Low levels of high-density lipoprotein cholesterol (HDL-C) are clearly associated with atherosclerotic cardiovascular disease (ASCVD), but the risk curve is not well defined, especially at very high and very low HDL-C levels. Current proportional hazards prediction models assume inverse linearity of effect, which may not accurately represent risk at these levels. Clinical inattention to risk associated with low HDL-C may stem partly from trials of various pharmacologic interventions aimed at raising HDL-C which have mostly failed to reduce ASCVD events when used with statin-based therapy. However, these trials enrolled patients with HDL-C largely in the 35-45 mg/dL range. Mounting post hoc evidence from clinical trials as well as new genetic and observational data suggests that very low HDL-C (less than 30 or 35 mg/dL) may signal a further increase in cardiovascular events. Moreover, when HDL-C exceeds 90 mg/dL, monotonic reduction of ASCVD risk appears to reverse. Because there is now a pervasively agnostic view of the importance of both very low and high levels of HDL-C, consideration should be given to incorporating nonlinear effects of HDL-C into risk prediction models. If current knowledge does not justify this strategy, very low HDL-C and/or very high HDL-C could be considered as new risk-enhancing factors to promote optimal risk stratification. When revision of the U.S. Cholesterol Guideline recommences, consideration should be given to the question of whether HDL-associated risk matches the assumptions of the statistical model. Thus, it may be both timely and opportune to revisit the “HDL Hypothesis” based on evolving evidence.

In this JCL Roundtable, we bring together three experts to discuss women's cardiovascular health throughout the lifespan, viewed from the standpoint of clinical lipidology. Overall, heart disease leads to one out of every 3 deaths of American women, but unfortunately patient awareness of cardiovascular risk actually has declined since 2009. Younger women are not exempt, since their risk can be increased by smoking, birth control, adverse lifestyle and diet, and genetic disorders. Age at menarche can influence lifetime risk. Polycystic ovary syndrome, noted in 5-13% of women of reproductive age, has been linked to increased cardiovascular risk, partly through atherogenic dyslipidemia. Oral contraception has improved greatly since its introduction, but remains a risk for venous thromboembolism and stroke, particularly in smokers. Fetal nutritional and metabolic requirements in pregnancy impose high vascular demand on the placenta and lead to escalating maternal triglycerides and cholesterol especially in the 3rd trimester. Triglycerides may require special management. Adverse pregnancy outcomes associated with placental dysfunction signal subsequent increased risk for maternal atherosclerotic disease. Early menopause has long been recognized as a risk enhancing factor for atherosclerosis with pathophysiology remaining unclear. The menopause transition represents a period when cardiovascular risk for women increases rapidly and approaches that of men. Current studies are evaluating hormonal changes and even clonal hematopoiesis as potential causes. At the same time, lifestyle habits and routine chronic conditions such as hypertension and obesity/diabetes/metabolic syndrome play a large role and need attention.

The Journal of Clinical Lipidology will move forward with new leadership in its next issue. I'm delighted to announce that P. Barton Duell, M.D., and Kevin C. Maki, Ph.D., will serve as Co-Editors-in-Chief (co-EICs).

