Patrick W. O’Leary

Usefulness of the myocardial performance index for assessing right ventricular function in congenital heart disease.

Quantitative assessment of ventricular function in patients with congenital heart disease is often challenging due to distorted ventricular geometry. A myocardial performance index (MPI) has been reported in adults and children that is a Doppler-derived nongeometric measure of ventricular function. The MPI measures the ratio of isovolumic time intervals (isovolumic contraction time and isovolumic relaxation time) to ventricular ejection time. The effects of altered ventricular preload or afterload on the MPI have yet to be determined. This study assesses the impact of altered preload or afterload on right ventricular (RV) function and the RV MPI in the clinical setting of congenital heart disease. Patient groups were compared with normal pediatric and adult populations before and after repair of their congenital heart lesion. Patients with large atrial septal defects (ASDs) represented the clinical setting of increased ventricular preload, whereas patients with isolated pulmonary valve stenosis represented increased RV afterload. Patients with congenitally corrected transposition of the great arteries (CC-TGA) with severe left atrioventricular valve regurgitation represented a combined increase in RV preload and afterload. The RV MPI in 152 normal children (ages 3 to 18 years) and 37 adults (ages 18 to 51 years) was 0.32 +/- 0.03 and 0.28 +/- 0.04, respectively. In pediatric patients (n = 45) and adult patients (n = 40) with ASD, the RV MPI was 0.35 +/- 0.09 (p = NS) and 0.38 +/- 0.04 (p < 0.01 compared with normal adults), respectively. Patients with pulmonary stenosis (n = 21, ages 1 day to 19 years) had a RV MPI of 0.32 +/- 0.06 (p = NS). CC-TGA patients had a RV MPI of 0.72 +/- 0.17 (p < 0.001). No significant change in the RV MPI was seen in any postoperative patient group despite relief of RV volume or pressure overload. Thus, the MPI is a quantitative measure of RV performance that is appears to be relatively independent of changes in preload or afterload in the clinical setting.

40-Year Follow-Up After the Fontan Operation: Long-Term Outcomes of 1,052 Patients.

BACKGROUND There are limited long-term, single-cohort, follow-up studies available about patients after the Fontan operation. OBJECTIVES This study sought to determine the long-term outcome of all patients who had a Fontan operation at the Mayo Clinic. METHODS Records of all patients who had a modified Fontan operation between 1973 and 2012 were reviewed. A follow-up questionnaire was mailed to all patients alive at the time of the study. RESULTS Overall, 10-, 20-, and 30-year survival for 1,052 patients was 74%, 61%, and 43%, respectively. Factors associated with decreased overall or late survival in multivariate analysis included pre-operative diuretic use, longer cardiopulmonary bypass time, operation prior to 1991, atrioventricular valve (AVV) replacement at the time of Fontan operation, elevated post-bypass Fontan (>20 mm Hg) or left atrial (>13 mm Hg) pressures, prolonged chest tube drainage (>21 days), post-operative ventricular arrhythmias, renal insufficiency, and development of protein-losing enteropathy (PLE). Pre-operative and intraoperative sinus rhythm were associated with improved survival. Long-term survival was similar for patients regardless of ventricular morphology. The most common reoperations were pacemaker insertion/revision in 212 patients (20%), Fontan revision/conversion in 117 patients (11%), and AVV repair/replacement in 66 patients (5%). Clinically significant late atrial or ventricular arrhythmias occurred in 468 patients (44%). Ninety-five patients (9%) developed PLE, and 5-, 10-, and 20-year survival after diagnosis of PLE was 50%, 35%, and 19%, respectively. CONCLUSIONS As the surgical techniques for the Fontan operation have changed over the last 40 years, survival has improved. However, development of PLE and arrhythmias and the need for reoperation during long-term follow-up pose significant management challenges.

