Natural AMPK Activators in Cardiovascular Disease Prevention

Cardiovascular diseases (CVD), as a life-threatening global disease, is receiving worldwide attention. Seeking novel therapeutic strategies and agents is of utmost importance to curb CVD. AMP-activated protein kinase (AMPK) activators derived from natural products are promising agents for cardiovascular drug development owning to regulatory effects on physiological processes and diverse cardiometabolic disorders. In the past decade, different therapeutic agents from natural products and herbal medicines have been explored as good templates of AMPK activators. Hereby, we overviewed the role of AMPK signaling in the cardiovascular system, as well as evidence implicating AMPK activators as potential therapeutic tools. In the present review, efforts have been made to compile and update relevant information from both preclinical and clinical studies, which investigated the role of natural products as AMPK activators in cardiovascular therapeutics.

Recent Advances in Nanomaterials for Therapy and Diagnosis of Cardiovascular Disease

Cardiovascular diseases (CVDs) are among the world’s widely affected disorders, including ischemia and stroke. Acute Myocardial ischemia (AMI) is a deadly disease caused by irreversible damage to the left ventricular heart tissues. The thromboembolic plaque stops the oxygen supply to the main blood vessels and ventricles. During chronic inflammation, myocardial infarction and free radicals damage stable myocardium, smooth muscles cell, and epithelial cells caused by outer membrane loss and ventricular wall smoothing and dilation. Specially constructed scaffolds made of biological and nanoparticles have been created to shield the left ventricle from further injury and recover ischemic endothelial cells. Preclinical experiments have demonstrated that scaffolds containing growth factors and cells will regenerate ischemic tissue into a stable pericardium in good working order. Various medicinal approaches that treat cardiovascular disease conditions at different stages are discussed in this review article, with biomaterials receiving special attention. This review further addresses the manipulation and manufacturing of biomedical implantable devices using nanomedicine methods and drug delivery principles. The use of graphene and exosomal nanovesicle in cardiovascular therapeutics recently progressed in research studies.

Mechanisms and Models in Heart Failure

Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review, we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for 4 new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The 4 new therapeutic classes discussed are ARNIs, SGLT2 (sodium-glucose cotransporter 2) inhibitors, soluble guanylate cyclase stimulators, and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances was informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2 inhibitors is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades and may lead to rethinking or expanding our current conceptual models for HFrEF.

Providing Validation Evidence for a Clinical-Science Module: Improving Testing Reliability with Quizzes

Description of the Problem: High-stakes decision-making should have sound validation evidence; reliability is vital towards this. A short exam may not be very reliable on its own within didactic courses, and so supplementing it with quizzes might help. But how much? This study’s objective was to understand how much reliability (for the overall module-grades) could be gained by adding quiz data to traditional exam data in a clinical-science module. The Innovation: In didactic coursework, quizzes are a common instructional strategy. However, individual contexts/instructors can vary quiz use formatively and/or summatively. Second-year PharmD students took a clinical-science course, wherein a 5-week module focused on cardiovascular therapeutics. Generalizability Theory (G-Theory) combined seven quizzes leading to an exam into one module-level reliability, based on a model where students were crossed with items nested in eight fixed testing occasions (mGENOVA used). Furthermore, G-Theory decision-studies were planned to illustrate changes in module-grade reliability, where the number of quiz-items and relative-weighting of quizzes were altered. Critical Analysis: One-hundred students took seven quizzes and one exam. Individually, the exam had 32 multiple-choice questions (MCQ) (KR-20 reliability=0.67), while quizzes had a total of 50MCQ (5-9MCQ each) with most individual quiz KR-20s less than or equal to 0.54. After combining the quizzes and exam using G-Theory, estimated reliability of module-grades was 0.73; improved from the exam alone. Doubling the quiz-weight, from the syllabus’ 18% quizzes and 82% exam, increased the composite-reliability of module-grades to 0.77. Reliability of 0.80 was achieved with equal-weight for quizzes and exam. Next Steps: Expectedly, more items lent to higher reliability. However, using quizzes predominantly formatively had little impact on reliability, while using quizzes more summatively (i.e., increasing their relative-weight in module-grade) improved reliability further. Thus, depending on use, quizzes can add to a course’s rigor.

Epoxy Fatty Acids: From Salt Regulation to Kidney and Cardiovascular Therapeutics

Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.

Simvastatin Therapy Attenuates Memory Deficits that Associate to Brain Monocyte Infiltration in Chronic Hypercholesterolemic ApoE-/- Mice

Background and PurposeMetabolic and cardiovascular disease is the most prevalent disease burden in the world and risk factor for progressive cognitive decline. Evidence associates cardiovascular risk factors to unfavorable systemic and neuro-inflammation and to cognitive decline. Cardiovascular therapeutics (e.g., statins and antihypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown.Experimental ApproachBy using flow cytometry, Elisa, qPCR, Western blotting and object recognition tasks, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice.Key resultsChronic hypercholesterolemia associated to moderate BP elevations and apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation associated to chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, linking to memory dysfunction. Therapeutic administration of cholesterol-lowering simvastatin reduced BP, systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice. BP-lowering therapy alone (i.e. hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. When administered in combination, it reduced effectiveness of statin therapy in some instances.Conclusions and ImplicationsOur study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment. Cholesterol-lowering therapy provides effectiveness to attenuate memory impairment and inflammatory events and hence, emerges as safe therapeutic strategy to control hypercholesterolemia-associated memory decline.What is already knowncardiovascular risk factors link to unfavorable systemic and neuro-inflammation and to cognitive declinecardiovascular therapeutics possess immune-modulatory functions in parallel to their principle cholesterol- or blood pressure-lowering propertiesWhat this study addslinks chronic hypercholesterolemia in mice to specific immune responses and the development of memory impairmentfavorable outcomes in respect to neuro-inflammation and memory function in hypercholesterolemic mice after statin therapyClinical significanceopens the door for available CVD therapeutics with long-term safety profiles to managing cognitive dysfunctiontargeted monitoring of inflammatory signature in patients with high cardiovascular burden (surrogate biomarker of cognitive decline)