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This is a case of acute coronavirus disease 2019 pneumonia that revealed an incidental large atrial myxoma with obstructive physiology that ultimately required emergent treatment with a definitive atriotomy and resection of the underlying myxoma.
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Compound heterozygous familial hypercholesterolemia patients are phenotypically similar to homozygous familial hypercholesterolemia patients, present with significant elevations of low-density lipoprotein cholesterol, and are at risk of cardiovascular disease. Although new treatment options are emerging, the stepwise approach to the use of different therapies has not been well described. (Level of Difficulty: Intermediate.).
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BACKGROUND: The F11 Receptor (F11R; aka JAM-A, JAM-1) is a cell adhesion protein present constitutively on the membrane surface of circulating platelets and within tight junctions of endothelial cells (ECs). Previous reports demonstrated that exposure of ECs to pro-inflammatory cytokines causes insertion of F11R molecules into the luminal surface of ECs, ensuing with homologous interactions between F11R molecules of platelets and ECs, and a resultant adhesion of platelets to the inflamed ECs. The main new finding of the present report is that the first step in this chain of events is the de-novo transcription and translation of F11R molecules, induced in ECs by exposure to inflammatory cytokines. METHODS: The experimental approach utilized isolated, washed human platelet suspensions and cultured human venous endothelial cells (HUVEC) and human arterial endothelial cells (HAEC) exposed to the proinflammatory cytokines TNF-alpha and/or IFN-gamma, for examination of the ability of human platelets to adhere to the inflamed ECs thru the F11R. Our strategy was based on testing the effects of the following inhibitors on this activity: general mRNA synthesis inhibitors, inhibitors of the NF-kappaB and JAK/STAT pathways, and small interfering F11R-mRNA (siRNAs) to specifically silence the F11R gene. RESULTS: Treatment of inflamed ECs with the inhibitors actinomycin, parthenolide or with AG-480 resulted in complete blockade of F11R- mRNA expression, indicating the involvement of NF-kappaB and JAK/STAT pathways in this induction. Transfection of ECs with F11R siRNAs caused complete inhibition of the cytokine-induced upregulation of F11R mRNA and inhibition of detection of the newly- translated F11R molecules in cytokine-inflamed ECs. The functional consequence of the inhibition of F11R transcription and translation was the significant blockade of the adhesion of human platelets to inflamed ECs. CONCLUSION: These results prove that de novo synthesis of F11R in ECs is required for the adhesion of platelets to inflamed ECs. Because platelet adhesion to an inflamed endothelium is crucial for plaque formation in non-denuded blood vessels, we conclude that the de-novo translation of F11R is a crucial early step in the initiation of atherogenesis, leading to atherosclerosis, heart attacks and stroke.
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Aterosclerosis/genética , Moléculas de Adhesión Celular/genética , Citocinas/farmacología , Mediadores de Inflamación/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Receptores de Superficie Celular/genética , Transcripción Genética/efectos de los fármacos , Aorta/patología , Aterosclerosis/patología , Moléculas de Adhesión Celular/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Inflamación/genética , Inflamación/patología , Interferón gamma/farmacología , Adhesividad Plaquetaria/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores de Superficie Celular/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/farmacología , Venas Umbilicales/patologíaRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) is a syndrome that has been associated with multiple cardiac complications including myopericarditis. The pathophysiology and treatment for myopericarditis in the setting of COVID-19 infection is still under investigation. CASE SUMMARY: We present a case of a 60-year-old male admitted for dyspnoea due to COVID-19. He developed new ST-segment elevation, elevated cardiac enzymes, severe left ventricular dysfunction, and high inflammatory markers in the setting of haemodynamic and respiratory collapse from the viral illness. He was diagnosed with COVID-19-induced myopericarditis. He showed rapid clinical improvement with a rapid wean off pressure support, resolution of electrocardiogram (ECG) findings, and recovery of left ventricular systolic function following treatment with intravenous immunoglobulin (IVIG) and methylprednisolone. DISCUSSION: COVID-19's complex and devastating complications continue to create new challenges for clinicians. Cardiac complications, specifically, have been shown to be a signal for worse prognosis in these patients. IVIG and steroids can inhibit the inflammatory cascade and decrease myocardial injury, with implications in treatment of severe myopericarditis.
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Drug rash with eosinophilia and systemic symptoms (DRESS)-associated myocarditis is a rare but life-threatening adverse drug reaction with a very high mortality rate and no effective therapies. We report a case of DRESS-associated myocarditis complicated by cardiogenic shock successfully treated with a novel targeted therapy. (Level of Difficulty: Advanced.).
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Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.
