-3.66, P = 0.037) are only associated with the risk of ischemic stroke while its counterpart genotype (TT + CT) is associated with the risks of HF with preserved ejection fraction (HFpEF) (rs1799858, OR = 3.46, 95% CI: 2.31-5.18, P < 0.001) and HF with mildly reduced ejection fraction (HFmrEF) (rs141294036, OR = 2.74, 95% CI: 1.05-7.15, P = 0.039). Furthermore, the 3 variants are associated with increased risks of abnormal serum levels of triglyceride (TIRG) (≥ 1.70 mmol/L), low-density lipoprotein cholesterol (LDL-C) (≥ 1.40 mmol/L), apolipoprotein B (ApoB) (≥ 80 mg/dL), apolipoprotein A-I (ApoA-I) level (< 120 mg/dL), lipoprotein(a) Lp(a) (≥ 300 mg/dL) and high-sensitivity C-reactive protein (HsCRP) (≥ 3.0 mg/L) but exhibited heterogeneity (all P < 0.05). The KATP rs2285676, rs1799858, and rs141294036 are associated with increased risks of T2D and its related cardiovascular phenotypes (ACS, stroke, HF, and AF), but show heterogeneity. The 3 KATP variants may be promising markers for diabetic cardiovascular events favoring "genotype-phenotype" oriented prevention and treatment strategies.

Association of Digoxin Application Approaches With Long-Term Clinical Outcomes in Rheumatic Heart Disease Patients With Heart Failure: A Retrospective Study.

Objective: This retrospective, case-control study was executed to assess the effects of digoxin (DGX) use approaches [continuous use of DGX (cDGX) vs. intermittent use of DGX (iDGX)] on the long-term prognosis in rheumatic heart disease (RHD) patients with heart failure (HF). Methods: A total of 642 RHD patients were enrolled to this study after propensity matching. The associations of DGX application approaches with the risks of all-cause mortality, cardiovascular death (CVD), HF re-hospitalization (1-, 3-, and 5-year), and new-onset atrial fibrillation (AF) were analyzed by multivariate Cox proportional hazards or binary logistic regression models, respectively. Results: cDGX was associated with increased risks of all-cause mortality (adjusted HR = 1.84, 95% CI: 1.27-2.65, P = 0.001) and CVD (adjusted HR = 2.23, 95% CI: 1.29-3.83, P = 0.004) in RHD patients with HF compared to iDGX. With exception of 1-year HF re-hospitalization risk, cDGX was associated with increased HF re-hospitalization risk of 3-year (adjusted OR = 1.53, 95% CI: 1.03-2.29, P = 0.037) and 5-year (adjusted OR = 1.61, 95% CI: 1.05-2.50, P = 0.031) as well as new-onset AF (adjusted OR = 2.06, 95% CI: 1.09-3.90, P = 0.027). Conclusion: cDGX was significantly associated with increased risks of all-cause mortality, CVD, medium-/long-term HF re-hospitalization, and new-onset AF in RHD patients with HF.

Impact of renin-angiotensin system inhibitors on long-term clinical outcomes of patients with rheumatic heart disease.

