Evolution of Cardiovascular Findings in Multisystem Inflammatory Syndrome in Children (MIS-C) Across COVID-19 Variants: Common Trends and Unusual Presentations.

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following COVID-19 infection. Cardiac involvement is common and includes left ventricular systolic dysfunction, cardiac marker elevation, electrocardiogram (ECG) changes, and coronary artery dilation. This single-center retrospective cohort study compares cardiovascular disease between three major SARS-CoV-2 variants and describes the evolution of findings in medium-term follow-up. Of 69 total children (mean age 9.2 years, 58% male), 60 (87%) had cardiovascular involvement with the most common features being troponin elevation in 33 (47%) and left ventricular dysfunction in 22 (32%). Based on presumed infection timing, 61 patients were sorted into variant cohorts of Alpha, Delta, and Omicron. Hospitalization was longer for the Delta group (7.7 days) vs Alpha (5.1 days, p = 0.0065) and Omicron (4.9 days, p = 0.012). Troponin elevation was more common in Delta compared to Alpha (13/20 vs 7/25, p = 0.18), and cumulative evidence of cardiac injury (echocardiographic abnormality and/or troponin elevation) was more common in Delta (17/20) compared with Alpha (12/25, p = 0.013) or Omicron (8/16, p = 0.034). Forty-nine (77%) of the original cohort (n = 69) had no cardiac symptoms or findings beyond 3 months post-hospitalization. Cardiac MRI was performed in 28 patients (between 3 and 6 months post-hospitalization) and was normal in 25 patients (89%). The differences in the variant cohorts may be due to alteration of the immune landscape with higher severity of COVID-19 infection. Despite overall reassuring cardiac outcomes, it is important to note the variability of presentation and remain vigilant with future variants.

Progressive Dilation of Coronary Artery Ectasia Causing Recurrent Myocardial Infarction.

We present a case of recurrent myocardial infarction with coronary artery ectasia that had progressive dilation. Both implanting drug-eluting stent and antithrombotic therapy with warfarin plus P2Y12 inhibitor were feasible. The careful follow-up including morphologic evaluation may be needed for this specific lesion. (Level of Difficulty: Intermediate.).

Life long surveillance is warranted as coronary artery remodels variably after treatment of adult patients with anomalous left coronary artery origin from pulmonary artery.

Anomalous left coronary artery origin from pulmonary artery causes heart failure in infancy from ischemia and secondary mitral regurgitation. Rich intramyocardial collateralization may permit survival to adult age, where coronaries become tortuous and aneurysmally dilated. Surgery in adults involves left coronary ligation and providing a bypass graft to the left system, unlike coronary translocation adopted in infants. Unfavorable coronary remodeling in operated adults may lead to late coronary thrombotic occlusions. Two adults with markedly dilated tortuous coronary arteries showed variable remodeling after corrective intervention that impacted outcomes on follow-up. We stress the need for lifelong angiographic surveillance in older patients.

Clinical Course and Outcome of Cardiovascular Manifestations in Children With Multisystem Inflammatory Syndrome Associated With SARS-CoV-2 Infection in Georgia.

A SARS-CoV-2 infection is usually characterized by a very mild clinical course in the pediatric population. However, children can be severely affected, and clinical manifestations may differ from adults, mainly in terms of post-COVID-19 infection complications already known as multisystem inflammatory syndrome in children (MIS-C). As the name suggests, this condition involves many systems, including the cardiovascular system, clinical manifestations of which include myocarditis, coronary artery aneurysms, conduction abnormalities, and arrhythmias. This research aims to define the cardiac manifestations caused by multi-inflammatory processes occurring after acute SARS-CoV-2 infection, possibly find a correlation between a certain cardiac abnormality and inflammatory markers, and evaluate the dynamics of cardiovascular complications and how treatment affects it. From February 2020 to March 2022, 103 patients with MIS-C were hospitalized and treated at M.Iashvili Children's Central Hospital, Tbilisi, Georgia. Based on our results, 55% of them had cardiovascular involvement with various manifestations involving coronary artery dilation, valvular insufficiencies, heart rate abnormalities, and pericardial effusion. Our study revealed that only one statistically significant correlation was observed between D-dimer levels and heart rate abnormalities, but there was no correlation between these two values. All of the MIS-C patients reported in our study have received standardized treatment courses with steroids, intravenous immune globulin (IVIG), or IVIG combined with steroids; each patient's illness has resolved without any sequelae, and cardiac manifestations have returned to baseline. Nevertheless, systematic longer-term follow-up is needed to provide clarity on the evolution of medium- and long-term cardiac outcomes in MIS-C.

