Right Ventricular Electromechanical Dyssynchrony and Its Relation to Right Ventricular Remodeling, Dysfunction, and Exercise Capacity in Ebstein Anomaly.

BACKGROUND: Abnormal atrioventricular and intraventricular electrical conduction and dysfunction of the functional right ventricle (fRV) are common in Ebstein anomaly (EA). However, fRV mechanical dyssynchrony and its relation to fRV function are poorly characterized. We evaluated fRV mechanical dyssynchrony in EA patients in relation to fRV remodeling, dysfunction, and exercise intolerance. METHODS: We retrospectively analyzed data from nonoperated EA patients and age-matched controls who underwent echocardiography, cardiovascular magnetic resonance imaging, and cardiopulmonary exercise testing to quantify right ventricular (RV) remodeling, dysfunction, and exercise capacity. The relation of these to fRV dyssynchrony was retrospectively investigated. Right ventricular mechanical dyssynchrony was defined by early fRV septal activation (right-sided septal flash), RV lateral wall prestretch/late contraction, postsystolic shortening, and intra-RV delay using two-dimensional strain echocardiography. The SD of time to peak shortening among the fRV segments was calculated as a parameter of mechanical dispersion. RESULTS: Thirty-five EA patients (10 of whom were <18 years of age) and 35 age-matched controls were studied. Ebstein anomaly patients had worse RV function and increased intra-RV dyssynchrony versus controls. Nineteen of 35 (54%) EA patients had early septal activation with simultaneous stretch and consequent late activation and postsystolic shortening of RV lateral segments. Intra-fRV mechanical delay correlated with fRV end-diastolic volume index (r = 0.43, P < .05) and fRV end-systolic volume index (r = 0.63, P < .001). The fRV ejection fraction was lower in EA with versus without right-sided septal flash (44.9 ± 11.0 vs 54.2 ± 8.2, P = .012). The fRV mechanical dispersion correlated with the percentage of predicted peak VO2 (r = -0.35, P < .05). CONCLUSIONS: In EA, fRV mechanical dyssynchrony is associated with fRV remodeling, dysfunction, and impaired exercise capacity. Mechanical dyssynchrony as a therapeutic target in selected EA patients warrants further study.

Reversal of right ventricular pressure loading improves biventricular function independent of fibrosis in a rabbit model of pulmonary artery banding.

Right ventricular (RV) pressure loading leads to RV and left ventricular (LV) dysfunction through RV hypertrophy, dilatation and fibrosis. Relief of RV pressure load improves RV function. However, the impact and mechanisms on biventricular reverse-remodelling and function are only partially characterized. We evaluated the impact of RV pressure overload relief on biventricular remodelling and function in a rabbit model of reversible pulmonary artery banding (PAB). Rabbits were randomized to three groups: (1) Sham-operated controls (n = 7); (2) PAB (NDef, n = 7); (3) PAB followed by band deflation (Def, n = 5). Sham and NDef animals were sacrificed at 6 weeks after PAB surgery. Def animals underwent PAB deflation at 6 weeks and sacrifice at 9 weeks. Biventricular geometry, function, haemodynamics, hypertrophy and fibrosis were compared between groups using echocardiography, magnetic resonance imaging, high-fidelity pressure-tipped catheters and histology. RV pressure loading caused RV dilatation, systolic dysfunction, myocyte hypertrophy and LV compression which improved after PAB deflation. RV end-diastolic pressure (RVEDP) decreased after PAB deflation, although remaining elevated vs. Sham. LV end-diastolic pressure (LVEDP) was unchanged following PAB deflation. RV and LV collagen volumes in the NDef and Def group were increased vs. Sham, whereas RV and LV collagen volumes were similar between NDef and Def groups. RV myocyte hypertrophy (r = 0.75, P < 0.001) but not collagen volume was related to RVEDP. LV myocyte hypertrophy (r = 0.58, P = 0.016) and collagen volume (r = 0.56, P = 0.031) correlated with LVEDP. In conclusion, relief of RV pressure overload improves RV and LV geometry, hypertrophy and function independent of fibrosis. The long-term implications of persistent fibrosis and increased biventricular filling pressures, even after pressure load relief, need further study. KEY POINTS: Right ventricular (RV) pressure loading in a pulmonary artery banding rabbit model is associated with RV dilatation, left ventricular (LV) compression; biventricular myocyte hypertrophy, fibrosis and dysfunction. The mechanisms and impact of RV pressure load relief on biventricular remodelling and function has not been extensively studied. Relief of RV pressure overload improves biventricular geometry in conjunction with improved RV myocyte hypertrophy and function independent of reduced fibrosis. These findings raise questions as to the importance of fibrosis as a therapeutic target.

