Blumenthal, Roger S.

Background Hepatocyte growth factor (HGF) is a biomarker with potential for use in the diagnosis, treatment and prognostication of cardiovascular disease (CVD). Elevated HGF is associated with calcification in the coronary arteries. However, knowledge is limited on the role HGF may play in extracoronary calcification (ECC). This study examined whether HGF is associated with ECC in the aortic valve (AVC), mitral annulus (MAC), ascending thoracic aorta and descending thoracic aortic (DTAC). Methods At baseline, adults aged 45–84 years, free of CVD, in the Multi-Ethnic Study of Atherosclerosis had HGF and ECC measured by ELISA and cardiac CT scan, respectively. ECC measurements were repeated after an average of 2.4 years of follow-up. Prevalent ECC was defined as Agatston score >0 at baseline. Incident ECC was defined as Agatston score >0 at follow-up among participants with Agatston score=0 at baseline. We used Poisson and linear mixed-effects regression models to estimate the association between HGF and ECC, adjusted for sociodemographic and CVD risk factors. Results Of 6648 participants, 53% were women. Mean (SD) age was 62 (10) years. Median (IQR) of HGF was 905 (757-1087) pg/mL. After adjustment for CVD risk factors, the highest HGF levels (tertile 3) were associated with greater prevalence and extent of AVC, MAC and DTAC at baseline compared with the lowest tertile (tertile 1). Additionally, the risk of incident AVC and MAC increased by 62% and 45%, respectively, in demographic-adjusted models. However, the associations were not statistically significant in fully adjusted models. The highest HGF levels were also associated with 10% and 13% increase in MAC and DTAC progression, respectively, even after adjustment for CVD risk factors. Conclusion Higher HGF levels were significantly associated with a greater risk of calcification at some extracoronary sites, suggesting an alternate biological pathway that could be targeted to reduce CVD risk.

Introduction: Big data techniques offer a novel opportunity to characterize individuals with extreme phenotypes. In this context, we aimed to describe the prevalence of classical Fredrickson-Levy dyslipidemia phenotypes at the extremes of HDL-C levels in a cross-sectional big data study. Methods: We examined 848,801 U.S. adults and children from the Very Large Database of Lipids 1.0 who were referred for lipoprotein testing from 2009 to 2011. We categorized patients into HDL-C percentile categories (<0.1th, 0.1th to 99th to 99.9th, and >99.9th). We examined the prevalence of Fredrickson-Levy dyslipidemia phenotypes (I, IIa, IIb, III, IV and V) within these categories. We identified those who did not meet criteria for any classical dyslipidemia phenotype as the continuum group. Results: Type I and V were mostly present at extremely low HDL-C levels. Type IIa was more prevalent in high vs. low HDL-C levels. Type III was 2-fold more prevalent in extremely low vs. high HDL-C levels. Type IV was the most prevalent classical dyslipidemia phenotype in our population, and was the most frequent at low HDL-C percentiles. About 50% of the extremely low and 90% of the extremely high HDL-C levels were classified into the continuum group. Conclusion: In our cross-sectional big data analysis, there was a significantly higher prevalence of most classical dyslipidemia phenotypes at extremely low HDL-C compared with extremely high HDL-C levels. Only types I and V were more prevalent in extreme groups than general population. To some extent, very low HDL-C levels may be determined by inheritable, highly atherogenic dyslipidemias.

Abstract Aim The 2018 American Heart Association/American College of Cardiology/Multi-Society Cholesterol Guidelines recommended the addition of non-statins to statin therapy for high-risk secondary prevention patients above a low-density lipoprotein cholesterol (LDL-C) threshold of ≥70 mg/dL (1.8 mmol/L). We compared effectiveness and safety of treatment to achieve lower (&lt;70) vs. higher (≥70 mg/dL) LDL-C among patients receiving intensive lipid-lowering therapy (statins alone or plus ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors). Methods and results Eleven randomized controlled trials (130 070 patients), comparing intensive vs. less-intensive lipid-lowering therapy, with follow-up ≥6 months and sample size ≥1000 patients were selected. Meta-analysis was reported as random effects risk ratios (RRs) [95% confidence intervals] and absolute risk differences (ARDs) as incident cases per 1000 person-years. The median LDL-C levels achieved in lower LDL-C vs. higher LDL-C groups were 62 and 103 mg/dL, respectively. At median follow-up of 2 years, the lower LDL-C vs. higher LDL-C group was associated with significant reduction in all-cause mortality [ARD −1.56; RR 0.94 (0.89–1.00)], cardiovascular mortality [ARD −1.49; RR 0.90 (0.81–1.00)], and reduced risk of myocardial infarction, cerebrovascular events, revascularization, and major adverse cardiovascular events (MACE). These benefits were achieved without increasing the risk of incident cancer, diabetes mellitus, or haemorrhagic stroke. All-cause mortality benefit in lower LDL-C group was limited to statin therapy and those with higher baseline LDL-C (≥100 mg/dL). However, the RR reduction in ischaemic and safety endpoints was independent of baseline LDL-C or drug therapy. Conclusion This meta-analysis showed that treatment to achieve LDL-C levels below 70 mg/dL using intensive lipid-lowering therapy can safely reduce the risk of mortality and MACE.

Abstract We tested whether the association between bone mineral density (BMD) and coronary artery calcification (CAC) varies according to dyslipidemia in community-living individuals. Between 2002 and 2005, 305 women and 631 men (mean age of 64 years), who were not taking lipid-lowering medications or estrogen were assessed for spine BMD, CAC, and total (TC), HDL- and LDL-cholesterol and triglycerides. Participants were a random sample from the Multi-Ethnic Study of Atherosclerosis (MESA) without clinical cardiovascular disease. Spine BMD at the L3 vertebrate was performed by computer tomography (CT). CAC prevalence was measured by CT. The total cholesterol to HDL ratio (TC:HDL) ≥ 5.0 was used as the primary marker of hyperlipidemia. The association of BMD with CAC differed in women with TC:HDL &lt; 5.0 versus higher (p-interaction = 0.01). In age- and race-adjusted models, among women with TC:HDL &lt; 5.0, each SD (43.4 mg/cc) greater BMD was associated with a 25% lower prevalence of CAC (prevalence ratio [PR] 0.75, 95% confidence interval [CI] 0.63–0.89), whereas among women with higher TC:HDL, higher BMD was not significantly associated with CAC (PR 1.22, 95% CI 0.82–1.82). Results were similar using other definitions of hyperlipidemia. In contrast, no consistent association was observed between BMD and CAC in men, irrespective of the TC:HDL ratio (p interaction 0.54). The inverse association of BMD with CAC is stronger in women without dyslipidemia. These data argue against the hypothesis that dyslipidemia is the key factor responsible for the inverse association of BMD with atherosclerosis. © 2011 American Society for Bone and Mineral Research