Author Interviews, CDC, JAMA, Lipids, Nutrition / 02.12.2016 Interview with: Asher Rosinger, PHD, MPH Epidemic Intelligence Service Officer, Centers for Disease Control and Prevention Division of Health and Examination Nutrition Examination Surveys, Analysis Branch National Center for Health Statistic What is the background for this study? Response: Total cholesterol, triglycerides, and low-density lipoprotein (LDL) levels are linked to coronary heart disease and cardiovascular events. Between 1999 and 2010, total cholesterol, triglycerides, and LDL levels declined among U.S. adults. We used new data from the 2011-2014 nationally representative National Health and Nutrition Examination Survey (NHANES) to determine if earlier trends continued. (more…)
Author Interviews, Genetic Research, Lipids, NEJM / 01.12.2016 Interview with: Brian A. Ference, M.D Division of Cardiovascular Medicine Wayne State University School of Medicine Detroit, MI What are the main findings? Response: Lifelong exposure to modestly lower plasma LDL-C levels caused by rare loss-of-function mutations in the PCSK9 gene is associated with a substantially lower lifetime risk of developing cardiovascular disease. This discovery motivated the development of monoclonal antibodies directed against PCSK9 which have now been shown to reduce plasma LDL-C levels by 50-60%. The cardiovascular medicine community is early anticipating the results of two large cardiovascular outcome trials that will determine if lowering LDL-C levels by inhibiting PCSK9 will reduce the risk of cardiovascular events. Because monoclonal antibodies and other therapies directed against PCSK9 are designed to recapitulate the phenotype of PCSK9 loss-of-function mutations, we reasoned that it may be possible to anticipate the efficacy and safety results of the ongoing cardiovascular outcome studies by more precisely characterizing the effect of genetic variants in the PCSK9 gene on the risk of both cardiovascular events and new onset diabetes. To do this, we a constructed genetic score consisting of multiple independently inherited variants in the PCK9 gene to create an instrument that mimics the effect of PCSK9 inhibitors. We then compared the effect of genetic variants that mimic the effect of PCSK9 inhibitors with the effect of genetic variants in the HMGCR gene that mimic the effect of statins to make inferences about the likely effect of PCSK9 inhibitors on the risk of cardiovascular events and new onset diabetes as compared to treatment with a statin. (more…)
Author Interviews, Heart Disease, Lipids, NEJM, Pharmacology / 14.11.2016 Interview with: Kevin Fitzgerald, Ph.D. Alnylam Pharmaceuticals Cambridge, MA 02142 What is the background for this study? Response: Inclisiran (ALN-PCSsc) is a subcutaneously administered RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia. The Phase 1 trial of inclisiran was conducted in the U.K. as a randomized, single-blind, placebo controlled, single ascending-and multi-dose, subcutaneous dose-escalation study in 69 volunteer subjects with elevated baseline LDL-C (≥ 100 mg/dL). The primary objective of the study was to evaluate the safety, side effect profile, and pharmacodynamics effects of inclisiran. (more…)
Author Interviews, Gastrointestinal Disease, JAMA, Lipids / 09.11.2016 Interview with: Borge G. Nordestgaard, MD, DMSc Professor, University of Copenhagen Chief Physician, Dept. Clinical Biochemistry, Herlev and Gentofte Hospital Copenhagen University Hospital Herlev, Denmark What is the background for this study? What are the main findings? Response: Acute pancreatitis is an inflammatory disorder of the pancreas with gallstones and high-alcohol consumption as leading risk factors, while mild-to-moderately increased plasma triglycerides hitherto has been overlooked. We surprisingly found that the risk of developing acute pancreatitis was increased already from triglycerides of 175 mg/dL (2 mmol/L) and above. When triglycerides were above 443mg/dL (5mmol/L) the risk was increased a massive 9-fold. Interestingly, this risk was higher than the corresponding 3.4-fold higher risk for myocardial infarction. (more…)
Author Interviews, Lipids, Pharmacology / 23.08.2016 Interview with: Prof. Dr. Ioana Gouni-Berthold MD Center for Endocrinology, Diabetes and Preventive Medicine (ZEDP) University of Cologne Cologne, Germany What is the background for this study? Response: In Europe, up to half of the population aged between 35 and 64 has hypercholesterolemia (high levels of low-density lipoprotein cholesterol [LDL-C]), putting them at risk of heart disease. Despite increased treatment rates in recent years, many patients still do not receive adequate therapy, and heart disease remains the biggest cause of death in the USA and most European countries. Two drugs, alirocumab and evolocumab, have recently been approved for lowering LDL-C in patients with hypercholesterolaemia as an ‘add-on’ therapy to other lipid-lowering medication, or for use alone in patients unable to tolerate statins. These drugs have a unique mode of action– they inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that binds to LDL receptors and targets them for degradation. In the absence of PCSK9, the LDL receptor recycling is restored and the receptors are able to remove LDL from the blood. Both alirocumab and evolocumab have been tested in numerous patient populations in phase 3 trials; albeit evolocumab has an additional indication of homozygous familial hypercholesterolemia. We therefore felt that there was a need to collate the available data to assess the efficacy and safety of each agent. We chose reduction in LDL-C as our outcome of interest, because this was the primary endpoint of the pivotal clinical trials. (more…)
