Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial.

BACKGROUND: Dietary restriction of sodium has been suggested to prevent fluid overload and adverse outcomes for patients with heart failure. We designed the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) to test whether or not a reduction in dietary sodium reduces the incidence of future clinical events. METHODS: SODIUM-HF is an international, open-label, randomised, controlled trial that enrolled patients at 26 sites in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand). Eligible patients were aged 18 years or older, with chronic heart failure (New York Heart Association [NYHA] functional class 2-3), and receiving optimally tolerated guideline-directed medical treatment. Patients were randomly assigned (1:1), using a standard number generator and varying block sizes of two, four, or six, stratified by site, to either usual care according to local guidelines or a low sodium diet of less than 100 mmol (ie, <1500 mg/day). The primary outcome was the composite of cardiovascular-related admission to hospital, cardiovascular-related emergency department visit, or all-cause death within 12 months in the intention-to-treat (ITT) population (ie, all randomly assigned patients). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT02012179, and is closed to accrual. FINDINGS: Between March 24, 2014, and Dec 9, 2020, 806 patients were randomly assigned to a low sodium diet (n=397) or usual care (n=409). Median age was 67 years (IQR 58-74) and 268 (33%) were women and 538 (66%) were men. Between baseline and 12 months, the median sodium intake decreased from 2286 mg/day (IQR 1653-3005) to 1658 mg/day (1301-2189) in the low sodium group and from 2119 mg/day (1673-2804) to 2073 mg/day (1541-2900) in the usual care group. By 12 months, events comprising the primary outcome had occurred in 60 (15%) of 397 patients in the low sodium diet group and 70 (17%) of 409 in the usual care group (hazard ratio [HR] 0·89 [95% CI 0·63-1·26]; p=0·53). All-cause death occurred in 22 (6%) patients in the low sodium diet group and 17 (4%) in the usual care group (HR 1·38 [0·73-2·60]; p=0·32), cardiovascular-related hospitalisation occurred in 40 (10%) patients in the low sodium diet group and 51 (12%) patients in the usual care group (HR 0·82 [0·54-1·24]; p=0·36), and cardiovascular-related emergency department visits occurred in 17 (4%) patients in the low sodium diet group and 15 (4%) patients in the usual care group (HR 1·21 [0·60-2·41]; p=0·60). No safety events related to the study treatment were reported in either group. INTERPRETATION: In ambulatory patients with heart failure, a dietary intervention to reduce sodium intake did not reduce clinical events. FUNDING: Canadian Institutes of Health Research and the University Hospital Foundation, Edmonton, Alberta, Canada, and Health Research Council of New Zealand.

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.

BACKGROUND: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1ß, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1ß, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo. CONCLUSIONS: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1ß, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).

Relationship of parental feeding practices and diet with children's diet among South Asians in Canada.

BACKGROUND: South Asian children's diets are considered unhealthy, yet the relationship with food parenting among South Asians is understudied. METHODS: In a cross-sectional study, questionnaires were administered to dyads of Canadian South Asian elementary and high school children and a parent. Relationships between parental factors (perceived responsibility, restriction, pressure to eat, monitoring, home food environment, nutrition knowledge and intake of fruits and vegetables (FV), sugary beverages (SB) and sweets and fast foods (SWFF) and children's intake of FV, SB and SWFF were assessed by linear regression adjusted for sociodemographics. Subgroup differences by children's age and acculturation were explored by interaction analysis. RESULTS: 291 children (age 9.8 ± 3.2 years) had mean daily intake frequencies of 3.1 ± 2.0 FV, 1.0 ± 0.9 SB and 2.1 ± 1.5 SWFF. Positive associations were found between parent and child intake of FV (standardized beta (ß) = 0.230, [95%CI 0.115, 0.345], p < 0.001), SB (ß = 0.136 [0.019, 0.252], p = 0.02), and SWFF (ß = 0.167 [0.052, 0.282], p = 0.005). Parental monitoring was associated with lower children's SWFF intake (ß = -0.131 [-0.248, -0.015], p = 0.03). Among those expressing less Western culture, parental SWFF intake was associated with child's SB intake (ß = 0.255 [0.085, 0.425], p = 0.004). Among those expressing less traditional culture, positive home food environment was associated with lower child SWFF intake (ß = -0.208 [-0.374, -0.042], p = 0.015). CONCLUSION: South Asian children's diets have stronger relationships with their parents' diets than with food parenting practices or nutrition knowledge, though parental monitoring was associated with lower unhealthy food intake. However, with greater acculturation, the home food environment was more important for unhealthy food intake.

Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients.

BACKGROUND: Lorcaserin, a selective serotonin 2C receptor agonist that modulates appetite, has proven efficacy for weight management in overweight or obese patients. The cardiovascular safety and efficacy of lorcaserin are undefined. METHODS: We randomly assigned 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to receive either lorcaserin (10 mg twice daily) or placebo. The primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) was assessed at an interim analysis to exclude a noninferiority boundary of 1.4. If noninferiority was met, the primary cardiovascular efficacy outcome (a composite of major cardiovascular events, heart failure, hospitalization for unstable angina, or coronary revascularization [extended major cardiovascular events]) was assessed for superiority at the end of the trial. RESULTS: At 1 year, weight loss of at least 5% had occurred in 1986 of 5135 patients (38.7%) in the lorcaserin group and in 883 of 5083 (17.4%) in the placebo group (odds ratio, 3.01; 95% confidence interval [CI], 2.74 to 3.30; P<0.001). Patients in the lorcaserin group had slightly better values with respect to cardiac risk factors (including blood pressure, heart rate, glycemic control, and lipids) than those in the placebo group. During a median follow-up of 3.3 years, the rate of the primary safety outcome was 2.0% per year in the lorcaserin group and 2.1% per year in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P<0.001 for noninferiority); the rate of extended major cardiovascular events was 4.1% per year and 4.2% per year, respectively (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55). Adverse events of special interest were uncommon, and the rates were generally similar in the two groups, except for a higher number of patients with serious hypoglycemia in the lorcaserin group (13 vs. 4, P=0.04). CONCLUSIONS: In a high-risk population of overweight or obese patients, lorcaserin facilitated sustained weight loss without a higher rate of major cardiovascular events than that with placebo. (Funded by Eisai; CAMELLIA-TIMI 61 ClinicalTrials.gov number, NCT02019264 .).

Lorcaserin and Renal Outcomes in Obese and Overweight Patients in the CAMELLIA-TIMI 61 Trial.

BACKGROUND: Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). METHODS: CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. RESULTS: At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) <60 mL·min-1·1.73 m-2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min-1·1.73 m-2, those with an eGFR 60-90 and those <60 mL·min-1·1.73 m-2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (<30 mg/g), those microalbuminuria and those with macroalbuminuria had HRs of 1.46 (95% CI, 1.22, 1.74) and 2.10 (95% CI, 1.58, 2.80), respectively ( P for trend <0.0001). CONCLUSIONS: Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.

A qualitative investigation of optimal perinatal health: the perspectives of south Asian grandmothers living in southern Ontario, Canada.

BACKGROUND: Perinatal health-seeking behaviours are influenced by various factors, including personal beliefs. South Asian women, who often live within a wide kinship system, can be influenced by the advice and guidance of their mothers and/or mothers-in-law. METHODS: To explore the cultural health perceptions of South Asian grandmothers within this context, we used constructivist grounded theory to sample and interview 17 South Asian grandmothers who reside in Southern Ontario, Canada. Interviews were audio-recorded, transcribed verbatim, and coded/analyzed by three independent coders. RESULTS: Many grandmothers emphasized that the preconception phase should focus on building healthy habits around nutrition, physical activity, and mental wellness; the pregnancy period should encompass an enriched environment (positive relationships, healthy routines, nutritional enhancement); and the postpartum phase should emphasize healing and restoration for both the mother and newborn (self-care, bonding, rebuilding healthy habits). Many of the grandmothers conceptualized these stages as a cyclical relationship where healing and restoration transitions gradually to re-establishing healthy habits before having a subsequent child. They also expressed responsibility in supporting their daughters and/or daughters-in-law with their family units and encouraging the transfer of perinatal health information. CONCLUSIONS: South Asian grandmothers are involved in supporting the family units of their children and involving them in perinatal health programming can be an effective way to translate health knowledge to South Asian women. Video abstract. In order to impact a broad, diverse audience of community members, we collaborated with a South Asian film-maker to distil the research findings, write an impactful script, and produce a short digital story based on the research findings. Currently available on social media (https://www.youtube.com/watch?v=tjcNUVOwatU), the film was celebrated with a CIHR Institute for Human Development, Child and Youth Health Video Talks Prize in 2016.

Validity and Reproducibility of a Semi-Quantitative Food-Frequency Questionnaire Designed to Measure the Nutrient Intakes of Canadian South Asian Infants at 12 Months of Age.