AIMS: Rheumatic heart disease (RHD) remains a major global health problem. Renin-angiotensin-aldosterone system inhibitors (RAASi) are commonly administered in the treatment of cardiovascular disease, but its role in RHD patients is still limited. We performed a retrospective study to determine the effect of RAASi on long-term outcomes for RHD patients. METHODS AND RESULTS: A 1:1 propensity score matching was implemented to balance baseline characteristics between groups RAASi and non-RAASi. Cox proportional hazards regression model was used to investigate the associations of RAASi with the risks of all-cause mortality, cardiovascular death (CVD), and cerebrovascular death. Binary logistic regression analysis was used to evaluate the associations of RAASi with the risks of 1, 3, and 5 year heart failure (HF) rehospitalization, new-onset atrial fibrillation (AF), and new-onset stroke. A total of 734 RHD patients were enrolled as study participants; nearly half of these participants had combined valve damage (54.4%), worse New York Heart Association functional class status (III and IV, 55.2%), surgical treatment (54.2%), and AF (65.0%). After propensity score matching, 514 RHD patients were finally analysed. RAASi treatment was associated with decreased risks of all-cause mortality [adjusted hazard ratio (HR) = 0.52, 95% confidence interval (CI): 0.37-0.73, P < 0.001], CVD (adjusted HR = 0.48, 95% CI: 0.30-0.76, P = 0.002), and cerebrovascular death (adjusted HR = 0.22, 95% CI: 0.08-0.60, P = 0.003). Further subgroup analysis showed that RAASi treatment was associated with decreased risks of all-cause mortality (adjusted HR = 0.50, 95% CI: 0.31-0.79, P = 0.004), CVD (adjusted HR = 0.48, 95% CI: 0.25-0.91, P = 0.025), and cerebrovascular death (adjusted HR = 0.19, 95% CI: 0.05-0.65, P = 0.008) in RHD patients without surgical treatment, and better effect was observed in RHD patients with surgical treatment on the risks of all-cause mortality (adjusted HR = 0.47, 95% CI: 0.26-0.85, P = 0.012) and CVD (adjusted HR = 0.43, 95% CI: 0.21-0.90, P = 0.024) except cerebrovascular death (adjusted HR = 0.52, 95% CI: 0.08-3.36, P = 0.491). RAASi treatment was associated with decreased HF rehospitalization risk of 1 year [adjusted odds ratio (OR) = 0.38, 95% CI: 0.23-0.61, P < 0.001], 3 year (adjusted OR = 0.43, 95% CI: 0.28-0.68, P < 0.001), and 5 year (adjusted OR = 0.48, 95% CI: 0.30-0.77, P = 0.002) as well as new-onset AF risk (adjusted OR = 0.38, 95% CI: 0.21-0.68, P = 0.001). RAASi treatment had nothing to do with new-onset stroke risk (adjusted OR = 0.80, 95% CI: 0.47-1.38, P = 0.428). CONCLUSION: Renin-angiotensin-aldosterone system inhibitor treatment was significantly associated with decreased risks of mortality, HF rehospitalization, and new-onset AF in RHD patients in median 5.9 year follow-up.

Cardiovascular and Other Competing Causes of Death in Male Breast Cancer Patients: A Population-Based Epidemiologic Study.

PURPOSE: Male breast cancer (MBC) is a rare disease that tends to occur in elderly men. Little is known about the causes of death in MBC because of the small sample size of most studies. This study aimed to investigate the causes of death in MBC patients. PATIENTS AND METHODS: MBC patient data were obtained from the Surveillance, Epidemiology, and End Results database (1975-2016). Time trends of MBC mortality in the US population were analyzed using Joinpoint software. We calculated the proportion of each cause of death in the overall cohort and in different patient subgroups. Competing risk models were used to calculate cumulative mortality at different follow-up times. The risk of cardiovascular death (CVD) in MBC patients was compared to that of the age-matched general population by calculating standardized mortality ratio (SMR). RESULTS: In total, 6426 patients were included in the analysis. MBC mortality rate increased between 2004 and 2019 (annual percentage change=1.16, 95% confidence interval [CI]: 0.50, 1.80). There were 1757 patients (27.3%) who died of non-breast cancer causes. CVD was the leading cause of death in patients who were elderly or had localized disease. MBC patients had a 6.58-fold higher risk of CVD than the general population (SMR=6.58, 95% CI: 6.14, 7.05). CONCLUSION: Non-breast cancer death accounts for the majority of deaths in MBC patients who are elderly or have localized cancer. Compared to the general population, MBC patients have an increased risk of CVD. These results highlight the importance of monitoring cardiovascular comorbidities in MBC patients.

Cardiovascular Death Risk in Primary Central Nervous System Lymphoma Patients Treated With Chemotherapy: A Registry-Based Cohort Study.

PURPOSE: To study the cardiovascular death (CVD) risk in primary central nervous system lymphoma (PCNSL) patients with chemotherapy. METHODS: We obtained 2,020 PCNSL participants and 88,613 non-central nervous system lymphoma (NCNSL) participants with chemotherapy from Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. A 1:3 propensity score matching (PSM) was used to reduce the imbalance between PCNSL participants with and without chemotherapy, as well as the imbalance between PCNSL and NCNSL participants with chemotherapy. Competing risks regressions were conducted to evaluate the independent influence of chemotherapy on CVD. RESULTS: After 1:3 PSM, the CVD risk in PCNSL patients with chemotherapy was lower than those without chemotherapy [decreased 53%, adjusted HR, 0.469 (95% CI, 0.255-0.862; P = 0.015)] as well as NCNSL patients with chemotherapy [decreased 36%, adjusted HR in model 1, 0.636 (95% CI, 0.439-0.923; P = 0.017)]. The CVD risk of chemotherapy decreased in PCNSL patients with age at diagnosis >60 years old [adjusted HR, 0.390 (95% CI, 0.200-0.760; P = 0.006)], and those patients diagnosed at 2010 to 2015 [adjusted HR, 0.339 (95% CI, 0.118-0.970; P = 0.044)]. CONCLUSION: PCNSL patients with chemotherapy are associated with lower CVD risk. Our findings may provide new foundations for that chemotherapy is the first-line treatment for PCNSL patients, according to a cardiovascular risk perspective.

