Jeremiah Stamler was born in 1919 in New York City, the son of George Stamler, a dentist, and Rose Baras Stamler, a school teacher. Both of his parents were Russian Jews and immigrants from Russia. He was raised in West Orange, New Jersey, where the family moved when he was six months old. He attended the Columbia University in New York as an undergraduate and the Long Island College Hospital Medical School, now SUNY Downstate Medical Center. Jerry has stated that his research career began in 1946 when he read papers claiming that diet had no effect on serum cholesterol levels. He did not accept this concept and set out to disprove it over his subsequent career. After the Army service, he became a research associate with Louis Katz in the laboratories of Michael Reese Hospital in Chicago. He and Katz worked for years on the interactions of diet, hormones, blood pressure and lipids in experimental vascular disease, producing a classic monograph in 1958: "Experimental Atherosclerosis". His first epidemiological pursuit was an article on trends in vascular mortality. In his first clinical trial, he administered estrogens to men post-infarction, resulting in a dramatic example of unintended (negative) consequences. Jerry moved to the Chicago Board of Health in 1958, where he set up the first Heart Disease Control Program (later the Chronic Disease Control Division). One of us (A.M. G.) first met Jerry in 1972 at the venerable Passavant Hospital in downtown Chicago. This site visit provided an insight into Jerry's intellect, diligence, and ability to defend his ideas. Some of these were in conflict with the staff of the National Heart Lung and Blood Institute, but Jerry held firm. Jerry had previously shown his courage and ability to defend his views when he testified before the United States House of Representatives Committee on Unamerican Activities. This committee, which investigated and summoned suspected Communists, accused Jerry of having Communist ties. The government pursued legal measures against him after he walked out of the congressional hearing. Jerry sued the US government. Both the US government and Jerry later dropped their suits, and the matter was settled. This episode showed that Jerry never wavered on what he believed was right and that his integrity and principles were impeccable. In 1972, he was appointed chair of the newly formed Department of Community Health and Preventive Medicine at the Feinberg School of Medicine at Northwestern University. In the 1970s, he launched the largest study he would ever conduct. This was called the Multiple Risk Factor Intervention Trial (MRFIT) and was a multicenter institution studying the effect of serum cholesterol, blood pressure, and cigarette smoking on coronary heart disease mortality. When the study was published after 6 years, the results showed that cholesterol had a graded relationship with coronary heart disease mortality, beginning at cholesterol levels as low as 160 mg per dL (4 mmol/L). This study essentially abolished the concept of cholesterol risk had a threshold level. The relationship was deemed to be continuous, graded, and strong, and was actually reconfirmed after a 25-year follow-up after the end of the trial. During the 1970s and 1980s, his group took part in observational epidemiologic studies. His work, along with that of the Framingham study, led to the coining of the concept of the "risk factor" for cardiovascular disease. Jerry later collaborated on international studies of salt, protein, and other nutrients and risk of hypertension. He became an Emeritus Professor and remained active into an advanced age. In the authors' opinions, Jerry deserves to be called the "Father of Preventative Cardiology". Jerry married Rose Steinberg (1922–1998), a sociologist, in 1942; they worked together on cardiovascular research until her death in 1998. They had one son, Paul J. Stamler (b. 1950). In 2004, Stamler married Gloria Brim Beckerman, a childhood friend, the widow of the scholar Bernard Beckerman. Gloria died in April 2021. In his 90s, Jerry was involved in the study of the effects of sodium on blood pressure. Amazingly, he had his NIH grant renewed at age 102, an event that made him extremely happy as he shared the news with his good friends. Jerry developed a huge international friendship. He and Rose spent a great deal of time enjoying the coast of Italy, often together with Italian friends and colleagues. He was particularly in love with Italy. Jerry was bestowed multiple honors and awards. After reaching 102, Jerry's health began to diminish. The fact that he lived quite healthily until 102 years certainly bears the testimony that Jeremiah Stamler walked the walk as well as talked the talk. The two authors remember him fondly and share many happy memories of being with him. His legacy will long live and his MRFIT study was a major contributor to the launching of the National Cholesterol Education program of the National Institutes of Health, as well as the joint European Society of Cardiology and European Atherosclerosis Society Guidelines for Management of Dyslipidemias.

