Frailty related all-cause mortality or hospital readmission among adults aged 65 and older with stage-B heart failure inpatients.

BACKGROUND: Frailty increases the adverse outcomes of clinical heart failure; however, the relationship between frailty and stage-B heart failure (SBHF) remains unknown. We aimed to explore the epidemiology and predictive value of frailty in older adults with SBHF. METHODS: A prospective cohort of SBHF inpatients aged 65 years or older who were hospitalized between September 2018 and February 2019 and were followed up for 6 months were included. SBHF was defined as systolic abnormality, structural abnormality (left ventricular enlargement, left ventricular hypertrophy, wall motion abnormalities, valvular heart disease), or prior myocardial infarction. Frailty was assessed by the Fried frailty phenotype. Multivariable Cox proportional hazards regression was used to explore the independent risk and prognostic factors. RESULTS: Data of 443 participants (age: 76.1 ± 6.79 years, LVEF: 62.8 ± 4.92%, men: 225 [50.8%], frailty: 109 [24.6%]) were analyzed. During the 6-month follow-up, 83 (18.7%) older SBHF inpatients experienced all-cause mortality or readmission, and 29 (6.5%) of them developed clinical HF. Frail individuals had a 1.78-fold (95%CI: 1.02-3.10, P = 0.041) higher risk of 6-month mortality or readmission and a 2.83-fold (95%CI 1.24-6.47, P = 0.014) higher risk of developing clinical HF, independent of age, sex, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide level. CONCLUSIONS: Frailty is common in older SBHF inpatients and should be considered to help identify individuals with an increased risk of mortality or readmission, and developing clinical HF. TRIAL REGISTRATION: ChiCTR1800017204 .

Predicting non-elective hospital readmission or death using a composite assessment of cognitive and physical frailty in elderly inpatients with cardiovascular disease.

BACKGROUND: We aimed to assess the utility of the combination of the mini-mental state examination (MMSE) + clock drawing test (CDT) and the Fried phenotype for predicting non-elective hospital readmission or death within 6 months in elderly inpatients with cardiovascular disease (CVD). METHODS: A single-center prospective cohort was conducted from September 2018 to February 2019. Inpatients ≥65 years old were recruited. Predictive validity was tested using a Cox proportional hazards regression model analysis, and the discriminative ability was evaluated by the receiver operating characteristic (ROC) curve. RESULTS: A total of 542 patients were included. Overall, 12% (64/542) screened positive for cognitive impairment, 16% (86/542) were physically frail and 8% (44/542) had cognitive impairment combined with physical frailty, showing an older age (P < 0.001) and a lower education level (P < 0.001) than physically frail patients. A total of 113 patients (20.9%) died or were readmitted at 6 months. Frail participants with a normal (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.06-2.82, P = 0.028) or impaired cognition (HR: 2.50, 95% CI: 1.27-4.91, P = 0.008) had a higher risk of non-elective hospital readmission or death than robust patients after adjusting for the age, sex, education level, marital status, the presence of diabetes mellitus, heart failure, and history of stroke. The area under the ROC curve (AUC) showed that the discriminative ability in relation to 6 months readmission and death for the MMSE + CDT + Fried phenotype was 0.65 (95% CI: 0.60-0.71), and the AUC for men was 0.71 (95% CI: 0.63-0.78), while that for women was 0.60 (95% CI: 0.51-0.69). CONCLUSIONS: Accounting for cognitive impairment in the frailty phenotype may allow for the better prediction of non-elective hospital readmission or death in elderly inpatients with CVD in the short term. TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018.

Glycated Hemoglobin Variability Is Associated With Adverse Outcomes in Patients With Heart Failure Irrespective of Diabetic Status.

