Clinical Implications of Estimating Glomerular Filtration Rate with Different Equations in Heart Failure Patients with Preserved Ejection Fraction.

INTRODUCTION: The prognostic values of estimated glomerular filtration rate (eGFR) calculated by different formulas have not been adequately compared in patients with heart failure with preserved ejection fraction (HFpEF). AIM: We compared the predictive values of serum creatinine-based eGFRs calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, Modification of Diet in Renal Disease Study (MDRD) formula, and full-age-spectrum creatinine (FAS Cr) equation in 1751 HFpEF patients. METHODS: The area under the receiver-operating characteristic curve (AUC), integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were employed. RESULTS: eGFR values were lowest calculated with FAS Cr equation (p < 0.001). When patients were classified into 4 subgroups (eGFR ≥ 90, 89-60, 59-30, and  < 30 ml/min/1.73 m2) or only 2 subgroups (≥ 60 or  < 60 ml/min/1.73 m2), the 3 formulas correlated significantly, with the best correlation found between the MDRD and CKD-EPI formulas (kappa = 0.871 and 0.963, respectively). The 3 formulas conveyed independent prognostic information. After adjusting for potential cofounders, risk prediction for all-cause mortality was more accurate (p = 0.001) using the CKD-EPI equation than MDRD formula as assessed by AUC. Compared with MDRD formula, CKD-EPI equation exhibited superior predictive ability assessed by IDI and NRI of 0.32% (p < 0.001)/10.4% (p = 0.010) for primary endpoint and 0.37% (p = 0.010)/10.8% (p = 0.010) for HF hospitalization. The risk prediction for deterioration of renal function was more accurate (p ≤ 0.040) using the CKD-EPI equation than FAS Cr equation as assessed by AUC, IDI, and NRI. CONCLUSION: The CKD-EPI formula might be the preferred creatinine-based equation in clinical risk stratification in HFpEF patients.

Prognostic Significance of Blood Pressure at Rest and After Performing the Six-Minute Walk Test in Patients With Acute Heart Failure.

BACKGROUND: It remains unclear whether systolic (SBP) and diastolic (DBP) pressure and BP response after six-minute walk test (6MWT) are associated with adverse outcomes in patients with acute heart failure (AHF). METHODS: We investigated these associations in 98 AHF patients (24.5% women; mean age, 70.5 years) enrolled in the ROSE trial (The Low-dose Dopamine or Low-dose Nesiritide in Acute Heart Failure with Renal Dysfunction). The primary endpoint consisted of any death or rehospitalization within 6 months after randomization. We computed hazard ratios (HRs) of the risks associated with 1-SD increase in post-exercise BP levels and BP ratios, calculated as BP immediately after 6MWT divided by BP before 6MWT. RESULTS: The BP before and after 6MWT averaged 110.6/117.5 mm Hg for SBP and 61.9/64.7 mm Hg for DBP. In multivariable-adjusted analyses including clinic BP measured at the same day of 6MWT, higher DBP after 6MWT was associated with lower risk of the primary endpoint (HR, 0.49; 95% confidence interval [CI], 0.26-0.95; P = 0.034). Both higher SBP and DBP immediately after 6MWT were associated with lower risk of 6-month mortality (HRs, 0.39/0.16; 95% CI, 0.17-0.90/0.065-0.40; P ≤ 0.026). The post-exercise SBP ratio was associated with the risk of 6-month mortality in multivariable-adjusted analyses (HR, 0.44; P = 0.023). CONCLUSIONS: Higher BP levels and BP ratios immediately after 6MWT conferred lower risk of adverse health outcomes. Our observations highlight that 6MWT-related BP level and response may refine risk estimates in patients hospitalized AHF and may help further investigation for the development of HF preventive strategies.

Associations between long-term averages of metabolic parameters in adulthood and cardiac structure and function in later life.