Author Interviews, Heart Disease, JAMA, Lipids, Nutrition, Omega-3 Fatty Acids / 18.08.2016 Interview with: David Iggman, MD, PhD Unit for Clinical Nutrition and Metabolism Department of Public Health and Caring Sciences Uppsala University, Uppsala Center for Clinical Research Dalarna Falun, Sweden What is the background for this study? What are the main findings? Response: There is some controversy regarding which dietary fats are preferable and in what amounts, not least regarding the polyunsaturated fats. It is also challenging to adequately assess peoples intakes of dietary fats. The main findings of this study was that among fatty acids in the body (reflecting the intake during the last year or so), linoleic acid (omega-6) was associated with lower mortality in 71-year-old men with 15 years follow-up. (more…)
Author Interviews, JAMA, Lipids / 16.08.2016 Interview with: Dr. David Grossman M.D., M.P.H. Vice chair of the U.S. Preventive Services Task Force and Professor at the University of Washington Schools of Public Health and Medicine What is the background for this recommendation? Response: The Task Force recognizes the importance of cardiovascular health for young people. Children and adolescents with high cholesterol are more likely to become adults with high cholesterol, and high cholesterol in adulthood can lead to serious health outcomes such as heart attacks and strokes. However, when the Task Force reviewed evidence for cholesterol screening in children and adolescents without any signs or symptoms, we found that there is not enough evidence to recommend for or against screening. In the face of unclear evidence, the Task Force is calling on the research community to prioritize studies on screening and treatment of lipid disorders in children and teens to help us all learn more about the impact that screening at an early age may have on the cardiovascular health of adults. (more…)
Author Interviews, Heart Disease, Lipids / 14.08.2016 Interview with: Ziyad Al-Aly, MD, FASN Assistant Professor of Medicine Washington University School of Medicine Co-Director, Clinical Epidemiology Center Associate Chief of Staff for Research and Education Veterans Affairs Saint Louis Health Care System What is the background for this study? What are the main findings? Response: I think the most important, and novel finding is that elevated levels of HDL-cholesterol (which is thought of as the good cholesterol) are associated with increased risk of death. Previously it was thought that high HDL (increased good cholesterol) is a good thing. We used Big Data approach (over 16 million person-years; 1.7 million people followed for over 9 years) to evaluate the relationship between HDL-Cholesterol (the good cholesterol) and risk of death. We found that low HDL is associated with increased risk of death (which is expected and consistent with prior knowledge). The novel and unexpected finding is the observation that high HDL-Cholesterol is also associated with increased risk of death. The relationship between HDL-Cholesterol levels and risk of death is a U-shaped curve where risk is increased at both ends of the HDL-C values spectrum (at both low and high end); Too low and too high is associated with higher risk of death. The findings may explain why clinical trials aimed at increasing HDL-Cholesterol levels failed to show improvement of clinical outcomes. This finding was not expected, and has not been reported previously in large epidemiologic studies such as Framingham Heart Study and others. The Framingham Heart study and others significantly advanced our understanding of the relationship between cholesterol parameters (including HDL-Cholesterol) and clinical outcomes. However, these studies are limited in that the number of patients in these cohorts was several thousands which is relatively small compared to what a Big Data approach (millions of patients) enables us to see. Big Data approach allows a more nuanced (a more detailed) examination of the relationship between HDL and risk of death across the full spectrum of HDL levels. (more…)
Author Interviews, JAMA, Lipids, Pediatrics / 10.08.2016 Interview with: Paula Lozano, MD MPH Associate Medical Director, Research and Translation Group Health Physicians Senior Investigator Group Health Research Institute Metropolitan Park East Seattle, WA 98101 What is the background for this study? Response: This wasn’t a study, but rather a study of studies, to support the US Preventive Services Task Force in updating its previous recommendation of I: insufficient to assess the balance of benefits and harms. We conducted two systematic evidence reviews of screening children and adolescents: 1. for familial hypercholesterolemia (FH, a genetic disorder that interferes with the body’s ability to metabolize cholesterol and can result in early coronary heart disease); and 2. for multifactorial dyslipidemia—which we defined as elevated LDL cholesterol or total cholesterol, not caused by familial hypercholesterolemia. LDL and total cholesterol were of interest because they are considered atherogenic. One of the challenges of lipid screening in youth is that blood levels of these atherogenic lipids are known to fluctuate during the course of childhood and adolescence. It’s sort of a W-shaped curve, with a peak at age 9-11 years. So for a given child, the definition of what’s an elevated LDL or total cholesterol level will change with age. Also, two-thirds of kids identified as having high cholesterol through universal screening would not go on to have high cholesterol as adults. (more…)
