On Left Ventricle Stroke Work Efficiency in Children with Moderate Aortic Valve Regurgitation or Moderate Aortic Valve Stenosis.

The optimal timing for management of pediatric patients with moderate aortic valve disease [moderate aortic stenosis (modAS) or moderate aortic regurgitation (modAR)] remains unknown and largely unexplored. Although usually asymptomatic, the risk of increased left ventricular (LV) wall stress, irreversible myocardial fibrosis and sudden death in untreated moderate conditions warrants clearer risk stratification for appropriate timely intervention. In this study, we explore the use of a patient-specific mathematical model to introduce a new evaluative parameter of LV performance in patients with moderate aortic valve disease. Synthetic patient data (N = 520) representing healthy patients, and patients with modAS or modAR were first generated. Then, data from twenty-five pediatric patients were included in this study (healthy = 9; moderate AS = 8; modAR = 8). The effect of modAS or modAR on LV performance was evaluated by LV stroke work (LVSW) efficiency, a new non-invasive parameter. The results demonstrate that healthy patients possess a very high LVSW efficiency (synthetic data: 91 ± 2%, in vivo data: 92 ± 3%). However, modAS patients have a significant reduction in LVSW efficiency (synthetic data: 78 ± 2%, in vivo data: 76 ± 5%, p < 0.05), whereas modAR patients had the lowest LVSW efficiency (synthetic data: 58 ± 3%, in vivo data: 66 ± 7%; p < 0.05). This highlights that patients with moderate aortic valve disease require careful myocardial assessment, regardless of onset of clinical symptoms as their LV performance is significantly reduced. The evaluation of LVSW efficiency offers a promising avenue for future stratification of mixed aortic valve disease for optimal timing of management and intervention.

Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention after Kawasaki Disease: The Pediatric Canadian Series.

Coronary artery (CA) aneurysms are serious complications of Kawasaki disease (KD) responsible for ischemic events. Percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are reported with limited data on indications and comparative efficacy. Retrospective multicenter comparison of CA intervention following KD is performed in this study. Twenty two cases were available from 5 centers, of whom 11 underwent CABG, 10 PCI and 1 systemic thrombolysis. Age at intervention (8.3 ± 3.9 vs 11.3 ± 4.9 years, p = 0.14) and interval from diagnosis (5.6 ± 4.1 vs 6.5 ± 4.7 years, p = 0.64) were similar between CABG and PCI. Interventions were based on angiography in 15 patients or cardiac event in 7, with no difference between CABG and PCI (p = 0.24). Patients with CABG were more likely to undergo multivessel intervention (73 vs 10 %, p = 0.006). None of the patients needed reintervention after CABG, compared to 6 after PCI and 1 after systemic thrombolysis (p = 0.004). Signs of ischemia on stress testing or MIBI were present in 15 patients before intervention and persisted in 9 patients following last intervention, in a significantly higher proportion after CABG than PCI (80 vs 17 %, p = 0.01). In this series, CABG, which mostly involved multivessel intervention, was superior to PCI. Nevertheless, larger-scale studies may help define patient selection criteria for a beneficial PCI approach.

Profiling left and right ventricular proportional output during fetal life with a novel systolic index in the aortic isthmus.

OBJECTIVE: Left ventricular ejection causes forward flow in the fetal aortic isthmus while the right ventricle has a retrograde influence. The aim of this study was to create reference values for an isthmic systolic index (ISI) reflecting the changing influence of right and left ventricular performance on Doppler flow velocity waveforms of the aortic isthmus throughout normal pregnancy. METHODS: Doppler recordings of 260 normal fetuses with a gestational age of 18-37 weeks were reviewed. Peak systolic velocity (PSV) and end-systolic velocity (or systolic nadir; Ns) were measured on all aortic isthmus waveforms. An ISI was derived from the ratio Ns/PSV. Left and right ventricular outputs were also calculated. RESULTS: Up to 22-23 weeks' gestation, the mean ISI is stable at around 0.2. At about 28 weeks, a brief end-systolic deceleration wave is observed on the aortic isthmus waveforms, progressing steadily with gestation and causing a fall of ISI towards a mean value of zero between 30 and 31 weeks. This trend continues thereafter and a mean value of -0.4 was observed at the end of pregnancy. An inverse correlation was found between right ventricular output and Ns (r = -0.334, P = 0.001). Simultaneous recordings of the isthmus and the ductus arteriosus Doppler waveforms demonstrated that the primary cause of the end-systolic deceleration and ultimate reversal of flow at the isthmus is the increasingly dominant flow from the right ventricle. CONCLUSION: The transitional changes of the respective right and left ventricular outputs throughout pregnancy are well profiled by the ISI. This index highlights the physiological increase in fetal right ventricle flow preponderance as pregnancy progresses. Alteration of the ISI profile could be expected in clinical conditions associated with unbalanced alteration of the fetal ventricular outputs.

