Improved Cardiac Rehabilitation Referral Rate Utilizing a Multidisciplinary Quality Improvement Team.

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.

Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator.

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.

ST-segment elevation myocardial infarction in Nail-Patella syndrome with anomalous coronary anatomy and aneurysms: a case report.

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.

Surgically repaired tetralogy of Fallot in the 7th decade: a late presentation of severe pulmonic regurgitation.

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.

Viral SERPINS-A Family of Highly Potent Immune-Modulating Therapeutic Proteins.

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.

RNA Virus Gene Signatures Detected in Patients With Cardiomyopathy After Chemotherapy; A Pilot Study.

Background: Viral infections are pervasive and leading causes of myocarditis. Immune-suppression after chemotherapy increases opportunistic infections, but the incidence of virus-induced myocarditis is unknown. Objective: An unbiased, blinded screening for RNA viruses was performed after chemotherapy with correlation to cardiac function. Methods: High-throughput sequencing of RNA isolated from blood samples was analyzed following chemotherapy for hematological malignancies (N = 28) and compared with left ventricular ejection fraction (LVEF). Results: On initial rigorous analysis, low levels of influenza orthomyxovirus and avian paramyxovirus sequences were detectable, but without significant correlation to LVEF (r = 0.208). A secondary broad data mining analysis for virus sequences, without filtering human sequences, detected significant correlations for paramyxovirus with LVEF after chemotherapy (r = 0.592, P < 0.0096). Correlations were similar for LVEF pre- and post- chemotherapy for orthomyxovirus (R = 0.483, P < 0.0421). Retrovirus detection also correlated with LVEF post (r = 0.453, p < 0.0591), but not pre-chemotherapy, but is suspect due to potential host contamination. Detectable phage and anellovirus had no correlation. Combined sequence reads (all viruses) demonstrated significant correlation (r = 0.621, P < 0.0078). Reduced LVEF was not associated with chemotherapy (P = NS). Conclusions: This is the first report of RNA virus screening in circulating blood and association with changes in cardiac function among patients post chemotherapy, using unbiased, blinded, high-throughput sequencing. Influenza orthomyxovirus, avian paramyxovirus and retrovirus sequences were detectable in patients with reduced LVEF. Further analysis for RNA virus infections in patients with cardiomyopathy after chemotherapy is warranted.

Distinct Coagulopathy With Myocardial Injury and Pulmonary Embolism in COVID-19.

In this article, we report a case of a 61-year-old male who was diagnosed with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), presenting with acute respiratory distress syndrome requiring intubation and hemodynamic support, marked D-Dimer and troponin I elevation, worsening ST-elevation myocardial infarction on repeat electrocardiograms, and a negative coronary angiogram ruling out a coronary artery thrombosis or occlusion. With worsening diffuse ST-segment elevation on electrocardiograms and reduced ejection fraction on echocardiography in the setting of systemic inflammation, fulminant myocarditis was highly suspected. Despite optimal medical treatment, the patient's condition deteriorated and was complicated by cardiac arrest that failed resuscitation. Although myocarditis was initially suspected, the autopsy revealed no evidence of myocarditis or pericarditis but did demonstrate multiple microscopic sites of myocardial ischemia together with thrombi in the left atrium and pulmonary vasculature. Additionally, scattered microscopic cardiomyocyte necrosis with pathological diagnosis of small vessel micro-thrombotic occlusions. These findings are potentially exacerbated by inflammation-induced coagulopathy, hypoxia, hypotension, and stress, that is, a multifactorial etiology. Further research and an improved understanding are needed to define the precise pathophysiology of the coagulopathic state causing widespread micro-thrombosis with subsequent myocardial and pulmonary injury.

Incidental Finding of a Large Right Atrial Thrombus in a Patient With Cerebral Lymphoma.

Right atrial (RA) masses are rare, challenging to diagnose, and potentially life-threatening with high mortality if untreated. We present a patient presenting with diffuse large B-cell lymphoma in the brain that was incidentally found to have a large RA mass. For a better definition of the RA mass, extensive workup using multimodality imaging including chest computed tomography, transthoracic echocardiography, transesophageal echocardiography, cardiac magnetic resonance imaging, and left heart catheterization was warranted. The imaging demonstrated a large RA mass extending through the tricuspid valve into the right ventricle and superior and inferior vena cava without a mobile component. The mass was then successfully resected, and further histology examination was performed to rule out lymphoma and rare subtypes of diffuse large B-cell lymphoma. The comprehensive workup proved the RA mass to be a calcified thrombus rather than a direct metastatic spread of lymphoma.

