Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association.

BACKGROUND: Acute rheumatic fever remains a serious healthcare concern for the majority of the world's population despite its decline in incidence in Europe and North America. The goal of this statement was to review the historic Jones criteria used to diagnose acute rheumatic fever in the context of the current epidemiology of the disease and to update those criteria to also take into account recent evidence supporting the use of Doppler echocardiography in the diagnosis of carditis as a major manifestation of acute rheumatic fever. METHODS AND RESULTS: To achieve this goal, the American Heart Association's Council on Cardiovascular Disease in the Young and its Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee organized a writing group to comprehensively review and evaluate the impact of population-specific differences in acute rheumatic fever presentation and changes in presentation that can result from the now worldwide availability of nonsteroidal anti-inflammatory drugs. In addition, a methodological assessment of the numerous published studies that support the use of Doppler echocardiography as a means to diagnose cardiac involvement in acute rheumatic fever, even when overt clinical findings are not apparent, was undertaken to determine the evidence basis for defining subclinical carditis and including it as a major criterion of the Jones criteria. This effort has resulted in the first substantial revision to the Jones criteria by the American Heart Association since 1992 and the first application of the Classification of Recommendations and Levels of Evidence categories developed by the American College of Cardiology/American Heart Association to the Jones criteria. CONCLUSIONS: This revision of the Jones criteria now brings them into closer alignment with other international guidelines for the diagnosis of acute rheumatic fever by defining high-risk populations, recognizing variability in clinical presentation in these high-risk populations, and including Doppler echocardiography as a tool to diagnose cardiac involvement.

Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association.

BACKGROUND: Infective endocarditis is a potentially lethal disease that has undergone major changes in both host and pathogen. The epidemiology of infective endocarditis has become more complex with today's myriad healthcare-associated factors that predispose to infection. Moreover, changes in pathogen prevalence, in particular a more common staphylococcal origin, have affected outcomes, which have not improved despite medical and surgical advances. METHODS AND RESULTS: This statement updates the 2005 iteration, both of which were developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It includes an evidence-based system for diagnostic and treatment recommendations used by the American College of Cardiology and the American Heart Association for treatment recommendations. CONCLUSIONS: Infective endocarditis is a complex disease, and patients with this disease generally require management by a team of physicians and allied health providers with a variety of areas of expertise. The recommendations provided in this document are intended to assist in the management of this uncommon but potentially deadly infection. The clinical variability and complexity in infective endocarditis, however, dictate that these recommendations be used to support and not supplant decisions in individual patient management.

Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association.

A link between oral health and cardiovascular disease has been proposed for more than a century. Recently, concern about possible links between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) has intensified and is driving an active field of investigation into possible association and causality. The 2 disorders share several common risk factors, including cigarette smoking, age, and diabetes mellitus. Patients and providers are increasingly presented with claims that PD treatment strategies offer ASVD protection; these claims are often endorsed by professional and industrial stakeholders. The focus of this review is to assess whether available data support an independent association between ASVD and PD and whether PD treatment might modify ASVD risks or outcomes. It also presents mechanistic details of both PD and ASVD relevant to this topic. The correlation of PD with ASVD outcomes and surrogate markers is discussed, as well as the correlation of response to PD therapy with ASVD event rates. Methodological issues that complicate studies of this association are outlined, with an emphasis on the terms and metrics that would be applicable in future studies. Observational studies to date support an association between PD and ASVD independent of known confounders. They do not, however, support a causative relationship. Although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent ASVD or modify its outcomes.

Immunosuppressant-induced endothelial damage and pulmonary arterial hypertension.

Cyclosporine A, used to prevent graft-versus-host-disease, is known to induce endothelial injury. Endothelial dysfunction is an important feature of pulmonary arterial hypertension (PAH). In this article, we describe 2 children who developed cyclosporine-induced acute respiratory distress syndrome. Lung biopsy showed patchy loss of endothelial caveolin-1 and von Willebrand factor to occur early. Significant loss of endothelial caveolin-1 was associated with robust expression of caveolin-1 in smooth muscle cells with subsequent neointima formation leading to fatal PAH. Thus, patients who develop acute respiratory distress syndrome after immunosuppressive therapy are at risk of developing PAH.

Progressive endothelial cell damage in an inflammatory model of pulmonary hypertension.

