A novel RUNX1 exon 3 - 7 deletion causing a familial platelet disorder.

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM) is a rare inherited disorder confirmed with the presence of a pathogenic germline RUNX1 variant and is thought to be heavily underdiagnosed. RUNX1 has also been found to be mutated in up to 10% of adult AML cases and other cell malignancies. We performed targeted next-generation sequencing and subsequent MLPA analysis in a kindred with multiple affected individuals with low platelet counts and a bleeding history. We detected a novel heterozygous exon 3-7 large deletion in the RUNX1 gene in all affected family members which is predicted to remove all of the Runt-homology DNA-binding domain and a portion of the Activation domain. Our results show that the combination of targeted NGS and MLPA analysis is an effective way to detect copy number variants (CNVs) which would be missed by conventional sequencing methods. This precise diagnosis offers the possibility of accurate counseling and clinical management in such patients who could go onto develop other cell malignancies.

Secondary repair of incompetent pulmonary valves after previous surgery or intervention: Patient selection and outcomes.

OBJECTIVES: Pulmonary valve (PV) regurgitation (PR) is common after intervention for a hypoplastic right ventricular outflow tract. Secondary PV repair is an alternative to replacement (PVR), but selection criteria are not established. We sought to elucidate preoperative variables associated with successful PV repair and to compare outcomes between repair and PVR. METHODS: Patients who underwent surgery for secondary PR from 2010 to 2017 by a single surgeon were studied. The PV annulus and leaflets were measured on the preoperative echocardiogram and magnetic resonance images, and the primary predictor variable was leaflet area indexed to ideal PV annulus area (iPLA) by magnetic resonance imaging. PV repair and PVR groups were compared using multivariable logistic regression, and with a conditional inference tree. Freedom from PV dysfunction and from reintervention were assessed with Kaplan-Meier survival analyses. RESULTS: Of 85 patients, 31 (36%) underwent PV repair. By multivariable analysis, longer PV total leaflet length (cm/m2) (ß = 3.00, standard error [SE] = 0.82, P < .001), larger PV z score (ß = 1.34, SE = 0.39, P = .001), and larger iPLA (ß = 8.13, SE = 2.62, P = .002) were associated with repair. iPLA of 0.90 or greater was 91% sensitive and 83% specific for achieving PV repair. At a median of 4.1 years follow-up, there was greater freedom from significant PR in the PV repair group (log rank P = .008). CONCLUSIONS: Patients with an iPLA >0.9, and those with an iPLA between 0.7 and 0.9 with a PV annulus z score >0 should be considered for a native PV repair. At midterm follow-up, patients with a PV repair were not more likely to develop PR or to require reintervention when compared with patients undergoing PVR.

Plakoglobin immunolocalization as a diagnostic test for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: A recent study using an anti-plakoglobin antibody and immunofluorescence methods in endomyocardial tissue specimens found that a marked reduction in plakoglobin staining was highly sensitive and specific for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). The purpose of our study was to determine the diagnostic utility of plakoglobin immunolocalization using more standard immunoperoxidase methods suitable for clinical laboratories. METHODS: Between January 2007 and October 2010, all patients at our center with suspected ARVC underwent noninvasive and genetic testing, right ventricular (RV) angiography, electrophysiologic studies, and endomyocardial biopsy from the RV septum. Several studies using anti-plakoglobin antibodies were performed using standard immunoperoxidase methods at concentrations of 1:50,000 and 1:75,000 after serial dilutions. RESULTS: Among 16 patients, nine patients fulfilled the clinical criteria for ARVC, and seven patients were found to have other cardiac diagnoses. In the initial study (1:50,000) only one of nine ARVC patients showed reduced plakoglobin signal while the others had normal staining. On repeat staining (1:75,000), reduced signal was observed in three of five of the ARVC patients compared to none in controls (four patients did not have adequate tissue for the repeat experiment). CONCLUSION: These results confirm that abnormal plakoglobin staining can differentiate biopsies from patients with ARVC from those with other myopathies, but with low sensitivity. Further, each specimen must be studied at a particular concentration due to variable antibody reactivity. The necessity for such fine-tuning of the reaction, as well as the subjectivity involved in interpretation of the results, would make this method difficult to utilize in routine hospital laboratories.

