Spectrum of Viral Pathogens Identified in Children with Clinical Myocarditis (Pre-Coronavirus Disease-2019, 2000-2018): Etiologic Agent Versus Innocent Bystander.

OBJECTIVE: To identify the etiologies of viral myocarditis in children in the pre-coronavirus disease 2019 era. STUDY DESIGN: This was a retrospective review of all patients (age <18 years) diagnosed with myocarditis and hospitalized at Rady Children's Hospital San Diego between 2000 and 2018. RESULTS: Twenty-nine patients met inclusion criteria. Of 28 (97%) patients who underwent testing for viruses, polymerase chain reaction was used in 24 of 28 (86% of cases), and 16 of 24 (67%) detected a virus. Pathogens were rhinovirus (6), influenza A/B (4), respiratory syncytial virus (RSV) (3), coronavirus (3), parvovirus B19 (2), adenovirus (2), and coxsackie B5 virus, enterovirus, and parainfluenza virus type 2 in one case each. Six (21%) patients had no pathogen detected but imaging and other laboratory test results were compatible with myocarditis. Age 0-2 years was associated with RSV, influenza A/B, coronavirus, and enteroviruses (P < .001). Twenty-one patients (72%) experienced full clinical recovery. Three patients (10%) required venoarterial extracorporeal membrane oxygenation (VA-ECMO), and all 3 recovered. Three others (10%) required and underwent successful cardiac transplantation without complications. Two patients (7%) died 9-10 days after hospitalization (1 had RSV and 1 had influenza A/B). Two other patients presented with complete atrioventricular block; 1 case (rhinovirus) resolved spontaneously, and 1 (coronavirus) resolved after support with VA-ECMO. Age <2 years, female sex, lower ejection fraction at admission, and greater initial and peak levels of brain natriuretic peptide were significant predictors of critical outcomes (use of VA-ECMO, listing for cardiac transplantation, and death). CONCLUSIONS: Viral nucleic acid-based testing revealed a wider spectrum of viruses that could be associated with myocarditis in children than previously reported and traditionally anticipated. A predilection of certain pathogens in the very young patients was observed. Whether the observed range of viral agents reflects an undercurrent of change in viral etiology or viral detection methods is unclear, but the wider spectrum of viral pathogens found underscores the usefulness of polymerase chain reaction testing to explore possible viral etiologies of myocarditis in children.

Self-limited myocarditis presenting with chest pain and ST segment elevation in adolescents after vaccination with the BNT162b2 mRNA vaccine.

Two adolescent males presented within 3 days after the first and second dose of the BNT162b2 vaccine with chest pain. Elevated troponin levels, ST segment elevation, and enhancement of the myocardium in cardiac MRI suggested myocarditis. Left ventricular function remained normal, symptoms resolved, and patients were discharged in 4 days. BNT162b2 vaccine may be associated with self-limited myocarditis in youth.

Junctional tachycardia due to multisystem inflammatory syndrome in children with SARS-CoV-2 infection in a 12-year-old female.

A 12-year-old girl presented with fever and signs of systemic inflammation, and was found to have junctional tachycardia. She was subsequently diagnosed with Multisystem Inflammatory Syndrome in Children and treated with intravenous immunoglobulin and steroids, which led to resolution of the arrhythmia.

The Importance of Echocardiogram during the Second Week of Illness in Children with Kawasaki Disease.

OBJECTIVE: To determine the timing of peak coronary artery dilation and the characteristics of patients who present with new-onset coronary artery dilation during the acute phase of Kawasaki disease with an initial normal echocardiogram. STUDY DESIGN: This retrospective study analyzed 231 children hospitalized for Kawasaki disease in Hawai'i over a period of 7 years. Clinical and echocardiographic data were collected to calculate the timing of peak z score, and study subjects were compared based on the timing of coronary dilation. RESULTS: Peak coronary artery dilation was observed on average at 11.5 days from the onset of fever (median 8, IQR 7-13 days). Among study subjects with normal z scores in both coronary arteries during the initial encounter and echocardiogram (n = 164), 16 (10%) developed coronary artery dilation or aneurysm at the second echocardiogram, and 5 (3%) continued to have coronary artery dilation or aneurysm at the convalescent phase. CONCLUSIONS: A repeat echocardiogram during the second week of illness (day 7-14 from fever onset) in patients with normal initial echocardiogram could identify new-onset coronary artery dilation or aneurysm and could be useful in the timely adjustment of antithrombotic or anti-inflammatory therapies.

