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To determine whether time-averaged cumulative blood pressure (cumBP) is associated with the risk of cardiovascular outcomes among patients with heart failure with preserved ejection fraction.Three thousand, three hundred and thirty participants from Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were included in this analysis with a median follow-up of 3 years. CumBP, expressed as mmHg-years, was the sum of mean BP for each pair of successive examinations multiplied by the time. Time-averaged cumBP was calculated by dividing cumBP by total exposure time, also expressed as mmHg. Clinical outcomes of our study including primary endpoint, all-cause death, cardiovascular death and heart failure hospitalization. Multivariable Cox hazard regression models and a restricted cubic spline model were used to assess the association and linearity between time-averaged cumBP and adverse outcomes.There is a U-shaped relationship between time-averaged cumBP and primary endpoint, all-cause death, cardiovascular death and heart failure hospitalization among participants with HFpEF, with the nadir risk around 120-129 mmHg of SBP and 70-79 mmHg of DBP after adjusting for confounding variables. Treatment with spironolactone did not affect the association significantly. The finding remained robust across sensitivity analyses.Higher or lower time-averaged cumBP was significantly associated with a higher risk of adverse events. Control of time-averaged cumulative BP within a reasonable range was an important component of hypertension management in HFpEF.

Background Coronary artery calcification (CAC) is a crucial indicator of subclinical atherosclerotic cardiovascular disease. The relationship between long‐term insulin resistance (IR) trajectory and CAC has been explored in few studies. Therefore, this study aimed to investigate whether the long‐term IR time series of young adults are associated with the incidence of CAC in midlife. Methods and Results In a cohort study comprising 2777 participants from the CARDIA (Coronary Artery Risk Development in Young Adults) study, the homeostasis model assessment for IR was used to measure IR levels, and group‐based trajectory modeling was used to fit three 25‐year homeostasis model assessments for IR trajectories. Logistic regression was used to estimate the association between the 3 homeostasis model assessments for IR trajectories and CAC events at year 25. The results showed that among 2777 participants (mean age, 50.10±3.58 years; 56.2% women; 46.4% Black), there were 780 incident CAC events after a 25‐year follow‐up. After full adjustment, the prevalence of CAC was higher in the moderate‐ (odds ratio [OR], 1.40 [1.10–1.76]) and the high‐level homeostasis model assessments for IR trajectories (OR, 1.84 [1.21–2.78]) than in the low‐level trajectory. This association was observed in obese individuals despite the negative interaction between IR and different types of obesity (all P interactions >0.05). Conclusions Our study revealed that young adults with a higher level of IR were more likely to develop CAC in middle age. Furthermore, this association persisted in obese individuals. These findings highlight the importance of identifying subclinical cardiovascular risk factors and implementing primary prevention measures.

Background and aims Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia-inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization. Approach and results We addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT-qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up-regulation and -mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v-rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator. Conclusions In conclusion, inhibiting HIF1α expression or stabilization represents an anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.

Background The associations of time‐averaged cumulative blood pressure (BP) from midlife to late life with microvasculature expressed as retinal vessel diameters is not well studied. The aim of this study was to evaluate the association of cumulative systolic BP and diastolic BP (DBP) with retinal vessel calibers, focusing on race differences. Methods and Results The analysis included 1818 adults from the ARIC (Atherosclerosis Risk in Communities) study attending the fifth visit (2011–2013; age 77±5 years, 17.1% Black participants). Time‐averaged cumulative BPs were calculated as the sum of averaged BPs from adjacent consecutive visits (visits 1–5) indexed to total observation time (24±1 years). Summarized estimates for central retinal arteriolar equivalent and central retinal venular equivalent at the fifth visit represent average retinal vessel diameters. The arteriole:venule ratio was calculated. We tested for effect modification by race. Results from multiple linear regression models suggested that higher time‐averaged cumulative DBP (β [95% CI] per 1‐SD increase: −1.78 [−2.53, −1.02], P P =0.004, respectively) but not systolic BP (−0.52 [−1.30, 0.26], P =0.189 and 0.001 [−0.002, 0.005], P =0.485, respectively) was associated with smaller central retinal arteriolar equivalent and arteriole:venule ratio. The association between time‐averaged cumulative DBP and arteriole:venule ratio was strongest in White participants (interaction P =0.007). The association of cumulative systolic BP and DBP with central retinal venular equivalent was strongest in Black participants (interaction P =0.015 and 0.011, respectively). Conclusions Exposure to higher BP levels, particularly DBP, from midlife to late life is associated with narrower retinal vessel diameters in late life. Furthermore, race moderated the association of cumulative BP exposure with retinal microvasculature.