The SARS-CoV-2 pandemic has not yet run its course, especially in some parts of the world, but its impact is less confining now. Life and work in most places are beginning to return to normal, or better, a new normal. Throughout the pandemic heroes have appeared in our midst, and they have been recognized, albeit inconstantly, by society. Most of them are ordinary people including healthcare providers, first responders, front-line workers. We should recall an even more significant group of heroes who preceded the pandemic and will always remain. A week ago I had a televideo visit with a dear patient, a woman in her late 60s whom I have followed for 20 years, providing lipid management in the setting of what turned out to be inclusion body myositis, a disorder giving slowly progressive weakness, presently incurable. About halfway through this time, she fell in love with a wonderful man, they married, and their faith and love have been an inspiration to many others in their church and elsewhere, including me. Another woman about 12 years ago presented with familial hypercholesterolemia, history of vigorous exercise, coronary stenting before age 40, and 3 cm Achilles tendon xanthomas. We added new lipid medications. Achilles tendinitis flared, and 2 months later she re-appeared in clinic using a walker. Earlier in my career, John Brunzell had reassured me that such a flare of tendinitis could be a sign of cholesterol removal, and indeed the tendons regressed by 0.5 cm within 9 months, and the patient resumed walking normally (1Lakey WC Greyshock N Guyton JR. Adverse reactions of Achilles tendon xanthomas in three hypercholesterolemic patients after treatment intensification with niacin and bile acid sequestrants.J Clin Lipidol. 2013; 7: 178-181https://doi.org/10.1016/j.jacl.2012.11.002Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Her grit was awesome. She seemed destined for great things, which proved true. Add to these the pioneering environmental scientist who studied Pfiesteria, a unicellular organism causing fish kills in North Carolina rivers in the 1990s. A laboratory accident led to his toxic exposure along with 6 others, almost all of whom have died by now. Akin to a fish kill, the demyelinating toxin severely damaged his peripheral nerves giving constant pain. He has emerged from bedbound existence to frequent walks around the farm where he lives, with the help of a big stick for balance. Through periodic office visits our friendship has grown over the years. He and his wife support each other and their extended family – and me. My son Morgan, an ordained minister, helped me in 2011 write a Lipid Spin article about the unfairness of several patients’ travails and the inspiration gained while helping them live “normally,” which means remarkably in the face of challenge. We named them Ringbearers after the humble, yet venturesome hobbit, Frodo Baggins, who through no choice of his own encountered pain and shortened life while securing the salvation of Middle Earth (2Guyton JR Guyton MA. Ringbearers: a hobbit's perspective on genomic medicine.Lipid Spin. 2011; 9: 9-10Google Scholar). I won't repeat a detailed comparison with that allegory here. Suffice it to say that our patients and their loved ones are the enduring heroes. The title of this piece quotes J.R.R. Tolkien as a shout of praise. I doubt that the word “Eglerio” appears in any human language. It comes from the woodland elves (3Tolkien JRR. The Lord of the Rings. Part 3. The Return of the King. Ballantine Books, New York1955 and 1965: 285Google Scholar). A practical way to honor our patients is to study the lipid disorders that afflict them and to devise and test new modes of treatment. This issue of JCL features case reports of an infrequent cause of familial chylomicronemia and an unusual manifestation of cerebrotendinous xanthomatosis, as well as new insight on diagnosing pediatric familial hypercholesterolemia from France and characterization of homozygous familial hypercholesterolemia in China. An update provides recommendations from the Lipid Association of India for intensive LDL-C lowering applicable to South Asian patients with acute coronary syndrome. Poornima et al. review lipid risk factors for preeclampsia in pregnancy with a focus on hypertriglyceridemia. CERT2 (Coronary Event Risk Test 2) is a new risk score based on plasma ceramides and glycerophospholipids. Papazoglou and colleagues in this issue present a meta-analysis demonstrating the value of CERT2 for prediction of major adverse cardiovascular events in secondary prevention. Laufs et al. compile patient-level data from four phase 3 clinical trials on bempedoic acid taken alone or in combination with ezetimibe to show worthwhile LDL-C lowering and no evidence for adverse muscle effects in statin-intolerant patients. Also in this issue you will find success in persistence of PCSK9 inhibitor therapy, new data on clinical associations with oxysterols, and more.

The horrific events in Ukraine leave me begging for answers. Having grown up in Mississippi, I turn to William Faulkner for help.

A blend of emotions welled up as I arrived at the National Lipid Association Clinical Update in Washington DC 2 weeks ago. It was my first in-person meeting since the 2020 Denver meeting at the outset of the pandemic. As an at-risk senior, I took reassurance from the mandate for documented COVID vaccination. A 5-hour automobile drive and even the DC traffic proved less intimidating than anticipated. It felt good to travel again, and the start of the meeting simply brought undiluted joy while greeting friends old and new, assembling for our common purpose. Allison Fellers and the NLA staff deserve all our thanks for a smooth rollout of the hybrid in-person and virtual conference.

