Eicosapentaenoic acid and Arachidonic acid Protection Against Left Ventricle Pathology: the Multi-Ethnic Study of Atherosclerosis.

Background: We have shown that ω3 polyunsaturated fatty acids (PUFAs) reduce risk for heart failure, regardless of ejection fraction status. Ventricular remodeling and reduced ventricular performance precede overt hear failure, however there is little insight into how PUFAs contribute to maladaptive signaling over time. PUFAs are agonists for regulatory activity at g-protein coupled receptors such as Ffar4, and downstream as substrates for monooxygenases (e.g lipoxygenase, cytochrome p450, or cyclooxygenase (COX)) which mediate intracellular adaptive signaling. Methods: Plasma phospholipid PUFA abundance at Exam 1 as mass percent EPA, DHA, and arachidonic acid (AA) from the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using pathway modeling to determine the association with time-dependent changes in left ventricular (LV) mass (LVM), end-diastolic LV volume (EDV), and end-systolic volume (ESV) measured by cardiac MRI at Exams 1 and 5. Ejection fraction (EF) and mass:volume (MV) were calculated posteriorly from the first three. Results: 2,877 subjects had available MRI data. Participants with low AA and EPA had accelerated age-dependent declines in LVM. Males with low AA and EPA also had accelerated declines in EDV, but among females there was no PUFA association with EDV declines and exam 5 EDV status was positively associated with AA. Both sexes had nearly the same positive association of AA with changes in ESV. Conclusion: Plasma phospholipid AA and EPA are prospectively associated with indices of heart remodeling, including ventricular remodeling and performance. Combined AA and EPA scarcity was associated with the most accelerated age-related changes and exam 5 status, while the greatest benefits were found among participants with both PUFAs. This suggests that both PUFAs are required for optimal slowing of age-related declines in ventricular function.

Polycystic ovary syndrome: A review of diagnosis and management, with special focus on atherosclerotic cardiovascular disease prevention.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy worldwide with a heterogeneous clinical presentation including reproductive, metabolic, and endocrine elements. However, the assessment and management of PCOS remains inconsistent, with many women undiagnosed and untreated. We now also understand that the management of PCOS should extend throughout a woman's lifespan as many elements of the syndrome persist after menopause. Management has traditionally focused on the treatment of hyperandrogenism and oligomenorrhea. Women with PCOS often have dyslipidemia, hypertension, obesity, and metabolic syndrome, which may be worsened by the hormonal abnormalities, and are therefore at higher risk for cardiovascular disease morbidity and mortality, a risk that increases after menopause. While treatment with hormonal therapy, in particular combined oral contraceptives, may improve cardiovascular risk factors, management plans should incorporate specific diagnosis and management of these factors, if present, because of the strong contribution to the risk for atherosclerotic cardiovascular disease (ASCVD). Given the complexities of the syndrome, optimal management often requires a multi-disciplinary approach including the lipid and cardiometabolic specialist to provide counseling and support for lifestyle modification along with pharmacologic therapy as indicated to address the full range of any reproductive, endocrine, and cardiometabolic abnormalities.

Fatty acid desaturase insertion-deletion polymorphism rs66698963 predicts colorectal polyp prevention by the n-3 fatty acid eicosapentaenoic acid: a secondary analysis of the seAFOod polyp prevention trial.

