Novel nitric oxide donors are coronary vasodilators that also bind to the papain-like protease of SARS-CoV-2.

Several investigational nitric oxide donors were originally created to correct vascular endothelial dysfunction in cardiovascular diseases. These 48 compounds contain an urea-like moiety attached to the well-known NO donors isosorbide 2- and 5-mononitrate. CR-0305 and CR-0202 were synthesized and found to be nontoxic in the cell lines HMEC-1, A549/hACE2 and VeroE6. CR-0305 induced vasodilation in human coronary arteries ex vivo. Since NO can also have antiviral properties, a study of drug-protein interactions with SARS-CoV-2 was undertaken using in silico modeling. CR-0305 experimentally outperformed the other compounds, including CR-0202, in binding the catalytic site of SARS-CoV-2 papain-like protease (PLpro). PLpro is a primary target for therapeutic inhibition of SARS-CoV-2 as it mediates viral replication and modulates host innate immune responses. CR-0305 is predicted to sit firmly in the PLpro catalytic pocket as confirmed by molecular dynamics simulations, wherein stability of binding to the catalytic site of PLpro induces a conformational change in the BL2 loop to a more closed conformation as observed previously with GRL0617. Surface plasmon resonance was performed with CR-0305 and CR-0202 to characterize binding affinity to purified SARS-CoV-2 PLpro protein. CR-0305 and CR-0202 also inhibited SARS-CoV-2 infection compared to vehicle as measured by virus N protein staining with a specific antibody in A549-ACE2 and VeroE6 cells at 20 µM. CR-0305 is a coronary vasodilator that appears to bind to the catalytic site of the PLpro of SARS-CoV-2 while targeting delivery of antiviral NO to cells infected by SARS-CoV-2, suggesting multiple indications for future development.

Potential Role of Metal Chelation to Prevent the Cardiovascular Complications of Diabetes.

CONTEXT: For decades, there has been epidemiologic evidence linking chronic toxic metal exposure with cardiovascular disease, suggesting a therapeutic role for metal chelation. Given the lack of compelling scientific evidence, however, the indications for metal chelation were never clearly defined. To determine the safety and efficacy of chelation therapy, the National Institutes of Health funded the Trial to Assess Chelation Therapy (TACT). TACT was the first double-blind, randomized, controlled trial to demonstrate an improvement in cardiovascular outcomes with edetate disodium therapy in patients with prior myocardial infarction. The therapeutic benefit was striking among the prespecified subgroup of patients with diabetes. DESIGN: We review the published literature focusing on the atherogenic nature of diabetes, as well as available evidence from clinical trials, complete and in progress, of metal chelation with edetate disodium therapy in patients with diabetes. RESULTS: The TACT results support the concept that ubiquitous toxic metals such as lead and cadmium may be modifiable risk factors for cardiovascular disease, particularly in patients with diabetes. CONCLUSIONS: The purpose of this review is to discuss the potential mechanisms unifying the pathogenesis of atherogenic factors in diabetes with toxic metal exposure, and the potential role of metal chelation.

Prognostic significance of biomarkers in predicting outcome in patients with coronary artery disease and left ventricular dysfunction: results of the biomarker substudy of the Surgical Treatment for Ischemic Heart Failure trials.

BACKGROUND: Patients with heart failure and coronary artery disease often undergo coronary artery bypass grafting, but assessment of the risk of an adverse outcome in these patients is difficult. To evaluate the ability of biomarkers to contribute independent prognostic information in these patients, we measured levels in patients enrolled in the biomarker substudies of the Surgical Treatment for Ischemic Heart Failure (STICH) trials. Patients in STICH Hypothesis 1 were randomized to medical therapy or coronary artery bypass grafting, whereas those in STICH Hypothesis 2 were randomized to coronary artery bypass grafting or coronary artery bypass grafting with left ventricular reconstruction. METHODS AND RESULTS: In substudy patients assigned to STICH Hypothesis 1 (n=606), plasma levels of soluble tumor necrosis factor-α receptor-1 (sTNFR-1) and brain natriuretic peptide (BNP) were highly predictive of the primary outcome variable of mortality by univariate analysis (BNP: χ(2)=40.6; P<0.0001 and sTNFR-1: χ(2)=38.9; P<0.0001). When considered in the context of multivariable analysis, both BNP and sTNFR-1 contributed independent prognostic information beyond the information provided by a large array of clinical factors independent of treatment assignment. Consistent results were seen when assessing the predictive value of BNP and sTNFR-1 in patients assigned to STICH Hypothesis 2 (n=626). Both plasma levels of BNP (χ(2)=30.3) and sTNFR-1 (χ(2)=45.5) were highly predictive in univariate analysis (P<0.0001) and in multivariable analysis for the primary end point of death or cardiac hospitalization. In multivariable analysis, the prognostic information contributed by BNP (χ(2)=6.0; P=0.049) and sTNFR-1 (χ(2)=8.8; P=0.003) remained statistically significant even after accounting for other clinical information. Although the biomarkers added little discriminatory improvement to the clinical factors (increase in c-index ≤0.1), net reclassification improvement for the primary end points was 0.29 for BNP and 0.21 for sTNFR-1 in the Hypothesis 1 cohort, and 0.15 for BNP and 0.30 for sTNFR-1 in the Hypothesis 2 cohort, reflecting important predictive improvement. CONCLUSIONS: Elevated levels of sTNFR-1 and BNP are strongly associated with outcomes, independent of therapy, in 2 large and independent studies, thus providing important cross-validation for the prognostic importance of these 2 biomarkers.

Treatment of chronic heart failure in a managed care setting. Baseline results from the Achieving Cardiac Excellence Project.

BACKGROUND: Effective therapy for chronic heart failure (CHF) is underutilized despite a broad consensus regarding treatment recommendations. METHODS: As a quality improvement project designed to reduce preventable hospitalizations associated with CHF, we examined use of angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and beta-adrenergic receptor blockers (BB) in a population of patients enrolled in a managed care plan. Medicare and commercial enrollees were included. Patients with CHF were identified using claims data (International Classification of Disease 9th Clinical Modification code 428) covering January 1, 1998 through December 31, 1998. Drug utilization data were obtained from the plan's pharmacy benefits database. Data were available for 1220 patients. RESULTS: The mean age (+/- SD) was 71 +/- 12 years, 53% were female, and 84% were Medicare enrollees. Prescriptions for ACEI, ARB and BB were filled by 52%, 9% and 25% of patients, respectively. Prescriptions for diuretics, digitalis preparations, and calcium channel blockers (CCB) were filled by 69%, 34%, and 32%, respectively. Therefore, almost half of patients with CHF were not receiving ACEI therapy, even though it had been proven to reduce morbidity and mortality related to CHF. Furthermore, three-quarters of patients were not receiving BB therapy, a similarly effective therapy. In contrast, CCB and digitalis have not been convincingly shown to reduce mortality in patients with CHF broadly defined. Utilization of CCB and digitalis exceeded that of BB. CONCLUSIONS: Managed care organizations should develop, test, and implement network-level strategies designed to optimize the appropriate utilization of effective drug therapies for patients with CHF.