Left Ventricular Mechanical Property Changes During Acute AV Synchronous Right Ventricular Pacing in Children.

Prolonged RV pacing is recognized as a cause of LV dysfunction due to dyssynchronous activation. There are no specific longitudinal parameters known to help predict RV pacing-induced LV dysfunction. The aim of the study was to assess the acute effects of AV synchronous RV pacing on LV mechanics using echocardiographic speckle tracking. Nineteen children, aged 6-23 years, underwent echocardiographic evaluation prior to and following elective electrophysiology and ablation studies. The subjects were evaluated in sinus rhythm and later with AV synchronous RV pacing at a cycle length of 550 ms with a short AV delay of 80 ms. The echocardiographic clips were analyzed using speckle tracking methods to calculate LV circumferential and longitudinal strain, rotation and twist in all conditions. Acute RV apical pacing decreased LV longitudinal strain from 16.1 ± 3.7% in sinus rhythm to 14.4 ± 3.3% (p = 0.03) and LV base rotation from -8.4° ± 3.6° to -6.4° ± 4.0° (p = 0.04). The circumferential strain, apical rotation and LV twist were not affected. Separate analysis of subjects with no prior preexcitation showed that acute RV pacing caused significant twist reduction, from 15.9° ± 7.6° to 12.1° ± 7.0° (p = 0.02), and decreased longitudinal strain and base rotation. Patients with preexcitation had abnormalities that persisted acutely after ablation. Acute RV apical pacing causes reductions in LV base rotation, longitudinal strain and twist. The recognition of abnormal LV activation patterns may provide longitudinal clues to LV dysfunction in chronically paced patients and potential novel indices of effective CRT interventions to reverse these abnormalities.

Listening to Patients Makes Sense: Soliciting and Purposefully Addressing Written Patient Expectations at a Provider Visit Improve Patient Satisfaction.

Patient satisfaction is an important aspect of medical care. This study aimed to assess if patient satisfaction improved when patients shared their expectations with the provider in writing before a visit, and providers purposefully addressed those expectations during the visit. We gave 2 types of questionnaires to 343 patients: Version 1 asked for written expectations before the visit and assessed the visit quality after addressing those expectations, while Version 2 only evaluated the visit without soliciting expectations. Patient satisfaction and meeting expectations were measured on a 1-10 Likert-type scale. The grouped that shared written expectations before the visit (n = 169) showed a significantly higher patient satisfaction score (9.88) compared to the group without shared expectations (n = 136, score 9.43, P < .0001). Conveying written expectations to healthcare providers before the visit improved patient satisfaction, potentially enhancing compliance and overall medical outcomes.

Low dose tissue plasminogen activator treatment for vascular thrombosis following cardiac catheterization in children: a single center experience.

