Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Cardiac magnetic resonance parameters associated with successful conversion from a single ventricular to a one-and-a-half or biventricular circulation in patients with a hypoplastic right ventricle.

BACKGROUND: Some patients with pulmonary atresia with an intact ventricular septum (PA/IVS) or a left ventricle dominant atrioventricular canal defect (LDAVC) with a hypoplastic right ventricle (RV) and univentricular (1 V) circulation may be candidates for conversion to either a complete biventricular (2 V) repair or a one-and-a-half ventricle repair (1.5 V). We sought to identify pre-operative cardiovascular magnetic resonance (CMR) findings associated with successful conversion from 1V to 1.5V or 2V circulation. METHODS: In this single center retrospective study, subjects with PA/IVS or LDAVC and no conotruncal abnormalities were included if they had a 1 V circulation at the time of CMR followed by a surgical intervention intended to convert them to a 1.5 V or 2 V circulation. Conversion failure was defined as any of the following: (1) oxygen saturation < 90% at the most recent follow-up, (2) conversion back to a 1.5 V or 1 V circulation, or (3) death. RESULTS: In the PA/IVS cohort (n = 15, median age 1.32 years), 10 patients underwent surgical conversion to a 1.5 V circulation and 5 to a 2 V circulation. In the attempted 1.5 V group, there were 2 failures, and these cases had a lower RV mass (p = 0.04). In the attempted 2 V group, there was 1 failure, and no CMR parameters were significantly different compared to the successes. Among the successful 2 V group patients, the minimum RV end-diastolic volume (EDV) was 27 ml/m2. In the LDAVC cohort (n = 15, median age 1.0 years), 1 patient underwent surgical conversion to a 1.5 V circulation and 14 patients to a 2 V circulation. In the attempted 1.5 V group, the 1 conversion was a failure and had an RV EDV of 15 ml/m2. In the attempted 2 V group, there were 2 failures, and these cases had a smaller RV:LV stroke volume ratio (p = 0.05) and a lower RV ejection fraction (p = 0.05) compared to the successes. Among the successful 2 V group patients, the minimum RV EDV was 22 ml/m2. CONCLUSIONS: We identified multiple CMR parameters associated with successful conversion from 1 V circulation to 1.5 V or 2 V circulation in patients with PA/IVS and LDAVC. This information may improve patient selection for conversion procedures and encourage larger studies to better define the role of CMR.

Delayed Presentation of Traumatic Pericardial Rupture: Diagnostic and Surgical Considerations for Treatment.

Traumatic pericardial rupture is a rare event with high mortality. We present the case of a 15-year-old boy who sustained thoracic and abdominal trauma secondary to motor vehicle collision, with a delayed diagnosis of traumatic pericardial rupture with cardiac herniation. Out of concern for torsion and hemodynamic collapse, surgical repair was advised. We have developed a novel surgical approach to this rare condition, utilizing a combination of thoracoscopic and open surgical techniques. The guiding principles of our repair include the utilization of fenestrated pieces of bovine pericardium to create a tension free repair, minimizing the likelihood of pericardial effusion, and returning the cardiac mass to normal anatomic position.

A Method to Account for Variation in Congenital Heart Surgery Length of Stay.

OBJECTIVES: We sought to develop a risk-adjustment methodology for length of stay in congenital heart surgery, as none exist. DESIGN: Prospective cohort analysis combined with previously obtained retrospective cohort analysis of a Department of Cardiovascular Surgery clinical database. PATIENTS: Patients discharged from Boston Children's Hospital between October 1, 2006, and May 31, 2014, that underwent a congenital heart surgery procedure(s) linked to one of 103 surgical procedure types. MEASUREMENTS AND MAIN RESULTS: Six thousand two hundred nine discharges during the reporting period at Boston Children's Hospital comprised the cohort. Seven Surgical Length Categories were developed to group surgical procedure types. A multivariable model for outcome length of stay was built using a derivation cohort consisting of a 75% random sample, starting with Surgical Length Categories and considering additional a priori factors. Postoperative factors were then added to improve predictive performance. The remaining 25% of the cohort was used to validate the multivariable models. The coefficient of determination (R) was used to estimate the variability in length of stay explained by each factor. The Surgical Length Categories yielded an R of 42%. Model performance increased when the a priori factors preoperative status, noncardiac abnormality, genetic anomaly, preoperative catheterization during episode of care, weight less than 3 kg, and preoperative vasoactive support medication were introduced to the model (R = 60.8%). Model performance further improved when postoperative ventilation greater than 7 days, operating room time, postoperative catheterization during episode of care, postoperative reintubation, number of postoperative vasoactive support medications, postoperative ICU infection, and greater than or equal to one secondary surgical procedure were added (R = 76.7%). The validation cohort yielded an R of 76.5%. CONCLUSIONS: We developed a statistically valid procedure-based categorical variable and multivariable model for length of stay of congenital heart surgeries. The Surgical Length Categories and important a priori and postoperative factors may be used to pursue a predictive tool for length of stay to inform scheduling and bed management practices.

