Treatment of Cardiovascular Disease in Rheumatoid Arthritis: A Complex Challenge with Increased Atherosclerotic Risk

Rheumatoid arthritis (RA) carries significant risk for atherosclerotic cardiovascular disease (ASCVD). Traditional ASCVD risk factors fail to account for this accelerated atherosclerosis. Shared inflammatory pathways are fundamental in the pathogenesis of both diseases. Considering the impact of RA in increasing cardiovascular morbidity and mortality, the characterization of therapies encompassing both RA and ASCVD management merit high priority. Despite little progress, several drugs discussed here promote remission and or lower rheumatoid disease activity while simultaneously conferring some level of atheroprotection. Methotrexate, a widely used disease-modifying drug used in RA, is associated with significant reduction in cardiovascular adverse events. MTX promotes cholesterol efflux from macrophages, upregulates free radical scavenging and improves endothelial function. Likewise, the sulfonamide drug sulfasalazine positively impacts the lipid profile by increasing HDL-C, and its use in RA has been correlated with reduced risk of myocardial infraction. In the biologic class, inhibitors of TNF-α and IL-6 contribute to improvements in endothelial function and promote anti-atherogenic properties of HDL-C, respectively. The immunosuppressant hydroxychloroquine positively affects insulin sensitization and the lipid profile. While no individual therapy has elicited optimal atheroprotection, further investigation of combination therapies are ongoing.

Protective Effect of Ipomoea biloba on Myocardial Antioxidant Status in Isoproterenol Induced Myocardial Infarction Male Albino Rats

The protective effect of ethanolic leaf extract of Ipomoea biloba in isoproterenol (ISO)-induced cardiotoxicity and the antioxidant activity involved in this protection were investigated in rats. Myocardial infraction was produced in rats with 20 mg/kg b.wt of ISO administered subcutaneously twice at an interval of 24 h. Effect of EEIB oral treatment for 28 days at two doses (100 mg and 200 mg/kg body weight) was evaluated against ISO – induced cardiac necrosis. Level of enzymatic (SOD, CAT, GPx and GST), non-enzymatic (GSH, Vitamin C and E) and of membrane bound ATPases (Na+K+ATPase, Mg2+ATPase and Ca2+ATPase) were assayed in heart homogenate. Significant myocardial infarction, depletion of endogenous antioxidants enzymatic and non-enzymatic were observed in ISO-treated animals when compared with the normal animals. Rats induced with ISO, showed a significant (P<0.05), decrease in the activities of GSH, Vitamin C and Eon comparison with normal rats. EEIB elicited a significant cardioprotective activity by elevated the levels of GSH, SOD, CAT, GPx and GR. A significant decrease in the activity of Na+/K+ ATPase and a corresponding increase in the activities of Ca2+ ATPase and Mg2+ ATPase were observed in isoproterenol induced rats when compared to normal control rats. Pretreatment with EEIB was able to efficiently prevent the increase in activity of Mg2+ ATPase and maintain the activities of Na+ /K+ ATPase and Ca2+ ATPase at near normality. There is no significant difference between the control and plant alone treated rats. The aim of this investigation is to evaluate the antioxidant effects on the main cardioprotective activity of ethanolic leaf extract Ipomoea biloba.

Effect of Health Literacy on Decision Delay in Patients With Acute Myocardial Infarction

Background: Health literacy (HL) is a risk factor for adverse outcomes in patients with cardiovascular disease, and shorter pre-hospital delay time is crucial for successful treatment of acute myocardial infraction (AMI) patients. Most previous studies focused on the influencing factors of pre-hospital delay but ignore the essential contribution of decision delay.Aims: Therefore, the purpose of this study was to explore the effect of HL on decision delay.Methods: Continuously included AMI patients admitted to a grade A class three hospital in Chongqing. HL level was assessed using Brief Health Literacy Screen and categorized as adequate or inadequate. Mann-Whitney U-test and Chi-square test were used to compare the differences between groups, and binary logistic regression was used to analyze the association between HL and decision delay.Results: A total of 217 AMI patients were enrolled in this study, including 166 males (76.5%) and 51 females (23.5%), with the median age was 68 years old; 135 (62.2%) patients had delayed decision-making while 82 (37.8%) did not; 157 (72.7%) patients had inadequate HL and 59 (27.3%) had adequate HL. The total HL score of non-delayed group was higher than that in delayed group (9.22 vs. 7.02, P &lt; 0.000).Conclusion: After adjusting for covariates, HL was significantly negatively associated with decision time. AMI patients with inadequate HL were more likely to delay seeking timely medical care.