BACKGROUND: The effect of glycated hemoglobin (HbA1c) variability on adverse outcomes in patients with heart failure (HF) is unclear. We aim to investigate the predictive value of HbA1c variability on the risks of all-cause death and HF rehospitalization in patients with HF irrespective of their diabetic status. METHODS AND RESULTS: Using a previously validated territory-wide clinical data registry, HbA1c variability was assessed by average successive variability (ASV) or SD of all HbA1c measurements after HF diagnosis. Multivariable Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) and its corresponding 95% CI. A total of 65 950 patients with HF were included in the study. Over a median follow-up of 6.7 (interquartile range, 4.0-10.6) years, 34 508 patients died and 52 446 required HF rehospitalization. Every unit increment of variability in HbA1c was significantly associated with higher HF rehospitalization (HR ASV, 1.20 [95% CI, 1.18-1.23]) and all-cause death (HR ASV, 1.50 [95% CI, 1.47-1.53]). Diabetes significantly modified the association between HbA1c variability and outcomes (Pinteraction<0.001). HbA1c variability in patients with HF without diabetes conferred a higher risk of rehospitalization (HR ASV, 1.92 [95% CI, 1.70-2.17] versus HR ASV, 1.19 [95% CI, 1.17-1.21]), and all-cause death (HR ASV, 3.90 [95% CI, 3.31-4.61] versus HR ASV, 1.47 [95% CI, 1.43-1.50] compared with patients with diabetes). CONCLUSIONS: HbA1c variability is significantly associated with greater risk of rehospitalization and all-cause death in patients with HF, irrespective of their diabetic status. These observations were more pronounced in patients with HF without diabetes.

[Reduced estimated glomerular filtration rate and proteinuria are associated with increased cardiovascular events rate in octogenarian population].

OBJECTIVE: To determine the relationship between estimated glomerular filtration rate (eGFR) and proteinuria with cardiovascular events in subjects aged 80 years or older. METHODS: Data for this retrospective prognostic study were drawn from the patient database for routine checkup in Beijing hospital between January 2001 to December 2001. Baseline eGFR and proteinuria were evaluated in 340 subjects [mean age: (85.6 ± 4.0) years]. eGFR was calculated using the modified abbreviated MDRD equations based on the Chinese chronic kidney disease patients. The subjects were divided into normal renal function group and reduced renal function group (eGFR <60 ml·min(-1)·1.73 m(-2)). The subjects were divided into subjects without proteinuria and subjects with proteinuria group. Cardiovascular events included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke. RESULTS: The proportion of reduced renal function was 36.8% (125/340). The proportion of proteinuria was 10.3% (35/340). The proportion of reduced renal function or proteinuria was 41.8% (142/340). Follow-up time was 79 months (40-114 months). Cardiovascular events rate was significantly higher in reduced renal function group than in normal renal function group [37.6% (47/125) vs. 26.2% (55/210), P < 0.05 ] and in proteinuria group than in without proteinuria group [50.0% (17/34) vs. 28.2% (85/301), P < 0.01 ]. Cox multivariate analysis revealed that both eGFR (HR = 0.978, 95%CI:0.961-0.994, P < 0.05 ) and proteinuria (HR = 2.049, 95%CI:1.132-3.709, P < 0.05) were independent risk factors for cardiovascular events after adjusting for age, gender, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, uric acid, hypertension, coronary heart disease, diabetes mellitus. CONCLUSIONS: Reduced eGFR and presence of proteinuria are independent risk factors for cardiovascular event in subjects aged 80 years or older. eGFR and proteinuria can thus be used for cardiovascular event risk stratification in subjects aged 80 years or older.

[Glucometabolic abnormalities survey among outpatients without previous diabetes diagnosis and with coronary artery disease and hypertension].

OBJECTIVE: To explore the status of glucometabolic abnormalities in cardiological outpatients without previous diabetes diagnosis and with coronary artery disease (CAD) and hypertension. METHODS: Patients without previous diagnosis of diabetes but with hypertension and CAD aged 18 years or above were recruited from cardiology departments of 11 general hospitals in China. Demographic data, disease diagnosis and medical history were collected. Physical examination and questionnaire survey were performed after the random blood glucose test. Oral glucose tolerance test (OGTT) examination was made for patients with fasting blood glucose ≥ 6.1 mmol/L or postprandial random glucose ≥ 7.8 mmol/L. Adjusted prevalence rates were used in the study. RESULTS: A total of 7778 patients were included in 11 centers. After preliminary screening by fasting blood glucose and random blood glucose tests, 3861 patients were required to take OGTT, and 3019 (78.2%) patients actually took the test. 1287 out of 3019 patients screened with OGTT were diagnosed with diabetes, and the adjusted diabetes prevalence rate was 18.64% (1287/6904). The prevalence rate of diabetes was 19.87% (95/478), 9.22% (352/3819) and 14.81% (153/1033) in patients with CAD, hypertension, and CAD combined with hypertension, respectively. A total of 996 patients were diagnosed with impaired glucose tolerance (IGT) and its prevalence was 14.43% (996/6904). Of the enrolled population, 153 patients with random blood glucose lower than 7.8 mmol/L were also screened with OGTT test, 26.14% (40/153) patients met the diagnostic criteria of diabetes. CONCLUSION: A high prevalence of diabetes is found in patients without previous diagnosis of diabetes and with hypertension and CAD consulting at cardiology departments. We thus suggest to perform OGTT in this patient cohort to improve the early diagnosis of IGT and diabetes, and prevent missed detection of type 2 diabetes mellitus or IGT in cardiovascular patients with normal fasting blood glucose. Our results indicate that it was feasible to use OGTT as a screening tool for detecting diabetes in these patients and the patient compliance is satisfactory.