OBJECTIVES: To assess the efficacy and safety of low dose tissue plasminogen activator (tPA) therapy in children with vascular thrombosis following cardiac catheterization. BACKGROUND: Currently, heparin is the standard of care for vascular thrombosis, however, it may not be efficacious in dissolving existing thrombi. Although tPA is an accepted thrombolytic therapy for life-threatening thrombosis in children, it is not a well-established treatment for the thrombosis of femoral vessels following cardiac catheterization. METHODS: A retrospective analysis was performed from 1/1/2009 until 6/30/2011 at Rady Children's Hospital-San Diego (RCHSD) reviewing all cases with venous or arterial thrombosis at the vascular access site following cardiac catheterization, and a survey was conducted among the Congenital Cardiovascular Interventional Study Consortium members regarding their experience in tPA therapy. RESULTS: At RCHSD, out of 1,155 catheterizations, 12 children developed femoral thrombosis. In three children, where 12-h heparin therapy was unsuccessful in resolving thrombosis, we used low-dose tPA according to the following regime: 0.05 mg/kg/h for 30 min, followed by 0.1 mg/kg/h for 4 h. We achieved thrombolysis in all cases evidenced by repeat ultrasound and return of palpable pulse with normal limb circulation. No complications were encountered. The survey confirmed that adult tPA dose (0.1-0.5 mg/kg/h) has 100% efficacy in resolving thrombi in children with vascular thrombosis, however, the rate of serious complications was not negligible (15%). CONCLUSION: tPA is an efficacious therapy to dissolve thrombi that developed as a complication of cardiac catheterization in children. The rate of complications due to tPA may be reduced using a lower dose: 0.05-0.1 mg/kg/h.

Percutaneous stent implantation into coronary arteries in infants.

OBJECTIVES: To investigate the feasibility, procedural techniques, safety, and overall potential of percutaneous coronary angioplasty and stent implantation in infants with coronary artery disease and acute coronary syndrome. BACKGROUND: Despite extensive experience in adult patients, percutaneous coronary intervention remains uncommon in children and extremely rare in infants. METHODS: Retrospective review including all children who underwent percutaneous coronary angioplasty in Rady Children's Hospital-San Diego during a period of 4 years. RESULTS: Seven children including four children less than 15 months of age underwent percutaneous coronary intervention with coronary stent implantation in the proximal portion of the left or right coronary arteries. Successful stent placement with excellent revascularization was achieved in all cases. Mean coronary artery diameter was 0.65 mm prior to stent placement. Balloon angioplasty resulted in suboptimal resolution of coronary stenosis, thus bare metal stents were implanted in all cases, dilated to a mean of 2.5-mm internal diameter. Average intervention-free period was 434 days after stent implantation. In-stent re-stenosis and stent thrombosis did not occur if the implanted stent diameter was greater than 2.5 mm and the patient received dual anti-platelet therapy. CONCLUSIONS: Our experience suggests that coronary artery stent implantation is a feasible and relatively safe palliative option in infants and toddlers with coronary stenosis. It is a viable strategy for bridging patients with acute ischemia or poor ventricular function to elective surgical revascularization or transplantation.

Closure of perimembranous ventricular septal defects with aneurysmal tissue using the Amplazter Duct Occluder I: lessons learned and medium term follow up.

OBJECTIVES: The aim of this report is to describe our experience with closure of perimembranous ventricular septal defects (PMVSD) with aneurysm using the Amplatzer Duct Occluder I (ADO I). BACKGROUND: Atrio-ventricular block (AVB) remains the most troublesome complication of device closure of PMVSDs. Many PMVSDs are associated with an aneurysm that protrudes into the right ventricle. We believe that devices implanted entirely within the VSD aneurysm avoid the risk of AVB. METHODS: A retrospective analysis of patients with PMVSD and aneurysm who underwent attempted ADO I device closure between 3/2004 and 8/2010 [Rady Children's Hospital-San Diego (n = 16), Mattel Children's Hospital at UCLA (n = 4), and Straub Hospital in Honolulu (n = 1)]. RESULTS: Twenty-one patients (16 male) with PMVSD and aneurysm underwent cardiac catheterization for the purpose of VSD closure using an ADO I. Nineteen patients had successful ADO I implantation with the following devices: 10/8 (n = 8), 8/6 (n = 7), 6/4 (n = 3) and 12/10 (n = 2). The procedure was aborted in 2 cases due to temporary AVB and ventricular ectopy during catheterization. One patient developed hemolysis due device malposition and had surgical device retrieval and VSD closure. One patient had new trivial tricuspid regurgitation and in 5/19 the tricuspid regurgitation improved post device closure. Transient accelerated junctional rhythm occurred within 24 hr in 4 patients and nonsustained slow ventricular tachycardia occurred in one patient. At latest follow-up (up to 6 years, median 1.9 years) 11/18 had no residual shunt, 4/18 had trivial and 3/18 small residual shunt. No AVB has been observed. CONCLUSIONS: Percutaneous closure of PMVSD with aneurysm using the ADO I appears to have acceptable efficacy and risk. Atrio-ventricular block in up to mid-term follow up was not encountered.

