Trivial aortic valve regurgitation in children and adolescents with structurally normal hearts: physiologic or pathologic?

BACKGROUND: Trivial regurgitation from a normal aortic valve is rarely seen in healthy children and adolescents. The aim of this study was to evaluate timing of presentation, associated conditions, and medium-term prognosis of this incidental finding. METHODS: Paediatric patients observed to have trivial aortic valve regurgitation with otherwise normal echocardiograms were retrospectively analysed. Clinical and echocardiographic parameters were measured and categorised on presentation and follow-up. RESULTS: Sixty patients (39 males) were identified over a 13-year period. Age at presentation was 14.8 years (IQR 12.9-16.0), height z-score was + 0.71 (95% CI + 0.48- + 0.94), and body mass index z-score was + 0.66 (95% CI + 0.40- + 0.92). Median aortic regurgitation vena contracta diameter was 1.0 mm (IQR 0.8-1.3). Aortic valve strands were visualised in 28% and physiologic mitral regurgitation in 32%. Aortic annulus, sinotubular junction, and mid-ascending aorta diameters were normal, and mean aortic sinus diameter was only slightly increased (z-score + 0.23, 95% CI + 0.02- + 0.44). Follow-up data were obtained in 36 patients from 1 to 6.7 years later (median 2.1). Aortic regurgitation was no longer detectable in 28%, and none exhibited worsening. Mitral regurgitation prevalence was lower in those with aortic regurgitation resolution versus persistence (10% versus 50%, p = 0.03). CONCLUSIONS: Trivial aortic regurgitation in paediatric patients with normal hearts is more common in adolescents and is associated with an increased prevalence of aortic valve strands and physiologic mitral regurgitation. These findings do not worsen during growth and may resolve consistent with being physiologic rather than pathologic.

Right and left ventricular mass development in early infancy: Correlation of electrocardiographic changes with echocardiographic measurements.

BACKGROUND: Right ventricular mass indexed to body surface area (RVMI) decreases and left ventricular mass index (LVMI) increases rapidly and substantially during early infancy. The relationship between these sizeable mass transformations and simultaneous electrocardiographic changes have not been previously delineated. METHODS: Normal term infants (#45 initially enrolled) were prospectively evaluated at 2 days and at 2-week, 2-month, and 4-month clinic visits. Ventricular masses were estimated with 2D echocardiographic methods. QRS voltages were measured in leads V1, V6, I and aVF. RESULTS: Mean QRS axis shifted from 135 (95%CI 124, 146) to 65 degrees (95%CI 49, 81) and correlated with both RVMI decrease and LVMI increase (R = 0.46⁎ vs. 0.25†, respectively. *p < 0.01, †p < 0.05). As RVMI decreased from mean 28.1 (95%CI 27.1, 29.1) to 23.3 g/m2 (95%CI 21.4, 25.2) so did V1R and V6S voltages. RVMI changes correlated with V1R, V6S, and V1R + V6S voltages (R = 0.29*, 0.23† and 0.35*, respectively. *p < 0.01, †p < 0.05) but not with V1R/S ratio. As LVMI increased from 44.6 (95%CI 42.9, 46.3) to 55.4 g/m2 (95%CI 52.3, 58.5) V6R and V6Q increased but V1S voltage did not. LVMI changes correlated with V6R, V6R-S, and V6(Q + R)-S voltages (R = 0.31*, 0.34*, and 0.38* respectively. *p < 0.01) but not with V1S or V6R/S (R = 0.01 and 0.18 respectively, p = NS). CONCLUSIONS: During early infancy the RVMI decrease correlates best with the QRS axis shift and V1R + V6S voltage, and the LVMI increase correlates best with V6R-S and V6(Q + R)-S voltages.

Presentation and Prognosis of Excessive Asymptomatic Atrial Ectopy in Children and Adolescents With Structurally and Functionally Normal Hearts.