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Aterosclerosis/patología , Insulina/sangre , Islotes Pancreáticos/patología , Síndrome Metabólico/patología , Mutación , Elastasa Pancreática/sangre , Elastasa Pancreática/genética , Serina Endopeptidasas/genética , Adulto , Edad de Inicio , Aterosclerosis/sangre , Aterosclerosis/etiología , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Resistencia a la Insulina , Islotes Pancreáticos/metabolismo , Desequilibrio de Ligamiento , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/etiología , Persona de Mediana Edad , Linaje , Activación PlaquetariaRESUMEN
F11R is the gene name for an adhesion protein, called the F11-receptor, aka JAM-A, which under normal physiological conditions is expressed constitutively on the surface of platelets and localized within tight junctions of endothelial cells (EC). Previous studies of the interactions between human platelets and EC suggested that F11R/JAM-A plays a crucial role in inflammatory thrombosis and atherosclerosis. The study reported here obtained in-vivo confirmation of this conclusion by investigating F11R/JAM-A protein and mRNA in patients with aortic and peripheral vascular disease and in an animal model of atherosclerosis. Molecular and immunofluorescence determinations revealed very high levels of F11R/JAM-A mRNA and F11R/JAM-A protein in atherosclerotic plaques of cardiovascular patients. Similar results were obtained with 12-week-old atherosclerosis-prone apoE-/- mice, an age in which atherosclerotic plaques are well established. Enhanced expression of the F11R/JAM-A message in cultured EC from human aortic and venous vessels was observed following exposure of the cells to cytokines. Determinations of platelet adhesion to cultured EC inflamed by combined cytokine treatment in the presence of F11R/JAM-A - antagonists provided data indicating that de novo expression of F11R/JAM-A on the luminal surface of inflamed EC has an important role in the conversion of EC to a thrombogenic surface. Further studies of these interactions under flow conditions and under in-vivo settings could provide a final proof of a causal role for F11R/JAM-A in the initiation of thrombosis. Based on our in-vitro and in-vivo studies to date, we propose that therapeutic drugs which antagonize the function of F11R/JAM-A should be tested as novel means for the prevention and treatment of atherosclerosis, heart attacks and stroke.
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Aterosclerosis/metabolismo , Moléculas de Adhesión Celular/metabolismo , Células Endoteliales/metabolismo , Inmunoglobulinas/metabolismo , Receptores de Superficie Celular/metabolismo , Trombosis/metabolismo , Anciano , Animales , Apolipoproteínas E/genética , Aterosclerosis/sangre , Aterosclerosis/patología , Plaquetas/metabolismo , Moléculas de Adhesión Celular/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Interferón gamma/metabolismo , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Péptidos/farmacología , Adhesividad Plaquetaria , ARN Mensajero/metabolismo , Trombosis/sangre , Trombosis/patología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. METHODS AND RESULTS: We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. CONCLUSIONS: Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.
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Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/genética , Exoma , Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/terapia , Bases de Datos Genéticas , Muerte Súbita Cardíaca/etiología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Herencia , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Factores de RiesgoAsunto(s)
Tejido Adiposo/patología , Cardiomiopatías/genética , Muerte Súbita Cardíaca/etiología , Ventrículos Cardíacos/patología , Mutación , Sarcoglicanopatías/genética , Sarcoglicanos/genética , Tabique Interventricular/patología , Tejido Adiposo/diagnóstico por imagen , Adulto , Cardiomiopatías/diagnóstico , Cardiomiopatías/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Ventrículos Cardíacos/diagnóstico por imagen , Herencia , Homocigoto , Humanos , Masculino , Linaje , Fenotipo , Sarcoglicanopatías/diagnóstico , Tabique Interventricular/diagnóstico por imagenRESUMEN
RATIONALE AND OBJECTIVE: Our previous studies have determined that the F11 receptor (F11R; aka JAM-A) exerts a critical force in the adhesion of human platelets to inflamed endothelial cells (ECs), and thus can play a significant role in the initiation of atherosclerotic plaque formation. In the present study, we focus on a subsequent event in plaque development--the migration of smooth muscle cells (SMCs) from the media to the intima of inflamed vessels. Here we report our investigation of the expression of F11R in atherosclerotic arteries of coronary artery disease (CAD) patients, and of the role of F11R in the migration of SMCs involved in atherogenesis. METHODS AND RESULTS: Histological staining and specific-antibody immunofluorescence of excised, human atherosclerotic coronary arteries revealed the expression of F11R in the SMCs of the intima. RT-PCR and SDS-PAGE followed by immunoblotting procedures demonstrated that F11R mRNA and the F11R protein levels were enhanced by the stimulation of cultured human aortic SMCs with a combined treatment of proinflammatory cytokines (TNFalpha+INFgamma+IL-beta1). Neither the F11R message nor protein was expressed in non-stimulated SMCs. The functional role of F11R in SMCs' migration was studied in cytokine-stimulated SMCs by interference of F11R expression with siRNA. Silencing of the F11R gene of cytokines-treated SMCs inhibited the expression of both F11R mRNA and F11R protein. Functionally, silencing of the F11R gene blocked the proliferation and migration of these inflamed SMCs, both critical events in atherogenesis. CONCLUSIONS: The new findings of this study are that F11R mRNA and F11R protein are expressed in SMCs of the intima (but not in the media) of atherosclerotic arteries of CAD patients, and that F11R is required for the proliferation and migration of inflamed SMCs. Based on these findings, we conclude that in addition to the previously reported role of F11R in the initiation of plaque formation, F11R plays also an important role in the subsequent growth of atherosclerotic plaques. Identification of drugs that interfere with these pathophysiologic actions of F11R thus represents an effective new approach for the prevention and treatment of atherosclerosis, heart attacks and stroke.