MENSA, a Media Enriched with Newly Synthesized Antibodies, to Identify SARS-CoV-2 Persistence and Latent Viral Reactivation in Long-COVID.

Post-acute sequelae of SARS-CoV-2 (SARS2) infection (PASC) is a heterogeneous condition, but the main viral drivers are unknown. Here, we use MENSA, Media Enriched with Newly Synthesized Antibodies, secreted exclusively from circulating human plasmablasts, to provide an immune snapshot that defines the underlying viral triggers. We provide proof-of-concept testing that the MENSA technology can capture the new host immune response to accurately diagnose acute primary and breakthrough infections when known SARS2 virus or proteins are present. It is also positive after vaccination when spike proteins elicit an acute immune response. Applying the same principles for long-COVID patients, MENSA is positive for SARS2 in 40% of PASC vs none of the COVID recovered (CR) patients without any sequelae demonstrating ongoing SARS2 viral inflammation only in PASC. Additionally, in PASC patients, MENSAs are also positive for Epstein-Barr Virus (EBV) in 37%, Human Cytomegalovirus (CMV) in 23%, and herpes simplex virus 2 (HSV2) in 15% compared to 17%, 4%, and 4% in CR controls respectively. Combined, a total of 60% of PASC patients have a positive MENSA for SARS2, EBV, CMV, and/or HSV2. MENSA offers a unique antibody snapshot to reveal the underlying viral drivers in long-COVID thus demonstrating the persistence of SARS2 and reactivation of viral herpes in 60% of PASC patients.

Type of Alcohol and Blood Pressure: The Copenhagen General Population Study.

BACKGROUND: Most adults ingest alcoholic beverages. Alcohol shows strong and positive associations with blood pressure (BP). We hypothesized that intake of red wine, white wine, beer, and spirits and dessert wine show similar associations with BP in the general population. METHODS: We included 104,467 males and females aged 20-100 years in the analysis of the Danish general population. Alcohol use and type of alcohol were assessed by questionnaire. Blood pressure was measured by automated digital BP manometer. Multivariable linear regression models were used when analyzing the association between number of drinks per week and BP, stratified by sex and adjusted for relevant confounders. Each alcohol type (red wine, white wine, beer, and spirits and dessert wine) was analyzed in similar models including adjustment for other alcohol types. RESULTS: Most of the subjects (76,943 [73.7%]) drank more than 1 type of alcohol. However, 12,093 (12.6%) consumed red wine only, 4288 (4.5%) beer only, 1815 (1.9%) white wine only, and 926 (1.0%) spirits and dessert wine only. There was a dose-response association between total drinks per week and systolic and diastolic BP (SBP, DBP) (P < .001). The crude difference was 11 mmHg SBP and 7 mmHg DBP between high (>35 drinks per week) and low (1-2 drinks per week) alcohol intake. Overall, SBP was increased by 0.15-0.17 mmHG, and DBP was increased by 0.08-0.15 mmHg per weekly drink. After stratification for age and sex, effects were slightly higher among females and among individuals aged less than 60 years. CONCLUSION: Alcohol intake is associated with highly significant increased SPB and DBP. The effect is similar for red wine, white wine, beer, and spirits.

Omega-3 fatty acids in primary and secondary prevention of cardiovascular diseases.

Even with substantial progress in primary and secondary prevention, cardiovascular disease (CVD) persists as a major cause of mortality and morbidity globally. Omega-3 polyunsaturated fatty acids (Ω-3 PUFAs) have gained considerable attention for their ability to improve CV health and prognosis. Metanalyses of randomized controlled trials have demonstrated Ω-3 PUFAs' positive impact on CVD outcomes for both primary and secondary prevention endpoints. Marine Ω-3 PUFAs also improve CVD risk factors including blood pressure, lipids, and inflammation; however, many physicians do not recommend Ω-3 PUFAs, largely due to inconsistent results in randomized trials. In this comprehensive review article, we evaluate both historic and current data concerning primary and secondary prevention of CVD with use of Ω-3 PUFAs, delve into the potential causes for the varied results, and examine the most current recommendations on the usage of Ω-3 PUFAs.

Circulating Docosahexaenoic Acid and Risk of All-Cause and Cause-Specific Mortality.