Prevalence and prognosis of frailty in older patients with stage B heart failure with preserved ejection fraction.

AIMS: Frailty in older patients with stage B heart failure with preserved ejection fraction (HFpEF) has not been fully explored. We evaluated the prevalence and prognostic significance of frailty in older patients diagnosed with stage B HFpEF. METHODS: Our prospective cohort study included inpatients aged ≥65 years who were followed up for 3 years. Stage B HFpEF was defined as cardiac structural or functional abnormalities with a left ventricular ejection fraction (LVEF) ≥ 50% without signs or symptoms. Frailty was assessed using the Fried phenotype. The primary outcome was 3-year all-cause mortality or readmission. RESULTS: Overall, 520 older inpatients diagnosed with stage B HFpEF [mean ± standard deviation age: 75.5 ± 6.25 years, male: 222 (42.7%)] were included in the study. Of these, 145 (27.9%) were frail. Frail patients were older (78.5 ± 6.23 vs. 74.3 ± 6.22 years, P < 0.001), with a lower body mass index (24.6 ± 3.60 vs. 25.7 ± 3.27 kg/m2 , P = 0.001), higher level of N-terminal pro-B-type natriuretic peptide [279 (interquartile range: 112.4, 596) vs. 140 (67.1, 266) pg/mL, P < 0.001], longer timed up-and-go test result (19.9 ± 9.71 vs. 13.3 ± 5.08 s, P < 0.001), and poorer performance in the short physical performance battery (4.1 ± 3.26 vs. 8.2 ± 2.62, P < 0.001), basic activities of daily living (BADL, 4.7 ± 1.71 vs. 5.7 ± 0.57, P < 0.001), and instrumental activities of daily living (IADL, 4.4 ± 2.73 vs. 7.4 ± 1.33, P < 0.001). Frail patients were more likely to have a Mini-Mental State Examination (MMSE) score <24 (55.9% vs. 28.8%, P < 0.001) and take more than five medications (64.1% vs. 47.2%, P = 0.001). Frail patients had a higher incidence of all-cause mortality or readmission (62.8% vs. 47.7%, P = 0.002), all-cause readmission (56.6% vs. 45.9%, P = 0.029), and readmission for non-heart failure (55.2% vs. 41.3%, P = 0.004) during the 3-year follow-up, with a 1.53-fold (95%CI 1.11-2.11, P = 0.009) higher risk of all-cause mortality or readmission, a 1.52-fold (95%CI 1.09-2.11, P = 0.014) higher risk of all-cause readmission, and a 1.70-fold (95%CI 1.21-2.38, P = 0.002) higher risk of readmission for non-clinical heart failure, adjusted for sex, age, polypharmacy, Athens Insomnia Scale, MMSE, LVEF, BADL, and IADL. CONCLUSIONS: Frailty is common in elderly patients with stage B HFpEF. Physical frailty, particularly low physical activity, can independently predict the long-term prognosis in these patients.

Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population.

Cytochrome 2C9 (CYP2C9), one of the most important drug metabolic enzymes in the human hepatic P450 superfamily, is required for the metabolism of 15% of clinical drugs. Similar to other CYP2C family members, CYP2C9 gene has a high genetic polymorphism which can cause significant racial and inter-individual differences in drug metabolic activity. To better understand the genetic distribution pattern of CYP2C9 in the Chinese Han population, 931 individuals were recruited and used for the genotyping in this study. As a result, seven synonymous and 14 non-synonymous variations were identified, of which 4 missense variants were designated as new alleles CYP2C9*72, *73, *74 and *75, resulting in the amino acid substitutions of A149V, R150C, Q214H and N418T, respectively. When expressed in insect cell microsomes, all four variants exhibited comparable protein expression levels to that of the wild-type CYP2C9 enzyme. However, drug metabolic activity analysis revealed that these variants exhibited significantly decreased catalytic activities toward three CYP2C9 specific probe drugs, as compared with that of the wild-type enzyme. These data indicate that the amino acid substitution in newly designated variants can cause reduced function of the enzyme and its clinical significance still needs further investigation in the future.

