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Objective: To update recommendations issued by the American Heart Association last published in 1990 for the prevention of bacterial endocarditis in individuals at risk for this disease.Participants: An ad hoc writing group appointed by the American Heart Association for their expertise in endocarditis and treatment with liaison members representing the American Dental Association, the Infectious Diseases Society of America, the American Academy of Pediatrics, and the American Society for Gastrointestinal Endoscopy.Evidence: The recommendations in this article reflect analyses of relevant literature regarding procedure-related endocarditis, in vitro susceptibility data of pathogens causing endocarditis, results of prophylactic studies in animal models of endocarditis, and retrospective analyses of human endocarditis cases in terms of antibiotic prophylaxis usage patterns and apparent prophylaxis failures. MEDLINE database searches from 1936 through 1996 were done using the root words endocarditis, bacteremia, and antibiotic prophylaxis. Recommendations in this document fall into evidence level III of the US Preventive Services Task Force categories of evidence.Consensus Process: The recommendations were formulated by the writing group after specific therapeutic regimens were discussed. The consensus statement was subsequently reviewed by outside experts not affiliated with the writing group and by the Science Advisory and Coordinating Committee of the American Heart Association. These guidelines are meant to aid practitioners but are not intended as the standard of care or as a substitute for clinical judgment.Conclusions: Major changes in the updated recommendations include the following: (1) emphasis that most cases of endocarditis are not attributable to an invasive procedure; (2) cardiac conditions are stratified into high-, moderate-, and negligible-risk categories based on potential outcome if endocarditis develops; (3) procedures that may cause bacteremia and for which prophylaxis is recommended are more clearly specified; (4) an algorithm was developed to more clearly define when prophylaxis is recommended for patients with mitral valve prolapse; (5) for oral or dental procedures the initial amoxicillin dose is reduced to 2 g, a follow-up antibiotic dose is no longer recommended, erythromycin is no longer recommended for penicillin-allergic individuals, but clindamycin and other alternatives are offered; and (6) for gastrointestinal or genitourinary procedures, the prophylactic regimens have been simplified. These changes were instituted to more clearly define when prophylaxis is or is not recommended, improve practitioner and patient compliance, reduce cost and potential gastrointestinal adverse effects, and approach more uniform worldwide recommendations. [ABSTRACT FROM AUTHOR]

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.

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, β-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 β-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 β catenin, increased gp130 and Glut1 expression, or prevent the PTEN loss, indicating cav-1 dysfunction in hypoxia-induced PH.

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., Competing Interests: Conflict-of-interest statement: None of the authors has conflict of interest.

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.

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., (© 2015 American Heart Association, Inc.)

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., (© 2015 American Heart Association, Inc.)

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.

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 β 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.

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.

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.

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.

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.

Kawasaki disease (KD) is an acute inflammatory vasculitis of childhood which was initially described more than 4 decades ago, yet the specific etiology remains unknown. It has become the most common cause of acquired cardiovascular disease in children in the United States. Advances in clinical therapies have reduced, but not eliminated, the incidence of coronary artery abnormalities in affected children. Pathophysiology seems to include an intense elaboration of cytokines, endothelin, and other vasoactive mediators resulting in the development of vascular endothelial changes that may leave a permanent impact on vascular integrity. Treatment with intravenous immune globulin and aspirin remains the primary management strategy and steroid therapy remains contoversial. In severe circumstances, coronary reperfusion strategies are required, and coronary artery surgery in children with KD has been required, albeit infrequently. KD may be a harbinger for early onset coronary artery disease in adults. Recently developed AHA recommendations have amended diagnostic strategies and indicated a stratified approach to the long-term follow up of this enigmatic yet widespread disease.

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.

Barth syndrome is an X-linked disorder characterized by dilated cardiomyopathy, cyclic neutropenia, skeletal myopathy, abnormal mitochondria, and growth deficiency. The primary defect is a mutation in the TAZ gene on the X chromosome at Xq28, resulting in abnormal phospholipid biosynthesis and cardiolipin deficiency. To date, there has been no systematic evaluation of the cardiac phenotype. We report five cases of cardiac arrest and/or placement of an internal cardiac defibrillator with documented ventricular arrhythmia. We suggest that ventricular arrhythmia is part of the primary phenotype of the disorder and that patients should be screened accordingly.

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.