Monocrotaline (MCT)-induces progressive disruption of endothelial cell membrane and caveolin-1 leading to pulmonary arterial hypertension (PAH). Treatment instituted early rescues caveolin-1 and attenuates PAH. To test the hypothesis that the poor response to therapy in established PAH is due to progressive deregulation of multiple signaling pathways, the authors investigated time-dependent changes in the expression of caveolin-1, gp130, PY-STAT3, Bcl-xL, and the molecules involved in NO signaling pathway (endothelial nitric oxide synthase [eNOS], heat sock protein 90 [HSP90], Akt, soluble guanylate cyclase [sGC] alpha1 and beta1 subunits). PAH and right ventricular hypertrophy (RVH) were observed at 2 and 3 weeks. Progressive loss of endothelial caveolin-1 and sGC (alpha1, beta1), PY-STAT3 activation, and Bcl-xL expression were observed at 1 to 3 weeks post-MCT. The expression of gp130 increased at 48 hours and 1 week, with a subsequent loss at 2 and 3 weeks. The expression of eNOS increased at 48 hours and 1 week post-MCT, with a significant loss at 3 weeks. The expression of HSP90 and Akt decreased at 2 and 3 weeks post-MCT concomitant with PAH. Thus, MCT induces progressive loss of membrane and cytosolic proteins, resulting in the activation of proliferative and antiapoptotic factors, and deregulation of NO signaling leading to PAH. An attractive therapeutic approach to treat PAH may be an attempt to rescue endothelial cell membrane integrity.

Myocarditis in Multisystem Inflammatory Syndrome in Children Associated With Coronavirus Disease 2019.

Cardiac involvement as a complication of severe acute respiratory syndrome coronavirus 2 infection in children is a relatively new entity. We present our initial experience managing children with coronavirus disease 2019-related acute myocardial injury. The 3 patients presented here represent a spectrum of the cardiac involvement noted in children with coronavirus disease 2019-related multisystem inflammatory syndrome, including myocarditis presenting as cardiogenic shock or heart failure with biventricular dysfunction, valvulitis, coronary artery changes, and pericardial effusion.

Hypoxia-induced pulmonary hypertension and chronic lung disease: caveolin-1 dysfunction an important underlying feature.

Caveolin-1 (cav-1) has been shown to play a significant role in the pathogenesis of pulmonary hypertension (PH). In the monocrotaline model of PH, the loss of endothelial cav-1 as well as reciprocal activation of proliferative and anti-apoptotic pathways initiate the disease process and facilitate its progression. In order to examine the role of cav-1 in hypoxia-induced PH, we exposed rats and neonatal calves to hypobaric hypoxia and obtained hemodynamic data and assessed the expression of cav-1 and related proteins eNOS, HSP90, PTEN, gp130, PY-STAT3, ß-catenin, and Glut1 in the lung tissue. Chronic hypoxic exposure in rats (48 h-4 weeks) and calves (two weeks) did not alter the expression of cav-1, HSP90, or eNOS. PTEN expression was significantly decreased accompanied by PY-STAT3 activation and increased expression of gp130, Glut1, and ß-catenin in hypoxic animals. We also examined cav-1 expression in the lung sections from steers with chronic hypoxic disease (Brisket disease) and from patients with chronic lung disease who underwent lung biopsy for medical reasons. There was no cav-1 loss in Brisket disease. In chronic lung disease cases, endothelial cav-1 expression was present, albeit with less intense staining in some cases. In conclusion, hypoxia did not alter the cav-1 expression in experimental models. The presence of cav-1, however, did not suppress hypoxia-induced activation of PY-STAT3 and ß catenin, increased gp130 and Glut1 expression, or prevent the PTEN loss, indicating cav-1 dysfunction in hypoxia-induced PH.

Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America.