The effects of long-term levels of body mass index (BMI), blood pressure (BP), plasma lipids and fasting blood glucose (FBG) on the cardiac structure and function in later life in general population are to evaluate. We included adult participants without heart failure from Framingham Heart Study. The respective averages over a span of 30-36 years of seven parameters were pooled into linear regression models simultaneously to evaluate their associations with subsequent left atrial internal dimension (LAID), left ventricular mass index (LVMi), internal dimension (LVID), ejection fraction (LVEF), global longitudinal strain (GLS) and mitral inflow velocity to early diastolic mitral annular velocity (E/é). In 1838 participants (56.0% female, mean age 66.1 years), per 1-standard deviation (SD) increment of mean BMI correlated with larger LAID and LVID (ß 0.05~0.17, standard error [SE] 0.01 for all), greater LVMi (ß [SE], 1.49 [0.46]), worse E/é (ß [SE], 0.28 [0.05]). Per 1-SD increment of mean systolic BP correlated with greater LVMi (ß [SE], 4.70 [0.69]), LVEF (ß [SE], 0.73 [0.24]), E/é (ß [SE], 0.52 [0.08]), whereas increase of mean diastolic BP correlated with smaller LVMi (ß [SE], -1.61 [0.62]), LVEF (ß [SE], -0.46 [0.22]), E/é (ß [SE], -0.30 [0.07]). Per 1-SD increment of mean high density lipoprotein cholesterol (HDL-c) correlated with smaller LVID (ß [SE], -0.03 [0.01]) and better systolic function (LVEF, ß [SE], 0.63 [0.19]; GLS, ß [SE], -0.20 [0.10]). The variabilities of BMI, BP and HDL-c also correlated with certain cardiac measurements. In long-term, BMI affected the size and mass of heart chambers, systolic and diastolic BP differently influenced left ventricular mass and function, higher HDL-c linked to better systolic function. Clinical trial registration: URL: https://clinicaltrials.gov . Identifier: NCT00005121.

Associations of long-term mortality with serum uric acid at admission in acute decompensated heart failure with different phenotypes.

BACKGROUND AND AIMS: It remains unclear whether the long-term prognostic value of serum uric acid (SUA) at admission differs in acute decompensated heart failure (HF) patients across the spectrum of left ventricular ejection fraction (EF). METHODS AND RESULTS: In 2375 patients (38.9% women; mean age, 68.8 years), we assessed the risk of long-term (>1 year) all-cause mortality associated with per 1-SD increase in SUA at admission, using multivariable Cox regression in HF with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) EF. During a median follow-up of 4.1 years, the long-term mortality rate was 39.9%. In all patients, the multivariable-adjusted hazard ratio (HR) expressing the risk of long-term mortality associated with SUA was 1.18 (95% CI, 1.11-1.26; P < 0.001). Compared with the low tertile of the SUA distribution, the sex- and age-adjusted cumulative incidence of long-term mortality was higher in the top tertile. In patients with HFpEF and HFrEF, SUA predicted the risk of long-term mortality with HRs amounting to 1.12 (95% CI, 1.02-1.21; P = 0.012) and 1.28 (95% CI, 1.12-1.47; P < 0.001), respectively. However, there were no associations between the risk of mortality and SUA in HFmrEF. Furthermore, age, sex, NYHA class, and the prevalence of coronary heart disease interacted significantly with SUA for predicting long-term mortality. CONCLUSION: Higher levels of SUA at admission were associated with higher risk of long-term mortality in patients with different HF subtypes. The risk conferred by SUA was age and sex dependent. Our observations highlight that measuring SUA at admission may help to improve risk stratification.

Association of the Triglyceride-Glucose Index With Risk of Alzheimer's Disease: A Prospective Cohort Study.