The effect of renin-angiotensin-aldosterone system (RAAS) blockers [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers] on Contrast-induced nephropathy (CIN) is unclear in patients with renal insufficiency. Thus, we conduct a meta-analysis to evaluate the association between the administration of RAAS blockers and CIN in patients with renal insufficiency. We searched PubMed, EMBASE, and Cochrane Library for relevant studies published before September 2019. The primary outcome was the incidence of CIN, and the secondary outcome was the changes in serum creatinine (SCr) from baseline to postprocedure (ΔSCr). Pooled odds ratio (OR) or weighted mean difference (WMD) with their 95% confidence interval (CIs) for the CIN incidence, ΔSCr were used to calculate original data. A total of 8 studies were included in the meta-analysis. Compared with controls, ACEI/angiotensin receptor blocker increased the risk of CIN (OR = 1.61, 95% CI 1.14-2.28, I = 30%; P = 0.007), whereas this association was not significant in Chinese patients (OR = 1.07, 95% CI 0.65-1.77, I = 19%, P = 0.79). The total weighted mean differences of the ΔSCr were 0.06 mg/dL (95% CI: 0.01-0.11, I = 82%; P = 0.03). Administration of RAAS blockers in patients with renal insufficiency was associated with a significantly higher incidence of CIN, whereas it did not show a significant effect on Chinese patients.

Background The association between blood pressure control and clinical outcomes is unclear among patients with heart failure with preserved ejection fraction. Both too high and too low of systolic blood pressure (SBP) have been reported to be related to poor clinical prognosis. This study aimed to assess the association between time in SBP target range and adverse clinical events among patients with heart failure with preserved ejection fraction. Methods and Results This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, a randomized clinical trial that compared the efficacy and safety of spironolactone in patients with heart failure with preserved ejection fraction. Time in target range (TTR) was calculated using linear interpolation, with the target range of SBP defined as 110 to 130 mm Hg. The association between TTR with adverse outcomes was estimated using multivariable Cox regression to adjust for multiple confounders. Participants with greater TTR were younger, more likely to be White, had less comorbidities, and lower body mass index. After adjusting for multiple covariates including mean SBP, 1‐SD increment (38.3%) of TTR was significantly associated with a decreased risk of primary composite end point (hazard ratio [HR], 0.81 [0.73–0.90]), as well as a lower risk of all‐cause mortality (HR, 0.81 [0.73–0.90]), cardiovascular death (HR, 0.78 [0.68–0.90]), and heart failure hospitalization (HR, 0.85 [0.74–0.97]). Results were similar when participants were categorized by TTR groups. Subgroup analyses showed that the associations were more significant in young people than in the old ( P interaction =0.028). Conclusions In patients with heart failure with preserved ejection fraction, greater time in SBP target range was statistically associated with a decreased risk of cardiovascular outcomes and mortality events beyond blood pressure level, especially among younger patients.

