Cardiac autonomic neuropathy modified the association between obesity and hypoglycemia in type 2 diabetes.

BACKGROUND: Previous studies have shown that increasing body mass index (BMI) was associated with decreased hypoglycemia in type 2 diabetes, but it remains uncertain whether this finding could be applied to patients with and without cardiac autonomic neuropathy (CAN). METHODS: The study included 7789 participants with type 2 diabetes from action to control cardiovascular risk in diabetes (ACCORD) trail. CAN was defined as SDNN < 8.2 ms and RMSSD < 8.0 ms. Obesity was defined as BMI ≥ 30 kg/m2. Outcomes were identified as severe hypoglycemia requiring any assistance (HAA) or requiring medical assistance (HMA). We assessed the association between obesity and severe hypoglycemia in type 2 diabetes with or without CAN using COX regression models adjusted for baseline characteristics. RESULTS: Over a median follow-up of 4.7 years, a total of 893 participants developed HAA and 584 participants developed HMA. Compared with non-obesity, obesity was associated with lower risk of severe hypoglycemia (HAA: hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.38-0.68, P < 0.001; HMA: HR 0.57, 95% CI 0.40-0.82, P = 0.002) in CAN present group, but not in CAN absent group (HAA: HR 0.98, 95% CI 0.83-1.16, P = 0.830; HMA: HR 0.97, 95% CI 0.79-1.19, P = 0.754). Similarly, increasing BMI was associated with reduced severe hypoglycemic events in participants with CAN, but not in participants without CAN. CONCLUSIONS: CAN modifies the association between obesity and hypoglycemia in type 2 diabetes. Type 2 diabetic individuals with CAN who are under weight control should pay attention to hypoglycemic events. TRIAL REGISTRY: http://www. CLINICALTRIALS: gov . Unique identifier: NCT00000620.

Effects of a competence-based approach for clerkship teaching under alternating clinical placements: An explanatory sequential mixed-methods research.

BACKGROUND: It is unclear whether alternating placements during clinical clerkship, without an explicit emphasis on clinical competencies, would bring about optimal educational outcomes. METHODS: This is an explanatory sequential mixed-methods research. We enrolled a convenience sample of 41 eight-year programme medical students in Sun Yat-sen University who received alternating placements during clerkship. The effects of competence-based approach (n = 21) versus traditional approach (n = 20) to clerkship teaching were compared. In the quantitative phase, course satisfaction was measured via an online survey and academic performance was determined through final scores on summative assessment. Then, in the qualitative phase, students were invited for semi-structured interviews about their learning experiences, and the transcripts were used for thematic analysis. RESULTS: Quantitative findings showed that students in the study group rated high course satisfaction and performed significantly better in their final scores compared with those in the control group. Qualitative findings from thematic analysis showed that students were relatively neutral about their preference on placement models, but clearly perceived, capitalised, and appreciated that their competencies were being cultivated by an instructor who was regarded as a positive role model. CONCLUSION: A competence-based approach to clerkship teaching resulted in better course satisfaction and academic performance, and was perceived, capitalised, and appreciated by students.

Adaptive Metabolic Responses Facilitate Blood-Brain Barrier Repair in Ischemic Stroke via BHB-Mediated Epigenetic Modification of ZO-1 Expression.

Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta-hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood-brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO-ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO-1 by enhancing local ß-hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO-ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.

Prognostic Significance of Aortic Valve Calcification in Relation to Coronary Artery Calcification for Cardiovascular Diseases.

AIMS: Both coronary artery calcification (CAC) and aortic valve calcification (AVC) are strongly associated with cardiovascular diseases (CVD), but data about the prognostic significance of multiple cardiovascular calcifications are limited. We aim to investigate the interaction relationship of AVC and CAC for major events. METHODS: We included 6,695 participants from the Multi-Ethnic Study of Atherosclerosis at baseline, and divided them into four groups: 1) no AVC or CAC; 2) only AVC; 3) only CAC; 4) with CAC and CAC. Cox regression model and Kaplan-Meier method were used to analyze CVD outcomes. We evaluated the interaction between AVC and CAC, and their added predictive value based on the pooled cohort equations (PCEs). The subgroup analyses were also explored. RESULTS: Among 6,695 participants (mean age 62.2 ± 10.2 years, 47.2% male), after follow-up, 943 cases (14.1%) of CVD and 1274 cases (19.0%) of all-cause death occurred. For participants with both AVC and CAC, the risk of CVD significantly increased {HR =3.43 (2.69-4.37), P <0.001}, even higher than the sum of the ones with only AVC and only CAC. This trend remained the same for all-cause death and among subgroup analysis. The addictive interaction was statistically significant (P <0.001). When added AVC and CAC, the predictive value of PCEs increased. CONCLUSIONS: Our results indicated a synergistical interaction between valve calcification and coronary calcification to cardiovascular diseases. Management for both AVC and CAC may bring health co-benefits in preventing poor outcomes.