INTRODUCTION: Triglyceride-glucose index (TyG) is a reliable surrogate marker of insulin resistance, and insulin resistance has been implicated in Alzheimer's disease pathophysiology. However, the relationship between the TyG index and Alzheimer's disease remains unclear. This study aimed to evaluate the association of the TyG index with the risk of Alzheimer's disease. METHODS: This prospective study included 2,170 participants free of Alzheimer's disease from the Framingham Heart Study Offspring Cohort Exam 7 (1998-2001), whose follow-up data were collected until 2018. The TyG index was calculated as Ln(fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2). The association of the TyG index with Alzheimer's disease was evaluated by competing risk regression model. Statistical analyses were performed in 2023. RESULTS: During a median follow-up of 13.8 years, 163 (7.5%) participants developed Alzheimer's disease. When compared with the reference (TyG index ≤8.28), a significantly elevated risk of Alzheimer's disease was seen in the group with a triglyceride-glucose index of 8.68-9.09 (adjusted hazard ratio=1.69, 95% CI=1.02, 2.81). When the TyG index was considered as a continuous variable, each unit increment in the TyG index was not significantly associated with the risk of Alzheimer's disease (adjusted hazard ratio=1.32, 95% CI=0.98, 1.77). CONCLUSIONS: This study showed that moderately elevated TyG index was independently associated with a higher incidence of Alzheimer's disease. TheTyG index might be used to define a high-risk population of Alzheimer's disease.

Association between epicardial adipose tissue and incident heart failure mediating by alteration of natriuretic peptide and myocardial strain.

BACKGROUND: Epicardial adipose tissue (EAT) has been suggested to exert deleterious effects on myocardium and cardiovascular disease (CVD) consequence. We evaluated the associations of EAT thickness with adverse outcomes and its potential mediators in the community. METHODS: Participants without heart failure (HF) who had undergone cardiac magnetic resonance (CMR) to measure EAT thickness over the right ventricular free wall from the Framingham Heart Study were included. The correlation of EAT thickness with 85 circulating biomarkers and cardiometric parameters was assessed in linear regression models. The occurrence of HF, atrial fibrillation, coronary heart disease (CHD), and other adverse events was tracked since CMR was implemented. Their associations with EAT thickness and the mediators were evaluated using Cox regression and causal mediation analysis. RESULTS: Of 1554 participants, 53.0% were females. Mean age, body mass index, and EAT thickness were 63.3 years, 28.1 kg/m2, and 9.8 mm, respectively. After fully adjusting, EAT thickness positively correlated with CRP, LEP, GDF15, MMP8, MMP9, ORM1, ANGPTL3, and SERPINE1 and negatively correlated with N-terminal pro-B-type natriuretic peptide (NT-proBNP), IGFBP1, IGFBP2, AGER, CNTN1, and MCAM. Increasing EAT thickness was associated with smaller left ventricular end-diastolic dimension, thicker left ventricular wall thickness, and worse global longitudinal strain (GLS). During a median follow-up of 12.7 years, 101 incident HF occurred. Per 1-standard deviation increment of EAT thickness was associated with a higher risk of HF (adjusted hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.19-1.72, P < 0.001) and the composite outcome consisting of myocardial infarction, ischemic stroke, HF, and death from CVD (adjusted HR [95% CI], 1.23 [1.07-1.40], P = 0.003). Mediation effect in the association between thicker EAT and higher risk of HF was observed with NT-proBNP (HR [95% CI], 0.95 [0.92-0.98], P = 0.011) and GLS (HR [95% CI], 1.04 [1.01-1.07], P = 0.032). CONCLUSIONS: EAT thickness was correlated with inflammation and fibrosis-related circulating biomarkers, cardiac concentric change, myocardial strain impairment, incident HF risk, and overall CVD risk. NT-proBNP and GLS might partially mediate the effect of thickened EAT on the risk of HF. EAT could refine the assessment of CVD risk and become a new therapeutic target of cardiometabolic diseases. TRIAL REGISTRATION: URL: https://clinicaltrials.gov . Identifier: NCT00005121.

Clinical information from repeated blood pressure measurements in the management of heart failure with preserved ejection fraction.