BACKGROUND: A fatty acid desaturase (FADS) insertion-deletion (Indel) polymorphism (rs66698963) influences the expression of FADS1, which controls the synthesis of n-6 highly unsaturated fatty acid (HUFA) arachidonic acid (AA). The anti-inflammatory activity of the n-3 HUFA eicosapentaenoic acid (EPA) may be explained by competition with AA for proinflammatory lipid mediator synthesis. A precision medicine approach based on stratification by FADS Indel genotype could identify individuals, who benefit from greatest disease risk reduction by n-3 HUFAs. OBJECTIVES: We tested the hypothesis that the FADS insertion (I) allele predicts colorectal polyp risk reduction in a secondary analysis of the randomized, placebo-controlled, 2×2 factorial seAFOod polyp prevention trial of EPA 2000 mg daily and aspirin 300 mg daily for 12 mo (ISRCTN05926847). METHODS: Participant Indel genotype was determined by polymerase chain reaction (PCR) blind to trial outcomes. Colorectal polyp outcomes were included in negative binomial (polyp number) and logistic (polyp detection rate [PDR; percentage with one or more polyps]) regression models comparing each active intervention with its placebo. Presence of ≥1 Indel I allele and an interaction term (I allele × active intervention) were covariates. RESULTS: In 528 participants with colonoscopy and FADS Indel data, EPA use irrespective of Indel genotype, was not associated with reduced colorectal polyp number (incidence rate ratio [IRR]: 0.92; 95% confidence interval: 0.74, 1.16), mirroring original seAFOod trial analysis. However, the presence of ≥1 I allele identified EPA users with a significant reduction in colorectal polyp number (IRR: 0.50 [0.28, 0.90]), unlike aspirin, for which there was no interaction. Similar findings were obtained for the PDR. CONCLUSIONS: The FADS Indel I allele identified individuals, who displayed colorectal polyp prevention by EPA with a similar effect size to aspirin. Assessment of rs66698963 as a biomarker of therapeutic response to n-3 HUFAs in other populations and healthcare settings is warranted. The seAFOod polyp prevention trial and STOP-ADENOMA study were registered at International Standard Randomised Controlled Trial Number registry as ISRCTN05926847.

Estimating Ejection Fraction from the 12 Lead ECG among Patients with Acute Heart Failure.

Background: Identifying patients with low left ventricular ejection fraction (LVEF) in the emergency department using an electrocardiogram (ECG) may optimize acute heart failure (AHF) management. We aimed to assess the efficacy of 527 automated 12-lead ECG features for estimating LVEF among patients with AHF. Method: Medical records of patients >18 years old and AHF-related ICD codes, demographics, LVEF %, comorbidities, and medication were analyzed. Least Absolute Shrinkage and Selection Operator (LASSO) identified important ECG features and evaluated performance. Results: Among 851 patients, the mean age was 74 years (IQR:11), male 56% (n=478), and the median body mass index was 29 kg/m2 (IQR:1.8). A total of 914 echocardiograms and ECGs were matched; the time between ECG-Echocardiogram was 9 hours (IQR of 9 hours); ≤30% LVEF (16.45%, n=140). Lasso demonstrated 42 ECG features important for estimating LVEF ≤30%. The predictive model of LVEF ≤30% demonstrated an area under the curve (AUC) of 0.86, a 95% confidence interval (CI) of 0.83 to 0.89, a specificity of 54% (50% to 57%), and a sensitivity of 91 (95% CI: 88% to 96%), accuracy 60% (95% CI:60 % to 63%) and, negative predictive value of 95%. Conclusions: An explainable machine learning model with physiologically feasible predictors may be useful in screening patients with low LVEF in AHF.

Integrative review of electrocardiographic characteristics in patients with reduced, mildly reduced, and preserved heart failure.