We investigated the interaction relationship between AVC and CAC in 6,695 participants with measurements for cardiovascular calcifications at baseline in MESA study, and the prognostic significance of AVC in relation to CAC. Our study found that CAC and AVC worked independently and synergistically to predict the risk of cardiovascular diseases and all-cause death. Our results have shown that patients suffering from both CAC and AVC are more likely to develop a poor prognosis, therefore it's necessary to implement earlier and more positive intervention for CVD prevention in this certain subpopulation.

The gut microbe-derived metabolite trimethylamine-N-oxide induces aortic valve fibrosis via PERK/ATF-4 and IRE-1α/XBP-1s signaling in vitro and in vivo.

BACKGROUND AND AIMS: The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular fibrosis. Endoplasmic reticulum (ER) stress occurs after the dysfunction of ER and its structure. The three signals PERK/ATF-4, IRE-1α/XBP-1s and ATF6 are activated upon ER stress. Recent reports have suggested that the activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling contributes to cardiovascular fibrosis. However, whether TMAO mediates aortic valve fibrosis by activating PERK/ATF-4 and IRE-1α/XBP-1s signaling remains unclear. METHODS: Human aortic valve interstitial cells (AVICs) were isolated from aortic valve leaflets. PERK IRE-1α, ATF-4, XBP-1s and CHOP expression, and production of collagen Ⅰ and TGF-ß1 were analyzed following treatment with TMAO. The role of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in TMAO-induced fibrotic formation was determined using inhibitors and small interfering RNA. RESULTS: Diseased valves produced greater levels of ATF-4, XBP-1, collagen Ⅰ and TGF-ß1. Interestingly, diseased cells exhibited augmented PERK/ATF-4 and IRE-1α/XBP-1s activation after TMAO stimulation. Inhibition and silencing of PERK/ATF-4 and IRE-1α/XBP-1s each resulted in enhanced suppression of TMAO-induced fibrogenic activity in diseased cells. Mice treated with dietary choline supplementation had substantially increased TMAO levels and aortic valve fibrosis, which were reduced by 3,3-dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) treatment. Moreover, a high-choline and high-fat diet remodeled the gut microbiota in mice. CONCLUSIONS: TMAO promoted aortic valve fibrosis through activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in vitro and in vivo. Modulation of diet, gut microbiota, TMAO, PERK/ATF-4 and IRE1-α/XBP-1s may be a promising approach to prevent aortic valve fibrosis.

Physical Activity and Weight Loss Among Adults With Type 2 Diabetes and Overweight or Obesity: A Post Hoc Analysis of the Look AHEAD Trial.

Importance: Prior findings from the Look AHEAD trial showed no significant reduction in the risk of cardiovascular events by lifestyle-induced weight loss among individuals with type 2 diabetes (T2D) and overweight or obesity. However, physical activity (PA) may modify the changes in cardiovascular risk associated with weight loss. Objective: To examine the joint association of weight loss and PA with the risk of adverse cardiovascular events in patients with T2D and overweight or obesity. Design, Setting, and Participants: This cohort study was a post hoc analysis of the Look AHEAD randomized clinical trial, which compared the cardiovascular effects of weight loss by intensive lifestyle intervention vs diabetes support and education among individuals with T2D and overweight or obesity. The study was conducted from June 2001 to September 2012, and participants were patients in the substudy of accelerometry-measured PA from 8 locations in the United States. Data were analyzed from June to August 2023. Exposures: Body weight change and accelerometer-derived PA volume across the first 4 years. Main Outcomes and Measures: The primary outcome was a composite cardiovascular outcome including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. Results: Among a total of 1229 participants (mean [SD] age, 60 [7] years; 533 male [43%]), 333 (27%) achieved and maintained weight loss for the first 4 years. Among the individuals who maintained weight loss, 105 (32%) maintained high PA volume. During a median of 9.5 years of follow-up, 198 participants (16.1%) experienced the primary outcome. Compared with those with low PA volume and no weight loss (105 [15.8%]), maintaining high PA volume and weight loss was associated with a 61% lower risk of the primary end point (hazard ratio, 0.39; 95% CI, 0.19-0.81; P = .01). However, there was no significant difference in the risk of the primary end point among those with either weight loss only or high PA only. The multiplicative interaction between weight loss and PA for the risk of cardiovascular events was also significant (P for interaction = .01). Conclusions and Relevance: In this cohort study, maintaining weight loss and higher PA volume was associated with a lower risk of the composite cardiovascular outcome. The findings suggest that the cardiovascular benefits of PA may vary and be enhanced by weight loss among individuals with T2D and overweight or obesity.