The nitric oxide-cyclic guanosine monophosphate signal-transduction mechanism plays a key role in the regulation of vascular tone and structure. Monocrotaline-induced pulmonary hypertension is associated with low bioavailability of nitric oxide. To characterize the mechanism(s) involved in this dysfunction, rats received a single subcutaneous injection of monocrotaline, normal saline (control), or monocrotaline plus daily L-arginine, a precursor of nitric oxide, in drinking water. Pulmonary artery pressure and right ventricular hypertrophy were assessed 2 weeks later. In addition, the authors evaluated the expression of endothelial nitric oxide synthase messenger RNA, endothelial nitric oxide synthase protein, cyclic guanosine monophosphate, and sulfhydryl levels in the lungs. Sulfhydryls are needed for the dynamic modulation of soluble guanylate cyclase by nitric oxide, which results in cyclic guanosine monophosphate formation. L-arginine treatment did not attenuate monocrotaline-induced pulmonary hypertension or right ventricular hypertrophy. Monocrotaline did not alter the expression of endothelial nitric oxide synthase messenger RNA or endothelial nitric oxide synthase protein in the lungs. Protein-bound sulfhydryls (28 +/- 5 vs. 75 +/- 16 pmol/microg protein) and cyclic guanosine monophosphate (0.63 +/- 0.05 vs. 1.06 +/- 0.017 pmol/microg protein) levels in the monocrotaline group were significantly low compared with controls. The low sulfhydryl levels, an indicator of oxidant stress, may account for the impaired availability of bioactive nitric oxide and low cyclic guanosine monophosphate levels. These results suggest that oxidative stress may, in part, contribute to the pathogenesis of pulmonary hypertension in the monocrotaline model.

Abnormalities of pulmonary artery pressure and resistance continue to complicate many varieties of cardiovascular problems in childhood. Much recent effort has been devoted to understanding the cellular mechanisms underlying the pathophysiology of pulmonary hypertension, centering on endothelial cell dysfunction as a principal factor. Defects in the vasodilation machinery of the endothelial cell, such as overexpression of vasoconstrictor elements, have been implicated in various forms of pulmonary hypertension. This includes pulmonary hypertension that is secondary to congenital heart disease, and the primary forms that occur in older children and in neonates. In addition, experimental methods assessing cyclic adenosine monophosphate-mediated and cyclic guanosine monophosphate-mediated vasoreactivity suggest a possible genetic basis in the responses of the pulmonary microvasculature. This article reviews some of the current information that has been developed along these lines, and explores the implications of these data for therapeutic strategies to treat this complex problem.

To determine the effects of chronic nitric oxide (NO) blockade on the pulmonary vasculature, 58-day-old spontaneously hypertensive rats of the stroke-prone substrain (SHRSP) and Wistar-Kyoto rats (WKY) received N(omega)-nitro-L-arginine (L-NNA; 15 mg. kg(-1). day(-1) orally for 8 days). Relaxation to acetylcholine (ACh) in hilar pulmonary arteries (PAs), the ratio of right ventricular (RV) to body weight (RV/BW) to assess RV hypertrophy (RVH), and the percent medial wall thickness (WT) of resistance PAs were examined. L-NNA did not alter the PA relaxation, RV/BW, or WT in WKY. Although the PA relaxation and RV/BW in control SHRSP were comparable to those in WKY, the WT was increased (31 +/- 2 vs. 19 +/- 1%). L-NNA-treated SHRSP showed two patterns: in one group, the relaxation, RV/BW, and WT were comparable to those in the control SHRSP; in the other, impaired relaxation (36 +/- 7 vs. 88 +/- 4% for WKY) was associated with an increase in WT (37 +/- 1%) and RV/BW (0. 76 +/- 0.05). Thus the abnormal pulmonary vasculature in SHRSP at <10 wk of age is not accompanied by impaired relaxation in PAs or RVH; however, impaired relaxation is associated with increased WT and RVH.

Objectives: To describe the orthostatic tachycardia syndrome (OTS) in adolescents, similarities to and differences from chronic fatigue syndrome (CFS), and patterns of orthostatic intolerance during head-up tilt (HUT)., Study Design: Using electrocardiography and arterial tonometry, we investigated the heart rate and blood pressure responses during HUT in 20 adolescents with OTS compared with 25 adolescents with CFS, 13 healthy control subjects, and 20 patients with simple faint., Results: Of the control subjects, 4 of 13 experienced typical vasovagal faints with an abrupt fall in blood pressure and heart rate, and 14 of 20 patients with simple faint experienced similar HUT responses. All patients with CFS (25/25) experienced severe orthostatic symptoms with syncope in 2 of 25, early orthostatic tachycardia during HUT in 16 of 23 (13/16 hypotensive), and delayed orthostatic tachycardia in 7 of 23 (6/7 hypotensive). Acrocyanosis and edema occurred in 18 of 25. Early orthostatic tachycardia occurred in 10 of 20 patients with OTS. Of these, 9 of 10 were hypotensive, but hypotension was delayed in 4 of 9. Delayed tachycardia occurred in 10 of 20 (all hypotensive). Acrocyanosis and edema occurred in most patients with CFS, fewer patients with OTS, and in one patient with simple faint. Orthostatic symptoms were similar but more severe in patients with CFS compared with patients with OTS., Conclusions: Symptoms and patterns of orthostatic heart rate and blood pressure change in OTS overlap strongly with those of CFS. Orthostatic intolerance in OTS may represent an attenuated form of chronic fatigue pathophysiology.