Author Interviews, Diabetes, Lipids, PLoS / 20.07.2016 Interview with: Dr. Fumiaki Imamura Ph.D. MRC Epidemiology Unit University of Cambridge What is the background for this study? What are the main findings? Response: There was insufficient evidence for effects of polyunsaturated fatty acids (PUFA) intake or blood biomarkers on the development of type 2 diabetes. For instance, previous studies using PUFA biomarkers had a maximum of only 673 type 2 diabetes cases. In the EPIC-InterAct Study - a large European collaborative, prospective study where 12,132 diabetes cases were ascertained during its follow-up - we found diverse associations of blood levels of different types of PUFAs with incidence of type 2 diabetes. Despite this diversity, clinically relevant results were observed for major polyunsaturated fatty acids. Higher blood levels of total omega-6 PUFAs and the major omega-6 PUFA (linolenic acid) were associated with a lower risk of developing type 2 diabetes. Likewise, levels of alpha linolenic acid, known as a plant-origin omega-3 PUFA, were associated with lower type 2 diabetes risk. Marine-origin omega-3 PUFAs, including docosahexaenoic acid (DHA), showed inconsistent associations with type 2 diabetes risk. (more…)
AHA Journals, Author Interviews, Heart Disease / 18.07.2016 Interview with: Seamus Kent, MSc, Research Fellow and Borislava Mihaylova, MSc DPhil, Associate Professor Health Economics Research Centre, Nuffield Department of Population Health University of Oxford, UK What is the background for this study? Response: Niacin lowers the LDL cholesterol and increases the HDL cholesterol and it was hoped this would translate into reduced risks of vascular events. This hypothesis was assessed in the Heart Protection Study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial in which over 25,000 adults aged 50 to 80 years with prior cardiovascular disease were randomised to either niacin-laropiprant or placebo, in addition to effective LDL-cholesterol lowering therapy, and followed for about 4 years. Previously published results from the study demonstrated that niacin-laropiprant did not significantly reduce the risk of major vascular events but did significantly increase the risk of various adverse events including infections, bleeding, gastrointestinal, musculoskeletal, skin, and diabetes-related events. (more…)
Author Interviews, Heart Disease, Lipids / 11.07.2016 Interview with: Joost Besseling, PhD-student Academic Medical Center Dept. of Vascular Medicine Amsterdam What is the background for this study?  Response: It was unkown to what extent statin therapy reduces the risk for coronary artery disease and mortality in patients with heterozygous familial hypercholesterolemia (FH). One previous study found that the relative risk reduction was 76%, but the study population in this study consisted of with a very severe FH phenotype. This result is therefore an overestimation of the risk reduction in the general heterozygous familial hypercholesterolemia population. (more…)
AHA Journals, Author Interviews, Heart Disease, Lipids / 07.07.2016 Interview with: Amanda M. Perak, MD Division of Cardiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, and Department of Preventive Medicine Northwestern University Feinberg School of Medicine Donald M Lloyd-Jones, MD/ScM (senior author) Senior Associate Dean for Clinical and Translational Research; Chair, Department of Preventive Medicine Director, Northwestern University Clinical and Translational Sciences Institute (NUCATS) and Eileen M. Foell Professor Professor in Preventive Medicine-Epidemiology and Medicine-Cardiology What is the background for this study? Response: Heterozygous familial hypercholesterolemia, or FH, affects up to 1 in 200 individuals in the United States. FH is a genetic disorder that should be suspected in individuals with very high levels of low-density lipoprotein cholesterol (LDL-C; at least 190 mg/dL) plus a first-degree relative with similar degree of high cholesterol or with premature coronary heart disease. Individuals with FH are exposed to high levels of "bad" cholesterol from birth, so if they are not treated with cholesterol-lowering therapy, they are at elevated risk for atherosclerotic cardiovascular disease (ASCVD; diseases related to hardening of the arteries, including heart attack and stroke). However, these risks previously had not been well quantified in untreated individuals with familial hypercholesterolemia in the general US population. (more…)