BACKGROUND: Despite advances in medical, surgical, and critical care interventions, infective endocarditis remains a disease that is associated with considerable morbidity and mortality. The continuing evolution of antimicrobial resistance among common pathogens that cause infective endocarditis creates additional therapeutic issues for physicians to manage in this potentially life-threatening illness. METHODS AND RESULTS: This work represents the third iteration of an infective endocarditis "treatment" document developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It updates recommendations for diagnosis, treatment, and management of complications of infective endocarditis. A multidisciplinary committee of experts drafted this document to assist physicians in the evolving care of patients with infective endocarditis in the new millennium. This extensive document is accompanied by an executive summary that covers the key points of the diagnosis, antimicrobial therapy, and management of infective endocarditis. For the first time, an evidence-based scoring system that is used by the American College of Cardiology and the American Heart Association was applied to treatment recommendations. Tables also have been included that provide input on the use of echocardiography during diagnosis and treatment of infective endocarditis, evaluation and treatment of culture-negative endocarditis, and short-term and long-term management of patients during and after completion of antimicrobial treatment. To assist physicians who care for children, pediatric dosing was added to each treatment regimen. CONCLUSIONS: The recommendations outlined in this update should assist physicians in all aspects of patient care in the diagnosis, medical and surgical treatment, and follow-up of infective endocarditis, as well as management of associated complications. Clinical variability and complexity in infective endocarditis, however, dictate that these guidelines be used to support and not supplant physician-directed decisions in individual patient management.

Hematological disorders and pulmonary hypertension.

Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. Several hematological disorders such as sickle cell disease, thalassemia and myeloproliferative diseases develop PH which worsens the prognosis. Associated oxidant injury and vascular inflammation cause endothelial damage and dysfunction. Pulmonary vascular endothelial damage/dysfunction is an early event in PH resulting in the loss of vascular reactivity, activation of proliferative and antiapoptotic pathways leading to vascular remodeling, elevated pulmonary artery pressure, right ventricular hypertrophy and premature death. Hemolysis observed in hematological disorders leads to free hemoglobin which rapidly scavenges nitric oxide (NO), limiting its bioavailability, and leading to endothelial dysfunction. In addition, hemolysis releases arginase into the circulation which converts L-arginine to ornithine, thus bypassing NO production. Furthermore, treatments for hematological disorders such as immunosuppressive therapy, splenectomy, bone marrow transplantation, and radiation have been shown to contribute to the development of PH. Recent studies have shown deregulated iron homeostasis in patients with cardiopulmonary diseases including pulmonary arterial hypertension (PAH). Several studies have reported low iron levels in patients with idiopathic PAH, and iron deficiency is an important risk factor. This article reviews PH associated with hematological disorders and its mechanism; and iron homeostasis and its relevance to PH.

Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association.

BACKGROUND: Kawasaki disease is an acute self-limited vasculitis of childhood that is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop in approximately 15% to 25% of untreated children and may lead to ischemic heart disease or sudden death. METHODS AND RESULTS: A multidisciplinary committee of experts was convened to revise the American Heart Association recommendations for diagnosis, treatment, and long-term management of Kawasaki disease. The writing group proposes a new algorithm to aid clinicians in deciding which children with fever for > or =5 days and < or =4 classic criteria should undergo echocardiography, receive intravenous gamma globulin (IVIG) treatment, or both for Kawasaki disease. The writing group reviews the available data regarding the initial treatment for children with acute Kawasaki disease, as well for those who have persistent or recrudescent fever despite initial therapy with IVIG, including IVIG retreatment and treatment with corticosteroids, tumor necrosis factor-alpha antagonists, and abciximab. Long-term management of patients with Kawasaki disease is tailored to the degree of coronary involvement; recommendations regarding antiplatelet and anticoagulant therapy, physical activity, follow-up assessment, and the appropriate diagnostic procedures to evaluate cardiac disease are classified according to risk strata. CONCLUSIONS: Recommendations for the initial evaluation, treatment in the acute phase, and long-term management of patients with Kawasaki disease are intended to assist physicians in understanding the range of acceptable approaches for caring for patients with Kawasaki disease. The ultimate decisions for case management must be made by physicians in light of the particular conditions presented by individual patients.

Enhanced caveolin-1 expression in smooth muscle cells: Possible prelude to neointima formation.