Monocrotaline-induced pulmonary hypertension (PH) in rats is preceded by an inflammatory response in the lungs, and interleukin-6 (IL-6) is expressed in response to inflammation. To evaluate the role of IL-6 in monocrotaline-induced PH, rats received a single subcutaneous injection of monocrotaline (60 mg/kg) or an equivalent amount of normal saline. Pulmonary artery pressure (Ppa), right ventricular hypertrophy (RVH), expression of IL-6 mRNA, and bioactivity of IL-6 in the lungs of these rats were examined 48 hours and 1 and 2 weeks after administration of monocrotaline. The effects of dexamethasone treatment on monocrotaline-induced PH also were evaluated. Two weeks after administration of monocrotaline, significant PH and RVH developed in these rats. Reverse transcription-polymerase chain reaction (RT-PCR) revealed expression of IL-6 mRNA in the lungs 48 hours and 1 and 2 weeks after administration of monocrotaline. This was confirmed using ribonuclease protection assay. The bioactivity of IL-6 in lung extracts progressively increased. Dexamethasone markedly inhibited expression of IL-6 mRNA and IL-6 bioactivity in the lungs, with concomitant attenuation of monocrotaline-induced PH and RVH. Our data show that monocrotaline induces expression of IL-6 mRNA in rat lungs and that inhibition of IL-6 results in attenuation of PH. These findings indicate that IL-6 may play a role in the pathogenesis of PH.

Objectives: To demonstrate the association between orthostatic intolerance and the chronic fatigue syndrome (CFS) in adolescents and to delineate the form that orthostatic intolerance takes in these children., Study Design: We investigated the heart rate and blood pressure (BP) responses to head-up tilt (HUT) in 26 adolescents aged 11 to 19 years with CFS compared with responses in adolescents referred for the evaluation of simple faint and to responses in 13 normal healthy control children of similar age., Results: A total of 4/13 of the controls and 18/26 simple faint patients experienced typical faints with an abrupt decrease in BP and heart rate associated with loss of consciousness. One CFS patient had a normal HUT. A total of 25/26 CFS patients experienced severe orthostatic symptoms associated with syncope in 7/25, orthostatic tachycardia with hypotension in 15/25, and orthostatic tachycardia without significant hypotension in 3/25. Acrocyanosis, cool extremities, and edema indicated venous pooling in 18/25. None of the control or simple faint patients experienced comparable acral or tachycardic findings., Conclusions: We conclude that chronic fatigue syndrome is highly related to orthostatic intolerance in adolescents. The orthostatic intolerance of CFS often has heart rate and BP responses similar to responses in the syndrome of orthostatic tachycardia suggesting that a partial autonomic defect may contribute to symptomatology in these patients.

Purpose: We studied whether umbilical artery catheters (UACs) affect blood flow in the superior mesenteric artery (SMA) of neonates., Methods: Noninvasive duplex pulsed Doppler sonography was used to measure peak systolic velocity, end-diastolic velocity, and mean flow velocity in the SMA. The resistance index and pulsatility index were calculated from these data. Thirty-two infants weighing 450-2,520 g at birth were enrolled in the study. Gestational age at birth was 24-37 weeks. Eighteen infants were studied before and after UAC insertion. Twenty infants were studied before and after UAC removal. Eleven infants with UACs were studied before and during aspiration of blood from the UAC and during bolus infusion of 5% dextrose solution into the UAC. Data were compared before and after UAC insertion; before and after UAC removal; and before and during aspiration and during bolus infusion., Results: Blood flow velocities and vascular resistance were similar in all comparisons except for increases in end-diastolic and mean velocities after UAC insertion., Conclusions: Insertion and removal of UACs, aspiration of blood from UACs, and bolus infusion of fluids into UACs do not diminish blood flow velocity or increase vascular resistance in the SMA.

