Aruna Das Pradhan

Background: Traditional cardiovascular risk assessment entails investigator‐defined exposure levels and individual risk markers in multivariable analysis. We sought to determine whether an alternative unbiased learning analysis might provide further insights into vascular risk. Methods: We conducted an unsupervised learning (k‐means cluster) analysis in the Women's Health Study (N=26 443) using baseline levels of triglycerides, high‐sensitivity C‐reactive protein, and low‐density lipoprotein cholesterol to form novel exposures. We then evaluated cluster‐based risk of incident coronary, cerebrovascular, and limb events using the Kaplan–Meier method and multivariable Cox models, followed by comparison with established clinical biomarker thresholds. Finally, we illustrated clinical applicability to a nonvascular outcome (type 2 diabetes). Results: Four clusters emerged and were named according to aggregate biomarker profiles: Cluster 1 (“healthy,” n=12 101), cluster 2 (“hypercholesterolemic,” n=7424), cluster 3 (“inflammatory,” n=5056), and cluster 4 (“triglyceride‐rich,” n=1862). Triglyceride‐rich cluster identity conferred the highest risk of future cardiovascular events (adjusted hazard ratio [HR _adj ], 2.24 [95% CI, 1.93–2.60]) compared with those in the healthy cluster (reference group). Risk was intermediate in the hypercholesterolemic (predominantly elevated low‐density lipoprotein cholesterol) and inflammatory (predominantly elevated high‐sensitivity C‐reactive protein) clusters (HR _adj , 1.44 [95% CI, 1.28–1.61]; and 1.54 [95% CI, 1.35–1.75], respectively). Clustering yielded stronger total cardiovascular disease risk associations than traditionally defined mixed dyslipidemia with modest improvement in reclassification statistics. Cluster identities also predicted incident type 2 diabetes, with the greatest risk among the triglyceride‐rich cluster (HR _adj , 3.78 [95% CI, 3.29–4.35]). Conclusions: Unsupervised learning analyses demonstrated associations that may be useful when refining cardiovascular risk and may inform atherosclerosis development in healthy individuals better than traditional classification methods. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT00000479.

Background: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk. Methods: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies. Results: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; P =0.003) and CAD (marginal inclusion probability, 0.92; P =0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84–0.91]; P =9×10 ⁻¹⁰ ) and CAD (odds ratio,0.66 [95% CI, 0.63–0.69]; P =4×10 ⁻⁷³ ), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29–4.60]; P −6 ). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; P =2.3×10 ⁻⁴ ), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; P =0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 [95% CI, 1.03–1.04]; P =1.0×10 ⁻³³ ). Conclusions: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.

Objective: Case-control studies have identified plasma homocysteine as a risk marker for venous thromboembolism (VTE). Prospective data, particularly among women, are sparse. We examined whether plasma homocysteine associates with incident VTE in 2 large prospective cohorts of women. Approach and Results: In the WHS (Women’s Health Study), a prospective cohort study of 27 555 women ≥45 years old and free of cardiovascular disease and VTE, we assessed baseline homocysteine concentration along with other thrombotic biomarkers for association with future VTE (n=743), pulmonary embolism (n=363), and deep vein thrombosis (n=545). We used a second cohort of 2672 women (n=102 VTE events) in the WAFACS (Women’s Antioxidant and Folic Acid Cardiovascular Study) to corroborate our findings. In age-adjusted analyses, elevated homocysteine, hsCRP (high-sensitivity C-reactive protein), fibrinogen, and sICAM-1 (soluble intercellular adhesion molecule-1) were associated with incident VTE ( P for extreme quartile comparisons and P -trend Q4 , 1.31 [95% CI, 1.06–1.63]). Elevated homocysteine levels were associated with unprovoked pulmonary embolism (HR _Q4 , 2.13 [95% CI, 1.30–3.51]) and deep vein thrombosis (HR _Q4 , 1.59 [95% CI, 1.05–2.40]) but not provoked events. In WAFACS, elevated homocysteine levels were also associated with VTE events ( P -trend 0.023). Conclusions: Higher plasma homocysteine levels associate with VTE events in 2 cohorts of middle-aged and older women. Among VTE subtypes, homocysteine was associated with unprovoked, but not provoked, events. These data suggest a plausible biological role for homocysteine in the development of VTE. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00000479, NCT00000541.

The cardiovascular community has been debating for decades whether to treat mild-tomoderate hypertriglyceridemia. Results of the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT)1 position this controversy as front matter for deliberation. For lipid experts, dominating the discourse will be the strength of experimental evidence, mechanism of benefit, identification of treatment response parameters, and prioritizing treatment options. For the practitioner, the question ultimately will be whether potential gains are worth the disruption to clinical care that accompanies a new paradigm in prevention.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.