AIM: To study the genesis of neointima formation in pulmonary hypertension (PH), we investigated the role of caveolin-1 and related proteins. METHODS: Male Sprague Dawley rats were given monocrotaline (M, 40 mg/kg) or subjected to hypobaric hypoxia (H) to induce PH. Another group was given M and subjected to H to accelerate the disease process (M + H). Right ventricular systolic pressure, right ventricular hypertrophy, lung histology for medial hypertrophy and the presence of neointimal lesions were examined at 2 and 4 wk. The expression of caveolin-1 and its regulatory protein peroxisome proliferator-activated receptor (PPAR) γ, caveolin-2, proliferative and anti-apoptotic factors (PY-STAT3, p-Erk, Bcl-xL), endothelial nitric oxide synthase (eNOS) and heat shock protein (HSP) 90 in the lungs were analyzed, and the results from M + H group were compared with the controls, M and H groups. Double immunofluorescence technique was used to identify the localization of caveolin-1 in pulmonary arteries in rat lungs and in human PH lung tissue. RESULTS: In the M + H group, PH was more severe compared with M or H group. In the 4 wk M+H group, several arteries with reduced caveolin-1 expression in endothelial layer coupled with an increased expression in smooth muscle cells (SMC), exhibited neointimal lesions. Neointima was present only in the arteries exhibiting enhanced caveolin-1 expression in SMC. Lung tissue obtained from patients with PH also revealed neointimal lesions only in the arteries exhibiting endothelial caveolin-1 loss accompanied by an increased caveolin-1 expression in SMC. Reduction in eNOS and HSP90 expression was present in the M groups (2 and 4 wk), but not in the M + H groups. In both M groups and in the M + H group at 2 wk, endothelial caveolin-1 loss was accompanied by an increase in PPARγ expression. In the M + H group at 4 wk, increase in caveolin-1 expression was accompanied by a reduction in the PPARγ expression. In the H group, there was neither a loss of endothelial caveolin-1, eNOS or HSP90, nor an increase in SMC caveolin-1 expression; or any alteration in PPARγ expression. Proliferative pathways were activated in all experimental groups. CONCLUSION: Enhanced caveolin-1 expression in SMC follows extensive endothelial caveolin-1 loss with subsequent neointima formation. Increased caveolin-1 expression in SMC, thus, may be a prelude to neointima formation.

Caveolin-1 expression during the progression of pulmonary hypertension.

Caveolin-1 plays a pivotal role in maintaining vascular health. Progressive loss of endothelial caveolin-1 and activation of proliferative and anti-apoptotic pathways occur before the onset of monocrotaline (MCT)-induced pulmonary hypertension (PH), and the rescue of endothelial caveolin-1 attenuates PH. Recently, we reported endothelial caveolin-1 loss associated with enhanced expression of caveolin-1 in smooth muscle cells (SMC) with subsequent neointima formation in human PH. To examine whether the loss of endothelial caveolin-1 followed by an enhanced expression in SMC is a sequential event in the progression of PH, we studied rats at two and four weeks post-MCT. Right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary vascular histology, and the expression of caveolin-1 and endothelial membrane proteins (platelet/endothelial cell adhesion molecule-1 [PECAM-1], both α and ß subunits of soluble guanylate cyclase [sGC]), von Willebrand factor (vWF), smooth muscle α-actin, proliferative and anti-apoptotic factors (PY-STAT3 and Bcl-xL) and matrix metalloproteinase (MMP) 2 in the lungs were examined. PH was accompanied by a progressive loss of endothelial caveolin-1, activation of PY-STAT3, increased Bcl-xL expression and vascular remodeling at two and four weeks post-MCT. Loss of PECAM-1 and sGC (both subunits) paralleled that of caveolin-1, whereas vWF was well preserved at two weeks post-MCT. At four weeks post-MCT, 29% of the arteries showed a loss of vWF in addition to endothelial caveolin-1, and 70% of these arteries exhibited enhanced expression of caveolin-1 in SMC; and there was increased expression and activity of MMP2. In conclusion, MCT-induced endothelial injury disrupts endothelial cell membrane with a progressive loss of endothelial caveolin-1, and the activation of proliferative and antiapoptotic pathways leading to PH. Subsequent extensive endothelial cell damage results in enhanced expression of caveolin-1 in SMC. In addition, there is a progressive increase in MMP2 expression and activity. These alterations may further facilitate cell proliferation, matrix degradation and cell migration, thus contributing to the progression of the disease.

Associated inflammation or increased flow-mediated shear stress, but not pressure alone, disrupts endothelial caveolin-1 in infants with pulmonary hypertension.