TRB3 mediates homocysteine-induced inhibition of endothelial cell proliferation.

Hyperhomocysteinemia (HHcy) has been shown to induce endothelial dysfunction, an early event in the progression of atherosclerosis. However, the underlying mechanism of endothelial cell injury in HHcy has not been clearly elucidated. In this study, we examined the effect of homocysteine on tribbles-related protein 3 (TRB3)-mediated cell-cycle arrest in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with homocysteine (0-250 µmol/L) resulted in inhibition of cell proliferation assessed by [(3)H]-thymidine incorporation into DNA. Homocysteine induced cell-cycle arrest in the G1 phase by up-regulating the protein levels of p27(kip1). Under these conditions, homocysteine did not induce endoplasmic reticulum stress. However, homocysteine up-regulated the expression of TRB3, thus leading to the dephosphorylation of Akt (Thr308). Knock-down of endogenous TRB3 using siRNA significantly suppressed the inhibitory effect of homocysteine on the proliferation of HUVECs. Homocysteine-induced TRB3 expression was mediated by the cAMP/cAMP response element-binding protein (CREB) pathway. These results demonstrate that TRB3 is a critical molecule in the homocysteine-mediated cell-cycle arrest in endothelial cells.

Adding high-sensitivity C-reactive protein to frailty assessment to predict mortality and cardiovascular events in elderly inpatients with cardiovascular disease.

OBJECTIVE: Chronic inflammation is associated with major adverse cardiovascular events (MACEs), mortality, and frailty. Our aim was to add high-sensitivity C-reactive protein (hsCRP) to the frailty assessment to predict its association with prognosis of older adults with cardiovascular disease (CVD). METHODS: A comprehensive geriatric assessment was conducted at baseline in 720 in-patients aged ≥65 years with CVD. We divided the population into frailty and non-frailty groups according to the Fried phenotype, and hsCRP was further combined with frailty to stratify all patients into c-frailty and non-c-frailty groups. Predictive validity was tested using Cox proportional hazards regression model analysis and the discriminative ability was evaluated by receiver operating characteristic (ROC) curves. RESULTS: Of all the subjects enrolled, 51.0% were male and the mean age was 75.32 ± 6.52 years. The all-cause death and MACE rate was 6.4% at the 1-year follow-up. Frailty and c-frailty were independent predictors of all-cause death and MACE (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.35-4.83, p = 0.004; HR: 3.67, 95% CI: 1.83-7.39, p < 0.001). Adding hsCRP to the frailty model resulted in a significant increase in the area under the ROC curve from 0.74 (95% CI: 0.70-0.77) to 0.77 (95% CI: 0.71-0.84) (p = 0.0132) and a net reclassification index of 7.9% (95% CI: 1.96%-12.56%, p = 0.012). CONCLUSION: Adding hsCRP to the frailty assessment is helpful to identify a subgroup of older CVD patients with a higher risk of death and MACE over a period of 1 year. TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018. URL: http://www.chictr.org.cn/showproj.aspx?proj=28931.

Development and Validation of an Electronic Frailty Index Using Routine Electronic Health Records: An Observational Study From a General Hospital in China.

