The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR.

Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2–10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) and thrombolysis (clot dissolution), complement activation in immune responses and also programmed cell death (apoptosis). Virus-derived serpins have co-evolved with mammalian proteases and serpins, developing into highly effective inhibitors of mammalian proteolytic pathways. Through interacting with extracellular and intracellular serine and cysteine proteases, viral serpins provide a new class of highly active virus-derived coagulation-, immune-, and apoptosis-modulating drug candidates. Viral serpins have unique characteristics: (1) function at micrograms per kilogram doses; (2) selectivity in targeting sites of protease activation; (3) minimal side effects at active concentrations; and (4) the demonstrated capacity to be modified, or fine-tuned, for altered protease targeting. To date, the virus-derived serpin class of biologics has proven effective in a wide range of animal models and in one clinical trial in patients with unstable coronary disease. Here, we outline the known viral serpins and review prior studies with viral serpins, considering their potential for application as new sources for immune-, coagulation-, and apoptosis-modulating therapeutics.

Introduction Cardiac rehabilitation (CR) is an underutilized resource in patients with ischemic heart disease, despite being a Class IA recommendation. In this study, a multidisciplinary quality improvement (QI) team aimed to improve CR referrals by standardizing the ordering process at our hospital system. Method By using a collaborative approach involving the electronic medical record (EMR), medical provider education, and hospital protocols, our two-hospital healthcare system was able to successfully identify barriers to CR referral rates and implement interventions for these barriers. All physicians and medical providers, including ancillary staff, were educated on the EMR order sets to improve compliance by using automated order sets in the EMR. The CR referral order in the EMR included a statement regarding the application of evidence-based medicine, and a computerized provider order entry was included as a reminder to the ordering provider. The use of EMR was monitored monthly by the QI committee. Chi-square test and odds ratios were obtained for statistical analysis. Results Through provider-EMR education and patient education on discharge, CR referral rates significantly improved from 51.2 to 87.1% (p = 0.0001) in a 12-month period. The study included 1,499 patients in total. The improvement was statistically significant regardless of patient gender, race, or insurance coverage. Additionally, subgroup analysis in this study found that prior to standardization of the ordering process, African American patients were significantly less likely to be referred to CR compared to Caucasian patients. (51.2% vs. 41.0%, p=0.01). There was no statistically significant difference in the likelihood of CR referral between Caucasian and African American patients following the intervention (84.0% vs. 78.0%, p = 0.166). Conclusion This study shows that CR is an underutilized resource and that effective QI initiatives may not only increase CR referral rates but also close the gap between racial inequities in referral rates. Future research with multi-center randomized control trials is needed to further enhance its external generalizability to other institutions.

No present guidelines exist regarding the inclusion of atherogenic cancer or chemotherapy into atherosclerotic cardiovascular disease (ASCVD) screening or imaging screening guidelines. Individual physician preference often determines screening, and this is typically symptom guided. A 30-year-old woman with early-stage breast cancer received atherogenic chemotherapy, with no prior atherogenic risk factors. She presented with angina and dyspnea on exertion 3 years after her last round of chemotherapy. An ischemic work-up was performed, and the patient was found to have premature critical stenosis in her proximal left anterior descending artery. Because more patients are living with cancer and survivors of atherogenic chemotherapy emerge, it is becoming more critical to improve ASCVD screening modalities. Expert consensus for patients with early-stage cancer treated with atherogenic chemotherapy should derive either their unique ASCVD algorithm, be included into pre-existing algorithms, or have their own multimodal imaging pathway.

Background: Surgically repaired tetralogy of Fallot (TOF) is a congenital heart disease with a cumulative survival rate of 72% in the 4th decade of life in longitudinal single-cohort studies. Debate surrounds conservative versus surgical management in adults with TOF once pulmonary regurgitation occurs. Case presentation: A 73-year-old male with surgically corrected TOF presented with heart failure symptoms. He underwent ToF repair with a classic right Blalock–Taussig shunt at 2 years of age with transannular patching at 18 years of age. Echocardiography revealed elevated right ventricular systolic pressures, severe right ventricular dilatation, and pulmonary regurgitation. Our patient’s new-onset right-sided heart failure was managed medically with diuresis. He received a new pulmonic valve via percutaneous approach on a later planned hospitalization with resolution of symptoms and improved tricuspid regurgitation. Conclusion: It is a class I recommendation for pulmonic valve intervention once greater than moderate PR occurs; however, medical optimization should take place first. Following adequate RV load optimization, our patient underwent successful transcatheter pulmonic valve implantation with resolution of symptoms and cessation of diuretic.

Background: Nail–Patella syndrome (NPS) is an autosomal-dominant pleiotropic condition characterized by pelvic and skeletal abnormalities and most commonly affecting a tetrad of nails, knees, elbows, and iliac horns, the iliac horns being pathognomonic for the condition. The most well-documented extra-skeletal manifestation is renal involvement with alteration in Type III collagen. No documented cases of NPS with anomalous coronary arteries or aneurysms, acute coronary occlusion, or successfully coronary interventions exist in the medical literature. Case summary: A 62-year-old female with a medical history significant for NPS diagnosed 50 years ago presented to the emergency department with a chief complaint of chest pain. She recently developed end-stage renal disease managed with peritoneal dialysis within the last year. Angiography revealed 100% right coronary artery occlusion with an anomalous take-off from the left circumflex artery. She demonstrated diffuse coronary aneurysms in the right coronary artery, mid-left anterior descending artery, and other epicardial vessels. Two drug-eluting stents were placed in overlapping fashion. Following careful apposition, the aneurysmal segment was successfully stented without complication. The patient was discharged without complication 2 days later. Discussion: Our case shows the first reported case of coronary vascular anomalies and successful coronary revascularization in a patient with NPS in the medical literature. Given the recently reported vascular anomalies and known collagen alterations seen in patients with the genetic disorder, clinicians should suspect further systemic vascular anomalies with their own unique therapeutic challenges when encountering patients with this rare genetic syndrome.