Author Interviews, Brigham & Women's - Harvard, JAMA, Lipids, Nutrition, Omega-3 Fatty Acids / 06.07.2016 Interview with: Daniel (Dong) Wang, MD, ScD, Research Fellow Department of Nutrition | Harvard T.H. Chan School of Public Health Boston, MA 02115 What is the background for this study? What are the main findings? Response: There has been widespread confusion in the biomedical community and the general public about the health effects of specific types of fat in the diet. In particular, the role of unsaturated fats vs. saturated fat in cardiovascular disease prevention remains controversial. Our study is by far the most detailed and powerful examination of this very important research topic, i.e., health effects of specific types of dietary fats, because of very large sample size (more than 120,000 men and women), repeated and validated measurements of diet and lifestyle over an extended follow-up (up to 32 years). In addition, our study is able to examine a much broader range of outcomes, including total mortality and mortality due to cardiovascular disease, cancer, neurodegenerative disease and respiratory disease. We found that different types of dietary fat had different associations with mortality. Consuming higher amounts of unsaturated fats- mainly from plant-based foods like olive oil, canola oil, soybean oil and nuts - was associated with lower mortality, while higher consumption of saturated-found in red meat, butter, cheese, and ice cream- and trans fats- predominantly from hydrogenated oils- was linked with higher mortality compared with the same number of calories from carbohydrates. Most importantly, replacing saturated fats with unsaturated fats conferred substantial health benefits, including lowering risk of all-cause premature death and premature death due to cardiovascular disease, cancer, neurodegenerative disease and respiratory disease. (more…)
AHA Journals, Author Interviews, Heart Disease, Lipids / 13.05.2016 Interview with: Michael Miller, MD, FACC, FAHA Professor of Cardiovascular Medicine, Epidemiology & Public Health University of Maryland School of Medicine Staff Physician, Baltimore VAMC Director, Center for Preventive Cardiology University of Maryland Medical Center Baltimore, Maryland What is the background for this study? Dr. Miller: It has become an article of faith that HDL (the good cholesterol) is an independent risk factor for heart disease. However, previous studies did not examine the importance of HDL after accounting for both LDL (bad cholesterol) and triglycerides (blood fats).  This is important because HDL is associated with LDL and triglycerides. We hypothesized that if HDL is truly an independent risk factor, then low HDL levels in isolation would continue to be linked to an increased risk of heart disease while high HDL levels would continue to protect the heart even if LDL and triglycerides levels were elevated. (more…)
Author Interviews, Lipids, Pharmacology / 06.05.2016 Interview with: Martha M. Rumore, PharmD, JD, MS, LLM, FAPhA Associate Professor, Social, Behavioral & Administrative Pharmacy Touro College of Pharmacy New York, NY 10027 & Of Counsel Sorell, Lenna, & Schmidt, LLP What is the background for this study? Dr. Rumore: The management of lipid therapy is only one component that affects overall cardiovascular outcomes.This study is one of the first to look at the benefits of dose titration versus intensity-based statin therapy.  To evaluate whether patients titrated on statin therapy using ATPIII algorithm with an LDL goal of <100mg/dL also met the 2013 ACC/AHA Guideline for Management of Blood Cholesterol goal of ≥40% LDL reduction from baseline compared to inpatients initiated on high-moderate intensity statin (HIS).  Other objectives included comparison of algorithms to lower LDL ≥40%, final dose, adverse drug events (ADEs), clinic visits to goal, and cardiovascular event occurrence. What are the main findings? Dr. Rumore: 981 patients were included- 43% were titrated and 57% achieved LDL<100; 38% achieved both LDL <100mg/dL and LDL ≥40% reduction; 58% received HIS and 53% achieved LDL <100; 43% achieved both LDL <100mg/dL and LDL ≥40% reduction. Initiating patients on  High Intensity statins was not more effective than dose titration in achieving <100mg/dL and ≥40% LDL reduction;X2=0.006,N=159,p=0.938. A 50% LDL reduction in patients that also achieved an LDL <100 was 54% and 48%, in titration and HIS groups, respectively; X2=0.611,N=159,p=0.434.  The titration group required an average of 4.3 clinic visits to achieve goal, compared to 3.1 visits for HIS; p=0.309; 95% CI(-1.36,1.06). (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease, Lipids / 18.03.2016 Interview with: Dr. Sarah de Ferranti MD MPH Boston Children’s Hospital Director, Preventive Cardiology Program Assistant Professor of Pediatrics Harvard Medical School  What are the main findings? Dr. de Ferranti: Familial hypercholesterolemia, or FH, is a genetic condition that causes severely elevated cholesterol levels from birth and is a leading cause of early heart attack. It is generally slowly progressive without symptoms until there is serious heart disease in the 3rd and 4th decade of life, making it important to look for it at a young age. Prior to this analysis it was thought that FH affected about 1 in 500 adults. The current study used data from 36,949 adults who took part in the 1999-2012 National Health and Nutrition Examination Survey (NHANES) and extrapolated to the 210 million U.S. adults aged 20 years and older. We identified cases of probably or definite Familial hypercholesterolemia in our analysis by using a combination of high levels of low-density-lipoprotein cholesterol (considered “bad” because it contributes to plaque buildup in arteries) and early heart disease in a person or close relative. (more…)