It remains unclear whether cumulative blood pressure (BP) exposure is associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF). The aim was to investigate the associations of adverse health outcomes with cumulative BP exposure as captured by weighted BP, cumulative BP and trends in BP over a 1-year timespan from baseline to a 12-month visit among 1303 patients with HFpEF (49.5% women; mean age, 71.5 years) enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. The primary endpoints consisted of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure.We computed hazard ratios with a 1-SD increase in weighted BP and cumulative BP. In the spironolactone group, compared with patients with a downward trend in BP, those with an upward trend had higher event rates. However, there were no differences in event rates between those with upward and downward trends in BP in the placebo group. In multivariable-adjusted analyses that additionally accounted for baseline BP, weighted systolic BP and cumulative systolic BP predicted (P ≤ 0.037) the primary composite endpoint (hazard ratio [HR], 1.21; 95% CI, 1.05-1.39/1.15; 1.01-1.31) and hospitalization for HF (1.29; 1.09-1.52/1.18; 1.02-1.37), respectively. Among patients aged ≤72 years, cumulative systolic BP increased (P ≤ 0.016) the risk of the primary endpoint and hospitalization for HF. Higher cumulative systolic BP exposure conferred a higher risk of the primary endpoint and hospitalization for HF, independent of baseline BP. Our findings underscore that longitudinal BP measurements may refine risk stratification for patients with HFpEF.

Essen Stroke Risk Score Predicts Clinical Outcomes in Heart Failure Patients with Preserved Ejection Fraction: Evidence from the TOPCAT trial.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with increased risks of stroke and other adverse outcomes. AIMS: This study sought to determine whether the Essen Stroke Risk Score (ESRS) could predict the risks of adjudicated clinical outcomes in patients with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. METHODS: We evaluated associations of baseline ESRS with clinical outcomes by using the Cox proportional hazard model with competing risk regression. The diagnostic accuracy of the ESRS was assessed using the C-index and calibration data. RESULTS: Of 3,441 HFpEF patients with a mean follow-up of 3.3 years, the risk of stroke ranged from 0.32% per year at an ESRS of 1 to 2 points to 1.71% per year at a score of ≥6 points. Each point increase in ESRS was associated with increased risks of primary composite outcome (hazard ratios [HRs] = 1.31; 95% confidence intervals [CIs]: 1.23-1.40; C-index = 0.68), stroke (HR = 1.33 [95% CI: 1.16-1.53]; C-index = 0.68), myocardial infarction (HR = 1.60 [95% CI: 1.40-1.83]; C-index = 0.75), HF hospitalization (HR = 1.30 [95% CI: 1.20-1.41]; C-index = 0.71), any hospitalization (HR = 1.20, 95% CI: 1.15-1.26; C-index = 0.68), cardiovascular death (HR = 1.32 [95% CI: 1.20-1.44]; C-index = 0.68), and all-cause death (HR = 1.37, [95% CI: 1.28-1.48]; C-index = 0.68). The calibration curves showed that the ESRS had a better agreement between predicted and observed stroke risks compared with the R2CHADS2, CHADS2, or CHA2DS2-VASC stroke scores. CONCLUSION: The ESRS had modest discriminatory abilities for predicting stroke as well as other adverse outcomes including myocardial infarction, hospitalization, and death in HFpEF patients. ESRS might have better calibration performance than R2CHADS2, CHADS2, or CHA2DS2-VASC in HFpEF at high risk for stroke. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302.

Prognostic Implication of Admission Mean and Pulse Pressure in Acute Decompensated Heart Failure With Different Phenotypes.

BACKGROUND: It remains unknown whether admission mean (MAP) and pulse pressure (PP) pressure are associated with short- and long-term mortality in Chinese patients with heart failure with preserved (HFpEF), mid-range (HFmrEF), and reduced (HFrEF) ejection fraction. METHODS: In 2,706 acute decompensated heart failure (HF) patients, we assessed the risk of 30-day, 1-year, and long-term (>1 year) mortality with 1-SD increment in MAP and PP, using multivariable logistic and Cox regression, respectively. RESULTS: During a median follow-up of 4.1 years, 1,341 patients died. The 30-day, 1-year, and long-term mortality were 3.5%, 16.7%, and 39.4%, respectively. A lower MAP was associated with a higher risk of 30-day mortality in women (P = 0.023) and a higher risk of 30-day and 1-year mortality in men (P ≤ 0.006), while higher PP predicted long-term mortality in men (P ≤ 0.014) with no relationship observed in women. In adjusted analyses additionally accounted for PP, 1-SD increment in MAP was associated with 30-day mortality in HFpEF (odds ratio [OR], 0.63; 95% CI, 0.43 to 0.92; P = 0.018), with 1-year mortality in HFmrEF (OR, 0.46; 95% CI, 0.32 to 0.66; P < 0.001) and HFrEF (OR, 0.54; 95% CI, 0.40 to 0.72; P < 0.001). In the adjusted model additionally accounted for MAP, 1-SD increment in PP was associated with long-term mortality in HFpEF (hazard ratio, 1.16; 95% CI, 1.05 to 1.28; P = 0.003). CONCLUSIONS: A lower MAP was associated with a higher risk of short-term mortality in all HF subtypes, while a higher PP predicted a higher risk of long-term mortality in men and in HFpEF. Our observations highlight the clinical importance of admission blood pressure for risk stratification in HF subtypes.