Long-term cardiovascular outcomes in survivors of Kawasaki disease.

BACKGROUND AND OBJECTIVE: Kawasaki disease (KD) may result in coronary aneurysm formation, but there is incomplete knowledge regarding its long-term effects. Our objective was to quantify the longer-term rates of adverse cardiac events in a modern North American KD cohort. METHODS: Using the Kaiser Permanente Northern California population, we performed a retrospective cohort study in patients with a history of KD versus matched patients without KD. Chart review was used to confirm the diagnosis of KD and all outcomes of interest, including acute coronary syndrome, coronary revascularization, heart failure, ventricular arrhythmia, valve disease, aortic aneurysm, and all-cause mortality. All outcomes occurring at age ≥15 years were included in the primary analysis. Outcome rates were compared between the 2 groups by using Cox proportional hazards analysis. RESULTS: The study included 546 KD patients and 2218 matched patients without KD. Seventy-nine percent of the KD patients received intravenous immunoglobulin and 5% had persistent coronary aneurysm. The average follow-up time was 14.9 years. Only 2 KD patients experienced outcomes after age 15 (0.246 events per 1000 person-years) compared with 7 events in the non-KD group (0.217 events per 1000 person-years), a nonsignificant difference (hazard ratio: 0.81; 95% confidence interval: 0.16-4.0). Within the KD subgroup, persistent coronary aneurysm predicted the occurrence of adverse events (P = .007). CONCLUSIONS: This is the largest US study of longer-term cardiac outcomes after KD and reveals a low rate of adverse cardiovascular events through age 21. Additional validation studies, including studies with longer-term follow-up, should be performed.

CMR assessment of right ventricular function in patients with combined pulmonary stenosis and insufficiency after correction of tetralogy of Fallot.

BACKGROUND: Tetralogy of Fallot (TOF) is one of the most common types of congenital heart disease and requires prompt surgical correction. Post-correction pulmonary insufficiency (PI) often ensues in adulthood. At times, the PI is accompanied by residual pulmonary stenosis (PS). Little is known regarding right ventricular (RV) function in the setting of combined PS and PI. PURPOSE: To compare cardiac magnetic resonance (CMR) parameters for the assessment of RV function between patients with combined pulmonary stenosis and pulmonary insufficiency (PSPI) and isolated PI following surgical repair of TOF. MATERIAL AND METHODS: Retrospective review of patients with comparable corrected TOF and similar PI was performed. Seventeen patients (median age, 24 years; range, 10-52 years) had combined PSPI and 30 patients (median age, 30 years; range, 6-70 years) had isolated PI. Cine magnetic resonance (MR) images (Philips Medical Systems, Best, The Netherlands) in the short-axis plane were used to calculate end-systolic, end-diastolic, and stroke volumes (RVESV, RVEDV, RVSV) and to measure RV wall thickness. Velocity-encoded cine MR images were used to measure pulmonary regurgitation fraction (PRF) by calculating the ratio of backward flow and total forward flow, obtained from the main pulmonary flow analysis. Peak pressure gradient across the pulmonary valve was obtained from spectral Doppler echocardiography. RESULTS: RVEF was 51 ± 8% in the PSPI patients and 39 ± 11%, in the patients with isolated PI (P = 0.001). Additionally, RV wall thickness was 5.2 ± 0.8 mm in the PSPI patients compared to 2.6 ± 0.9 mm in the isolated PI patients (P = 0.001). RVESVi and RVEDVi were significantly lower (P < 0.05) in patients with combined PSPI (60 ± 21 mL/m(2), 121 ± 35 mL/m(2), respectively) compared to the patients with isolated PI (95 ± 48 mL/m(2), 152 ± 61 mL/m(2), respectively). CONCLUSION: RV function is preserved in patients with PSPI when compared to patients with PI following surgical repair of TOF.