New Insights into Rate Control: Time in Target Range of Resting Heart Rate and Major Adverse Outcomes in Atrial Fibrillation.

Background: Few studies have examined the relationship between the fluctuation of heart rate control over time and cardiovascular outcomes in patients with atrial fibrillation. Our study sought to evaluate the independent association between time in target range (TIR) of resting heart rate and cardiovascular outcomes in the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) study. Methods: Target range of resting heart was defined as less than 80 beats per minute (bpm) for both rate and rhythm control groups. Time in target range was estimated over the first 8 months of follow-up using Rosendaal interpolation method. The association between TIR of resting heart rate and cardiovascular outcomes was estimated using adjusted Cox proportional hazards regression models. Results: Time in target range of resting heart rate (months 0 through 8) was 71 ± 34% in the rate control group and 83 ± 27% in the rhythm control group. Each 1-SD increase in TIR of resting heart rate was significantly associated with lower risk of major adverse cardiovascular events after full adjustment for demographics, medical history and history of prior heart surgery, as well as all-cause mortality. Conclusions: Time in target range of resting heart rate independently predicts the risk of cardiovascular outcomes in patients with atrial fibrillation. Long-term maintenance of heart rate on target is of great importance for patients with atrial fibrillation.

Effect of Intensive Lifestyle Intervention on Cardiovascular Risk Factors: Analysis From the Perspective of Long-Term Variability.

BACKGROUND: An association between variability of cardiovascular risk factors and cardiovascular events has been reported. We examined whether intensive lifestyle intervention (ILI) for weight loss decreased variability of cardiovascular risk factors with a view to additional cardiometabolic benefits. METHODS AND RESULTS: This study was a post hoc secondary analysis of the Look AHEAD (Action for Health in Diabetes) study. Cardiovascular risk factors were measured at 1-year intervals for 4 years in 4249 adults with overweight or obesity and type 2 diabetes who were randomly assigned to ILI or diabetes support and education. Long-term variability was defined as the SD of cardiovascular risk factors during 4-year follow-up. At multiple linear regression analysis, compared with the diabetes support and education group, the ILI group was associated with reduced variability of fasting blood glucose (ß=-1.49 [95% CI, -2.39 to -0.59]), total cholesterol (ß=-1.12 [95% CI, -1.75 to -0.48]), and low-density lipoprotein cholesterol (ß=-1.04 [95% CI, -1.59 to -0.49]), as well as increased variability of systolic blood pressure (ß=0.27 [95% CI, 0.00-0.54]). No significant effect of ILI was found on the variability of diastolic blood pressure (ß=-0.08 [95% CI, -0.22 to 0.05]). CONCLUSIONS: Among adults with overweight or obesity and type 2 diabetes, ILI may reduce long-term variability of fasting blood glucose, total cholesterol, and low-density lipoprotein cholesterol. Our results support that ILI should be recommended to individuals with diabetes as part of management of long-term glycemic and blood lipid control.

The impact of visit-to-visit heart rate variability on all-cause mortality in atrial fibrillation.