Genetic predisposition and bioinformatics analysis of ATP-sensitive potassium channels polymorphisms with the risks of elevated apolipoprotein B serum levels and its related arteriosclerosis cardiovascular disease.

Serum concentration of apolipoprotein B (Apo B) is causally associated with arteriosclerosis cardiovascular disease (ASCVD) risk. Whether ATP-sensitive potassium channels (KATP) variants predict the risk of increased Apo B concentration (≥ 80 mg/dL) and related ASCVD remain less clear. We recruited 522 subjects with elevated Apo B concentration (≥ 80 mg/dL) and 522 counterpart subjects (< 80 mg/dL) from South China to assess the associations of KATP variants (rs11046182, rs78148713, rs145456027 and rs147265929) with the risks of increased Apo B serum concentration (≥ 80 mg/dL), carotid artery stenosis (CAS) ≥ 50% and new-onset ischemic stroke (IS). Our results showed that only KATP SNP rs11046182 (GG genotype) was associated with increased risk of Apo B ≥ 80 mg/dL (adjusted OR=2.17, P<0.001) and CAS ≥ 50% (adjusted OR=2.63, P=0.011). After median 50.6-months follow-up, subjects carrying GG genotype of rs11046182 were associated with higher risk of new-onset IS (adjusted HR=2.24, P=0.024). Further, the exosome-derived microRNAs (exo-miRs) expression profile was identified by next-generation sequencing. 41 exo-miRs were significantly differentially expressed under cross-talk status between high Apo B level (≥ 80 mg/dL) and KATP rs11046182. Our study demonstrated that KATP variant rs11046182 was associated with higher risks of elevated serum Apo B levels and its related ASCVD, and the possible mechanism was related to specific exo-miRs expression profile of KATP rs11046182.

Association of ACE2 variant rs4646188 with the risks of atrial fibrillation and cardioembolic stroke in Uygur patients with type 2 diabetes.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Type 2 diabetes (T2D) is an independent risk factor for AF. The cardioembolic stroke (CS) risk is increased when both conditions coexist. Whether angiotensin-converting enzyme 2 (ACE2) genetic variants predict increased risks AF and CS in Uygur patients with T2D remain elusive. METHODS: A total of 547 Uygur subjects (272 controls and 275 T2D patients) were recruited to the study from south Xinjiang. Eight ACE2 variants were identified by MassARRAY system. RESULTS: ACE2 rs2074192 (CC, adjusted RR = 2.55, 95% CI 1.35-4.80, P = 0.004), rs4240157 (CC + CT, adjusted RR = 2.26, 95% CI 1.27-4.04, P = 0.006) and rs4646188 (TT, adjusted RR = 2.37, 95% CI 1.16-4.86, P = 0.018) were associated with higher AF risk. ACE2 rs4240157 (CC + CT, adjusted RR = 2.68, 95% CI 1.36-5.27, P = 0.004) and rs4646188 (TT, adjusted RR = 2.56, 95% CI 1.06-6.20, P = 0.037) were further associated with higher CS risk. The 3 ACE2 variants were related to larger left atrial end-systolic diameter (LAD) (all P < 0.05), but not all of the 3 ACE2 variants were related to increased levels of serum sodium (rs4240157 and rs4646188, all P < 0.05), HsCRP (rs4240157 and rs4646188, all P < 0.05) as well as decreased serum potassium levels (rs2074192 and rs4646188, all P < 0.05). The 3 ACE2 variants exhibited heterogeneity on circulating RAAS activation. In particular, ACE2 rs4646188 was associated with higher levels of ACE (P = 0.017 and 0.037), Ang I (P = 0.002 and 0.001), Ang II (both P < 0.001) and ALD (P = 0.005 and 0.011). CONCLUSION: These results indicated ACE2 rs4646188 was associated with increased risk of AF and CS among diabetic patients in Uygurs, which could be a promising genetic predisposition marker for early and personalized prevention strategies for the aforementioned clinical pathologies.

Association of KATP Gene Polymorphisms with Dyslipidemia and Ischemic Stroke Risks Among Hypertensive Patients in South China.