Excessive premature atrial complexes (PACs) in pediatric patients with a structurally normal heart are presumed to be benign and self-resolving, but no studies have confirmed this. Adults with excessive PACs, however, are at increased risk for future sustained atrial arrhythmias and cardiovascular morbidity and mortality. Therefore, we sought to evaluate the clinical course of frequent PACs in asymptomatic children. Patients < 21 years old with numerous asymptomatic PACs (>50/24 hours) were retrospectively selected over a 10-year period. Demographics, clinical characteristics, and results of cardiovascular testing were tabulated. Two groups were defined: those with a significant (>20%) reduction in burden of atrial ectopy versus those with an insignificant (<20%) reduction or increase. Of 6,902 patients, 343 patients (5%) met criteria. Initial median age was 8.3 (interquartile range [IQR] 4.1 to 14) years with comparable male:female ratio. Follow-up Holters were performed on 188 patients (54.8%) at a median interval of 2.2 (IQR 1.3 to 3.6) years. Overall, there was a significant decrease in atrial ectopy burden from 4.2% (IQR 1.9 to 6.5) down to 0.5% (IQR 0.01 to 2.3), with 166 patients (88.3%), demonstrating a decrease of over 20%. Five percent had a small increase, and 6% had an insignificant decrease. None developed cardiac symptoms or sustained supraventricular tachydysrhythmia. Male gender, athletic participation, and discontinuation of stimulant medications were the chief predictors for a reduction of PAC burden on follow-up. Atrial triplets at presentation were associated with a 5.4% increase. In conclusion, this study confirms that excessive asymptomatic childhood PACs with structurally normal hearts are rare and short-term to medium-term prognosis is benign.

Prominent prolapsing Chiari network: presentation and prognosis in paediatric patients.

Chiari network is an infrequently visualized web-like structure in the right atrium that is usually thin and small. Rarely, it can be prominent and elongated with protrusion into the right ventricle during diastole and complications have been reported. Thirty-eight patients (median age 2.5 years) with prolapsing Chiari network were identified and associated cardiac abnormalities documented. Echocardiographic right and left heart parameters were measured and compared to normative data. At presentation, the extent of Chiari network prolapse below the tricuspid annulus was 9.1 ± 3.5 mm (mean ± standard deviation), mean pulmonary valve annulus diameter z-value was reduced (-0.91 ± 0.64), and mean aortic valve z-value was enlarged (+0.97 ± 0.87). Fourteen patients exhibited no other cardiac abnormality. Eight were noted to have atrial septal defects, eight demonstrated supraventricular dysrhythmias, six had mild to moderate tricuspid valve regurgitation, and one patient each had an atrial septal aneurysm, severe pulmonic valve stenosis, small perimembranous ventricular septal defect, bicuspid aortic valve, and mild right upper pulmonary vein stenosis. Fourteen patients (37%) were seen in follow-up from 1 to 8.5 years later (median 3.2 years). During that time, the magnitude of prolapse across the tricuspid valve decreased by up to 7 mm (median 2 mm). Interventions were required in three patients, but many associated cardiac abnormalities resolved spontaneously with growth. Thus, the presence of a prolapsing Chiari network has a substantial risk of associated CHDs. However, the extent of Chiari network prolapse gradually decreases and many related abnormalities resolve during growth.

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. RESULTS: The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

Exosome removal as a therapeutic adjuvant in cancer.

Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30-100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2) over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin®. Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT™ (adaptive dialysis-like affinity platform technology) system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles < 200 nm from the entire circulatory system. This strategy is supported by clinical experience in hepatitis C virus-infected patients using an ADAPT™ device, the Hemopurifier®, to reduce the systemic load of virions having similar sizes and glycosylated surfaces as cancer exosomes. This review discusses the possible therapeutic approaches for targeting immune suppressive exosomes in cancer patients, and the anticipated significance of these strategies for reversing immune dysfunction and improving responses to standard of care treatments.

Modeling hepatitis C virus therapies combining drugs and lectin affinity plasmapheresis.

Hepatitis C virus (HCV) infection can be cured by standard pegylated interferon (IFN) + ribavirin drug therapy in 30-50% of treatment-naïve genotype 1 HCV patients. Cure rate is defined as a sustained viral response measured 6 months after the end of treatment. Recently, Fujiwara et al. [Hepatol Res 2007;37:701-710], using a double-filtration plasmapheresis (DFPP) technique, showed that simple physical reduction in circulating HCV using a 1-week pretreatment increased the cure rate for treatment-naïve type 1 HCV patients from 50 (controls) to 78% (treated). For previous nonresponders, the cure rate increased from 30 to 71%. This effect occurs even though the DFPP per treatment HCV viral load reduction averaged 26%. In clinical studies discussed here, a lectin affinity plasmapheresis (LAP) device caused an estimated 41% decrease in viral load as previously reported. A more detailed analysis using normalized data to correct for any variations in initial viral load gave an average 29% per treatment viral load reduction in 5 HCV-positive dialysis patients. The latter data indicate that continuous application of LAP could bring HCV viral load to undetectable levels in 4.1 days. Compared to DFPP, the LAP approach has the advantage that no plasma losses are incurred. In addition hemopurification can be carried out for extended periods of time analogous to continuous renal replacement therapy for the treatment of acute kidney failure, making the process much more effective. Calculations based on these data predict that continuous hemopurification would substantially increase the rate of viral load reduction (approx. 14-fold) and therefore increase the cure rate for HCV standard-of-care drug therapies without adding additional drugs and their associated side effects.