Cyclic AMP-Rap1A signaling activates RhoA to induce α(2c)-adrenoceptor translocation to the cell surface of microvascular smooth muscle cells.

Intracellular signaling by the second messenger cyclic AMP (cAMP) activates the Ras-related small GTPase Rap1 through the guanine exchange factor Epac. This activation leads to effector protein interactions, activation, and biological responses in the vasculature, including vasorelaxation. In vascular smooth muscle cells derived from human dermal arterioles (microVSM), Rap1 selectively regulates expression of G protein-coupled α(2C)-adrenoceptors (α(2C)-ARs) through JNK-c-jun nuclear signaling. The α(2C)-ARs are generally retained in the trans-Golgi compartment and mobilize to the cell surface and elicit vasoconstriction in response to cellular stress. The present study used human microVSM to examine the role of Rap1 in receptor localization. Complementary approaches included murine microVSM derived from tail arteries of C57BL6 mice that express functional α(2C)-ARs and mice deficient in Rap1A (Rap1A-null). In human microVSM, increasing intracellular cAMP by direct activation of adenylyl cyclase by forskolin (10 µM) or selectively activating Epac-Rap signaling by the cAMP analog 8-pCPT-2'-O-Me-cAMP (100 µM) activated RhoA, increased α(2C)-AR expression, and reorganized the actin cytoskeleton, increasing F-actin. The α(2C)-ARs mobilized from the perinuclear region to intracellular filamentous structures and to the plasma membrane. Similar results were obtained in murine wild-type microVSM, coupling Rap1-Rho-actin dynamics to receptor relocalization. This signaling was impaired in Rap1A-null murine microVSM and was rescued by delivery of constitutively active (CA) mutant of Rap1A. When tested in heterologous HEK293 cells, Rap1A-CA or Rho-kinase (ROCK-CA) caused translocation of functional α(2C)-ARs to the cell surface (~4- to 6-fold increase, respectively). Together, these studies support vascular bed-specific physiological role of Rap1 and suggest a role in vasoconstriction in microVSM.

Normal values and methodologic recommendations for signal-averaged electrocardiography in children and adolescents.

Signal-averaged electrocardiography was performed in 153 normal children and adolescents (1 day to 18.3 years old) to examine the effects of age, sex, and race on different electrocardiographic variables, and to evaluate whether the current methods for analysis of the signal-averaged electrocardiogram are applicable to small children. Tracing with inaccurate automatic determination of the QRS end point or high noise levels were excluded. Filtered QRS duration, root-mean-square voltage, and low-amplitude signal duration were measured using 25, 40, and 80 Hz filters. All variables were significantly different (p <0.01) in infants compared with subjects aged >15 years. These differences gradually resolved with increasing age. Sex differences were present for some variables in adolescents only, and there was no significant race-related difference. Because of the shorter QRS duration, the terminal activities were more accurately reflected at the terminal duration of 30 ms in infants and 35 ms in children aged at least 1 year to <6 years. Normative data for filtered QRS duration, root-mean-square voltage, and low-amplitude signal duration are provided for different age groups.

Segmental myocardial contractility versus perfusion in Kawasaki disease with coronary arterial aneurysm.