Clinical lipidology practice works best when implemented by a health care team. The 3 discussants for this JCL Roundtable are National Lipid Association leaders representing essential areas on the team - Registered Dietitian Nutritionist, Advanced Practice Provider, and Clinical Pharmacist. The team approach has been shown more effective than traditional sole provider management for controlling chronic asymptomatic conditions like hypercholesterolemia. Teams also fit better as health care transitions away from fee-for-service into value-based reimbursement. It's worth noting that medicine and even surgery were never entirely solo endeavors. Here we discuss a more expansive team model, which began in the U.S. more than 2 decades ago in the Veterans Administration and certain managed care organizations such as Kaiser Permanente. These health care organizations place themselves at risk, comprising both normative and financial risk, for maintaining their patients' health. Academic medical centers and private health care groups increasingly are adopting the at-risk model and medical teams. Electronic health records facilitate the transition. Team members include not only licensed professionals like our discussants, but also medical assistants, front desk staff, and schedulers. All share decision making and responsibility. Ideally the patient becomes the central member, not merely the focal point, of the team. We explore specific roles within the lipidology team, and we identify continuing barriers to implementation.

Clinical effort in lipidology focuses largely on mitigating effects of atherosclerosis, a pathologic process localized to the intimal layer of larger arteries. This JCL Roundtable brings together 3 leading researchers to discuss the current understanding of pathogenesis in atherosclerosis. We begin by recognizing that low density lipoprotein concentrations in arterial intima far exceed concentrations in other connective tissues, consistent with the response-to-retention hypothesis of atherogenesis. High density lipoproteins facilitate reverse cholesterol transport and also have antioxidant and anti-inflammatory roles. New evidence points to remnants of triglyceride-rich lipoproteins as promoters of atherogenesis, highlighted by deleterious effects of apolipoprotein C-III. The multifaceted role of inflammation is becoming clearer through discoveries related to leukocyte recruitment, efferocytosis, resolution of inflammation, and crystal formation. MicroRNAs represent a new, complex mode of gene regulation bearing on lipoprotein and inflammation biology. Progress in understanding atherosclerosis portends a future in which residual risk related to obesity, diabetes, and other factors will yield to new targeted therapies.

By the time these words are published, most clinical providers hopefully will have received vaccination against SARS-CoV-2, at least a first injection. The pandemic surges now after holiday gatherings, but amazing medical science and heroic public health effort enable us to predict the waning of viral subjugation. Lessons will be learned. I plowed through a packed virtual clinic last week. It gives a hint that telehealth might provide a broader reach for lipidology and other kinds of preventive medicine. More importantly, appalling inequities in mortality from the virus have competed for media time with broader issues of systemic racism and naked self-interest. Perhaps these revelations, along with forced isolation of people into small family, friend, and individual bubbles over the past year, can recoil in a public recognition that "We're in this together," which could motivate restructuring of social, governmental, and economic determinants of health. The time to think hard about these things comes rapidly upon us. Pause just a moment, and take a deep breath. The virus may linger for years, but its dominance will fade. Summon up energy for the home stretch in the pandemic marathon. Grieve the lost, continue to support the afflicted, but also look ahead. A new time for humanity beckons. Twenty-three articles in this issue of JCL demonstrate growth in the field of clinical lipidology despite the pandemic. We have a detailed scientific statement from the National Lipid Association on coronary artery calcium scoring. New drugs often take the spotlight, but quantification of coronary atherosclerosis by calcium scoring is one of the most profound innovations in lipid practice today. Expect further progress in coming decades. Our JCL Roundtable conducted by teleconference on lipid and inflammatory mechanisms in atherosclerosis took me back to the early phase of my career. I hope you find the progress as astounding as I do. You may notice an informal collegiality in the conversation, which rings true for laboratory science. As a caution and apology, let me say that many names of contributors are mentioned, but it's not possible to represent proportionately everyone who has significantly impacted our understanding of atherosclerosis. In a systematic review in this issue, Anish Adhikari and colleagues comprehensively summarize current knowledge about statin use and cognitive function. Epidemiologist Lew Kuller extends the viewpoint in an editorial, identifying areas where new studies are needed. Better understanding is important, as Leonie Picton et al. document a sharply decreasing trend for statin use in Australian patients with dementia. In a timely observational study, Gianfranco Mitacchione et al. affirm the working hypothesis that outpatient statin therapy does not appear to affect inpatient hospital mortality in COVID-19 patients. The current popularity of ketogenic diets forms the backdrop for a stunning clinical observation by Ira Goldberg and colleagues of extreme hypercholesterolemia in some ketogenic diet adherents. This is the first report in the medical literature of a phenomenon already known on the internet as "lean mass hyper-responders," as discussed by these authors. Hypertriglyceridemia gets attention in 6 articles–genetic determinants in combined hyperlipidemia and in differing ancestral groups, diagnostic criteria for type III hyperlipoproteinemia and for hypertriglyceridemic pancreatitis, effects on adverse pregnancy outcomes, and associations with insulin resistance and family diabetes history. A related article looks at apolipoprotein C3 in type 1 diabetes. In addition, you will find new research on familial hypercholesterolemia, infantile manifestations of cerebrotendinous xanthomatosis, marine omega-3 fatty acids, estradiol effects on risk factors, cholesterol efflux capacity in H. pylori infection, and other topics.