A challenging case of granulomatosis with polyangiitis with cardiac involvement: a rare case report.

Background: Granulomatosis with polyangiitis (GPA), a systemic antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, is characterized by inflammation of the small arteries, arterioles, and capillaries classically manifesting with glomerulonephritis and necrotizing granulomatous lesions of the upper and lower respiratory tract. With an incidence of approximately 12 cases per one million individuals per year it is an uncommon diagnosis that typically presents as frequent pulmonary and sinus infections; however, if left without definitive treatment progresses to more severe manifestations specifically hemoptysis and hematuria. Case Description: This case report highlights a 15-year-old woman who had both classic and non-classic findings making the diagnosis challenging. Specifically, her age of presentation, improvement with anti-microbials, and coronary dilation were not classic. Additionally, her lab work was negative for the cytoplasmic subset antineutrophil cytoplasmic autoantibody (c-ANCA), but positive for serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) which further delayed the ultimate diagnosis as this is typically c-ANCA positive. Conclusions: Other systemic vasculitides, such as mucocutaneous lymph node disease, are associated with cardiac pathology necessitating further medical management and follow-up to prevent increased morbidity and mortality. Knowing this, we conclude that further evaluation for cardiac pathology would be prudent as part of the initial workup of patients with a diagnosis of GPA. Included is a brief review of available literature on GPA to emphasize the typical presentation, lab findings, and importance of early diagnosis.

Mechanism of the switch from NO to H2O2 in endothelium-dependent vasodilation in diabetes.

Coronary microvascular dysfunction is prevalent among people with diabetes and is correlated with cardiac mortality. Compromised endothelial-dependent dilation (EDD) is an early event in the progression of diabetes, but its mechanisms remain incompletely understood. Nitric oxide (NO) is the major endothelium-dependent vasodilatory metabolite in the healthy coronary circulation, but this switches to hydrogen peroxide (H2O2) in coronary artery disease (CAD) patients. Because diabetes is a significant risk factor for CAD, we hypothesized that a similar NO-to-H2O2 switch would occur in diabetes. Vasodilation was measured ex vivo in isolated coronary arteries from wild type (WT) and microRNA-21 (miR-21) null mice on a chow or high-fat/high-sugar diet, and B6.BKS(D)-Leprdb/J (db/db) mice using myography. Myocardial blood flow (MBF), blood pressure, and heart rate were measured in vivo using contrast echocardiography and a solid-state pressure sensor catheter. RNA from coronary arteries, endothelial cells, and cardiac tissues was analyzed via quantitative real-time PCR for gene expression, and cardiac protein expression was assessed via western blot analyses. Superoxide was detected via electron paramagnetic resonance. (1) Ex vivo coronary EDD and in vivo MBF were impaired in diabetic mice. (2) Nω-Nitro-L-arginine methyl ester, an NO synthase inhibitor (L-NAME), inhibited ex vivo coronary EDD and in vivo MBF in WT. In contrast, polyethylene glycol-catalase, an H2O2 scavenger (Peg-Cat), inhibited diabetic mouse EDD ex vivo and MBF in vivo. (3) miR-21 was upregulated in diabetic mouse endothelial cells, and the deficiency of miR-21 prevented the NO-to-H2O2 switch and ameliorated diabetic mouse vasodilation impairments. (4) Diabetic mice displayed increased serum NO and H2O2, upregulated mRNA expression of Sod1, Sod2, iNos, and Cav1, and downregulated Pgc-1α in coronary arteries, but the deficiency of miR-21 reversed these changes. (5) miR-21-deficient mice exhibited increased cardiac PGC-1α, PPARα and eNOS protein and reduced endothelial superoxide. (6) Inhibition of PGC-1α changed the mRNA expression of genes regulated by miR-21, and overexpression of PGC-1α decreased the expression of miR-21 in high (25.5 mM) glucose treated coronary endothelial cells. Diabetic mice exhibit a NO-to-H2O2 switch in the mediator of coronary EDD, which contributes to microvascular dysfunction and is mediated by miR-21. This study represents the first mouse model recapitulating the NO-to-H2O2 switch seen in CAD patients in diabetes.

Coronary artery ectasia in post-pericardiotomy syndrome.

