Discordance among apoB, non-high-density lipoprotein cholesterol, and triglycerides: implications for cardiovascular prevention.

BACKGROUND AND AIMS: Despite growing evidence that apolipoprotein B (apoB) is the most accurate marker of atherosclerotic cardiovascular disease (ASCVD) risk, its adoption in clinical practice has been low. This investigation sought to determine whether low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), and triglycerides are sufficient for routine cardiovascular care. METHODS: A sample of 293 876 UK Biobank adults (age: 40-73 years, 42% men), free of cardiovascular disease, with a median follow-up for new-onset ASCVD of 11 years was included. Distribution of apoB at pre-specified levels of LDL-C, non-HDL-C, and triglycerides was examined graphically, and 10-year ASCVD event rates were compared for high vs. low apoB. Residuals of apoB were constructed after regressing apoB on LDL-C, non-HDL-C, and log-transformed triglycerides and used as predictors in a proportional hazards regression model for new-onset ASCVD adjusted for standard risk factors, including HDL-C. RESULTS: ApoB was highly correlated with LDL-C and non-HDL-C (Pearson's r = .96, P < .001 for both) but less so with log triglycerides (r = .42, P < .001). However, apoB ranges necessary to capture 95% of all observations at pre-specified levels of LDL-C, non-HDL-C, or triglycerides were wide, spanning 85.8-108.8 md/dL when LDL-C 130 mg/dL, 88.3-112.4 mg/dL when non-HDL-C 160 mg/dL, and 67.8-147.4 md/dL when triglycerides 115 mg/dL. At these levels (±10 mg/dL), 10-year ASCVD rates for apoB above mean + 1 SD vs. below mean - 1 SD were 7.3 vs. 4.0 for LDL-C, 6.4 vs. 4.6 for non-HDL-C, and 7.0 vs. 4.6 for triglycerides (all P < .001). With 19 982 new-onset ASCVD events on follow-up, in the adjusted model, residual apoB remained statistically significant after accounting for LDL-C and HDL-C (hazard ratio 1.06, 95% confidence interval 1.0-1.07), after accounting for non-HDL-C and HDL-C (hazard ratio 1.04, 95% confidence interval 1.03-1.06), and after accounting for triglycerides and HDL-C (hazard ratio 1.13, 95% confidence interval 1.12-1.15). None of the residuals of LDL-C, non-HDL-C, or of log triglycerides remained significant when apoB was included in the model. CONCLUSIONS: High variability of apoB at individual levels of LDL-C, non-HDL-C, and triglycerides coupled with meaningful differences in 10-year ASCVD rates and significant residual information contained in apoB for prediction of new-onset ASCVD events demonstrate that LDL-C, non-HDL-C, and triglycerides are not adequate proxies for apoB in clinical care.

Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis.

BACKGROUND: Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms. OBJECTIVES: The aim of this study was to discover novel biomarkers with potentially causal associations with AS. METHODS: We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue. RESULTS: Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor-related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis. CONCLUSIONS: These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression.

Is hypertriglyceridemia a reliable indicator of cholesterol-depleted Apo B particles?

OBJECTIVES: Because cholesterol-depleted Apo B particles are thought to be a hallmark of hypertriglyceridemia, American, Canadian and European Lipid Guidelines suggest screening for Apo B only in patients with hypertriglyceridemia. Accordingly, this study examines the relationship of triglycerides to the LDL-C/Apo B and non-HDL-C/Apo B ratios. METHODS: The study cohort consisted of 6272 NHANES subjects adjusted for a weighted sample size of 150 million subjects without previously diagnosed cardiac disease. Data was reported by LDL-C/Apo B tertiles as weighted frequencies and percent. Sensitivity, specificity, negative predictive and positive predictive values were calculated for triglycerides thresholds of >150 mg/dL and >200 mg/dL. The range of values of Apo B for decisional levels of LDL-C and non-HDL-C were also determined RESULTS: Among patients with triglycerides >200 mg/dL, 75.9% were amongst the lowest LDL-C/Apo B tertile. However, this represents only 7.5% of the total population. Of patients with the lowest LDL-C/Apo B ratio, 59.8% had triglycerides <150 mg/dL. Moreover, there was an inverse relationship between non-HDL-C/Apo B such that elevated triglycerides were associated with the highest tertile of non-HDL-C/Apo B. Finally, the range of values of Apo B for decisional levels of LDL-C and non-HDL-C was determined and is so broad- 30.3-40.6 mg/dl Apo B for different levels of LDL-C and 19.5 to 27.6 mg/dl Apo B for different levels of non-HDL-C- that neither is an adequate clinical surrogate for Apo B. CONCLUSION: Plasma triglycerides should not be used to restrict the measurement of Apo B since cholesterol-depleted Apo B particles may be present at any level of triglyceride.

