Inflammatory Burden and Immunomodulative Therapeutics of Cardiovascular Diseases

Phenotyping cardiovascular illness and recognising heterogeneities within are pivotal in the contemporary era. Besides traditional risk factors, accumulated evidence suggested that a high inflammatory burden has emerged as a key characteristic modulating both the pathogenesis and progression of cardiovascular diseases, inclusive of atherosclerosis and myocardial infarction. To mechanistically elucidate the correlation, signalling pathways downstream to Toll-like receptors, nucleotide oligomerisation domain-like receptors, interleukins, tumour necrosis factor, and corresponding cytokines were raised as central mechanisms exerting the effect of inflammation. Other remarkable adjuvant factors include oxidative stress and secondary ferroptosis. These molecular discoveries have propelled pharmaceutical advancements. Statin was suggested to confer cardiovascular benefits not only by lowering cholesterol levels but also by attenuating inflammation. Colchicine was repurposed as an immunomodulator co-administered with coronary intervention. Novel interleukin-1β and −6 antagonists exhibited promising cardiac benefits in the recent trials as well. Moreover, manipulation of gut microbiota and associated metabolites was addressed to antagonise inflammation-related cardiovascular pathophysiology. The gut-cardio-renal axis was therein established to explain the mutual interrelationship. As for future perspectives, artificial intelligence in conjunction with machine learning could better elucidate the sequencing of the microbiome and data mining. Comprehensively understanding the interplay between the gut microbiome and its cardiovascular impact will help identify future therapeutic targets, affording holistic care for patients with cardiovascular diseases.

Celastrol and thymoquinone alleviate aluminum chloride-induced neurotoxicity: behavioral psychomotor performance, neurotransmitter level and oxidative-inflammatory burden in brain of rats

The exposure to metal aluminum such as aluminum chloride (AlCl3) induces inflammatory-oxidative reactions with progressive neurodegeneration in different brain regions in animal models. The current study was designed to assess the role of celastrol or thymoquinone (TQ) in alleviating AlCl3 induced behavioral psychomotor changes and oxidative-inflammatory burden in albino male rats. Four groups were used in this study, (i) vehicle control group, (ii) AlCL3 control group: rats received intraperitoneal injection (i.p.) of AlCl3 (10 mg/kg), (iii) AlCl3+TQ (10 mg/kg, i.p.) group and (iv) AlCl3+celastrol (1 mg/kg, i.p.) group. In general, all injections remained for 6 weeks. Behavioral psychomotor evaluation (open field test, rotarod test and forced Swimming test) were done to assess locomotor, motor coordination, anxiety-like behavior and depressive-like behavioral. Markers of oxidative stress, malondialdehyde (MDA), total antioxidant capacity (TAC) and catalase enzyme activity (CAT) and the proinflammatory mediators, tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6) were measured in the rat brains. Neurotransmitters including acetylcholine (ACh), dopamine and serotonin in addition to acetylcholinesterase enzyme (AChE) level were measured in brain homogenates. Our results demonstrated that daily injection of TQ or celastrol significantly improved behavior psychomotor deficits, decreased AChE activity towards their normal levels. Tissue oxidative stress and proinflammatory markers were modulated by TQ and celastrol. These results concluded that TQ and celastrol have useful in alleviating AlCl3-induced neurotoxicity by their antioxidant and anti-inflammatory properties. Hence, they are looking promising for investigating their preventive effect in animal models of neurodegenerative diseases.

Th1, Th2 and Th17 inflammatory pathways synergistically correlate with cardiometabolic processes. A case study in COVID-19.

A predominant source of complication in SARS-CoV-2 patients arises from the cytokine storm, an elevated expression of inflammatory helper T-cell associated cytokines that can lead to tissue damage and organ failure. The high inflammatory burden of this viral infection often results in cardiovascular comorbidities. A better understanding of the interaction between the cytokine storm and cardiovascular proteins might inform medical decisions and therapeutic approaches. We hypothesized that all major helper T-cell inflammatory pathways (Th1, Th2 and Th17) synergistically contribute to cardiometabolic modifications in serum of COVID-19 patients. We proved our hypothesis by integrating Th1, Th2 and Th17 cytokines to predict expression of cardiometabolic proteins profiled by OLINK proteomics.