A major review of the American Heart Association guidelines for endocarditis prophylaxis was published in 1997. In view of changing perspectives on the population at risk for endocarditis and new information on the likelihood of particular procedures to place patients at risk, simplified guidelines have been developed. The role of invasive procedures as a risk factor is deemphasized, simplified single-dose strategies are suggested, and parenteral regimens are required less frequently. In addition, more extensive alternatives to erythromycin, including the newer macrolide antibiotics, are now part of the recommendations for patients who are unable to take penicillins. The new report also discusses the appropriateness of prophylaxis in the presence of the complicated issue of mitral valve prolapse and the relationship of valvar flow patterns to risk for endocarditis. Although no definitive randomized trials have been performed unequivocally establishing the benefits of endocarditis prophylaxis, the new guidelines represent an effort to favorably modify the risk-benefit ratio for use of antibiotics in the patient at risk. In addition to the new guidelines, other recent reports emphasize the importance of associated nonpharmacologic methods to prevent endocarditis, such as meticulous skin care and personal hygiene, and the need for a determined educational approach in the patient at risk to minimize risk. Recent reports have also emphasized the need for pediatric awareness of the changing patient population at risk for endocarditis and the need for increased vigilance in particular patients.

Monocrotaline (MCT)-induced pulmonary hypertension (PH) is associated with impaired endothelium-dependent nitric oxide (NO)-mediated relaxation. To examine the role of NO in PH, Sprague-Dawley rats were given a single subcutaneous injection of normal saline [control (C)], 80 mg/kg MCT, or the same dose of MCT and a continuous subcutaneous infusion of 2 mg.kg-1.day-1 of molsidomine, a NO prodrug (MCT+MD). Two weeks later, plasma NO3- levels, pulmonary arterial pressure (Ppa), ratio of right-to-left ventricular weights (RV/LV) to assess right ventricular hypertrophy, and pulmonary histology were evaluated. The plasma NO3- level in the MCT group was reduced to 9.2 +/- 1.5 microM (n = 12) vs. C level of 17.7 +/- 1.8 microM (n = 8; P < 0.02). In the MCT+MD group, plasma NO3- level was 12.3 +/- 2.0 microM (n = 8). Ppa and RV/LV in the MCT group were increased compared with C [Ppa, 34 +/- 3.4 mmHg (n = 6) vs. 19 +/- 0.8 mmHg (n = 8) and 0.41 +/- 0.01 (n = 9) vs. 0.25 +/- 0.008 (n = 8), respectively; P < 0.001]. In the MCT+MD group, Ppa and RV/LV were not different when compared with C [19 +/- 0.5 mmHg (n = 5) and 0.27 +/- 0.01 (n = 9), respectively; P < 0.001 vs. MCT]. Medial wall thickness of lung vessels in the MCT group was increased compared with C [31 +/- 1.5% (n = 9) vs. 13 +/- 0.66% (n = 9); P < 0.001], and MD partially prevented MCT-induced pulmonary vascular remodeling [22 +/- 1.2% (n = 11); P < 0.001 vs. MCT and C]. These results indicate that a defect in the availability of bioactive NO may play an important role in the pathogenesis of MCT-induced PH.

1. Pacing-induced congestive heart failure (CHF) in dogs is associated with increased plasma levels of atrial natriuretic factor (ANF) and inhibition of receptor-mediated cyclic AMP-dependent relaxation in isolated pulmonary arteries (PA). Since ANF is known to be negatively coupled to adenylate cyclase, we studied cyclic AMP-mediated relaxation to isoprenaline (Iso) and arachidonic acid (AA) in PA from control dogs (C), dogs with pacing-induced CHF (CHF) and dogs with bilateral atrial appendectomy and CHF (ATR APP+CHF). 2. In CHF, plasma ANF levels increased from a baseline of 80 +/- 8 pg ml-1 to 283 +/- 64 pg ml-1 (P < 0.05), but the ATR APP+CHF group failed to show this increase (67 +/- 7 pg ml-1 vs 94 +/- 15 pg ml-1, P = NS). Plasma ANF levels, however, did not influence myocardial dysfunction in CHF. 3. The relaxation of 49 +/- 5% to 1 microM Iso in C was reduced to 23 +/- 4% in CHF (P < 0.05), but relaxation of 49 +/- 12% was observed in the ATR APP+CHF group (P = NS vs C). Relaxation responses to 10 microM AA were as follows: 77 +/- 5% (C, n = 8), 27 +/- 8% (CHF, n = 10, P < 0.05 vs C), and 93 +/- 5% (ATR APP+CHF, n = 5). The presence of CHF, or the plasma ANF levels, did not affect responses to cyclic GMP-mediated relaxing agents in PA. 4. These data indicate that the myocardial performance in CHF is not influenced by plasma ANF levels. However, altered cyclic AMP-mediated relaxation in PA during CHF is, in part, modulated by circulating ANF levels.