Serine Proteases and Chemokines in Neurotrauma: New Targets for Immune Modulating Therapeutics in Spinal Cord Injury.

Progressive neurological damage after brain or spinal cord trauma causes loss of motor function and treatment is very limited. Clotting and hemorrhage occur early after spinal cord (SCI) and traumatic brain injury (TBI), inducing aggressive immune cell activation and progressive neuronal damage. Thrombotic and thrombolytic proteases have direct effects on neurons and glia, both healing and also damaging bidirectional immune cell interactions. Serine proteases in the thrombolytic cascade, tissue- and urokinase-type plasminogen activators (tPA and uPA), as well as the clotting factor thrombin, have varied effects, increasing neuron and glial cell growth and migration (tPA), or conversely causing apoptosis (thrombin) and activating inflammatory cell responses. tPA and uPA activate plasmin and matrix metalloproteinases (MMPs) that break down connective tissue allowing immune cell invasion, promoting neurite outgrowth. Serine proteases also activate chemokines. Chemokines are small proteins that direct immune cell invasion but also mediate neuron and glial cell communication. We are investigating a new class of therapeutics, virus-derived immune modulators; One that targets coagulation pathway serine proteases and a second that inhibits chemokines. We have demonstrated that local infusion of these biologics after SCI reduces inflammation providing early improved motor function. Serp-1 is a Myxomavirus-derived serine protease inhibitor, a serpin, that inhibits both thrombotic and thrombolytic proteases. M-T7 is a virus-derived chemokine modulator. Here we review the roles of thrombotic and thrombolytic serine proteases and chemoattractant proteins, chemokines, as potential therapeutic targets for SCI. We discuss virus-derived immune modulators as treatments to reduce progressive inflammation and ongoing nerve damage after SCI.

Elective Inguinal Hernia Surgery in the Setting of Unfollowed Congenital Complete Heart Block With No Postponement.

Most preoperatively discovered complete heart block cases without cardiac clearance in a non-emergent situation are managed with deferral of elective surgery until a cardiology workup can be completed. The medical consequences of surgical delays can manifest in increased costs to the healthcare system via the treatment of more advanced disease, often requiring more intense and more costly treatment in addition to the emotional burden of delay on a patient that has been waiting months for a particular surgery. Delays in surgery have real impacts on patient health outcomes, hospital finances, and patient satisfaction. We present a rare case in which a proactive anesthesiologist was able to take measures to stratify patient safety risk and safely prevent the delay of the surgery in an asymptomatic and unfollowed congenital third-degree heart block patient. The anesthesiologist demonstrates the use of established guidelines for non-elective noncardiac surgery to safely and effectively prevent the delay of an elective inguinal hernia repair in the setting of a situation that normally warrants its delay. Using these pre- and intraoperative measures, the anesthesiologist was able to prevent the delay of elective surgery, and this should set a precedent of the necessary steps involved to safely manage a patient with an unfollowed third-degree congenital heart block.

Chronological Impact of Earthquakes on Blood Pressure: A Literature Review and Retrospective Study of Hypertension in Haiti Before and After the 2010 Earthquake.

Objective: We review prior studies on the incidence of hypertension (HTN) after earthquakes and present a retrospective analysis of HTN after the 2010 earthquake in Haiti. Methods: Prior reports on HTN incidence were reviewed and a retrospective chart review for diagnosis of HTN in 4,308 patient charts was performed over a 7 year period (five clinics). A retrospective cohort study (RCS) was then performed on 11 patients with linear follow-up. Results: The Literature review revealed a significant increase in acute and subacute HTN following earthquakes. However, the chronic effects of earthquakes varied. Our chart review uncovered no significant difference in diagnosed HTN in a Fort-Liberté clinic 128 kilometers (km) distant and 4 weeks post-event. A secondary linear RCS for 11 individuals, prior to and after the earthquake, also did not detect a significant change in HTN prevalence. Conclusion: Prior studies demonstrate acute and subacute, increases in HTN after earthquakes, but late changes have varied. Retrospective studies in the Fort-Liberté clinic, 128 km distant and 4 weeks post-event, revealed no significant change in HTN, confirming prior findings that changes in HTN after earthquakes are early and local events. Further work examining HTN after earthquakes is needed to improve early health care after natural disasters.