Advances in pediatric cardiac MRI.

PURPOSE OF REVIEW: Spurred by numerous recent technological advances, cardiac MRI (CMR) is now the gold standard for anatomic evaluation, quantitative assessment of chamber size and function, flow quantification, and tissue characterization. This review focuses on recent advances in pediatric and congenital CMR, highlighting recent safety data, and discussing future directions. RECENT FINDINGS: CMR has become an important component of risk stratification and procedural planning in numerous congenital and pediatric heart diseases. Innovative approaches to image acquisition and reconstruction are leading the way toward fast, high-resolution, three- and four-dimensional datasets for delineation of cardiac anatomy, function, and flow. In addition, techniques for assessing the composition of the myocardium may help elucidate the pathophysiology of late complications, identify patients at risk for heart failure, and assist in the evaluation of therapeutic strategies. SUMMARY: CMR provides invaluable morphologic, hemodynamic, and functional data that help guide diagnosis, assessment, and management of pediatric and adult congenital heart disease. As imaging techniques advance and data accumulate on the relative and additive value of CMR in patient care, its role in a multimodality approach to the care of this population of patients is becoming clear and is likely to continue to evolve.

Transcatheter balloon dilation for recurrent right ventricular outflow tract obstruction following valve-sparing repair of tetralogy of Fallot.

BACKGROUND: Valve-sparing repair in patients with tetralogy of Fallot (TOF) carries the risk of residual or recurrent right ventricular outflow tract (RVOT) obstruction, which is often treated with transcatheter balloon dilation (BD). The outcomes and associated complications of BD of the RVOT in this scenario remain unknown. METHODS: Retrospective review of the records of the Department of Cardiology at Boston Children's Hospital from 2000 to 2013 was performed. RESULTS: 34 patients had initial valve-sparing repair of tetralogy of Fallot followed by BD of the RVOT during the study period. Following BD, the RVOT gradient decreased from a median of 43 mm Hg (range 13 to 79 mm Hg) to 28 mm Hg (range 0 to 73 mm Hg) (P < 0.001). Freedom from reintervention was 64% at 1 year and 46% at 3 years. Trivial to mild PR pre-BD was present in 56% (n = 19) of patients and decreased to 37% (n = 11) post-BD. Exclusively valvar obstruction was associated with a longer freedom from reintervention (P = 0.05), while a ratio of RV pressure to aortic systolic pressure pre-BD of >1 and a final RVOT gradient of ≥40 post-BD were associated with shorter freedom from reintervention (P < 0.001). CONCLUSION: BD in patients with recurrent RVOT obstruction following valve-sparing repair of TOF acutely reduces the RVOT gradient, but commonly results in increased PR and is associated with a high reintervention rate. Patients with stenosis solely at the level of the valve had a better response to this type of intervention.