Reduction of hepatitis C virus using lectin affinity plasmapheresis in dialysis patients.

BACKGROUND/AIMS: To test the safety and efficacy of the Aethlon Hemopurifier, a lectin affinity cartridge, in clearing hepatitis C virus (HCV) from the blood of HCV-positive end-stage renal disease patients undergoing dialysis. Viral RNA was measured using real-time quantitative reverse transcriptase polymerase chain reaction. RESULTS: HCV clearance from plasma or blood was measured using either direct capture on immobilized Galanthus nivalis agglutinin (GNA) or using miniature plasmapheresis cartridges containing immobilized GNA. HCV in plasma samples was rapidly cleared by direct affinity capture (t(1/2) = approx. 20 min) and HCV in human blood was cleared using the Hemopurifier (t(1/2) = 2-3 h). Institutional-review-board-sanctioned clinical safety studies were conducted at the Apollo and Fortis Hospitals in India. At Apollo, 4 patients were treated 3 times/week for 2 weeks. HCV captured on the Hemopurifier averaged 8.9 x 10(8) viral copies/cartridge (n = 5), representing approximately 30% of the initial viral body burden. At Fortis, 3 patients treated 3 times/week for 1 week completed the viral load studies. Two patients showed measurable viral load reduction, while the third showed both increases and decreases in viral load. After Hemopurifier treatment, average HCV viral load was reduced by 57%. Surprisingly, average viral load was also 82% lower 7 days after treatment. Control samples also showed a marked transient reduction in HCV viral load as previously reported. CONCLUSION: The Hemopurifier rapidly cleared HCV from blood treated in vitro. In patients, the combination of the Hemopurifier plus dialysis decreased HCV viral load by 57% in 1 week. Moreover, viral load reduction continued up to 7 days after treatment.

Exosomes as a tumor immune escape mechanism: possible therapeutic implications.

Advances in cancer therapy have been substantial in terms of molecular understanding of disease mechanisms, however these advances have not translated into increased survival in the majority of cancer types. One unsolved problem in current cancer therapeutics is the substantial immune suppression seen in patients. Conventionally, investigations in this area have focused on antigen-nonspecific immune suppressive molecules such as cytokines and T cell apoptosis inducing molecules such as Fas ligand. More recently, studies have demonstrated nanovesicle particles termed exosomes are involved not only in stimulation but also inhibition of immunity in physiological conditions. Interestingly, exosomes secreted by cancer cells have been demonstrated to express tumor antigens, as well as immune suppressive molecules such as PD-1L and FasL. Concentrations of exosomes from plasma of cancer patients have been associated with spontaneous T cell apoptosis, which is associated in some situations with shortened survival. In this paper we place the "exosome-immune suppression" concept in perspective of other tumor immune evasion mechanisms. We conclude by discussing a novel therapeutic approach to cancer immune suppression by extracorporeal removal of exosomes using hollow fiber filtration technology.

Right ventricular abnormalities in sickle cell anemia: evidence of a progressive increase in pulmonary vascular resistance.

OBJECTIVE: To assess the effects of sickle cell anemia (SCA) on the right ventricle (RV). STUDY DESIGN: Echocardiograms of 32 children with SCA were compared with age-matched healthy controls. RV measurements included diastolic area index, fractional area change, free-wall mass index, ejection time corrected for heart rate (ET(c)), and tricuspid regurgitation (TR) gradient. RESULTS: SCA subjects had elevated RV ETc (mean +/- standard deviation, 0.369 +/- 0.030 sec vs 0.351 +/- 0.022 sec; P < .01), diastolic area index (19.9 +/- 2.4 cm(2)/m(2) vs 13.2 +/- 2.1 cm(2)/m(2); P < .01) and free-wall mass index (33.2 +/- 4.4 g/m(2) vs 23.9 +/- 4.3 g/m(2); P < .01), whereas RV fractional area change (37 +/- 8% vs 36 +/- 4%) was not different from controls. Although RV diastolic area index in SCA paralleled the normal range over time, RV free-wall mass index continued to gradually rise throughout childhood (r = .42; P < .05). TR gradients > 2.5 m/sec, consistent with pulmonary hypertension, were found in 5 (16%) of SCA subjects, all older than 9 years. CONCLUSIONS: RV preload and systolic function do not worsen during childhood in SCA; however, RV mass index and the prevalence of pulmonary hypertension increase consistent with rising pulmonary vascular resistance.

