Highlights of Cardiovascular Disease Prevention Studies Presented at the 2022 American Heart Association Scientific Sessions.

PURPOSE OF REVIEW: Summarize selected late-breaking science on cardiovascular (CV) disease prevention presented at the 2022 scientific session of the American Heart Association (AHA). RECENT FINDINGS: The PROMINENT trial compared pemafibrate to a placebo in patients with type 2 diabetes mellitus (DM) and mild-to-moderate hypertriglyceridemia and high-density lipoprotein cholesterol (HDL-C)<40 mg/dL who were already on guideline-directed statin therapy. The RESPECT-EPA trial compared purified eicosapentaenoic acid (EPA) and statin therapy to statin therapy alone for secondary prevention of atherosclerotic CV disease (ASCVD). SPORT compared the efficacy of low-dose statin therapy with a placebo and six commonly used dietary supplements on lipid and inflammatory markers. Data from long-term follow-up of the FOURIER-OLE study was presented to evaluate the efficacy of very low low-density lipoprotein cholesterol (LDL-C) levels with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Patient-level meta-analyses evaluated the association of statin therapy with new-onset DM and worse glycemic control. PROMPT-LIPID evaluated if automated electronic alerts to physicians with guideline-based recommendations improved the management of hyperlipidemia in patients at very high risk. NOTIFY-1 trial evaluated if notifying physicians and patients about coronary artery calcium (CAC) scores in non-ECG gated computed tomography scans led to increased prescription of statin therapy for primary ASCVD prevention. The DCP trial compared hydrochlorothiazide and chlorthalidone for blood pressure control and CV outcomes in hypertension. The CRHCP study compared the effectiveness of a village doctor for hypertension management and CV outcomes in rural areas of China. The QUARTET USA trial compared the effectiveness and safety of 4 antihypertensive medications in ultra-low doses with angiotensin-receptor blocker monotherapy. The late-breaking science presented at the 2022 scientific session of the AHA paves the way for future pragmatic trials and provides meaningful information to guide management strategies in cardiovascular disease prevention.

Diagnosing Frailty in Primary Care Practice.

Frailty is a complex age-related clinical condition with increased vulnerability to negative health outcomes that manifest as a multidimensional syndrome and hence, a challenge to identify at-risk populations. We aim to summarize the implementation of strategies to diagnose fragility in family practice using current evidence. We searched the PubMed and Google Scholar databases for relevant articles, using the Medical Subject Headings (MeSH) terms "Frailty," "Frailty Scales," and "Primary Health Care." All original research articles on the elderly population (65 years of age or older) published in English and the last five years were included. Frailty diagnosis has resulted in positive outcomes in the overall literature. Recent hospital admission may indicate a health problem that can end up in a negative outcome and has been often described as associated with frailty. It was also shown to affect the intensive care units' mortality, in-hospital mortality, and long-term mortality. However, multiple screening instruments have been developed and validated to improve feasibility in clinical practice. The frequent lack of agreement between frailty instruments has slowed the broad implementation of these tools. The impacts of frailty warrant an upstream, proactive, holistic, interprofessional primary care approach to its identification, assessment, and management. It is a preventable disorder; identifying elderly patients at risk in primary care can help shape appropriate care processes tailored to their needs. This literature review aims to demonstrate the importance and strategies in identifying frailty in primary care settings and assess its impact on several outcomes.

Supplemental calcium and vitamin D and long-term mortality in aortic stenosis.