ATP-sensitive potassium channels (KATP) couple vascular reactivity and metabolism with ischemic protection which makes them potential targets for prevention and management of ischemic stroke (IS). This study investigates the potential association between KATP polymorphisms and hypertension (HTN), dyslipidemia, and consequently ischemic stroke (IS). Nine hundred and fourteen (914) patients genotyped for KATP polymorphisms (rs2285676, rs1799858, rs4148671, rs61928479, and rs141294036) were analyzed. KATP rs141294036 (CC, adjusted OR = 1.59, 95%CI: 1.17-2.14, P = 0.003) was related to higher HTN risk. Meanwhile, rs2285676 (AA + GA, adjusted OR = 1.53, 95%CI: 1.08-2.19, P = 0.018) was associated with increased triglyceride level (≥ 1.7 mmol/L). rs2285676 (AA + GA, adjusted OR = 1.80, 95% CI: 1.24-2.61, P = 0.002), rs1799858 (TT + CT, adjusted OR = 1.68, 95% CI: 1.17-2.42, P = 0.005), and rs141294036 (TT + CT, adjusted OR = 1.90, 95% CI: 1.30-2.78, P = 0.001) were related to increased low-density lipoprotein cholesterol (≥ 1.8 mmol/L). rs2285676 (AA + GA, adjusted OR = 2.57, 95% CI: 1.74-3.82, P < 0.001) and rs141294036 (TT + CT, adjusted OR = 1.93, 95% CI: 1.27-2.93, P = 0.002) were related to increased apolipoprotein B (≥ 65 mg/dL). In addition, the 5 KATP polymorphisms were non-correlated with three types of dyslipidemia (total cholesterol, high-density lipoprotein cholesterol, and apolipoprotein AI). After median 50.6 month of follow-up, participants carrying CC genotype of rs141294036 showed correlation with elevated risk of new onset IS (adjusted HR = 2.55, 95% CI: 1.23-5.27, P = 0.012). These novel findings suggest that KATP rs141294036 is associated with increased risk of HTN, dyslipidemia, and IS. Based on these correlations, KATP rs141294036 could be a promising target for early and personalized therapeutics as well as prevention strategies for the aforementioned clinical pathologies.

Outcomes of diuretics in rheumatic heart disease with compensated chronic heart failure: a retrospective study.

AIMS: The purpose of this retrospective propensity score-matched study was to evaluate the superiority of different application approaches [continuous diuretics use (CDU) vs. intermittent diuretics use (IDU)] and types [loop diuretics (LDs) vs. thiazide diuretics (TDs)] of diuretics on long-term outcomes for rheumatic heart disease (RHD) patients with compensated chronic heart failure (CHF). METHODS AND RESULTS: A total of 494 RHD patients with compensated CHF were analysed after propensity score matching. Cox proportional hazards regression model was used to investigate the associations of different diuretic application approaches and types with all-cause mortality, cardiovascular death (CVD), and cerebrovascular death. Binary logistic regression analyses were used to evaluate the associations of different diuretic application approaches and types with 1-, 3-, and 5-year heart failure (HF) re-hospitalization as well as new-onset atrial fibrillation (AF). In the comparison between IDU and CDU strategies for RHD patients with compensated CHF, CDU was associated with increased risks of all-cause mortality [adjusted hazard ratio (HR) = 2.47, 95% confidence interval (CI): 1.54-3.97, P < 0.001] and CVD (adjusted HR = 3.67, 95% CI: 1.95-6.89, P < 0.001) except cerebrovascular death (adjusted HR = 1.07, 95% CI: 0.34-3.41, P = 0.905). CDU was also associated with increased risks of 3-year [adjusted odds ratio (OR) = 1.80, 95% CI: 1.09-2.96, P = 0.022] and 5-year (adjusted OR = 2.02, 95% CI: 1.18-3.45, P = 0.010) HF re-hospitalization risk and new-onset AF (adjusted OR = 2.34, 95% CI: 1.31-4.20, P = 0.004) except 1-year HF re-hospitalization risk (adjusted OR = 1.54, 95% CI: 0.88-2.70, P = 0.130). In the comparison between TDs and LDs among study participants receiving IDU strategy, LDs were only associated with decreased 1-year HF re-hospitalization risk (adjusted OR = 0.30, 95% CI: 0.12-0.77, P = 0.012) rather than all-cause mortality, CVD, cerebrovascular death, 3- and 5-year HF re-hospitalization, and new-onset AF (all adjusted P > 0.05). In the comparison between TDs and LDs among study participants receiving CDU strategy, LDs were not associated with cerebrovascular death and 1-year HF re-hospitalization (both adjusted P > 0.05) but with increased risks of all-cause mortality (adjusted HR = 1.80, 95% CI: 1.09-2.99, P = 0.023), CVD (adjusted HR = 1.89, 95% CI: 1.04-3.44, P = 0.037), 3-year (adjusted OR = 1.91, 95% CI: 1.06-3.43, P = 0.031) and 5-year (adjusted OR = 2.16, 95% CI: 1.12-4.19, P = 0.022) HF re-hospitalization, and new-onset AF (adjusted OR = 2.66, 95% CI: 1.25-5.68, P = 0.012). CONCLUSIONS: Continuous diuretics use (especially LDs) was associated with increased risks of all-cause mortality, CVD, medium-term/long-term HF re-hospitalization, and new-onset AF in RHD patients with compensated CHF.