Endothelial caveolin-1 loss is an important feature of pulmonary hypertension (PH); the rescue of caveolin-1 abrogates experimental PH. Recent studies in human PH suggest that the endothelial caveolin-1 loss is followed by an enhanced expression of caveolin-1 in smooth muscle cells (SMC) with subsequent neointima formation. In order to evaluate caveolin-1 expression in infants with PH, we examined the available clinical histories, hemodynamic data, and the expression of caveolin-1, PECAM-1, vWF, and smooth muscle α-actin in the lung biopsy/autopsy specimens obtained from infants with congenital heart disease (CHD, n = 8) and lung disease (n = 9). In CHD group, PH associated with increased pulmonary blood flow exhibited loss of endothelial caveolin-1 and PECAM-1 in pulmonary arteries; additional vWF loss was associated with enhanced expression of caveolin-1 in SMC. In the absence of PH, increased or decreased pulmonary blood flow did not disrupt endothelial caveolin-1, PECAM-1, or vWF; nor was there any enhanced expression of caveolin-1 in SMC. In Lung Disease + PH group, caveolin-1, PECAM-1, and vWF were well preserved in seven infants, and importantly, SMC in these arteries did not exhibit enhanced caveolin-1 expression. Two infants with associated inflammatory disease exhibited loss of endothelial caveolin-1 and PECAM-1; additional loss of vWF was accompanied by enhanced expression of caveolin-1 in SMC. Thus, associated flow-induced shear stress or inflammation, but not elevated pulmonary artery pressure alone, disrupts endothelial caveolin-1. Subsequent vWF loss, indicative of extensive endothelial damage is associated with enhanced expression of caveolin-1 in SMC, which may worsen the disease.

Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension.

Monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) in rats is preceded by an inflammatory response, progressive endothelial cell membrane disruption, reduction in the expression of caveolin-1, and reciprocal activation of STAT3 (PY-STAT3). Superoxide and NF-kappaB have been implicated in PAH. To evaluate the role of caveolin-1, PY-STAT3 activation, and superoxide in PAH, MCT-injected rats were treated daily with pyrrolidine dithiocarbamate (PDTC; starting on days 1, 3, and 14 x 2 wk), an inhibitor of inflammation and NF-kappaB activation. Hemodynamic data, the expression of inhibitory (I)-kappaBalpha, caveolin-1, and Tie2 (a membrane protein), activation of PY-STAT3 and NF-kappaB, and superoxide chemiluminescence were examined. Rats developed progressive PAH at 2 wk post-MCT. There was progressive reduction in the expression of caveolin-1, Tie2, and activation of PY-STAT3 in the lungs. Reduction in I-kappaBalpha expression was present at 2 and 4 wk post-MCT. Superoxide chemiluminescence and NF-kappaB activation were observed only at 2 wk post-MCT and both decreased by 4 wk post-MCT despite progressive PAH. PDTC (starting on days 1 and 3) rescued caveolin-1 and Tie2, reversed MCT-induced PY-STAT3 activation, and attenuated PAH. In addition, PDTC restored I-kappaBalpha expression and reduced superoxide chemiluminescence at 2 wk but did not inhibit NF-kappaB activation despite attenuation of PAH. PDTC had no effect on established PAH. Increased superoxide chemiluminescence and NF-kappaB activation appear to be a transient phenomenon in the MCT model. Thus the disruption of endothelial cell membrane integrity resulting in caveolin-1 loss and reciprocal activation of PY-STAT3 plays a key role in the MCT-induced PAH.

Pulmonary artery hypertension: caveolin-1 and eNOS interrelationship: a new perspective.

Pulmonary artery hypertension (PAH) is a sequela of a number of disparate diseases, often with a fatal consequence. Endothelial dysfunction is considered to be an early event during the development of PAH. Impaired availability of bioactive nitric oxide (NO) is a key underlying feature in most forms of clinical and experimental PAH. NO, generated by catalytic activity of endothelial NO synthase (eNOS) on l-arginine, modulates vascular function and structure. For optimal activation, eNOS is targeted to caveolae, the flask-shaped invaginations found on the surface of plasmalemmal membrane of a variety of cells, including endothelial cells. Caveolin-1, the major coat protein of caveolae, regulates eNOS activity. Evidence is accumulating to suggest that caveolin-1 may play a significant role in the pathogenesis of PAH. This review is intended to summarize recent findings indicating a role for caveolin-1 and caveolin-1/eNOS interrelationship in PAH.