OBJECTIVE: Calcium metabolism has long been implicated in aortic stenosis (AS). Studies assessing the long-term safety of oral calcium and/or vitamin D in AS are scarce yet imperative given the rising use among an elderly population prone to deficiency. We sought to identify the associations between supplemental calcium and vitamin D with mortality and progression of AS. METHODS: In this retrospective longitudinal study, patients aged ≥60 years with mild-moderate native AS were selected from the Cleveland Clinic Echocardiography Database from 2008 to 2016 and followed until 2018. Groups were stratified into no supplementation, supplementation with vitamin D alone and supplementation with calcium±vitamin D. The primary outcomes were mortality (all-cause, cardiovascular (CV) and non-CV) and aortic valve replacement (AVR), and the secondary outcome was AS progression by aortic valve area and peak/mean gradients. RESULTS: Of 2657 patients (mean age 74 years, 42% women) followed over a median duration of 69 months, 1292 (49%) did not supplement, 332 (12%) took vitamin D alone and 1033 (39%) supplemented with calcium±vitamin D. Calcium±vitamin D supplementation was associated with a significantly higher risk of all-cause mortality (absolute rate (AR)=43.0/1000 person-years; HR=1.31, 95% CI (1.07 to 1.62); p=0.009), CV mortality (AR=13.7/1000 person-years; HR=2.0, 95% CI (1.31 to 3.07); p=0.001) and AVR (AR=88.2/1000 person-years; HR=1.48, 95% CI (1.24 to 1.78); p<0.001). Any supplementation was not associated with longitudinal change in AS parameters in a linear mixed-effects model. CONCLUSIONS: Supplemental calcium with or without vitamin D is associated with lower survival and greater AVR in elderly patients with mild-moderate AS.

Multivariate approach for optimization of galactomannan extraction from seeds of Egyptian Trigonella foenum-graecum with insights on its pharmacological activities.

Response surface methodology (RSM), based on the central composite design (CCD), was used for the systemic optimization of galactomannan (GAL) extraction from Trigonella foenum-graecum. GAL was reported to possess a variety of pharmacological effects and is commercialized as adjuvant therapy for diabetes, obesity, and hypercholesterolemia. Seven process variables were evaluated (12 experiments in a Plackett-Burman design) to screen the significant factors affecting the extraction yield. The three most significant variables were evaluated in CCD at two levels (twenty experimental designs) to obtain the utmost percentage yield. The yield of GAL extraction was influenced by the volume of the precipitating solvent to the volume of the soaking water and reached a maximum of 10.1% at a ratio of 3.633:1. Exploring the antioxidant, cytotoxic, and anti-microbial activities of GAL revealed cytotoxic activity against LS174-T colorectal cancer cells, weak antioxidant activity, and moderate antimicrobial activity against Candida tropicalis and Micrococcus species.

Over a century since ephedrine discovery: an updated revisit to its pharmacological aspects, functionality and toxicity in comparison to its herbal extracts.

Ephedrine, a sympathomimetic amine that exhibits several adrenaline actions, is a plant alkaloid that is a common ingredient in several cold, asthma and narcolepsy treatment preparations, and in obesity management and sport medicine. Its principal action mechanism relies on its direct adrenergic actions as well as indirect role that involves the release of epinephrine and norepinephrine, thus increasing the activity of epinephrine and norepinephrine at the postsynaptic α and ß receptors. Nevertheless, its serious side effects, including stroke, heart attack, drug abuse and interactions, have never been comprehensively reviewed. We conducted a systematic review of data on ephedrine, including its occurrence in functional foods, pharmacological aspects, metabolism, pharmaco/toxicokinetics and clinical features. Furthermore, a review of ephedrine natural structural analogues with regards to their differential adrenergic receptor binding affinities, food interaction, and their impact on the pharmacokinetics and effects relative to ephedrine are presented for the first time, and in comparison to its action when present in herbs.

Oral Calcium Supplements Associate With Serial Coronary Calcification: Insights From Intravascular Ultrasound.