Purpose: Validated methods to assess diet of non-European infants are sparse. We assessed the validity and reliability of a semi-quantitative food-frequency questionnaire (FFQ) for South Asian infants in Canada.Methods: We developed an 80-item FFQ to assess infant nutrient intake in the South Asian Birth Cohort study (START). Caregivers completed the FFQ twice along with two 24-hour diet recalls. We measured infant plasma ferritin to cross-validate reported iron intake. We evaluated validity using Spearman's rho (ρ), and reliability using the intraclass correlation coefficient.Results: Seventy-six caregivers provided 2 FFQs and 2 24-hour diet recalls. Energy-adjusted, de-attenuated correlations between the FFQs and 24-hour diet recalls ranged from -0.29 (monounsaturated fat) through 1.00 (cholesterol). The FFQ overestimated energy intake by 128%. Iron intake by 24-hour diet recalls correlated with plasma ferritin (r = 0.41; P = 0.01; n = 37), but iron intake by FFQ did not. The average reproducibility coefficient of the FFQ ranged from 0.24 (macronutrients) to 0.65 (minerals).Conclusions: Among South Asian infants living in Canada, at least 2 days of diet recall completed with the primary caregiver yields more valid and reproducible estimates of nutrient intakes than a semi-quantitative FFQ, and it highlights that careful selection of FFQ portion sizes is important for assessing dietary intake with an FFQ.

Atherosclerotic Cardiovascular Disease in South Asians in the United States: Epidemiology, Risk Factors, and Treatments: A Scientific Statement From the American Heart Association.

South Asians (from Bangladesh, Bhutan, India, the Maldives, Nepal, Pakistan, and Sri Lanka) make up one quarter of the world's population and are one of the fastest-growing ethnic groups in the United States. Although native South Asians share genetic and cultural risk factors with South Asians abroad, South Asians in the United States can differ in socioeconomic status, education, healthcare behaviors, attitudes, and health insurance, which can affect their risk and the treatment and outcomes of atherosclerotic cardiovascular disease (ASCVD). South Asians have higher proportional mortality rates from ASCVD compared with other Asian groups and non-Hispanic whites, in contrast to the finding that Asian Americans (Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese) aggregated as a group are at lower risk of ASCVD, largely because of the lower risk observed in East Asian populations. Literature relevant to South Asian populations regarding demographics and risk factors, health behaviors, and interventions, including physical activity, diet, medications, and community strategies, is summarized. The evidence to date is that the biology of ASCVD is complex but is no different in South Asians than in any other racial/ethnic group. A majority of the risk in South Asians can be explained by the increased prevalence of known risk factors, especially those related to insulin resistance, and no unique risk factors in this population have been found. This scientific statement focuses on how ASCVD risk factors affect the South Asian population in order to make recommendations for clinical strategies to reduce disease and for directions for future research to reduce ASCVD in this population.

Socio-economic, environmental and nutritional characteristics of urban and rural South Indian women in early pregnancy: findings from the South Asian Birth Cohort (START).

OBJECTIVE: High frequency of low birth weight (LBW) is observed in rural compared with urban Indian women. Since maternal BMI is known to be associated with pregnancy outcomes, the present study aimed to investigate factors associated with BMI in early pregnancy of urban and rural South Indian women. DESIGN: Prospective observational cohort. SETTING: A hospital-based study conducted at an urban and a rural health centre in Karnataka State. SUBJECTS: Pregnant women (n 843) aged 18-40 years recruited in early pregnancy from whom detailed sociodemographic, environmental, anthropometric and dietary intake information was collected. RESULTS: A high proportion of low BMI (32 v. 26 %, P<0·000) and anaemia (48 v. 23 %, P<0·000) was observed in the rural v. the urban cohort. Rural women were younger, had lower body weight, tended to be shorter and less educated. They lived in poor housing conditions, had less access to piped water and good sanitation, used unrefined fuel for cooking and had lower standard of living score. The age (ß=0·21, 95 % CI 0·14, 0·29), education level of their spouse (ß=1·36, 95 % CI 0·71, 2·71) and fat intake (ß=1·24, 95 % CI 0·20, 2·28) were positively associated with BMI in urban women. CONCLUSIONS: Our findings indicate that risk factors associated with BMI in early pregnancy are different in rural and urban settings. It is important to study population-specific risk factors in relation to perinatal health.

Harmonization of Food-Frequency Questionnaires and Dietary Pattern Analysis in 4 Ethnically Diverse Birth Cohorts.