Post-pericardiotomy syndrome (PPS) is a common inflammatory process following cardiac surgery, in which the pericardial space was opened. Pericardial effusion (PE) is a common manifestation in PPS; however, coronary artery dilation is not associated with PPS. Inflammatory vasculitis in children are known to cause coronary dilation, in conditions such as in Kawasaki Disease (KD). We report a patient with PPS and concomitant coronary dilation by transthoracic echocardiography (TTE) following repair of her ventricular septal defect (VSD).

Refractory Kawasaki Disease-a Challenge for the Pediatrician.

Kawasaki disease (KD) is an acute, self-limiting febrile illness of childhood associated with vasculitis, mainly of the medium-sized arteries. The clinical significance and impact of this condition arise from its predilection for the coronary arteries. The criteria for classic Kawasaki disease are clearly defined, but many children present with atypical forms, and clinicians need to consider this possibility. Although most diagnosed cases respond to intravenous immunoglobulin (IVIG) and aspirin, some have proven resistant to the standard treatment. This article aims to provide a brief overview of Kawasaki disease, focusing on the resistant/refractory cases, and the treatment options available for such cases.

Longitudinal Echocardiographic Assessment of Coronary Arteries and Left Ventricular Function following Multisystem Inflammatory Syndrome in Children.

Myocardial dysfunction and coronary artery dilation have been reported in the acute setting of severe acute respiratory syndrome coronavirus disease-2-related multisystem inflammatory syndrome in children. Through a longitudinal echocardiographic single-center study of 15 children, we report the short-term outcomes of cardiac dysfunction and coronary artery dilation in severe acute respiratory syndrome coronavirus disease-2-related multisystem inflammatory syndrome in children.

Management of Multisystem Inflammatory Syndrome in Children Associated with COVID-19 Infection.

Purpose of review: The purpose of this review is to summarize what is known about multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 infection. Recent findings: The timing of presentation and features of diagnosis are described. Cardiac involvement is common and is the focus of this review. Arrhythmias, heart block, acute heart failure, shock, cardiac dysfunction, and coronary dilation have all been reported. Therapies used to treat children with this hyperinflammation syndrome include supportive care and agents that modulate the immune system. Therapies commonly described include intravenous immunoglobulin, steroids, and cytokine-directed agents, particularly tumor necrosis factor-alpha blockade and interleukin receptor blockade. The threshold for diagnosing coronary involvement in MIS-C is coronary artery dimensions indexed to body surface that exceed the normative values (Z score >2). Those hospitalized with MIS-C are evaluated by electrocardiogram and echocardiogram; outpatient assessment by a cardiologist is indicated prior to sports clearance. Summary: The prognosis of treated MIS-C patients is good. Future work is needed to understand the scope of cardiac involvement associated with acute COVID-19 and MIS-C in children and to define the optimal therapeutic targets for these distinct entities.

Role of peroxisome proliferators-activated receptor-gamma in advanced glycation end product-mediated functional loss of voltage-gated potassium channel in rat coronary arteries.

BACKGROUND: High blood glucose impairs voltage-gated K+ (Kv) channel-mediated vasodilation in rat coronary artery smooth muscle cells (CSMCs) via oxidative stress. Advanced glycation end product (AGE) and receptor for AGE (RAGE) axis has been found to impair coronary dilation by reducing Kv channel activity in diabetic rat small coronary arteries (RSCAs). However, its underlying mechanism remain unclear. Here, we used isolated arteries and primary CSMCs to investigate the effect of AGE incubation on Kv channel-mediated coronary dilation and the possible involvement of peroxisome proliferators-activated receptor (PPAR) -γ pathway. METHODS: The RSCAs and primary CSMCs were isolated, cultured, and treated with bovine serum albumin (BSA), AGE-BSA, alagrebrium (ALA, AGE cross-linking breaker), pioglitazone (PIO, PPAR-γ activator) and/or GW9662 (PPAR-γ inhibitor). The groups were accordingly divided as control, BSA, AGE, AGE + ALA, AGE + PIO, or AGE + PIO + GW9662. Kv channel-mediated dilation was analyzed using wire myograph. Histology and immunohistochemistry of RSCAs were performed. Western blot was used to detect the protein expression of RAGE, major Kv channel subunits expressed in CSMCs (Kv1.2 and Kv1.5), PPAR-γ, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2). RESULTS: AGE markedly reduced Forskolin-induced Kv channel-mediated dilation of RSCAs by engaging with RAGE, and ALA or PIO significantly reversed the functional loss of Kv channel. In both RSCAs and CSMCs, AGE reduced Kv1.2/1.5 expression, increased RAGE and NOX-2 expression, and inhibited PPAR-γ expression, while ALA or PIO treatment partially reversed the inhibiting effects of AGE on Kv1.2/1.5 expression, accompanied by the downregulation of RAGE and decreased oxidative stress. Meanwhile, silencing of RAGE with siRNA remarkably alleviated the AGE-induced downregulation of Kv1.2/1.5 expression in CSMCs. CONCLUSION: AGE reduces the Kv channel expression in CSMCs and further impairs the Kv channel-mediated dilation in RSCAs. The AGE/RAGE axis may enhance oxidative stress by inhibiting the downstream PPAR-γ pathway, thus playing a critical role in the dysfunction of Kv channels.