Impaired innate immune signaling due to combined Toll-like receptor 2 and 4 deficiency affects both periodontitis and atherosclerosis in response to polybacterial infection.

Plasma membrane-associated Toll-like receptor (TLR2 and TLR4) signaling contributes to oral microbe infection-induced periodontitis and atherosclerosis. We recently reported that either TLR2 or TLR4 receptor deficiency alters recognition of a consortium of oral pathogens, modifying host responses in periodontitis and atherosclerosis. We evaluated the effects of combined TLR2-/-TLR4-/- double knockout mice on innate immune signaling and induction of periodontitis and atherosclerosis after polybacterial infection with Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum in a mouse model. Multispecies infections established gingival colonization in all TLR2-/-TLR4-/- mice and induced production of bacterial-specific IgG antibodies. In combined TLR2-/-TLR4-/- deficiency there was, however, reduced alveolar bone resorption and mild gingival inflammation with minimal migration of junctional epithelium and infiltration of inflammatory cells. This indicates a central role for TLR2 and TLR4 in periodontitis. Atherosclerotic plaque progression was markedly reduced in infected TLR2-/-TLR4-/- mice or in heterozygotes indicating a profound effect on plaque growth. However, bacterial genomic DNA was detected in multiple organs in TLR2-/-TLR4-/- mice indicating an intravascular dissemination from gingival tissue to heart, aorta, kidney and lungs. TRL2 and TLR4 were dispensable for systemic spread after polybacterial infections but TLR2 and 4 deficiency markedly reduces atherosclerosis induced by oral bacteria.

Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection.

UNLABELLED: In establishing a respiratory infection, vaccinia virus (VACV) initially replicates in airway epithelial cells before spreading to secondary sites of infection, mainly the draining lymph nodes, spleen, gastrointestinal tract, and reproductive organs. We recently reported that interferon gamma (IFN-γ) produced by CD8 T cells ultimately controls this disseminated infection, but the relative contribution of IFN-γ early in infection is unknown. Investigating the role of innate immune cells, we found that the frequency of natural killer (NK) cells in the lung increased dramatically between days 1 and 4 postinfection with VACV. Lung NK cells displayed an activated cell surface phenotype and were the primary source of IFN-γ prior to the arrival of CD8 T cells. In the presence of an intact CD8 T cell compartment, depletion of NK cells resulted in increased lung viral load at the time of peak disease severity but had no effect on eventual viral clearance, disease symptoms, or survival. In sharp contrast, RAG(-/-) mice devoid of T cells failed to control VACV and succumbed to infection despite a marked increase in NK cells in the lung. Supporting an innate immune role for NK cell-derived IFN-γ, we found that NK cell-depleted or IFN-γ-depleted RAG(-/-) mice displayed increased lung VACV titers and dissemination to ovaries and a significantly shorter mean time to death compared to untreated NK cell-competent RAG(-/-) controls. Together, these findings demonstrate a role for IFN-γ in aspects of both the innate and adaptive immune response to VACV and highlight the importance of NK cells in T cell-independent control of VACV in the respiratory tract. IMPORTANCE: Herein, we provide the first systematic evaluation of natural killer (NK) cell function in the lung after infection with vaccinia virus, a member of the Poxviridae family. The respiratory tract is an important mucosal site for entry of many human pathogens, including poxviruses, but precisely how our immune system defends the lung against these invaders remains unclear. Natural killer cells are a type of cytotoxic lymphocyte and part of our innate immune system. In recent years, NK cells have received increasing levels of attention following the discovery that different tissues contain specific subsets of NK cells with distinctive phenotypes and function. They are abundant in the lung, but their role in defense against respiratory viruses is poorly understood. What this study demonstrates is that NK cells are recruited, activated, and contribute to protection of the lung during a severe respiratory infection with vaccinia virus.