Background: This study aimed to develop and validate an electronic frailty index (eFI) based on routine electronic health records (EHR) for older adult inpatients and to analyze the correlations between frailty and hospitalized events and costs. Methods: We created an eFI from routine EHR and validated the effectiveness by the consistency of the comprehensive geriatric assessment-frailty index (CGA-FI) with an independent prospective cohort. Then, we analyzed the correlations between frailty and hospitalized events and costs by regressions. Results: During the study period, 49,226 inpatients were included in the analysis, 42,821 (87.0%) of which had enough data to calculate an eFI. A strong correlation between the CGA-FI and eFI was shown in the validation cohort of 685 subjects (Pearson's r = 0.716, P < 0.001). The sensitivity and specificity for an eFI≥0.15, the upper tertile, to identify frailty, defined as a CGA-FI≥0.25, were 64.8 and 88.7%, respectively. After adjusting for age, sex, and operation, an eFI≥0.15 showed an independent association with long hospital stay (odds ratio [OR] = 2.889, P < 0.001) and death in hospital (OR = 19.97, P < 0.001). Moreover, eFI values (per 0.1) were positively associated with total costs (ß = 0.453, P < 0.001), examination costs (ß = 0.269, P < 0.001), treatment costs (ß = 0.414, P < 0.001), nursing costs (ß = 0.381, P < 0.001), pharmacy costs (ß = 0.524, P < 0.001), and material costs (ß = 0.578, P < 0.001) after adjusting aforementioned factors. Conclusions: We successfully developed an effective eFI from routine EHR from a general hospital in China. Frailty is an independent risk factor for long hospital stay and death in hospital. As the degree of frailty increases, the hospitalized costs increase accordingly.

Urinary 8-OxoGsn as a Potential Indicator of Mild Cognitive Impairment in Frail Patients With Cardiovascular Disease.

Oxidative RNA damage has been found to be associated with age-related diseases and 8-oxo-7,8-dihydroguanosine (8-oxoGsn) is a typical marker of oxidative modification of RNA. Urine tests are a feasible non-invasive diagnostic modality. The present study aimed to assess whether the measurement of urinary 8-oxoGsn could represent a potential early maker in mild cognitive impairment (MCI) of frail patients with cardiovascular disease (CVD). In this cross-sectional study performed in China from September 2018 to February 2019. Urinary 8-oxoGsn was measured in frail (Fried phenotype: 3-5) in patients with CVD and was adjusted by urinary creatinine (Cre) levels. Cognitive function was assessed by the Chinese version of the Mini-Mental State Examination (MMSE) and participants were classified into non-MCI (≥24) and MCI (<24) groups. Univariate and multivariate logistic regression models were used to determine the relationship between 8-oxoGsn/Cre and MCI. Receiver operating characteristic (ROC) curve analysis was used to assess the 8-oxoGsn/Cre ratio in relation to MCI in frail patients with CVD. A total of 106 elderly patients were enrolled in this study. The mean age of participants was 77.9 ± 6.8 years, the overall prevalence of MCI was 22.6% (24/106), and 57.5% (61/106) of participants were women. In the multivariate logistic regression analysis, urinary 8-oxoGsn/Cre was independently associated with MCI (odds ratio [OR] = 1.769, 95% confidence interval [CI] = 1.234-2.536, P = 0.002), after adjusting for age, sex, education level, marital status, and serum prealbumin levels. The area under the ROC curve was 0.786 (0.679-0.893) (P < 0.001), and the optimal cut-off value was 4.22 µmol/mol. The urinary 8-oxoGsn/Cre ratio showed a sensitivity of 87.5% and a specificity of 69.5%. The present study suggests the urinary 8-oxoGsn/Cre ratio may be a useful indicator for the early screening of MCI in frail patients with CVD. CLINICAL TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018. URL: http://www.chictr.org.cn/showproj.aspx?proj=28931.

Prevalence and Prognostic Value of Heart Failure Stages: An Elderly Inpatient Based Cohort Study.

Background: The prevalence and prognostic value of heart failure (HF) stages among elderly hospitalized patients is unclear. Methods: We conducted a prospective, observational, multi-center, cohort study, including hospitalized patients with the sample size of 1,068; patients were age 65 years or more, able to cooperate with the assessment and to complete the echocardiogram. Two cardiologists classified all participants in various HF stages according to 2013 ACC/AHA HF staging guidelines. The outcome was rate of 1-year major adverse cardiovascular events (MACE). The Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. Survival classification and regression tree analysis were used to determine the optimal cutoff of N-terminal pro-brain natriuretic peptide (NT-proBNP) to predict MACE. Results: Participants' mean age was 75.3 ± 6.88 years. Of them, 4.7% were healthy and without HF risk factors, 21.0% were stage A, 58.7% were stage B, and 15.6% were stage C/D. HF stages were associated with worsening 1-year survival without MACE (log-rank χ2 = 69.62, P < 0.001). Deterioration from stage B to C/D was related to significant increases in HR (3.636, 95% CI, 2.174-6.098, P < 0.001). Patients with NT-proBNP levels over 280.45 pg/mL in stage B (HR 2; 95% CI 1.112-3.597; P = 0.021) and 11,111.5 pg/ml in stage C/D (HR 2.603, 95% CI 1.014-6.682; P = 0.047) experienced a high incidence of MACE adjusted for age, sex, and glomerular filtration rate. Conclusions : HF stage B, rather than stage A, was most common in elderly inpatients. NT-proBNP may help predict MACE in stage B. Trial Registration: ChiCTR1800017204; 07/18/2018.