Acute Adult-Onset Kawasaki Disease Complicated by Coronary Artery Aneurysms, Thrombosis, and ST-Segment Elevation Myocardial Infarction.

A 21-year-old man who had an initial misdiagnosis of chest wall cellulitis and sepsis presented to the emergency department with chest pain. Electrocardiogram demonstrated ST-segment elevation in the inferior leads. Cardiac catheterization identified diffuse aneurysmal dilation and thrombosis of the distal right coronary artery. Clinical signs were consistent with acute Kawasaki disease. (Level of Difficulty: Intermediate.).

Junctional Tachycardia as a Diagnostic Criterion in Acute Rheumatic Fever.

Acute rheumatic fever (ARF) is an acute inflammatory process resulting in rheumatic carditis, one of the most common acquired heart diseases in youth. Among the clinical manifestations of carditis, pathologic valve regurgitation and atrioventricular block are included in the criteria for the diagnosis of ARF. Besides atrioventricular block, ARF may often present with other arrhythmias, such as junctional tachycardia (JT). However, JT is currently not recognized as a criterion for the diagnosis of ARF. Three adolescents presented in our hospital with JT, polyarthralgia, and laboratory signs of inflammation with evidence of preceding group A Streptococcus infection. None of the patients fulfilled the diagnostic criteria of ARF. On the basis of the presumed diagnosis of ARF, all 3 patients were treated with intravenous steroids. Steroid therapy was given, and JT converted to sinus rhythm within an average of 62 hours. Subsequent electrocardiograms revealed variable degree of atrioventricular block in all 3 patients, providing clinical evidence and fulfilling the diagnostic criteria of ARF. Patients were monitored for a total 2 to 8 days before discharge on standard antiinflammatory treatment. Follow-up electrocardiograms and Holter monitoring revealed resolution of the atrioventricular block and lack of JT recurrence in all patients. On the basis of these sentinel cases, we propose that JT should be included as a diagnostic criterion for the diagnosis of ARF.

Osteoporosis treatment rates after hip fracture 2011-2019 in Hawaii: Undertreatment of men after hip fractures.

OBJECTIVES: To investigate trends of osteoporosis treatment rates, and factors affecting osteoporosis treatment after hip fracture admission within a single health care system in Hawaii. METHODS: A retrospective chart review was conducted of patients aged 50 years or older and hospitalized for hip fractures between January 1, 2011 and December 31, 2019 at Hawaii Pacific Health, a large health care system in Hawaii. We collected data on basic demographics and osteoporosis medication prescription from electronic medical records. We evaluated trends of osteoporosis treatment rates and performed logistic regression to determine factors associated with osteoporosis treatment. RESULTS: The mean for treatment rates for osteoporosis from 2011 to 2019 was 17.2% (range 8.8%-26.0%). From 2011 to 2019 there was a small increase in treatment rates from 16.3% in 2011 to 24.1% in 2019. Men were less likely to receive osteoporosis treatment after admission for hip fracture. Patients discharged to a facility were more likely to receive osteoporosis treatment. As compared to women, men who had a hip fracture were less likely to receive dual-energy X-ray absorptiometry scan, and osteoporosis medication before hip fracture admission. CONCLUSIONS: The use of osteoporosis medication for secondary prevention after admission for hip fracture in Hawaii from 2011 to 2019 was low. However, there was a small increase in treatment rates from 2011 to 2019. Disparities in treatment of osteoporosis after hip fracture were noted in men. Significant work is needed to increase treatment rates further, and to address the disparity in osteoporosis treatment between men and women.