Complications of non-compaction of the left ventricular myocardium in a paediatric population: a prospective study.

AIMS: Non-compaction of the left ventricular myocardium (NCVM) is reportedly exceedingly rare and associated with a high morbidity and mortality. A different genetic background has been suggested for NCVM with [non-isolated NCVM (ni-NCVM)] and without [isolated NCVM (i-NCVM)] other congenital heart defects. We prospectively evaluated both the NCVM subgroups regarding frequency of occurrence and cardiovascular complications in a paediatric population. Results In a prospective, single-centre study, 66/5220 consecutive patients (1.26%) were diagnosed (25 i-NCVM, 41 ni-NCVM). The median age was 4 years (range 0-21), the median follow-up 12 months (range 0-51). The occurrence of congestive heart failure (CHF) at follow-up was 68.0%. CHF was as frequently seen in i-NCVM and ni-NCVM patients (77.5 vs. 62.1%, P = 0.322). The occurrence of arrhythmias (20.0%) and thrombo-embolic events (13.9%) was not different between subgroups. The cardiomyopathy related mortality was 7.1%, with three and one deaths in the i-NCVM and ni-NCVM groups, respectively (P = 0.126). CONCLUSION: When prospectively evaluated, NCVM appears to have been previously under-diagnosed. Whereas arrhythmias and thrombo-embolic events were rare, CHF was frequently found. An equally aggressive anticongestive treatment regimen would seem indicated for both the NCVM subgroups.

Parental preference regarding hospitals for children undergoing surgery: a trade-off between travel distance and potential outcome improvement.

OBJECTIVE: To explore parental preference in the choice between a local and a referral hospital for children undergoing heart surgery. METHODS: One hundred three parents or adult primary caregivers of children referred to a pediatric cardiology clinic were interviewed. Participants were presented with hypothetical scenarios in which they or their children had a heart condition requiring elective surgery. The surgery could be performed at either a local hospital or a regional referral hospital. The travel time to the referral hospital was initially presented as 2 h, and the mortality rate was set at 3% for both the local and the referral hospitals. The parents were then presented with scenarios that sequentially increased the mortality of the local hospital and the distance to the referral hospital, and were asked to choose between the local and regional referral hospitals. RESULTS: When the regional referral hospital was 2 h away and the mortality rates for the referral hospital and the local hospital were equal at 3%, 82.5% of participants chose the local hospital for their children. The percentage of participants choosing the local hospital decreased progressively as the mortality rate of the local hospital increased (to 9.7% at 18% mortality). Between 5% and 10% more participants chose the local hospital when the distance to the referral hospital was increased from 2 h to 4 h. There was no difference in age, sex, ethnicity, language, type of insurance, level of education and availability of personal transportation between participants who chose the regional referral hospital and those who chose the local hospital. Participants who lived closer to the hospital at which the survey was conducted were more likely to choose the local hospital. CONCLUSION: The present study defines a relation between potential outcome improvement and increasing travel distance from a patient or parent's perspective. This trade-off is an important consideration when planning for regionalization.

Normal right and left ventricular mass development during early infancy.

The average newborn's right ventricular mass, indexed to body surface area, is approximately 20% above the adult level, consistent with in utero physiologic hypertrophy. In contrast, the left ventricular mass index is underdeveloped by about 30% at birth, resulting in a ratio of right to left ventricular mass that is nearly 75% higher than at maturity. Left ventricular mass index increases rapidly during the first 2 weeks of life and then more slowly thereafter, whereas the right ventricular mass index decreases steadily during the first 4 months of life.

Echocardiographic assessment of the right ventricular stress-velocity relationship under normal and chronic overload conditions.

