Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease.

IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.

A tool to help patients visualize ASCVD risk and the potential impact of risk-lowering interventions.

Risk assessment is a fundamental step in the current approach to primary prevention of atherosclerotic cardiovascular disease (ASCVD). When considering pharmacotherapy for primary prevention of ASCVD, current prevention guidelines in the United States recommend the use of the pooled cohort equations (PCE) to assess 10-year ASCVD risk and begin the important process of shared decision-making between patients and clinicians. Clinicians should support patients in the decisionmaking process by turning raw data into information that is easily understood and more effectively utilized for decisions around the treatment plan. In this work, we present a tool to help patients visualize ASCVD risk and the projected impact of risk-lowering interventions. We believe this visual tool can facilitate communication of ASCVD risk to patients, and improve patient understanding of risk and the potential impact of risklowering interventions, which we believe may help patients make more informed, empowered decisions that achieve greater risk reduction.

Considerations for carotid artery disease management in a frail population.

Carotid artery stenosis is highly prevalent in older adults. Generally, symptomatic patients are treated with medical therapy and revascularization by either a carotid endarterectomy (CEA), carotid artery stent (CAS), or transcarotid artery revascularization (TCAR). In asymptomatic patients it remains unclear whether revascularization is beneficial. Novel and less invasive techniques mitigate some of the risk of revascularization, allowing patients who previously were too high risk to now be candidates. Despite this, any invasive procedure has risks and potential for complications. Furthermore, it can be unclear whether certain patient populations, such as older adults and those with multiple chronic medical conditions will derive benefit from an intervention. Frailty is an assessment tool that can be used to guide decision-making process for older patients. In this review we discuss the management of carotid artery stenosis in older adults, its relationship with frailty, and how a frailty assessment can be integrated into the shared decision-making process to determine the optimal treatment plan for each patient.

Evolution of Knowledge in the Treatment of Long-Standing Atrial Fibrillation in a UK Tennis Champion.

During the last several decades, there have been major advances in the evolution of drug therapies for the rate management of atrial fibrillation (AF). Initially, the drug of choice was digoxin but currently, the drug of choice is beta-adrenergic blockers. Drug therapies for stroke prevention in AF have also evolved. Initially, the drug of choice was aspirin, then became warfarin, and now in the current era, there are newer oral anticoagulants, such as apixaban, which are the preferred drugs. In this case report, we present the details of a 79-year-old athletic man who developed palpitations due to rapid AF at age 31. At the time of his initial presentation, he was treated with digoxin and aspirin and has remained on these drugs to the present. In 1973, 28 years after his initial presentation, he became the United Kingdom (UK) amateur tennis champion in the 55 and over division at age 59.  At present, the clinical applications of advances in the management of AF should include quality of life considerations in the context of patient preferences. This patient is an active and vigorous 79-year-old man who plays competitive tennis and pickleball. He steadfastly adheres to an antediluvian regimen for the management of his AF, but this may be viewed in the context of the famous quotation by Bert Lance, Director of the Office of Management and Budget in the US under President Carter who said "sometimes, if it ain't broke, don't fix it." In addition to the evolution of drug therapies from digoxin to beta-adrenergic blockers for rate control as well as from aspirin to warfarin to apixaban for the prevention of stroke, there have been other recent remarkable advances. For example, recent promising findings from randomized trials include that early rhythm control was more effective than rate control as well as that cryoballoon ablation was superior to drug therapies. These findings require confirmation in additional randomized trials designed a priori to test these promising but unproven hypotheses.

Risks of Cardiovascular Disease and Beyond in Prescription of Nonsteroidal Anti-Inflammatory Drugs.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, naproxen, diclofenac, and ibuprofen, as well as selective cyclooxygenase 2 inhibitors such as celecoxib. Their use is common, as well as their side effects which cause 100 000 hospitalizations and 17 000 deaths annually. Recently, the US Food and Drug Administration strengthened its warning about the risks of cardiovascular disease (CVD) attributed to nonaspirin NSAIDs. METHODS: When the sample size is large, randomization provides control of confounding not possible to achieve with any observational study. Further, observational studies and, especially, claims data have inherent confounding by indication larger than the small to moderate effects being sought. RESULTS: While trials are necessary, they must be of sufficient size and duration and achieve high compliance and follow-up. Until then, clinicians should remain uncertain about benefits and risks of these drugs. Conclusions: Since the totality of evidence remains incomplete, health-care providers should consider all these aforementioned benefits and risks, both CVD and beyond, in deciding whether and, if so, which, NSAID to prescribe. The factors in the decision of whether and, if so, which NSAID to prescribe for relief of pain from inflammatory arthritis should not be limited to risks of CVD or gastrointestinal side effects but should also include potential benefits including improvements in overall quality of life resulting from decreases in pain or impairment from musculoskeletal pain syndromes. The judicious individual clinical decision-making about the prescription of NSAIDs to relieve pain based on all these considerations has the potential to do much more good than harm.

Disseminated Central Nervous System Histoplasmosis: A Case Report.

Central nervous system (CNS) histoplasmosis is a rare manifestation of disease, often misdiagnosed due to the wide spectrum of neurological presentation. We present a rare case of CNS histoplasmosis in a 62-year-old male with untreated myeloproliferative disease who presented with altered mental status. This case emphasizes the clinical presentation and diagnostic difficulty in a patient with CNS histoplasmosis. We also highlight the importance of implementing a multidisciplinary approach in the medical management of disseminated histoplasmosis with CNS involvement.

Benefits and Risks of Nonsteroidal Anti-inflammatory Drugs: Methodologic Limitations Lead to Clinical Uncertainties.

Nonsteroidal anti-inflammatory drugs (NSAIDs) include traditional (tNSAIDs), such as ibuprofen, naproxen, and diclofenac, as well as selective cyclooxygenase-2 inhibitors (COXIBs), principally celecoxib. COXIBs were developed to decrease gastrointestinal side effects. Recently, the US Food and Drug Administration strengthened its warning about the risks of non-aspirin NSAIDs on myocardial infarction and stroke. The Cyclooxygenase 2 and Non-Steroidal Anti-Inflammatory Drug Trialist collaboration conducted a comprehensive worldwide meta-analysis using individual patient data exploring the risks of various COXIBs and NSAIDs on cardiovascular disease (CVD). Recently, the results of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial were published that tested risks of COXIBs and NSAIDs on CVD. Generally, data from meta-analyses of trials not designed a priori to test hypotheses are less reliable than large-scale randomized trials to test small to moderate benefits or harm. When the sample size is large, randomization provides control of confounding not possible to achieve in any observational study. Further, observational studies, and especially claims data, have inherent confounding by indication larger than the effects being sought. Nonetheless, trials must be of sufficient size and duration and achieve high compliance and follow-up to avoid bias and confounding. In this regard, PRECISION has high rates of nonadherence and losses to follow-up that may have introduced bias and confounding. At present, therefore, it may be most prudent for clinicians to remain uncertain about benefits and risks of these drugs and make individual clinical judgments for each of their patients.