Late results of bioprosthetic tricuspid valve replacement in Ebstein’s anomaly

BACKGROUND Historically, porcine bioprosthetic valves have poor durability in pediatric patients; nearly half will require replacement within 5 years. However, our early experience with patients having Ebsteins anomaly suggests that tricuspid bioprostheses in this anomaly might have better durability. METHODS One hundred fifty-eight patients who received a primary tricuspid bioprosthesis because of tricuspid valve anatomy unsuitable for repair between April 1972 and January 1997 were reviewed. Results were analyzed and Kaplan-Meier curves were constructed to estimate patient survival and probability of remaining free of reoperation. RESULTS Follow-up of 149 patients (94.3%) who survived 30 days ranged up to 17.8 years (mean, 4.5 years). Ten-year survival was 92.5%+/-2.5% (SE), 129 late survivors (92.1%) were in New York Heart Association class I or II, and 93.6% were free of anticoagulation. Freedom from bioprosthesis replacement was 97.5%+/-1.9% at 5 years and 80.6%+/-7.6% at 10 and 15 years. CONCLUSIONS Bioprosthesis durability in the tricuspid position in patients with Ebsteins anomaly compares very favorably with bioprosthesis durability in other cardiac valve positions, especially for pediatric patients, and also compares favorably with tricuspid bioprosthesis durability in patients with other diagnoses.

Partial Anomalous Pulmonary Venous Connection: Diagnosis by Transesophageal Echocardiography

OBJECTIVE This study sought to demonstrate that with proper technique, identification of the normal and abnormal pulmonary venous connection can be made with confidence using transesophageal echocardiography (TEE). BACKGROUND Partial anomalous pulmonary venous connection (PAPVC) is an uncommon congenital anomaly whose diagnosis has classically been made using angiography. METHODS We performed a retrospective review of all patients of all ages with PAPVC diagnosed at the Mayo Clinic who had undergone TEE because of either right ventricular volume overload or suspected intracardiac shunting by transthoracic echocardiography or intraoperatively. RESULTS A total of 66 PAPVCs were detected in 43 patients (1.5/patient); in 2 additional patients, TEE suggested, but did not diagnose, PAPVCs. Shortness of breath was the most common presenting symptom (42.2%), followed by heart murmur and supraventricular tachycardia. Right-sided anomalous veins were identified in 35 patients (81.4%), left-sided in 7 (16.3%) and bilateral in 1 (2.3%). There was a single anomalous connecting vein in 23 patients (53.5%), two in 18 (41.9%), three in 1 (2.3%) and four in 1 (2.3%). The connecting site was the superior vena cava (SVC) in 39 veins (59.1%), right atrial-SVC junction in 6 (9.1%), right atrium in 8 (12.1%), inferior vena cava in 1 (1.5%) and the coronary sinus in 2 (3.0%). Ten anomalous left pulmonary veins were connected by a vertical vein to the innominate vein (15.1%). Sinus venosus atrial septal defect (ASD) was the most common associated anomaly in 22 patients (49%), followed by ostium secundum ASD in 6 and patent foramen ovale in 4. Fifteen patients had an intact atrial septum. Thirty-one patients (68.8%) underwent surgical repair. PAPVC was confirmed in all patients, including the two whose TEE results were suggestive of PAPVC. All 49 PAPVCs detected by TEE preoperatively were confirmed at the time of operation. CONCLUSIONS TEE is highly diagnostic for PAPVC and can obviate angiography. Accurate anatomic diagnosis may influence the need for medical and surgical management. TEE should be performed in patients with right ventricular volume overload when the precordial examination is inconclusive.

PERCUTANEOUS ECHOCARDIOGRAPHICALLY GUIDED PERICARDIOCENTESIS IN PEDIATRIC PATIENTS : EVALUATION OF SAFETY AND EFFICACY

The purpose of this study was to evaluate the safety and efficacy of echocardiographically (echo) guided pericardiocentesis in pediatric patients. Echo-guided pericardiocenteses performed in pediatric patients (age >/=16 years) at the Mayo Clinic between 1980 and 1997 were identified. Presentation, cause and characteristics of the effusion, details of the pericardiocentesis procedure, and outcome were determined by comprehensive chart review supplemented by telephone interviews when necessary. Seventy-three pediatric patients, median age 6.7 years (range 1 day to 16 years), underwent 94 consecutive echo-guided pericardiocenteses for effusions of various causes. Twenty-one (22%) procedures were performed in children younger than 2 years. All but 1 procedure were successful (99%). A mean fluid volume of 237 mL (range 4 to 970 mL) was withdrawn. Only a single attempt was needed for entry into the pericardial space in 87 (93%) procedures. No deaths were associated with the pericardiocentesis procedure. Only 1 major complication occurred (1%), a pneumothorax requiring chest tube reexpansion. Three (3%) minor complications-2 instances of right ventricular puncture and a small pneumothorax-did not require treatment. Extended catheter drainage for a mean of 5.2 +/- 4.5 days (range 1 to 19 days) was used with 30 (32%) of the 94 procedures. For the 52 patients who underwent pericardiocentesis without catheter drainage as the initial management strategy, 18 required 21 repeat pericardiocenteses for recurrence of effusion. In contrast, for the 21 patients who had pericardial catheterization as the initial management strategy, none had recurrences necessitating a repeat procedure (P <.001). Increased utilization of a pericardial catheter was associated with a concomitant decrease in the number of surgical pericardial procedures over the study period. Echo-guided pericardiocentesis was the only therapeutic modality for the management of effusion in 73% of all patients. Echo-guided pericardiocentesis is safe and effective in pediatric patients, including children younger than 2 years. The increasing use of pericardial catheterization in conjunction with this technique was associated with significant reduction of recurrence and decreased frequency of surgical interventions for treatment of pericardial effusion. Echo-guided pericardiocentesis with extended catheter drainage should be considered as primary management strategy for clinically significant pericardial effusions in pediatric patients.