OBJECTIVE: We aimed to investigate the association between visit-to-visit heart rate variability (VVHRV) and all-cause mortality in patients diagnosed with atrial fibrillation (AF). Previous studies have shown a positive correlation between VVHRV and several adverse outcomes. However, the relationship between VVHRV and the prognosis of AF remains uncertain. METHODS: In our study, we aimed to examine the relationship between VVHRV and mortality rates among 3983 participants with AF, who were part of the AFFIRM study (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). We used the standard deviation of heart rate (HRSD) to measure VVHRV and divided the patients into four groups based on quartiles of HRSD (1st, <5.69; 2nd, 5.69-8.00; 3rd, 8.01-11.01; and 4th, ≥11.02). Our primary endpoint was all-cause death, and we estimated the hazard ratios for mortality using the Cox proportional hazard regressions. RESULTS: Our analysis included 3983 participants from the AFFIRM study and followed for an average of 3.5 years. During this period, 621 participants died from all causes. In multiple-adjustment models, we found that the lowest and highest quartiles of HRSD independently predicted an increased risk of all-cause mortality compared to the other two quartiles, presenting a U-shaped relationship (1st vs 2nd, hazard ratio = 2.28, 95% CI = 1.63-3.20, p < .01; 1st vs. 3rd, hazard ratio = 2.23, 95% CI = 1.60-3.11, p < .01; 4th vs. 2nd, hazard ratio = 1.82, 95% CI = 1.26-2.61, p < .01; and 4th vs. 3rd, hazard ratio = 1.78, 95% CI = 1.25-2.52, p < .01). CONCLUSION: In patients with AF, we found that both lower VVHRV and higher VVHRV increased the risk of all-cause mortality, indicating a U-shaped curve relationship.

Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality.

BACKGROUND: The association between 25-hydroxyvitamin D and mortality remains controversial. Klotho, a biomarker of vitamin D activation and metabolism, may play a key role in this association. However, it is unclear whether the association between vitamin D deficiency and mortality risk is modified by klotho levels. Therefore, this study investigated the joint association of serum 25-hydroxyvitamin D [25(OH)D] and klotho with mortality risk in American community-dwelling adults. METHODS: A total of 9870 adults from the National Health and Nutrition Examination Survey (2007-2016) were included in our study. Mortality data were ascertained by linking participants to National Death Index records. Cox proportional hazards models were used to assess the association among serum 25(OH)D, serum klotho, and all-cause and cardiovascular disease (CVD) mortality. RESULTS: We found a significant interaction between klotho and serum 25(OH)D in all-cause mortality (P = .028). With klotho > 848.4 pg/mL (risk threshold on mortality), no significant all-cause and CVD mortality risk was observed at any level of serum 25(OH)D. However, with klotho < 848.4 pg/mL, a significant all-cause and CVD mortality risk was observed with serum 25(OH)D < 50 nmol/L [hazards ratio (HR), 1.36; 95% confidence interval (CI), 1.10-1.69; HR, 1.78; 95% CI, 1.16-3.45) and serum 25(OH)D of continuous variable (HR, 0.98; 95% CI, .97-.99; HR, 0.98; 95% CI, .98-.99). In addition, vitamin D metabolism disruption accessed by the combination of decreasing serum 25(OH)D (<50 nmol/L) and klotho (<848.4 pg/mL) was associated with significant all-cause mortality (HR, 1.48; 95% CI, 1.11-1.96) and CVD mortality (HR, 2.36; 95% CI, 1.48-3.75). CONCLUSIONS: Vitamin D-associated mortality risk is observed only with concurrently decreasing klotho, indicating that vitamin D metabolism dysfunction increases the risk of mortality. Klotho levels could help predict long-term mortality outcomes and thus may be useful concurrently for guiding vitamin D supplementation therapy decision-making in populations with vitamin D deficiency.

Intensive Glycemic Therapy in Type 2 Diabetes Patients With Cardiac Autonomic Dysfunction: The ACCORD Trial.

OBJECTIVE: To assess whether the presence of cardiac autonomic dysfunction denoted by low heart rate variability (HRV) modifies the effect of intensive glycemic therapy on outcomes in patients with type 2 diabetes. PATIENTS AND METHODS: This study included 7946 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial from January 2001 through June 2009. Heart rate variability measures included standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). Abnormal values were defined based on less than the 10th percentile for SDNN and rMSSD. RESULTS: Compared with standard therapy, intensive therapy was associated with improved primary outcome (composite of cardiovascular events) in the low-HRV group (SDNN: HR, 0.57; 95% CI, 0.39 to 0.84; rMSSD: HR, 0.57; 95% CI, 0.38 to 0.84), but not in the normal-HRV group (SDNN: HR, 0.90; 95% CI, 0.77 to 1.05; rMSSD: HR, 0.90; 95% CI, 0.77 to 1.05). A similar pattern was found for coronary heart disease. Conversely, intensive therapy had a neutral effect on all cause death in the low-HRV group (SDNN: HR, 0.88; 95% CI, 0.54 to 1.41; rMSSD: HR, 0.71; 95% CI, 0.43 to 1.17;), but increase risk of all-cause death in the normal-HRV group (SDNN: HR, 1.21; 95% CI, 1.00 to 1.46; rMSSD: HR, 1.25; 95% CI, 1.03 to 1.51). Intensive therapy induced a greater risk of hypoglycemia in the normal-HRV group than that in the low-HRV group. CONCLUSION: Cardiac autonomic dysfunction expressed as low HRV identified subpopulations in ACCORD with more benefits and less harms from intensive therapy.