Functional characterization of the defective CYP2C9 variant CYP2C9*18.

Cytochrome P450 2C9 (CYP2C9) is one of the most important drugs metabolizing enzymes and accounts for the metabolism of about 13%-17% of clinical drugs. Like other members in CYP2 family, CYP2C9 gene exhibits great genetic polymorphism among different races and individuals. CYP2C9*18 is one CYP2C9 allelic variant identified in a Southeast Asian population and is estimated to cause the amino acid substitutions of I359L and D397A in CYP2C9 enzyme simultaneously. Limited by the low expression level in bacteria and COS-7 cells, no valuable enzyme kinetics have been reported on this CYP2C9 variant. In this study, the baculovirus-based system was used for the high expression of recombinant CYP2C9 s in insect cells. As a result, together with I359L substitution, D397A could significantly decrease the protein expression of CYP2C9.18 in insect cells, although substitution of D397A alone had no effect on the expression of CYP2C9 in vitro. As compared with that of wild-type enzyme, both CYP2C9.18 variant and D397A variant could decrease more than 80% of the catalytic activity of CYP2C9 enzyme toward three probe substrates, suggesting that caution should be exercised when patients carrying CYP2C9*18 taking medicines metabolized by CYP2C9 enzyme with a narrow therapeutic window.

Identification of Co-expressed Genes Between Atrial Fibrillation and Stroke.

Atrial fibrillation (AF) increases the risk of ischemic stroke and systemic arterial embolism. However, the risk factors or predictors of stroke in AF patients have not been clarified. Therefore, it is necessary to find effective diagnostic and therapeutic targets. Two datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differently expressed genes (DEGs) were identified between samples of atrial fibrillation without stroke and atrial fibrillation with stroke. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) by Gene Set Enrichment Analysis (GSEA), construction and analysis of protein-protein interaction (PPI) network and significant module, and the receiver operator characteristic (ROC) curve analysis were performed. A total of 524 DEGs were common to both datasets. Analysis of KEGG pathways indicated that the top canonical pathways associated with DEGs were ubiquitin-mediated proteolysis, endocytosis, spliceosome, and so on. Ten hub genes (SMURF2, CDC42, UBE3A, RBBP6, CDC5L, NEDD4L, UBE2D2, UBE2B, UBE2I, and MAPK1) were identified from the PPI network and were significantly associated with a diagnosis of atrial fibrillation and stroke (AFST). In summary, a total of 524 DEGs and 10 hub genes were identified between samples of atrial fibrillation without stroke and atrial fibrillation with stroke. These genes may serve as the target of early diagnosis or treatment of AF complicated by stroke.

Trimethylamine N-Oxide, a Gut Microbiota-Dependent Metabolite, is Associated with Frailty in Older Adults with Cardiovascular Disease.

OBJECTIVE: Our study aimed to explore the association between trimethylamine N-oxide and frailty in older adults with cardiovascular disease. PATIENTS AND METHODS: This cross-sectional study analyzed a total of 451 people aged 65 years or older who underwent comprehensive geriatric assessments. Frailty status was determined using a frailty index constructed with 48 variables according to the cumulative deficits model. Physical frailty and cognitive frailty were also assessed in detail. Fasting plasma TMAO was measured by mass spectrometry. RESULTS: The proportion of frail subjects was 29.9% (135/451). Plasma TMAO levels were significantly higher in frail patients than in nonfrail individuals (4.04 [2.84-7.01] vs 3.21 [2.13-5.03] µM; p<0.001). Elevated plasma TMAO levels were independently associated with the likelihood of frailty (OR 2.12, 95% CI 1.01-4.38, p=0.046). Dose-response analysis revealed a linear association between the TMAO concentration and the OR for frailty. A 2-unit increase in TMAO was independently correlated with physical frailty (OR 1.23, 95% CI 1.08-1.41, p for trend 0.002) and cognitive frailty (OR 1.21, 95% CI 1.01-1.45, p for trend 0.04). CONCLUSION: Elevated circulating TMAO levels are independently associated with frailty among older adults with cardiovascular disease.