Cardiovascular magnetic resonance techniques and findings in children with myocarditis: a multicenter retrospective study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used to diagnose myocarditis in adults but its use in children is not well-established. We sought to describe the presentation, CMR protocol and findings, and outcomes in a multicenter cohort of children with myocarditis. METHODS: Thirteen hospitals retrospectively identified patients meeting the following inclusion criteria: 1) diagnosis of myocarditis by the managing physicians, 2) age <21 years, 3) CMR examination within 30 days of presentation, and 4) no congenital heart disease. Clinical data and test results, including CMR findings, were abstracted from the medical record. RESULTS: For the 143 patients meeting inclusion criteria, the median age was 16.0 years (range, 0.1-20.3) and 139 (97 %) were hospitalized at the time of CMR. The median time from presentation to CMR was 2 days (0-28). The median left ventricular ejection fraction at CMR was 56 % (10-74), with 29 (20 %) below 45 %. The median right ventricular ejection fraction was 54 % (15-72), with 11 (8 %) below 40 %. There was significant variability among centers in the types of tissue characterization techniques employed (p < 0.001). Overall, late gadolinium enhancement (LGE) was used in 100 % of studies, followed by T2-weighted imaging (T2W) in 69 %, first-pass contrast perfusion (FPP) in 48 %, and early gadolinium enhancement (EGE) in 28 %. Abnormalities were most common with LGE (81 %), followed by T2W (74 %), EGE (55 %), and FPP (8 %). The CMR study was interpreted as positive for myocarditis in 117 patients (82 %), negative in 18 (13 %), and equivocal in 7 (5 %), yielding a sensitivity of 82 %. At a median follow-up of 7.1 months (0-87), all patients were alive and 5 had undergone cardiac transplantation. CMR parameters at presentation associated with persistent left ventricular dysfunction were larger left ventricular end-diastolic volume and lower left and right ventricular ejection fraction but not abnormal LGE. CONCLUSIONS: Despite significant practice variation in imaging protocol among centers, CMR had a high sensitivity for the diagnosis of myocarditis in pediatric patients. Abnormalities were most often seen with LGE followed by T2W, EGE, and FPP. These findings should be useful in designing future prospective studies.

Left Ventricular Remodeling and Function in Children with Biventricular Circulation After Fetal Aortic Valvuloplasty.

Fetal aortic valvuloplasty (FAV) has shown promise in averting the progression of fetal aortic stenosis to hypoplastic left-heart syndrome. Altered loading conditions due to valvar disease, intrinsic endomyocardial abnormalities, and procedures that alter endomyocardial mechanics may place patients with biventricular circulation (BiV) after FAV at risk of abnormal LV remodeling and function. Using the most recent echo data on BiV patients after technically successful FAV (n = 34), we evaluated LV remodeling pattern, risk factors for pathologic LV remodeling, and the association between LV remodeling pattern and LV function. Median age at follow-up was 4.7 years (range 1.0-12.5). Cardiac interventions were common. At latest follow-up, no patient had hypoplastic LV. Nineteen patients (55 %) had dilated LV, and five (16 %) patients had severely dilated LV. LV remodeling patterns were as follows: 12 (35 %) normal ventricle, 11 (32 %) mixed hypertrophy, 8 (24 %) eccentric hypertrophy or remodeling, and 3 (9 %) concentric hypertrophy. Univariate factors associated with pathologic LV remodeling were long-standing AR, ≥2 cardiac interventions, EFE resection, and aortic or mitral regurgitation ≥ moderate at most recent follow-up. In multivariate analysis, only long-standing AR fraction remained associated with pathologic remodeling. Pathologic LV remodeling was associated with depressed ejection fraction, lower septal E´, and higher E/E´. Pathologic LV remodeling, primarily eccentric or mixed hypertrophy, is common in BiV patients after FAV and is related to LV loading conditions imposed by valvar disease. Pathologic remodeling is associated with both systolic and diastolic dysfunction in this population.

Development of a charge adjustment model for cardiac catheterization.

A methodology that would allow for comparison of charges across institutions has not been developed for catheterization in congenital heart disease. A single institution catheterization database with prospectively collected case characteristics was linked to hospital charges related and limited to an episode of care in the catheterization laboratory for fiscal years 2008-2010. Catheterization charge categories (CCC) were developed to group types of catheterization procedures using a combination of empiric data and expert consensus. A multivariable model with outcome charges was created using CCC and additional patient and procedural characteristics. In 3 fiscal years, 3,839 cases were available for analysis. Forty catheterization procedure types were categorized into 7 CCC yielding a grouper variable with an R (2) explanatory value of 72.6%. In the final CCC, the largest proportion of cases was in CCC 2 (34%), which included diagnostic cases without intervention. Biopsy cases were isolated in CCC 1 (12%), and percutaneous pulmonary valve placement alone made up CCC 7 (2%). The final model included CCC, number of interventions, and cardiac diagnosis (R (2) = 74.2%). Additionally, current financial metrics such as APR-DRG severity of illness and case mix index demonstrated a lack of correlation with CCC. We have developed a catheterization procedure type financial grouper that accounts for the diverse case population encountered in catheterization for congenital heart disease. CCC and our multivariable model could be used to understand financial characteristics of a population at a single point in time, longitudinally, and to compare populations.

MRI guided iron assessment and oral chelator use improve iron status in thalassemia major patients.