BACKGROUND: Canada is an ethnically diverse nation, which introduces challenges for health care providers tasked with providing evidence-based dietary advice. OBJECTIVES: We aimed to harmonize food-frequency questionnaires (FFQs) across 4 birth cohorts of ethnically diverse pregnant women to derive robust dietary patterns to investigate maternal and newborn outcomes. METHODS: The NutriGen Alliance comprises 4 prospective birth cohorts and includes 4880 Canadian mother-infant pairs of predominantly white European [CHILD (Canadian Healthy Infant Longitudinal Development) and FAMILY (Family Atherosclerosis Monitoring In earLY life)], South Asian [START (SouTh Asian birth cohoRT)-Canada], or Aboriginal [ABC (Aboriginal Birth Cohort)] origins. CHILD used a multiethnic FFQ based on a previously validated instrument designed by the Fred Hutchinson Cancer Research Center, whereas FAMILY, START, and ABC used questionnaires specifically designed for use in white European, South Asian, and Aboriginal people, respectively. The serving sizes and consumption frequencies of individual food items within the 4 FFQs were harmonized and aggregated into 36 common food groups. Principal components analysis was used to identify dietary patterns that were internally validated against self-reported vegetarian status and externally validated against a modified Alternative Healthy Eating Index (mAHEI). RESULTS: Three maternal dietary patterns were identified-"plant-based," "Western," and "health-conscious"-which collectively explained 29% of the total variability in eating habits observed in the NutriGen Alliance. These patterns were strongly associated with self-reported vegetarian status (OR: 3.85; 95% CI: 3.47, 4.29; r2 = 0.30, P < 0.001; for a plant-based diet), and average adherence to the plant-based diet was higher in participants in the fourth quartile of the mAHEI than in the first quartile (mean difference: 46.1%; r2 = 0.81, P < 0.001). CONCLUSION: Dietary data collected by using FFQs from ethnically diverse pregnant women can be harmonized to identify common dietary patterns to investigate associations between maternal dietary intake and health outcomes.

Should dual antiplatelet therapy be used in patients following coronary artery bypass surgery? A meta-analysis of randomized controlled trials.

BACKGROUND: We assessed the effectiveness of dual antiplatelet therapy (DAPT) post elective or urgent (i.e., post acute coronary syndrome [ACS]) coronary artery bypass graft surgery (CABG). METHODS: We systematically searched MEDLINE, EMBASE, and the Cochrane Registry from inception to August 2015. Randomized controlled trials (RCTs) in adults undergoing CABG comparing either dual vs. single antiplatelet therapy or higher- vs. lower-intensity DAPT were identified. RESULTS: Nine RCTs (n = 4,887) with up to 1y follow-up were included. Five RCTs enrolled patients post-elective CABG (n = 986). Two multi-centre RCTs enrolled ACS patients who subsequently underwent CABG (n = 2,155). These 7 RCTs compared clopidogrel plus aspirin to aspirin alone. Two other multi-centre RCTs reported on ACS patients who subsequently underwent CABG comparing higher intensity DAPT with either ticagrelor (n = 1,261) or prasugrel (n = 485) plus aspirin to clopidogrel plus aspirin. Post-operative anti-platelet therapy was started when chest tube bleeding was no longer significant, typically within 24-48 h. There were no differences in all-cause mortality in clopidogrel plus aspirin vs. aspirin RCTs; conversely, all-cause mortality was significantly lower in ticagrelor and prasugrel vs. clopidogrel RCTs (risk ratio[RR] 0.49, 95% confidence interval[CI] 0.33-0.71, p = 0.0002; 2 RCTs, n = 1695; I(2) = 0%; interaction p < 0.01 compared to clopidogrel plus aspirin vs aspirin RCTs). There were no differences in myocardial infarctions, strokes, or composite outcomes. Overall, major bleeding was not significantly increased (RR 1.31, 95% CI 0.81-2.10, p = 0.27; 7 RCTs, n = 4500). There was heterogeneity (I(2) = 42%) due almost entirely to higher bleeding reported for the prasugrel RCT which included mainly CABG-related major bleeding (RR 3.15, 95% CI 1.45-6.87, p = 0.004; 1 RCT, n = 437). CONCLUSIONS: Most RCT data for DAPT post CABG is derived from subgroups of ACS patients in DAPT RCTs requiring CABG who resume DAPT post-operatively. Limited RCT data with heterogeneous trial designs suggest that higher intensity (prasugrel or ticagrelor) but not lower intensity (clopidogrel) DAPT is associated with an approximate 50% lower mortality in ACS patients who underwent CABG based on post-randomization subsets from single RCTs. Large prospective RCTs evaluating the use of DAPT post-CABG are warranted to provide more definitive guidance for clinicians.

