👤 Ian Blumenthal

Elevated atherogenic lipoproteins increase risk of atherosclerotic cardiovascular disease (ASCVD), though long-term risk for adults without ASCVD who have low-normal levels has not been well described. This study used pooled data from 16,384 individuals in 3 population-based prospective cohorts. At baseline all participants were without ASCVD and were not taking lipid-lowering therapy. We evaluated ASCVD events by baseline LDL-C, non-HDL-C and apoB, including low-normal values. ASCVD risk was assessed using multivariable Cox proportional hazards. The study cohort had a mean age of 52 (SD 18) years with 56.5% women, 64.7% of White race and 35.3% of Black race. Over a median follow-up of 18.8 years, unadjusted ASCVD event incidence was similar for adults with baseline LDL-C < 70 mg/dL and 70 to 99 mg/dL, and higher with LDL-C ≥ 100 mg/dL; trends were similar for non-HDL-C and apoB categories. Compared to having baseline LDL-C 70 to 99 mg/dL, LDL-C < 70 mg/dL was associated with similar ASCVD risk (adjusted HR 1.16 [95% Confidence Interval, 95% CI 0.90-1.50]) and LDL-C ≥ 130 mg/dL was associated with higher risk (adjusted HR 1.31 [95% CI 1.14-1.50]) after multivariable adjustment; adults with non-HDL-C ≥ 160 mg/dL or apoB ≥ 90 mg/dL also had higher risk after multivariable adjustment. Among adults without ASCVD not taking lipid-lowering therapy at baseline, ASCVD risk for adults with low-normal and high-normal LDL-C, non-HDL-C and apoB was similar, and their risk remained less than in adults with elevated lipoproteins. These findings emphasize the importance of achieving normal atherogenic lipoprotein levels for primary prevention of ASCVD from early adulthood through middle age. Show less

Lipoprotein(a) [Lp(a)] and LDL cholesterol (LDL-C) are causally linked to aortic valve calcium (AVC) and aortic stenosis (AS). Lipoprotein(a) has anti-fibrinolytic properties; therefore, aspirin may reduce cardiovascular disease risk among individuals with high Lp(a). This analysis sought to determine the association of aspirin with incident AVC and AS across Lp(a) and LDL-C levels. This observational study included up to 6598 participants in the Multi-Ethnic Study of Atherosclerosis. Aortic valve calcium was measured on non-contrast cardiac computed tomography. Multivariable Cox hazards regression assessed the association of self-reported regular aspirin use (≥3 days/week) with incident AVC and severe AS, stratified by Lp(a) and LDL-C. Aortic valve calcium and Lp(a) values were not reported to participants. Mean age was 62 years, 53% were women, 23% reported regular aspirin use, 8% developed AVC (median 8.9 years), and 1% developed severe AS (median 16.7 years). Among individuals with elevated Lp(a), regular aspirin use was associated with a lower risk of incident AVC (Lp(a) ≥75 mg/dL: hazard ratio (HR) .42, 95% confidence interval (CI) .19-.93; Lp(a) ≥100 mg/dL: HR .17, 95% CI .04-.67) and severe AS (Lp(a) ≥50 mg/dL: HR .13, 95% CI: .04-.47; Lp(a) ≥75 mg/dL: HR .02, 95% CI .001-.29). For participants with elevated LDL-C, there was no association of regular aspirin use with incident AVC (LDL-C ≥130 mg/dL: HR 1.02, 95% CI .66-1.58; LDL-C ≥160 mg/dL: HR 1.51, 95% CI .53-4.28) or severe AS (LDL-C ≥100 mg/dL: HR .70, 95% CI .39-1.26; LDL-C ≥130 mg/dL: HR .46, 95% CI .14-1.47). In this exploratory analysis of prospective observational cohort data, regular aspirin use was associated with a lower risk of AVC and severe AS in persons with high Lp(a), but not high LDL-C. Confirmatory studies are required to determine the role of aspirin in the prevention of AVC and AS for persons with high Lp(a). Show less