The impact of Kawasaki-related coronary injury on the myocardium was evaluated in 13 patients with persistent coronary aneurysm after a follow-up period of 7.92+/-3.97 years (range 1.8 to 14.3). Myocardial segmental perfusion and contractility integrity were assessed by resting and exercise echocardiography and technetium-99 (Tc-99m) sestamibi scan. Eight patients (61.5%) had giant aneurysms (> or = 8 mm) and 9 had multivessel involvement; the mean diameter of the largest aneurysm was 8.6+/-2.5 mm (range 5 to 14). During the acute phase, myocardial infarction occurred in 1 patient and coronary thrombosis in another. At the latest echocardiographic evaluation, the mean aneurysm diameter was 6.8+/-2.4 mm (range 4.5 to 12), there was persistent giant aneurysms in 5 of 8 patients, and 3 of 9 patients had multivessel involvement. Coronary angiography demonstrated stenosis in 7 of 10 patients, with multiple levels in 2. At sestamibi scan, all 13 patients had perfusion anomalies at rest, whereas only 7 had detectable hypokinesia on echocardiography. With exercise, perfusion returned to near normal in 3 patients, improved in 3, remained unchanged in 4, and worsened in 3 patients. Segmental contractility similarly deteriorated in the latter 3 patients but also in 2 patients whose perfusion scan had improved with exercise. Three patients, normal at rest, developed segmental hypokinesia during exercise. When present, the location of observed changes in contractility on stress echocardiography corresponded to that of perfusion defect. In conclusion, abnormal myocardial perfusion is present long term after complicated Kawasaki disease, the worst anomalies accompanying persistent giant aneurysms. Unfavorable perfusion response was coupled with abnormal contractility; however, enhanced perfusion with exercise correlated poorly with segmental contractility response.

Endothelial dysfunction in cerebral microcirculation during hypothermic cardiopulmonary bypass in newborn lambs.

OBJECTIVES: Inflammatory stimuli or mechanical stresses associated with hypothermic cardiopulmonary bypass could potentially impair cerebrovascular function, resulting in inadequate cerebral perfusion. We hypothesize that hypothermic cardiopulmonary bypass is associated with endothelial or vascular smooth muscle dysfunction and associated cerebral hypoperfusion. Therefore we studied the cerebrovascular response to endothelium-dependent vasodilator, acetylcholine, endothelium-independent nitric oxide donor, sodium nitroprusside, and vasoactive amine, serotonin, in newborn lambs undergoing hypothermic cardiopulmonary bypass (nasopharygeal temperature = 18 degrees C). METHODS: Studies were performed on 13 newborn lambs equipped with a closed cranial window, allowing for direct visualization of surface pial arterioles. Six animals were studied while undergoing hypothermic cardiopulmonary bypass, whereas seven served as nonbypass, warm (37 degrees C) controls. Pial arteriolar caliber (range = 111 to 316 microm diameter) was monitored using video microscopy. RESULTS: Topical application of acetylcholine caused a dose-dependent increase in arteriolar diameter in the control group that was absent in animals undergoing hypothermic cardiopulmonary bypass. Hypothermic cardiopulmonary bypass did not alter the vasodilation in response to sodium nitroprusside. Furthermore, the contractile response to serotonin was fully expressed during hypothermic cardiopulmonary bypass. CONCLUSIONS: The specific loss of acetylcholine-induced vasodilation suggests endothelial cell dysfunction rather than impaired ability of vascular smooth muscle to respond to nitric oxide. It is speculated that loss of endothelium-dependent regulatory factors in the cerebral microcirculation during hypothermic cardiopulmonary bypass may enhance vasoconstriction, and impaired cerebrovascular function may be a basis for associated neurologic injury during or after hypothermic cardiopulmonary bypass.

Use of radiofrequency then stent implantation for recanalization of complete aorta coarctation.

Recanalization of a complete coarctation with isthmus occlusion was successfully accomplished in a 16-year-old patient using radiofrequency. This allowed the insertion and deployment of a covered stent to reestablish flow continuity across the isthmus. No complications were encountered. To the authors' knowledge this is the first case of radiofrequency use for complete coarctation, and among the rare cases of complete coarctation addressed primarily percutaneously to be reported.

First recanalization of a coronary artery chronic total obstruction in an 11-year-old child with Kawasaki disease sequelae using the CROSSER catheter.

This is a case of an 11(1/2)-year-old diagnosed with Kawasaki disease at 6 months of age. Distal left main coronary aneurysm involving the proximal anterior descending and circumflex had progressed into a chronic total occlusion. We report the first application of a novel percutaneous technique using the CROSSER catheter system in a child. The CROSSER is a high-frequency mechanical vibration catheter-based technology developed to safely penetrate through calcific and noncalcific coronary artery occlusions. This is also the first Kawasaki disease patient to benefit from this technology; in this disease, coronary artery stenosis is typically associated with heavy calcification.

Endocardial fibroelastosis in L-transposition of the great arteries with Ebstein's anomaly: revisited.

