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.

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.

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.

C2HEST score predicts clinical outcomes in heart failure with preserved ejection fraction: a secondary analysis of the TOPCAT trial.

BACKGROUND: The C2HEST score has been validated for predicting AF in the general population or post-stroke patients. We aimed to assess whether this risk score could predict incident AF and other clinical outcomes in heart failure with preserved ejection fraction (HFpEF) patients. METHODS: A total of 2202 HFpEF patients without baseline AF in the TOPCAT trial were stratified by baseline C2HEST score. Cox proportional hazard model and competing risk regression model was used to explore the relationship between C2HEST score and outcomes, including incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The discriminative ability of the C2HEST score for various outcomes was assessed by calculating the area under the curve (AUC). RESULTS: The incidence rates of incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization were 1.79, 0.70, 3.81, 2.42, 15.50, and 3.32 per 100 person-years, respectively. When the C2HEST score was analyzed as a continuous variable, increased C2HEST score was associated with increased risk of incident AF (HR 1.50, 95% CI 1.29-1.75), as well as increased risks of all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The AUC for the C2HEST score in predicting incident AF (0.694, 95% CI 0.640-0.748) was higher than all-cause death, cardiovascular death, any hospitalization, or HF hospitalization. CONCLUSIONS: The C2HEST score could predict the risk of incident AF as well as death and hospitalization with moderately good predictive abilities in patients with HFpEF. Its simplicity may allow the possibility of quick risk assessments in busy clinical settings.

Living Alone and Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: In patients with heart failure with preserved ejection fraction (HFpEF), whether living alone could contribute to a poor prognosis remains unknown. We sought to investigate the association of living alone with clinical outcomes in patients with HFpEF. METHODS: Symptomatic patients with HFpEF with a follow-up of 3.3 years (data collected from August 2006 to June 2013) in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial were classified as patients living alone and those living with others. The primary outcome was defined as a composite of cardiovascular death, aborted cardiac arrest, or HF hospitalization. RESULTS: A total of 3103 patients with HFpEF were included; 25.2% of them were living alone and were older, predominantly female, and less likely to be White and have more comorbidities compared with the other patients. After multivariate adjustment for confounders, living alone was associated with increased risks of HF hospitalization (hazard ratio [HR] = 1.29, 95% confidence interval [CI] = 1.03-1.61) and any hospitalization (HR = 1.26, 95% CI = 1.12-1.42). A significantly increased risk of any hospitalization (HR = 1.16, 95% CI = 1.01-1.34) was also observed in the Americas-based sample. In addition, each year increase in age, female sex, non-White race, New York Heart Association functional classes III and IV, dyslipidemia, and chronic obstructive pulmonary disease were independently associated with living alone. CONCLUSIONS: We assessed the effect of living arrangement status on clinical outcomes in patients with HFpEF and suggested that living alone was associated with an independent increase in any hospitalization.Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00094302.

Association of physical activity and risk of atrial fibrillation in heart failure with preserved ejection fraction.

BACKGROUND AND AIMS: Physical activity (PA) could modify the risk of atrial fibrillation (AF) in the general population and mortality in heart failure patients with preserved ejection fraction (HFpEF). HFpEF patients are frequently concomitant with AF, but whether PA could modify the risk of AF in HFpEF patients remains undiscovered. METHOD AND RESULTS: We performed a post hoc analysis of the TOPCAT trial. Patients without AF at baseline and with data on PA (n = 652) were included. The association between PA and risk of AF occurrence was explored using the Cox proportional hazard model. During a median follow-up of 2.84 years, 9.4% of the studied patients (n = 60) had an occurrence of AF. When PA was analyzed as a continuous variable, every ten-fold increase of PA was associated with a 42.8% risk reduction of AF occurrence (hazard ratio [HR] 0.572, 95% CI 0.357-0.916, p = 0.020). When HFpEF patients were divided into three tertile groups according to PA levels, patients in the second tertile (HR 0.507, 95% CI 0.272-0.946, p = 0.033) and the third tertile (HR 0.487, 95% CI 0.261-0.908, p = 0.024) had significantly lower risks of AF occurrence when compared to those in the first tertile. CONCLUSIONS: Our current results suggest that a higher PA level associates with a lower risk of AF in HFpEF patients. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302.