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Interplay of Atherogenic Particle Number and Particle Size and the Risk of Coronary Heart Disease.

BACKGROUND: We examined the interplay of apolipoprotein B (apoB) and LDL particle size, approximated by the LDL-cholesterol (LDL-C)/apoB ratio, on the risk of new-onset coronary heart disease (CHD). METHODS: Participants without cardiovascular disease from the UK Biobank (UKB; n = 308 182), the Women's Health Study (WHS; n = 26 204), and the Framingham Heart Study (FHS; n = 2839) were included. Multivariable Cox models were used to assess the relationship between apoB and LDL-C/apoB ratio and incidence of CHD (14 994 events). Our analyses were adjusted for age, sex (except WHS), HDL-cholesterol (HDL-C), systolic blood pressure, antihypertensive treatment, diabetes, and smoking. RESULTS: In all 3 studies, there was a strong positive correlation between apoB and LDL-C (correlation coefficients r = 0.80 or higher) and a weak inverse correlation of apoB with LDL-C/apoB ratio (-0.28 ≤ r ≤ -0.14). For all 3 cohorts, CHD risk was higher for higher levels of apoB. Upon multivariable adjustment, the association between apoB and new-onset CHD remained robust and statistically significant in all 3 cohorts with hazard ratios per 1 SD (95% CI): 1.24 (1.22-1.27), 1.33 (1.20-1.47), and 1.24 (1.09-1.42) for UKB, WHS, and FHS, respectively. However, the association between LDL-C/apoB and CHD was statistically significant only in the FHS cohort: 0.78 (0.64-0.94). CONCLUSIONS: Our analysis confirms that apoB is a strong risk factor for CHD. However, given the null association in 2 of the 3 studies, we cannot confirm that cholesterol-depleted LDL particles are substantially more atherogenic than cholesterol-replete particles. These results lend further support to routine measurement of apoB in clinical care.

An adverse lipoprotein phenotype-hypertriglyceridaemic hyperapolipoprotein B-and the long-term risk of type 2 diabetes: a prospective, longitudinal, observational cohort study.