Objective: Nitric oxide (NO) and endothelin-1 (ET-1) have both been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, we examined NO-related relaxation and ET-1 levels in rat hilar pulmonary arteries (PA) during the progression of monocrotaline (MCT)-induced PH., Methods: Rats were studied 1 and 2 weeks after a single subcutaneous injection of MCT (80 mg/kg). Pulmonary artery pressure (PAP), right ventricular hypertrophy (RVH), NO-related relaxation and tissue ET-1 levels in PA were evaluated and compared with control (C)., Results: One week post-MCT, endothelium (E)-dependent relaxation to 10(-5) M adenosine diphosphate (ADP), 10(-5) M A23187 and 10(-5) M acetylcholine (ACh) and tissue ET-1 levels in PA were normal. Rats in this group did not develop PH or RVH. Two weeks post-MCT, E-dependent relaxation was impaired (ADP, 7 +/- 3% VS. c, 62 +/- 5%; A23187, 2 +/- 7% vs. C, 58 +/- 2%; ACh, 33 +/- 7% vs. C, 86 +/- 2%; P < 0.05) and ET-1 levels were elevated (1925 +/- 244 pg/g wwt vs. C, 469 +/- 59 pg/g wwt, P < 0.05), In addition, significant PH and RVH were present (PAP 33 +/- 4 mmHg vs. C 18 +/- 0.8 mmHg, P < 0.05; RVH index 0.40 +/- 0.006 vs. C, 0.25 +/- 0.01, P < 0.05). Incubation with 10 microM indomethacin, 150 U/ml superoxide dismutase or 300 microM L-arginine failed to restore impaired relaxation to ACh. In E-intact rings, relaxation to 10(-6) M glyceryl trinitrate (GTN) was inhibited at 1 week post-MCT (72 +/- 2% vs. C, 87 +/- 3%, P < 0.05) with further inhibition at 2 weeks (39 +/- 4%). Response to GTN in E-denuded rings was normal in MCT groups., Conclusions: These results indicate that MCT injection in rats results in delayed but progressive endothelial injury and PH. Despite mild endothelial dysfunction 1 week post-MCT, NO-related relaxation and ET-1 levels are normal. At 2 weeks post-MCT, inhibition of E-dependent NO-related relaxation and elevation of ET-1 levels are associated with PH and RVH. Thus inhibition of NO production associated with elevated ET-1 levels may play an important role in the pathophysiology of MCT-induced PH.

To assess the contributions of systolic and diastolic dysfunction to congestive heart failure (CHF) in ventricular septal defect (VSD), we studied 13 children with VSD at catheterization using a Millar catheter. Eight children had CHF, whereas five did not. Phenylephrine was infused at a rate of 5 micrograms.kg-1.min-1, and M-mode echocardiography and pressure were measured simultaneously. Systolic left ventricular (LV) function was assessed by maximum LV pressure (LVP), rate of pressure development (dP/dt), and by the end-systolic pressure-diameter relation (ESPDR). Systolic myocardial function was assessed by the end-systolic stress-strain relation. Diastolic chamber function was assessed by the isovolumic relaxation time constant (tau) and by the end-diastolic pressure-diameter relation (EDPDR). Diastolic myocardial function was measured by the end-diastolic stress-strain relationship. With phenylephrine, maximum LVP increased from 99 +/- 5 to 119 +/- 4 mmHg with CHF and from 106 +/- 6 to 149 +/- 10 mmHg without CHF. +dP/dt was lower with CHF (1,582 +/- 96 mmHg/s) than without CHF (2,300 +/- 200 mmHg/s). The maximum slope of the ESPDR was 39 +/- 8 with CHF and 94 +/- 14 mmHg/cm without CHF. The maximum slope of the midwall stress-strain relation was 223 +/- 37 with CHF and 395 +/- 93 g/cm2 without CHF. tau was 25 +/- 2 without CHF compared with 32 +/- 3 ms with CHF. The EDPDR was shifted leftward with failure, whereas the stress-strain relation was similar for all patients. CHF in patients with VSD results primarily from systolic dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Impairment of humoral and neural regulation of blood pressure may contribute to preoperative and postoperative hypertension in coarctation of the aorta and may also affect the release of vasopressin and atrial natriuretic factor. Because vasopressin and atrial natriuretic factor have potent vasoactive effects, we measured plasma vasopressin and atrial natriuretic factor levels by radioimmunoassay before operation and for 5 days after operation in 11 patients aged 9 months to 12 years undergoing coarctation repair and in 12 control patients undergoing other cardiovascular operations. Six patients in the coarctation group required minimal antihypertensive therapy (group I) and five required prolonged intravenous antihypertensive therapy (group II). Before operation, vasopressin levels correlated with systolic blood pressure for all patients in the coarctation group (r = 0.83, p < 0.01) whereas atrial natriuretic factor levels did not. Before operation, atrial natriuretic factor levels were lower (28 +/- 5 vs 41 +/- 7 and 50 +/- 8 pg/ml, p < 0.05) and vasopressin levels were higher (28 +/- 6 vs 5.4 +/- 0.9 and 7 +/- 3 pg/ml, p < 0.05) in group II than in group I or control patients. Vasopressin levels were higher (p < 0.05) on the day of operation and on postoperative days 2 through 5 in group II than in group I and in control patients. Atrial natriuretic factor levels were lower during the day of operation in group II than in group I or in control patients (26 +/- 7 vs 51 +/- 16 and 50 +/- 7 pg/ml, p < 0.05) and remained lower than control values on postoperative days 1 and 3 through 5. Elevated vasopressin and lowered atrial natriuretic factor levels may contribute to preoperative and postoperative hypertension in coarctation.

