Rajesh Punn

Physiologic and molecular characterization of a murine model of right ventricular volume overload

Pulmonary insufficiency (PI) is a common long-term sequel after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We describe the physiologic and molecular characteristics of the first murine model of RV volume overload. PI was created by entrapping the pulmonary valve leaflets with sutures. Imaging, catheterization, and exercise testing were performed at 1, 3, and 6 mo and compared with sham controls. RNA from the RV free wall was hybridized to Agilent whole genome oligonucleotide microarrays. Volume overload resulted in RV enlargement, decreased RV outflow tract shortening fraction at 1 mo followed by normalization at 3 and 6 mo (39 ± 2, 44 ± 2, and 41 ± 2 vs. 46 ± 3% in sham), early reversal of early and late diastolic filling velocities (E/A ratio) followed by pseudonormalization (0.87 ± 0.08, 0.82 ± 0.08, and 0.96 ± 0.08 vs. 1.04 ± 0.03; P < 0.05), elevated end-diastolic pressure (7.6 ± 0.7, 6.9 ± 0.8, and 7 ± 0.5 vs. 2.7 ± 0.2 mmHg; P < 0.05), and decreased exercise duration (26 ± 0.4, 26 ± 1, and 22 ± 1.3 vs. 30 ± 1.1 min; P < 0.05). Subendocardial RV fibrosis was evident by 1 mo. At 1 mo, 372 genes were significantly downregulated. Mitochondrial pathways and G protein-coupled receptor signaling were the most represented categories. At 3 mo, 434 genes were upregulated and 307 downregulated. While many of the same pathways continued to be downregulated, TNF-α, transforming growth factor-β(1) (TGF-β(1)), p53-signaling, and extracellular matrix (ECM) remodeling transitioned from down- to upregulated. We describe a novel murine model of chronic RV volume overload recapitulating aspects of the clinical disease with gene expression changes suggesting early mitochondrial bioenergetic dysfunction, enhanced TGF-β signaling, ECM remodeling, and apoptosis.

Echocardiographic Diagnosis and Prognosis of Fetal Left Ventricular Noncompaction

BACKGROUND Left ventricular noncompaction (LVNC) has rarely been described in the fetus. METHODS The presence of associated congenital heart disease and rhythm disturbance was identified and the presence of heart failure was assessed using the cardiovascular profile score in all fetuses with LVNC presenting from January 1999 to July 2010. The left ventricle was divided into 12 segments-four segments each at the base, midpapillary, and apical regions-in the short-axis view to calculate the noncompaction/compaction ratio for each segment. RESULTS Of 24 fetuses with LVNC included in the study, 22 had significant congenital heart disease, and 15 had complete heart block. Of the 16 patients with adequate follow-up and not electively terminated, 12 (81%) died or progressed to heart transplantation. The average noncompaction/compaction ratios were 2.02 in patients who died or underwent heart transplantation and 1.67 in survivors (P = .2034). Fifty-seven of 93 measured segments (61%) of the left ventricle in the patients who died or underwent heart transplantation had noncompaction/compaction ratios ≥ 2 compared with five of 17 measured segments (29%) in survivors (P = .0837). The average cardiovascular profile score was 6. The apical region had greater involvement of noncompaction than the midpapillary and basal regions, with ratios of 2.27, 2.14, and 1.10, respectively (P = .00035). CONCLUSIONS Fetuses with LVNC have a poor prognosis that may be related to associated congenital heart disease, increased segmental involvement of noncompaction, and complete heart block and can be predicted by the cardiovascular profile score.

Cardiac Segmental Analysis in Left Ventricular Noncompaction: Experience in a Pediatric Population

BACKGROUND Echocardiography has been used to diagnose and describe left ventricular noncompaction (LVNC). No other study has investigated LVNC using the 16-segment model described by the American Heart Association and the American Society of Echocardiography in children, some of whom have congenital heart disease. Using the ratio of noncompaction to compaction, the authors analyzed the 16 segments and determined if severity was correlated with poor outcomes in a pediatric population. METHODS The 16-segment noncompaction/compaction ratio, shortening, and ejection fractions were measured retrospectively in all children with LVNC at a single institution from January 1, 2000, to June 30, 2008. RESULTS Forty-four patients had LVNC, an incidence of 0.3% of laboratory admissions. Twenty-eight patients (64%) who remained alive were assigned to group 1, and 16 patients (36%) who either died or were transplanted constituted group 2. Group 2 had more patients with significant associated congenital heart disease than group 1 (50% vs 18%, P < .05). We found similar regions of involvement in the 16-segment model with sparing of basal segments and involvement of the midpapillary and apical regions (P < .001); however, patients in group 2 were noted to have more segments involved (6 vs 4, P < .05), lower shortening fractions (16% vs 29%, P < .001), and lower ejection fractions (24% vs 47%, P < .001). The ejection fraction was inversely related to the number of segments (r = -0.63, P < .01), suggesting that more noncompaction portends a worse outcome. CONCLUSIONS In younger patients with noncompaction, poor outcomes such as low ejection fractions, death, and transplantation are related to the number of left ventricular segments involved. There is more associated congenital heart disease in the pediatric population, which carries a poorer prognosis than the disease reported in adult populations.