OBJECTIVE: To assess the associations of docosahexaenoic acid (DHA), a marine omega-3 fatty acid, with long-term all-cause mortality, cardiovascular (CV) mortality, and cancer mortality. PATIENTS AND METHODS: We analyzed data from UK Biobank, which included 117,702 subjects with baseline plasma DHA levels and 12.7 years of follow-up between April 2007 and December 2021. Associations with risk for mortality endpoints were analyzed categorically by quintile of DHA plasma levels. RESULTS: Comparing the lowest to highest quintiles of circulating levels of DHA, there was 21% lower risk of all-cause mortality (HR, 0.79; 95% CI, 0.74 to 0.85; P<.0001). In a secondary analysis, we merged the UK Biobank findings with those from a recent FORCE (Fatty Acid and Outcome Research Consortium) meta-analysis that included 17 prospective cohort studies and 42,702 individuals examining DHA and mortality associations. The cumulative sample population included 160,404 individuals and 24,342 deaths during a median of 14 years of follow-up. After multivariable adjustment for relevant risk factors comparing the lowest to the highest quintiles of DHA, there was 17% lower risk of all-cause mortality (95% CI, 0.79 to 0.87; P<.0001), 21% lower risk for CV disease mortality (95% CI, 0.73 to 0.87; P<.001), 17% lower risk for cancer mortality (95% CI, 0.77 to 0.89; P<.0001), and 15% lower risk for all other mortality (95% CI, 0.79 to 0.91; P<.001). CONCLUSION: Higher DHA levels were associated with significant risk reductions in all-cause mortality, as well as reduced risks for deaths due to CV disease, cancer, and all other causes. The findings strengthen the hypothesis that DHA, a marine-sourced omega-3, may support CV health and lifespan.

Estrogen and cardiovascular disease.

A large body of scientific research accumulated over the past twenty years documents the cardiovascular (CV) benefits of estradiol (E2) and progesterone (P4) in reproductive aged women. In contrast, accelerated development of CV disease (CVD) occurs in the absence of ovarian produced E2 and P4. Hormone replacement therapy (HRT) with E2 and P4 has been shown to cause no harm to younger menopausal women. This robust scientific data supports a reconsideration of the prescriptive use of E2 and P4 as preventative therapeutics for the reduction of CVD, even without additional large-scale studies of the magnitude of the Women's Health Initiative (WHI). With the current expanded understanding of the critical modulatory role played by E2 on a multitude of systems and enzymes impacting CVD onset, initiation of HRT shortly after cessation of ovarian function, known as the "Timing Hypothesis", should be considered to delay CVD in recently postmenopausal women.

Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Comparing a Data Entry Tool to Provider Insights Alone for Assessment of COVID-19 Hospitalization Risk: Pilot Matched Cohort Comparison Study.

BACKGROUND: In March 2020, the World Health Organization declared COVID-19 a global pandemic, necessitating an understanding of factors influencing severe disease outcomes. High COVID-19 hospitalization rates underscore the need for robust risk prediction tools to determine estimated risk for future hospitalization for outpatients with COVID-19. We introduced the "COVID-19 Risk Tier Assessment Tool" (CRTAT), designed to enhance clinical decision-making for outpatients. OBJECTIVE: We investigated whether CRTAT offers more accurate risk tier assignments (RTAs) than medical provider insights alone. METHODS: We assessed COVID-19-positive patients enrolled at Emory Healthcare's Virtual Outpatient Management Clinic (VOMC)-a telemedicine monitoring program, from May 27 through August 24, 2020-who were not hospitalized at the time of enrollment. The primary analysis included patients from this program, who were later hospitalized due to COVID-19. We retroactively formed an age-, gender-, and risk factor-matched group of nonhospitalized patients for comparison. Data extracted from clinical notes were entered into CRTAT. We used descriptive statistics to compare RTAs reported by algorithm-trained health care providers and those produced by CRTAT. RESULTS: Our patients were primarily younger than 60 years (67% hospitalized and 71% nonhospitalized). Moderate risk factors were prevalent (hospitalized group: 1 among 11, 52% patients; 2 among 2, 10% patients; and ≥3 among 4, 19% patients; nonhospitalized group: 1 among 11, 52% patients, 2 among 5, 24% patients, and ≥3 among 4, 19% patients). High risk factors were prevalent in approximately 45% (n=19) of the sample (hospitalized group: 11, 52% patients; nonhospitalized: 8, 38% patients). Approximately 83% (n=35) of the sample reported nonspecific symptoms, and the symptoms were generally mild (hospitalized: 12, 57% patients; nonhospitalized: 14, 67% patients). Most patient visits were seen within the first 1-6 days of their illness (n=19, 45%) with symptoms reported as stable over this period (hospitalized: 7, 70% patients; nonhospitalized: 3, 33% patients). Of 42 matched patients (hospitalized: n=21; nonhospitalized: n=21), 26 had identical RTAs and 16 had discrepancies between VOMC providers and CRTAT. Elements that led to different RTAs were as follows: (1) the provider "missed" comorbidity (n=6), (2) the provider noted comorbidity but undercoded risk (n=10), and (3) the provider miscoded symptom severity and course (n=7). CONCLUSIONS: CRTAT, a point-of-care data entry tool, more accurately categorized patients into risk tiers (particularly those hospitalized), underscored by its ability to identify critical factors in patient history and clinical status. Clinical decision-making regarding patient management, resource allocation, and treatment plans could be enhanced by using similar risk assessment data entry tools for other disease states, such as influenza and community-acquired pneumonia. The COVID-19 pandemic has accelerated the adoption of telemedicine, enabling remote patient tools such as CRTAT. Future research should explore the long-term impact of outpatient clinical risk assessment tools and their contribution to better patient care.