Collateral flow measurement by phase-contrast magnetic resonance imaging for the assessment of systemic venous baffle patency after atrial switch repair for transposition of the great arteries.

PURPOSE: We aimed to describe and compare azygos vein flow patterns of patients with obstructed and unobstructed systemic venous baffle after atrial switch repair for d-transposition of the great arteries (TGA). We hypothesized that phase-contrast magnetic resonance imaging would enable characterization of retrograde collateral flow across the azygos vein in cases of systemic venous baffle obstruction. MATERIALS AND METHODS: This is a retrospective, cross-sectional study. Twelve patients with atrial switch repair for TGA were examined. Azygos flow index was measured with phase-contrast magnetic resonance imaging; comparison was made between patients with documented systemic venous baffle obstruction (n=3) and a control group of patients without baffle obstruction (n=9). RESULTS: Patients with systemic venous baffle obstruction had a distinctive azygos flow pattern that was retrograde and an increased amount of azygos flow compared with patients without obstruction [median (range), -436 (-455/-399) vs. 103 (51/125) mL/min/m2; P=0.01]. CONCLUSIONS: Patients with systemic venous baffle obstruction have a characteristic collateral flow across the azygos vein. Azygos vein flow measurement may be used for the assessment of baffle patency in patients after atrial switch repair for TGA. However, diagnostic accuracy needs to be tested in a larger population.

Impaired regional left ventricular strain after repair of tetralogy of Fallot.

PURPOSE: To test the potential of magnetic resonance imaging (MRI) in early detection of left ventricular (LV) dysfunction in patients with pulmonary regurgitation and normal LV ejection fraction after repair of tetralogy of Fallot. MATERIALS AND METHODS: Patients (n = 18) with repaired tetralogy of Fallot and pulmonary regurgitation were prospectively recruited. Healthy volunteers (n = 10) were used as control. Tagging MR images were acquired at the base, mid, and apical LV levels for assessing segmental rotation and circumferential strain. Cine MR images and velocity-encoded MR images were also acquired for assessment of biventricular volumes and biventricular function and pulmonary regurgitant fraction, respectively. Mean values were compared between groups using unpaired Student's t-test. RESULTS: Patients presented with preserved global LV function (LVEF of 59 ± 5%). A significant decrease in LV peak circumferential strain was seen in patients compared with normal volunteers at the basilar (-15.6 ± 4.5% vs. -17.6 ± 4.4%; P < 0.01) and apical (-14.4± 6.1% vs. -17.3± 5.1%, P < 0.01) slices. LV peak rotation was also delayed in patients compared with volunteers at the basilar (6.1 ± 2.6° vs. 4.2 ± 0.6°; P < 0.01) and mid (8.0 ± 1.7° vs. 4.9 ± 1.0°; P < 0.01) slices. CONCLUSION: MRI can detect early regional LV dysfunction in patients with preserved LVEF after repair of tetralogy of Fallot. MR may be a useful technique for guiding clinical decisions in these patients in order to prevent future global LV deterioration.

Usefulness of cardiovascular magnetic resonance imaging to predict the need for intervention in patients with coarctation of the aorta.