Effects of Sodium-Glucose Transporter 2 Inhibitors (SGLT2-I) in Patients With Ischemic Heart Disease (IHD) Treated by Coronary Artery Bypass Grafting via MiECC: Inflammatory Burden, and Clinical Outcomes at 5 Years of Follow-Up

Introduction: Minimally invasive extracorporeal circulation (MiECC) reduced inflammatory burden, leading to best clinical outcomes in patients treated with coronary artery bypass grafting (CABG). Despite this, the patients with type 2 diabetes mellitus (T2DM) vs those without T2DM (non-T2DM) have a worse prognosis, caused by over-inflammation and modulated by sodium-glucose transporter 2 receptors. However, we evaluated the inflammatory burden and clinical outcomes in non-T2DM vs T2DM patients under sodium-glucose transporter 2 inhibitors (SGLT2-I users) vs non-SGLT2-I users at 5 years of follow-up post-CABG via MiECC.Materials and methods: In a multicenter study, we screened consecutive patients with indications to receive CABG. The study endpoints were the inflammatory burden (circulating serum levels of tumor necrosis factor-alpha (TNF-α), interleukin 1 and 6 (IL-1 and IL-6), C-reactive protein (CRP), and leucocytes count) and the clinical outcomes at follow-up of 5 years in non-T2DM vs SGLT2-I users, in non-T2DM vs non-SGLT2-I users, and SGLT2-I users vs non-SGLT2-I users.Results: At baseline, and at one year and 5 years of follow-up, the non-T2DM vs SGLT2-I users, non-T2DM vs non-SGLT2-I users, and SGLT2-I users vs non-SGLT2-I users had the lowest values of IL-1, IL-6, and TNF-α (p < 0.05). At one year of follow-up, SGLT2-I users vs non-T2DM and non-SGLT2-I users vs non-T2DM users had a higher rate of all deaths, cardiac deaths, re-myocardial infarction, repeat revascularization, and stroke, and of the composite endpoint (p < 0.05). In a multivariate Cox regression analysis, the composite endpoint was predicted by IL-1 [2.068 (1.367–3.129)], TNF-α [1.989 (1.081–2.998)], and SGLT2-I [0.504 (0.078–0.861)].Conclusion: In T2DM patients, the SGLT2-I significantly reduced the inflammatory burden and ameliorated clinical outcomes at 5 years of follow-up post-CABG via MiECC.

A European pharmacotherapeutic agent Roflumilast exploring integrated preclinical and clinical evidences for SARS CoV-2 mediated inflammation to organ damage

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma), seems more susceptible to serious illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline, right heart thickning in animal prophylactic. The current study reviewed existing data that the PDE-4 inhibitor protects not just renal tissues but also other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related with a decrease in oxidative and inflammatory burden, caspase-3 suppression, and increased PKA/cAMP levels in renal and other organ tissue.

COVID-19 Infection and Myocardial Infarction Pathophysiology and Therapy

The relationship between COVID-19 and cardiovascular disease has been of interest since the beginning of the pandemic, with the focus more recently shifting towards thrombotic complications, including myocardial infarction (MI). While the inflammatory burden of infection has previously been implicated in the pathogenesis of MI, at least early in the pandemic, many hospitals were seeing fewer ST-elevation MI admissions and the delivery of acute coronary syndrome care was disrupted in multiple ways. Furthermore, patients presenting with both COVID-19 infection and MI have been noted in small studies to have unique characteristics that pose clinical challenges, and there is reason to believe that standard therapy for both the prevention and treatment of all thrombotic events, including MI, may not be adequate. The aim of this article is to review the data regarding MI and other thrombotic events during the pandemic, to explore the link between inflammation and thrombosis, and to suggest possible novel therapeutic options for the treatment and prevention of thrombosis in patients with COVID-19.

Inflammatory Burden and Persistent CT Lung Abnormalities in COVID-19 Patients

Inflammatory burden is associated with COVID-19 severity and outcomes. Residual computed tomography (CT) lung abnormalities have been reported after COVID-19. The aim was to evaluate the association between inflammatory burden during COVID-19 and residual lung CT abnormalities collected on follow-up CT scans performed 2–3 and 6–7 months after COVID-19, in severe COVID-19 pneumonia survivors. C-reactive protein (CRP) curves describing inflammatory burden during the clinical course were built, and CRP peaks, velocities of increase, and integrals were calculated. Other putative determinants were age, sex, mechanical ventilation, lowest PaO2/FiO2 ratio, D-dimer peak, and length of hospital stay (LOS). Of the 259 included patients (median age 65 years; 30.5% females), 202 (78%) and 100 (38.6%) had residual, predominantly non-fibrotic, abnormalities at 2-3 and 6-7 months, respectively. In age- and sex-adjusted models, best CRP predictors for residual abnormalities were CRP peak (odds ratio [OR] for one standard deviation [SD] increase=1.79; 95% confidence interval [CI]=1.23-2.62) at 2-3 months and CRP integral (OR for one SD increase=2.24; 95%CI=1.53-3.28) at 6-7 months. Hence, inflammation is associated with short- and medium-term lung damage in COVID-19. Other severity measures, including mechanical ventilation and LOS, but not D-dimer, were mediators of the relationship between CRP and residual abnormalities.