Oral iron chelators and magnetic resonance imaging (MRI) assessment of heart and liver iron burden have become widely available since the mid 2000s, allowing for improved patient compliance with chelation and noninvasive monitoring of iron levels for titration of therapy. We evaluated the impact of these changes in our center for patients with thalassemia major and transfusional iron overload. This single center, retrospective observational study covered the period from 2005 through 2012. Liver iron content (LIC) was estimated both by a T2* method and by R2 (Ferriscan® ) technique. Cardiac iron was assessed as cT2*. Forty-two patients (55% male) with transfused thalassemia and at least two MRIs were included (median age at first MRI, 17.5 y). Over a mean follow-up period of 5.2 ± 1.9 y, 190 MRIs were performed (median 4.5 per patient). Comparing baseline to last MRI, 63% of patients remained within target ranges for cT2* and LIC, and 13% improved from high values to the target range. Both the median LIC and cT2* (cR2* = 1000/cT2*) status improved over time: LIC 7.3 to 4.5 mg/g dry weight, P = 0.0004; cR2* 33.4 to 28.3 Hz, P = 0.01. Individual responses varied widely. Two patients died of heart failure during the study period. Annual MRI iron assessments and availability of oral chelators both facilitate changes in chelation dose and strategies to optimize care.

Cardiovascular magnetic resonance parameters associated with early transplant-free survival in children with small left hearts following conversion from a univentricular to biventricular circulation.

BACKGROUND: We sought to identify cardiovascular magnetic resonance (CMR) parameters associated with successful univentricular to biventricular conversion in patients with small left hearts. METHODS: Patients with small left heart structures and a univentricular circulation who underwent CMR prior to biventricular conversion were retrospectively identified and divided into 2 anatomic groups: 1) borderline hypoplastic left heart structures (BHLHS), and 2) right-dominant atrioventricular canal (RDAVC). The primary outcome variable was transplant-free survival with a biventricular circulation. RESULTS: In the BHLHS group (n = 22), 16 patients (73%) survived with a biventricular circulation over a median follow-up of 40 months (4-84). Survival was associated with a larger CMR left ventricular (LV) end-diastolic volume (EDV) (p = 0.001), higher LV-to-right ventricle (RV) stroke volume ratio (p < 0.001), and higher mitral-to-tricuspid inflow ratio (p = 0.04). For predicting biventricular survival, the addition of CMR threshold values to echocardiographic LV EDV improved sensitivity from 75% to 93% while maintaining specificity at 100%. In the RDAVC group (n = 10), 9 patients (90%) survived with a biventricular circulation over a median follow-up of 29 months (3-51). The minimum CMR values were a LV EDV of 22 ml/m² and a LV-to-RV stroke volume ratio of 0.19. CONCLUSIONS: In BHLHS patients, a larger LV EDV, LV-to-RV stroke volume ratio, and mitral-to-tricuspid inflow ratio were associated with successful biventricular conversion. The addition of CMR parameters to echocardiographic measurements improved the sensitivity for predicting successful conversion. In RDAVC patients, the high success rate precluded discriminant analysis, but a range of CMR parameters permitting biventricular conversion were identified.

Interstudy variability in cardiac magnetic resonance imaging measurements of ventricular volume, mass, and ejection fraction in repaired tetralogy of Fallot: a prospective observational study.

PURPOSE: To assess the interstudy variability of cardiac magnetic resonance imaging (CMR) parameters of ventricular size and function in repaired tetralogy of Fallot (TOF). MATERIALS AND METHODS: Patients with TOF (n = 30, median age 23.5 years, 43% male) were enrolled prospectively. Each patient underwent two consecutive CMR examinations on the same day. Each examination was analyzed for ventricular size and function by two observers and multiple comparisons were made with assessment of agreement using Bland-Altman analysis and intraclass correlation coefficients (ICC). RESULTS: Agreement for most measures of ventricular size and function was high when a single observer analyzed both studies. Agreement was worse when different observers analyzed sequential studies. This effect was most prominent on measurements of right ventricular (RV) mass and there was slight improvement when mass was measured during systole. Aside from ventricular mass, agreement was similar for RV and left ventricular (LV) parameters. CONCLUSION: CMR measures of ventricular size and function have acceptable repeatability across serial examinations in patients with repaired TOF. Measurements of RV mass are subject to higher variability. For most parameters, agreement limits are wider when measurements are performed by multiple operators. These results will aid in the interpretation of study-to-study variations in the follow-up of individual patients and in designing future clinical trials.

Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616.

BACKGROUND: MK-0616 is an oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of hypercholesterolemia. OBJECTIVES: This Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia. METHODS: This trial was planned to include 375 adult participants with a wide range of atherosclerotic cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The primary endpoints included percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the 8-week treatment period. RESULTS: Of the 381 participants randomized, 49% were female, and the median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group. CONCLUSIONS: MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia [MK-0616-008]; NCT05261126).

Factors associated with morbidity, mortality, and hemodynamic failure after biventricular conversion in borderline hypoplastic left hearts.

OBJECTIVE: A subset of patients with borderline hypoplastic left heart may be candidates for single to biventricular conversion, but long-term morbidity and mortality persist. Prior studies have shown conflicting results regarding the association of preoperative diastolic dysfunction and outcome, and patient selection remains challenging. METHODS: Patients with borderline hypoplastic left heart undergoing biventricular conversion from 2005 to 2017 were included. Cox regression identified preoperative factors associated with a composite outcome of time to mortality, heart transplant, takedown to single ventricle circulation, or hemodynamic failure (defined as left ventricular end-diastolic pressure >20 mm Hg, mean pulmonary artery pressure >35 mm Hg, or pulmonary vascular resistance >6 international Woods units). RESULTS: Among 43 patients, 20 (46%) met the outcome, with a median time to outcome of 5.2 years. On univariate analysis, endocardial fibroelastosis, lower left ventricular end-diastolic volume/body surface area (when <50 mL/m2), lower left ventricular stroke volume/body surface area (when <32 mL/m2), and lower left:right ventricular stroke volume ratio (when <0.7) were associated with outcome; higher preoperative left ventricular end-diastolic pressure was not. Multivariable analysis demonstrated that endocardial fibroelastosis (hazard ratio, 5.1, 95% confidence interval, 1.5-22.7, P = .033) and left ventricular stroke volume/body surface area 28 mL/m2 or less (hazard ratio, 4.3, 95% confidence interval, 1.5-12.3, P = .006) were independently associated with a higher hazard of the outcome. Approximately all patients (86%) with endocardial fibroelastosis and left ventricular stroke volume/body surface area 28 mL/m2 or less met the outcome compared with 10% of those without endocardial fibroelastosis and with higher stroke volume/body surface area. CONCLUSIONS: History of endocardial fibroelastosis and smaller left ventricular stroke volume/body surface area are independent factors associated with adverse outcomes among patients with borderline hypoplastic left heart undergoing biventricular conversion. Normal preoperative left ventricular end-diastolic pressure is insufficient to reassure against diastolic dysfunction after biventricular conversion.

Natural history of exercise function in patients with Ebstein anomaly: A serial study.

BACKGROUND: The clinical manifestations of Ebstein anomaly (EA) vary greatly; criteria for surgical intervention remain undefined. Decisions regarding surgical intervention in asymptomatic/mildly symptomatic patients would be helpfully informed by a detailed, quantitative understanding of the natural history of exercise intolerance in these patients. However, past studies of exercise function in EA have been of a cross-sectional, rather than a serial, nature. We, therefore, analyzed serial cardiopulmonary exercise (CPX) tests from patients with unrepaired EA to better appreciate the natural history of their exercise function. METHODS: All patients with EA who had had at least 2 CPX tests, separated by at least 6 months, between November 2002 and October 2010 were identified. Patients with prior tricuspid valve surgery were excluded from the study. RESULTS: Cardiopulmonary exercise data from 23 patients (64 CPX tests; 2.8 ± 1.0 tests/patient) were analyzed. The median time interval between the first and last CPX tests was 3.3 (range, 0.6-7.3) years. The percentage of predicted peak oxygen consumption declined slowly (1.87 ± 8.04 percentage points/y) during the follow-up period. The decline was more pronounced (3.04 ± 6.78 percentage points/y) in patients <18 years old. On multivariate modeling, only the change in oxygen pulse at peak exercise (a surrogate for forward stroke volume) and the change in peak heart rate over time emerged as statistically significant correlates of the change in percentage of predicted peak oxygen consumption. CONCLUSION: The exercise function of patients with EA tends to deteriorate over time. This deterioration appears to be related to a progressive decline in their ability to augment their forward stroke volume and heart rate during exercise.