Goldberg and colleagues recently shared in this Journal 5 remarkable cases of extreme hypercholesterolemia associated with increasingly popular very low carbohydrate, high fat diets. 1 Goldberg IJ Ibrahim N Bredefeld C Foo S Lim V Gutman D et al. Ketogenic diets, not for everyone. J Clin Lipidol. 2021; 15: 61-67https://doi.org/10.1016/j.jacl.2020.10.005 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar The authors concluded by advising caution to those employing such diets, given the potential for individuals both with and without underlying genetic hyperlipidemia to develop momentous and potentially harmful increases in cholesterol. We add to that report by sharing 3 cases of our own. Ketogenic diets, not for everyoneJournal of Clinical LipidologyVol. 15Issue 1PreviewThe adoption of low-carbohydrate diets can lead to weight loss in many patients. However, these now widespread diets also have the potential to exacerbate hypercholesterolemia. Full-Text PDF

One sign of the pandemic's waning influence has been the return of competitive sports, though confined largely to televised matches interrupted haphazardly by quarantines. I'm just a bit addicted to Duke basketball and any sport at my alma mater Ole Miss. At its best, competition in sports can maximize the effort of individuals and teams. The exciting result can remain consistent with friendship among rivals, enhancing the twin goals of doing our best and enjoying the game.

Deutsche is a language famous for stringing words and modifiers together, then expounding on the new construction to broaden the reach of human thought. In English, despite its German roots, such a practice occasionally looks awkward. So I wonder if there is a German counterpart to the word “connectedness” and whether the full scope of that word has been explored somewhere.

South Asian risk for atherosclerotic cardiovascular disease (ASCVD) has received special emphasis in the 2018 US AHA/ACC/Multisociety Cholesterol Guidelines. The term "South Asian" refers specifically to the countries of India, Pakistan, Nepal, Bhutan, Bangladesh, Sri Lanka, and Maldives and to the worldwide diaspora of families from these countries. With this definition, approximately 25% of the world's population is South Asian, but about 50% of ASCVD occurs in this group. In this JCL Roundtable, we discuss the roles of visceral adiposity, diabetes, and features of the metabolic syndrome; lipoprotein(a); and diet and lifestyle, including the transition of both diet and lifestyle over the past 40 to 50 years. Genetic and/or hidden risk is an area of ongoing research. Individual patient assessment and intervention should recognize the earlier onset of ASCVD and the value of screening for traditional risk factors as well as waist circumference, coronary artery calcium scoring, and lipoprotein(a) assay. Culturally acceptable dietary strategies are available, although not widely implemented or evaluated as yet. In very-high-risk cases of secondary prevention, one should consider combining medications to drive low-density lipoprotein cholesterol much lower than 70 mg/dL. Our discussion concludes by insisting that the signal of alarm must be accompanied by decisive action.