SGLT inhibitors for improving Healthspan and lifespan.

Sodium-glucose cotransporter inhibitor/inhibition (SGLTi), initially approved as a glucose-lowering therapy for type 2 diabetes, is associated with decreased risks for many of the most common conditions of aging, including heart failure, chronic kidney disease, all-cause hospitalization, atrial fibrillation, cancer, gout, emphysema, neurodegenerative disease/dementia, emphysema, non-alcoholic fatty liver disease, atherosclerotic disease, and infections. Studies also show that SGLTi improves overall life expectancy and reduces risks of cardiovascular death and cancer death. These wide-ranging health benefits are largely unexplained by the SGLTi's modest improvements in standard risk factors. SGLTi produces upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling. This in turn promotes autophagy, which helps to optimize cellular integrity and prevent apoptotic cell death. SGLTi decreases oxidative stress and endoplasmic reticulum stress, restores of mitochondrial health, stimulates mitochondrial biogenesis, and diminishes proinflammatory and profibrotic pathways. These actions help to revitalize senescent cells, tissues, and organs. In summary, SGLTi appears to slow aging, prevent disease, and improve life expectancy, and its mechanisms of action lend strong biological plausibility to this hypothesis. Further randomized trials are warranted to test whether SGLTi, a safe and well-tolerated, once-daily pill, might improve healthspan and lifespan.

Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation.

BACKGROUND: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial. OBJECTIVES: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF. METHODS: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively. CONCLUSIONS: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.

Height Explains Sex Difference in Atrial Fibrillation Risk: Copenhagen General Population Study.

OBJECTIVE: To test the hypothesis that the increased risk of atrial fibrillation (AF) in men compared with women is explained by height. METHODS: From the Copenhagen General Population Study, we included 106,207 individuals (47,153 men and 59,054 women) from 20 to 100 years of age, without a prior diagnosis of AF, examined between November 25, 2003, and April 28, 2015. The main outcome was AF incidence from national hospital registers until April 2018. The association of risk factors with AF incidence was assessed by cause-specific Cox proportional hazards regression and Fine-Gray subdistribution hazards regression analysis. RESULTS: During a maximum of 14.4 years of follow-up (median, 8.9 years), incident AF was observed in 3449 men and 2772 women with 845 (95% CI, 815 to 875) and 514 (95% CI, 494 to 535) events per 100,000 person-years, respectively. The age-adjusted hazard of incident AF was 63% (95% CI, 55% to 72%) higher in men compared with women. Risk factors for AF were generally similar in men and women, except men were taller than women (179 cm vs 166 cm, respectively; P<.001). When controlling for height, the difference in hazard of incident AF between sexes disappeared. For population attributable risk of AF, height was the most important risk factor investigated and explained 21% and 19% of the risk of incident AF in men and women, respectively. CONCLUSION: A 63% higher risk of incident AF in men compared with women is explained by differences in height.

Training Strategies to Optimize Cardiovascular Durability and Life Expectancy.