Ebstein's anomaly is a congenital deformity of the tricuspid valve consisting mainly of leaflet malinsertion. Clinical presentation varies from asymptomatic patients to those with congestive heart failure secondary to significant valvular regurgitation and low right ventricular output. We report here the case of an infant with a diagnosis of corrected transposition of the great arteries and Ebstein's deformity of the left-sided tricuspid valve who developed pulmonary hypertension and endocardial fibroelastosis, two unusual associations with this lesion. We also discuss the pathophysiology of this association and related literature.

Electrocardiographic depolarization and repolarization: long-term after Kawasaki disease.

To assess myocardial electric potentials late after Kawasaki disease (KD) we measured signal-averaged electrocardiography (SAECG) and QT dispersion parameters. Thirteen patients with persistent coronary aneurysm (group I), 12 with late resolution of the aneurysm (>3 months) (group II), and 13 with early resolution (group III) were studied 7.9 +/- 3.9, 6.7 +/- 3.9, and 7.2 +/- 3.6 years after the initial diagnosis (p = NS). In group I, myocardial infarction occurred in one patient during the acute illness, and coronary thrombosis in another; all except two patients had giant aneurysm (n = 8) and/or stenosis (n = 7). At 40-Hz high-pass filter SAECG, terminal 40-msec root mean square amplitude (RMS40) was significantly lower in group I versus II and III (64.1 +/- 40.8 microV, 79.9 +/- 47.2 microV, and 115 +/- 65.4 microV, respectively; p <0.05). Global QT dispersion was significantly greater in group I versus III (52 +/- 11 msec and 37 +/- 11 msec, respectively; p <0.05), but not in comparison to group II (45 +/- 13 msec). The same trend was present for rate-corrected QT dispersion, without reaching statistical significance (84.0 +/- 34, 71.5 +/- 31, and 61.8 +/- 21 respectively). Both depolarization and repolarization parameters are altered in patients with persistent coronary artery aneurysms long-term after KD. This may represent risk factors for developing ventricular arrhythmia in a growing population.

Phosphorylation in coronary artery cold-induced contraction in the newborn lamb.

Myocardial dysfunction after hypothermic protection has been linked to various mechanisms. Coronary vasospasm in particular may be responsible for ischemic injury during reperfusion. Herein we hypothesized that coronary arteries (CA) sustain a cold-induced contraction during hypothermia mediated by a protein tyrosine kinase (PTK)-/protein tyrosine phosphatase (PTP)-dependent pathway. Isolated newborn lamb CA rings were studied in a tissue bath for isometric contraction during 2-h profound (17 degrees C) or ultra-profound (7 degrees C) hypothermia. In parallel, protein tyrosine phosphorylation was evaluated by use of the Western blot technique. Na-orthovanadate (SOV) and genestein (GEN) were used separately and in combination to evaluate the effect of PTK/PTP activation on CA contraction and tyrosine phosphorylation during cooling (17 or 7 degrees C) vs 37 degrees C. Cooling from 37 to 7 degrees C induced transient contraction at approximately 17 degrees C (29% KCl response), which was more prominent during rewarming to 37 degrees C (36% KCl). Cooling to 17 degrees C resulted in sustained contraction (7-10% KCl), which was reversible upon rewarming. Cold-induced contraction was significantly enhanced by SOV (7- to 10-fold at 17 degrees C; 2-fold at 7 degrees C) and abolished by GEN. Concurrently, tyrosine phosphorylation of 33-, 45-, and 104-kDa proteins increased during cooling (35-100% at 17 degrees C; 46-66% at 7 degrees C). Tyrosine phosphorylation was similarly enhanced by SOV (1.7- to 2.3-fold at 17 degrees C; 2.9- to 3.9-fold at 7 degrees C) and abolished by GEN in the presence or absence of SOV. These results support a prominent role for the PTK/PTP signal transduction pathway in the coronary artery cold-induced contraction. This information provides one possible biomolecular mechanism linked to ischemia/reperfusion pathophysiology of CA in neonatal hearts exposed to hypothermic myocardial protection.

Severe pulmonary hypertensive vascular disease in two newborns with aneurysmal vein of galen.

Arteriovenous malformation of the vein of Galen (AVG) is a rare entity in the newborn with a high morbidity and mortality. We present two cases of fatal AVG with persistent pulmonary hypertension of the newborn and significant pulmonary hypertension documented by autopsy histopathology. The pathophysiology is reviewed and a proposed mechanism of the association between AVG and pulmonary hypertension is discussed.

