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.

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.

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.

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.

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.

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.

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.

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.

Long-Term High Level of Insulin Resistance Is Associated With an Increased Prevalence of Coronary Artery Calcification: The CARDIA Study.

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.

Visceral adiposity index and the risk of heart failure, late-life cardiac structure, and function in ARIC study.

BACKGROUND: It is well established that obesity is associated with the risk of heart failure (HF). However, the data about relationship between visceral fat and the risk of HF are limited. AIMS: We aim to evaluate the association between visceral obesity assessed by visceral adiposity index (VAI) and incident HF and left ventricular (LV) structure and function in Atherosclerosis Risk in Communities (ARIC) study. METHODS: We included 12 161 participants (aged 54.1 ± 5.8 years) free of history of HF and coronary heart disease at baseline (1987-89) in ARIC study. We used multivariable Cox hazard regression models to assess the association between the VAI and incident HF. We further explored the effects of the VAI on LV geometry and function among 4817 participants with echocardiographic data using multivariable linear regression analysis and multinomial logistic regression. RESULTS: During a median follow-up of 22.5 years, a total of 1904 (15.7%) participants developed HF. After adjustment for traditional HF risk factors, 1 unit increase in the baseline VAI was associated with an 8% higher risk of incident HF [hazard ratio (HR): 1.08, 95% confidence interval (CI): 1.06-1.11]. Results were similar when participants were categorized by VAI tertiles. Compared with participants in the lowest tertile of VAI, those in the second tertile and third tertile had a greater risk of incident HF [HR (95% CI): 1.19 (1.05-1.34) and 1.42 (1.26-1.61), respectively]. For the analyses of the HF subtypes, the higher VAI was only associated with the risk of HF with preserved ejection fraction, not with HF with reduced ejection fraction. In addition, the greater VAI was associated with worse LV diastolic function and abnormal LV geometry including concentric remodelling, concentric hypertrophy, and eccentric hypertrophy. CONCLUSION: This study shows that higher VAI was independently associated with the increased risk of incident HF and abnormal LV geometry and LV diastolic dysfunction.

We investigated the relationship between visceral adiposity index (VAI) and incident heart failure (HF) in 12 161 participants and further evaluated the possible effect of the VAI on late-life left ventricular (LV) structure and function in 4817 participants who underwent echocardiography examination at Visit 5 in Atherosclerosis Risk in Communities study.Our study found that VAI, a simple alternative indicator of visceral obesity, was positively associated with the risk of HF.Our results shown that VAI was significantly associated with abnormal LV geometry and worse LV diastolic function in late life.

Predictive performance of established cardiovascular risk scores in the prediabetic population: external validation using the UK Biobank data set.

AIMS: Prediabetes is a highly heterogenous metabolic state with increased risk of cardiovascular disease (CVD). Current guidelines raised the necessity of CVD risk scoring for prediabetes without clear recommendations. Thus, this study aimed to systematically assess the performance of 11 models, including five general population-based and six diabetes-specific CVD risk scores, in prediabetes. METHODS AND RESULTS: A cohort of individuals aged 40-69 years with prediabetes (HbA1c ≥ 5.7 and <6.5%) and without baseline CVD or known diabetes was identified from the UK Biobank, which was used to validate 11 prediction models for estimating 10- or 5-year risk of CVD. Model discrimination and calibration were evaluated by Harrell's C-statistic and calibration plots, respectively. We further performed decision curve analyses to assess the clinical usefulness.Overall, 56 831 prediabetic individuals were included, of which 4303 incident CVD events occurred within a median follow-up of 8.9 years. All the 11 risk scores assessed had modest C-statistics for discrimination ranging from 0.647 to 0.680 in prediabetes. Scores developed in the general population did not outperform those diabetes-specific models (C-statistics, 0.647-0.675 vs. 0.647-0.680), while the PREDICT-1° Diabetes equation developed for Type 2 diabetes performed best [0.680 (95% confidence interval, 0.672-0.689)]. The calibration plots suggested overall poor calibration except that the PREDICT-1° Diabetes equation calibrated well after recalibration. The decision curves generally indicated moderate clinical usefulness of each model, especially worse within high threshold probabilities. CONCLUSION: Neither risk stratification schemes for the general population nor those specific for Type 2 diabetes performed well in the prediabetic population. The PREDICT-1° Diabetes equation could be a substitute in the absence of better alternatives, rather than the general population-based scores. More precise and targeted risk assessment tools for this population remain to be established.

Changes in Cardiovascular Health during Young Adulthood and Subclinical Atherosclerosis in Middle Age: The CARDIA Study.

Background and aims: The benefits of reaching ideal cardiovascular health (CVH) are well known, but it is unclear whether positive CVH changes from young adulthood to middle age reduce subclinical atherosclerosis risk. This study examined associations of changes in CVH from young adulthood to middle age and CVH in young adulthood with subclinical atherosclerosis. Methods: Data was analyzed from the Coronary Artery Risk Development in Young Adults (CARDIA) study. CVH was examined at years 0 and 20 using Life Simple 7 metrics from AHA guideline. Coronary artery calcium (CAC) was identified at years 20 and 25. Carotid intima-media thickness (IMT) was identified at year 20. Results: Among 2,935 participants (56.2% women, 46.7% black), the change of CVH score was -1.26 (2.13). For per 1-unit increase in CVH at baseline, the adjusted odds ratios (ORs) of presence of CAC and IMT were 0.81 (95% CI 0.78, 0.86) and 0.85 (95% CI 0.76, 0.94), respectively. For per 1-unit increase in CVH changes, the adjusted ORs of CAC and IMT were 0.86 (95% CI 0.82, 0.90) and 0.81 (95% CI 0.73, 0.90). Compared with stable moderate CVH, improvement from moderate to high was associated with a lower risk of CAC (0.64 [95% CI 0.43, 0.96]), while retrogression from moderate to low was associated with a higher risk of CAC (1.45 [95% CI 1.19, 1.76]). Conclusions: Positive changes of CVH during young adulthood are associated with negative subclinical atherosclerosis risk in middle age, indicating the importance of reaching an ideal cardiovascular health status through young adulthood.