N-terminal pro-B-type natriuretic peptide testing patterns in patients with heart failure with reduced ejection fraction.

AIMS: The N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a commonly used biomarker in heart failure for diagnosis and prognostication. We aimed to determine the prevalence of NT-proBNP testing, distribution of NT-proBNP concentrations, and factors associated with receiving an NT-proBNP test in patients with heart failure with reduced ejection fraction (HFrEF), including the subset with a worsening heart failure event (WHFE). METHODS AND RESULTS: This was a retrospective cohort study using two US databases: (i) the de-identified Humana Research Database between January 2015 and December 2018 and (ii) the Veradigm PINNACLE Registry® between July 2013 and September 2017. We included adult patients with a confirmed diagnosis of HFrEF. In each data source, a subgroup of patients with a WHFE was identified, where a WHFE was defined as a heart failure-related hospitalization or receipt of intravenous diuretics. Bivariate and multivariate analyses were conducted to assess factors associated with receiving NT-proBNP testing. In Cohort 1 (n = 249 238), 9.2% of patients with HFrEF and 10.8% of patients with a WHFE received NT-proBNP testing. When restricted to patients with at least one laboratory claim, 11.3% of patients with HFrEF and 13.2% of those with a WHFE received NT-proBNP testing. In Cohort 2 (n = 91 444), 2.3% of patients with HFrEF were tested. Median (inter-quartile range) NT-proBNP concentrations among patients with HFrEF were 1399 (423-4087) pg/mL in Cohort 1 and 394 (142-688) pg/mL in Cohort 2. Median (inter-quartile range) NT-proBNP concentrations in the subset of patients with a WHFE in each cohort were 2209 (740-5894) and 464 (174-783) pg/mL, respectively. In Cohort 1, 13.4% of all HFrEF patients receiving NT-proBNP testing and 18.9% of patients with a WHFE had NT-proBNP values >8000 pg/mL; in Cohort 2, these percentages were 1.0% and 2.5%, respectively. CONCLUSIONS: In US clinical practice, NT-proBNP testing was not frequently performed in patients with HFrEF. NT-proBNP concentrations varied across data sources and subpopulations within HFrEF.

Practice variability and outcomes of coil embolization of aortopulmonary collaterals before Fontan completion: a report from the Pediatric Heart Network Fontan Cross-Sectional Study.

BACKGROUND: The practice of coiling aortopulmonary collaterals (APCs) before Fontan completion is controversial, and published data are limited. We sought to compare outcomes in subjects with and without pre-Fontan coil embolization of APCs using the Pediatric Heart Network Fontan Cross-Sectional Study database which enrolled survivors of prior Fontan palliation. METHODS: We compared hospital length of stay after Fontan in 80 subjects who underwent APC coiling with 459 subjects who did not. Secondary outcomes included post-Fontan complications and assessment of health status and ventricular performance at cross-sectional evaluation (mean 8.6 ± 3.4 years after Fontan). RESULTS: Centers varied markedly in frequency of pre-Fontan APC coiling (range 0%-30% of subjects, P < .001). The coil group was older at Fontan (P = .004) and more likely to have single right ventricular morphology (P = .054) and pre-Fontan atrioventricular valve regurgitation (P = .03). The coil group underwent Fontan surgery more recently (P < .001), was more likely to have a prior superior cavopulmonary anastomosis (P < .001), and more likely to undergo extracardiac Fontan connection (P < .001) and surgical fenestration (P < .001). In multivariable analyses, APC coiling was not associated with length of stay (hazard ratio for remaining in-hospital 0.91, 95% CI 0.70-1.18, P = .48) or postoperative complications, except more post-Fontan catheter interventions (hazard ratio 1.74, 95% CI 1.04-2.91, P = .03), primarily additional APC coils. The groups had similar outcomes at cross-sectional evaluation. CONCLUSION: Management of APCs before Fontan shows marked practice variation. We did not find an association between pre-Fontan coiling of APCs and shorter postoperative hospital stay or with better late outcomes. Prospective studies of this practice are needed.

What is the clinical utility of routine cardiac catheterization before a Fontan operation?