Infectious disease epidemics used to happen frequently, a woeful recurrent theme of life on this planet. Now they are uncommon at least in the developed world. My grandparents experienced the influenza pandemic of 1918, but my parents, born shortly thereafter and now departed, never experienced what we are going through today. The lipidology community is adapting, mostly learning to do telemedicine from home. Some are providing front-line service in emergency departments, hospital wards, intensive care units, testing stations, and research studies. While most of the concerns of COVID-19 relate to the lungs and to hyperinflammation, pre-existing atherosclerotic cardiovascular disease increases risk for adverse outcomes. Add the ongoing risk of "routine" heart attack and stroke, and it's clear that lipid practice remains important. Two articles in this issue of the Journal deal with COVID-19. Wei and colleagues, reporting from the original epicenter in Wuhan, China, found hypolipidemia in almost 600 patients presenting with SARS-CoV-2 infection. LDL cholesterol (LDL-C) levels correlated inversely with clinical severity and with markers of inflammation, and positively with lymphocyte counts.1Wei X. Zeng W. Su J. et al.Hypolipidemia is associated with the severity of COVID 19.J Clin Lipidol. 2020; 14: 297-304Scopus (221) Google Scholar While the variability of baseline LDL-C makes it difficult to view an isolated test as a biomarker, some of our patients will have known baseline levels, and a precipitous fall in LDL-C might give a rapid assessment of metabolic stress associated with infection. Also of importance in this issue, Dean Karalis in an editorial cites evidence for safety of statin medications in patients at risk for COVID-19 and even in those with infection up to the point of hospitalization. Observational experience suggests that statin users compared to non-users could have a small improvement in clinical outcomes from seasonal influenza. Early observational data in coronavirus infection also trends favorably.2Karalis D.G. Are statins safe in patients with COVID 19?.J Clin Lipidol. 2020; 14 ([THIS ISSUE])Google Scholar There is no data, however, to support continuation of statin therapy in patients hospitalized with COVID-19, and given the known infrequent risks, statin continuation in hospitalized COVID-19 patients should probably be limited to randomized clinical trials. This issue also features a systematic review by Dixon and colleagues of 26 randomized controlled trials that strongly support the roles of clinical interventions by pharmacists in reducing LDL-C.3Dixon D.L. Khaddage S. Bhagat S. Koenig R.A. Salgado T.M. Baker W.L. Effect of pharmacist interventions on reducing low-density lipoprotein cholesterol (LDL-C) levels: a systematic review and meta-analysis.J Clin Lipidol. 2020; 14: 282-292.e4Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Our Roundtable discussion, which might make you hungry, outlines the good and bad in South Asian and Hispanic diets, as well as the mostly beneficial effects of the authentic Mediterranean diet as opposed to some variants in the US and other places.4Felando M. Rasmussen H. Karmally W. Guyton J.R. JCL Roundtable: healthy ethnic diets.J Clin Lipidol. 2020; 14: 271-281Google Scholar Further topics addressed in this issue include economic aspects of lipid treatment, genetic identification of familial hypercholesterolemia, use of alirocumab in pediatric patients, asymptomatic intracranial atherosclerosis, and others. An afterthought about the viral pandemic: Will life return to "normal" after COVID-19 runs its course, or will life, including medical practice, be forever changed? Could it even improve? One of the feelings of this stressful time is a sense of community. We're all in it together. The sense of community extends to our nation and more broadly to the world. William Mitchell Ramsay described a plague that struck Athens around 500 BCE5Ramsay W.M. Gifford Lecture on Epimenides, chap. 3 in Asianic Elements in Greek Civilisation, University of Edinburgh, 1915-1916. Yale University Press, New Haven1928: 20-39http://www.elfinspell.com/ClassicalTexts/Ramsay-AsianicElementsInGreekCivilization/Chap3-Epimenides.htmlDate accessed: August 14, 2016Google Scholar:Under the Pisistratidae Athens grew from a small town into an important city; but in this too rapid increase it outgrew healthy conditions. The laws of sanitation, which the old religion had prescribed for small social groups, were quite inadequate for a large city. Athens was ripe for a pestilence; and, after the tyrants were expelled, the slackness and want of forethought which attended Athenian democracy aggravated the evils of city management, while party strife distracted attention. The result was as recorded by Maximus, Diogenes, and others; a plague struck the city. The Athenians decided to bring in a consultant, Epimenides of Crete. According to the ancient historian Diogenes Laertes6Diogenes LaertiusThe lives and opinions of eminent philosophers.in: Yonge C.D. Translator. Henry G. Bohn, London1853http://classicpersuasion.org/pw/diogenes/dlepimenides.htmDate accessed: August 16, 2016Google Scholar:He was considered by the Greeks as a person especially beloved by the Gods, on which account, when the Athenians were afflicted by a plague, and the priestess at Delphi enjoined them to purify their city; they sent a ship and Nicias the son of Niceratus to Crete, to invite Epimenides to Athens; and he, coming there in the forty-sixth Olympiad, purified the city and eradicated the plague for that time…. Epimenides brought more than sanitation and social distancing to Athens. He encouraged an entirely new way of thinking. Within 2 generations Athens entered the golden age of Pericles, Socrates, and Plato. The legacy of Epimenides persists today in the form of 2 quotations and 1 object described in the biblical New Testament, though his name does not appear there. Let's take inspiration anyway from his example. We can do better and make progress for humanity as they did in Athens. The briefer and more famous quote from Epimenides bespeaks a sense of humor, humility, or sly wisdom – "Cretans, always liars." Was he lying? Dr. Guyton has received research grants from Amarin, Regeneron, and Sanofi.