Introduction: The benefits of reaching ideal cardiovascular health (CVH) is well known, but it is unclear whether positive CVH changes form young adulthood to middle age reduces subclinical atherosclerosis risk. Hypothesis: This study examined whether changes in CVH form young adulthood to middle age was associated with subclinical atherosclerosis. Methods: Data was analyzed from the Coronary Artery Risk Development in Young Adults (CARDIA) study. CVH was examined at Year 0 and 20 using 7 metrics (smoking, body mass index, diet, physical activity, blood pressure, fasting glucose, total cholesterol), each categorized as high (12 to 14 points), moderate (8 to 11) and low (0 to 7). Coronary artery calcium (CAC) was identified at Year 20 and 25. Carotid intima-media thickness (IMT) was identified at Year 20. Results: Among 2935 participants (56.2% women, 46.7% black), change of CVH metrics was -1.26 (2.13). For per 1-unit increase in CVH changes, the adjusted odds ratio of presence of CAC is 0.86 (95% CI 0.82, 0.90) and of IMT is 0.81 (95% CI 0.73, 0.90). Compared with stable moderate CVH, improvement from moderate to high CVH was associated with a lower risk of CAC (OR, 0.64 [95% CI 0.43, 0.96]), while retrogression from moderate to low CVH was associated with a higher risk of CAC (OR, 1.45 [95% CI 1.19, 1.76]). Conclusions: Positive changes of CVH during young adulthood is associated with negative subclinical atherosclerosis risk in middle age, indicating the importance of reaching an ideal cardiovascular health status through young adulthood.

Introduction: The activation of NF-κB is the dominant process that correlates with the pathogenesis of diabetic cardiomyopathy (DCM). Recently, accumulating evidence shows that long noncoding RNAs (lncRNAs) play crucial roles in sustaining the NF-κB pathway. However, the underlying mechanisms remain unclear. In this study, we identified the upregulated expressed lncRNA NBR2 in adipocyte-derived exosomes (AdEXO) and investigated its regulatory role in diabetic myocardial fibrosis. Hypothesis: We hypothesized that AdEXO-NBR2 promotes diabetic myocardial fibrosis through regulating the IκBα/NF-κB pathway. Methods: We examined the effect of exosomes from diabetic (db/db) mice-derived adipocytes on ANG-II-induced cardiac fibrosis and function in non-diabetic (C57BL/6J mice). In the invitro study, HG (33mmol/L)-stimulated AdEXO were cultured with adult human cardiac fibroblasts (aHCFs). Differentially expressed lncRNAs in AdEXO were screened using lncRNA sequencing. Results: Intramyocardial injection of diabetic AdEXO in the non-diabetic heart significantly exacerbated myocardial fibrosis, as evidenced by poorer cardiac function and enhancer collagen deposition. Whereas administration of a exosomes biogenesis inhibitor mitigated cardiac fibrosis in diabetic mice. We found lncRNA-NBR2 is a common molecule significantly increased in diabetic AdEXO and HG-stimulated non-diabetic AdEXO. After four weeks of ANG II infusion, EXO-db/dbWT-injected mice displayed fibrosis in the heart. However, interestingly, mice receiving NBR2-deficient db/db-EXO showed a decrease in cardiac fibrosis. Similarly, AdEXO-NBR2 promoted aHCFs proliferation and transformation capabilities in vitro. Mechanistically, NBR2 was loaded to AdEXO by directly interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK). Subsequently, AdEXO-NBR2 was internalized by aHCFs and epigenetically downregulated IκBα expression by recruitment of hnRNPK/SETDB1 and increasing the H3K9 trimethylation level in the IκBα promoter, ultimately activating the NF-κB pathway. Conclusions: Our findings highlight a novel epigenetic mechanism of AdEXO lncRNA-mediated diabetic cardiac fibrosis and identify NBR2 as a therapeutic target of DCM.