Perioperative cardiovascular system failure in South Asians undergoing cardiopulmonary bypass is associated with prolonged inflammation and increased Toll-like receptor signaling in inflammatory monocytes.

BACKGROUND: South Asian ethnicity is an independent risk factor for mortality after coronary artery bypass. We tested the hypothesis that this risk results from a greater inflammatory response to cardiopulmonary bypass (CPB). METHODS: This was a single-site prospective cohort study. We compared the inflammatory response to CPB in 20 Caucasians and 17 South Asians undergoing isolated coronary artery bypass grafting surgery. RESULTS: Plasma levels of proinflammatory cytokines (interleukin [IL]-6, IL-8, IL-12, interferon gamma, and tumor necrosis factor) and anti-inflammatory mediators (IL-10 and soluble TNF receptor I) were measured. The Toll-like receptor (TLR) signaling pathway was examined in peripheral blood monocytes by flow cytometry, measuring surface expression of TLR2, TLR4, and coreceptor CD14 and activation of downstream messenger molecules (interleukin-1 receptor-associated kinase 4, nuclear factor kappa from B cells (NF-κB), c-Jun amino-terminal kinase, p38 mitogen-activated protein kinase, and Protein Kinase B). South Asians had persistently higher plasma levels of IL-6 and exhibited increased TLR signaling through the p38 mitogen-activated protein kinase and Protein Kinase B pathways in inflammatory monocytes after CPB. This increased inflammatory response was paralleled clinically by a higher sequential organ failure assessment score (5.1 ± 1.4 versus 1.5 ± 1.6, P = 0.027) and prolonged cardiovascular system failure (23.5% versus 0%) 48 h after CPB. CONCLUSIONS: South Asians develop an exacerbated systemic inflammatory response after CPB, which may contribute to the higher morbidity and mortality associated with coronary artery bypass in this population. These patients may benefit from targeted anti-inflammatory therapies designed to mitigate the adverse consequences resulting from this response.

MicroRNA-145 targeted therapy reduces atherosclerosis.

BACKGROUND: MicroRNA are essential posttranscriptional modulators of gene expression implicated in various chronic diseases. Because microRNA-145 is highly expressed in vascular smooth muscle cells (VSMC) and regulates VSMC fate and plasticity, we hypothesized that it may be a novel regulator of atherosclerosis and plaque stability. METHODS AND RESULTS: Apolipoprotein E knockout mice (ApoE(-/-)) mice were treated with either a microRNA-145 lentivirus under the control of the smooth muscle cell (SMC)-specific promoter SM22α or a SM22α control lentivirus before commencing the Western diet for 12 weeks. The SMC-targeted microRNA-145 treatment markedly reduced plaque size in aortic sinuses, ascending aortas, and brachiocephalic arteries. It also significantly increased fibrous cap area, reduced necrotic core area, and increased plaque collagen content. Cellular plaque composition analyses revealed significantly less macrophages in ApoE(-/-) mice treated with the SMC-specific microRNA-145. These mice also demonstrated marked increases in calponin levels and α-smooth muscle actin-positive SMC areas in their atherosclerotic lesions. Furthermore, lentiviral delivery of microRNA-145 resulted in reduced KLF4 and elevated myocardin expression in aortas from ApoE(-/-) mice, consistent with an effect of microRNA-145 to promote a contractile phenotype in VSMC. CONCLUSIONS: VSMC-specific overexpression of microRNA-145 is a novel in vivo therapeutic target to limit atherosclerotic plaque morphology and cellular composition, shifting the balance toward plaque stability vs plaque rupture.

Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis.

BACKGROUND: Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known. DESIGN: The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants. SUMMARY: CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.

Rationale and design of South Asian Birth Cohort (START): a Canada-India collaborative study.

BACKGROUND: People who originate from the Indian subcontinent (South Asians) suffer among the highest rates of type 2 diabetes in the world. Prior evidence suggests that metabolic risk factors develop early in life and are influenced by maternal and paternal behaviors, the intrauterine environment, and genetic factors. The South Asian Birth Cohort Study (START) will investigate the environmental and genetic basis of adiposity among 750 South Asian offspring recruited from highly divergent environments, namely, rural and urban India and urban Canada. METHODS: Detailed information on health behaviors including diet and physical activity, and blood samples for metabolic parameters and DNA are collected from pregnant women of South Asian ancestry who are free of significant chronic disease. They also undergo a provocative test to diagnose impaired glucose tolerance and gestational diabetes. At delivery, cord blood and newborn anthropometric indices (i.e. birth weight, length, head circumference and skin fold thickness) are collected. The mother and growing offspring are followed prospectively and information on the growth trajectory, adiposity and health behaviors will be collected annually up to age 3 years. Our aim is to recruit a minimum of 750 mother-infant pairs equally divided between three divergent environments: rural India, urban India, and Canada. SUMMARY: The START cohort will increase our understanding of the environmental and genetic determinants of adiposity and related metabolic abnormalities among South Asians living in India and Canada.