Remote Telemedical Interpretation of Neonatal Echocardiograms: Impact on Clinical Management in a Primary Care Setting

OBJECTIVE The purpose of this study was to evaluate the utility of telemedical echocardiographically assisted neonatal cardiovascular evaluation in a primary care setting. BACKGROUND Neonates with congenital heart disease are frequently born far from pediatric subspecialty centers and can be clinically unstable at presentation. Recent advances in telecommunication technology have made it possible to transmit echocardiographic images over long distances. This technology may be beneficial to newborns with heart defects who are born in primary care centers. METHODS A retrospective review of all telemedical echocardiograms obtained from neonates (aged 1 day to 30 days) was performed. A telemedical link was created using a T-1 transmission line and a standard voice telephone line between the Mayo Clinic, Rochester, Minnesota (pediatric cardiology site), and the Altru Clinic, Grand Forks, North Dakota (primary care site), which is a general pediatric practice 400 miles from Rochester. Neonates with possible cardiac disorders were identified by the general pediatricians, who then requested telemedical echocardiography. RESULTS The 133 neonates had 161 T-1 echocardiograms. Median patient age was two days (range, one day to 29 days). One hundred thirty-two of 133 initial echocardiograms (99%) were obtained because of urgent indications. Transmitted images provided adequate diagnostic information in all patients. Seventy-nine neonates (59%) had a change in medical management or required cardiology follow-up. An immediate change in management occurred in 32 patients (24%), including seven in whom emergency transfer was either arranged or avoided. CONCLUSIONS Telemedical echocardiography provides accurate diagnostic data in neonates. Rapid telediagnosis facilitates appropriate care of sick neonates with possible congenital heart disease in the primary care setting. Unnecessary long-distance transfers can be avoided with this technology.

Magnetic Resonance Elastography. A Novel Technique for the Detection of Hepatic Fibrosis and Hepatocellular Carcinoma After the Fontan Operation

OBJECTIVE To evaluate the utility of magnetic resonance elastography (MRE) in screening patients for hepatic fibrosis, cirrhosis, and hepatocellular carcinoma after the Fontan operation. PATIENTS AND METHODS Hepatic MRE was performed in conjunction with cardiac magnetic resonance imaging in patients who had undergone a Fontan operation between 2010 and 2014. Liver stiffness was calculated using previously reported techniques. Comparisons to available clinical, laboratory, imaging, and histopathologic data were made. RESULTS Overall, 50 patients at a median age of 25 years (range, 21-33 years) who had undergone a Fontan operation were evaluated. The median interval between Fontan operation and MRE was 22 years (range, 16-26 years). The mean liver stiffness values were increased: 5.5 ± 1.4 kPa relative to normal participants. Liver stiffness directly correlated with liver biopsy-derived total fibrosis score, time since operation, mean Fontan pressure, γ-glutamyltransferase level, Model for End-Stage Liver Disease score, creatinine level, and pulmonary vascular resistance index. Liver stiffness was inversely correlated with cardiac index. All 3 participants with hepatic nodules exhibiting decreased contrast uptake on delayed postcontrast imaging and increased nodule stiffness had biopsy-proven hepatocellular carcinoma. CONCLUSION The association between hepatic stiffness and fibrosis scores, Model for End-Stage Liver Disease scores, and γ-glutamyltransferase level suggests that MRE may be useful in detecting (and possibly quantifying) hepatic cirrhosis in patients after the Fontan operation. The correlation between stiffness and post-Fontan time interval, mean Fontan pressure, pulmonary vascular resistance index, and reduced cardiac index suggests a role for long-term hepatic congestion in creating these hepatic abnormalities. Magnetic resonance elastography was useful in detecting abnormal nodules ultimately diagnosed as hepatocellular carcinoma. The relationship between stiffness with advanced fibrosis and hepatocellular carcinoma provides a strong argument for additional study and broader application of MRE in these patients.