The optimal dose of physical activity and best types of exercise for improving cardiovascular (CV) durability and optimizing longevity are unknown. The purpose of this article is to review the recent literature on the effects of duration and intensity of exercise, physical fitness, and specific types of training/sports on long-term CV health and life expectancy. A systematic review of recent studies (2011 to 2022) was conducted using PubMed. Studies were included if they addressed the topic of fitness and/or exercise dose/type and CV health and/or life expectancy. Epidemiological studies show that cardiorespiratory fitness (is inversely related to risk of all-cause mortality, with no increased mortality risk in the most fit cohort. Being unfit is among most potent risk factors for all-cause mortality. Moderate PA (MPA) and vigorous PA (VPA) were associated with reduced CV and all-cause mortality in a recent definitive study. Paradoxically, high doses of MPA reduced both CV and all-cause mortality better than did high doses of VPA. A large meta-analysis showed that strength training was independently associated with lower rates of all-cause mortality and CV disease, though the best outcomes were associated with a cumulative dose of about 60 minutes/week. Physical interactive play is strongly associated with improved life expectancy. Physical fitness is a key determinant of CV health and life expectancy. Moderate to vigorous exercise, strength training and interactive sports are associated with improved life expectancy. Very large volumes of strenuous exercise and/or weightlifting may not be the ideal for optimizing longevity.

PCSK9 inhibitor, ezetimibe, and bempedoic acid: Evidence-based therapies for statin-intolerant patients.

Statins are first-line therapy for treating dyslipidemia because of their low-density lipoprotein cholesterol (LDL-C) lowering efficacy, superior event-reduction data and unrivaled cost-effectiveness. Yet, many people are intolerant of statins, whether due to true adverse events or the nocebo effect, so within one year about two-thirds of primary prevention patients and one-third of secondary prevention patients are no longer taking their prescription. Statins still dominate this landscape, but other agents, often used in combination, potently reduce LDL-C levels, regress atherosclerosis and lower risk of major adverse cardiovascular events (MACE). Ezetimibe lowers LDL-C by reducing intestinal absorption of cholesterol. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower LDL-C by increasing the number and durability of hepatic LDL receptors. Bempedoic acid reduces hepatic cholesterol synthesis. Ezetimibe, PCSK9i and bempedoic are evidence-based, non-statin therapies that synergistically lower LDL-C and reduce risk of MACE; they also have benign side-effect profiles and are generally well tolerated.

Nutraceutical activation of Sirt1: a review.

The deacetylase sirtuin 1 (Sirt1), activated by calorie restriction and fasting, exerts several complementary effects on cellular function that are favourable to healthspan; it is often thought of as an 'anti-aging' enzyme. Practical measures which might boost Sirt1 activity are therefore of considerable interest. A number of nutraceuticals have potential in this regard. Nutraceuticals reported to enhance Sirt1 synthesis or protein expression include ferulic acid, tetrahydrocurcumin, urolithin A, melatonin, astaxanthin, carnosic acid and neochlorogenic acid. The half-life of Sirt1 protein can be enhanced with the natural nicotinamide catabolite N1-methylnicotinamide. The availability of Sirt1's obligate substrate NAD+ can be increased in several ways: nicotinamide riboside and nicotinamide mononucleotide can function as substrates for NAD+ synthesis; activators of AMP-activated kinase-such as berberine-can increase expression of nicotinamide phosphoribosyltransferase, which is rate limiting for NAD+ synthesis; and nutraceutical quinones such as thymoquinone and pyrroloquinoline quinone can boost NAD+ by promoting oxidation of NADH. Induced ketosis-as via ingestion of medium-chain triglycerides-can increase NAD+ in the brain by lessening the reduction of NAD+ mediated by glycolysis. Post-translational modifications of Sirt1 by O-GlcNAcylation or sulfonation can increase its activity, suggesting that administration of glucosamine or of agents promoting hydrogen sulfide synthesis may aid Sirt1 activity. Although resveratrol has poor pharmacokinetics, it can bind to Sirt1 and activate it allosterically-as can so-called sirtuin-activating compound drugs. Since oxidative stress can reduce Sirt1 activity in multiple ways, effective antioxidant supplementation that blunts such stress may also help preserve Sirt1 activity in some circumstances. Combination nutraceutical regimens providing physiologically meaningful doses of several of these agents, capable of activating Sirt1 in complementary ways, may have considerable potential for health promotion. Such measures may also amplify the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in non-diabetic disorders, as these benefits appear to reflect upregulation of Sirt1 and AMP-activated protein kinase activities.

Nutraceutical Prevention of Diabetic Complications-Focus on Dicarbonyl and Oxidative Stress.