Introduction: LDL-C reduction by statins is the mainstay pharmacologic strategy for ASCVD risk reduction. Despite adherence, some patients fail to achieve LDL-C goals, a phenomenon known as statin resistance. Current LDL-C assays include cholesterol content on both lipoprotein(a) [Lp(a)] and LDL particles. Because statins do not lower Lp(a), Lp(a)-cholesterol may represent a statin insensitive pool within LDL-C. Hypothesis: Elevated Lp(a) contributes to statin resistance in patients treated with high-intensity statin therapy. Methods: A secondary analysis was performed on 2338 patients from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, randomized to receive atorvastatin 80mg or placebo; baseline and week 16 lipid parameters were analyzed. Results: In the atorvastatin group (n = 1092), mean (SD) baseline LDL-C, absolute LDL-C reduction, median percent LDL-C change from baseline (IQR), and Lp(a) were 123.8 (33.5) mg/dL, 52.2 (36.7) mg/dL, -47.6% (-59.1- -29.9%), and 10.6 (5.1-29.1) mg/dL, respectively. Median (IQR) baseline Lp(a) was higher [12.1 (5.9-38.1) vs 9.2 (4.4-22.4) mg/dL, p < 0.001] in patients with attenuated percent LDL-C reduction compared to group median. The median percent LDL-C reduction on atorvastatin was 42.3% (24.3-52.5%) in patients with baseline Lp(a) between 50 - 99 mg/dL, and 32.6% (11.5-43.7%) with Lp(a) > 100 mg/dL prevalent in ~10% of the population, both significantly attenuated compared to patients with Lp(a) <30 mg/dL (50.4% [33.3-61.1%]), p < 0.001. An LDL-C target of 70 mg/dL or less was achieved in 62.3% of patients with baseline Lp(a) <30 mg/dL, compared to 55.2%, 43.3%, and 24.1% of those with Lp(a) 30 - 49 mg/dL, 50 - 99 mg/dL, and > 100 mg/dL (p < 0.001), respectively [Figure 1]. Conclusions: Elevated Lp(a) is associated with statin resistance and may identify patients who require additional or more potent lipid lowering therapies to achieve LDL-C goals.

Two prospective epidemiological studies have pointed to the importance of triglyceride rich lipoproteins in causing atherosclerosis. Lipoprotein analyses show that it is the cholesterol content of the lipoproteins that relates to atherosclerotic cardiovascular disease. As high blood levels of these lipoproteins are mostly seen in obese people changes in lifestyle seem to be the most relevant therapeutic measure.