Physician Diagnosis and Knowledge of Mild Cognitive Impairment

Background: Older adults with mild cognitive impairment (MCI) receive fewer guideline-concordant treatments for multiple health conditions than those with normal cognition. Reasons for this disparity are unclear. Objective: To better understand this disparity, we describe physician understanding and experience with patient MCI, particularly physician identification of MCI, ability to distinguish between MCI and dementia, and perspectives on education and training in MCI and dementia. Methods: As part of a mixed-methods study assessing the influence of patient MCI on physician recommendations for acute myocardial infraction and stroke treatments, we conducted a descriptive qualitative study using semi-structured interviews of physicians from three specialties. Key question topics included participants’ identification of MCI, impressions of MCI and dementia awareness within their practice specialty, and perspectives on training and education in MCI. Results: The study included 22 physicians (8 cardiologists, 7 neurologists, and 7 internists). We identified two primary themes: There is 1) a lack of adequate understanding of the distinction between MCI and dementia; and 2) variation in physician approaches to identifying whether an older adult has MCI. Conclusion: These findings suggest that physicians have a poor understanding of MCI. Our results suggest that interventions that improve physician knowledge of MCI are needed.

High Plasma Apolipoprotein(a) Concentration and Low Plasmin Tpa Enzymatic Activity in Hospitalized Patients with COVID-19

Thrombotic and thromboembolic complications in patients diagnosed with coronavirus disease 2019 (COVID-19) are emerging as important sequelae that contribute to mortality, including disseminated intravascular coagulation, pulmonary embolism, deep vein thrombosis, ischemic stroke, and myocardial infraction. Reported incidence of thrombotic and thromboembolic complications in moderate/severe COVID-19 patients is from 21% to 49%, while even higher incidence in non-surviving COVID-19 patients. However, the underlying mechanism between thrombosis and COVID-19 is still unclear. Tissue-type plasminogen activator (tPA) plays an important role on initiating fibrinolysis by converting zymogen plasminogen to plasmin, a serine protease that degrades the fibrin clot, and therefore preventing excessive pathological blood clots. A homologous protein to plasminogen is apolipoprotein(a) [apo(a)], a major component of lipoprotein(a). The apo(a) inhibits fibrinolysis and exacerbates thrombosis through blocking the conversion from Glu-plasminogen to Lys-plasminogen, which has a higher binding affinity to fibrin and is a better substrate to tPA. The population distribution of plasma apo(a) level is positively skewed (most values are clustered around the left tail of the distribution close to zero), and the plasma apo(a) level in most people is less than 300 μg/mL. High plasma concentration of apo(a) (&gt; 300 μg/mL), or genetic variants of LPA, the gene that encodes for apo(a), correlates with thrombotic cardiovascular risk and thromboembolic risk in many population-based clinical or genetic studies. To investigate the potential correlation between infection of SARS-COV-2 and thrombosis, we tested de-identified plasma samples collected from hospitalized patients with or without positivity of SARS-CoV-2 testing results and COVID-19 diagnosis (ICD10CM:U07.1) through the COVD-19 Tissue Bank at the Medical College of Wisconsin. The tPA enzymatic activity was measured by the release of p-nitroaniline chromophore from a plasmin-specific synthetic substrate with exogenous human plasminogen, with the intensity of color proportional to tPA activity. The apo(a) concentration is measured by ELISA capturing total apo(a) antigen. Our results show that the SARS-CoV-2-positive inpatients have higher plasma tPA concentration than the SARS-CoV-2 negative inpatients (6.0 versus 3.0 ng/mL, p&lt;0.05), while plasma tPA enzymatic activity is lower in SARS-CoV-2-positive inpatients than the SARS-CoV-2 negative inpatients (15.2 versus 25.5 ΔA/min/mL/10 4, p&lt;0.0001) (Figure A). The plasma apo(a) concentration is significantly higher in SARS-CoV-2-positive inpatients than in the plasma from SARS-CoV-2-negative inpatients (the median of the two groups are 114.8 versus 34.4 μg/mL, p&lt;0.05) (Figure B). Among the 20 hospitalized patients with COVID-19, 13 survived. The 13 survived patients have one additional plasma sample collected after recovering from COVID-19 (date range between the two blood collections of onset and after recovery is from 19 to 87 days, the mean duration is 42 days). After recovery, 11 out of 13 surviving patients have increased plasma tPA enzymatic activity (the mean value at onset versus recovery is 5.2 versus 7.1 ΔA/min/mL/10 4, p&lt;0.05) (Figure C). Consistently, 11 out of 13 surviving patients have decreased plasma apo(a) concentration compared to the plasma collected during the onset of COVID-19 from the same individuals (the median values of the onset and recovery are 141.1 versus 106.5 μg/mL, p&lt;0.001) (Figure D). In summary, our study shows lower tPA enzymatic activity and higher apo(a) concentration in SARS-CoV-2-positive hospitalized patients compared to SARS-CoV-2-negative hospitalized patients. Among the survived patients, the reduction of apo(a) concentration after recovering from COVID-19 is accordance with the increase of tPA enzymatic activity. Considering the role of apo(a) in inhibiting fibrinolysis through limiting tPA-mediated plasminogen to plasmin conversion, the alteration in apo(a) concentration provide a possible explanation of change of tPA activity in patients with severe COVID-19. Figure 1 Figure 1. Disclosures Baumann Kreuziger: CSL Behring: Consultancy; Quercegen Pharmaceuticals: Consultancy; Vaccine Injury Compensation Program: Consultancy.