OBJECTIVES: This study sought to evaluate and assess the extent of serial coronary artery calcification in response to oral calcium supplementation. BACKGROUND: Oral calcium supplements are frequently used despite their cardiovascular safety remaining controversial. Their effects on serial coronary calcification are not well established. METHODS: In a post hoc patient-level analysis of 9 prospective randomized trials using serial coronary intravascular ultrasound, changes in serial percentage of atheroma volume (PAV) and calcium indices (CaI) were compared in matched segments of patients coronary artery disease who were receiving concomitant calcium supplements (n = 447) and in those who did not receive supplements (n = 4,700) during an 18- to 24-month trial period. RESULTS: Patients (mean age 58 ± 9 years; 73% were men; 43% received concomitant high-intensity statins) demonstrated overall annualized changes in PAV and CaI with a mean of -0.02 ± 1.9% (p = 0.44) and a median of 0.02 (interquartile range: 0.00 to 0.06) (p < 0.001) from baseline, respectively. Following propensity-weighted mixed modeling adjusting for treatment and a range of demographic, clinical, ultrasonic, and laboratory parameters (including but not limited to sex, race, baseline, and annualized change in PAV, baseline CaI, concomitant high-intensity statins, diabetes mellitus, renal function), there were no significant between-group differences in annualized changes in PAV (least-squares mean: 0.09; 95% confidence interval [CI]: -0.20 to 0.37 vs. 0.01; 95% CI: -0.27 to 0.29; p = 0.092) according to calcium supplement intake. Per a multivariable logistic regression model accounting for the range of covariates described, calcium supplementation independently associated with an increase in annualized CaI (odds ratio: 1.15; 95% CI: 1.05 to 1.26; p = 0.004). CONCLUSIONS: Oral calcium supplementation may increase calcium deposition in the coronary vasculature independent of changes in atheroma volume. The impact of these changes on plaque stability and cardiovascular outcomes requires further investigation.

The Utility of Rapid Atrial Pacing Immediately Post-TAVR to Predict the Need for Pacemaker Implantation.

OBJECTIVES: The aim of this study was to determine the utility of rapid atrial pacing immediately after transcatheter aortic valve replacement (TAVR) to predict the need for permanent pacemaker implantation (PPI). BACKGROUND: Risk stratification for patients without high-grade atrioventricular block (AVB) after TAVR is imprecise and based on anatomic considerations, electrocardiographic characteristics, and clinical suspicion. A more reliable assessment is necessary to minimize inpatient rhythm monitoring and/or reduce unnecessary PPI. METHODS: Consecutive patients undergoing TAVR at 2 centers were included. After valve implantation in patients without pacemakers who did not have complete heart block or atrial fibrillation, the temporary pacemaker was withdrawn from the right ventricle and placed in the right atrium. Rapid atrial pacing was performed from 70 to 120 beats/min, and patients were assessed for the development of Wenckebach AVB. Patients were then followed for clinical outcomes, including PPI. RESULTS: A total of 284 patients were included. Of these, 130 (45.8%) developed Wenckebach AVB. There was a higher rate of PPI within 30 days of TAVR among the patients who developed Wenckebach AVB (13.1% vs. 1.3%; p < 0.001), with a negative predictive value for PPI in the group without Wenckebach AVB of 98.7%. A greater percentage of patients receiving self-expanding valves required PPI than those receiving a balloon-expandable valves (15.9% vs. 3.7%; p = 0.001), though these rates were still relatively low among patients who did not develop Wenckebach AVB (2.9% and 0.8%). CONCLUSIONS: Atrial pacing post-TAVR is easily performed and can help identify patients who may benefit from extended rhythm monitoring. Patients who did not develop pacing-induced Wenckebach AVB demonstrated an extremely low likelihood of PPI.

Hyperbaric oxygen and aerobic exercise in the long-term treatment of fibromyalgia: A narrative review.

Chronic pain is one of the most common clinical presentations in the primary care settings. In the US, Fibromyalgia (FM) affects about 1-3% of adults and commonly occurs in adults between the ages of 40-50 years. FM causes widespread muscular pain and tenderness with hyperalgesia and allodynia and may be associated with other somatic complaints. Hyperbaric oxygen therapy (HBOT) has been utilized and has recently shown promising effects in the management of FM and other chronic pain disorders. In HBOT, the intermittent breathing of 100% oxygen in a pressurized chamber where the pressure is higher than 1 atmosphere absolute (ATA) has been utilized. HBOT exhibits a significant anti-inflammatory effect through reducing production of glial cells and inflammatory mediators which results in pain alleviation in different chronic pain conditions. HBOT can also influence neuroplasticity and affects the mitochondrial mechanisms resulting in functional brain changes. In addition to that, HBOT stimulates nitric oxide (NO) synthesis which helps in alleviating hyperalgesia and NO-dependent release of endogenous opioids which seemed to be the primary HBOT mechanism of antinociception. Moreover, aerobic exercise and meditative movement therapies (MMT) have gained attention for their role in pain alleviation through different anti-inflammatory and antioxidant mechanisms. In this review, we aim to elucidate the different mechanisms of HBOT and aerobic exercise in attenuating pain as adjuvant therapy in the multidisciplinary treatment strategy of chronic pain, and more particularly fibromyalgia.