Human versus non-human sex steroid use in hormone replacement therapies part 1: Preclinical data.

Prior to 2002, hormone replacement therapy (HRT) was considered to be an important component of postmenopausal healthcare. This was based on a plethora of basic, epidemiological and clinical studies demonstrating the health benefits of supplementation with human sex steroids. However, adverse findings from the Women's Health Initiative (WHI) studies that examined the 2 major forms of HRT in use in the US at that time - Premarin (conjugated equine estrogens; CEE) and Prempro (CEE + medroxyprogesterone acetate; MPA), cast a shadow over the use of any form of HRT. Here we review the biochemical and physiological differences between the non-human WHI study hormones - CEE and MPA, and their respective human counterparts 17ß-estradiol (E2) and progesterone (P4). Preclinical data from the last 30 years demonstrate clear differences between human and non-human sex steroids on numerous molecular, physiological and functional parameters in brain, heart and reproductive tissue. In contrast to CEE supplementation, which is not always detrimental although certainly not as optimal as E2 supplementation, MPA is clearly not equivalent to P4, having detrimental effects on cognitive, cardiac and reproductive function. Moreover, unlike P4, MPA is clearly antagonistic of the positive effects of E2 and CEE on tissue function. These data indicate that minor chemical changes to human sex steroids result in physiologically distinct actions that are not optimal for tissue health and functioning.

Coronary artery dilation and left ventricular hypertrophy do not predict morbidity in children with sickle cell disease.

BACKGROUND: Little is known about the clinical significance of coronary artery dilation (CAD) and left ventricular hypertrophy (LVH) in patients with sickle cell disease (SCD). PROCEDURE: In a retrospective cohort, we studied the prevalence of CAD and LVH in 101 children with SCD in comparison to 93 healthy African-American patients without SCD. Hospital days, number of admissions, and intensive care unit admission after the echocardiogram were assessed as measures of morbidity. RESULTS: Multivariable analysis of echocardiographic measures of LVH and CAD did not predict subsequent intensive care unit admission, hospital days/year or number of hospital admissions/year during a median follow-up time of 6.1 years. LVH as measured by left ventricular mass index was present in 46% of children with SCD and was inversely related to age (P = 0.0004). Height-indexed dimensions in children with SCD demonstrated that the prevalence of dilation was 49% for the left main coronary artery (LMCA), 29% for the left anterior descending (LAD), and 6% for the right coronary artery (RCA). LMCA dilation was related to relative wall thickness (P = 0.006), inversely to age (P < 0.0006) and weakly to disease severity as determined by hemoglobin (P = 0.03). CAD and LVH were not related to a clinical history of vaso-occlusive pain episode, acute chest syndrome, or cerebrovascular accident. CONCLUSION: LVH and CAD are common findings in children with SCD; however, they are not associated with need for subsequent hospital or intensive care unit admission.

Síndrome de Kawasaki: a propósito de un infante con meningitis aséptica y cambios en la cicatriz de BCG / Kawasaki syndrome: a child with aseptic meningitis and changes at BCG scar site

Presentamos el caso de un niño de 12 meses de edad referido al Hospital Nacional de Niños con diagnóstico presuntivo de exantema súbito, meningitis aséptica y choque incipiente. El paciente se ingresa, tras múltiples consultas a un hospital periférico, al día 14 de fiebre como síntoma más importante. A su ingreso se documentó meningitis aséptica, induración y enrojecimiento en el sitio de aplicación de la vacuna de la BCG, aparte de los criterios clásicos para Síndrome de Kawasaki. El ecocardiograma inicial mostró dilatación coronaria. El Síndrome de Kawasaki debe formar parte del diagnóstico diferencial del infante y niño con enfermedad eruptiva febril, y debe tenerse un alto índice de sospecha clínica de esta entidad