BACKGROUND: This study examines the risk of new-onset diabetes in patients with hypertriglyceridaemic hyperapolipoprotein B (high triglycerides, high apolipoprotein B [apoB], low LDL cholesterol to apoB ratio, and low HDL cholesterol). The aim was to establish whether this lipoprotein phenotype identified a substantial group at high risk of developing diabetes over the next 20 years. METHODS: In this prospective, longitudinal, observational cohort study, we used data from the Framingham Offspring cohort (recruited in Framingham, MA, USA). Participants were aged 40-69 years and free of diabetes and cardiovascular disease at a baseline examination done between April, 1987, and November, 1991, and were followed up until March, 2014. Cox proportional hazards regression with hierarchical adjustment for age and sex, waist circumference, and fasting blood glucose were used to model the relationship between each lipid marker and incident diabetes, as well as the relationship between hypertriglyceridaemic hyperapoB (defined as values greater than sample medians of triglycerides and apoB, and less than medians of HDL cholesterol and LDL cholesterol to apoB ratio) and incident diabetes. FINDINGS: Of 3446 individuals aged 40-69 years who completed baseline examination, 2515 participants were eligible and included in all analyses. During median 21·1 years (IQR 11·1-23·1) of follow-up, 402 (16·0%) individuals developed diabetes. Age (p=0·032), waist circumference (p<0·0001), fasting blood glucose (p<0·0001), and natural logarithm-transformed triglycerides (p<0·0001) were associated with new-onset diabetes, as were apoB (p=0·0016), LDL cholesterol to apoB ratio (p=0·0018), and HDL cholesterol (p=0·0016) when added to this model. The age and sex-adjusted incidence of diabetes in the hypertriglyceridaemic hyperapoB group was 32·4% (95% CI 27·8-37·7) versus 5·5% (3·5-8·6) in the optimal lipid phenotype group and 15·5% (13·5-17·7) in the mixed lipid phenotype group. The fully adjusted hazard ratio, including glucose and waist circumference, for individuals with hypertriglyceridaemic hyperapoB was 3·30 (95% CI 2·06-5·30; p=0·0008) and for mixed lipid phenotype was 2·17 (1·38-3·40; p<0·0001) compared with those with the optimal lipid phenotype. INTERPRETATION: Our findings suggest that individuals with hypertriglyceridaemic hyperapoB are at high risk of new-onset diabetes and might benefit from intensive measures to prevent diabetes. The association between this phenotype and incident diabetes is consistent with a pro-diabetic effect due to increased clearance of apoB particles from plasma, which could injure pancreatic islet cells. This mechanism might explain the increased risk of diabetes with statin therapy. FUNDING: Doggone Foundation.

Bioactive Scaffolds in Stem Cell-Based Therapies for Myocardial Infarction: a Systematic Review and Meta-Analysis of Preclinical Trials.

The use of bioactive scaffolds in conjunction with stem cell therapies for cardiac repair after a myocardial infarction shows significant promise for clinical translation. We performed a systematic review and meta-analysis of preclinical trials that investigated the use of bioactive scaffolds to support stem cell-aided cardiac regeneration, in comparison to stem cell treatment alone. Cochrane Library, Medline, Embase, PubMed, Scopus, Web of Science, and grey literature were searched through April 23, 2020 and 60 articles were included in the final analysis. The overall effect size observed in scaffold and stem cell-treated small animals compared to stem cell-treated controls for ejection fraction (EF) was 7.98 [95% confidence interval (CI): 6.36, 9.59] and for fractional shortening (FS) was 5.50 [95% CI: 4.35, 6.65] in small animal models. The largest improvements in EF and FS were observed when hydrogels were used (MD = 8.45 [95% CI: 6.46, 10.45] and MD = 5.76 [95% CI: 4.46, 7.05], respectively). Subgroup analysis revealed that cardiac progenitor cells had the largest effect size for FS, and was significant from pluripotent, mesenchymal and endothelial stem cell types. In large animal studies, the overall improvement of EF favoured the use of stem cell-embedded scaffolds compared to direct injection of cells (MD = 10.49 [95% CI: 6.30, 14.67]). Significant publication bias was present in the small animal trials for EF and FS. This study supports the use of bioactive scaffolds to aid in stem cell-based cardiac regeneration. Hydrogels should be further investigated in larger animal models for clinical translation.

A Comparison of Lipids and apoB in Asian Indians and Americans.

