Abstract Heart failure (HF) affects 5.7 million in the U.S., and despite well-established pharmacologic therapy, the 5-year mortality rate remains near 50%. Furthermore, the mortality rate for HF has ...not declined in years, highlighting the need for new therapeutic options. Omega-3 polyunsaturated fatty acids (ω3-PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are important regulators of cardiovascular health. However, questions of efficacy and mechanism of action have made the use of ω3-PUFAs in all cardiovascular disease (CVD) controversial. Here, we review recent studies in animal models of HF indicating that ω3-PUFAs, particularly EPA, are cardioprotective, with the results indicating a threshold for efficacy. We also examine clinical studies suggesting that ω3-PUFAs improve outcomes in patients with HF. Due to the relatively small number of clinical studies of ω3-PUFAs in HF, we discuss EPA concentration-dependency on outcomes in clinical trials of CVD to gain insight into the perceived questionable efficacy of ω3-PUFAs clinically, with the results again indicating a threshold for efficacy. Ultimately, we suggest that the main failing of ω3-PUFAs in clinical trials might be a failure to reach a therapeutically effective concentration. We also examine mechanistic studies suggesting that ω3-PUFAs signal through free fatty acid receptor 4 (Ffar4), a G-protein coupled receptor (GPR) for long-chain fatty acids (FA), thereby identifying an entirely novel mechanism of action for ω3-PUFA mediated cardioprotection. Finally, based on mechanistic animal studies suggesting that EPA prevents interstitial fibrosis and diastolic dysfunction, we speculate about a potential benefit for EPA-Ffar4 signaling in heart failure preserved with ejection fraction.
In cross-sectional studies and short-term clinical trials, it has been suggested that there is a positive dose-response relation between alcohol consumption and HDL concentrations. However, ...prospective data have been limited.
We sought to determine the association between total alcohol intake, the type of alcohol-containing beverage, and the 6-y (2006-2012) longitudinal change in HDL-cholesterol concentrations in a community-based cohort.
A total of 71,379 Chinese adults (mean age: 50 y) who were free of cardiovascular diseases and cancer and did not use cholesterol-lowering agents during follow-up were included in the study. Alcohol intake was assessed via a questionnaire in 2006 (baseline), and participants were classified into the following categories of alcohol consumption: never, past, light (women: 0-0.4 servings/d; men: 0-0.9 servings/d), moderate (women: 0.5-1.0 servings/d; men: 1-2 servings/d), and heavy (women: >1.0 servings/d; men: >2 servings/d). HDL-cholesterol concentrations were measured in 2006, 2008, 2010, and 2012. We used generalized estimating equation models to examine the associations between baseline alcohol intake and the change in HDL-cholesterol concentrations with adjustment for age, sex, smoking, physical activity, obesity, hypertension, diabetes, liver function, and C-reactive protein concentrations.
An umbrella-shaped association was observed between total alcohol consumption and changes in HDL-cholesterol concentrations. Compared with never drinkers, past, light, moderate, and heavy drinkers experienced slower decreases in HDL cholesterol of 0.012 mmol · L
· y
(95% CI: 0.008, 0.016 mmol · L
· y
), 0.013 mmol · L
· y
(95% CI: 0.010, 0.016 mmol · L
· y
), 0.017 mmol · L
· y
(95% CI: 0.009, 0.025 mmol · L
· y
), and 0.008 mmol · L
· y
(95% CI: 0.005, 0.011 mmol · L
· y
), respectively (
< 0.0001 for all), after adjustment for potential confounders. Moderate alcohol consumption was associated with the slowest increase in total-cholesterol:HDL-cholesterol and triglyceride:HDL-cholesterol ratios. We observed a similar association between hard-liquor consumption and the HDL-cholesterol change. In contrast, greater beer consumption was associated with slower HDL-cholesterol decreases in a dose-response manner.
Moderate alcohol consumption was associated with slower HDL-cholesterol decreases; however, the type of alcoholic beverage had differential effects on the change in the HDL-cholesterol concentration.
The American Heart Association 2020 Strategic Impact Goals target an improvement in overall cardiovascular health, as assessed by 7 health metrics (smoking, body weight, physical activity, diet, ...plasma glucose level, plasma cholesterol level, and blood pressure).