Oxidative and dicarbonyl stress, driven by excess accumulation of glycolytic intermediates in cells that are highly permeable to glucose in the absence of effective insulin activity, appear to be the chief mediators of the complications of diabetes. The most pathogenically significant dicarbonyl stress reflects spontaneous dephosphorylation of glycolytic triose phosphates, giving rise to highly reactive methylglyoxal. This compound can be converted to harmless lactate by the sequential activity of glyoxalase I and II, employing glutathione as a catalyst. The transcription of glyoxalase I, rate-limiting for this process, is promoted by Nrf2, which can be activated by nutraceutical phase 2 inducers such as lipoic acid and sulforaphane. In cells exposed to hyperglycemia, glycine somehow up-regulates Nrf2 activity. Zinc can likewise promote glyoxalase I transcription, via activation of the metal-responsive transcription factor (MTF) that binds to the glyoxalase promoter. Induction of glyoxalase I and metallothionein may explain the protective impact of zinc in rodent models of diabetic complications. With respect to the contribution of oxidative stress to diabetic complications, promoters of mitophagy and mitochondrial biogenesis, UCP2 inducers, inhibitors of NAPDH oxidase, recouplers of eNOS, glutathione precursors, membrane oxidant scavengers, Nrf2 activators, and correction of diabetic thiamine deficiency should help to quell this.

Debunking the vegan myth: The case for a plant-forward omnivorous whole-foods diet.

Vegan diets are widely promoted as protective against cardiovascular disease (CVD); however, removing all animal foods from a human's diet usually causes unfavorable health consequences. Our hominin ancestors began consuming meat, fish, seafood, and eggs >2 million years ago. Consequently, humans are genetically adapted to procure nutrients from both plant and animal sources. In contrast, veganism is without evolutionary precedent in Homo sapiens species. Strict adherence to a vegan diet causes predictable deficiencies in nutrients including vitamins B12, B2, D, niacin, iron, iodine, zinc, high-quality proteins, omega-3, and calcium. Prolonged strict veganism increases risk for bone fractures, sarcopenia, anemia, and depression. A more logical diet is a plant-forward omnivorous eating pattern that emphasizes generous consumption of natural, unprocessed foods predominantly from plants. To balance this diet, modest amounts of wholesome animal foods, such wild-caught fish/seafood, pasture-raised meat and eggs, and fermented unsweetened dairy should be consumed regularly.

Monounsaturated Fat vs Saturated Fat: Effects on Cardio-Metabolic Health and Obesity.

For over 40 years saturated fat, the fat found primarily in animal foods, was thought to be the main culprit for increasing cholesterol levels and causing heart disease. During this same time vegetable oils were promoted as being heart healthy because they could lower cholesterol. However, recently the evidence implicating saturated fat as being harmful to heart health has been challenged and more studies are beginning to show the harms from consuming industrially produced vegetable oils. Furthermore, monounsaturated fats, found in olives, olive oil, certain nuts and avocadoes have been promoted as being part of a healthy Mediterranean diet. This paper will provide a brief review comparing the effects of saturated fat to monounsaturated fat.

Could Repeated Cardio-Renal Injury Trigger Late Cardiovascular Sequelae in Extreme Endurance Athletes?

Regular exercise confers multifaceted and well-established health benefits. Yet, transient and asymptomatic increases in markers of cardio-renal injury are commonly observed in ultra-endurance athletes during and after competition. This has raised concerns that chronic recurring insults could cause long-term cardiac and/or renal damage. Indeed, extreme endurance exercise (EEE) over decades has sometimes been linked with untoward cardiac effects, but a causal relation with acute injury markers has not yet been established. Here, we summarize the current knowledge on markers of cardiac and/or renal injury in EEE athletes, outline the possible interplay between cardiac and kidney damage, and explore the roles of various factors in the development of potential exercise-related cardiac damage, including underlying diseases, medication, sex, training, competition, regeneration, mitochondrial dysfunction, oxidative stress, and inflammation. In conclusion, despite the undisputed health benefits of regular exercise, we speculate, based on the intimate link between heart and kidney diseases, that in rare cases excessive endurance sport may induce adverse cardio-renal interactions that under specific, hitherto undefined conditions could result in persistent cardiac damage. We highlight future research priorities and provide decision support for athletes and clinical consultants who are seeking safe strategies for participation in EEE training and competition.