Investigation of brain-derived neurotrophic factor (BDNF) gene expression in hypothalamus of obese rats: Modulation by omega-3 fatty acids.

PURPOSE: The aim of this study was investigating the effect of omega-3 fatty acids (ω-3 FAs) on brain-derived neurotrophic factor (BDNF) gene expression, using in vivo and in vitro models, to unravel the potential mechanisms of polyunsaturated fatty acids use in obesity. MATERIALS AND METHODS: Twenty-nine Sprague-Dawley rats were divided into three groups; lean controls fed normal chow diet for 14 weeks, obese controls fed 60% of their diet as saturated fats for 14 weeks, and ω-3 FAs-treated rats fed 60% saturated fat diet for 14 weeks with concomitant oral administration of 400 mg/kg/day ω-3 FAs, mainly docosahexaenoic acid and EPA, from week 12 to week 14. For the in vitro experiment, hypothalamic cells from six obese rats were cultured in the presence of different concentrations of ω-3 FAs to determine its direct effect on BDNF expression. RESULTS: In vivo results showed that obesity has negative effect on BDNF gene expression in rat hypothalamus that was reversed by administration of ω-3 FAs. Obese rats showed hypercholesterolemia, hypertriglyceridemia, normoinsulinemia, hyperglycemia and hyperleptinemia. Treatment with ω-3 FAs showed significant decrease in serum total cholesterol and TAG. Also serum glucose level and HOMA index were decreased significantly. In vitro results demonstrated the increase in BDNF expression by ω-3 FAs in a dose-dependent manner. CONCLUSIONS: Obesity causes down-regulation of BDNF gene expression that can be reversed by ω-3 FAs treatment, making them an interesting treatment approach for obesity and metabolic disease.

Investigating the cardio-protective abilities of supplemental L-arginine on parameters of endothelial function in a hypercholesterolemic animal model.

Endothelial dysfunction is now widely recognized as an early marker of cardiovascular disease, making its treatment, or complete avoidance, an emerging, interesting therapeutic target. This study investigated the ability of the highly intriguing amino acid L-arginine to influence endothelial function. Its therapeutic potential is also compared to that of known cardiovascular medications, namely nitroglycerin [a nitric oxide (NO) donor] and enalapril [an angiotensin-converting enzyme (ACE) inhibitor]. Fifty male New Zealand rabbits were included in the study, divided into 5 equal groups: control, hypercholesterolemia (untreated), hypercholesterolemia (+L-arginine), hypercholesterolemia (+enalapril), and hypercholesterolemia (+nitroglycerin). Biochemical investigations included measurement of circulating NOx, malondialdehyde (MDA), and lipid profile markers, as well as dimethylarginine dimethylaminohydrolase (DDAH) and ACE activities. Furthermore, aortic ACE activity and blood platelet aggregation were estimated. A histopathological examination and intimal thickness measurement were also conducted. Compared to the untreated hypercholesterolemic group, all agents were capable of positively influencing MDA levels, platelet aggregation and intimal thickness; however, only the L-arginine group was capable of beneficially and significantly altering both NOx levels and serum and aortic ACE activities. No agents were capable of modulating serum DDAH activity inhibited by hypercholesterolemia. Based on the results of this study, L-arginine appears to be a novel cardio-protective agent, illustrated by its ability to ameliorate the deleterious effects of hypercholesterolemia on endothelial function, in a manner comparable to, and sometimes more potent than, commonly used cardiovascular medications.

Vitamin D deficiency and cardiovascular disease: potential mechanisms and novel perspectives.