To examine whether trajectories of overall cardiovascular health over time, as assessed by the cardiovascular health score (CHS) in 2006, 2008, and 2010, are associated with subsequent risk of CVD.
The Kailuan study is a prospective, population-based study that began in 2006. The cohort included 74 701 Chinese adults free of myocardial infarction, stroke, and cancer in or before 2010. In the present study, CHS trajectories were developed from 2006 to 2010 to predict CVD risk from 2010 to 2015. Data analysis was performed from January 1, 2006, to December 31, 2015.
The CHS trajectories during 2006-2010 were identified using latent mixture models.
Incident CVD events (myocardial infarction and stroke) during 2010-2015 were confirmed by review of medical records. The CHS trajectories were determined using 7 cardiovascular health metrics scored as poor (0 points), intermediate (1 point), and ideal (2 points); total score ranges from 0 (worst) to 14 (best). Based on the baseline CHS and patterns over time, 5 trajectories were categorized (low-stable, moderate-increasing, moderate-decreasing, high-stable I, and high-stable II).
Of the 74 701 adults included in the study (mean SD age at baseline, 49.6 11.8 years), 58 216 (77.9%) were men and 16 485 (22.1%) were women. Five CHS trajectories were identified from 2006 to 2010: low-stable (n = 4393; range, 4.6-5.2), moderate-increasing (n = 4643; mean increase from 5.4 to 7.8), moderate-decreasing (n = 14 853; mean decrease from 7.4 to 6.3), high-stable I (n = 36 352; range, 8.8-9.0), and high-stable II (n = 14 461; range, 10.9-11.0). During 5 years of follow-up, 1852 incident CVD cases were identified. Relative to the low-stable trajectory, the high-stable II trajectory was associated with a lower subsequent risk of CVD (adjusted hazard ratio, 0.21; 95% CI, 0.16-0.26, after adjusting for age, sex, educational level, income, occupation, alcohol intake, and serum high-sensitivity C-reactive protein concentration at baseline).
Cardiovascular health trajectories may be associated with subsequent CVD risk.
High temperature (HT) severely limits rice production, but effective measures can reduce the adverse effects of HT. A 2-year experiment was conducted involving five sowing dates to investigate the ...effects of potassium dihydrogen phosphate (KH
2
PO
4
), salicylic acid (SA), and the sowing date on the physiological characteristics, yield and quality of rice subjected to HT. Under ambient HT conditions (daily average temperature ≥ 30 °C for ≥ 3 days or maximum temperature ≥ 35 °C for ≥ 3 days), KH
2
PO
4
(KP
1
-KP
2
: 22.05 and 36.75 mmol L
−1
), SA (SA
1
-SA
2
: 0.5 and 1.5 mmol L
−1
), and their combinations were applied to leaves from the late-booting stage to the flowering stage, with deionized water as a control (CK). Compared with CK, KP
1
, KP
2
, SA
1
, KP
1
+ SA
1
, and KP
2
+ SA
1
alleviated the adverse effects of HT on the number of grains per panicle, seed set, and yield, among which SA
1
, KP
2
+ SA
1
, and KP
1
were the best. The antioxidant enzyme (superoxide dismutase, peroxidase, and catalase) activities, levels of osmotic protective substances (soluble sugars, soluble proteins, and proline), and chlorophyll content were increased and the malonaldehyde content and leaf temperature were decreased in the SA
1
, KP
2
+ SA
1
, and KP
1
treatments. Compared with those sown on April 25 and May 5, plants sown on May 15, May 25, and June 5 had suitable temperature conditions and presented increased grain yield and quality. Therefore, the application of SA
1
, KP
2
+ SA
1
, and KP
1
and the use of an optimal sowing date (from May 15 to June 5) increased the rice yield and quality under HT.
The relation between tea consumption and age-related changes in high-density lipoprotein cholesterol (HDL-C) concentrations remains unclear, and longitudinal human data are limited. The aim of ...current study was to examine the relation between tea intake and longitudinal change in HDL-C concentrations.
