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Background Triglycerides, cholesterol, and their metabolism are linked due to shared packaging and transport within circulating lipoprotein particles. While a case for a causal role of cholesterol-carrying low-density lipoproteins (LDLs) in atherosclerosis is well made, the body of scientific evidence for a causal role of triglyceride-rich lipoproteins (TRLs) is rapidly growing, with multiple lines of evidence (old and new) providing robust support. Content This review will discuss current perspectives and accumulated evidence that an overabundance of remnant lipoproteins stemming from intravascular remodeling of nascent TRLs—chylomicrons and very low-density lipoproteins (VLDL)—results in a proatherogenic milieu that augments cardiovascular risk. Basic mechanisms of TRL metabolism and clearance will be summarized, assay methods reviewed, and pivotal clinical studies highlighted. Summary Remnant lipoproteins are rendered highly atherogenic by their high cholesterol content, altered apolipoprotein composition, and physicochemical properties. The aggregate findings from multiple lines of evidence suggest that TRL remnants play a central role in residual cardiovascular risk.

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 <0.05). In multivariable models adjusting for body mass index and other traditional VTE risk factors, only the association for homocysteine persisted (HR 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.

BackgroundPathologic angiogenesis is a hallmark of type 2 diabetes mellitus (T2DM) microvascular complications and may modulate adipogenesis and precede the onset of clinical diabetes mellitus; however, longitudinal data are unavailable. Placental growth factor is a potent proangiogenic factor that stimulates the formation of mature and durable vessels but is understudied in human diseases.Methods and ResultsWe conducted a prospective case‐cohort study of baseline placental growth factor and incident T2DM within the WHS (Women's Health Study). A random sample of incident T2DM cases (n=491) occurring over a 15‐year follow‐up period was selected and compared with a reference subcohort (n=561). Case subjects were matched to the reference risk set on 5‐year age groups and race. All subjects in this analysis were required to have a hemoglobin A1c <6.5% at WHS enrollment. Median baseline levels of placental growth factor were higher in case subjects compare to the reference subcohort (18.0 pg/mL versus 17.2 pg/mL) but were only weakly correlated with glycemic measures and not associated with obesity. The risk of diabetes mellitus increased across placental growth factor quartile in the base model (hazard ratios, 1.00, 1.14, 1.46, and 2.14; P‐trend<0.001) and in multivariable‐adjusted models accounting for clinical T2DM risk factors (hazard ratios, 1.00, 1.17, 1.45, and 2.61; P‐trend<0.001). These findings were not substantially altered by further adjustment for high‐sensitivity C‐reactive protein, hemoglobin A1c, or fasting insulin and remained robust in sensitivity analyses excluding those diagnosed within 2 years of enrollment and those with baseline hemoglobin A1c ≥6.0%.ConclusionsElevated placental growth factor levels are associated with future T2DM independent of traditional risk factors, measures of glycemia, insulin resistance, and high‐sensitivity C‐reactive protein. These prospective data suggest that pathologic angiogenesis may occur well before the clinical onset of T2DM and thus may have relevance to vascular complications of this disease.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479.

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Meta-analysis of LDL-C Lowering and MortalityTo The Editor In a meta-analysis by Dr Navarese and colleagues concerning low-density lipoprotein cholesterol (LDL-C) levels and mortality after LDL-C lowering, 1 we identified several potential errors related to trials conducted by our research group.First, in reporting data from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), Navarese and colleagues presented a cardiovascular mortality rate ratio (RR) of 0.53 (95% CI, 0.41-0.69). These values, however, are for the trial end point of myocardial infarction, stroke, or death from cardiovascular disease. 2 The correct published values for confirmed deaths from cardiovascular causes in the rosuvastatin and placebo groups of JUPITER were 35 and 43, respectively, with a corresponding hazard ratio (HR) of 0.82 (95% CI, 0.52-1.27). 3 Second, regarding the Studies of PCSK9 Inhibition and the Reduction of Vascular Events 1 (SPIRE-1) trial, Navarese and colleagues reported a cardiovascular mortality RR of 1.14 (95% CI, 0.80-1.62). The correct published HR was 1.20 (95% CI, 0.74-1.95). 4 Third, Navarese and colleagues reported a cardiovascular mortality RR of 0.91 (95% CI, 0.63-1.32) in the SPIRE-2 trial. The correct published HR was 0.82 (95% CI, 0.50-1.36). 4 The above errors do not reflect differences between RRs and HRs.

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