INTRODUCTION: Electrocardiographic (ECG) changes in heart failure with reduced, mildly reduced, and preserved ejection fractions can be critical in clinical assessment while waiting to perform echocardiograms or when it is unavailable. This integrative review aimed to identify ECG characteristics among hospitalized patients demonstrating three types of heart failure during acute decompensation. METHODS: We searched an electronic database of PubMed, Web of Science, EMBASE, Scopus, Google Scholar, and ClinicalTrials.gov using medical subject headings (MeSH) terms and keywords. Sixteen studies were synthesized and reported. RESULTS: Heart failure with reduced ejection fraction (HFrEF) was more common in men, comorbid with coronary artery diseases and diabetes mellitus, higher BNP/Pro-BNP, wide QRS, and left bundle branch block on ECG. On average, clients with heart failure with preserved ejection fraction (HFpEF) were older and more likely to have a history of atrial fibrillation, valvular heart diseases, hypertension, chronic obstructive pulmonary, and atrial fibrillation (AF) on ECG. Patients with mildly reduced (HFmrEF) were more similar to HFpEF in older patients, comorbid with hypertension, AF and valvular diseases, and AF on ECG. CONCLUSIONS: ECG characteristics might be related to left ventricular ejection fraction. Demographics, BNP/Pro-BNP, and ECG changes might help differentiate different heart failure types. Therefore, ECG might be a prognostic tool while caring for heart failure patients when highly skilled resources are unavailable. These identified ECG characteristics help generate research hypotheses and warrant validation in future research.

Frequency of lipoprotein(a) measurements in patients with or at risk of cardiovascular disease.

Knowledge of lipoprotein(a) measurement in community practice is limited. The objective of this study is to evaluate the frequency of Lp(a) screening across the University of Rochester Medical Center (URMC). Descriptive data were collected for all URMC patients >= 18 years old who have had at least one Lp(a) measurement from January 2011 to August 2022 from the URMC electronic health record (EHR). Cardiovascular diagnoses were queried to define yearly frequency and demographic information. We identified 2,698 patients with at least one Lp(a) result. An increasing number of patients were tested per year. There were more women than men, and about 11% having more than one Lp(a) measured with the majority having a level <30 mg/dL (the normal-range in the UMRC lab). The majority do not have a listed diagnosis of cerebral infarction, peripheral vascular disease, myocardial infarction, coronary artery disease, or aortic stenosis. Across URMC, there has been a steady increase of Lp(a) measurements in the past several years.

Translating Evidence-based Approaches into optimal Care for individuals at High-risk of ASCVD: Pilot testing of case-based e-learning modules and design of the TEACH-ASCVD study.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States. Case-based learning using electronic delivery of the modules can educate clinicians and improve translation of evidence-based guidelines into practice for high-risk ASCVD patients. OBJECTIVE: To develop and optimize module design, content, and usability of e-learning modules to teach clinicians evidence-based management in accordance with multi-society guidelines for high-risk ASCVD patients that will be implemented and evaluated in U.S. health systems in the TEACH-ASCVD study. METHODS: Seven e-learning modules were created by a committee of lipid experts. Focus groups were conducted with lipid experts to elicit feedback on case content followed by interviews with a target audience of clinicians to assess usability of the online module platform. Responses from both groups were evaluated, and appropriate changes were made to improve the e-learning modules. Design of the TEACH-ASCVD study is presented. RESULTS: Feedback regarding case content by lipid experts included providing more detailed patient histories, clarifying various diagnostic criteria, and emphasizing clinical best practices based on evidence-based guidelines. The target audience clinician group reported an agreeable experience with the e-learning modules but noted a discordance between the evidence-based guidelines and clinical decision-making in their own practices. Participants felt the modules would help educate clinicians in managing high-risk ASCVD patients. CONCLUSION: Clinicians must be informed of best practices as the field of lipidology continues to evolve. E-learning modules provide a concise, valuable, and accessible mechanism for educating clinicians regarding changes in the field to deliver the best patient care.

Association of Domains of Sedentary Behavior with Cardiovascular Disease Events in The Multi-Ethnic Study of Atherosclerosis.