Background and aims: To measure the association between intensity of hypertensive exposure and myocardial structure and function during a 25-year period in young adulthood. Methods: The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled 5,115 healthy black and white American aged 18-30 years at baseline (March 1985 to May 2011). Intensity of hypertensive exposure was estimated based on their durations of hypertension over 25 years. Myocardial structure and function was identified by echocardiogram at year 25. Results: Of 2027 participants, 1315 were women (64.9%) and 906 were black (44.7%); mean (SD) age was 24.9 (3.6) at baseline. Duration of stage 1 hypertension was associated with higher left ventricular (LV) structure: LV mass (β [SE], 3.69 [1.80], P < 0.001), relative wall thickness (β [SE], 0.009 [0.003], P = 0.001), worse longitudinal strain (β [SE], 0.27 [0.008], P < 0.001), worse diastolic function: e’ (β [SE], -0.25 [0.07], P < 0.001), E/e’ (β [SE], 0.23 [0.007], P < 0.001). Duration of stage 2 hypertension was associated with higher left ventricular (LV) structure: LV mass (β [SE], 7.30 [2.23], P = 0.001), worse longitudinal strain (β [SE], 0.44 [0.13], P = 0.001), worse diastolic function: e’ (β [SE], -0.77 [0.12], P < 0.001), E/e’ (β [SE], 0.48 [0.13], P < 0.001). Conclusions: In early adulthood, more severe intensity of hypertensive exposure is associated with myocardial structure and diastolic dysfunction in middle age. Key Words: cardiac structure, cardiac dysfunction, hypertension, young adult

Background and aims: To measure the association between intensity of hypertensive exposure and coronary artery calcification (CAC) during a 25-year period in young adulthood. Methods: The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled 5,115 healthy black and white American aged 18-30 years at baseline (March 1985-June 1986 to June 2010-May 2011). Durations of hypertension was estimated based on their identification at examinations 7, 10, 15, 20, and 25 years later, and cumulative BP exposure (millimeters of mercury х year) were used to represent long-term exposure to BP levels. CAC was identified by computed tomography (CT) at years 15, 20, and 25. Results: Among 2057 participants at year 0, 30.8% (634 of 2057) developed stage 1 hypertension and 13.8% (284 of 2057) developed stage 2 hypertension. After adjustment, the hazard ratio for the presence CAC was 1.07 (95% CI 0.99, 1.17) and 1.14 (95% CI 1.02, 1.29) times higher for each follow-up years longer duration of stage 1 and stage 2 hypertension respectively. For cumulative BP exposure at year 25, the odds ratio (ORs) for CAC were 1.58 (95% CI 1.39, 1.80) in cumulative SBP, 1.45 (95% CI 1.28, 1.64) in cumulative DBP, 1.26 (95% CI 1.13, 1.41) in cumulative PP, and 1.55 (95% CI 1.36, 1.76) in cumulative MAP for each SD increment. Conclusions: In early adulthood, more severe intensity of hypertensive exposure, durations of hypertension or exposure to BP, is associated with subclinical atherosclerosis in middle age. Key Words: coronary artery calcification, hypertension, young adult

Background The influences of low‐carbohydrate diets in cardiovascular disease are controversial. Few studies have examined the relationship of carbohydrate intake and risk of incident atrial fibrillation ( AF ). We aimed to evaluate the association between carbohydrate intake and the risk of incident AF in the ARIC (Atherosclerosis Risk in Communities) Study. Methods and Results We included 13 385 participants (age, 54.2±5.8 years; 45.1% men and 74.7% white) who completed a dietary questionnaire at baseline (1987–1989) in the ARIC Study. The primary outcome was incident AF , which was identified by ECG performed during study examinations, hospital discharge codes, and death certificates. We used multivariable Cox hazard regression models to assess the association between carbohydrate intake and incident AF . We further explored the effects of specific food source (animal versus plant based) used to replace carbohydrate intake in the low‐carbohydrate intake setting. During a median follow‐up of 22.4 years, 1808 cases (13.5%) of AF occurred. The hazard ratio for incident AF associated with a 1‐ SD (9.4%) increase in carbohydrate intake as a percentage of energy intake was 0.82 (95% CI , 0.72–0.94), after adjustment for traditional AF risk factors and other diets factors. Results were similar when individuals were categorized by carbohydrate intake quartiles (hazard ratio, 0.64; 95% CI , 0.49–0.84; comparing extreme quartiles). No association was found between the type of protein or fat used to replace the carbohydrate and risk of incident AF . Conclusions Low‐carbohydrate diets were associated with increased risk of incident AF , regardless of the type of protein or fat used to replace the carbohydrate.