Protein-Losing Enteropathy and the Fontan Operation

Protein-losing enteropathy (PLE) is a complex disorder characterized by enteric protein loss and often is associated with cardiovascular abnormalities, particularly those with elevated central venous pressure. The Fontan operation is a surgical procedure used to palliate patients with a functional single ventricle. Although the Fontan operation eliminates cyanosis and decreases the workload of the functionally single ventricle, it also elevates central venous pressure. This can result in hepatic and enteric congestion as well as PLE. Despite the universal elevation in central venous pressure, only a fraction of patients who have had a Fontan operation develop PLE. However, PLE is associated with significant morbidity and mortality. Presenting signs and symptoms of PLE include abdominal bloating, diarrhea, edema, pleural effusions, ascites, and failure to thrive. In this review, the authors discuss the diagnosis and prevalence of PLE after the Fontan operation and review currently available therapeutic strategies.

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Background—The molecular underpinnings of hypoplastic left heart are poorly understood. Staged surgical palliation has dramatically improved survival, yet eventual failure of the systemic right ventricle necessitates cardiac transplantation in a subset of patients. We sought to identify genetic determinants of hypoplastic left heart with latent right ventricular dysfunction in individuals with a Fontan circulation. Methods and Results—Evaluation of cardiac structure and function by echocardiography in patients with hypoplastic left heart and their first-degree relatives identified 5 individuals with right ventricular ejection fraction ⩽40% after Fontan operation. Whole genome sequencing was performed on DNA from 21 family members, filtering for genetic variants with allele frequency <1% predicted to alter protein structure or expression. Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6, encoding myosin heavy chain 6, in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms. Protein modeling of the 4 highly conserved amino acid substitutions, residing in both head and tail domains, predicted perturbation of protein structure and function. Conclusions—In contrast to dominant MYH6 mutations with variable penetrance identified in other congenital heart defects and dilated cardiomyopathy, this study reveals compound heterozygosity for recessive MYH6 mutations in patients with hypoplastic left heart and reduced systemic right ventricular ejection fraction. These findings implicate a shared molecular basis for the developmental arrest and latent myopathy of left and right ventricles, respectively.

Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) that necessitates staged, single ventricle surgical palliation. An increased frequency of bicuspid aortic valve (BAV) has been observed among relatives. We postulated number of mutant alleles as a molecular basis for variable CHD expression in an extended family comprised of an HLHS proband and four family members who underwent echocardiography and whole-genome sequencing (WGS). Dermal fibroblast-derived induced pluripotent stem cells (iPSC) were procured from the proband–parent trio and bioengineered into cardiomyocytes. Cardiac phenotyping revealed aortic valve atresia and a slit-like left ventricular cavity in the HLHS proband, isolated bicuspid pulmonary valve in his mother, BAV in a maternal 4° relative, and no CHD in his father or sister. Filtering of WGS for rare, functional variants that segregated with CHD and were compound heterozygous in the HLHS proband identified NOTCH1 as the sole candidate gene. An unreported missense mutation (P1964L) in the cytoplasmic domain, segregating with semilunar valve malformation, was maternally inherited and a rare missense mutation (P1256L) in the extracellular domain, clinically silent in the heterozygous state, was paternally inherited. Patient-specific iPSCs exhibited diminished transcript levels of NOTCH1 signaling pathway components, impaired myocardiogenesis, and a higher prevalence of heterogeneous myofilament organization. Extended, phenotypically characterized families enable WGS-derived variant filtering for plausible Mendelian modes of inheritance, a powerful strategy to discover molecular underpinnings of CHD. Identification of compound heterozygous NOTCH1 mutations and iPSC-based functional modeling implicate mutant allele burden and impaired myogenic potential as mechanisms for HLHS.