Association of hyponatraemia and renal function in type 1 cardiorenal syndrome.

BACKGROUND: Hyponatraemia predicts type 1 cardiorenal syndrome in acute decompensated heart failure patients, which associates with poor outcome. Recovery from hyponatraemia has been found to associate with better outcome in acute decompensated heart failure patients, but its prognostic value regarding renal function remains unknown. METHODS: We performed a secondary analysis of CARRESS-HF trial, and all patients included had worsening renal function (≥0.3 mg/dL increase in serum creatinine than the nadir). The serum sodium levels of patients were evaluated at baseline and day 4 and day 7 after randomization. Patients were grouped according to the status of hyponatraemia: recovery from hyponatraemia; no hyponatraemia; persistent hyponatraemia; and new-onset hyponatraemia. Their associations with persistent worsening renal function (serum creatinine ≥ 0.3 mg/dL higher than the nadir at discharge) were explored. RESULTS: A total of 118 patients suffered from persistent worsening renal function. Baseline hyponatraemia was not associated with persistent worsening renal function (odds ratio = 0.495, P = .086). Patients in the recovery from hyponatraemia group had a lowest risk of persistent worsening renal function among the study population. Further, baseline serum sodium level was not associated with the risk of persistent worsening renal function (odds ratio = 1.055, P = .233), while the increases in serum sodium level at day 4 (odds ratio = 0.858, P = .003) and at day 7 (odds ratio = 0.821, P < .001) significantly predicted a lower risk of persistent worsening renal function. CONCLUSIONS: Recovery from hyponatraemia associates with a lower risk of persistent worsening renal function, suggesting that hyponatraemia correction may improve renal outcomes in acute decompensated heart failure patients with type 1 cardiorenal syndrome.

CHA2DS2-VASc and ATRIA Scores and Clinical Outcomes in Patients with Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Heart failure (HF) patients have high risks of thromboembolic events regardless of the category of left ventricular ejection fraction. We sought to assess whether the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, and female sex) and ATRIA (anticoagulation and risk factors in atrial fibrillation) scores could predict clinical outcomes in HF patients with preserved ejection fraction (HFpEF). METHODS: We performed a retrospective analysis in a multicenter, America-based population of 1766 HFpEF patients who were stratified according to their baseline CHA2DS2-VASc or ATRIA scores. The CHA2DS2-VASc and ATRIA scores were analyzed as a continuous or categorical variable. The outcomes were stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. RESULTS: When score was considered as a continuous variable, each point increase in CHA2DS2-VASc was associated with increased risks of stroke (hazard ratio (HR) 1.22, 95% confidence interval (CI) = 1.06-1.41, C-index = 0.62), HF hospitalization (HR 1.08, 95% CI = 1.01-1.17, C-index = 0.59), and any hospitalization (HR 1.06, 95% CI = 1.01-1.11, C-index = 0.57) whereas each point increase in ATRIA was associated with increased risks of stroke (HR 1.11, 95% CI = 1.01-1.21, C-index = 0.62), all-cause death (HR 1.09, 95% CI = 1.05-1.14, C-index = 0.61), cardiovascular death (HR 1.08, 95% CI = 1.02-1.14, C-index = 0.59), HF hospitalization (HR 1.07, 95% CI = 1.03-1.12, C-index = 0.58), and any hospitalization (HR 1.04, 95% CI = 1.01-1.06, C-index = 0.57). When score was regarded as a categorical variable, compared with controls, CHA2DS2-VASc ≥ 4 was associated with increased risks of stroke and hospitalization whereas ATRIA ≥ 8 was associated with increased risks of stroke, death, and hospitalization. CONCLUSIONS: The CHA2DS2-VASc and ATRIA scores are associated with risks of adverse outcomes in HFpEF patients. However, the predictive abilities of CHA2DS2-VASc and ATRIA are modest, and their clinical utility in HFpEF remains to be determined. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov . Identifier: NCT00094302.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.