Two types of humoral response in acute myocardial infraction

Background Atherothrombosis and myocardial infarction are accompanied by the development of an inflammatory reaction. The severity of the immune reaction and its role in the acute myocardial infarction (AMI) remain contradictory to date. Purpose The objective of this study was to analyze 39 cytokines and chemokines in the serum of patients hospitalized with AMI compared to the healthy volunteers. Methods All patients included in the study were COVID-19 negative. Patients' blood was collected within 1–2 days after hospitalization in the cardiology department. Cytokine and chemokine detection in the serum of patients (n=20) and donors (n=20) was performed using a 39-plex set of cytometric beads. Results Among all factors analyzed TGFa, IL-17A, IL-1b, 3, 5, 9 were not detected both in patient and donor sera. Three groups of factors were identified in the normal serum: housekeeping chemokines and vascular factors (F1) ranged from 1000 to 22000 pg/mL (Fig. a); sentinel innate immunity factors F2 (Fig. b), 30–200 pg/mL; and acute phase factors F3 (Fig. c, d), 0–30 pg/mL, detected only in 0–30% of donors but in all AMI patients. Severe imbalance was found in AMI sera at all three levels including chemokine, growth factors, and cytokines. Among AMI patients 65% (Gr1) demonstrated 2–4 times increased level (Fig. a, grey brackets) while 35% (Gr2) had a decreased level of F1 factors in a comparison with donor sera. There was not significant difference between clinical features of the patients in Gr1 and Gr2. GRO, PDGF-AA, and sCD40L levels decreased 35, 15, and 10 times accordingly. Gr1 and Gr2 also differed in F2 and some F3 concentrations: Gr1 had 3–5 times increased level of multiple factors (Fig, b), among them – IL-6, IL-8, and IL-10 were increased 5, 6, and 14 times. At the same time Gr2 had a normal level of these factors (Fig, b, blue brackets). Finally, multiple cytokines and growth factors F3 were significantly increased in both AMI groups (Fig, b, d, red brackets). Of note, IL-12, IFN-g, IL-15, GM-CSF, FLT-3T were increased 8, 6, 5, 5, 5 times accordingly in pooled Gr1+Gr2. There were no correlations found between cytokine profiles in Gr1 and Gr2 and their clinical parameters. Conclusions Two types of humoral response in AMI patients were identified which differed in the levels of GRO, PDGF-AA, and sCD40L. IL-6 as well as TNF-a can not serve as master cytokines because their levels were increased only in Gr1 patients. These data show that Th1 cytokine increase is specific for AMI. Further studies are needed to identify groups of patients who may be exposed to new therapeutic targets. FUNDunding Acknowledgement Type of funding sources: None.

Cardioprotective Action of Glycyrrhizin on Diabetic Rats with Myocardial Remodeling

Introduction. Cardiovascular disorders are one of the prominent causes of risks of mortality which accounts for high rate of the deaths at a global level. The risk of deadly myocardial infraction grows because of diabetes which even causes the development of heart failure. Objective. The objective of this study was to understand and study the effect of glycyrrhizin on diabetes suffering rats with myocardial remodeling. Materials and Methods. Streptozotocin was used for induction of diabetes, and 8–12 weeks later, the assessment of inflammation, fibrosis, and cardiac damage was evaluated. Histopathological analysis and immunohistochemistry was performed to analyze the effect in various groups. Western blotting was performed to understand the proteins expressed in diabetes, and also, their expression was noted in treatment groups. Results. There was a significant rise in TNF-α, dense fibrosis, and collagen deposits in the STZ diabetes group. The effects of hyperglycemia were significantly improved in the glycyrrhizin-treated group. DAPI, BrDu, and caspase staining was also performed to understand apoptosis in tissues where the diabetic groups reported significant apoptosis, while the effects were significantly lower in the treated group. Conclusion. All the observations indicate that glycyrrhizin has cardioprotective action in diabetic rats with myocardial remodeling and is due to the inhibition of the NF-κB signaling pathway in the myocardial layer.