Background: Sedentary behavior is associated with an increased risk for adverse health outcomes, including cardiovascular disease (CVD), independent of physical activity status. Little is known about this relationship in an ethnically diverse population. The objective of our study is to assess the effects of leisure time and occupational sedentary behavior on multiple cardiovascular outcomes in a multi-ethnic cohort. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) includes 2619 Caucasian, 1495 Hispanic, 1891 Black, and 804 Chinese-American adults aged 45-84 years and free of clinical CVD at enrollment, Sedentary behavior was self-reported at baseline. Participants were followed for an average of 13.6 years, and 14 types of cardiovascular outcomes were ascertained. Hazards of each cardiovascular outcome were modeled with adjustment for potential confounders, including physical activity. Results: Every one hour per day increase in leisure time sedentary behavior predicts a 6% increase in the adjusted hazards for CVD death ( P < 0.05). Every one hour increase in occupational sedentary time predicts a 21% and 20% decrease in the hazard for PVD and other revascularization, respectively ( P < 0.05). Conclusions: Leisure time sedentary behavior was associated with increased hazards for CVD death, but occupational sedentary time appears to be protective of peripheral vascular disease and other revascularization. Condensed Abstract: Sedentary behavior has been consistently associated with an increased risk for adverse health outcomes, including cardiovascular disease (CVD), independent of physical activity status. The Multi-Ethnic Study of Atherosclerosis (MESA) consists of a racially and ethnically diverse cohort of adults age 45-84, free from CVD at baseline. Greater levels of leisure time sedentary behavior predicted increased hazards for PVD and CVD death after an average follow up of 13.6 years whereas occupational sedentary behaviors predicted reduced PVD. These results underscore the importance of reducing time spent sitting in addition to advocating for meeting physical activity targets across ethnicities.

The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Indicators of Self-Determination in Therapeutic Songwriting Lyrics Created by Adults with High LDL Cholesterol.

Individuals with low-density lipoprotein cholesterol ≥190 mg/dL are at high risk for atherosclerotic cardiovascular disease events. Our goal was to determine if adults with this condition would express important psychological, health, and motivation themes when generating lyrics during music therapy. Thirty-one participants each created their own original song with the help of a music therapist. The lyrics were analyzed using a deductive approach guided by Self-Determination Theory (specifically the satisfaction or frustration of basic psychological needs): (1) for each entire song (macro-analysis) and (2) line-by-line (micro-analysis). Song lyrics generated during music therapy sessions by patients with a low-density lipoprotein cholesterol ≥190 mg/dL revealed the presence of the three basic needs (autonomy, competence, and relatedness) of Self-Determination Theory. The most prevalent theme identified in the macro-analysis of songs was autonomy satisfaction, coded in 25 songs (27.17% of all macro codes), and followed by competence satisfaction in 17 songs (18.48%) and relatedness satisfaction in 15 songs (16.3%). Line-by-line micro-analysis of lyrics revealed that at least one basic need of Self-Determination Theory was present in 277 of the unique lyric lines (50%); 107 (19%) for relatedness, 101 (18%) for autonomy, and 69 (13%) for competence. Need satisfaction occurred more frequently than need frustration in both analyses. However, depending on the level of analysis (macro or micro), results differed as to which themes were most prevalent. These results indicate that therapeutic songwriting may be a unique way to identify the basic psychological needs that, when satisfied, indicate self-determination.

Prevention and treatment of atherothrombosis: Potential impact of nanotechnology.

Complications with atherosclerosis can often lead to fatal clot formation and blood vessel occlusion - also known as atherothrombosis. A key component to the development of atherosclerosis and atherothrombosis is the endothelium and its ability to regulate the balance between prothrombotic and antithrombotic activities. Endothelial surface glycocalyx has a critical role in maintenance of vascular integrity. The endothelial glycocalyx, nitric oxide, prostacyclins, heparan sulfate, thrombomodulin, and tissue factor pathway inhibitor all prevent thrombosis, while P-selectin, among many other factors, favors thrombosis. However, endothelial dysfunction gives rise to the acceleration of thrombotic development and eventually the requirement of antithrombotic therapy. Most FDA-approved anticoagulant and antiplatelet therapies today carry a side effect profile of major bleed. Within the past five years, several preclinical studies using different endothelial targets and nanotechnology as a drug delivery method have emerged to target the endothelium and to enhance current antithrombosis without increasing bleed risk. While clinical studies are required, this review illustrates the proof-of-concept of nanotechnology in promoting a greater safety and efficacy profile through multiple in vitro and in vivo studies.