ATP-sensitive potassium channels gene polymorphism rs1799858 affects the risk of macro-/micro-vascular arteriosclerotic event in patients with increased low-density lipoprotein cholesterol levels.

BACKGROUND: Plasma concentration of low-density lipoprotein cholesterol (LDL-C) is causally related to the risk of arteriosclerotic events. Whether ATP-sensitive potassium channels (KATP) genetic variants predict increased LDL-C concentration (≥1.8 mmol/L) and risk of macro-/micro-vascular arteriosclerotic event remain elusive. METHODS: A total of 320 subjects with increased LDL-C concentration (≥1.8 mmol/L) and 320 counterpart subjects (< 1.8 mmol/L) from the South China were enrolled in this study. Three KATP polymorphisms (rs1799858, rs4148671 and rs78148713) were genotyped by the Sequenom MassARRAY system. Binary logistic regression analysis was used to evaluate the association of the 3 KATP variants with increased LDL-C concentration and carotid artery stenosis (CAS) ≥50%. Two-way ANOVA was used to analyze the association of the 3 KATP variants with microalbumin in urine (MAU) and high-sensitivity C-reactive protein (HsCRP) levels. Cox proportional hazards regression analysis was used to retrospectively analyse the association of the optimal variant with the risk of new onset/recurrent acute myocardial infarction (AMI). RESULTS: Among the 3 studied KATP gene single nucleotide polymorphisms (SNPs), only rs1799858 (TT + CT genotype) was associated with elevated risk of LDL-C ≥ 1.8 mmol/L (adjusted OR = 2.25, 95% CI: 1.31-3.85, P = 0.003) and CAS ≥50% (adjusted OR = 2.80, 95% CI: 1.12-6.98, P = 0.028). KATP SNP rs1799858 was also associated with increased MAU (P = 0.013) and HsCRP (P = 0.027) levels. The follow-up for an average of 51.1-months revealed that participants carrying the T-allele (TT + CT) of rs1799858 was associated with high risk of new onset/recurrent AMI (adjusted HR = 2.90, 95% CI: 1.06-7.94, P = 0.038). CONCLUSION: The KATP SNP rs1799858 may be an optimal genetic predisposition marker for increased LDL-C concentration (≥1.8 mmol/L) and its related macro-/micro-vascular arteriosclerotic event risk. The KATP variant rs1799858 was associated with higher risk of macro-/micro-vascular arteriosclerotic events in patients with elevated serum LDL-C levels.

Prognostic Impacts of Tumour Size on Patients With Primary Cardiac Sarcoma.

BACKGROUND: Primary cardiac sarcoma (PCS) is a deadly disease. The impacts of tumour size on prognosis and surgical outcomes in PCS patients remains unclear. Here, we evaluate the impact of tumour size on overall survival (OS) and cancer-specific survival (CSS) of PCS patients to provide a reference for the surgical treatment. METHODS: A total of 261 PCS participants enrolled from 1983 to 2016 were identified from the Surveillance, Epidemiology, and End Results database. Using the X-tile program, we classified the tumour size into 2 subgroups: ≤ 4.0 cm and > 4.0 cm. The Kaplan-Meier method was used to determine OS and CSS. Univariate and multivariate Cox regression analyses were used to identify the independent prognostic impacts of tumour size and surgery in the 2 subgroups (≤ 4.0 cm vs > 4.0 cm). RESULTS: With the use of 4.0 cm as a cutoff value, tumour size seemed to be an independent prognostic factor for OS (P = 0.009) and CSS (P = 0.014) of PCS patients. Surgery improved the OS (P = 0.017) and CSS (P = 0.040) in PCS patients with tumour size > 4.0 cm but not in with tumour size ≤ 4.0 cm (both P > 0.05). CONCLUSIONS: Tumour size of > 4.0 cm is an independent predictor of poor prognosis and is associated with the surgical outcomes in PCS patients. Surgery significantly improves the prognosis in PCS patients with tumour size > 4.0 cm. Our findings have the potential to assist clinicians to better evaluate the prognosis of PCS patients and develop optimal therapeutic strategies.