Background and aims: Apolipoprotein B (apoB) integrates and extends the information from the conventional measures of atherogenic cholesterol and triglyceride. To illustrate how apoB could simplify and improve the management of dyslipoproteinemia, we compared conventional lipid markers and apoB in a sample of Americans and Asian Indians. Methods: Data from the US National Health and Nutrition Examination Survey (NHANES) (11,778 participants, 2009-2010, 2011-2012), and the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) cohort study in Delhi, India (4244 participants), 2011 were evaluated. We compared means and distributions of plasma lipids, and apo B using the Mann-Whitney U test and Fisher's exact test. A p value of < 0.05 was considered significant. Results: The plasma lipid profile differed between Asian Indians and Americans. Plasma triglycerides were greater, but HDL-C lower in Asian Indians than in Americans. By contrast, total cholesterol, non-HDL-C, and LDL-C were all significantly higher in Americans than Asian Indians. However, apoB was significantly higher in Asian Indians than Americans. The LDL-C/apoB ratio and the non-HDL-C/apoB ratio were both significantly lower in Asian Indians than Americans. Conclusion: Whether Americans or Asian Indians are at higher risk from apoB lipoproteins cannot be determined based on their lipid levels because the information from lipids cannot be integrated. ApoB, however, integrates and extends the information from triglycerides and cholesterol. Replacing the conventional lipid panel with apoB for routine follow ups could simultaneously simplify and improve clinical care.

Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels-Brief Report.

OBJECTIVE: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P≤5×10-8). In addition to validating previous associations at LPA, APOE, and CETP, we identified a novel variant at the APOH locus, encoding ß2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (ß [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; P=2.8×10-13) and demonstrated a stronger effect after adjustment for variation at the LPA locus (ß [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; P=3.8×10-42). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (ß [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; P=0.0071). CONCLUSIONS: In a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of ß2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.

Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis.

Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events.

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09). CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Bioactive scaffolds in stem-cell-based therapies for cardiac repair: protocol for a meta-analysis of randomized controlled preclinical trials in animal myocardial infarction models.

BACKGROUND: Acute myocardial infarction (MI) remains one of the leading causes of death worldwide with no curative therapy available. Stem cell therapies have been gaining interest as a means to repair the cardiac tissue after MI and prevent the onset of heart failure. Many in vivo reports suggest that the use of stem cells is promising, yet clinical trials suggest that the cells fail to integrate into the native tissue, resulting in limited improvements in cardiac function and repair. To battle this limitation, the combination of using stem cells embedded in a bioactive scaffold that promotes cell retention is growing in interest. Yet, a systematic review of the literature on the use of stem cells embedded in bioactive scaffolds for cardiac repair has not yet been performed. In this protocol, we outline a systematic review and meta-analysis of preclinical trials in animal MI models that utilize stem cell-embedded scaffolds for cardiac repair and compare their effects to stem cell-treated animals without the use of a scaffold. METHODS/DESIGN: We will search the following electronic databases: Cochrane Library, MEDLINE, Embase, PubMed, Scopus and Web of Science, and gray literature: Canadian Agency for Drugs and Technologies in Health and Google Scholar. We will only include randomly controlled preclinical trials that have directly investigated the effects of stem cells embedded in a scaffold for cardiac repair in an animal MI model. Two investigators will independently review each article included in the final analysis. The primary endpoint that will be investigated is left ventricular ejection fraction. Secondary endpoints will include infarct size, end systolic volume, end diastolic volume, fractional shortening and left ventricular wall thickness. Pooled analyses will be conducted using the DerSimonian-Laird random effects and Mantel-Haenszel fixed-effect models. Between-studies heterogeneity will be quantified and determined using the Tau2 and I2 statistics. Publication bias will be assessed using visual inspection of funnel plots and complemented by Begg's and Egger's statistical tests. Possible sources of heterogeneity will be assessed using subgroup-meta analysis and meta-regression. DISCUSSION: To date, the use of scaffolds in myocardial repair has not yet been systematically reviewed. The results of this meta-analysis will aid in determining the efficacy of stem cell-embedded scaffolds for cardiac repair and help bring this therapy to the clinic.

Observational and Genetic Associations of Resting Heart Rate With Aortic Valve Calcium.