Associations of short- and long-term mortality with admission blood pressure in Chinese patients with different heart failure subtypes.

It remains unknown whether systolic (SBP) and diastolic (DBP) pressure on admission are associated with short- and long-term mortality in Chinese patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction. In 2706 HF patients (39.1% women; mean age, 68.8 years), we assessed the risk of 30-day, 1-year, and long-term (> 1 year) mortality with 1-SD increment in SBP and DBP, using multivariable logistic and Cox regression, respectively. During a median follow-up of 4.1 years, 1341 patients died. The 30-day, 1-year, and long-term mortality were 3.5%, 16.7%, and 39.4%, respectively. In multivariable-adjusted analyses additionally accounted for DBP or SBP, a higher SBP conferred a higher risk of long-term mortality (hazard ratio, 1.11; 95% CI, 1.02-1.22; p = .017) and a lower DBP was associated with a higher risk of all types of mortality (p ≤ .011) in all HF patients. Independent of potential confounders including DBP or SBP, in patients with HFpEF, higher SBP and lower DBP levels predicted a higher risk of long-term mortality with hazard ratios amounting to 1.16 (95% CI, 1.04-1.29; p = .007) and .89 (95% CI, .80-.99; p = .028), respectively. In patients with HFmrEF and HFrEF, irrespective of adjustments of potential confounders, DBP was associated with 1-year mortality with odds ratios ranging from .49 to .62 (p ≤ .006). In conclusion, lower DBP and higher SBP levels on admission were associated with a higher risk of different types of all-cause mortality in Chinese patients with different HF subtypes. Our observations highlight that admission BP may help to improve risk stratification.

Modified Exosomes: a Good Transporter for miRNAs within Stem Cells to Treat Ischemic Heart Disease.

Stem cell-based therapy for ischemic heart disease (IHD) has become a promising but controversial strategy during the past two decades. The fate and effects of stem cells engrafted into ischemia myocardium are still not fully understood. Stem cell-derived exosomes, a subcategory of extracellular vesicles with nano size, have been considered as an efficient and safe transporter for microRNAs (miRNAs) and a central mediator of the cardioprotective potentials of the parental cells. Hypoxia, pharmacological intervention, and gene manipulation could alter the exosomal miRNAs cargos from stem cells and promote therapeutic potential. Furthermore, several bioengineering methods were also successfully applied to modify miRNAs content and components of exosomal membrane proteins recently. In this review, we outline relevant results about exosomal miRNAs from stem cells and focus on the current strategies to promote their therapeutic efficiency in IHD.

Ischemic risk in patients with heart failure with preserved ejection fraction: A post hoc analysis of the TOPCAT data.