Background: Alterations in myocardial function and systemic vascular tone are well documented in congestive heart failure (CHF), but little information is available on the effects of CHF on pulmonary vessels. We examined the mechanisms of tone regulation of canine pulmonary arteries during pacing-induced CHF., Methods and Results: Rings 3-4 mm wide from lobar pulmonary arteries were prepared from normal dogs, dogs paced at 210 beats per minute for 3 weeks (paced group, nonfailure), and dogs also paced at 240 beats per minute during the fourth week to induce severe heart failure (CHF group). Contractile responses to 60 mmol/L KCl and phenylephrine and relaxation responses to acetylcholine, bradykinin (endothelium-dependent cyclic GMP [cGMP]-mediated), isoproterenol, arachidonic acid, prostacyclin (receptor-dependent cyclic AMP [cAMP]-mediated), forskolin (direct stimulator of adenylate cyclase), a forskolin analogue (devoid of adenylate cyclase-dependent activity), and RO 20-1724 (phosphodiesterase inhibitor) were characterized. The paced group did not show alterations in vascular reactivity. Contractile response to phenylephrine and cGMP-mediated relaxation responses were not altered in the CHF group; however, receptor-mediated cAMP-induced relaxation responses were significantly inhibited (p < 0.05). Relaxation responses to isoproterenol (10(-6) mol/L), arachidonic acid (10(-5) mol/L), and prostacyclin (10(-5) mol/L) were reduced by 56%, 72%, and 74%, respectively. The relaxation response to RO 20-1724 was not affected by CHF, and this probe did not enhance the impaired relaxation response to isoproterenol. Forskolin-induced relaxation was not altered, and the forskolin analogue produced minimal relaxation compared with forskolin., Conclusions: These findings suggest that in pacing-induced CHF, canine pulmonary arteries show a selective defect in receptor coupling to cAMP-dependent relaxation mechanisms. There is no evidence of enhanced degradation of cAMP.

We have demonstrated previously that in response to hypoxia, isolated rat pulmonary arteries show an initial endothelium-dependent relaxation followed by an endothelium-independent transient contraction. In the presence of increased extracellular Ca2+, both of these responses were enhanced in endothelium-intact arteries. Nitro-L-arginine, a blocker of the biosynthesis of endothelium-derived relaxing factor (EDRF), abolished the initial endothelium-dependent relaxation and Ca(2+)-induced enhancement of hypoxic contraction in endothelium-intact arteries but did not alter responses in endothelium-denuded vessels. Inhibition of prostaglandin formation with indomethacin had no effect on the hypoxia-elicited responses. Preincubation with LY 83583, an inhibitor of guanylate cyclase activation, abolished the initial hypoxia-elicited relaxation and subsequent contraction. M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor, decreased tone under O2 but not under N2, causing an apparent enhancement of the contraction to hypoxia. Thus the modulation of hypoxic responses by the endothelium is dependent on changes in EDRF production, and a decrease in smooth muscle cGMP not involving an EDRF mechanism appears to mediate the endothelium-independent hypoxic contraction observed in the isolated rat pulmonary artery.

The atrial appendages contain most of the atrial natriuretic factor (ANF) in the mammalian heart, and atrial appendage mechanical function predicts ANF secretion during volume loading. To demonstrate the crucial role of the atrial appendages in ANF release, we first measured hemodynamics and changes in plasma ANF after injection of 1,000 ml i.v. normal saline in conscious dogs and again after bilateral atrial appendectomy; we next measured changes in renal function using infusions of atriopeptin 24 to achieve plasma levels corresponding to levels achieved during volume loading; and we lastly measured renal function during acute volume expansion and also after atrial appendectomy. Plasma ANF increased from 65 +/- 11 to 246 +/- 54 pg/ml after volume loading but did not increase after atrial appendectomy. Atrial appendectomy did not alter the tachycardia or hemodynamic effects of volume loading. Infusion of 10 ng/kg/min atriopeptin 24 increased plasma ANF from 50 +/- 9 to 234 +/- 54 pg/ml, increased urine output 34 +/- 10%, and increased sodium excretion 62 +/- 10% in dogs with intact atrial appendages. Renal function was compared in dogs before atrial appendectomy: 20, 40, and 60 minutes after volume loading, urine flow rate increased by 5.9 +/- 0.5, 6.9 +/- 0.4, and 4.4 +/- 0.8 ml/min, while sodium excretion increased by 717 +/- 60, 839 +/- 84, and 582 +/- 57 mueq/min. After atrial appendectomy urine flow rate increased 2.1 +/- 0.7, 2.7 +/- 0.7, and 2.0 +/- 0.6 ml/min, and sodium excretion increased only by 327 +/- 110, 324 +/- 77, and 340 +/- 92 mueq/min (p less than 0.01) during volume loading.(ABSTRACT TRUNCATED AT 250 WORDS)