Time-averaged cumulative blood pressure and cardiovascular outcomes in heart failure with preserved ejection fraction: analysis from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

High triglyceride-glucose index in young adulthood is associated with incident cardiovascular disease and mortality in later life: insight from the CARDIA study.

BACKGROUND: This study aimed to investigate the associations between the triglyceride-glucose (TyG) index in young adulthood with incident cardiovascular disease (CVD) and mortality. METHODS: We included 4,754 participants from the Coronary Artery Risk Development in Young Adults study at baseline. The TyG index was calculated as ln (fasting TG [mg/dl] × fasting glucose [mg/dl]/2), and the TyG index trajectories were identified by using the latent class growth mixture model. We evaluated the association between the baseline and trajectories of the TyG index with incident CVD events and all-cause mortality using Cox proportional hazards regression analysis. The added value of the TyG index included in pooled cohort equations for CVD prediction was also analyzed. RESULTS: Among 4754 participants (mean age 24.72 years, 45.8% male, 51.2% black), there were 158 incident CVD events and 246 all-cause mortality during a median 25 years follow-up. After adjusting for multiple confounding variables, each one-unit increase in the TyG index was associated with a 96% higher CVD risk (hazard ratio [HR] 1.96, 95% confidence interval [CI] 1.44-2.66) and a 85% higher all-cause mortality risk (HR 1.85, 95% CI 1.45-2.36). Three distinct trajectories of the TyG index along the follow-up duration were identified: low (44.0%), moderate (45.5%), and high (10.5%). Compared with those participants in the low TyG index trajectory group, those in the high TyG index trajectory group had a greater risk of CVD events (HR 2.35, 95% CI 1.34-4.12) and all-cause mortality (HR 3.04, 95% CI 1.83-5.07). The addition of baseline TyG index to pooled cohort equations for CVD improved the C-statistics (P < 0.001), integrated discrimination improvement value (P < 0.001), and category-free net reclassification improvement value (P = 0.003). CONCLUSIONS: Higher baseline TyG index levels and higher long-term trajectory of TyG index during young adulthood were significantly associated with an increased risk of incident CVD events and all-cause mortality in later life.

Cardiovascular effects of intensive lifestyle intervention in adults with overweight/obesity and type 2 diabetes according to body weight time in range.

Background: We aimed to assess whether the cardiovascular effects of intensive lifestyle intervention (ILI) vary for those who can maintain the lower body weight after weight loss through ILI. Methods: In the secondary analysis of the Look AHEAD trial, we identified the status of weight loss for the participants in the ILI arm based on body weight time in range (TIR). These participants were allocated to three groups according to body weight TIR: 0% (n = 727), >0% to 50% (n = 656), and >50% to 100% (n = 811). For each group, cardiovascular outcomes were compared with matched participants receiving diabetes support & education (DSE) using 1:1 propensity score matching and Cox regression. Findings: During a median of 9·5 years of follow-up, participants with TIR of >50% to 100% can effectively maintain their body weight after weight loss through ILI; participants with TIR of 0% or >0% to 50% do not achieve or maintain weight loss. Compared with the corresponding matched participants in the DSE arm, participants with TIR of >50% to 100% in the ILI arm had a 45% lower risk of the primary outcome (HR 0·55, 95% CI 0·40-0·76), and no significant effects were found on the risk of the primary outcome in participants with TIR of 0% (HR 1·12, 95% CI 0·86-1·46) or >0% to 50% (HR 1·14, 95% CI 0·85-1·52). Interpretation: In adults with overweight/obesity and type 2 diabetes, ILI might help in lowering the risk of cardiovascular events when the lower body weight is maintained after weight loss. Funding: None.

Triglyceride-glucose index in the development of heart failure and left ventricular dysfunction: analysis of the ARIC study.

AIMS: We aimed to investigate whether the triglyceride-glucose (TyG) index, an easy-calculated and reliable surrogate of insulin resistance, was associated with the development of heart failure (HF) and left ventricular (LV) dysfunction. METHODS AND RESULTS: A total of 12 374 participants (mean age: 54.1 ± 5.7 years, male: 44.7%) free of history of HF and coronary heart disease at baseline from the Atherosclerosis Risk in Communities study were included. The TyG index was calculated as ln[fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The long-term TyG index was calculated as the updated cumulative average TyG index using all available TyG index from baseline to the events of HF or the end of follow-up. We evaluated the associations of both the baseline and the long-term TyG index with incident HF using Cox regression analysis. We also analysed the effect of the TyG index on LV structure and function among 4889 participants with echocardiographic data using multivariable linear regression analysis. There were 1958 incident HF cases over a median follow-up of 22.5 years. After adjusting for potential confounders, 1-SD (0.60) increase in the baseline TyG index was associated with a 15% higher risk of HF development [hazard ratio (HR): 1.15, 95% confidence interval (CI): 1.10-1.21]. Compared with participants in the lowest quartile of the baseline TyG index, those in the highest quartile had a greater risk of incident HF [HR (95% CI): 1.25 (1.08-1.45)]. In terms of LV structure and function, a greater baseline TyG index was associated with adverse LV remodelling and LV dysfunction. Similar results were found for the long-term TyG index. CONCLUSION: In a community-based cohort, we found that a greater TyG index was significantly associated with a higher risk of incident HF and impaired LV structure and function.