BACKGROUND AND AIMS: Heart failure with preserved ejection fraction (HFpEF) patients have a high burden of comorbidities that could predispose them to ischemic vascular event. The profile of ischemic risk among HFpEF patients is not fully understood. We aim to evaluate the risk, risk factors, and prognostic significance of ischemic events among HFpEF patients. METHODS: A total of 1767 HFpEF patients from Americas in the TOPCAT trial were included in our analysis. Ischemic event was defined as myocardial infarction or ischemic stroke during follow-up. Multivariate competing risks regression model was used to identify risk factors of ischemic event. Time-dependent Cox models were constructed to evaluate the association of incident ischemic event and mortality risk. RESULTS: During a median follow-up period of 2.9 years, 164 (9.3%) patients had at least 1 ischemic event. The crude incidence rate was 3.3% per year. Body mass index, prior myocardial infarction, insulin use, peripheral artery disease, hypertension, and current smoking were independent risk factors of ischemic event in HFpEF patients. HF hospitalization turned out to be an important trigger of ischemic event. Risk of ischemic event increased 4.7-fold (hazard ratio 4.70, 95% confidence interval: 2.23-9.89, p < 0.001) within the first month after the first HF hospitalization, and dropped rapidly thereafter. Incident ischemic event was associated with significant higher short-term risks of all-cause mortality and cardiovascular mortality. CONCLUSIONS: HFpEF patients from Americas were at a high risk of ischemic events, which was associated with mortality risk. A subset of baseline characteristics and HF hospitalization during follow-up could predict ischemic event.

Associations of BMI with mortality in HFpEF patients with concomitant diabetes with insulin versus non-insulin treatment.

BACKGROUND: Obesity confers paradoxical survival benefits in heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to examine the impact of DM and insulin treatment status on the associations of body mass index (BMI) with the death risks in HFpEF patients. METHODS: HFpEF patients from the TOPCAT trial were included. Cox regression model was constructed to assess the relationship of BMI with the risks of all-cause death and cardiovascular death. Restricted cubic splines were used to characterize the dose-response associations of BMI with risks of death. RESULTS: Compared with normal weight, hazard ratios of all-cause death in overweight and class I obesity were 0.62 (0.45-0.85), 0.67 (0.47-0.94) in no DM HFpEF patients, and 0.48 (0.25-0.91), 0.41 (0.22-0.79) in non-insulin-treated DM patients. However, insulin treatment removed this beneficial effect. Consistent results were found when modeling for time-updated BMI. Cubic spline analyses suggested a linear trend of increased death risk with higher BMI in insulin-treated DM patients. CONCLUSIONS: The "obesity paradox" was present in HFpEF patients without DM or with non-insulin-treated DM but absent in those with insulin-treated DM. Insulin treatment may be a crucial confounder of the obesity paradox in HFpEF patients. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302.

Prognostic significance of blood urea nitrogen/creatinine ratio in chronic HFpEF.

BACKGROUND: The prognostic significance of blood urea nitrogen (BUN)/creatinine ratio specifically in chronic heart failure with preserved ejection fraction (HFpEF) patients remained unclear. We aimed to evaluate the association of BUN/creatinine ratio (baseline level and visit-to-visit variation) with the risk of adverse clinical outcomes among patients with chronic HFpEF. METHODS AND RESULTS: This is a secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Of the enrolled 3445 participants in the TOPCAT trial, associations between BUN/creatinine and clinical outcomes were examined in a subset of 1521 (baseline measurements level) and 1453 (visit-to-visit variation) participants. A multivariable Cox proportional hazard model was used to assess the prognostic significance of BUN/creatinine ratio and BUN/creatinine ratio variation for the prespecified clinical outcomes. A higher BUN/creatinine ratio was associated with a higher risk of all-cause mortality (hazard ratio [HR] = 1.52, 95%CI, 1.21-1.91; p < .001) as well as cardiovascular disease mortality (HR = 1.83, 95%CI, 1.35-2.49; p < .001) in the fully adjusted model. Greater visit-to-visit variability in BUN/creatinine ratio tended to be independently associated with a higher risk of heart failure hospitalization and primary endpoint (p < .001 for both outcomes). Furthermore, those findings were consistent across participants stratified by the presence of chronic kidney disease at baseline. CONCLUSIONS: Higher BUN/creatinine ratio and greater BUN/creatinine ratio variability are independently associated with adverse outcomes in HFpEF participants in the TOPCAT trial.

Role of N6-methyladenosine Modification in Cardiac Remodeling.