Cerebral and coronary embolization of a valvular tumor.

Stroke and myocardial infarction are not commonly seen in children; the occurrence of both conditions in the same well child is unusual. Undifferentiated cardiac tumors are rarely encountered in the pediatric population. We present a case of stroke and myocardial infarction as a consequence of an undifferentiated valvular tumor in a previously healthy child. This case emphasizes the critical importance of serial clinical examinations as part of a complete stroke workup. It suggests the need for additional research on the use of thrombolytic therapy for pediatric cerebral and myocardial infarction and stresses individualization of cardiac tumor treatment plans.

Effects of hypothermosol, an experimental acellular solution for tissue preservation and cardiopulmonary bypass, on isolated newborn lamb coronary vessels subjected to ultra profound hypothermia and anoxia.

Ultra profound hypothermia (4 to 10 degrees C) is an experimental method aiming at safely prolonging organ and total body preservation. For this purpose, Hypothermosol (HTS), an investigational acellular solution for blood substitution, was demonstrated to be beneficial in animal models undergoing cardiopulmonary bypass. We investigated the beneficial versus deleterious effects of cold preservation and the role of HTS on isolated coronary arteries (CA) during cold exposure, rewarming, and post-rewarming exposure to anoxia. Newborn lamb CA rings were studied using a tissue bath technique. CA were subjected to cold (7 degrees C for 3 h) and treated with either Krebs' buffer (Krebs/hypothermia) or HTS (HTS/hypothermia) (n = 15 each). A third group maintained at 37 degrees C (Krebs/normothermia) (n = 18) served as a time control. After rewarming (37 degrees C), precontracted CA were exposed to anoxia. In Krebs/hypothermia a substantial hypercontraction (g) occurred during rewarming (1.21+/-0.07) (mean +/- SEM) but not in HTS/hypothermia (0.79+/-0.03); P<0.05. Precontraction force generated by indomethacin/U46619 was identical in all three groups. However, Krebs/hypothermia vessels demonstrated a significantly higher relative vasoconstriction (percentage) in the early (approximately 10 min) and late (30 min) anoxia exposure than the HTS/hypothermia and time control (119.5%+/- 3.7 vs. 109.5%+/-4.4 and 101.5%+/-3, and 71%+/-7.6 vs. 38.9%+/-7 and 51.5%+/-5.9, respectively; P<0.05). In conclusion, Ultra profound hypothermia promotes coronary vasoconstriction upon rewarming, which is detrimental to relaxant response to hypoxia. Both phenomena are alleviated by performing ultra profound hypothermia under HTS protection.

A national survey on the pediatric cardiologist's clinical approach for patients with Kawasaki disease.

In 1994, the American Heart Association (AHA) published the most recent guidelines for long-term cardiovascular management of Kawasaki disease. Since then, recent publications have shed new light on different diagnostic, prognostic, and management issues. We sought the opinion of pediatric cardiologists practicing in U.S. fellowship programs on the subject by means of a multiple-choice survey. Two questions addressed therapy in the acute phase, each preceded by a statement from related literature. Ten duplicate questions addressed the long-term cardiovascular management in five sets of paired questions; each question was first given in reminiscence of a clinical situation and then preceded by a statement from particular publications representative of new information that has become available since the publication of the 1994 AHA guidelines. All questions were provided in the same mailing. Replies were received from 97 participants practicing at 29 institutions. For the acute illness, 21% of respondents do not use high-dose aspirin, and 50% support reassessment of current guidelines. Universal intravenous immune globulin (IVIG) administration is followed by 97%, among whom 20% agree that evaluation of selection criteria is needed. For long-term management, 60-75% advocate regular follow-up of risk level I patients, and 80% favor periodic follow-up, with stress imaging (34-40%), for risk level II. For risk level IV more respondents favor stress echocardiography as opposed to nuclear imaging, in consonance with recent literature. For risk levels III and IV, 36-40% perform coronary angiography on a regular basis, whereas 60% do so when coronary symptoms are present or when stress imaging suggests myocardial ischemia. Finally, 19-25% of respondents do not routinely advise healthy lifestyle to patients free of coronary artery lesions. In conclusion, the guidelines for conventional therapy in the acute phase and long-term cardiovascular management need to be revised.