Holmes, Michael V; Simon, Tabassome; Exeter, Holly J; Folkersen, Lasse; Asselbergs, Folkert W; Guardiola, Montse; Cooper, Jackie A; Palmen, Jutta; Hubacek, Jaroslav A; Carruthers, Kathryn F; +103 more... Horne, Benjamin D; Brunisholz, Kimberly D; Mega, Jessica L; van Iperen, Erik PA; Li, Mingyao; Leusink, Maarten; Trompet, Stella; Verschuren, Jeffrey JW; Hovingh, G Kees; Dehghan, Abbas; Nelson, Christopher P; Kotti, Salma; Danchin, Nicolas; Scholz, Markus; Haase, Christiane L; Rothenbacher, Dietrich; Swerdlow, Daniel I; Kuchenbaecker, Karoline B; Staines-Urias, Eleonora; Goel, Anuj; van ’t Hooft, Ferdinand; Gertow, Karl; de Faire, Ulf; Panayiotou, Andrie G; Tremoli, Elena; Baldassarre, Damiano; Veglia, Fabrizio; Holdt, Lesca M; Beutner, Frank; Gansevoort, Ron T; Navis, Gerjan J; Mateo Leach, Irene; Breitling, Lutz P; Brenner, Hermann; Thiery, Joachim; Dallmeier, Dhayana; Franco-Cereceda, Anders; Boer, Jolanda MA; Stephens, Jeffrey W; Hofker, Marten H; Tedgui, Alain; Hofman, Albert; Uitterlinden, André G; Adamkova, Vera; Pitha, Jan; Onland-Moret, N Charlotte; Cramer, Maarten J; Nathoe, Hendrik M; Spiering, Wilko; Klungel, Olaf H; Kumari, Meena; Whincup, Peter H; Morrow, David A; Braund, Peter S; Hall, Alistair S; Olsson, Anders G; Doevendans, Pieter A; Trip, Mieke D; Tobin, Martin D; Hamsten, Anders; Watkins, Hugh; Koenig, Wolfgang; Nicolaides, Andrew N; Teupser, Daniel; Day, Ian NM; Carlquist, John F; Gaunt, Tom R; Ford, Ian; Sattar, Naveed; Tsimikas, Sotirios; Schwartz, Gregory G; Lawlor, Debbie A; Morris, Richard W; Sandhu, Manjinder S; Poledne, Rudolf; Maitland-van der Zee, Anke H; Khaw, Kay-Tee; Keating, Brendan J; van der Harst, Pim; Price, Jackie F; Mehta, Shamir R; Yusuf, Salim; Witteman, Jaqueline CM; Franco, Oscar H; Jukema, J Wouter; de Knijff, Peter; TybjaergHansen, Anne; Rader, Daniel J; Farrall, Martin; Samani, Nilesh J; Kivimaki, Mika; Fox, Keith AA; Humphries, Steve E; Anderson, Jeffrey L; Boekholdt, S Matthijs; Palmer, Tom M; Eriksson, Per; Paré, Guillaume; Hingorani, Aroon D; Sabatine, Marc S; Mallat, Ziad; Casas, Juan P; Talmud, Philippa J; (2013) Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study. Journal of the American College of Cardiology, 62 (21). pp. 1966-1976. ISSN 0735-1097 DOI: https://doi.org/10.1016/j.jacc.2013.06.044

OBJECTIVE Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4–12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random). RESULTS At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68–0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for >= 3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C >= 100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; P-interaction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for >= 3 years, if baseline LDL-C is >= 100 mg/dL, or if achieved LDL-C is low.

Background and Aims: Elevated lipoprotein(a) has been established as a risk factor for cardiovascular disease in the general population, but its relevance in patients under statin therapy is uncertain.

Background High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). Methods The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. Results Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P =.81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. Conclusions Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.