Awareness Among Primary Care Physicians in Canada of Guideline Recommendations for Lowering LDL-Cholesterol in High-Risk Patients.

Background: Cardiovascular (CV) risk management for high-risk patients is often provided by primary care physicians (PCPs). We surveyed Canadian PCPs regarding their awareness and implementation of the 2021 Canadian Cardiovascular Society (CCS) lipid guideline recommendations for patients following an acute coronary syndrome (ACS) and those with diabetes but without CV disease. Methods: A committee of PCPs and specialists with lipid expertise, including some 2021 CCS lipid guideline coauthors, designed a survey to probe PCP awareness and practice patterns regarding CV risk management. From a national database, a total of 250 PCPs completed the survey between January and April 2022. Results: Almost all PCPs (97.2%) concurred that a post-ACS patient should be seen by their PCP within 4 weeks of hospital discharge (81.2% said within 2 weeks). Almost half (44.4%) responded that discharge summaries provided inadequate information, and 41.6% felt that lipid management post-ACS was the responsibility primarily of specialists. A total of 58.4% articulated that they face challenges when seeing a post-ACS patient, related to inadequate discharge information, complexities of polypharmacy and duration of therapies, and managing statin intolerance. A total of 63.2% and 43.6% correctly identified low-density lipoprotein cholesterol (LDL-C) intensification thresholds of 1.8 mmol/L in post-ACS patients, and 2.0 mmol/L in diabetes patients, respectively, and 81.2% incorrectly thought that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were indicated for patients with diabetes but without CV disease. Conclusions: One year following publication of the 2021 CCS lipid guidelines, our survey reveals knowledge gaps among responding PCPs regarding intensification thresholds and treatment options for patients post-ACS, or those with diabetes. Innovative and effective knowledge-translation programs to address these gaps are desirable.

Contexte: La prise en charge du risque cardiovasculaire (CV) chez les patients à risque élevé est souvent réalisée par les médecins en soins primaires (MSP). Nous avons donc sondé les MSP canadiens quant à leur connaissance des lignes directrices 2021 de la Société cardiovasculaire du Canada (SCC) sur les lipides et leur mise en œuvre auprès des patients ayant subi un syndrome coronarien aigu (SCA) et auprès des patients atteints de diabète qui ne présentent pas de maladie CV. Méthodologie: Un comité de MSP et de spécialistes ayant une expertise sur la question des lipides, y compris certains coauteurs des lignes directrices 2021 de la SCC sur les lipides, a conçu un sondage pour évaluer la connaissance des mesures de prise en charge du risque CV et les habitudes de pratique des MSP en la matière. Au total, 250 MSP provenant d'une banque de données nationale ont rempli le sondage entre janvier et avril 2022. Résultats: Presque tous les MSP (97,2 %) étaient d'accord pour dire que les patients ayant subi un SCA devraient avoir une consultation avec leur MSP dans les quatre semaines suivant leur congé de l'hôpital (81,2 % ont dit deux semaines). Près de la moitié des répondants (44,4 %) ont indiqué que le sommaire d'hospitalisation fournit une information inadéquate, et 41,6 % estimaient que la gestion des lipides après un SCA relevait des spécialistes. Au total, 58,4 % des répondants ont mentionné rencontrer des difficultés lors de la consultation avec un patient après une SCA, surtout quant à l'information inadéquate contenue dans le sommaire d'hospitalisation, aux complexités de la polypharmacie, à la durée des traitements et à l'intolérance aux statines. De plus, 63,2 % et 43,6 % des répondants ont correctement indiqué les seuils d'intensification du traitement pour le cholestérol à lipoprotéines de basse densité (LDL), soit 1,8 mmol/l chez les patients après un SCA et 2,0 mmol/l chez les patients diabétiques, respectivement. Par ailleurs, 81,2 % des répondants croyaient à tort que les inhibiteurs de la proprotéine convertase subtilisine/kexine de type 9 (PCSK9) étaient indiqués pour les patients diabétiques ne présentant pas de maladie CV. Conclusions: Un an après la publication des lignes directrices 2021 de la SCC sur les lipides, notre sondage montre des lacunes dans les connaissances des MSP quant aux seuils d'intensification du traitement et aux options de traitement pour les patients ayant subi un SCA ou atteints de diabète. Des programmes novateurs et efficaces de transmission du savoir sont souhaitables pour combler ces lacunes.