Interest in contemporary vitamin D research has been sparked in recent years, stemming from the identification of vitamin D receptors in virtually all cells as well as the enzymatic machinery necessary to produce its active form. Both epidemiological and in-vitro studies have linked vitamin D deficiency to enigmatic diseases including cardiovascular disease; however, a clear mechanistic link remains missing. This review highlights conclusions of observational studies, in-vitro experiments and randomized-controlled trials that aimed to link deficiency of the sunshine vitamin to one of the leading causes of death in the world, cardiovascular disease. Furthermore, putative mechanisms viewed from a novel perspective are also discussed.

Protective effect of L-arginine in experimentally induced myocardial ischemia: comparison with aspirin.

OBJECTIVE: Coronary artery diseases including myocardial ischemia (MI) remain one of the leading causes of death worldwide. This study was designed to compare the protective effect of L-arginine versus aspirin from the biochemical changes associated with MI injury. EXPERIMENTAL DESIGN: Four groups of male New Zealand white rabbits were investigated. Normal group (n = 8) rabbits were fed standard chow pellets, untreated MI group (n = 16), where hypercholesterolemia was induced by feeding the animals with a diet containing 2% cholesterol for 28 days, L-arginine group (n = 12) rabbits were fed a 2% cholesterol-enriched diet in conjunction with L-arginine (2.25 g %) in drinking water for 28 days, and aspirin group (n = 12) rabbits were fed 2% cholesterol-enriched diet in conjunction with aspirin administered orally (0.7 mg/kg per d) for 28 days. After 28 days, MI was induced in all groups, except the normal group, by a single subcutaneous (sc) injection of isoproterenol hydrochloride (0.2 mg/kg body weight [bw]). Animals were sacrificed 6 hours later. RESULTS: Our results showed that L-arginine was more effective than aspirin in reducing platelet aggregation, reducing low-density lipoprotein (LDL) oxidizability, preventing aortic intimal thickening, and maintaining histological architecture of the myocardium. Both drugs, however, had similar positive effects on plasma fibrinogen levels and on the prevention of myocardial release of cardiac troponin I and creatine kinase-MB. The effect on hypercholesterolemia was insignificant for both drugs. Aspirin was more effective than L-arginine in prolonging prothrombin time. CONCLUSION: L-arginine supplementation represents a potentially novel nutritional strategy for preventing and treating coronary artery diseases especially in cases of aspirin resistance and/or hypersensitivity.

Biochemical study of the anti-diabetic action of the Egyptian plants fenugreek and balanites.

Fenugreek and Balanites are two plants commonly used in Egyptian folk medicine as hypoglycemic agents. In the present study, the effects of 21 days oral administration of Fenugreek seed and Balanites fruit extracts (1.5 g/kg bw) on the liver and kidney glycogen content and on some key liver enzymes of carbohydrate metabolism in STZ-diabetic rats were studied. In addition, the effects of these two plant extracts on the intestinal alpha-amylase activity in vitro and starch digestion and absorption in vivo were also examined. Results indicated that single injection of STZ (50 mg/kg bw) caused 5-folds increase in the blood glucose level, 80% reduction in serum insulin level, 58% decrease in liver glycogen and 7-folds increase in kidney glycogen content as compared to the normal levels. The activity of glucose-6-phosphatase was markedly increased, whereas, the activities of both glucose-6-phosphate dehydrogenase and phospho-fructokinase were significantly decreased in the diabetic rat liver. Administration of Fenugreek extract to STZ-diabetic rats reduced blood glucose level by 58%, restored liver glycogen content and significantly decreased kidney glycogen as well as liver glucose-6-phosphatase activity. Meanwhile, Balanites extract reduced blood glucose level by 24% and significantly decreased liver glucose-6-phosphatase activity in diabetic rats. On the other hand, our results demonstrated that both the Fenugreek and Balanites extracts were able to in vitro inhibit alpha-amylase activity in dose-dependent manner. Fenugreek was more potent inhibitor than Balanites. This inhibition was reversed by increasing substrate concentration in a pattern which complies well with the effect of competitive inhibitors. Furthermore, this in vitro inhibition was confirmed by in vivo suppression of starch digestion and absorption induced by both plant extracts in normal rats. These findings suggest that the hypoglycemic effect of Fenugreek and Balanites is mediated through insulinomimetic effect as well as inhibition of intestinal alpha-amylase activity.