Cardiovascular effects of weight loss in old adults with overweight/obesity according to change in skeletal muscle mass.

BACKGROUND: Patients with overweight/obesity and type 2 diabetes are encouraged to lose weight, but not all losing weight gain better cardiovascular health, especially old adults. The change in skeletal muscle mass (SMM) could be the key that explains the heterogenous cardiovascular effects of weight loss. This study aims to assess whether the cardiovascular effects of weight loss vary for those gaining skeletal muscle along with weight loss. METHODS: The old adults with overweight/obesity and type 2 diabetes in the Look AHEAD study having muscle measurement from dual-energy X-ray absorptiometry were included. Based on the weight change (WC) and SMM change (SMMC) between baseline and the 4-year follow-up, participants were allocated into three groups-weight gain (WG) group, weight loss with muscle loss (WL-ML) group and weight loss with muscle gain (WL-MG) group. Cox proportional hazards regression was performed to evaluate the cardiovascular risk of those gaining or losing SMM with weight loss compared with those gaining weight. Among the participants with weight loss, the ratio of SMMC/WC was calculated, and the association of SMMC/WC with primary cardiovascular outcome was assessed. RESULTS: A total of 491 participants were included in the study with an average age of 64.56 ± 3.81 years old. A total of 47.0% were male and 49.9% were from the intensive lifestyle intervention arm. Based on their WC and SMMC, 43 were assigned to the WG group, 373 to the WL-ML group and 75 to the WL-MG group. Over a follow-up of almost 10 years, 97 participants encountered the primary endpoint. The WG group had the highest incidence of 25.59%, the WL-MG group had the lowest incidence of 9.33% and the WL-ML group had 21.18% (P = 0.040). In the fourth adjusted Cox model, the WL-MG group achieved significantly decreased odds of the primary endpoint compared with the WG group (hazard ratio [HR] 0.33, 95% confidence interval [CI] [0.12, 0.87], P = 0.026), whilst the WL-ML group did not (HR 0.91, 95% CI [0.47, 1.78], P = 0.670). Among the participants with weight loss, when SMMC/WC reached around 50%, this HR soared to approximately two-fold. CONCLUSIONS: The participants gaining SMM along with weight loss achieved the lowest odds of adverse cardiovascular events, whilst those who lost SMM along with weight loss had comparable cardiovascular risk with those gaining weight. The more muscle lost during weight loss, the greater the harm. The cardiovascular effects of weight loss were modulated by whether the participants gained SMM meanwhile losing weight.

Long-term physical activity time-in-target range in young adults with cardiovascular events in later life.

AIMS: Achieving at least 150 min per week of moderate-to-vigorous physical activity (PA) is a 'Class I, A level' recommendation for the primary prevention of cardiovascular disease. However, long-term PA is a complex behaviour and varied by lifetime, which was insufficiently reflected by the current studies. This study used time-in-target range (TTR) to measure the long-term PA level during young adulthood and investigated its relationship with cardiovascular events in later life. METHODS AND RESULTS: Participants in the Coronary Artery Risk Development in Young Adults study were recruited (n = 2902) and allocated into four groups by PA TTR: <25% (n = 1028), 25 to <50% (n = 444), 50 to <75% (n = 424), 75 to 100% (n = 1006). TTR was estimated with linear interpolation across the first 15 years. The primary outcome was a composite of cardiovascular events. The mean (SD) age after the exposure period was 40.3 (3.6) years. After a median follow-up for an additional 18.9 years, the participants with a TTR of at least 75% had a 40% lower risk of the primary outcome (HR: 0.60; 95%CI: 0.38 to 0.95) compared with the lowest TTR group. Each 1-SD increase in TTR was also significantly associated with a 21% decreased risk of the primary outcome (HR: 0.79; 95%CI: 0.65-0.97). CONCLUSION: Increasing PA is essential in young adulthood. In young adults, maintaining long-term guidelines-recommended PA levels may help to lower the risk of cardiovascular events in later life. Maintaining the guidelines-recommended PA level for at least 75% of time across young adulthood may be preferable.

Maintaining long-term guidelines-recommended PA levels may decrease the risk of cardiovascular events in later life, and young adults maintaining that PA level for at least 75% of time may be preferable.