Cardiovascular magnetic resonance (CMR) imaging can predict hemodynamically significant coarctation of the aorta (CoA) with a high degree of discrimination. However, the ability of CMR to predict important clinical outcomes in this patient population is unknown. Therefore, we sought to define the ability of CMR to predict the need for surgical or transcatheter intervention in patients with CoA. We retrospectively reviewed the data from 133 consecutive patients who had undergone CMR for the evaluation of known or suspected CoA. The characteristics of the CMR-derived variables predicting the need for surgical or transcatheter intervention for CoA within 1 year were determined through logistic regression analysis. Therapeutic aortic intervention was performed in 41 (31%) of the 133 patients during the study period. The indexed minimum aortic cross-sectional area was the strongest predictor of subsequent intervention (area under the receiver operating characteristic curve 0.975) followed by heart rate-corrected deceleration time in the descending aorta (area under the receiver operating characteristic curve 0.951), and the percentage of flow increase (area under the receiver operating characteristic curve 0.867). The combination of the indexed minimum aortic cross-sectional area and rate-corrected deceleration time in the descending aorta provided the best predictive model (area under the receiver operating characteristic curve 0.986). In conclusion, CMR findings can predict the need for subsequent intervention in CoA. These findings reinforce the "gate-keeper role" of CMR to cardiac catheterization by providing valuable diagnostic and powerful prognostic information and could guide additional treatment of patients with CoA with the final intent of reducing the number of diagnostic catheterizations in such patients.

Prediction of hemodynamic severity of coarctation by magnetic resonance imaging.

A published formula containing minimal aortic cross-sectional area and the flow deceleration pattern in the descending aorta obtained by cardiovascular magnetic resonance predicts significant coarctation of the aorta (CoA). However, the existing formula is complicated to use in clinical practice and has not been externally validated. Consequently, its clinical utility has been limited. The aim of this study was to derive a simple and clinically practical algorithm to predict severe CoA from data obtained by cardiovascular magnetic resonance. Seventy-nine consecutive patients who underwent cardiovascular magnetic resonance and cardiac catheterization for the evaluation of native or recurrent CoA at Children's Hospital Boston (n = 30) and the University of California, San Francisco (n = 49), were retrospectively reviewed. The published formula derived from data obtained at Children's Hospital Boston was first validated from data obtained at the University of California, San Francisco. Next, pooled data from the 2 institutions were analyzed, and a refined model was created using logistic regression methods. Finally, recursive partitioning was used to develop a clinically practical prediction tree to predict transcatheter systolic pressure gradient ≥ 20 mm Hg. Severe CoA was present in 48 patients (61%). Indexed minimal aortic cross-sectional area and heart rate-corrected flow deceleration time in the descending aorta were independent predictors of CoA gradient ≥ 20 mm Hg (p <0.01 for both). A prediction tree combining these variables reached a sensitivity and specificity of 90% and 76%, respectively. In conclusion, the presented prediction tree on the basis of cutoff values is easy to use and may help guide the management of patients investigated for CoA.

Magnetic resonance imaging images in adult congenital heart disease.

The use of cardiac magnetic resonance imaging has become an indispensable tool for the evaluation of patients with congenital heart disease. With the emergence of several generations of congenital heart disease survivors, there are now as many adults with these conditions as children, and complications are the rule rather than the exception. It is increasingly important, therefore, that the general cardiology community becomes aware of these defects and potential pitfalls to avoid. Among its many uses, cardiac magnetic resonance can provide an assessment of right ventricular function, flow, pulmonary artery anatomy, and aortic visualization that are often important considerations in these patients. This review provides an introductory visual glimpse into the varied conditions encountered and clinical questions addressed in the field of adult congenital heart disease.

Diagnostic value of the flow profile in the distal descending aorta by phase-contrast magnetic resonance for predicting severe coarctation of the aorta.

PURPOSE: To compare aortic flow profiles at the level of the proximal descending (PDAo) and distal descending aorta (DDAo) in patients investigated for coarctation of the aorta (CoA), and compare their respective diagnostic value for predicting severe CoA. Diastolic flow decay in the PDAo predicts severe CoA, but flow measurements at this level are limited by flow turbulence, aliasing, and stent-related artifacts. MATERIALS AND METHODS: We studied 49 patients evaluated for CoA with phase contrast magnetic resonance imaging (PC-MRI). Parameters of diastolic flow decay in the PDAo and DDAo were compared. Their respective diagnostic value was compared with the standard reference of transcatheter peak gradient ≥20 mmHg. RESULTS: Flow measurement in the PDAo required repeated acquisition with adjustment of encoding velocity or location of the imaging plane in 69% of patients; measurement in the DDAo was achieved in single acquisition in all cases. Parameters of diastolic flow decay in the PDAo and DDAo, including rate-corrected (RC) deceleration time and RC flow deceleration yielded a good correlation (r = 0.78; P < 0.01, and r = 0.92; P < 0.01), and a similar diagnostic value for predicting severe CoA. The highest diagnostic accuracy was achieved by RC deceleration time at DDAo (sensitivity 85%, specificity 85%). CONCLUSION: Characterization of aortic flow profiles at the DDAo offers a quick and reliable noninvasive means of assessing hemodynamically significant CoA.