Cardiac remodeling is the critical process in heart failure due to many cardiovascular diseases including myocardial infarction, hypertension, cardiovascular disease and cardiomyopathy. However, treatments for heart failure focusing on cardiac remodeling show relatively limited effectiveness. In recent decades, epitranscriptomic modifications were found abundantly present throughout the progression of cardiac remodeling, and numerous types of biochemical modifications were identified. m6A modification is the methylation of the adenosine base at the nitrogen-6 position, and dysregulation of m6A modification has been implicated in a wide range of diseases. However, function of m6A modifications still remain largely unknown in cardiac diseases, especially cardiac remodeling. LncRNAs are also shown to play a vital role in the pathophysiology of cardiac remodeling and heart failure. The crosstalk between lncRNAs and m6A modification provides a novel prospective for exploring possible regulatory mechanism and therapeutic targets of cardiac remodeling. This review summarizes the role of m6A modification in cardiac remodeling in the current researches.

Clinical Significance of Mean and Pulse Pressure in Patients With Heart Failure With Preserved Ejection Fraction.

It remains debated whether pulse pressure is associated with left ventricular traits and adverse outcomes over and beyond mean arterial pressure (MAP) in patients with heart failure (HF) with preserved ejection fraction. We investigated these associations in 3428 patients with HF with preserved ejection fraction (51.5% women; mean age, 68.6 years) enrolled in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist). We computed association sizes and hazards ratios with 1-SD increase in MAP and pulse pressure. In multivariable-adjusted analyses, association sizes (P≤0.039) for MAP were 0.016 cm and 0.014 cm for septal and posterior wall thickness, -0.15 for E/A ratio, -0.66 for E/e', and -0.64% for ejection fraction, independent of pulse pressure. With adjustment additionally applied for MAP, E/A ratio and longitudinal strain increased with higher pulse pressure with association sizes amounting to 0.067 (P=0.026) and 0.40% (P=0.023). In multivariable-adjusted analyses of both placebo and spironolactone groups, lower MAP and higher pulse pressure predicted the primary composite end point (P≤0.028) and hospitalized HF (P≤0.002), whereas MAP was also significantly associated with total mortality (P≤0.007). Sensitivity analyses stratified by sex, median age, and region generated confirmatory results with exception for the association of adverse outcomes with pulse pressure in patients with age ≥69 years. In conclusion, the clinical application of MAP and pulse pressure may refine risk estimates in patients with HF with preserved ejection fraction. This finding may help further investigation for the development of HF with preserved ejection fraction preventive strategies targeting pulsatility and blood pressure control.

LncRNA MNX1-AS1 promotes ovarian cancer process via targeting the miR-744-5p/SOX12 axis.

PURPOSE: Ovarian cancer (OC) is the most common malignancy in women with high mortality. Increasing studies have revealed that long non-coding RNA (lncRNA) MNX1-AS1 has a promoting effect on various cancers. However, the mechanisms of MNX1-AS1 in OC are still unclear. Therefore, this study focused on exploring the mechanisms of MNX1-AS1 in OC. MATERIALS AND METHODS: The expression of SOX12 at the protein level was detected by western blot. Cell proliferation was detected by CCK8 assay and colony formation assay. Cell cycle and cell apoptosis were detected by flow cytometry. Wound-healing assay, transwell assay and western blot were used to detect the ability of cell migration and invasion. The target binding was confirmed through the luciferase reporter assay. RESULTS: The expression of MNX1-AS1 was increased in OC tumor tissues and cells. Elevated MNX1-AS1 expression is associated with advanced stage and lower overall survival rate. Knockdown of MNX1-AS1 inhibited cell proliferation, migration and invasion, blocked cell cycle, and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. MNX1-AS1 was competitively binding with miR-744-5p, and its downstream target gene was SOX12. miR-544-5p expression was decreased, while SOX12 expression was increased in OC tumor tissues and cells. Overexpression of miR-744-5p inhibited cell proliferation, migration, invasion and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. CONCLUSION: MNX1-AS1 promoted the development of OC through miR-744-5p/SOX12 axis. This study revealed a novel mechanism of MNX1-AS1 in OC, which may provide a new treatment or scanning target for OC.

Correlation analysis of Ki67 and CK7 expression with clinical characteristics and prognosis of postoperative cervical adenocarcinoma patients.