The Fontan procedure results in right atrial distention and is complicated by fluid retention. Since systemic fluid balance may be hormonally mediated in part and related to right atrium size, we measured plasma atrial natriuretic factor and plasma arginine vasopressin levels in 19 patients undergoing the Fontan procedure and in 12 control patients undergoing other types of heart operations. Preoperative plasma atrial natriuretic factor levels were higher in patients undergoing the Fontan procedure than in control patients (95 +/- 16 pg/ml preoperatively versus 50 +/- 8 pg/ml; p less than 0.05) and increased in patients undergoing the Fontan procedure to 330 +/- 48 pg/ml by postoperative day 2 (p less than 0.05) but not in control patients. Increased plasma atrial natriuretic factor levels could enhance capillary transudation, but elevated plasma atrial natriuretic factor levels should also enhance diuresis and prevent fluid retention. Vasopressin levels, however, were also increased in patients undergoing the Fontan procedure (from 9 +/- 2 pg/ml preoperatively to 144 +/- 37 pg/ml at end of operation) and were higher and remained elevated longer than in control patients undergoing heart operations (37 +/- 7, 20 +/- 4, 16 +/- 6 pg/ml on postoperative days 1, 2, and 3 to 10 for the Fontan group compared with 15 +/- 4, 4 +/- 1, 4 +/- 2 pg/ml for control patients). Vasopressin levels were highest in the Fontan group with the most severe fluid retention and effusions (for example, 51 +/- 10 pg/ml versus 23 +/- 4 pg/ml, on postoperative day 1). Increased vasopressin and atrial natriuretic factor could act synergistically to result in the development of effusions after the Fontan procedure when atrial natriuretic factor-induced capillary transudation is combined with vasopressin-induced antidiuresis.

The incidence of cardiac involvement in Lyme disease (LD) has been estimated to be 4 to 10% in adults, with conduction and rhythm disturbances noted most frequently. To assess the frequency of electrocardiographic abnormalities in children with LD, we prospectively performed 12-lead electrocardiograms in 32 randomly selected children presenting with LD between May and September 1989. No patient had symptoms of cardiac involvement. Using defined diagnostic criteria, combining symptoms, signs, serology, and residence in or travel to an endemic area, 14 patients were classified as having definite LD and 10 were categorized as probable. The incidence of electrocardiographic abnormalities in the definite group was 29% (4/14), including two patients with 1 degree atrioventricular block, one with left axis deviation, and one with ventricular ectopy. Thirty percent (3/10) of the probable group had abnormal ECGs, including one with ST-T wave abnormalities, one with prominent sinus arrhythmia, sinus bradycardia, and wandering atrial pacemaker, and one with ectopic atrial bradycardia. No patient required cardiac therapy. The incidence of abnormal ECG findings in this group of children with either probable or definite LD was thus 29%, with 1 degree atrioventricular block noted most frequently. When the diagnosis of LD is highly suspected, an electrocardiogram may be a useful screening test for cardiac involvement.

Study Objective: The aim was to measure changes in atrial wall function over a wide range of atrial filling pressures in order to determine the relationship governing the atrial stretch in vivo., Design: Acute graded haemorrhage, 30 ml.kg-1, was used to reduce atrial stretch, and volume loading with 1000 ml saline was used to increase atrial stretch., Experimental Material: Awake mongrel dogs (n = 6) were instrumented for the measurement of left atrial appendage pressure and diameter; awake mongrel dogs (n = 4) were instrumented for measurement of left and right atrial appendage pressures and diameters., Measurements and Main Results: During haemorrhage, left atrial pressure and diameter decreased progressively, and plasma atrial natriuretic factor fell from 44 (SEM 10) to 25(5) pg.ml-1 (p less than 0.05). Calculated left atrial wall stress and minute wall stress fell by 80(5.8)% and 72(15)% (p less than 0.05 from control). During volume expansion, however, atrial wall stress and minute wall stress markedly increased and plasma atrial natriuretic factor increased by more than 500%. The relationship between left atrial pressure and diameter was a typical exponential compliance curve during volume loading and haemorrhage for atrial systole, the A wave, and for atrial diastole, the V wave. During volume expansion right atrial pressure and diameter were also related exponentially. Left atrial passive stretch, as measured by V wave wall stress, increased more than right atrial stretch during volume loading. Changes in atrial filling in conscious dogs therefore result in typical exponential changes in atrial pressure and diameter in both atria. Plasma atrial natriuretic factor only increased at high filling pressures. The relationship between passive V wave minute wall stress and plasma atrial natriuretic factor also fitted an exponential curve. Thus when atrial filling was reduced, plasma atrial natriuretic factor fell by only 50% from control, while when atrial filling increased over the physiological range (up to 15 mm Hg left atrial pressure), it rose only to 100 pg.ml-1., Conclusions: Very high atrial appendage wall stresses are required to increase plasma atrial natriuretic factor markedly. Atrial stretch and the release of atrial natriuretic factor are non-linearly related. The stimulus for atrial natriuretic factor release is related to the exponential changes in atrial function due to the underlying atrial compliance relationship.