It is unknown if lifelong exposure to increased hemodynamic stress from an elevated resting heart rate (HR) may contribute to aortic valve calcium (AVC). We performed multivariate regression analyses using data from 1,266 Framingham Heart Study (FHS) Offspring cohort participants and 6,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We constructed a genetic risk score (GRS) for HR using summary-level data in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AVC Consortium to investigate if there was evidence in favor of a causal relation. AVC was present in 39% of FHS Offspring cohort participants and in 13% of MESA cohort participants. In multivariate adjusted models, participants in the highest resting HR quartiles had significantly greater prevalence of AVC, with a prevalence ratio of 1.19 (95% confidence interval [CI] 0.99 to 1.44) for the FHS Offspring cohort and 1.32 (95% CI 1.12 to 1.63) for the MESA cohort, compared with those in the lowest quartile. There was a similar increase in the prevalence of AVC per standard deviation increase in resting HR in both FHS Offspring (prevalence ratio 1.08, 95% CI 1.01 to 1.15) and MESA (1.10, 95% CI 1.03 to 1.17). In contrast with these observational findings, a HR associated GRS was not significantly associated with AVC. Although our observational analysis indicates that a higher resting HR is associated with AVC, our genetic results do not support a causal relation. Unmeasured environmental and/or lifestyle factors associated with both increased resting HR and AVC that are not fully explained by covariates in our observational models may account for the association between resting HR and AVC.

Association of LPA Variants With Aortic Stenosis: A Large-Scale Study Using Diagnostic and Procedural Codes From Electronic Health Records.

Importance: Elevated lipoprotein(a) levels are a risk factor for aortic stenosis (AS). However, a large-scale replication of associations between LPA variants and AS, their interactions with risk factors, and the effect of multiple risk alleles is not well established. Objective: To replicate the association between LPA variants with AS and identify subgroups who are at higher risk of developing AS. Design, Setting, and Participants: This case-control study of AS included 44 703 individuals (3469 cases) 55 years or older who were enrolled in the Genetic Epidemiology Research on Aging cohort and who were members of the Kaiser Permanente Northern California health care delivery system. The study leveraged the linkage of administrative health data, electronic medical records, genotypes, and self-reported questionnaire data. The 3469 AS cases were diagnosed between January 1996 and December 2015. Individuals with congential valvular heart disease were excluded. Exposures: Two single-nucleotide polymorphisms in the LPA locus, rs10455872 and rs3798220, that are known to associate with circulating plasma lipoprotein(a) levels and an LPA risk score. Main Outcomes and Measures: Aortic stenosis or aortic valve replacement. Results: The 44 703 participants were of European ancestry,of whom 22 019 (49.3%) were men. The mean (SD) age for the control group was 69.3 (8.3) years and the mean (SD) age for AS cases was 74.6 (8.5) years. Both LPA variants were associated with AS, with a per risk allele odds ratio of 1.34 (95% CI, 1.23-1.47; P = 1.7 × 10-10) for rs10455872 and 1.31 (95% CI, 1.09-1.58; P = 3.6 × 10-3) for rs3798220 after adjusting for age, age2, and sex. The results remained significant after adjusting for risk factors. The estimates were similar for an LPA risk score. Individuals with 2 risk alleles had a 2-fold or greater odds of AS compared with individuals with no risk alleles (for rs10455872, homozygous odds ratio, 2.05; 95% CI, 1.37-3.07; P = 5.3 × 10-4; for rs3798220, homozygous odds ratio, 3.74; 95% CI, 1.03-13.62; P = .05; and for compound heterygotes, odds ratio, 2.00; 95% CI, 1.17-3.44; P = .01). For rs10455872, the odds ratio for AS was greatest in individuals aged 55 to 64 years and declined with age (interaction P = .03). Each rs10455872 risk allele was also associated with AS that was diagnosed 0.71 years earlier (95% CI, -1.42 to 0; P = .05). Conclusions and Relevance: We provide a large-scale confirmation of the association between 2 LPA variants and AS, reaching genome-wide significance. In addition, individuals with 2 risk alleles have 2-fold or greater odds of developing AS. Age may modify these associations and identify subgroups who are at greater risk of developing AS.

Association of Triglyceride-Related Genetic Variants With Mitral Annular Calcification.