Author Interviews, Heart Disease, Lipids, Pharmacology, University of Pennsylvania / 03.03.2016 Interview with: Dr. Richard L. Dunbar MD MS Assistant Professor of Medicine, Attending Physician, Preventive Cardiovascular Medicine Clinic, Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of MedicineMember, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine and Dr. Harsh Goel WellSpan Academic Hospitalists Department of Medicine, York Hospital, PA What is the background for this analysis? Response: Niacin is the first cholesterol lowering treatment to prevent heart attacks and lower long term mortality. It thus provided the first proof that lowering cholesterol reduces cardiovascular risk. However, it is generally poorly tolerated due to almost universal flushing, limiting use. The better-tolerated statin drugs overshadowed niacin, rightly dominating hyperlipidemia therapy. Despite their advantages, statins are far from perfect, leaving important gaps. Firstly, at least 10% of patients simply don’t tolerate statins. Secondly, about 40% of patients have insufficient cholesterol lowering, leaving them far from their target LDL-cholesterol levels. Finally, even though statins lower cardiovascular risk, they by no means eliminate it and significant residual risk remains even in patients who respond to them. The relatively poor tolerance of niacin motivated development of an extended-release alternative which was dosed very differently from the established cardioprotective regimen used in the Coronary Drug Project (CDP) and the Stockholm Ischemic Heart Disease Study (SIHDS), the two landmark trials that proved niacin's benefits. These trailblazing trials used 3 grams of niacin divided throughout the fed portion of the day as 1 gram thrice daily with meals. In sharp contrast, the alternative regimen was severely handicapped by a profoundly lower dose of only 2 grams per day. Perhaps worse, the alternative regimen dosed all of the niacin at one sitting, at bedtime before the overnight fast, rather than three times a day before meals. We believe these were critical departures from the established cardioprotective niacin regimen, insofar as they severely undermined the alternative regimen’s efficacy. Accordingly, when added to statins, the alternative regimen failed to recapitulate the benefits seen with the established cardioprotective regimen in two recent large clinical trials, the AIM-HIGH trial and the HPS2-THRIVE trial. Besides the inherent flaws of the alternative regimen, there were also major issues with the trial designs which likely contributed to null results. From a practice standpoint, this is worrisome, because clinicians may draw erroneous conclusions from the trials of the alternative regimen, and thereby deny a significant population of hyperlipidemic patients the benefits of a well-proven cardioprotective therapy, i.e. the population which does not tolerate or does not respond adequately to statins (almost 50% of at risk patients). Hence, we embarked on a critical analysis and review of the alternative regimen with a special focus on the AIM-HIGH and HPS2-THRIVE trials to bring to light the pitfalls of comparing radically different regimens of what is nominally the same drug. (more…)
Author Interviews, Biomarkers, Heart Disease, Lipids / 19.02.2016 Interview with: Lorenz Räber, MD, PhD Director Division CAD and MI INSELSPITAL, Bern University Hospital Bern, Switzerland Medical Research: What is the background for this study? Response: Inflammation is a key player in the pathobiology of atheorsclerosis. Inflammatory markers and specifically C-reactive protein (CRP) associate with statin-mediated clinical event reduction and plaque burden reduction in patients with stable CAD. Whether CRP correlates with changes in plaque composition, ie. an important presumed substrate of plaque vulnerability, remains unknown. We thought to assess compositional atheroma changes by means of virtual histology IVUS in relation to levels of hs-CRP in STEMI patients. For this purpose, we performed intracoronary imaging using virtual histology IVUS in the proximal part of the two non-infarct related coronary arteries of STEMI patients at baseline and 13 months follow-up (IBIS-4 study). A total of 44 patients with 80 vessels had serial imaging and hsCRP measurements available. Medical Research: What are the main findings? Response: This is the first study to show that serial changes and on-treatment levels of hs-CRP correlate with virtual histology IVUS-defined necrotic core content in patients with STEMI receiving high-intensity statin therapy. Patients with a low inflammatory activity are more likely to achieve a reduction in necrotic core, which represents a presumed substrate of plaque vulnerability. These findings may provide the basis for assessing inflammation at follow-up to monitor disease activity in STEMI patients. (more…)
Author Interviews, Lipids, Nutrition / 18.02.2016 Interview with: Sachin A. Shah, Pharm.D. Residency Director & Regional Coordinator - Travis AFB Associate Professor of Pharmacy Practice TJ Long School of Pharmacy and Health Sciences University of the Pacific Medical Research: What is the background for this study? What are the main findings? Dr. Shah: The link between serum cholesterol and cardiovascular mortality has been well established. Dietary sources of cholesterol can play a major role toward a beneficiary or unfavorable lipid profile. Fatty acids in foods typically fall within one of the four categories: saturated fats (SFAs), common in animal sources, trans fats (TFAs), common in processed foods, polyunsaturated fats (PUFAs), and monounsaturated fats (MUFAs), both common in plant-derived sources. Although low-fat diets are generally recommended, studies have indicated that altering the types of fats you consume may further modify the risk of dyslipidemia. We performed a meta-analysis of existing studies to determine the impact of avocados on the lipid profile. Ten unique studies incorporating 229 subjects were included. Avocado consumption significantly reduced TC, LDL-C, and TG by 18.80 mg/dL, 16.50 mg/dL, 27.20 mg/dL respectively. HDL-C decreased non-significantly. (more…)