BACKGROUND: The purpose of this study is to investigate the correlation between cytokeratin 7 (CK7) and marker of proliferation Ki67 protein expression and clinical characteristics and prognosis of patients with cervical adenocarcinoma after surgery. METHODS: A total of 126 patients with cervical adenocarcinoma treated by surgery in our hospital from June 2011 to September 2015 were enrolled in this study. Immunohistochemistry (IHC) was used to detect the expression of CK7 and Ki67 in 126 cases of cervical adenocarcinoma tissues. The chi-square (χ2) test was used to compare the relationship between the positive expression rate of CK7 or Ki67 and clinicopathological features. Kaplan-Meier method was used to analyze the survival of different protein expression groups and Cox proportional hazards regression model was used to analyze the risk factors affecting the prognosis. RESULTS: The positive rate of CK7 was correlated with muscle invasion, vascular invasion, differentiation, and lymph node metastasis (all P<0.05). The positive expression rate of Ki67 was related to the degree of myometrial invasion and International Federation of Gynecology and Obstetrics (FIGO) stage (both P<0.05). Both CK7 and Ki67 may be independent risk factors for the prognosis of patients with cervical adenocarcinoma after surgery (both P<0.05), and their high expression heralds worse prognosis. CONCLUSIONS: The CK7 and Ki67 proteins may be key regulatory factors in the development of cervical adenocarcinoma after surgery, and their overexpression may lead to worse prognosis. Both CK7 and Ki67 may provide new markers for prognosis evaluation of cervical adenocarcinoma.

Association of Body-Weight Fluctuation With Outcomes in Heart Failure With Preserved Ejection Fraction.

Aims: To investigate the relationship between body-weight fluctuation and risks of clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results:We measured intra-individual variations in body weight from baseline and follow-up visits in 1,691 participants with HFpEF from the Americas from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. The primary endpoint was any cardiovascular events (a composite of death from cardiovascular disease, non-fatal myocardial infarction, aborted cardiac arrest, or hospitalization for HF). The body-weight fluctuation was measured according to average successive variability and high variability was defined as greater than or equal to the median. After adjustment for risk factors, mean body weight and weight change, each increase of 1 standard deviation in body-weight variability was significantly associated with increased risks of any cardiovascular events (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.15-1.33, P < 0.001). Patients with high variability had a 47% increased risk of any cardiovascular events and 27% increased risk of all-cause death compared with those with low variability. Such association was similar among patients with New York Heart Association functional class I/II vs. III/IV, obesity vs. non-obesity, and weight loss, gain vs. stability (the P-values for interaction were all insignificant). Conclusion: Among patients with HFpEF, body-weight fluctuation was associated with increased risks of cardiovascular events independent of traditional cardiovascular risk factors, and regardless of HF severity, baseline weight or weight change direction. Clinical Trial Registration: Aldosterone antagonist therapy for adults with heart failure and preserved systolic function (TOPCAT), https://clinicaltrials.gov, identifier [NCT00094302].

Weight Change and Mortality Risk in Heart Failure With Preserved Ejection Fraction.

Aims: The aim of the study was to determine the associations of weight loss or gain with all-cause mortality risk in heart failure with preserved ejection fraction (HFpEF). Methods and Results: Non-lean patients from the Americas from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist study were analyzed (n = 1,515). Weight loss and weight gain were defined as a decrease or increase in weight ≥5% between baseline and 1 year. To determine the associations of weight change and mortality risk, we used adjusted Cox proportional hazards models and restricted cubic spline models. The mean age was 71.5 (9.6) years. Weight loss and gain were witnessed in 19.3 and 15.9% patients, respectively. After multivariable adjustment, weight loss was associated with higher risk of mortality (HR 1.42, 95% CI 1.06-1.89, P = 0.002); weight gain had similar risk of mortality (HR 0.98, 95% CI 0.68-1.42, P = 0.932) compared with weight stability. There was linear relationship between weight change and mortality risk. The association of weight loss and mortality was different for patients with and without diabetes mellitus (interaction p = 0.009). Conclusion: Among patients with HFpEF, weight loss was independently associated with higher risk of all-cause mortality, and weight gain was not associated with better survival. Clinical Trial Registration: https://clinicaltrials.gov, Identifier: NCT00094302.