Advances in imaging: the impact on the care of the adult with congenital heart disease.

Recent advances in pediatric cardiology have dramatically changed the landscape of the field of congenital heart disease. This changing field is placing new demands on imaging to plan medical management as well as identify the need for, and timing of, reintervention. There are a number of imaging modalities available to the clinician when it comes to these evaluations, including echocardiography, computed tomography, and cardiac magnetic resonance imaging; each having their strengths and unique contributions. This article will discuss the advances in the aforementioned imaging modalities over the past decade and highlight how these tools can provide guidelines on the management of adults with congenital heart disease.

Tetralogy of Fallot: impact of the excursion of the interventricular septum on left ventricular systolic function and fibrosis after surgical repair.

PURPOSE: To quantify the excursion of interventricular septum (IVS) in patients after repair of tetralogy of Fallot (TOF), a marker of interventricular interaction, and assess its association with left ventricular (LV) ejection fraction, LV septal wall thickening, and LV fibrosis. MATERIALS AND METHODS: The HIPAA-compliant protocol received institutional board review approval. IVS excursion was measured at cardiovascular magnetic resonance (MR) imaging in 82 patients after repair of TOF and in 10 healthy volunteers. IVS excursion was correlated with LV ejection fraction, LV septal wall thickening, and LV delayed gadolinium enhancement. Independent predictors of reduced LV ejection fraction were identified, including significant univariable predictors with use of a multivariable logistic regression model. RESULTS: IVS excursion was greater in patients than in healthy volunteers (5.3 mm ± 3.1 vs 1.2 mm ± 0.4, P < .01). Patients (n = 68) with abnormal excursion of the IVS had reduced LV ejection fraction (57% ± 7 vs 61% ± 4, P < .01) and reduced LV septal wall thickening (24% ± 10 vs 29% ± 5, P = .01) compared with patients with normal IVS excursion. Maximal IVS excursion (odds ratio = 1.27 per millimeter, P = .03) and right ventricular (RV) ejection fraction (odds ratio = 0.92 per percentage, P = .031) were independent predictors of reduced LV ejection fraction (<55%). Among the 44 patients with delayed enhancement images, those with abnormal excursion of the IVS had higher LV delayed enhancement scores (median, 1.5 [interquartile range, 0-2] vs 0 [interquartile range, 0-0]; P < .01] than patients with normal IVS excursion. Notably, in all but one patient the delayed enhancement was located at the RV-LV hinge points. CONCLUSION: Abnormal IVS excursion after repair of TOF is associated with reduced global and septal LV systolic function and LV fibrosis at the RV-LV hinge points, suggesting a mechanism of adverse interventricular interaction.

Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns.