Giant coronary artery aneurysm associated with Kawasaki disease showing progressive dilation over 30 years.

A 33-year-old pregnant woman with a history of a giant coronary artery aneurysm (CAA) of the right coronary artery owing to Kawasaki disease (KD) was referred to our hospital for the management of pregnancy and delivery. The CAA was detected when she was 10 months old on the 24th day from the onset of KD and showed transient regression followed by progressive dilation and reached a size of 25 mm when she was 30 years old. The baby was delivered at 38 weeks of gestational age. Resection of the CAA and coronary artery bypass grafting were performed 5 months after the delivery. Pathological results suggest that progressive dilation of the CAA was owing to a reduction in elastic recoiling force caused by partial destruction of the internal elastic lamina and degenerated tunica media against an increase in blood pressure that accompanied the growth of the patient. The pathophysiology of CAAs with atypical clinical course may be different from that of typical CAAs owing to KD. .

Impaired right and left ventricular function and relaxation induced by pulmonary regurgitation are not reversed by tardive antifibrosis treatment.

Pulmonary regurgitation (PR) after repair of tetralogy of Fallot (rTOF) is associated with progressive right (RV) and left (LV) ventricular dysfunction and fibrosis. However, angiotensin II receptor blockade therapy has shown mixed and often disappointing results. The aim of this study was to serially assess changes in biventricular remodeling, dysfunction, and interactions in a rat model of isolated severe PR and to study the effects of angiotensin II receptor blockade. PR was induced in Sprague-Dawley rats by leaflet laceration. Shams (n = 6) were compared with PR (n = 5) and PR + losartan treatment (n = 6). In the treatment group, oral losartan (50 mg·kg-1·day-1) was started 6 wk after PR induction and continued for 6 wk until the terminal experiment. In all groups, serial echocardiography was performed every 2 wk until the terminal experiment where biventricular myocardium was harvested and analyzed for fibrosis. PR and PR + losartan rats experienced early progressive RV dilatation by 2 wk which then stabilized. RV systolic dysfunction occurred from 4 wk after insult and gradually progressed. In PR rats, RV dilatation caused diastolic LV compression and impaired relaxation. PR rats developed increased RV fibrosis compared with shams. Although losartan decreased RV fibrosis, RV dilatation and dysfunction were not improved. This suggests that RV dilatation is an early consequence of PR and affects LV relaxation. RV dysfunction may progress independent of further remodeling. Reduced RV fibrosis was not associated with improved RV function and may not be a viable therapeutic target in rTOF with predominant RV volume loading.NEW & NOTEWORTHY The time-course of RV dilatation and the mechanisms of biventricular dysfunction caused by PR have not been well characterized and the effect of losartan in volume-overloaded RV remains controversial. Our findings suggest that severe PR induces early onset of RV dilatation and dysfunction with little progression after the first 4 wk. The RV dilatation distorts LV geometry with associated impaired LV relaxation. Losartan reduced RV fibrosis but did not reverse RV dilatation and dysfunction.

Pseudoaneurysm of the sinus of Valsalva caused by infective endocarditis in a 7-year-old child with congenital heart disease.

We report a case of a pseudoaneurysm in the sinus of Valsalva, secondary to infective endocarditis in a child with trisomy 21. The patient had a history of subaortic stenosis, bicuspid aortic valve, and ventricular septal defect. Patch closure of the ostium of the pseudoaneurysm and aortic valve replacement was performed. The patient was discharged without severe complications.

Survival Outcomes of Two-Stage Intracardiac Repair in Large Ventricular Septal Defect and Trisomy 18.