Baseline (2006) tea consumption was assessed via a questionnaire, and plasma HDL-C concentrations were measured in 2006, 2008, 2010, and 2012 among 80 182 individuals (49±12 years of age) who did not have cardiovascular diseases or cancer, or did not use cholesterol-lowering agents both at baseline (2006) and during the follow-up period (2006-2012). The associations between baseline tea consumption and rate of change in HDL-C concentrations were examined using generalized estimating equation models. Tea consumption was inversely associated with a decreased rate of HDL-C concentrations (
-trend <0.0001) in the fully adjusted model. The adjusted mean difference in the HDL-C decreased rate was 0.010 (95% confidence interval, 0.008, 0.012) mmol/L per year for tea consumers versus nonconsumers (never or less than once/month group). Interactions between tea consumption and age, sex, lifestyle scores, and metabolic syndrome (all
-interaction <0.0001) were identified. The associations between greater tea consumption and slower decrease in HDL-C concentrations were more pronounced in men, individuals aged 60 or older, individuals with a lower lifestyle score, and individuals with metabolic syndrome (all
-trend <0.0001).
Tea consumption was associated with slower age-related decreases in HDL-C concentrations during 6 years of follow-up.
URL: www.chictr.org. Unique identifier: ChiCTR-TNRC-11001489.
Evidence for a role of delta-9-desaturase plasma (D9D) in heart failure (HF) is limited. We aimed to evaluate whether a biomarker for its activity, the oleic-to-stearic acid ratio, is associated with ...future heart failure risk in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort.
A total of 6562 participants aged 45 to 84 yr. old had their fatty acids measured at baseline. Cox regression was used to model the association between oleic-to-stearic acid ratio and risk for HF, including HF with reduced ejection fraction (EF) and HF with preserved EF, adjusting for potential covariates, including age, sex, race, study center, body mass index, diabetes mellitus, blood pressure, C-reactive protein, albuminuria, and lead fatty acid for non-oleic and non-stearic acid clusters. Mediation effects through hypertension, and diabetes were estimated using the causal mediation analysis.
After a median of 7.1 years follow-up, 184 incident HF cases were documented, with 64 HF with reduced EF, and 72 HF with preserved EF and 48 with unknown EF status. Oleic-to-stearic acid ratio was lower in HF-free participants (0.57 ± 0.13) compared to participants with HF (0.60 ± 0.12) (P = 0.002) and was associated with a higher risk for HF incidence. Hazard ratio for HF was 4.81 (95%Confidence Interval: 1.46, 15.88) per unit increase in oleic-to-stearic ratio in the fully adjusted model. Secondary analysis showed no dependence on HF type. Mediation analysis showed hypertension and diabetes were not mediating.
This study indicates that increased delta-9-desaturase activity predicts future HF risk, in a manner not mediated by either hypertension or diabetes.
This work was funded by grant from the National Heart, Lung, and Blood Institute.
Several lipid-related hormones and peptides, such as glucagon-like peptide-1 and leptin, are involved in the regulation of taste and smell function. However, to our knowledge, it remains unknown ...whether these chemosensory functions are associated with lipid profiles.
We examined the cross-sectional association between taste and smell dysfunction and blood cholesterol concentrations.
With the use of a questionnaire, we assessed chronic smell and taste dysfunction in 12,627 Chinese participants (10,418 men and 2209 women; mean age: 54.4 y) who did not take hypolipidemic agents. Participants were categorized into 3 groups based on the number of smell and taste dysfunctions, ranging from 0 (best) to 2 (worst). A general linear model was used to test differences in serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (TGs) across groups with different smell and taste status after adjusting for age, sex, education, occupation, smoking, drinking, obesity, and history of cardiovascular disease, cancer, and head injury.
The prevalence of smell and taste dysfunction was 2.4% and 1.2%, respectively. Worse smell and taste dysfunction was associated with higher total cholesterol concentrations (P-trend = 0.005). No significant differences were observed in LDL cholesterol, HDL cholesterol, and TG concentrations across groups with different numbers of chemosensory dysfunctions (P-trend > 0.1 for all). The associations between chemosensory dysfunction and total cholesterol concentrations were more pronounced in participants aged ≤60 y and in those who were nonsmokers relative to their counterparts (P-interaction < 0.05 for all).
