High-Fat High-Sugar Diet-Induced Changes in the Lipid Metabolism Are Associated with Mildly Increased COVID-19 Severity and Delayed Recovery in the Syrian Hamster

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an altered, but not significantly different, systemic IL-10 and IL-6 profile, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, partially recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.

Keratinocyte cellular damage induced by pesticide doses below the cytotoxic level evidenced by electrical impedance and broadband dielectric spectroscopy

Cellular response of a normal human keratinocyte cell line exposed to non-cytotoxic doses of a deltamethrin-based pesticide was investigated by means of two different electrical impedance data spectroscopy approaches: Nyquist plot and broadband dielectric spectroscopy. The measurements have shown that the membrane capacity increases with pesticide concentration and this facilitates the electric current through cell membranes. Furthermore, the impedance of the extracellular matrix also increases with pesticide concentration, thus reducing the electric current outside the cell. Dielectric permittivity changes in the cellular samples at frequency larger than 100 Hz. Fluorescence measurements emphasized an increase of neutral membrane lipids as consequence of the pesticide exposure. Comparison of fluorescence response of pesticide exposed cells with the control ones showed a time increase of the emission intensity, suggesting the existence of a membrane lipid response aimed at repairing of the cell damage due to pesticide exposure. Therefore, both the spectroscopic techniques have demonstrated to be potential means to investigate the response to cell stress and damage. This opens up new possibilities in the early diagnosis of cellular modifications related to pesticides exposure of cells.

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10−8/132 = 4 × 10−10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p < 8.0 × 10−7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10−3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

Western diet increases COVID-19 disease severity in the Syrian hamster

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an increased trend of systemic IL-10 and IL-6, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.

Severe Hypercholesterolemia in Very-Low-Carbohydrate Diet

There is growing popularity and interest in very-low-carbohydrate (VLC) diets for a variety of established and perceived health benefits. While some impacts have been seen in cardiometabolic diseases such as diabetes, hypertension and short-term weight loss (particularly when paired with caloric restriction), other effects such as in energy levels, mood and sense of well-being are variable. In the extreme, these diets suggest restriction of dietary carbohydrates (CHO) to less than 20 grams daily and often encourage a compensatory increase in dietary fat to promote ketogenesis. There has been concern about the long-term effects of these changes, as well as unintended consequences of increased saturated fat intake. A minority of patients, such as in the case below, may experience exaggerated lipid changes, thought to be influenced by underlying metabolic and genetic factors. Meta-analyses have shown conflicting results of the effects of VLC diets on low density lipoprotein cholesterol (LDL-C) levels. A 63-year-old woman presented for outpatient consultation for markedly elevated LDL-C 524 mg/dL. The rest of her lipid panel was as follows: total cholesterol 637 mg/dL, triglycerides 152 mg/dL, HDL-C 83 mg/dL. She was asymptomatic. Record review of annual laboratory testing from her primary care physician revealed baseline LDL-C 114–134 mg/dL between 2012 and 2017. Her lipid panel in 2017 was as follows: total cholesterol 216 mg/dL, triglycerides 82 mg/dL, HDL-C 68 mg/dL, LDL-C 132 mg/dL. She described that in late 2017 she began a VLC diet for perceived metabolic benefits, and in the past year intensified CHO restriction to less than 15 grams daily. In 2018–2019, her LDL-C level increased to 303–316 mg/dL, and in 2020 to 524 mg/dL. She had no history of diabetes, liver or kidney disease, nephrotic syndrome, hypothyroidism or alcohol use. She took no prescribed medications. She reported over-the-counter use of magnesium and potassium. She denied use of any other supplements or herbal remedies. Her past medical history included osteoarthritis. Her family history included hyperlipidemia in her mother, and coronary artery disease in both parents with age of onset in their 70s. She was a lifelong non-smoker and did not drink alcohol. Her BMI was 21.5. On examination, she was normotensive, euthyroid-appearing, and had no stigmata of familial hypercholesterolemia. Other labs were grossly normal, including blood counts, comprehensive metabolic panel, thyroid function tests, hemoglobin A1c and urinalysis. She was counseled extensively regarding her laboratory results and concerns about her cardiovascular safety. This case demonstrates an exaggerated lipid response to a VLC diet, and supports the National Lipid Association scientific statement Class IIa recommendation to obtain baseline and follow-up lipid profiles in patients who follow such diets due to variation in lipid response.

Lipidomic Signatures Align with Inflammatory Patterns and Outcomes in Critical Illness

Alterations in lipid metabolism have the potential to be markers as well as drivers of the pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. Early in the clinical course, Fresh Frozen Plasma administration led to improved survival in association with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers. Late over-representation of phosphatidylethanolamines with critical illness led to the validation of a Lipid Reprogramming Score that was prognostic not only in trauma but also severe COVID-19 patients. Our lipidomic findings provide a new paradigm for the lipid response underlying critical illness.

Lipid levels and major adverse cardiovascular events in patients initiated on statins for primary prevention: an international population-based cohort study protocol

BackgroundClinical guidelines recommend specific targets for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) for primary prevention of cardiovascular disease (CVD). Furthermore, individual variability in lipid response to statin therapy requires assessment of the association in diverse populations.AimTo assess whether lower concentrations of LDL-C and non-HDL-C are associated with a reduced risk of major adverse cardiovascular events (MACE) in primary prevention of CVD.Design & settingAn international, new-user, cohort study will be undertaken. It will use data from three electronic health record databases from three global regions: Clinical Practice Research Datalink, UK; PREDICT-CVD, New Zealand (NZ); and the Clinical Data and Analysis Reporting System, Hong Kong (HK).MethodNew statin users without a history of atherosclerotic CVD, heart failure, or chronic kidney disease, with baseline and follow-up lipid levels will be eligible for inclusion. Patients will be classified according to LDL-C (<1.4, 1.4–1.7, 1.8–2.5, and ≥2.6 mmol/l) and non-HDL-C (<2.2, 2.2–2.5, 2.6–3.3, and ≥3.4 mmol/l) concentrations 24 months after initiating statin therapy. The primary outcome of interest is MACE, defined as the first occurrence of coronary heart disease, stroke, or cardiovascular death. Secondary outcomes include all-cause mortality and the individual components of MACE. Sensitivity analyses will be conducted using lipid levels at 3 and 12 months after starting statin therapy.ConclusionResults will inform clinicians about the benefits of achieving guideline recommended concentrations of LDL-C for primary prevention of CVD.