UNLABELLED: The effects of chronic volume or pressure overload on the velocity of right ventricular ejection have not been previously well defined. We hypothesized that, as formerly shown for the left ventricle, there would be a direct relationship between the velocity of ejection and an estimate of systolic wall stress. METHODS: Echocardiograms of asymptomatic patients, not on cardiac medications, with either an isolated secundum atrial septal defect > or = 5 mm in diameter or isolated pulmonic stenosis with a peak instantaneous pressure gradient > or = 20 mmHg, were reviewed. Forty-one patients with an atrial septal defect and 34 with pulmonary stenosis met criteria, and were compared to age-matched normal controls. Total subjects were 127 with ages ranging from 1 day to 54 years. Right ventricular monoplane ejection fraction, ejection time corrected for heart rate (ETc), mean normalized systolic ejection rate (MNSERc) and meridianal peak-systolic wall stress (WSps) were measured. RESULTS: Compared to controls, ejection fractions were not significantly different, but WSps averaged 81% and 110% higher, ETc 8% and 9% longer, and MNSERc 5% and 9% slower in the atrial septal defect and pulmonary stenosis groups, respectively. Among all subjects WSps had a significant linear correlation with ETc (r = 0.61, P < 0.01), MNSERc (r =-0.46, P < 0.01), and ejection fraction (r =-0.19, P < 0.05). CONCLUSIONS: Increases in WSps cause an incremental slowing of MNSERc in the right ventricle, with a relationship that is linear over a wide range of normal and abnormal loading conditions.

Medtronic freestyle valves in right ventricular outflow tract reconstruction.

BACKGROUND: Various pulmonary valve substitutes, with their inherent limitations, have been used in children and young adults. We chose the Medtronic Freestyle (Medtronics, Minneapolis, MN) valve because of its excellent hemodynamics, known durability in adults, and design features that allow modifications during implantation. METHODS: Over a 3 1/2 year period the Freestyle valve was implanted in 47 patients age 2 to 58 years (mean 14.2, median 12.0) in the pulmonary position. All patients had pulmonic stenosis and(or) insufficiency from previous operations for tetralogy (27), pulmonary atresia (6), truncus (4), or other diagnosis (10). The indication for surgery was pure pulmonary insufficiency in 11 patients, pulmonic stenosis in 3, and mixed stenosis and insufficiency in 33. Root replacement technique was used with additional enlargement of the pulmonary artery branches in 10 patients. RESULTS: Intraoperatively, one patient sustained a right ventricle tear and one a circumflex coronary artery injury during the dissection. There was one postoperative death. Two patients developed late subvalvular pannus formation, one of whom required reoperation. One patient was found to have an echo gradient of 95 mm Hg due to decreased leaflet motion and underwent cardiac catheterization at which the peak systolic gradient was determined to be 50 mm Hg. He has not required reintervention during his 3 1/2 years of follow-up. The remaining 43 patients have minimal gradients or insufficiency. All surviving patients are in New York Heart Association (NYHA) Class I. CONCLUSIONS: The Medtronic Freestyle valve is an attractive alternative for RVOT (right ventricular outflow tract) reconstruction in children. It is readily available, versatile, and has excellent hemodynamic characteristics. Although long term follow-up is not yet available, longevity of this prosthesis, and freedom from complications, will hopefully be superior to valves with stents.

Parental preference for one-stage versus two-stage surgical repair for children with congenital heart disease.

BACKGROUND: Little is known regarding parental preference for a one-stage complete repair versus a two-staged approach with initial palliation, followed by repair, of the congenital cardiac malformation. METHODS: We interviewed 103 parents of healthy children referred to a clinic for pediatric cardiology. Participants were presented with a hypothetical scenario in which their children had a cardiac lesion requiring surgery. The surgery could be performed either by means of one-stage complete repair, or using a two-stage approach, with palliation first followed by complete repair a year later. The mortality rate for the one-stage repair was set at 5%. Participants were asked to choose between the one- and two-stage approaches, with differing mortality rates for the two-stage approach. The scenarios included options when the two-stage combined mortality rate was lower than the one-stage mortality, and the first stage mortality rate was at 1% and 3%, and when the two-stage combined mortality rate was the same as that for one-stage mortality, these being set at 1% and 3%. RESULTS: When the two-stage combined mortality rate was lower than that of the one-stage repair, participants were more likely to choose the two-stage approach if the first stage mortality rate was 1% as compared to 3% (57% and 44%, respectively, p = 0.04). When the two-stage combined mortality rate was the same as the one-stage approach, participants choosing the two-stage approach when the mortality rate was set at 1%, and when it was raised to 3%, were not significantly different (42% and 34%, respectively, p = 0.24). When the combined two-stage mortality was the same as that set for one-stage repair, participants with no insurance were less likely to choose the two-stage approach than those covered by insurance (p = 0.03). CONCLUSIONS: In the chosen scenarios, when the mortality for a two-stage combined approach is the same as that for one-staged repair, more parents choose the one-staged repair. If the two-stage combined mortality is lower than that for one-staged repair, parents are more likely to choose the two-stage repair if the mortality for the first stage is lower. When the mortality rates for the one-stage and two-stage approaches are the same, people without insurance are more likely to choose one-staged repair.