In this large cross-sectional study, chemosensory dysfunction was associated with higher serum total cholesterol concentrations among Chinese adults. Prospective studies are needed to investigate the temporal relation between these chemosensory dysfunctions and hypercholesterolemia.
Abstract
Aims
Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the ...function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress.
Methods and results
In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC.
Conclusion
Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.
Myocardial infarction (MI) is the most common form of coronary heart disease, which is by far the most common cardiovascular condition. Despite the improvement and increased use in evidence-based ...therapies and lifestyle interventions, it remains the number one cause of morbidity and mortality worldwide. Alcohol intake has both a beneficial and a harmful influence on atherosclerosis, which is the main pathological change in MI. Moderate alcohol intake has been found to be associated with a lower risk for MI in numerous epidemiological studies, and it is hypothesized that this protective effect is mainly mediated through high-density lipoprotein cholesterol (HDL-C) concentration. However, controversial results have been generated from epidemiological studies on this topic and the role of HDL-C concentration being a sufficient predictor for cardiovascular disease has been challenged.The objective of the first study in this dissertation was to determine the association between total alcohol intake and type of alcohol containing beverage, and 6-year (2006-2012) longitudinal change in HDL-C concentrations in a community-based cohort. In this study, we included 71,379 Chinese adults (mean age 50±11 yr.) who were free of cardiovascular diseases and cancer, and did not use cholesterol-lowering agents during follow-up. Alcohol intake was assessed by a questionnaire in 2006 (baseline) and participants were categorized as never, past, light (women: 0-0.4 servings/d, men: 0-0.9 servings/d), moderate (women: 0.5-1.0 servings/d, men: 1-2 servings/d), and heavy drinkers (women: >1.0 servings/d, men: >2 servings/d). HDL-C concentrations were measured in 2006, 2008, 2010, and 2012. We used generalized estimating equation models to examine the associations between baseline alcohol intake and change in HDL-C concentrations, adjusting for age, sex, smoking, physical activity, obesity, hypertension, diabetes, liver function and C-reactive protein concentrations. We observed an umbrella-shaped association between total alcohol consumption and changes in HDL-C concentration. Compared with never drinkers, past, light, moderate and heavy drinkers, respectively, experienced a 0.012 (95% CI: 0.008, 0.016), 0.013 (95% CI: 0.010, 0.016), 0.017 (95% CI: 0.009, 0.025), and 0.008 (95% CI: 0.005, 0.011) mmol/L per year slower decrease in HDL-C (P <0.0001 for all) after adjusting for potential confounders. Moderate alcohol consumption was associated with the slowest increase in total cholesterol/HDL-C and triglyceride/HDL-C ratios. We observed a similar association between hard liquor consumption and HDL-C change. In contrast, greater beer consumption was associated with slower HDL-C decreases, in a dose-response manner.The objective of the second study was to test the hypothesis that the lower risk of myocardial infarction (MI) associated with alcohol intake is mediated by raising HDL-C concentration. This study included 81,253 Chinese men and women (mean age: 51±12 yr.) from the Kailuan Study who were free of cardiovascular disease in 2006 (at baseline) and were followed up to Dec. 2016. At baseline, alcohol consumption was assessed via a questionnaire and the concentration of HDL cholesterol was measured. Incident MI at follow up was a first MI event, confirmed by medical record review. Multivariable Cox regression was used to model the association between habitual alcohol intake and risks of MI, adjusting for potential covariates including age, sex, education, monthly income, occupation, smoking status, physical activity, body mass index, waist circumferences, hypertension, diabetes and total cholesterol. Mediated effect through HDL cholesterol was assessed using a causal mediating analysis (SAS macro). During an average of 9.6 years of follow-up, we documented 1088 incident cases. The adjusted hazard ratio (HR) for MI was 0.74 (95% confidence interval (CI): 0.60, 0.91), 0.80 (95%CI: 0.56, 1.16), 0.56 (95%CI: 0.45, 0.70) for light, moderate, and heavy alcohol