Author Interviews, Lipids, Neurological Disorders / 18.01.2016

More on Lipids on Interview with: Noriko Osumi, DDS, PhD Director, Center for Neuroscience Professor, Department of Developmental Neuroscience Tohoku University School of Medicine Seiryo-machi, Aoba-ku, Sendai Japan  Medical Research: What is the background for this study? What are the main findings? Dr. Osumi: Omega-6 and omega-3 fatty acids are known to be important for brain growth. This is mainly because many researchers have shown that imbalance between these fatty acids during pregnancy causes several defects in future brain functions both in humans and rodents. Therefore, we asked the underlying mechanism how maternal intake of the omega-6 excess/omega-3 deficient dietary impairs brain development in mice using genetical rescue and comprehensive lipidomics together with neural stem cell biology. We have shown how these fatty acids affect brain growth, and revealed its molecular and cellular mechanisms. In particular, the reduced thickness of the cortex is due to precocious gliogenesis following neurogenesis, which may include epoxide metabolites of omega-6 fatty acids. (more…)
Author Interviews, Heart Disease, Lipids / 20.11.2015 Interview with: Dr. Héctor González-Pacheco MD Coronary Care Unit, National Institute of Cardiology Mexico City, Mexico Medical Research: What is the background for this study? Dr. González-Pacheco: Epidemiological studies have provided robust evidence for an inverse correlation between plasma levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular risk. At hospital admission, a high percentage of patients with an acute coronary syndrome (ACS) have low HDL-C levels. Currently, the association of very low levels of HDL-C with early mortality in patients with ACS is still a topic of considerable interest. However, the possible mechanisms are not clear. Since an acute coronary syndrome induces an inflammatory response, and several chronic systemic diseases and acute critical illnesses with clear pro-inflammatory components have been associated with significantly reduced HDL-C levels, and investigators have shown an inverse correlation between HDL-C levels and the levels of pro-inflammatory cytokines, we hypothesized that reduced HDL-C levels in acute coronary syndrome might be associated to inflammatory mediators. We therefore sought to evaluate the correlation between HDL-C levels and biomarkers of inflammation available in routine laboratory screenings (high-sensitivity C-reactive protein (hs-CRP), white blood cell (WBC) count, and serum albumin) in a retrospective cross-sectional study of patients with ST-elevation myocardial infarction (STEMI) or non-ST-elevation ACS (NSTE-ACS). Medical Research: What are the main findings? Dr. González-Pacheco: We found that approximately one-fifth of patients had very low HDL-C levels (<30 mg/dL). Baseline levels of hs-CRP were significantly higher in these patients than in those with low (30–39.9 mg/dL) and normal (≥40 mg/dL) HDL-C levels. In contrast, serum albumin values were lower in patients with very low HDL-C levels. WBC count did not differ significantly. Accordingly, hs-CRP levels ≥ 10 mg/L and serum albumin levels ≤ 3.5 mg/dL, were two strong independent predictors of very low HDL-C levels. We observed that patients with STEMI had higher expression of biomarkers of inflammation and lower levels of HDL-C, compared with NSTE-ACS patients, as well as a lack of significant difference in the extent of coronary disease among the categories of HDL-C levels. These findings suggest that the fall in HDL-C levels is in accordance with the severity of the inflammatory response and the extent of the myocardial damage. Our findings are consistent with previous studies, in which patients with very low HDL levels had a higher rate of in-hospital mortality compared with those of other HDL-C levels. (more…)
Author Interviews, Inflammation, Lipids, University of Pennsylvania / 04.08.2015

Carsten C. Skarke MD Research Assistant Professor of Medicine McNeil Fellow in Translational Medicine Institute for Translational Medicine and Therapeutics Perelman School of Medicine University of Interview with: Carsten C. Skarke MD Research Assistant Professor of Medicine McNeil Fellow in Translational Medicine Institute for Translational Medicine and Therapeutics Perelman School of Medicine University of Pennsylvania Medical Research: What is the background for this study? What are the main findings? Dr. Skarke: A growing body of publications suggests anti-inflammatory actions of fish oils. These health benefits are proposed to emerge from lipids called specialized pro-resolving mediators, (SPMs), which can be formed from omega-3 polyunsaturated fatty acids found in fish. A limitation to date, though, in this field is that there is little evidence of their formation in humans. And the cases where presence of these lipids is reported in humans, less rigorous analytical approaches, such as enzyme immunoassay (EIA), radioimmunoassay (RIA) or mass spectrometry without internal authentic standards, have been used. Thus, the specific aim for our study was to use state-of-the-art mass spectrometry to identify and quantify these specialized pro-resolving mediators. Several aspects of our study design set us apart from what was done in previous studies.