BACKGROUND: Surgical management has not been encouraged in patients with trisomy 18 (T18) and congenital heart diseases due to poor survival. This study aimed to investigate (1) the appropriateness of palliative surgeries followed by intracardiac repair (ICR) (i.e., two-stage ICR) for patients with a large ventricular septal defect (VSD) and T18, and (2) its impact on their long-term outcomes. METHODS: Medical charts of patients with VSD and T18 who underwent two-stage ICR at the Japanese Red Cross Medical Center between January 2005 and December 2019 were retrospectively reviewed. Demographic data, timing, and types of palliative surgeries, information related to ICR, peri- and postoperative clinical information, postoperative survival, and cause of death were collected. The long-term prognosis of patients treated with two-stage ICR was compared with that of patients treated with primary ICR and palliative surgery without ICR. RESULTS: Overall, 18 (2 male, 16 female) patients underwent two-stage ICR. Pulmonary artery banding was the initial palliative surgery in all patients after a median duration of 19.5 (range 6-194) days of life. The median age and the mean body weight at the time of ICR were 18.2 (7.6-50.7) months and 6.0 ± 1.0 kg, respectively. The mean pulmonary artery pressure and pulmonary vascular resistance index before ICR were 19.1 ± 7.3 mmHg and 3.4 ± 2.0 U m2, respectively. Overall, 17/18 (94%) patients were discharged after ICR. Fourteen (78%) patients were alive during data collection. None of the patients died of cardiac insufficiency, and the median duration of survival was 46.3 (14.3-186.4) months since birth. Most patients required cardiac medications rather than pulmonary vasodilators at the last follow-up. During the study period, three patients underwent primary ICR, and 46 underwent palliative surgery without ICR. Of those who underwent primary ICR, two died in the hospital on the first and 48th day following ICR, and the third died 179 days after the ICR. The Log-rank test revealed a significantly longer survival for the patients treated with two-stage ICR compared with those treated with palliative surgery without ICR (P = 0.003). CONCLUSION: Two-stage ICR improves the long-term survival of patients with VSDs and T18. This safe surgical strategy can also prevent pulmonary hypertension in such patients.

Asymmetric Regional Work Contributes to Right Ventricular Fibrosis, Inefficiency, and Dysfunction in Pulmonary Hypertension versus Regurgitation.

BACKGROUND: Right ventricular (RV) pressure loading from pulmonary hypertension (PH) and volume loading from pulmonary regurgitation (PR) lead to RV dysfunction, a critical determinant of clinical outcomes, but their impact on regional RV mechanics and fibrosis is poorly characterized. The aim of this study was to test the hypothesis that regional myocardial mechanics and efficiency in RV pressure and volume loading are associated with RV fibrosis and dysfunction. METHODS: Eight PH, six PR, and five sham-control rats were studied. The PH rat model was induced using Sugen5416, a vascular endothelial growth factor receptor 2 inhibitor, combined with chronic hypoxia. PR rats were established by surgical laceration of the pulmonary valve leaflets. Six (n = 4) or 9 (n = 4) weeks after Sugen5416 and hypoxia and 12 weeks after PR surgery, myocardial strain and RV pressure were measured and RV pressure-strain loops generated. We further studied RV regional mechanics in 11 patients with PH. Regional myocardial work was calculated as the pressure-strain loop area (mm Hg ∙ %). Regional myocardial work efficiency was quantified through wasted work (ratio of systolic lengthening to shortening work). The relation of regional myocardial work to RV fibrosis and dysfunction was analyzed. RESULTS: In rats, PH and PR induced similar RV dilatation, but fractional area change (%) was lower in PH than in PR. RV lateral wall work was asymmetrically higher in PH compared with sham, while septal work was similar to sham. In PR, lateral and septal work were symmetrically higher versus sham. Myocardial wasted work ratio was asymmetrically increased in the PH septum versus sham. Fibrosis in the RV lateral wall, but not septum, was higher in PH than PR. RV fibrosis burden was linearly related to regional work and to measures of RV systolic and diastolic function but not to wasted myocardial work ratio. Patients with PH demonstrated similar asymmetric and inefficient regional myocardial mechanics. CONCLUSIONS: Asymmetric RV work and increased wasted septal work in experimental PH are associated with RV fibrosis and dysfunction. Future investigation should examine whether assessment of asymmetric regional RV work and efficiency can predict clinical RV failure and influence patient management.

Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension.