Effect Compartment Model for the Evaluation of Tolerance to Psychological Highness Following Smoking Marijuana.

The purpose of this study is to evaluate the development of tolerance, using a population modeling approach, in recreational marijuana users after acute pulmonary administration of tetrahydrocannabinol (THC), a primary ingredient in marijuana. A total of 85 subjects in 3 separate studies smoked marijuana cigarettes (dose = 13-49 mg) under controlled conditions. Each study was designed as a randomized, crossover, double-blind, and placebo-controlled study. Up to 5 THC plasma samples and corresponding user-reported psychological highness were pooled for population modeling analyses. Age, sex, user status, and body mass index were evaluated as covariates. Population pharmacokinetic (PK) parameters were estimated in the 2-compartment PK model. PK parameters were fixed in the effect compartment model to describe the relationship between THC plasma concentration-psychological highness. The distribution rate constant in the effect compartment was estimated to be 0.988 (95%CI 0.964-1.010)/h. The population mean half-maximal effective concentration (EC50 ) was 23.8 (95%CI 22.7-24.9) ng/mL. Covariate analysis revealed that user status was a significant covariate, and that chronic users appear to need higher plasma concentrations compared with occasional users to achieve a similar degree of highness. The modeling results conclude that chronic users develop tolerance to euphoria, which is the primary central nervous system effect of smoking marijuana.

Statin therapy upregulates arachidonic acid status via enhanced endogenous synthesis in patients with plaque psoriasis.

Circulating fatty acids (FA) may be important in the psoriatic pro-inflammatory phenotype. FADS1 converts linoleic acid (LA) to arachidonic acid (AA), a precursor to potent signaling molecules. HMG-CoA reductase inhibitors (statins) increase FADS1/2 expression in vitro. Psoriasis patients (42 ± 14 years/age, 47% male) were randomized to 40 mg of atorvastatin (n = 20) or nothing (n = 10) for two weeks and plasma FA measured pre and post treatment. After treatment, LDL-C was 44% lower in the statin compared to the no-treatment group. Statins increased FADS1/2 expression, and lowered LA 12% (33% - > 29%, p<0.001) and raised AA 14% (7.7% - > 9.0%, p<0.01) with no change in the no-treatment group. In psoriasis, statins enhance AA and decrease LA, consistent with the action of enhanced FADS expression in vivo. Therapies intended to blunt the effects of AA on platelet aggregation, such as aspirin or omega-3 fatty acids, may require dose adjustment when co-administered with atorvastatin. NCT: NCT03228017.

Photoplethysmography Fast Upstroke Time Intervals Can Be Useful Features for Cuff-Less Measurement of Blood Pressure Changes in Humans.

OBJECTIVE: Photoplethysmography (PPG) waveform analysis is being increasingly investigated for continuous, non-invasive, and cuff-less blood pressure (BP) measurement. However, the efficacy of this approach and the useful features and models remain largely unclear. The objectives were to develop easy-to-understand models relating PPG waveform features to BP changes (after a cuff calibration) and to determine their value in BP measurement accuracy. METHODS: The study data comprised finger, toe, and ear PPG waveforms, an ECG waveform, and reference manual cuff BP measurements from 32 human subjects (25% hypertensive) before and after slow breathing, mental arithmetic, cold pressor, and nitroglycerin administration. Stepwise linear regression was employed to create parsimonious models for predicting the intervention-induced BP changes from popular PPG waveform features, pulse arrival time (PAT, time delay between ECG R-wave and PPG foot), and subject demographics. Leave-one-subject-out cross validation was applied to compare the BP change prediction root-mean-squared-errors (RMSEs) of the resulting models to reference models in which PPG waveform features were excluded. RESULTS: Finger b-time (PPG foot to minimum second derivative time interval) and ear "STT" (PPG amplitude divided by maximum derivative), when combined with PAT, reduced the systolic BP change prediction RMSE of reference models by 6-7% (p 0.022). Ear STT together with pulse width reduced the diastolic BP change prediction RMSE of the reference model by 13% (p = 0.003). CONCLUSION: The two PPG fast upstroke time intervals can offer some added value in cuff-less BP trending. SIGNIFICANCE: This study offers important information towards achieving non-invasive and passive BP monitoring without a cuff.