Temporal clustering of Kawasaki disease cases around the world.

In a single-site study (San Diego, CA, USA), we previously showed that Kawasaki Disease (KD) cases cluster temporally in bursts of approximately 7 days. These clusters occurred more often than would be expected at random even after accounting for long-term trends and seasonality. This finding raised the question of whether other locations around the world experience similar temporal clusters of KD that might offer clues to disease etiology. Here we combine data from San Diego and nine additional sites around the world with hospitals that care for large numbers of KD patients, as well as two multi-hospital catchment regions. We found that across these sites, KD cases clustered at short time scales and there were anomalously long quiet periods with no cases. Both of these phenomena occurred more often than would be expected given local trends and seasonality. Additionally, we found unusually frequent temporal overlaps of KD clusters and quiet periods between pairs of sites. These findings suggest that regional and planetary range environmental influences create periods of higher or lower exposure to KD triggers that may offer clues to the etiology of KD.

The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow-derived endothelial cells in brains of mice following cerebral ischemia.

Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow-derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (c-kit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)-expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow-derived angiogenesis, thus improving neuronal survival and functional outcome.

Elevated Levels of Pentraxin 3 Correlate With Neutrophilia and Coronary Artery Dilation During Acute Kawasaki Disease.

Kawasaki disease (KD) is the leading cause of acquired pediatric heart disease in the developed world as 25-30% of untreated patients and at least 5% of treated patients will develop irreversible coronary artery lesions (CAL). Pentraxin-3 (PTX-3) has been well-studied in inflammatory diseases, particularly in cardiovascular diseases associated with vascular endothelial dysfunction. We hypothesized that PTX-3 plays an important role in the development of KD-associated CAL and investigated the circulating levels of PTX-3 in the serum of KD patients. Children with acute KD were followed from diagnosis through normalization of the clinical parameters of inflammation (convalescent phase). Serum samples were obtained and echocardiograms were conducted at several phases of the illness: acute [prior to intravenous immunoglobulin (IVIG) treatment], sub-acute (5-10 days after IVIG treatment), and convalescent (1-4 months after KD diagnosis). Seventy children were included in the final cohort of the study, of whom 26 (37%) presented with CAL and 18 (26%) developed IVIG resistance. The patients included in this study came from diverse ethnic backgrounds, mostly with mixed ancestry/ ethnicity. Significantly increased PTX-3 levels were observed during the acute phase of KD compared to the sub-acute and the convalescent phases. The PTX-3 levels during acute KD were significantly higher among KD patients with CAL compared to patients with normal coronary arteries (NCA). Also, the PTX-3 levels were significantly higher in patients with IVIG resistance. Furthermore, the PTX-3 levels were significantly higher in IVIG-resistant KD patients with CAL as compared to the NCA group. Moreover, the PTX-3 levels were significantly correlated to coronary artery z-score during acute KD and to neutrophil counts throughout KD progression regardless of coronary artery z-score. Elevated PTX-3 levels correlated to elevated neutrophil counts, a known source of PTX-3 in acute inflammation and an important player in the development of KD vasculitis. We, therefore, suggest PTX-3 as a novel factor in the development of KD-associated CAL and propose neutrophil-derived PTX-3 as contributing to KD vascular dysfunction.

Mapping the Trends of Kawasaki Disease in Hawai'i from 1996 to 2018.