The association of maternal sugary beverage consumption during pregnancy and the early years with childhood sugary beverage consumption.

OBJECTIVES: A woman's food choices during pregnancy may be associated with her offspring's food choices. Several studies support an association between childhood sugary beverage (SB) consumption and poor cardiometabolic health. This study aimed to assess the association of maternal SB consumption during pregnancy and later, with her offspring's SB consumption in early infancy and childhood. METHODS: A total of 1945 women and 1595 children participating in 3 Canadian studies reported SB consumption during pregnancy, at 2 years of age, and/or at school age (5 to 8 years old). Mother and offspring SB intakes were self-reported by mothers. Multivariable linear regression analyses were conducted within each cohort and cohort data were combined using fixed effect meta-analyses. RESULTS: Maternal SB consumption during pregnancy was associated with higher offspring SB consumption at 2 years of age (standardized ß = 0.19 predicted change in the number of standard deviations of offspring SB intake for an increase of 1 standard deviation in maternal serving [95% CI: 0.16 to 0.22]). Concurrent maternal SB consumption was associated with higher offspring SB intake when children were aged 5 to 8 years (standardized ß= 0.25 [95% CI: 0.10 to 0.40]). CONCLUSION: Maternal SB consumption during pregnancy is associated with a marginally higher SB intake among their offspring at age 2, and concurrent maternal consumption is associated with a higher SB intake among school-aged offspring (5 to 8 years old). Future interventions tailored for pregnancy and early childrearing years to reduce SB intakes of mothers may reduce young children's SB intake.

RéSUMé: OBJECTIFS: Il peut y avoir un lien entre les choix alimentaires d'une femme pendant la grossesse et ceux de son enfant. Plusieurs études font état d'une association entre la consommation de boissons sucrées (BS) durant l'enfance et la mauvaise santé cardiométabolique. Notre étude visait à évaluer l'association entre la consommation de BS des mères pendant et après la grossesse et la consommation de BS de leurs enfants durant la petite enfance et l'enfance. MéTHODE: En tout, 1 945 femmes et 1 595 enfants participant à 3 études canadiennes ont fait état de leur consommation de BS pendant la grossesse, à l'âge de 2 ans et/ou à l'âge scolaire (5 à 8 ans). La consommation de BS des mères et des enfants a été déclarée par les mères. Des analyses de régression linéaire multivariée ont été menées dans chaque cohorte, et les données des cohortes ont été combinées à l'aide de méta-analyses à effets fixes. RéSULTATS: La consommation maternelle de BS pendant la grossesse était associée à une consommation de BS plus élevée chez les enfants à l'âge de 2 ans (le coefficient ß standardisé = 0,19 prédisait le changement du nombre d'écart-types de consommation de BS chez les enfants pour chaque hausse de 1 écart-type de la portion maternelle [IC de 95 % : 0,16 à 0,22]). La consommation maternelle concomitante de BS était associée à une consommation de BS plus élevée chez les enfants lorsqu'ils étaient âgés de 5 à 8 ans (coefficient ß standardisé = 0,25 [IC de 95 % : 0,10 à 0,40]). CONCLUSION: La consommation maternelle de BS pendant la grossesse est associée à une consommation de BS marginalement plus élevée chez l'enfant à l'âge de 2 ans, et la consommation maternelle concomitante est associée à une consommation de BS plus élevée chez l'enfant d'âge scolaire (5 à 8 ans). De futures interventions visant à réduire la consommation de BS des mères pendant la grossesse et durant les premières années où elles élèvent leurs enfants pourraient réduire la consommation de BS des jeunes enfants.

Real-World Insights into Evolocumab Use in Patients with Hyperlipidemia Across Five Countries: Analysis from the ZERBINI Study.

