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.

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.

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.

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.

The association of disparities in neighborhood median household income and mortality in patients admitted to the hospital with atrial fibrillation.

BACKGROUND: Lower neighborhood median household income (nMHI) is associated with increased adverse outcomes in patients with atrial fibrillation (AF). However, its effect on mortality is yet unknown. METHODS: Data from the regional United States (U.S.) electronic medical records database, Research Action for Health Network (REACHnet), was extracted for adult patients with AF at Tulane Medical Center over 10 years. Annual nMHI & neighborhood high school graduation (HSG) data was collected from the US Census bureau. Only African Americans (AA) and Caucasians (CC) who had socioeconomic data were included. Low nMHI and low HSG were defined as ≤$25,000 & <90% respectively. High nMHI and HSG were defined as >$50,000 & ≥90% respectively. Primary endpoints were all cause and cardiovascular (CV) mortality. Cox-proportional hazard ratios were used to evaluate the endpoints. RESULTS: We included 4616 patients diagnosed with AF. During a median follow up of 4.6 years, 434 patients died of which 32.7% patients had CV mortality. There was a stepwise decrease in incidence of both all-cause and CV mortality as nMHI increased. Patients with low nMHI had the greatest risk of all-cause mortality (HR 1.9, C.I. 1.2-3.2, P 0.004). The association between low nMHI and all-cause mortality persisted after adjusting for age, sex, race, HSG and stroke risk factors using CHA2DS2VASC, delta CHA2DS2VASC scores and oral anticoagulant use. CV mortality followed a similar trend as all-cause mortality, however, this association was not significant after adjusting for the above variables. Apart from low nMHI, CHA2DS2VASC delta CHA2DS2VASC were statistically significant independent predictors of both all-cause and CV mortality. CONCLUSION: Low nMHI is an independent risk factor for all cause and CV mortality in AF. Higher burden of co-morbidities is the driving force behind this disparity. Future studies should evaluate the role of educational and therapeutic intervention in these populations to reduce mortality.

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.

Early-Onset Cardiovascular Disease From Cocaine, Amphetamines, Alcohol, and Marijuana.

Cardiovascular disease (CVD), a disease typically associated with aging and the definitive leading cause of death worldwide, now threatens young and middle-aged populations. Recreational abuse of alcohol, marijuana, cocaine, and amphetamine-type stimulants has been an escalating public health problem for decades, but now use of these substances has become a significant contributor to early-onset CVD. While this remains a global phenomenon, the epicentre of substance abuse is rooted in North America, where it has been exacerbated by the response to the COVID-19 pandemic. For the first time in history, the United States crossed 100,000 overdose-related deaths in a calendar year. Sadly, Canada's recreational drug abuse problem closely mirrors that of the US. This is indicative of the larger public health crisis, as we now know that these substances are cardiotoxic and are contributing to the rising levels of premature chronic CVD, including hypertension, arrhythmias, heart failure, stroke, myocardial infarction, arterial dissection, sudden cardiac death, and early mortality.

Prevention and Treatment of Atrial Fibrillation via Risk Factor Modification.

Atrial fibrillation (AF) is the most common clinically significant arrhythmia, and it increases stroke risk. A preventive approach to AF is needed because virtually all treatments such as cardioversion, antiarrhythmic drugs, ablation, and anticoagulation are associated with high cost and carry significant risk. A systematic review was performed to identify effective lifestyle-based strategies for reducing primary and secondary AF. A PubMed search was performed using articles up to March 1, 2021. Search terms included atrial fibrillation, atrial flutter, exercise, diet, metabolic syndrome, type 2 diabetes mellitus, obesity, hypertension, stress, tobacco smoking, alcohol, Mediterranean diet, sodium, and omega-3 fatty acids. Additional articles were identified from the bibliographies of retrieved articles. The control of hypertension, ideally with a renin-angiotensin-aldosterone system inhibitor, is effective for preventing primary AF and recurrence. Obstructive sleep apnea is a common cause of AF, and treating it effectively reduces AF episodes. Alcohol increases the risk of AF in a dose-dependent manner, and abstinence reduces risk of recurrence. Sedentary behavior and chronic high-intensity endurance exercise are both risk factors for AF; however, moderate physical activity is associated with lower risk of AF. Recently, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 agonists have been associated with reduced risk of AF. Among overweight/obese patients, weight loss of ≥10% is associated with reduced AF risk. Lifestyle changes and risk factor modification are highly effective for preventing AF.

An Update on Omega-3 Polyunsaturated Fatty Acids and Cardiovascular Health.

Interest in the potential cardiovascular (CV) benefits of omega-3 polyunsaturated fatty acids (Ω-3) began in the 1940s and was amplified by a subsequent landmark trial showing reduced CV disease (CVD) risk following acute myocardial infarction. Since that time, however, much controversy has circulated due to discordant results among several studies and even meta-analyses. Then, in 2018, three more large, randomized trials were released-these too with discordant findings regarding the overall benefits of Ω-3 therapy. Interestingly, the trial that used a higher dose (4 g/day highly purified eicosapentaenoic acid (EPA)) found a remarkable, statistically significant reduction in CVD events. It was proposed that insufficient Ω-3 dosing (<1 g/day EPA and docosahexaenoic acid (DHA)), as well as patients aggressively treated with multiple other effective medical therapies, may explain the conflicting results of Ω-3 therapy in controlled trials. We have thus reviewed the current evidence regarding Ω-3 and CV health, put forth potential reasoning for discrepant results in the literature, highlighted critical concepts such as measuring blood levels of Ω-3 with a dedicated Ω-3 index and addressed current recommendations as suggested by health care professional societies and recent significant scientific data.

