Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

A biological rationale for the disparate effects of omega-3 fatty acids on cardiovascular disease outcomes.

The omega-3 fatty acids (n3-FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) rapidly incorporate into cell membranes where they modulate signal transduction pathways, lipid raft formation, and cholesterol distribution. Membrane n3-FAs also form specialized pro-resolving mediators and other intracellular oxylipins that modulate inflammatory pathways, including T-cell differentiation and gene expression. Cardiovascular (CV) trials have shown that EPA, administered as icosapent ethyl (IPE), reduces composite CV events, along with plaque volume, in statin-treated, high-risk patients. Mixed EPA/DHA regimens have not shown these benefits, perhaps as the result of differences in formulation, dosage, or potential counter-regulatory actions of DHA. Indeed, EPA and DHA have distinct, tissue-specific effects on membrane structural organization and cell function. This review summarizes: (1) results of clinical outcome and imaging trials using n3-FA formulations; (2) membrane interactions of n3-FAs; (3) effects of n3-FAs on membrane oxidative stress and cholesterol crystalline domain formation during hyperglycemia; (4) n3-FA effects on endothelial function; (5) role of n3-FA-generated metabolites in inflammation; and (6) ongoing and future clinical investigations exploring treatment targets for n3-FAs, including COVID-19.

COVID-19, the Pandemic of the Century and Its Impact on Cardiovascular Diseases.

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely ranks among the deadliest diseases in human history. As with other coronaviruses, SARS-CoV-2 infection damages not only the lungs but also the heart and many other organs that express angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2. COVID-19 has upended lives worldwide. Dietary behaviors have been altered such that they favor metabolic and cardiovascular complications, while patients have avoided hospital visits because of limited resources and the fear of infection, thereby increasing out-hospital mortality due to delayed diagnosis and treatment. Clinical observations show that sex, age, and race all influence the risk for SARS-CoV-2 infection, as do hypertension, obesity, and pre-existing cardiovascular conditions. Many hospitalized COVID-19 patients suffer cardiac injury, acute coronary syndromes, or cardiac arrhythmia. SARS-CoV-2 infection may lead to cardiomyocyte apoptosis and necrosis, endothelial cell damage and dysfunction, oxidative stress and reactive oxygen species production, vasoconstriction, fibrotic and thrombotic protein expression, vascular permeability and microvascular dysfunction, heart inflammatory cell accumulation and activation, and a cytokine storm. Current data indicate that COVID-19 patients with cardiovascular diseases should not discontinue many existing cardiovascular therapies such as ACE inhibitors, angiotensin receptor blockers, steroids, aspirin, statins, and PCSK9 inhibitors. This review aims to furnish a framework relating to COVID-19 and cardiovascular pathophysiology.

The Pathogenesis of COVID-19 Myocardial Injury: An Immunohistochemical Study of Postmortem Biopsies.

Rationale: Myocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide. Objective: This histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury. Methods and Results: Postmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1ß, IL-4, IL-6, CD163, TNF-α, TGF-ß, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts per high-power field in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1ß, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis. Conclusions: The pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-ß and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.

Coronavirus Disease 2019 (COVID-19) Coronary Vascular Thrombosis: Correlation with Neutrophil but Not Endothelial Activation.

Severe coronavirus disease 2019 (COVID-19) increases the risk of myocardial injury that contributes to mortality. This study used multiparameter immunofluorescence to extensively examine heart autopsy tissue of 7 patients who died of COVID-19 compared to 12 control specimens, with or without cardiovascular disease. Consistent with prior reports, no evidence of viral infection or lymphocytic infiltration indicative of myocarditis was found. However, frequent and extensive thrombosis was observed in large and small vessels in the hearts of the COVID-19 cohort, findings that were infrequent in controls. The endothelial lining of thrombosed vessels typically lacked evidence of cytokine-mediated endothelial activation, assessed as nuclear expression of transcription factors p65 (RelA), pSTAT1, or pSTAT3, or evidence of inflammatory activation assessed by expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor, or von Willebrand factor (VWF). Intimal EC lining was also generally preserved with little evidence of cell death or desquamation. In contrast, there were frequent markers of neutrophil activation within myocardial thrombi in patients with COVID-19, including neutrophil-platelet aggregates, neutrophil-rich clusters within macrothrombi, and evidence of neutrophil extracellular trap (NET) formation. These findings point to alterations in circulating neutrophils rather than in the endothelium as contributors to the increased thrombotic diathesis in the hearts of COVID-19 patients.