PURPOSE: To use time-resolved three-dimensional phase-contrast magnetic resonance (MR) imaging, also called four-dimensional flow MR imaging, to evaluate systolic blood flow patterns in the ascending aorta that may predispose patients with a bicuspid aortic valve (BAV) to aneurysm. MATERIALS AND METHODS: The HIPAA-compliant protocol received institutional review board approval, and informed consent was obtained. Four-dimensional flow MR imaging was used to assess blood flow in the thoracic aorta of 53 individuals: 20 patients with a BAV, 25 patients with a tricuspid aortic valve (TAV), and eight healthy volunteers. The Fisher exact test was used to evaluate the significance of flow pattern differences. RESULTS: Nested helical flow was seen at peak systole in the ascending aorta of 15 of 20 patients with a BAV but in none of the healthy volunteers or patients with a TAV. This flow pattern was seen both in patients with a BAV with a dilated ascending aorta (n = 6) and in those with a normal ascending aorta (n = 9), was seen in the absence of aortic stenosis (n = 5), and was associated with eccentric systolic flow jets in all cases. Fusion of right and left leaflets gave rise to right-handed helical flow and right-anterior flow jets (n = 11), whereas right and noncoronary fusion gave rise to left-handed helical flow with left-posterior flow jets (n = 4). CONCLUSION: Four-dimensional flow MR imaging showed abnormal helical systolic flow in the ascending aorta of patients with a BAV, including those without aneurysm or aortic stenosis. Identification and characterization of eccentric flow jets in these patients may help identify those at risk for development of ascending aortic aneurysm.

Clinical evaluation of aortic coarctation with 4D flow MR imaging.

PURPOSE: To show that 4D Flow is a clinically viable tool for evaluation of collateral blood flow and demonstration of distorted blood flow patterns in patients with treated and untreated aortic coarctation. MATERIALS AND METHODS: Time-resolved, 3D phase contrast magnetic resonance imaging (MRI) (4D Flow) was used to assess blood flow in the thoracic aorta of 34 individuals: 26 patients with coarctation (22 after surgery or stent placement) and eight healthy volunteers. RESULTS: Direct comparison of blood flow calculated with 2D and 4D phase contrast data at standard levels for analysis in coarctation patients showed good correlation and agreement (correlation coefficient r = 0.99, limits of agreement = -20% to 20% for collateral blood flow calculations). Abnormal blood flow patterns were demonstrated at peak systole with 4D Flow visualization techniques in the descending thoracic aorta of patients but not volunteers. Marked helical flow was seen in 9 of 13 patients with angulated aortic arch geometries after coarctation repair. Vortical flow was seen in regions of poststenotic dilation. CONCLUSION: 4D Flow is a fast and reliable means of evaluating collateral blood flow in patients with aortic coarctation in order to establish hemodynamic significance. It also can detect distorted blood flow patterns in the descending aorta after coarctation repair.

Transition and transfer from pediatric to adult care of young adults with complex congenital heart disease.

Many children with complex congenital heart disease are now surviving childhood with the potential to live meaningful and productive adult lives. The process of transitioning or preparing patients and families for transfer from pediatric to adult care is challenging and rarely implemented properly. An inadequate transition process results in delayed and inappropriate care, improper timing of transfer, and undue emotional and financial stress on the patients, their families, and the health care system. At worst, patients are lost to appropriate follow-up. This article discusses the general principles of transition and transfer for young adults with chronic illness, highlights the needs of young adults with congenital heart disease, discusses the barriers to transition, and proposes goals and key elements of a formal transition program.

Attitude toward and current practice of transfer and transition of adolescents with congenital heart disease in the United States of America and Europe.

The objective of this study was to explore the current practice and attitudes of pediatric cardiologists in the United States and Europe on the transfer and transition of children with congenital heart disease (CHD). A survey among pediatric cardiology programs in the United States and Europe was undertaken. Sixty-nine centers completed and returned the 61-item questionnaire that was specifically devised for this survey. Of 69 participating centers, 74% reported that they transfer their patients to adult-focused care. When a center transfers its patients, 80% transfer them to a formalized Adult Congenital Heart Disease Program. The median age of transfer is 18 years. Comorbidities, pregnancy, and patient/family request to leave pediatric cardiology were identified as initiators for transfer. Complexity of the heart defect was relatively less important when deciding whether to transfer patients. Only one-third of the centers that transfer their patients provide a structured preparation for patients and family. Development of a formal transition program is planned at 59% of the centers that transfer patients. In conclusion, timely transfer and a structured transition process of children with CHD are not implemented in all pediatric cardiology programs. Health-care providers working in pediatric cardiology should make their transfer policies explicit and transition programs ought to be developed.