Associations of Regular Marijuana Use by Adolescent Boys With Verbal Memory and Perseveration.

Many American and Dutch adolescents use marijuana regularly. There is concern that such use may impair cognitive function more in adolescents than adults. We examined effects of regular marijuana use on long-term memory and perseveration among American and Dutch adolescents. We administered Buschke's Selective Reminding Test (BSRT) to assess long-term memory and the Wisconsin Card Sorting Test (WCST) to assess perseveration in male teenagers. Usable test data were obtained for 12 American marijuana users, 13 American controls, 9 Dutch marijuana users, and 12 Dutch controls. In BSRT, users showed lower overall long-term storage than controls (adjusted means ± SE's for numbers of words per trial of 9.4 ± 0.2, 13.4 ± 0.3, 11.7 ± 0.2, and 12.4 ± 0.2 for American users, Dutch users, American controls, and Dutch controls, respectively). Marijuana was associated with memory effects only in American, not Dutch, users. Bivariate Pearson correlations for American and Dutch users combined showed associations of lower total recall with more uses in the previous year and lifetime (r = -0.61 and r = -0.53, respectively); and more perseverative errors with more uses in the previous year (r = 0.55). Some findings were consistent with the possibility that regular adolescent marijuana use causes deficits in cognition, especially memory. However, a causal interpretation cannot be inferred from our findings and is challenging to reconcile with the observation of memory deficits only in American users. Our study was novel in examining the influence of nationality on marijuana's cognitive effects. More studies of this topic should compare effects across nationalities or cultures.

Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.

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.

Aspirin and omega-3 polyunsaturated fatty acid use and their interaction in cardiovascular diseases and colorectal adenomas.

Aspirin (acetylsalicylic acid, ASA) is inexpensive and is established in preventing cardiovascular disease (CVD) and colorectal adenomas. Omega-3 (n3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have also shown benefit in preventing CVD. The combination could be an effective preventative measure in patients with such diseases. ASA and n3 PUFA reduced the risk of CVD in ASA-resistant or diabetic patients. EPA- and DHA-deficient patients also benefited the most from n3 PUFA supplementation. Synergistic effects between ASA and EPA and DHA are 'V-shaped' such that optimal ASA efficacy is dependent on EPA and DHA concentrations in blood. In colorectal adenomas, ASA (300 mg/d) and EPA reduced adenoma burden in a location- and subtype-specific manner. Low doses of ASA (75-100 mg/d) were used in CVD prevention; however, ultra-low doses (30 mg/d) can also reduce thrombosis. EPA-to-DHA ratio is also important with regard to efficacy. DHA is more effective in reducing blood pressure and modulating systemic inflammation; however, high-dose EPA can lower CVD events in high-risk individuals. Although current literature has yet to examine ASA and DHA in preventing CVD, such combination warrants further investigation. To increase adherence to ASA and n3 PUFA supplementation, combination dosage form may be required to improve outcomes.

Assessment of Calibration Models for Cuff-Less Blood Pressure Measurement After One Year of Aging.