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

Targeting Inflammatory Pathways in Cardiovascular Disease: The Inflammasome, Interleukin-1, Interleukin-6 and Beyond.

Recent clinical trials have now firmly established that inflammation participates causally in human atherosclerosis. These observations point the way toward novel treatments that add to established therapies to help stem the growing global epidemic of cardiovascular disease. Fortunately, we now have a number of actionable targets whose clinical exploration will help achieve the goal of optimizing beneficial effects while avoiding undue interference with host defenses or other unwanted actions. This review aims to furnish the foundation for this quest by critical evaluation of the current state of anti-inflammatory interventions within close reach of clinical application, with a primary focus on innate immunity. In particular, this paper highlights the pathway from the inflammasome, through interleukin (IL)-1 to IL-6 supported by a promising body of pre-clinical, clinical, and human genetic data. This paper also considers the use of biomarkers to guide allocation of anti-inflammatory therapies as a step toward realizing the promise of precision medicine. The validation of decades of experimental work and association studies in humans by recent clinical investigations provides a strong impetus for further efforts to target inflammation in atherosclerosis to address the considerable risk that remains despite current therapies.

The Heart in COVID-19: Primary Target or Secondary Bystander?

In the throes of the current coronavirus disease-2019 (COVID-19) pandemic, interest has burgeoned in the cardiovascular complications of this virulent viral infection. As troponin, a biomarker of cardiac injury, often rises in hospitalized patients, its interpretation and actionability require careful consideration. Fulminant myocarditis due to direct viral infection can certainly occur, but in patients with increased oxygen demands due to tachycardia and fever and reduced oxygen delivery due to hypotension and hypoxemia, COVID-19 disease can cause myocardial injury indirectly. Cytokines released during the acute infection can elicit activation of cells within pre-existing atherosclerotic lesions, augmenting thrombotic risk and risk of ischemic syndromes. Moreover, microvascular activation by cytokines can cause not only myocardial injury but can also harm other organ systems commonly involved in COVID-19 infections including the kidneys. Dealing with the immense challenge of COVID-19, confronted with severely ill patients in dire straits with virtually no rigorous evidence base to guide our therapy, we must call on our clinical skills and judgment. These touchstones can help guide us in selecting patients who might benefit from the advanced imaging and invasive procedures that present enormous logistical challenges in the current context. Lacking a robust evidence base, pathophysiologic reasoning can help guide our choices of therapy for individual clinical scenarios. We must exercise caution and extreme humility, as often plausible interventions fail when tested rigorously. But act today we must, and understanding the multiplicity of mechanisms of myocardial injury in COVID-19 infection will help us meet our mission unsupported by the comfort of strong data.

COVID-19 - A vascular disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to multi-system dysfunction with emerging evidence suggesting that SARS-CoV-2-mediated endothelial injury is an important effector of the virus. Potential therapies that address vascular system dysfunction and its sequelae may have an important role in treating SARS-CoV-2 infection and its long-lasting effects.

COVID-19 is, in the end, an endothelial disease.

The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.

Role for Anti-Cytokine Therapies in Severe Coronavirus Disease 2019.

The causative agent for coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, appears exceptional in its virulence and immunopathology. In some patients, the resulting hyperinflammation resembles a cytokine release syndrome. Our knowledge of the immunopathogenesis of coronavirus disease 2019 is evolving and anti-cytokine therapies are under active investigation. This narrative review summarizes existing knowledge of the immune response to coronavirus infection and highlights the current and potential future roles of therapeutic strategies to combat the hyperinflammatory response of patients with coronavirus disease 2019. DATA SOURCES: Relevant and up-to-date literature, media reports, and author experiences were included from Medline, national newspapers, and public clinical trial databases. STUDY SELECTION: The authors selected studies for inclusion by consensus. DATA EXTRACTION: The authors reviewed each study and selected approrpriate data for inclusion through consensus. DATA SYNTHESIS: Hyperinflammation, reminiscent of cytokine release syndromes such as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, appears to drive outcomes among adults with severe coronavirus disease 2019. Cytokines, particularly interleukin-1 and interleukin-6, appear to contribute importantly to such systemic hyperinflammation. Ongoing clinical trials will determine the efficacy and safety of anti-cytokine therapies in coronavirus disease 2019. In the interim, anti-cytokine therapies may provide a treatment option for adults with severe coronavirus disease 2019 unresponsive to standard critical care management, including ventilation. CONCLUSIONS: This review provides an overview of the current understanding of the immunopathogenesis of coronavirus disease 2019 in adults and proposes treatment considerations for anti-cytokine therapy use in adults with severe disease.

Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients.

The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2,118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system.