Interplay of heart rate variability and resting heart rate on mortality in type 2 diabetes.

AIMS: Heart rate variability (HRV) and resting heart rate (RHR) are usually analyzed and interpreted separately. We aimed to assess the interplay of HRV and RHR on mortality in type 2 diabetes. METHODS: The study included 7,529 participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. HRV metrics included standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). Abnormal values were defined based on <25th percentile for HRV and >75th percentile for RHR. Interactions of HRV status and RHR status were tested on multiplicative and additive scales. Results were validated in a subset of patients with type 2 diabetes (n = 745) from the Multi-Ethnic Study of Atherosclerosis. RESULTS: Low SDNN was associated with increased all-cause mortality in the high RHR group (HR 1.60; 95% CI 1.29-1.97), but not in the normal RHR group. Compared with those who had neither low SDNN nor high RHR, the presence of either low SDNN or high RHR was not significantly associated with an increased risk of all-cause mortality. In contrast, the combination of low SDNN and high RHR was associated with a significantly increased risk of all-cause mortality (HR 1.68; 95% CI 1.43-1.97). Significant multiplicative and additive interactions were found between HRV status and RHR status on risk of all-cause mortality (all Pinteraction < 0.05). Similar findings were observed for cardiovascular mortality, in analyses using rMSSD, and in the Multi-Ethnic Study of Atherosclerosis. CONCLUSIONS: The association between HRV and mortality risk is modified by RHR levels. Furthermore, low HRV and high RHR have interdependent and synergistic associations with mortality risk.

Remnant Cholesterol in Young Adulthood Is Associated With Left Ventricular Remodeling and Dysfunction in Middle Age: The CARDIA Study.

BACKGROUND: Recent studies have shown that remnant cholesterol (RC) is associated with incident heart failure; however, its association with left ventricular (LV) structure and function is unclear. We aimed to evaluate the association between RC levels in young adulthood and LV structure and function in middle age. METHODS: We included 3321 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults) at baseline. RC was calculated as total cholesterol minus high-density lipoprotein cholesterol minus calculated low-density lipoprotein cholesterol, and the RC trajectories that followed a similar pattern of change over time were identified using the latent class growth mixture model. LV structure and function were assessed using echocardiography at CARDIA study year 25. Multivariable linear regression models were performed to assess the associations of both baseline and trajectories of RC levels with LV structure and function. RESULTS: Among 3321 participants, the mean age was 24.99±3.62 years: 1450 (43.90%) were male, and 1561 (47.00%) were Black. After multivariate adjustment, higher baseline RC (per SD in log-transformed) was associated with higher LV mass index (ß=1.29; P=0.004), worse global longitudinal strain (ß=0.19; P<0.001), worse global circumferential strain (ß=0.16; P=0.014), lower septal e' (ß=-0.26; P<0.001), lower lateral e' (ß=-0.18; P=0.003), and higher E/e' (ß=0.15; P=0.003). Three RC trajectories were identified during follow-up: low increasing (42.4%), moderate increasing (45.5%), and high increasing (12.1%). Similarly, compared with the low-increasing group, the high-increasing RC trajectory group was related to higher LV mass index, worse global longitudinal strain, lower septal e', lower lateral e', and higher E/e'. CONCLUSIONS: Elevated RC levels in young adulthood were related to adverse LV structural and functional alterations in midlife. Long-term trajectories of RC levels during young adulthood help identify individuals at a higher risk for adverse LV remodeling and dysfunction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005130.

Association between the insulin resistance and all-cause mortality in patients with moderate and severe aortic stenosis: a retrospective cohort study.

BACKGROUND: The triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance (IR). However, whether the TyG index has prognostic value in patients with moderate to severe aortic stenosis (AS) remains unclear. METHODS: This study enrolled 317 patients with moderate to severe AS at the First Affiliated Hospital of Sun Yat-Sen University. The patients were grouped according to the cut-off value of the TyG index. Cox regression with Firth's penalized maximum likelihood method and restricted cubic splines regression were conducted to assess the association between the TyG index and all-cause mortality. The added value of the TyG index included in the traditional risk factors model for outcome prediction was also analyzed. RESULTS: Among 317 patients (mean age 67.70 years, 62.8% male), there was 84 all-cause mortality during a median 38.07 months follow-up. After fully adjusting for confounders, a per-unit increase in the TyG index was associated with a 62% higher all-cause mortality risk (HR 1.622, 95% CI 1.086-2.416, p = 0.018). The restricted cubic splines regression model revealed a linear association between the TyG index and the risk of all-cause mortality (p for nonlinearity = 0.632). The addition of the TyG index in the basic risk model has an incremental effect on the prediction of mortality [C-statistic change from 0.755 to 0.768; continuous net reclassification improvement (95% CI): 0.299 (0.051-0.546), p = 0.017; integrated discrimination improvement: 0.017 (0.001-0.033), p = 0.044]. CONCLUSIONS: Higher IR assessed by the TyG index was associated with a higher risk of all-cause mortality in patients with moderate and severe AS.