OBJECTIVE: Many calibration models for cuff-less blood pressure (BP) measurement must be periodically updated with cuff BP values to account for vascular aging. However, the time period required for these "cuff re-calibrations" is largely unknown. The impact of one year of aging on several calibration models was assessed. METHODS: Ten humans (6 males, 57±18 years, 3 hypertensives) were studied during multiple recording sessions that occurred one year apart. In each session, electrocardiography (ECG), ear photoplethysmography (PPG), finger PPG, and toe PPG waveforms and manual cuff BP were recorded before and after slow breathing, mental arithmetic, cold pressor, and nitroglycerin. Linear models based on each PPG waveform, which were previously shown to offer value in predicting the intervention-induced BP changes in a larger subject cohort, were employed. The model coefficients were determined for each subject via one session, and the fully-defined, subject-specific calibration models were then evaluated in the corresponding subjects via the session one year later. RESULTS: Only a linear model relating toe pulse arrival time (PAT) - time delay between ECG R-wave and toe PPG foot - to systolic BP (SBP) remained useful. After the year, this model changed little on average (root-mean-squared-error (RMSE) = 1.5 mmHg) and predicted the cuff BP values better than the average of the initial cuff BP values of the subject (RMSE = 9.6±0.8 mmHg vs. 12.7±1.0 mmHg; p < 0.05). CONCLUSION: These results suggest annual cuff recalibrations for the toe PAT-SBP model. SIGNIFICANCE: Toe PAT may offer a practical recalibration period that fosters user adherence.

Role of DNA methylation on the association between physical activity and cardiovascular diseases: results from the longitudinal multi-ethnic study of atherosclerosis (MESA) cohort.

BACKGROUND: The complexity of physical activity (PA) and DNA methylation interaction in the development of cardiovascular disease (CVD) is rarely simultaneously investigated in one study. We examined the role of DNA methylation on the association between PA and CVD. RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) cohort Exam 5 data with 1065 participants free of CVD were used for final analysis. The quartile categorical total PA variable was created by activity intensity (METs/week). During a median follow-up of 4.0 years, 69 participants developed CVD. Illumina HumanMethylation450 BeadChip was used to provide genome-wide DNA methylation profiles in purified human monocytes (CD14+). We identified 23 candidate DNA methylation loci to be associated with both PA and CVD. We used the structural equation modeling (SEM) approach to test the complex relationships among multiple variables and the roles of mediators. Three of the 23 identified loci (corresponding to genes VPS13D, PIK3CD and VPS45) remained as significant mediators in the final SEM model along with other covariates. Bridged by the three genes, the 2nd PA quartile (ß = - 0.959; 95%CI: - 1.554 to - 0.449) and the 3rd PA quartile (ß = - 0.944; 95%CI: - 1.628 to - 0.413) showed the greatest inverse associations with CVD development, while the 4th PA quartile had a relatively weaker inverse association (ß = - 0.355; 95%CI: - 0.713 to - 0.124). CONCLUSIONS: The current study is among the first to simultaneously examine the relationships among PA, DNA methylation, and CVD in a large cohort with long-term exposure. We identified three DNA methylation loci bridged the association between PA and CVD. The function of the identified genes warrants further investigation in the pathogenesis of CVD.

Integrating Patient-Reported Outcomes Into Clinical Genetic Testing for Familial Hypercholesterolemia.

Patient-reported outcomes (PROs) and PRO measures (PROMs) are often used to help clinicians and researchers understand patients' personal concerns, feelings, experiences, and perspectives following the implementation of an intervention. Notably, PROs and PROMs can inform health systems, health policy, and payers on the utility of clinical genetic testing based on each patient's personal values, perspectives, and potential health behaviors subsequent to testing. In this topic synopsis, we discuss the underexplored role of and implications for PROs and PROMs following genetic testing for familial hypercholesterolemia (FH), an autosomal dominant genetic disorder of cholesterol metabolism that can lead to highly premature fatal and nonfatal myocardial infarction and stroke. We also discuss why the use and consideration of patient perspectives, via PROs and PROMs, are critical to the process of optimizing patient care across various FH treatment contexts. As expert clinician groups consider the latest evidence when establishing recommendations for FH genetic testing, there is a ripe opportunity for clinicians and researchers to explore the value and utility of PROs to inform and possibly improve care for patients diagnosed with FH.