INTRODUCTION: This study characterizes patients receiving evolocumab in clinical practice and assesses treatment effectiveness, safety and persistence outcomes across five countries. METHODS: This retrospective and prospective observational study enrolled patients initiated on evolocumab during August 2017 to July 2019 at 49 sites across Canada, Mexico, Colombia, Saudi Arabia and Kuwait. Medical records data were extracted within 6 months prior to (baseline) and every 3 months for 12 months post evolocumab initiation and reported as available. RESULTS: A total of 578 patients were enrolled (40.1% female, median age 60 [interquartile range (IQR) 51-68] years); 83.7% had atherosclerotic cardiovascular disease and/or familial hypercholesterolemia. Median low-density lipoprotein cholesterol (LDL-C) at baseline was 3.4 (IQR 2.7-4.2) mmol/L (131.5 [IQR 104.4-162.4] mg/dL), with 75.6% of patients receiving a statin (59.2% high intensity). Compared to baseline, the median lowest LDL-C was reduced by 70.2% and remained stable over 12 months of treatment. Guideline-recommended LDL-C thresholds < 1.8, < 1.4 and < 1.0 mmol/L (< 70, < 55 and < 40 mg/dL) were achieved by 75.3%, 63.6% and 47.4% of patients. LDL-C outcomes were consistent across high- and very high-risk patients. Background lipid-lowering therapy remained relatively stable. No serious treatment-emergent adverse events were reported, and persistence to evolocumab was 90.2% at 12 months. CONCLUSION: These findings provide real-world evidence that evolocumab use is in accordance with its international guideline-recommended place in dyslipidemia therapy, as well as confirmation of its effectiveness and safety in a heterogeneous population. Evolocumab can address a healthcare gap in the management of dyslipidemia by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk.

Plasma renin activity predicts cardiovascular mortality in the Heart Outcomes Prevention Evaluation (HOPE) study.

AIMS: Plasma renin activity (PRA) has been proposed as an independent predictor of cardiovascular (CV) risk, but there are limited data from large prospective studies, particularly in patients with stable vascular disease and/or diabetes, without heart failure. METHODS AND RESULTS: We evaluated the predictive value of PRA as a marker of CV events and mortality in a large population of patients with stable chronic vascular disease and/or diabetes and one CV risk factor. Baseline PRA was measured in 2913 patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study. Subjects were followed for a median of 4.5 years. Compared with the referent lowest fifth, subjects in the highest fifth of the PRA distribution had a hazard ratio (HR) of 1.38 (95% confidence interval, 1.03-1.86; P = 0.03) for the composite of major vascular events, with an HR of 1.89 for CV death. These associations remained statistically significant after full adjustment for clinical characteristics, background use of ß-blockers, diuretics, allocation to ramipril, in addition to inflammatory biomarkers, high-sensitivity C-reactive protein, and N-terminal pro-brain natriuretic peptide. CONCLUSION: High PRA is an independent predictor of major vascular events and mortality in a stable population of high-risk patients with atherosclerosis and/or diabetes. Although an increase in PRA could be a marker of more intense antihypertensive therapy, our results suggest that PRA may represent a risk marker and potential target for therapy in high-risk patients with atherosclerosis and/or diabetes.

The effects of rosiglitazone on inflammatory biomarkers and adipokines in diabetic, hypertensive patients.

OBJECTIVE: To compare the effects of a 12-week treatment course of a rosiglitazone-based versus a metformin- or glyburide-based strategy on inflammatory biomarkers and adipokine levels in hypertensive, type 2 diabetes patients. METHODS: One hundred three treatment-naive patients or patients on monotherapy with either metformin or glyburide, and a hemoglobin A1C (A1C) ≥7.5%, were randomly assigned to either rosiglitazone add-on (4 mg/day ± titration to 8 mg/day) or a combination of metformin (250 mg twice per day [BID] titrated to 500 BID if A1C ≥7.5% and ≤8.0%; 500 mg BID titrated to 1 g BID if A1C >8.0%) and glyburide (2.5 mg BID titrated to 5 mg BID if A1C ≥7.5% and ≤8.0%; 5 mg BID titrated to 10 mg BID if A1C >8.0%). RESULTS: Rosiglitazone add-on produced significantly greater reductions in high-sensitivity C-reactive protein (2.1 mg/L to 0.9 mg/L) and increases in adiponectin (8.7 mg/mL to 14.8 mg/mL) levels compared with metformin/glyburide (both P<0.005). At close-out, all patients had improved fasting plasma glucose and A1C levels (8.5% to 7.4% and 8.8% to 7.1% for rosiglitazone add-on and metformin-glyburide, respectively [P<0.001 for both arms]) relative to the corresponding baseline values. CONCLUSIONS: The present study demonstrated that in hypertensive, diabetic subjects, a rosiglitazone-based treatment strategy results in favourable changes in inflammatory biomarkers compared with metformin/glyburide.