Effect of blood pressure index on clinical outcomes in patients with heart failure and chronic kidney disease.

AIMS: This study aimed to assess the effect of blood pressure (BP) index, in terms of level and variability, on the progression of cardiovascular and renal diseases in patients with both heart failure (HF) and chronic kidney disease (CKD). METHODS AND RESULTS: The study involved patients with HF and CKD from the database of the Chronic Renal Insufficiency Cohort (CRIC) study. The study endpoint includes the following: (i) primary endpoint, including cardiovascular disease (CVD) events, renal events, and all-cause death; (ii) CVD events; (iii) renal events; and (iv) all-cause death. Among 3939 participants in the CRIC study, a total of 382 patients were included. The duration of the follow-up was 6.3 ± 2.7 years, the age was 60.2 ± 8.9 years, and 57.6% were male. BP index included 20 indicators in relation to BP level and variability, 4 of which were analysed including baseline systolic BP (SBP), standard deviation of SBP, coefficient of variation of diastolic BP (DBP CV), and average real variability of pulse pressure. In the Cox regression analysis after adjustment, baseline SBP was significant for the risk of primary endpoint [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.03-1.44, P = 0.02] and renal events (HR 1.54, 95% CI 1.22-1.95, P < 0.001), and DBP CV was significant for the risk of primary endpoint (HR 1.03, 95% CI 1.01-1.06, P = 0.02) and CVD events (HR 1.04, 95% CI 1.02-1.07, P < 0.01). The result of the forest plot depicted that baseline SBP had a linear association with the risk of CVD and renal events (P = 0.04 and 0.001, respectively) and DBP CV with CVD events (P = 0.02). As the restricted cubic spline models displayed, DBP CV featured a J- or L-curved association with the primary endpoint, renal events, and all-cause death (P for nonlinearity = 0.01, <0.001, and 0.01, respectively). CONCLUSIONS: The baseline SBP and DBP CV may remain significant for clinical outcomes in patients with both HF and CKD. The increase in baseline SBP is associated with a higher risk of primary endpoint, CVD events, and renal events, and the increase in DBP CV with a higher risk of CVD events. Concerning nonlinear association, DBP CV features a J- or L-curved relationship with the primary endpoint, renal events, and all-cause death, with a higher risk at both low and high values. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; unique identifier: NCT00304148.

Alirocumab effect on preventing periprocedural ischaemic events in coronary heart disease patients undergoing coronary stenting (APPEASE trial): study protocol of a multicentre, open-label, randomised controlled trial.

INTRODUCTION: Percutaneous coronary intervention (PCI)-related myocardial infarction (type 4a MI) and major periprocedural myocardial injury have been demonstrated leading to poor prognosis of patients with coronary heart disease (CHD) undergoing elective PCI and still remain high occurrence even after the therapy of dual antiplatelet agents and statins. Proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has been shown to be effectively in reducing the risk of acute MI (AMI). However, the effect of alirocumab on preventing PCI-related MI or major periprocedural myocardial injury in patients with CHD undergoing elective PCI remains uncertain. METHODS AND ANALYSIS: Alirocumab effect on Preventing Periprocedural ischaemic Events in coronary heart diseAse patients undergoing coronary StEnting trial is a multicentre, open-label, randomised controlled trial aiming to determine whether alirocumab could reduce the incidence of type 4a MI or major periprocedural myocardial injury in patients with CHD undergoing elective PCI. In total, 422 non-AMI CHD patients planned to undergo elective PCI will be randomly assigned to receive standard pharmacotherapy of CHD (control group) or additional use of subcutaneous alirocumab 75 mg 1 day before procedure (alirocumab group). The primary outcome is type 4a MI or major periprocedural myocardial injury defined as high-sensitivity cardiac troponin elevating above 5×99 th percentile upper reference limit in 48 hours after PCI. Patients will continue receiving standard pharmacotherapy or additional biweekly subcutaneous alirocumab 75 mg for 3 months according to the initial randomisation group. We will follow up for 3 months and record all the major adverse cardiovascular events (MACEs). Incidence of PCI-related MI or major periprocedural myocardial injury, and MACE in 3 months after PCI will be compared between control group and alirocumab group. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University with approval number: (2022)02-140-01. The results of this study will be reported through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR2200063191.