Kawasaki disease is a systemic vasculitis of unknown etiology and is the leading cause of acquired heart disease in children in the developed world. Historically, Hawai'i has had the highest incidence of Kawasaki disease in the United States, likely due to the population's unique ancestral composition. To analyze the epidemiology, demographics and spatiotemporal distribution of Kawasaki disease in Hawai'i, a retrospective chart review was conducted utilizing data from Kapi'olani Medical Center for Women and Children encompassing the period of 1996-2018. A total of 858 patients were analyzed with 877 episodes of Kawasaki disease. On average, 37 episodes of Kawasaki disease were diagnosed annually over the 23-year period. The annual incidence was 32 per 100 000 children <5 years of age. Asian children (66.1%) accounted for the majority of cases, followed by Native Hawaiians and Other Pacific Islanders (16.6%). Unlike Japan and the continental United States, there was no characteristic seasonal pattern in the distribution of Kawasaki disease in Hawai'i, which may be attributed to its tropical climate or the recent changes in global weather patterns. Local geographical differences in the incidence of Kawasaki disease demonstrated that the Windward (Eastern) coast of O'ahu had a higher rate, while the Leeward (Western) coast displayed a lower incidence rate. This could be explained by variations in ethnic composition and weather patterns of certain areas. Future studies could provide geographical weather data and statistical analysis to determine what environmental triggers are correlated with Kawasaki disease trends in the State of Hawai'i.

Electrocardiogram Standards for Children and Young Adults Using Z-Scores.

BACKGROUND: Normative ECG values for children are based on relatively few subjects and are not standardized, resulting in interpersonal variability of interpretation. Recent advances in digital technology allow a more quantitative, reproducible assessment of ECG variables. Our objective was to create the foundation of normative ECG standards in the young utilizing Z-scores. METHODS: One hundred two ECG variables were collected from a retrospective cohort of 27 085 study subjects with no known heart condition, ages 0 to 39 years. The cohort was divided into 16 age groups by sex. Median, interquartile range, and range were calculated for each variable adjusted to body surface area. RESULTS: Normative standards were developed for all 102 ECG variables including heart rate; P, R, and T axis; R-T axis deviation; PR interval, QRS duration, QT, and QTc interval; P, Q, R, S, and T amplitudes in 12 leads; as well as QRS and T wave integrals. Incremental Z-score values between -2.5 and 2.5 were calculated to establish upper and lower limits of normal. Historical ECG interpretative concepts were reassessed and new concepts observed. CONCLUSIONS: Electronically acquired ECG values based on the largest pediatric and young adult cohort ever compiled provide the first detailed, standardized, quantitative foundation of traditional and novel ECG variables. Expression of ECG variables by Z-scores lends an objective and reproducible evaluation without interpreter bias that can lead to more confident establishment of ECG-disease correlations and improved automated ECG readings in high-volume cardiac screening efforts in the young. Graphic Abstract: A graphic abstract is available for this article.

CD45-positive blood cells give rise to uterine epithelial cells in mice.

The uterine endometrium is composed of epithelial and stromal cells, which undergo extensive degeneration and regeneration in every estrous cycle, and dramatic changes occur during pregnancy. The high turnover of cells requires a correspondingly high level of cell division by progenitor cells in the uterus, but the character and source of these cells remain obscure. In the present study, using a novel transgenic mouse, we showed that CD45-positive hematopoietic progenitor cells colonize the uterine epithelium and that in pregnancy more than 80% of the epithelium can derive from these cells. Since we also found green fluorescent protein (GFP)-positive uterine endothelial cells in long-term GFP bone marrow-transplanted mice, we conclude that circulating CD45+ cells play an important role in regenerating the uterine epithelium.

Epicardial Intraoperative Three-Dimensional Mapping of Wolff-Parkinson-White Syndrome in a Child With Ebstein's Anomaly.

Catheter ablation of arrhythmias in small patients has inherent significant risk because of the patient, catheter, and lesion size. Heart block, perforation, and coronary damage may occur. This report shows adaptation of a three-dimensional electroanatomic mapping system for intraoperative use in a small patient with Ebstein's anomaly who was undergoing a cone procedure and a bidirectional Glenn procedure. Use of this technique gave clear identification of the epicardial insertion points of two accessory pathways causing Wolff-Parkinson-White syndrome and resistant episodes of supraventricular tachycardia. Successful three-dimensional mapping and cryoablation were performed with a short procedure time and no complications. The patient remains without preexcitation or arrhythmia 6 months postoperatively.