Patients with single-ventricle circulation presenting for Fontan completion routinely undergo cardiac catheterization despite ongoing debate concerning its additive value. Increasing interest in noninvasive preoperative evaluation alone led the authors to analyze the utility of routine pre-Fontan catheterization and to determine whether a subset of patients could avoid this invasive procedure. Patients younger than 5 years referred for pre-Fontan evaluation were retrospectively reviewed. Medical records and catheter angiograms were examined, and catheterizations were categorized as "additive" based on predetermined criteria. Associations between precatheterization variables, catheterization findings, and short-term postoperative outcomes were evaluated. Cardiac catheterization was clinically nonadditive for 89 of 175 patients undergoing pre-Fontan evaluation (51%). There were no robust precatheterization predictors of a nonadditive catheterization. Echocardiography did not fully demonstrate the relevant anatomy of 115 patients (66%), most frequently due to inadequate visualization of the pulmonary arteries, and 22 patients had additive catheterizations due to new diagnostic findings alone. Interventions at catheterization were frequent and deemed "important" for 64 patients (37%). Catheterization hemodynamic data were not associated with early postoperative outcomes. Minor catheterization complications occurred for 51 patients (29%) and major complications for 4 patients (2%). Although at least 50% of the patients presenting for Fontan completion may be able to avoid routine catheterization safely, an echocardiography-based imaging strategy alone is insufficient to allow proper identification of those who could be evaluated noninvasively. A more comprehensive imaging strategy not based solely on echocardiography should be considered.

Changes in Prognosis of Heterotaxy Syndrome Over Time.

BACKGROUND: Long-term outcomes in heterotaxy syndrome (HS) are poorly described. Some reports suggest improved survival in the recent era, whereas others do not. We sought to describe long-term outcomes and assess whether outcomes have changed over time. METHODS: Patients with HS born between 1985 and 2014 who had cardiac care (except initial palliation) at our institution were divided into 4 birth eras and survival over time was compared. Independent risk factors for mortality were identified by using Cox proportional hazards regression. In patients who underwent surgery, association between surgical pathway (univentricular versus biventricular repair) and mortality after adjusting for baseline confounders was evaluated. A risk stratification model was created by using classification and regression analysis. RESULTS: Among 264 patients, 118 (44.7%) had asplenia and 146 (55.3%) had polysplenia syndrome. Overall mortality was 40.2% (n = 106), with median follow-up of 10.2 years (longest 31.5 years). In multivariable analysis, pulmonary vein stenosis, coarctation, univentricular circulation, asplenia phenotype, and at least mild atrioventricular valve regurgitation at presentation were associated with mortality, whereas birth era was not. Among patients who underwent surgery, univentricular repair remained associated with mortality after adjustment. In classification and regression analysis, patients with biventricular circulation (especially those with polysplenia) had lower mortality than those with univentricular circulation. CONCLUSIONS: In this large retrospective study of HS, outcomes remain poor and have not improved since the early 1990s. We identified risks factors associated with earlier mortality and found that those with univentricular circulation and totally anomalous pulmonary venous connection had the worst prognosis. Survival was higher in those with biventricular circulation.

Repair of double outlet right ventricle: Midterm outcomes.

OBJECTIVE: Double outlet right ventricle (DORV) is a complex cardiac malformation with many anatomic variations and various approaches for surgical repair. This study aimed to describe the clinical outcomes of biventricular (BiV) repair for DORV. METHODS: Patients with DORV, who underwent BiV repair between January 2000 and December 2017 were retrospectively reviewed. Group 1 underwent primary BiV repair, whereas group 2 underwent staged BiV repair over a series of operations. The decision to pursue staged approach included complexity of intracardiac anatomy, age of the patient, and the size and function of the ventricles and the atrioventricular valves. Time-dependent surgical reintervention for LVOTO and mortality were evaluated using Kaplan-Meier survival analysis. RESULTS: A total of 238 patients with DORV underwent BiV repair at a median age of 6.2 months (range, 1.1 month-27.5 years) (158 in group 1, 80 in group 2). Twenty-two patients (7.8%) required surgical reintervention within 30 days of BiV repair. Overall survival at 5 years was 89.0%. Freedom from LVOTO reoperation at 5 years was 84%. Primary outcomes were not significantly different between groups. CAVC repair and right ventricle to pulmonary artery conduit at BiV repair were associated with higher surgical reintervention (hazard ratio, 2.9 and 1.75, respectively). CONCLUSIONS: Patients with DORV and complex anatomy may undergo staged BiV repair with acceptable outcomes. Although LVOTO is a potential complication in these patients, the rate of surgical reintervention for LVOTO does not differ significantly from patients undergoing primary BiV repair.