Prevalence and Prognostic Significance of Frailty in Gerontal Inpatients With Pre-clinical Heart Failure: A Subgroup Analysis of a Prospective Observational Cohort Study in China.

Objective: To evaluate the prognostic value of frailty in gerontal pre-clinical heart failure (stage B heart failure, SBHF) inpatients. Background: The association between frailty and SBHF remains unknown. Methods: We conducted a subgroup analysis of a prospective observational cohort study on frailty. The previous study recruited 1,000 elderly inpatients who were consecutively admitted to a tertiary referral hospital in Beijing, China, from September 2018 to February 2019. The outcomes were all-cause death or readmission at 1-year follow-up. SBHF was diagnosed for asymptomatic cardiac structural or functional abnormalities. Frailty was assessed using the Comprehensive Geriatric Assessment-Frailty Index (CGA-FI). Results: Overall, 531 inpatients aged ≥65 years were deemed to have SBHF and followed up for 1 year. Of them, 34.5% exhibited frailty. During the follow-up period, all-cause death or readmission occurred in 157 (29.5%) participants. Of these participants, 36.6% (67/183) and 25.9% (90/348) belonged to the frail and non-frail groups, respectively (χ2 = 6.655, P = 0.010). Frailty, defined by the CGA-FI, rather than Fried frailty phenotype, could independently predict 1-year all-cause death or readmission (hazard ratio, 1.56; 95% confidence interval, 1.03-2.35; P = 0.034) and was more suitable for predicting all-cause death or readmission than N-terminal pro-B-type natriuretic peptide in female SBHF inpatients aged 80 years or over(AUCCGA-FI vs. AUCNT-proBNP 0.654 vs. 0.575, P = 0.017). Conclusions: Frailty is highly prevalent even among SBHF inpatients aged ≥65 years. The CGA-FI can independently predict 1-year all-cause death or readmission, rather than Fried frailty phenotype. Frailty in gerontal SBHF inpatients deserves more attention. Clinical Trial registration: ChiCTR1800017204; date of registration: 07/18/2018.

An identification and functional evaluation of a novel CYP2C9 variant CYP2C9*62.

Warfarin is the most commonly used anticoagulant in the clinical treatment of thromboembolic diseases. The dose of warfarin varies significantly within populations, and the dose is closely related to the genetic polymorphisms of the CYP2C9 and VKORC1 genes. In this study, a new CYP2C9 nonsynonymous mutation (8576C > T) was detected after the genetic screening of 162 patients took warfarin. This mutation, named as the new allele CYP2C9*62, can result in an arginine to cysteine amino acid substitution at position 125 of the CYP2C9 protein (R125C). When expressed in insect cells, the protein expression of CYP2C9.62 was significantly lower than that of the wild-type, and its metabolic activity was also significantly decreased after the addition of three typical CYP2C9 probe drugs, suggesting that the new mutant can dramatically affect the metabolism of CYP2C9 drugs in vitro.

Urinary 8-oxo-7,8-dihydroguanosine as a potential biomarker of frailty for elderly patients with cardiovascular disease.