Comparative efficacy of local and general anesthesia for transcatheter aortic valve implantation: a meta-analysis and systematic review

Background This meta-analysis aimed to compare the potential effects of local anesthesia (LA) and general anesthesia (GA) for transcather aortic value implantation (TAVI). Measurements All relevant studies were searched from the Pubmed, EMbase, Web of Science and the Cochrane Library (January 1, 2016 to June 1, 2021). The main outcomes of this literature meta-analysis were 30-day mortality, procedural time, new pacemaker implantation, total stay in hospital, the use of vasoactive drug, intra-and postoperative complications and emergencies, including conversion to open, myocardial infraction, pulmonary complication, vascular complication, renal injury/failure, stroke, transesophageal echocardiography, life-threatening/major bleeding, cardiac tamponade, emergency PCI. Pooled risk ratio (RR) and mean difference (MD) together with 95% confidence interval (CI) were calculated. Results A total of seventeen studies including 20938 patients in the final analysis fulfilled the inclusion criteria. Intra-and postoperative complications (myocardial infraction, vascular complication, renal injury/failure, stoke, cardiac tamponade) undergoing TAVI in serious AS patients under GA do not offer significant difference compared with LA. No differences are observed between LA and GA for new pacemaker implantation, total stay in hospital, transesophageal echocardiography, emergency PCI. GA is associated with more adverse events, like the more overall mortality (RR 0.69, p=0.600), pulmonary complications (RR 0.54, p=0.278), life-threatening/major bleeding (RR 0.85, p=0.855), the more times of coversion to open (RR 0.22, p=0.746). LA has many advantages, including a shorter procedure duration (MD=-0.38, p=0.000) and a reduction of the use of vasoactive drug (RR 0.57，P=0.000). Conclusions For TAVI, both LA with or without sedation and GA are feasible and safe. LA appears a feasible alternative to GA for AS patients undergo TAVI.

Cardiorenal outcomes with sodium/glucose cotransporter-2 inhibitors in patients with type 2 diabetes and low kidney risk: real world evidence

Background Randomized controlled trials showed that sodium/glucose cotransporter-2 inhibitors (SGLT2i) protect the heart and kidney in an array of populations with type 2 diabetes (T2D) and increased cardiorenal risk. However, the extent of these benefits also in lower kidney-risk T2D populations needs further investigation. Methods Members of Maccabi Healthcare Systems listed in their T2D registry who initiated new glucose lowering agents (GLA), were divided into SGLT2i initiators and other GLAs (oGLAs). Groups were propensity score-matched by baseline demographic and medical characteristics. Two composite cardiovascular outcomes were defined: all-cause mortality (ACM) or hospitalization for heart failure (hHF); and ACM, myocardial infraction (MI) or stroke. The cardiorenal outcome was: ACM, new end-stage kidney disease (ESKD) or ≥ 40% reduction from baseline estimated glomerular filtration rate (eGFR). Renal-specific outcome was new ESKD or ≥ 40% eGFR reduction. Single components of cardiovascular and kidney outcomes were also assessed. Three subgroup definitions of low baseline kidney-risk were used: eGFR > 90 ml/min/1.73 m2; urinary albumin below detectable levels; and low risk according to Kidney Disease: Improving Global Outcomes (KDIGO) classification. Analyses were performed utilizing an unadjusted model, and a model adjusted to baseline eGFR and urinary albumin-to-creatinine ratio. Results Between April 1, 2015 and June 30, 2018; 68,187 patients initiated new GLAs — 11,321 SGLT2i initiators and 42,077 oGLAs initiators were eligible. Propensity score-matching yielded two comparable cohorts; each included 9219 participants. Median follow-up was 1.7 years. Compared to oGLAs, SGLT2i initiators had lower incidence of ACM or hHF [HR95%CI = 0.62(0.51–0.75)]; ACM, MI or stroke [0.67(0.57–0.80)]; the cardiorenal outcome [0.65(0.56–0.76)]; and the renal-specific outcome [0.70(0.57–0.85)]. SGLT2i initiators also had lower risk for ACM, hHF and ≥ 30%, ≥ 40%, ≥ 50%, ≥ 57% eGFR reduction. No difference between groups was observed for MI or stroke. In the low baseline kidney-risk subgroups, SGLT2i initiation was generally associated with lower risk of the cardiovascular and cardiorenal outcomes, driven mainly by lower ACM incidence. Conclusions Our findings in the general population of patients with T2D demonstrates lower risk of cardiorenal outcomes associated with initiation of SGLT2i compared with oGLAs, including specifically in patients with low baseline kidney-risk.