The potential benefit of heart rate reduction (HRR), independent of ß-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg/kg/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure-volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca++ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell-derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH/PAB rats. RV systolic-elastance (control, 121 ± 116; MCT, 49 ± 36 vs. MCT+IVA, 120 ± 54; PAB, 70 ± 20 vs. PAB+IVA, 168 ± 76; SUHX, 86 ± 56 vs. SUHX +IVA, 218 ± 111; all P < 0.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6 ± 1%; MCT, 13.4 ± 6.5 vs. MCT+IVA, 6.7 ± 2.6%; PAB, 11.4 ± 4.5 vs. PAB+IVA, 6.4 ± 5.1%; SUHX, 10 ± 4.6 vs. SUHX+IVA, 3.9 ± 2.2%; all P < 0.001) were improved by IVA versus controls. IVA had a dose-response effect on induced pluripotent stem cell-derived cardiomyocytes beat rate by delaying Ca++ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of ß-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.

Right Ventricular Diastolic Function and Right Atrial Function and Their Relation With Exercise Capacity in Ebstein Anomaly.

BACKGROUND: Right ventricular (RV) diastolic function and right atrial (RA) function are poorly characterized in patients with Ebstein anomaly (EA) but may influence functional capacity. We aimed to evaluate RV diastolic function and RA function in EA and study their relationship with biventricular systolic function and exercise capacity. METHODS: Seventy-two patients with EA and 69 controls prospectively underwent echocardiography, cardiovascular magnetic resonance imaging, and cardiopulmonary exercise testing to investigate RV systolic and diastolic function, RA function, and exercise capacity. RESULTS: Altered RV diastolic function was indicated by the reduced tricuspid valve E/A ratio, percentage RV filling time, and early and late diastolic strain rate; and by the increased tricuspid valve E/E', isovolumic relaxation time, and RV myocardial performance index. The average of 6-RV-segment early diastolic strain rate correlated modestly with peak VO2 (r = 0.38, P < 0.01), RV ejection fraction (r = 0.41, P < 0.01), and left ventricular ejection fraction (r = 0.33, P < 0.05). Patients with EA had impaired RA reservoir, conduit, and pump function, which were associated with peak VO2 (r = 0.54, P < 0.001 for reservoir function). CONCLUSIONS: Altered RV diastolic function and RA function in patients with EA are associated with impaired biventricular systolic function and exercise capacity. The stronger correlation of RA vs RV function with exercise capacity suggests that it may be important to evaluate RA function in this population.

A premature low-birth-weight infant with congenital complete atrioventricular block and myocarditis successfully treated by staged pacemaker implantation.

Congenital complete atrioventricular block is a known lethal condition. Although antenatal diagnosis and the technical advances of pacemaker treatment have reduced its mortality, treatment of premature babies with significant myocardial damage remains a challenge. In this paper, we report the case of a premature low-birth-weight infant with congenital complete atrioventricular block and extremely low ventricular rate, fetal hydrops, and myocarditis who was successfully treated with staged permanent pacemaker implantation.

Difference in cerebral and peripheral hemodynamics among term and preterm infants during the first three days of life.

BACKGROUND: The relationship between cerebral and peripheral hemodynamics during the early postnatal period has not been clarified. OBJECTIVES: To evaluate cerebral and peripheral oxygenation and blood volumes between term and preterm infants during the first 3 days of life. MATERIALS AND METHODS: We performed near-infrared time-resolved spectroscopy on 32 term infants (term group) and 40 preterm infants (preterm group), with an optode placed on their forehead and upper arm. The cerebral blood volume (CBV), peripheral blood volume (PBV), cerebral Hb oxygen saturation (cSO2) and peripheral Hb oxygen saturation (pSO2) were measured at 3-6, 12, 24, 48 and 72 h after birth. RESULTS: The CBV in the term group (2.45 ± 0.47 ml/100 g) was significantly higher than that in the preterm group (1.97 ± 0.33 ml/100 g). In contrast to the CBV, the PBV in the preterm group (3.63 ± 0.76 ml/100 g) was significantly higher than that in the term group (3.26 ± 0.56 ml/100 g). In the preterm group, there was a significant positive relationship between the CBVs and PBVs at each time point except at 72 h after birth. Despite the differences in blood volumes, there were no differences in the cSO2 and pSO2 between the two groups. CONCLUSIONS: The contrasting results in the CBV and PBV between the term and preterm infants might be explained by differences in the maturation of the physiological mechanism to control CBV and PBV.

Comparison of changes in cerebral and systemic perfusion between appropriate- and small-for-gestational-age infants during the first three days after birth.