The diagnosis of frailty is usually subjective, which calls for objective biomarkers in clinical medicine. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGsn) and 8-oxo-7, 8-dihydroguanosine (8-oxoGsn) in urine are two aging biomarkers that have not been explored deeply in cases of frailty. A total of 508 elderly patients with cardiovascular disease (mean age 75.0 ± 6.5 years, 50.8% males) were enrolled consecutively. Frailty was assessed by the Fried phenotype (robust: 0 score; pre-frail: 1-2 scores; frail: 3-5 scores). The concentrations of 8-oxoGsn and 8-oxodGsn in urine were measured by improved ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Urinary creatinine (Cre) was tested to correct the 8-oxoGsn and 8-oxodGsn levels. According to the Fried phenotype score, the proportions of robust, pre-frail, and frail subjects were 20.5% (104/508), 53.9% (274/508), and 25.6% (130/508), respectively. The urinary 8-oxoGsn/Cre (P < 0.001) differed significantly among these 3 groups, but the urinary 8-oxodGsn/Cre (P = 0.600) showed no marked difference. Univariate and multivariate logistic regression showed that the age (odds ratio [OR] = 1.090, P < 0.001), systolic blood pressure (OR = 0.981, P = 0.008), 8-oxoGsn/Cre (OR = 1.203, P = 0.007), hemoglobin (OR = 0.980, P = 0.007), and sodium (OR = 0.915, P = 0.044) were independently associated with frailty. The sensitivity and specificity to identify frailty were 53.08% and 71.96%, respectively, for 8-oxoGsn/Cre at the optimal cut-off value of 3.879 µmol/mol according to the maximal Youden index. Urinary 8-oxoGsn, as a recognized biomarker of RNA oxidation, is independently associated with frailty in elderly patients with cardiovascular disease. However, the urinary 8-oxodGsn shows no obvious correlation with frailty. To obtain a better diagnostic performance for frailty, more biomarkers from different pathophysiological pathways should be explored in the future.

[Prognostic value of adenosine triphosphate myocardial perfusion tomography in octogenarians.].

OBJECTIVE: To evaluate the prognostic value of (99m)Tc-MIBI myocardial perfusion single-photon emission computed tomography (MPS) with adenosine triphosphate in patients aged 80 years or older. METHODS: A total of 265 patients [mean age (84.2 +/- 3.6) years old] who underwent adenosine triphosphate and rest (99m)Tc-MIBI myocardial SPECT imaging were followed-up for (36.7 +/- 22.8) months. RESULTS: During the period of follow-up, 57 patients (20.4%) suffered from cardiac events, including 20 major events: 5 cardiac death and 15 acute non-fatal myocardial infarction, 14 unstable angina pectoris, 7 heart failure and 16 cases undergoing PCI. The cardiac event rate in patients with fixed or mixed perfusion defects (n = 54) was 50%, which was significantly higher than that in patients with reversible perfusion defects (n = 67, 31.3%, P < 0.05) and normal perfusion imaging (n = 144, 6.2%, P < 0.01). The major cardiac event rate in patients with fixed or mixed perfusion defects was 27.8%, which was significantly higher than that in those with reversible perfusion defects (6.0%, P < 0.05) and normal perfusion imaging (0.7%, P < 0.01). Cox multivariate analysis revealed that an abnormal MPS was the most important independent predictor of major or total cardiac events. CONCLUSIONS: (99m)Tc-MIBI MPS with ATP is demonstrated to be a powerful tool for the prognostic evaluation in octogenarian population. Octogenarians with a normal MPS have a low risk of major or total cardiac events, but when an abnormal MPS is present, the risk is significantly higher, being highest in patients with fixed or mixed perfusion defects.

The mechanism of RNA oxidation involved in the development of heart failure.

Heart failure (HF) has become a global public health problem due to its unclear pathogenesis. Our previous studies have found that RNA oxidation is associated with the occurrence and development of a variety of chronic diseases in the elderly, but whether RNA oxidation is related to the pathogenesis of HF remains unclear. Male Dahl salt-sensitive rats (DSSR) were divided into 8% NaCl groups and 0.3% NaCl groups. The blood pressure of DSSR, HE staining of cardiac tissue, cardiac function index of colour Doppler echocardiography and plasma N-terminal probrain Natriuretic Peptide (NT-ProBNP) were used to evaluate the model making. The levels of 8-hydroxyguanosine (8-oxoGsn) and 8-hydroxydeoxyguanosine (8-oxodGsn) in myocardium and urine of DSSR were determined by high-performance liquid chromatography-mass spectrometry (LC-MS/MS). The expression of ERK-MAPK pathway and MTH1 was detected by Western blot (WB). Rats in the 8% NaCl group developed heart failure symptoms such as increased blood pressure, myocardial hypertrophy, decreased diastolic function, and increased plasma NT-ProBNP. The content of 8-oxoGsn in urine and heart tissue also increased, which was positively correlated with the related indicators of heart failure. This process is also accompanied by the sequential activation of ERK-MAPK pathway molecules and the increase of MTH1. The mechanism of RNA oxidation and inhibition is related to the occurrence and development of HF, which may be involved through ERK-MAPK pathway.