drinkers compared with non-drinkers. The ratio changed very slightly after further adjustment of HDL cholesterol concentration. Mediation analysis showed that HDL cholesterol concentrations mediated a small, non-significant proportion (Proportion mediated ~2%) of the association between alcohol and MI.The objective of the third study was to investigate whether and to what extent the association between alcohol intake and incident myocardial infarction (MI) is mediated through HDL-C concentration, HDL particles (HDL-P) concentration, and apoA-I concentrations. A total of 6,683 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) were included in the analysis. Alcohol consumption was assessed via a questionnaire at baseline (exam 1). HDL-C concentrations and HDL-P were both measured at exam 1. Cox regression was used to model the association of habitual alcohol intake and risk for MI before and after adjusting HDL-C and HDL-P, in addition to adjustment of all potential covariates. Mediated effects through HDL-C, and HDL-P were estimated using the causal mediation analysis. After a median of 8 years follow-up, 171 incident MI cases were documented. Higher alcohol intake was associated with a lower risk for incident MI (P for trend =0.039). The relation between alcohol intake and MI was slightly attenuated by adjustment of HDL-C and moderately by HDL-P. Mediation analysis showed no mediating effect of HDL-C (HRNIE: 0.98; 95%CI: 0.94, 1.02; P-value=0.26), whereas HDL-P slightly mediated the association of habitual alcohol intake and MI (HRNIE: 0.95, 95%CI: 0.90, 0.99; P-value=0.027). The proportion of the total effect of alcohol on MI mediated by HDL-P was 15.8%.In conclusion, we found that moderate alcohol consumption was associated with slower HDL-C decreases; however, the type of alcoholic beverage was differently associated with the change in HDL-C concentrations. Alcohol consumption was associated with a lower risk for MI incidence in both Chinese and MESA cohorts. Our results suggest that the benefits on MI associated with moderate alcohol consumption are not related to the effects of alcohol on HDL cholesterol. The lower risk of MI related to alcohol intake appears to partially work through increasing HDL-P. The mechanism for much of alcohol’s effect to reduce MI risk remains unexplained. This suggests that HDL-P can be a target for MI prevention, however the mediating effect of HDL-P is very moderate. Future studies are warranted to confirm our finding regarding HDL-P and further evaluate if HDL-P concentration may be a surrogate biomarker reflecting the anti-atherogenic HDL function to decide if HDL-P can be used as a new risk predictor and intervention target for CVD
The aim of this study was to determine if plasma eicosapentaenoic acid (EPA) abundance (%EPA) is associated with reduced hazard for primary heart failure (HF) events in the MESA (Multi-Ethnic Study ...of Atherosclerosis) trial.
Clinical trials suggest that omega-3 polyunsaturated fatty acids (ω3 PUFAs) prevent sudden death in coronary heart disease and HF, but this is controversial. In mice, the authors demonstrated that the ω3 PUFA EPA prevents contractile dysfunction and fibrosis in an HF model, but whether this extends to humans is unclear.
In the MESA cohort, the authors tested if plasma phospholipid EPA predicts primary HF incidence, including HF with reduced ejection fraction (EF) (EF <45%) and HF with preserved EF (EF ≥45%) using Cox proportional hazards modeling.
A total of 6,562 participants 45 to 84 years of age had EPA measured at baseline (1,794 black, 794 Chinese, 1,442 Hispanic, and 2,532 white; 52% women). Over a median follow-up period of 13.0 years, 292 HF events occurred: 128 HF with reduced EF, 110 HF with preserved EF, and 54 with unknown EF status. %EPA in HF-free participants was 0.76% (0.75% to 0.77%) but was lower in participants with HF at 0.69% (0.64% to 0.74%) (p = 0.005). Log %EPA was associated with lower HF incidence (hazard ratio: 0.73 95% confidence interval: 0.60 to 0.91 per log-unit difference in %EPA; p = 0.001). Adjusting for age, sex, race, body mass index, smoking, diabetes mellitus, blood pressure, lipids and lipid-lowering drugs, albuminuria, and the lead fatty acid for each cluster did not change this relationship. Sensitivity analyses showed no dependence on HF type.
Higher plasma EPA was significantly associated with reduced risk for HF, with both reduced and preserved EF. (Multi-Ethnic Study of Atherosclerosis MESA; NCT00005487).
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