Abstract Background Among patients with acute coronary syndrome (ACS) who do not have diabetes, incident diabetes is common and associated with an adverse prognosis. Some data suggest that high density lipoprotein (HDL) has favourable effects on beta cell function and that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes in conjunction with increased HDL cholesterol (HDL-C) concentration. Dalcetrapib is a CETP inhibitor under ongoing evaluation as a potential cardiovascular therapy. Purpose We compared the effect of treatment with dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome (ACS). Methods In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg or placebo daily, beginning 4–12 weeks after ACS. Absence of diabetes at baseline was based upon medical history, no use of diabetes medication, haemoglobin A1c <6.5%, and plasma glucose level <7 mmol/L (if measured under fasting conditions) or <11.1 mmol/L (if measured under non-fasting conditions). Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, use of a diabetes medication, HbA1c ≥6.5%, or two measurements of plasma glucose ≥7 mmol/L (fasting) or ≥11.1 mmol/L (non-fasting). The association of incident diabetes with baseline and on-treatment HDL-C was determined. Results At baseline, 10621 patients (67% of the trial cohort) did not have diabetes and formed the analysis cohort. Over median follow-up of 31 months, incident diabetes was identified in 392 of 5314 patients (7.4%) assigned to dalcetrapib and 505 of 5307 (9.5%) assigned to placebo (odds ratio [OR] 0.76; 95% confidence interval [CI] 0.66–0.87; P<0.001). This corresponds to an absolute reduction in incident diabetes of 2.1%, and a need to treat 47 patients (for 31 months) to prevent 1 case of diabetes. Kaplan-Meier estimates of the cumulative incidence of diabetes are shown in the Figure. Across both treatment groups, incident diabetes was inversely associated with baseline HDL-C (OR 0.98 for 1 mg/dL increase in baseline HDL-C; 95% CI 0.97–0.98, P<0.001). In the dalcetrapib group, there was a further inverse association of incident diabetes with the change in HDL-C on assigned treatment (OR 0.98 for 1 mg/dL increase in HDL-C from baseline; 95% CI 0.97–0.99, P=0.002). Dalcetrapib was safe and generally well-tolerated in the trial. Conclusions In patients with recent ACS who do not have diabetes at baseline, incident diabetes is common. Dalcetrapib treatment reduced the relative risk of incident diabetes by 24% and the absolute risk by 2.1% over a median of 31 months. The reduction in incident diabetes with dalcetrapib was associated with increased HDL-C on treatment. Acknowledgement/Funding The dal-OUTCOMES trial was funded by F. Hoffmann LaRoche

BACK GROUND Data on PCSK9 inhibition in chronic kidney disease (CKD) is limited. OBJECTIVES The purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function. METHODS The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) >= 70 mg/dl or non-high-density lipoprotein cholesterol >= 100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate. RESULTS There were 8,077 patients with preserved kidney function, 15,034 with stage 2 CKD, and 4,443 with >= stage 3 CKD. LDL-C reduction with evolocumab compared with placebo at 48 weeks was similar across CKD groups at 59%, 59%, and 58%, respectively. Relative risk reduction for the primary endpoint was similar for preserved function (hazard ratio [HR]: 0.82; 95% CI: 0.71 to 0.94), stage 2 (HR: 0.85; 95% CI: 0.77 to 0.94), and stage >= 3 CKD (HR: 0.89; 95% CI: 0.76 to 1.05); p(int) = 0.77. Relative risk reduction for the secondary endpoint was similar across CKD stages (p(int) = 0.75)-preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage >= 3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were -2.5% (95% CI: -0.4% to -4.7%) for stage >= 3 CKD compared with -1.7% (95% CI: 0.5% to -2.8%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage. CONCLUSIONS LDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (C) 2019 by the American College of Cardiology Foundation.

Drugs to raise HDL cholesterol (HDL-C) have generally failed to decrease major adverse cardiovascular events (MACE). HDL particle concentration (HDLP) has been proposed as a better predictor of MACE than HDL-C. We determined whether HDLP is associated with risk of MACE after acute coronary syndrome

Background Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. Methods Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and >= 50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. Findings Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1.04 (95% CI 0.91-1.18) for 15 mg/dL to less than 30 mg/dL, 1.11 (1.00-1.22) for 30 mg/dL to less than 50 mg/dL, and 1.31 (1.08-1.58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0.94 (0.81-1.10), 1.06 (0. 94-1.21), and 1.43 (1.15-1.76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0.010) and was more pronounced at younger ages (interaction p=0.008) without effect-modification by any other patient-level or study-level characteristics. Interpretation In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

This study sought to investigate the role of secretory phospholipase A 2 (sPLA 2 )-IIA in cardiovascular disease. Background Higher circulating levels of sPLA 2 -IIA mass or sPLA 2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA 2 inhibitor (varespladib) was stopped prematurely for lack of ef fi cacy. We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA 2 -IIA isoenzyme, as an instrumental variable. PLA2G2A rs11573156 C allele associated with lower circulating sPLA 2 -IIA mass (38% to 44%) and sPLA 2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% con fi dence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA 2 -IIA mass was 1.04 (95% CI:

BackgroundAldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. Methods and ResultsTo address this question, we examined data from the dal‐OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF <40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitalization for HF was a secondary endpoint. Over a median follow‐up of 37 months, the primary outcome occurred in 366 patients (9.0%), and hospitalization for HF occurred in 72 patients (1.8%). There was no association between aldosterone and either the time to first occurrence of a primary outcome (hazard ratio for doubling of aldosterone 0.92, 95% confidence interval 0.78‐1.09, P=0.34) or hospitalization for HF (hazard ratio 1.38, 95% CI 0.96‐1.99, P=0.08) in Cox regression models adjusted for covariates. ConclusionsIn patients with recent acute coronary syndrome but without advanced HF, aldosterone does not predict major cardiovascular events. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00658515.

Importance It is uncertain whether lipoprotein(a) [Lp(a)], which is associated with incident cardiovascular disease, is an independent risk factor for recurrent cardiovascular events after acute coronary syndrome (ACS). Objective To determine the association of Lp(a) concentration measured after ACS with the subsequent risk of ischemic cardiovascular events. Design, Setting, and Participants This nested case-cohort analysis was performed as an ad hoc analysis of the dal-Outcomes randomized clinical trial. This trial compared dalcetrapib, the cholesteryl ester transfer protein inhibitor, with placebo in patients with recent ACS and was performed between April 2008 and September 2012 at 935 sites in 27 countries. There were 969 case patients who experienced a primary cardiovascular outcome, and there were 3170 control patients who were event free at the time of a case event and had the same type of index ACS (unstable angina or myocardial infarction) as that of the respective case patients. Concentration of Lp(a) was measured by immunoturbidimetric assay. Data analysis for this present study was conducted from June 8, 2016, to April 21, 2017. Interventions Patients were randomly assigned to receive treatment with dalcetrapib, 600 mg daily, or matching placebo, beginning 4 to 12 weeks after ACS. Main Outcomes and Measures Death due to coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization for unstable angina, or resuscitated cardiac arrest), or fatal or nonfatal ischemic stroke. Results The mean (SD) age was 63 (10) years for the 969 case patients and 60 (9) years for the 3170 control patients, and both cohorts were composed of predominantly male (770 case patients [79%] and 2558 control patients [81%]; P = .40) and white patients (858 case patients [89%] and 2825 control patients [89%]; P = .62). At baseline, the median (interquartile range) Lp(a) level was 12.3 (4.7-50.9) mg/dL. There was broad application of evidence-based secondary prevention strategies after ACS, including use of statins in 4030 patients (97%). The cumulative distribution of baseline Lp(a) levels did not differ between cases and controls at P = .16. Case-cohort regression analysis showed no association of baseline Lp(a) level with risk of cardiovascular events. For a doubling of Lp(a) concentration, the hazard ratio (case to control) was 1.01 (95% CI, 0.96-1.06; P = .66) after adjustment for 16 baseline variables, including assigned study treatment. Conclusions and Relevance For patients with recent ACS who are treated with statins, Lp(a) concentration was not associated with adverse cardiovascular outcomes. These findings call into question whether treatment specifically targeted to reduce Lp(a) levels would thereby lower the risk for ischemic cardiovascular events after ACS. Trial Registration clinicaltrials.gov Identifier: NCT00658515

Introduction: Alkaline phosphatase (AP) may promote progression of atherosclerosis and vascular calcification. Like high sensitivity C-reactive protein (hsCRP), AP is also an inflammatory marker an...

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Author(s): Rosenson, Robert S; Larrey, Dominique; Waters, David D; Olsson, Anders G; Members of the Phase 3 Data Monitoring Committee for PRALUENT