BACKGROUND: Mitral annular calcium (MAC), commonly identified by cardiac imaging, is associated with cardiovascular events and predisposes to the development of clinically important mitral valve regurgitation and mitral valve stenosis. However, its biological determinants remain largely unknown. OBJECTIVES: The authors sought to evaluate whether a genetic predisposition to elevations in plasma lipids is associated with the presence of MAC. METHODS: The authors used 3 separate Mendelian randomization techniques to evaluate the associations of lipid genetic risk scores (GRS) with MAC in 3 large patient cohorts: the Framingham Health Study, MESA (Multiethnic European Study of Atherosclerosis), and the AGE-RS (Age, Gene/Environment Susceptibility-Reykjavik Study). The authors provided cross-ethnicity replication in the MESA Hispanic-American participants. RESULTS: MAC was present in 1,149 participants (20.4%). In pooled analyses across all 3 cohorts, a triglyceride GRS was significantly associated with the presence of MAC (odds ratio [OR] per triglyceride GRS unit: 1.73; 95% confidence interval [CI]: 1.24 to 2.41; p = 0.0013). Neither low- nor high-density lipoprotein cholesterol GRS was significantly associated with MAC. Results were consistent in cross-ethnicity analyses among the MESA Hispanic-Americans cohort (OR per triglyceride GRS unit: 2.04; 95% CI: 1.03 to 4.03; p = 0.04). In joint meta-analysis across all included cohorts, the triglyceride GRS was associated with MAC (OR per triglyceride GRS unit: 1.79; 95% CI: 1.32 to 2.41; p = 0.0001). The results were robust to several sensitivity analyses that limit both known and unknown forms of genetic pleiotropy. CONCLUSIONS: Genetic predisposition to elevated triglyceride levels was associated with the presence of MAC, a risk factor for clinically significant mitral valve disease, suggesting a causal association. Whether reducing triglyceride levels can lower the incidence of clinically significant mitral valve disease requires further study.

Genetic loci associated with ideal cardiovascular health: A meta-analysis of genome-wide association studies.

BACKGROUND: Multiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait. METHODS AND RESULTS: We examined 2 dichotomous phenotypes of ideal CV health-clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical+behavioral (clinical plus: not a current smoker, body mass index <25 kg/m(2))-among white participants aged 50±5 years. We performed a meta-analysis of 4 genome-wide association studies (total n=11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance (P<2.0 × 10(-9)). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol. CONCLUSION: A common single-nucleotide polymorphism in the APOC1/APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.

Association Between Family History, a Genetic Risk Score, and Severity of Coronary Artery Disease in Patients With Premature Acute Coronary Syndromes.

OBJECTIVE: A genetic risk score (GRS) for coronary artery disease has recently been shown to be independent of family history (FHx) in predicting future cardiovascular events. We sought to determine whether the presence of these risk factors, either individually or together, was associated with a higher burden of angiographic coronary artery disease. APPROACH AND RESULTS: We included 763 patients with premature acute coronary syndrome (median age, 50 [46-53] years; 30.8% women) with at least 1 major epicardial vessel stenosis enrolled in the Gender and Sex Determinants of Cardiovascular Disease From Bench to Beyond in Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, a multicentre prospective cohort study of premature patients with acute coronary syndrome (aged ≤55 years). The prevalence of multivessel disease (ie, ≥2 vessels with >50% stenosis) in individuals with FHx was 49.7% as compared with 37.9% in those without FHx (P<0.01 for comparison). In adjusted models for age, sex, traditional risk factors, and GRS, FHx was associated with a higher prevalence of 3-vessel disease (odds ratio [OR], 1.42; 95% confidence interval, 0.91-2.21; P=0.12 for 2-vessel disease and OR, 2.26; 95% confidence interval, 1.29-3.95; P=0.005 for 3-vessel disease). Individuals with a high GRS were also more likely to have multivessel disease (OR, 1.41; 95% confidence interval, 1.01-1.99; P=0.047) after adjustment for traditional risk factors, including FHx. Individuals with both a FHx and a high GRS as compared with those with neither had the highest ORs for multivessel disease (adjusted OR, 2.14; 95% confidence interval, 1.24-3.69; P=0.0064). CONCLUSIONS: In patients with premature acute coronary syndrome, the presence of either a high GRS or FHx is associated with greater severity of coronary artery disease at angiography. Whether preventive strategies targeted to genetically predisposed individuals will reduce the burden of early acute coronary syndrome warrants further study.