PURPOSE: The aims of the current study were to compare changes in cerebral and systemic perfusion in appropriate-for-gestational-age (AGA) and small-for-gestational-age (SGA) infants immediately after birth. METHODS: Cerebral blood volume (CBV), cerebral Hb oxygen saturation (cSO2) and cerebral fractional tissue oxygen extraction (cFTOE) among 57 AGA infants and 30 SGA infants were monitored using a newly developed time-resolved spectroscopy system during the first 3days of life. The left ventricular ejection fraction (LVEF), left ventricular cardiac output (LVCO) and E/e' values were determined by three-dimensional echocardiography and tissue Doppler imaging performed simultaneously. RESULTS: There were significant differences between the body weights of both the AGA and SGA infants, but not between the gestational age and head circumferences in both groups. Although CBV showed no significant difference between the groups, cSO2 was significantly higher and cFTOE was lower in SGA infants than in AGA infants. Hematocrit (Ht) levels were significantly higher and LVEF and LVCO were lower in SGA infants than in AGA infants. Negative correlation was observed between CBV and Ht levels in AGA infants, but not in SGA infants. CONCLUSIONS: The high Ht levels and vasoreactivity in SGA infants might be a compensatory mechanism in order to maintain oxygen delivery to the brain, which reflects the condition of chronic hypoxia during the fetal period and also reflects the weak contraction and low cardiac output of the left ventricle sustaining the relatively large brain from the fetal period to after birth.

Umbilical cord milking stabilizes cerebral oxygenation and perfusion in infants born before 29 weeks of gestation.

OBJECTIVE: To investigate the effects of umbilical cord milking at birth on cerebral perfusion and systemic perfusion in very low birth weight (VLBW) infants. STUDY DESIGN: Cerebral tissue oxygenation index and cerebral fractional tissue oxygen extraction were monitored in 50 stable VLBW infants (gestational age <29 weeks, birth weight <1250 g), with 26 allocated to the milked group and 24 to the control group. We used near-infrared spectroscopy 3-6, 12, 18, 24, 36, 48, and 72 hours after birth. Left ventricular end-diastolic dimension, left ventricular ejection fraction, left ventricle (LV) Tei index (measurement of left ventricular systolic and diastolic function), left ventricular cardiac output, and superior vena cava flow were measured concurrently using echocardiography. RESULTS: There were no significant differences in gestational age and birth weight between the 2 groups. Hematocrit, left ventricular end-diastolic dimension, left ventricular cardiac output, and superior vena cava flow were higher in the milked group than in the control group, with improvement in the LV Tei index despite the absence of left ventricular ejection fraction changes within 24 hours after birth. Tissue oxygenation index increased and cerebral fractional tissue oxygen extraction decreased in the milked group within 24 hours after birth. CONCLUSION: Umbilical cord milking stabilized cerebral oxygenation and perfusion in VLBW infants by improving LV diastolic function by increasing LV preload.

A Case of Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome with High ASLO Titer.

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare autoimmune disease and the pathogenesis is still unknown. We report a case of TINU syndrome with high ASLO titer. Uveitis improved and urine ß2-MG normalized with low dose systemic predonisolone and cyclosporin A. The high ASLO titer in early phase suggested that streptococcal infection might have triggered TINU syndrome. Lymphocyte phenotypes normalized after treatment with low dose systemic predonisolone and cyclosporin A.

Association of mannose-binding lectin gene polymorphisms with Kawasaki disease in the Japanese.

OBJECTIVE: Kawasaki disease (KD) is a systemic vasculitis in childhood; its etiology is unknown. The possibility that KD is an infectious disease has been discussed and investigated for decades, in light of the implication that infections are involved in the pathogenesis of KD. Young children rely on their innate immune system for protection against virus and micro-organisms. Human mannose binding lectin (MBL) is a C-type serum lectin synthesized by the liver as an acute phase protein and it plays an important role in the innate immune system. Here, we investigate the relationship between the MBL gene polymorphisms and the occurrence of KD in the Japanese population. METHOD: The frequencies of the genotypes, defined as mutations in codons 52, 54 and 57, and the functional promoter variants of the MBL were determined in 45 patients with KD. RESULTS: The MBL codon-54 polymorphism frequency of heterozygote (GGC/GAC) and promoter variants were significantly higher in the KD group than that in the control group (P < 0.05). Neither group showed codon 52 nor 57 polymorphisms. CONCLUSION: It is possible that mutations of the MBL gene might be related to the trigger of the pathogenesis of Kawasaki disease.