  • First, we biased our ability to detect SPMs formed in healthy volunteers by giving fish oil in high doses which had been previously shown to influence blood pressure and platelet aggregation under placebo-controlled conditions.
  • Second, we also looked at lower doses of fish oil, those more commonly consumed by the general public, for the formation of SPMs during an acute inflammatory response and its resolution.
  • Third, we relied in our measurements of SPMs on authentic internal standards. These deuterated lipids, d4-resolvin E1 for example, facilitate distinct identification of the naturally formed lipid.
  • And fourth, we achieved very low limit of detection levels, below 10 pg/ml for resolvin E1, for example.
The surprising finding of our studies is that we failed to detect a consistent signal of SPM formation in urine or plasma of healthy volunteers who had taken fish oil. Even more surprising was that we found no alteration in the formation of SPMs during the resolution of inflammation. These results let us question the relevance of endogenous specialized pro-resolving mediators to the putative anti-inflammatory effects of fish oils in humans. (more…)
AHA Journals, Author Interviews, Lipids, Race/Ethnic Diversity / 25.06.2015

Carlos J. Rodriguez, MD, MPH Division of Public Health Sciences Department of Medicine Wake Forest School of Medicine Winston‐Salem, NC Interview with: Carlos J. Rodriguez, MD, MPH Division of Public Health Sciences Department of Medicine Wake Forest School of Medicine Winston‐Salem, NC 27152 MedicalResearch: What prompted you to study cholesterol in the Latino population? Please explain in detail. Dr. Rodriguez: Early in my career I noted that there were race-ethnic differences in the cholesterol profile between hispanics, african americans and non-hispanic whites. Hispanics are the largest ethnic minority group in the us yet prior studies of cholesterol in hispanics were relatively small, lacked adequate representation of diverse hispanic background groups for comparisons, and were not necessarily representative of nor generalizable to the hispanic population. The hispanic/latino adults in the hispanic community health study / study of latinos helped filled this critical gap. MedicalResearch: What do you think are the most significant findings from your study? What could have the greatest clinical implications and applications? Dr. Rodriguez: Several findings are important: less than half of those with high cholesterol were aware of their condition; less than a third of those with high cholesterol were being treated; and  among those receiving treatment, only two-thirds had cholesterol concentrations that were adequately controlled. (more…)
Author Interviews, Brigham & Women's - Harvard, Cannabis, JAMA, Lipids, Pediatrics / 06.04.2015

Holly Gooding, MD, MS Harvard T.H. Chan School of Public Health Instructor in Pediatrics at Harvard Medical School Division of Adolescent/Young Adult Medicine, Boston Children’s Hospital Division of General Internal Medicine, Brigham and Women’s Hospital Boston, Interview with: Holly Gooding, MD, MS Harvard T.H. Chan School of Public Health Instructor in Pediatrics at Harvard Medical School Division of Adolescent/Young Adult Medicine, Boston Children’s Hospital Division of General Internal Medicine Brigham and Women’s Hospital Boston, MA Medical Research: What is the background for this study? What are the main findings? Dr. Gooding: As an adolescent medicine physician, I primarily care for patients between the ages of 12 and 30, although I first trained in internal medicine.  One of the things I noticed when I started working with this age group is that pediatric and adult guidelines differ for many conditions.  Cholesterol treatment is one condition that comes up frequently, because the NHLBI and the AAP recommend screening youth ages 17 to 21 for cholesterol problems. The study team and I set out to discover the proportion of American youth ages 17 to 21 who would meet criteria for pharmacologic treatment of abnormal cholesterol levels if clinicians applied the pediatric versus the adult guidelines.  We found that 2.6% of young people ages 17 to 21 would qualify for pharmacologic treatment of abnormal LDL cholesterol levels under the pediatric guidelines, but less than 1% would qualify under the adult guidelines.  This translates to almost 500,000 youth qualifying for treatment under the pediatric guidelines, but only about 78,000 under the adult guidelines.  Those who met pediatric criteria had lower LDL levels but higher proportions of high blood pressure, smoking, and obesity. (more…)
Author Interviews, Diabetes, Heart Disease, JAMA, Lipids, Statins / 11.03.2015

Joost Besseling PhD-student Academic Medical Center Dept. of Vascular Medicine Interview with: Joost Besseling PhD-student Academic Medical Center Dept. of Vascular Medicine Amsterdam Medical Research: What is the background for this study? What are the main findings? Response: Statins are associated with an increased risk for type 2 diabetes mellitus (DM). The exact mechanism for this adverse event is largely unknown, although the upregulation of the low-density lipoprotein receptor (LDLR) has been suggested to play a role. In familial hypercholesterolemia (FH) the uptake of LDL-cholesterol via the LDLR is decreased due to a genetic defect. We found that the prevalence of type 2 DM is 50% lower in relative terms in patients with familial hypercholesterolemia. Moreover, there was a dose-response relationship: the more severe the genetic defect that causes familial hypercholesterolemia, the lower the prevalence of type 2 DM. (more…)