Low- and very-low-carbohydrate diets have long attracted popular interest in the US and variably throughout the world. The potential value of these diets was recognized recently in a Consensus Report from the American Diabetes Association and expanded in a Scientific Statement from the National Lipid Association. Scientific evidence remains incomplete, but is beginning to catch up with popular trends. In this JCL Roundtable, 3 experts discuss the evidence behind these diets, their current place in nutrition practice, and areas needing more study. The carbohydrate-insulin model of obesity is presented as one explanation for dietary effectiveness. Ongoing research will delineate this model further. The experts, all clinicians, give practical advice for when and how to incorporate low-carbohydrate principles into dietary counseling. (C) 2020 Published by Elsevier Inc. on behalf of National Lipid Association.

Background and Aims: The alirocumab open-label extension study ODYSSEY OLE (NCT01954394) included patients diagnosed with heterozygous familial hypercholesterolaemia (HeFH) who had completed previous Phase 3 parent studies. Alirocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) and is administered subcutaneously in two dosages (75 mg or 150 mg every 2 weeks [75Q2W and 150Q2W, respectively]). This post-hoc analysis examined regional differences in physician dosing decisions.

BACKGROUND: The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial showed no incremental benefit of extended-release niacin (ERN) therapy added to simvastatin in subjects with cardiovascular disease (CVD). OBJECTIVES: To examine the effects of ERN treatment on lipoprotein particles and GlycA, a new marker of systemic inflammation, and their relations with incident CVD events including mortality. METHODS: GlycA and very low density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particle subclasses were quantified by nuclear magnetic resonance spectroscopy using available stored baseline (n = 2754) and 1-year in-trial (n = 2581) samples. Associations with CVD events and all-cause mortality were assessed using multivariable Cox proportional hazards regression adjusted for age, sex, diabetes, treatment assignment, and lipoproteins. RESULTS: Compared to placebo, ERN treatment lowered very low-density lipoprotein and LDL and increased HDL particle concentrations, increased LDL and HDL particle sizes (all P < .0001), but did not affect GlycA. Baseline and in-trial GlycA levels were associated with increased risk of CVD events: hazard ratio (HR) per SD increment, 1.17 (95% confidence interval [CI], 1.06-1.28) and 1.13 (1.02-1.26), respectively. However, none of the lipoprotein particle classes or subclasses was associated with incident CVD. By contrast, all-cause mortality was significantly associated with both GlycA (baseline HR: 1.46 [1.22-1.75]; in-trial HR: 1.41 [1.24-1.60]) and low levels of small HDL particles (baseline HR: 0.69 [0.56-0.86]; in-trial HR: 0.69 [0.56-0.86]). CONCLUSIONS: This Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial post hoc substudy indicates that inflammation, as indexed by GlycA, is unaffected by ERN treatment but is significantly associated with the residual risk of CVD and death in patients treated to low levels of LDL cholesterol. (C) 2018 National Lipid Association. Published by Elsevier Inc.