GP73 enhances the ox-LDL-induced inflammatory response in THP-1 derived macrophages via affecting NLRP3 inflammasome signaling.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease with its molecular basis incompletely understood. Here, we determined whether the Golgi phosphoprotein 73 (GP73), a novel protein highly related to inflammation and disrupted lipid metabolism, was involved in the development of atherosclerosis. METHODS: Public microarray databases of human vascular samples were analyzed for expression patterns. Apolipoprotein-E-gene-deficient (ApoE-/-) mice (8-week-old) were randomly assigned to either a chow diet group or a high-fat diet group. The levels of serum GP73, lipid profiles and key inflammatory cytokines were determined by ELISA. The aortic root plaque was isolated and used for by Oil Red O staining. PMA-differentiated THP-1 macrophages were transfected with GP73 small interfering RNA (siRNA) or infected with adenovirus expressing GP73, and then stimulated with oxidized low density lipoprotein (ox-LDL). The expressions of pro-inflammatory cytokines and signal pathway key targets were determined by ELISA kit and Western blot respectively. In addition, ichloro-dihydro-fluorescein diacetate (DCFH-DA) was used to measure the intracellular ROS levels. RESULTS: The expressions of GP73 and NLRP3 were substantially upregulated in human atherosclerotic lesions. There were significant linear correlations between GP73 and inflammatory cytokines expressions. High-fat diet-induced atherosclerosis and increased levels of plasma inflammatory mediators (IL-1ß, IL-18, and TNF-α) were observed in ApoE-/- mice. Besides, the expressions of GP73 in the aorta and serum were significantly upregulated and positively correlated with the NLRP3 expression. In the THP-1 derived macrophages, ox-LDL treatment upregulated the expressions of GP73 and NLRP3 proteins and activated the inflammatory responses in a concentration-dependent and time-dependent manner. Silencing of GP73 attenuated the inflammatory response and rescued the decreased migration induced by ox-LDL, inhibiting the NLRP3 inflammasome signaling and the ROS and p-NF-κB activation. CONCLUSIONS: We demonstrated that GP73 promoted the ox-LDL-induced inflammation in macrophages by affecting the NF-κB/NLRP3 inflammasome signaling, and may play a role in atherosclerosis.

Body weight time in target range and cardiovascular outcomes in adults with overweight/obesity and type 2 diabetes.

AIMS: Prescription of weight loss to individuals is often characterized by weight fluctuations. However, current body weight management metrics may have difficulty characterizing the changes in body weight over time. We aim to characterize the long-term changes using body weight time in target range (TTR) and test its independent association with cardiovascular outcomes. METHODS AND RESULTS: We included 4468 adults from the Look AHEAD (Action for Health in Diabetes) trial. Body weight TTR was defined as the percentage of time during which body weight was within the Look AHEAD weight loss goal range. The associations of body weight TTR with cardiovascular outcomes were analysed using multivariable Cox modelling and restricted cubic spline function. Among the participants (mean age 58.9 years, 58.5% women, 66.5% White), there were 721 incident primary outcomes [cumulative incidence: 17.5%, 95% confidence interval (CI): 16.3-18.8%] during a median of 9.5 years of follow-up. Each 1 SD increase in body weight TTR was significantly associated with a decreased risk of the primary outcome (hazard ratio: 0.84, 95% CI: 0.75-0.94) after adjusting for mean and variability of body weight and traditional cardiovascular risk factors. Further analyses using restricted cubic spline indicated the inverse association between body weight TTR and the primary outcome in a dose-dependent manner. Similar associations remained significant among the participants with lower baseline or mean body weight. CONCLUSION: In adults with overweight/obesity and type 2 diabetes, higher body weight TTR was independently associated with lower risks of cardiovascular adverse events in a dose-response manner.

We used time in target range (TTR) to characterize the long-term changes in body weight among 4468 adults with overweight/obesity and type 2 diabetes and assessed the associations of body weight TTR with cardiovascular outcomes.Participants with TTR of >50­100% achieved and maintained the target of body weight loss during the 10 years of follow-up.Higher body weight TTR was independently associated with lower risks of cardiovascular adverse events in a dose­response manner.