In anticipation of updates to cholesterol guidelines globally, evidence since the most recent iteration of recommendations across US and Europe for risk assessment and lipid management are reviewed. ASCVD risk estimation is at the core of determining lipid lowering goals and consideration for therapies. In primary prevention, incorporation of the PREVENT equations will be featured in updated guidelines, which will likely demarcate new, lower risk thresholds compared to the prior Pooled Cohort Equations. Additionally, the use of coronary artery calcium (CAC) improves risk estimation to inform medication allocation and LDL-C goals beyond traditional risk factor risk estimation. To achieve lower LDL-C, many adults will need multiple lipid-lowering medications. For high-risk individuals, combination therapy with low/moderate intensity statin and ezetimibe or bempedoic acid should be considered. Additionally, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapies can be used to attain lower LDL-C in high-risk individuals, including those with clinical ASCVD or a high CAC burden. In very-high risk patients, treatment to LDL-C values as low as <30 mg/dL further reduces ASCVD risk without significant adverse events. Among individuals treated with PSCK9i therapy, those with elevated Lp(a) may have greater ASCVD risk reduction and may be a patient population that is prioritized for PCSK9i until therapies directly targeting Lp(a) are available. An ASCVD risk-based approach should be the foundation for determining LDL-C goals with consideration that multiple lipid-lowering therapies are often necessary for high and very-high risk patients who were treated to very low LDL-C in more recent randomized controlled trials. Show less

In the era of the Predicting Risk of Cardiovascular Disease (CVD) EVENTs (PREVENT) equations, recalibrating definitions for low, borderline, intermediate, and high risk will be of primary importance. Similarly, the cardiovascular-kidney-metabolic construct calls for more robust assessment of residual risk among individuals with clinical CVD. Recent observational studies demonstrate long-term prognostic value of LDL-cholesterol, lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (hsCRP) for the prediction of CVD. These findings support prior randomized clinical trial data demonstrating a benefit of primary prevention statin therapy for individuals with elevated hsCRP, and that elevated Lp(a) and hsCRP are associated with residual CVD risk in those with clinical CVD and well-controlled LDL-C. Overall, such evidence supports universal measurement of LDL-C, Lp(a), and, for most patients, hsCRP across the spectrum of CVD to facilitate earlier lifestyle guidance and more precise allocation of preventive pharmacotherapies. Show less

Reciprocal copy-number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD), yet it is not completely penetrant and can manifest in a wide array of phenotypes. To explore its molecular consequences, we performed RNA sequencing of cerebral cortex from mouse models with CNV of the syntenic 7qF3 region and lymphoblast lines from 34 members of 7 multiplex ASD-affected families harboring the 16p11.2 CNV. Expression of all genes in the CNV region correlated well with their DNA copy number, with no evidence of dosage compensation. We observed effects on gene expression outside the CNV region, including apparent positional effects in cis and in trans at genomic segments with evidence of physical interaction in Hi-C chromosome conformation data. One of the most significant positional effects was telomeric to the 16p11.2 CNV and includes the previously described "distal" 16p11.2 microdeletion. Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), transcriptional regulation (e.g., TCF4, SATB2), and intellectual disability (e.g., FMR1, CEP290). However, there were differences between tissues and species, with the strongest effects being consistently within the CNV region itself. Our analyses suggest that through a combination of indirect regulatory effects and direct effects on nuclear architecture, alteration of 16p11.2 genes disrupts expression networks that involve other genes and pathways known to contribute to ASD, suggesting an overlap in mechanisms of pathogenesis. Show less

Structural chromosomal rearrangements occur commonly in the general population. Individuals that carry a balanced translocation are at risk of having unbalanced offspring; therefore, the frequency of translocations in couples with recurrent spontaneous abortions is higher than that in the general population. The constitutional t(11;22) translocation is the most common recurrent non-Robertsonian translocation in humans and may serve as a model to determine the mechanism that causes recurrent meiotic translocations. We previously localized the t(11;22) translocation breakpoint to a region on 22q11 within a low-copy repeat, termed "LCR22." To define the breakpoint on 11q23 and to ascertain whether this region shares homology with LCR22 sequences, we performed haplotype analysis on patients with der(22) syndrome. We found that the breakpoint on 11q23 occurred between two genetic markers, D11S1340 and APOC3-tetra, both being present within a single bacterial-artificial-chromosome clone. To determine whether the breakpoint occurred within the same region among a larger set of carriers, we performed FISH mapping studies. The breakpoints were all within the same clone, suggesting that this region may harbor sequences that are prone to breakage. We narrowed the breakpoint interval, in both derivative chromosomes from two unrelated carriers, to a 190-bp, AT-rich repeat, which indicates that this repeat may mediate recombination events on chromosome 11. Interestingly, the LCR22s harbor AT-rich repeats, suggesting that this sequence motif may mediate recombination events in nonhomologous chromosomes during meiosis. Show less