Reevaluating America's Latest Pharmaceutical Trend: The Cardiovascular Risk of Cannabis.

For the first time in the history of the modern era smoking tobacco is not the most popular inhaled product. After a flurry of legislature, cannabis has come to the forefront of both medicinal and recreational drug use. A confluence of evidence suggests, however, that marijuana consumption may confer a particularly worrisome cardiovascular risk profile. While combustible forms still contain many of the same harmful chemicals found in tobacco such as aromatic amines, polycyclic aromatic hydrocarbons (PAHs), and nitric oxide, some in even greater concentrations than tobacco, edible preparations have been evidenced to cause more cardiovascular-related emergency department visits. Importantly, this body of evidence suggests that cannabis use may be placing a younger, healthier population at risk of suffering major cardiovascular accidents particularly in the moments immediately following consumption. With males in their 30's apparently bearing the brunt of this burden, cannabis consumption has been associated with an increase in ischemic stroke-a blockage in the cerebral or cerebellar vasculature-and almost a fivefold increase in myocardial infarction. THC containing compounds have also been linked to vascular complications ranging from mild plaques to total arterial occlusion resulting in claudication, rest pain, ischemic ulceration and gangrene-recently termed cannabis arteritis. While this research remains in a nascent stage, marijuana consumption seems to be predisposing a youthful, traditionally low health risk cohort to a variety of major adverse cardiovascular events.

A Hunter-Gatherer Exercise Prescription to Optimize Health and Well-Being in the Modern World.

There has been considerable innovation and advancement in the field of exercise and physical activity (PA). In regards to the battle against chronic non-communicable disease, however, we believe the model of PA that would prove most salutary is one closely mimicking that of our hunter-gatherer ancestors. For the purpose of longevity, the human body and our genetic makeup have been evolutionarily adapted to respond best to moderate amounts of high-intensity interval training, in conjunction with high amounts of low intensity exercise. Moreover, to optimize resiliency and cardiorespiratory fitness, a hunter-gatherer fitness regimen must include cross training targeted at flexibility, balance and strength. Though not commonly understood, the health benefits from exercise comprise a reverse J-curve. The endurance athletes residing on the furthest reaches of the PA spectrum appear to lose a substantial portion of the exercise-related longevity and cardiovascular benefits due to cardiac overuse injury. Conversely, there is an emerging body of evidence suggesting leisure time exercise done with peers in a natural environment is significantly superior to that training done in solitude. This idea of the "power of play" lends support to the ancestral model of PA whereby humans are evolutionary adapted to be highly social, outdoor creatures capable of a diverse range of PA at varying intensities.

Takotsubo Syndrome: Cardiotoxic Stress in the COVID Era.

Takotsubo syndrome (TTS), also known as stress cardiomyopathy and broken heart syndrome, is a neurocardiac condition that is among the most dramatic manifestations of psychosomatic disorders. This paper is based on a systematic review of TTS and stress cardiomyopathy using a PubMed literature search. Typically, an episode of severe emotional or physical stress precipitates regions of left ventricular hypokinesis or akinesis, which are not aligned with a coronary artery distribution and are out of proportion to the modest troponin leak. A classic patient with TTS is described; one who had chest pain and dyspnea while watching an anxiety-provoking evening news program on the coronavirus disease 2019 (COVID-19) pandemic. An increase in the incidence of TTS appears to be a consequence of the COVID-19 pandemic, with the TTS incidence rising 4.5-fold during the COVID-19 pandemic even in individuals without severe acute respiratory syndrome coronavirus 2 infection. Takotsubo syndrome is often mistaken for acute coronary syndrome because they both typically present with chest pain, electrocardiographic changes suggesting myocardial injury/ischemia, and troponin elevations. Recent studies report that the prognosis for TTS is similar to that for acute myocardial infarction. This review is an update on the mechanisms underlying TTS, its diagnosis, and its optimal management.

Therapeutic Potential of TNF-α Inhibition for Alzheimer's Disease Prevention.

BACKGROUND: Alzheimer's disease (AD) is increasingly prevalent and over 99% of drugs developed for AD have failed in clinical trials. A growing body of literature suggests that potent inhibitors of tumor necrosis factor-α (TNF-α) have potential to improve cognitive performance. OBJECTIVE: In this review, we summarize the evidence regarding the potential for TNF-α inhibition to prevent AD and improve cognitive function in people at risk for dementia. METHODS: We conducted a literature review in PubMed, screening all articles published before July 7, 2019 related to TNF blocking agents and curcumin (another TNF-α inhibitor) in the context of AD pathology. The keywords in the search included: AD, dementia, memory, cognition, TNF-α, TNF inhibitors, etanercept, infliximab, adalimumab, golimumab, and curcumin. RESULTS: Three large epidemiology studies reported etanercept treated patients had 60 to 70% lower odds ratio (OR) of developing AD. Two small-randomized control trials (RCTs) demonstrated an improvement in cognitive performance for AD patients treated with etanercept. Studies using animal models of dementia also reported similar findings with TNF blocking agents (etanercept, infliximab, adalimumab, Theracurmin), which appeared to improve cognition. A small human RCT using Theracurmin, a well-absorbed form of curcumin that lowers TNF-α, showed enhanced cognitive performance and decreased brain levels of amyloid-ß plaque and tau tangles. CONCLUSION: TNF-α targeted therapy is a biologically plausible approach to the preservation of cognition, and warrants larger prospective RCTs to further investigate potential benefits in populations at risk of developing AD.