The present study examines the influence of the endothelium (E), Ca2+ concentration, cyanide and monocrotaline (MCT) pretreatment on the responses of isolated rat hilar pulmonary arterial rings (PA) to hypoxia. In PA precontracted with phenylephrine, hypoxia induced an initial E-dependent relaxation phase followed by an E-independent transient contraction and a final relaxation. An increase in Ca2+ concentration from 1.5 to 2.5 mM produced an E-dependent reduction in tone generation under O2 and a significant enhancement of the hypoxia-elicited initial relaxation and the transient contractile responses. Addition of cyanide (0.1 mM) to precontracted PA produced a transient contraction similar to that caused by hypoxia. Preincubation with cyanide led to inhibition of tone generation and abolition of the contraction to hypoxia. However, the final relaxation response to hypoxia was not inhibited by cyanide. Thus, hypoxia produces an E-independent contraction via a mechanism that appears also to be activated by cyanide, and this response is not altered by MCT. The endothelium alters the response to hypoxia in a Ca(2+)-dependent manner.

Chest pain in adolescents and children is usually not of cardiac origin. Of cardiac conditions commonly linked to chest pain in childhood, mitral valve prolapse (MVP) is the most prevalent, but this association has recently been questioned. In light of recent reports of gastroesophageal sources of chest pain in adults with MVP, we performed a comprehensive gastroesophageal evaluation of 17 preadolescents and adolescents with mitral valve prolapse who had chest pain as their presenting symptom. Evaluation consisted of esophageal manometry, Bernstein test, esophageal pH probe, and/or esophagogastroscopy. Fourteen of the 17 patients had at least one abnormal finding. Five patients had esophagitis, five had gastritis, one had high-amplitude esophageal contractions, one had abnormal esophageal manometry with positive Bernstein test, one had esophageal reflux and positive Bernstein test, and one had abnormal manometry with esophageal reflux. The 13 patients with esophagitis, gastritis, reflux, or positive Bernstein test were treated with antacid, with resolution of chest pain in 12 patients. Two of these patients underwent follow-up endoscopy with documentation of improvement. The patient with high-amplitude esophageal contractions was treated with dicyclomine, which resulted in resolution of chest pain. The observation that the chest pain was not related to mitral valve prolapse is important in clinical practice and raises further questions as to whether mitral valve prolapse causes chest pain.

Although atrial stretch is the primary stimulus for atrial natriuretic factor (ANF) secretion, hormones may directly affect ANF secretion or may indirectly influence ANF by changing left ventricular afterload, thereby altering atrial stretch. To determine whether direct effects are important for the release of ANF in vivo, we measured changes in plasma ANF and in atrial wall function in the conscious dog after the administration of vasopressin, angiotensin II, and phenylephrine and by mechanically increasing left ventricular afterload by partial aortic occlusion. Injections of phenylephrine, angiotensin II, and arginine vasopressin (AVP) that were chosen to cause similar changes in systemic arterial pressure resulted in similar changes in atrial pressure and diameter. Maximum V wave atrial wall stress increased to 283 +/- 12, 311 +/- 41, 327 +/- 24, and 277 +/- 22 g/cm2 for AVP, angiotensin, phenylephrine, and occlusion, respectively, and plasma ANF increased to 242 +/- 81, 248 +/- 62, 299 +/- 95, and 190 +/- 53 pg/ml. There were significant linear correlations between left ventricular afterload and left atrial pressure, and each method for increasing left ventricular afterload shifted the position to the left on an atrial pressure-diameter, compliance curve, by a similar degree. Thus changes in left ventricular afterload result in changes in atrial wall function and similar changes in plasma ANF. No hormonal-specific increase in plasma ANF was found in conscious dogs after increases in afterload.