Author Interviews, Heart Disease, JACC, Lipids / 28.01.2015 Interview with: Dong Zhao MD.PhD Deputy Director & Professor andDong Zhao MD.PhD Deputy Director & Professor and Dr. Que Qi, MD.PhD Assistant Professor Beijing Institute of Heart,Lung & Blood Vessel Diseases Capital Medical University Beijing Anzhen HospitalDr. Que Qi, MD.PhD Assistant Professor Beijing Institute of Heart,Lung & Blood Vessel Diseases Capital Medical University Beijing Anzhen Hospital Medical Research: What is the background for this study? What are the main findings? Dr. Dong Zhao: Lower serum HDL-C level used to be considered as a key risk factor of atherosclerotic cardiovascular diseases. This knowledge was based on very consistent findings from researcher of basic science and observational studies of epidemiology. HDL-C has been also introduced as "good cholesterol" to the public. However, this well accepted knowledge was challenged when two large RCTs demonstrated that increased serum HDL-C by CETP inhibitor (ILLUMINATE and dal-OUTCOMES) failed to show benefits on reducing the risk of atherosclerotic cardiovascular disease. Therefore, many researchers questioned whether serum HDL-C can fully represent the capacity of cholesterol reverse transport of HDL particle, an underpinning of the anti-atherogenic function of HDL. And HDL particle number was considered to be better than HDL-C as a proper parameter to assess the function of HDL. In fact, RCTs that increased serum HDL-C substantially by CETP inhibitor had little effect on HDL particle number, thus resulting in increased cholesterol-overloaded HDL particle. Previous experimental studies observed that cholesterol-overloaded HDL particle exerted a negative impact on cholesterol reverse transport. However, it remains unclear whether cholesterol-overloaded HDL is involved in the development of atherosclerosis in humans. In our study, we measured HDL particle number using nuclear magnetic resonance spectroscopy, and calculated the ratio of HDL-C to HDL particles number to estimate the cholesterol content per HDL particle (HDL-C/P ratio). We found that cholesterol-overloaded HDL particles, indicated by high HDL-C/P ratio, are independently associated with the progression of carotid atherosclerosis in asymptomatic individuals from a community-based cohort study of the Chinese Multi-provincial Cohort Study-Beijing Project. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease, Lipids / 15.01.2015

Jean-Claude Tardif MD Professor of Medicine Director of the Research Centre Montreal Heart Institute Montreal, Quebec Interview with: Jean-Claude Tardif MD Professor of Medicine Director of the Research Centre Montreal Heart Institute Montreal, Quebec Canada What is the background for this study? What are the main findings? Dr. Tardif: Epidemiological and mechanistic studies have suggested that high-density lipoproteins (HDL) could have beneficial cardiovascular properties. However, several medications targeting HDL have failed in recent clinical trials, including the CETP inhibitor dalcetrapib in the dal-Outcomes trial. We hypothesized that dalcetrapib would be beneficial in the subset of patients with the appropriate genetic profile. We conducted the pharmacogenomic analysis of approximately 6000 patients from the dal-Outcomes study which showed that patients with the AA genotype at a specific genetic location (rs1967309) of the adenylate cyclase (ADCY9) gene benefited from a 39% reduction in cardiovascular events including cardiovascular death, myocardial infarction, stroke, unstable angina and the need for coronary revascularization when treated with dalcetrapib compared to placebo. In contrast, patients with the GG genotype had a 27% increase in cardiovascular events. We then obtained confirmatory evidence from the dal-Plaque-2 imaging study which revealed that patients with the protective genotype (AA) had a reduction in their carotid artery wall thickness and that those with the genotype associated with clinical harm (GG) had an increase in their wall thickness. (more…)
Author Interviews, Heart Disease, Lipids, PLoS / 11.12.2014 Interview with: Prof. Erik Ingelsson, MD, PhD, FAHA Professor of Molecular Epidemiology and Andrea Ganna PhD student Uppsala University Medical Research: What is the background for this study? What are the main findings? Response: Coronary heart disease (CHD) comprises a major cause of morbidity and mortality throughout the world. Measurement of metabolites, small molecules, in the blood could allow earlier diagnosis and inform about mechanisms leading to CHD. We examined the metabolic profiles (including thousands of metabolites) of blood samples from more than 3,600 individuals from Sweden that had been followed-up for up to 10 years, and found two lipid-related metabolites, lysophosphatidylcholine and sphingomyelin that reduced the risk of developing coronary heart disease and another lipid metabolite, monoglycerides, that was instead associated with increased risk. (more…)