Lipoprotein(a) Interactions With Low-Density Lipoprotein Cholesterol and Other Cardiovascular Risk Factors in Premature Acute Coronary Syndrome (ACS).

BACKGROUND: Current recommendations for lipoprotein(a) (Lp[a]) focus on the control of other risk factors, including lowering low-density lipoprotein cholesterol (LDL-C), with little evidence to support this approach. Identifying interactions between Lp(a) and other risk factors could identify individuals at increased risk for Lp(a)-mediated disease. METHODS AND RESULTS: We used a case-only study design and included 939 participants (median age=49 years, interquartile range 46-53, women=33.1%) from the GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond-Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, a multicenter prospective cohort study of premature acute coronary syndrome. There was a higher prevalence of elevated Lp(a) levels (>50 mg/dL; 80th percentile) in PRAXY participants as compared to the general population (31% versus 20%; P<0.001). Lp(a) was strongly associated with LDL-C (adjusted ß 0.17; P<0.001). Individuals with high Lp(a) were more likely to have LDL-C >2.5 mmol/L, indicating a synergistic interaction (adjusted odds ratio 1.51; 95% CI 1.08-2.09; P=0.015). The interaction with high Lp(a) was stronger at increasing LDL-C levels (LDL-C >3.5, adjusted odds ratio 1.87; LDL-C >4.5, adjusted odds ratio 2.72). In a polytomous logistic model comparing mutually exclusive LDL-C categories, the interaction with high Lp(a) became attenuated at LDL-C ≤3.5 mmol/L (odds ratio 1.16; 95% CI 0.80-1.68, P=0.447). Other risk factors were not associated with high Lp(a). CONCLUSIONS: In young acute coronary syndrome patients, high Lp(a) is more prevalent than in the general population and is strongly associated with high LDL-C, suggesting that Lp(a) confers greater risk for acute coronary syndrome when LDL-C is elevated. Individuals with high Lp(a) and LDL-C >3.5 mmol/L may warrant aggressive LDL-C lowering.

Screening Strategies and Primary Prevention Interventions in Relatives of People With Coronary Artery Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Relatives of people with coronary artery disease are at high risk of cardiovascular (CV) disease, but the effect of focused screening and treatment of this population is uncertain. METHODS: We searched the Cochrane Library, Medline, and Embase from inception until June 30, 2014 for articles that described screening strategies and primary prevention interventions targeting family members of patients with coronary artery disease to reduce CV risk. Results were pooled using a random-effects meta-analysis. RESULTS: We identified 18 studies that reported screening strategies and 15 reporting interventions to reduce CV risk. Proband willingness to refer relatives for screening was high (n = 6 studies, pooled rate = 87%; 95% confidence interval [CI], 80%-95%). Studies using a screening strategy in which the relative was contacted by health care professionals reported a pooled participation rate of 88% (95% CI, 78%-99%). The quality of interventional studies was highly variable. Random-effects meta-analysis of the highest quality randomized studies (n = 6) consisting of a specialized risk factor intervention compared with usual care was consistent with modest improvements in low-density lipoprotein cholesterol control (-0.18 mmol/L low-density lipoprotein cholesterol, 95% CI, -0.35 to -0.001; P = 0.048). Improvements in diet, smoking rates, exercise, and blood pressure were also observed with active intervention; however, reported outcomes were heterogeneous precluding a formal meta-analysis. CONCLUSIONS: Screening strategies that target family members, particularly when led by a health care professional, achieve a high participation rate. Although the available evidence is of variable quality, interventions that target individuals with a family history of coronary artery disease appear to be feasible and might be effective in improving certain risk factors or health behaviours but their long-term CV benefits remain uncertain.