Surgical reconstruction of peripheral pulmonary artery stenosis in Williams and Alagille syndromes

OBJECTIVES Peripheral pulmonary artery stenosis is a rare congenital heart defect frequently found in association with Williams and Alagille syndromes. Controversy exists regarding the optimal treatment of peripheral pulmonary artery stenosis, with most centers favoring catheter-based interventions. In contrast, we have preferentially used surgical reconstruction of peripheral pulmonary artery stenosis. The purpose of the present study was to review our experience with surgical reconstruction of peripheral pulmonary artery stenosis. METHODS We performed a retrospective review of patients who underwent surgical reconstruction of peripheral pulmonary artery stenosis. A total of 16 patients were identified: 7 had Williams syndrome, 6 had Alagille syndrome, and 3 had no identifiable syndrome. Detailed pulmonary angiography was performed in all patients to define stenoses at the main, branch, lobar, and segmental arterial levels. The mean preoperative right ventricular/left ventricular pressure ratio was 0.88 ± 0.07. The surgical approach was a median sternotomy with cardiopulmonary bypass. All peripheral stenoses were augmented with pulmonary artery homograft tissue. The median age at surgery was 14 months, and concomitant procedures were performed in 9 of the 16 patients. RESULTS There was 1 operative mortality (6%). The mean right ventricular/left ventricular pressure ratio decreased to 0.40 ± 0.04 postoperatively (P < .005), representing a 55% reduction compared with the preoperative values. The patients were followed up for a median of 5 years. No late mortality occurred and reoperation was not required. CONCLUSIONS The data have demonstrate that this comprehensive surgical approach to the treatment of peripheral pulmonary artery stenosis was associated with low early and no late mortality. Surgical reconstruction of the peripheral pulmonary artery stenosis resulted in a significant decrease in right ventricular pressure. We hypothesize that this reduction in right ventricular pressures will confer a long-term survival advantage for this cohort of patients.

Near-infrared spectroscopy for detection of a significant patent ductus arteriosus.

Background:Near-infrared spectroscopy (NIRS) may assist with characterization of a hemodynamically significant patent ductus arteriosus (hsPDA) by measuring cerebral and renal saturation (Csat and Rsat) levels. We hypothesized that Csat and Rsat in preterm infants with an hsPDA would be decreased compared to those with no PDA or nonsignificant PDA.Methods:This non a-priori designed study retrospectively investigated clinical and ECHO characteristics of preterm infants <29 wk gestation who underwent routine NIRS monitoring. Logistic regression assessed association between NIRS measures and an hsPDA by ECHO.Results:Of 47 infants, 21 had a confirmed hsPDA by ECHO, 14 had a nonsignificant PDA, and 12 had no ECHO performed due to low clinical suspicion for PDA. Logistic regression adjusted for gestational age found that lower Rsat was associated with an hsPDA by ECHO (OR 0.9, 95% CI 0.83–0.98, P = 0.01). Using ROC curves, Rsat < 66% identified an hsPDA with a sensitivity of 81% and specificity of 77%, while Csat was not significant.Conclusion:Low Rsat < 66% was associated with the presence of an hsPDA in the preterm infant. Csat may be preserved if cerebral autoregulation is largely intact. Bedside NIRS monitoring may reasonably increase suspicion for a significant PDA in the preterm infant.

Predictors of bronchopulmonary dysplasia or death in premature infants with a patent ductus arteriosus

Background:Preterm infants with a patent ductus arteriosus (PDA) are at risk for death or development of bronchopulmonary dysplasia (BPD). However, PDA treatment remains controversial. We investigated if PDA treatment and other clinical or echocardiographic (ECHO) factors were associated with the development of death or BPD.Methods:We retrospectively studied clinical and ECHO characteristics of preterm infants with birth weight <1,500 g and ECHO diagnosis of a PDA. Logistic regression and classification and regression tree analyses were performed to assess variables associated with the combined outcome of death or BPD.Results:Of 187 preterm infants with a PDA, 75% were treated with indomethacin or surgical ligation and 25% were managed conservatively. Death or BPD occurred in 80 (43%) infants. The results of logistic regression analyses showed that lower gestational age (odds ratio (OR): 0.5), earlier year of birth during the study period (OR: 0.9), and larger ductal diameter (OR: 4.3) were associated with the decision to treat the PDA, whereas gestational age was the only variable associated with death or BPD (OR: 0.6; 95% confidence interval: 0.5–0.8).Conclusion:Only lower gestational age and not PDA treatment or ECHO score was associated with the adverse outcome of death or BPD. Further investigation of PDA management strategies and effects on adverse outcomes of prematurity is needed.

Surgical Reconstruction of Pulmonary Stenosis With Ventricular Septal Defect and Major Aortopulmonary Collaterals

BACKGROUND Pulmonary stenosis with ventricular septal defect and major aortopulmonary collaterals (PS/VSD/MAPCAs) is an extremely rare form of congenital heart defect. Although it has been assumed that PS/VSD/MAPCAs would be similar to pulmonary atresia (PA) with VSD/MAPCA, there are currently no data to support this conjecture. This study reviewed our surgical experience with reconstruction of PS/VSD/MAPCA. METHODS This was a retrospective review of 25 patients (14 boys, 11 girls) who were born with PS/VSD/MAPCA and underwent surgical reconstruction. Preoperative pulmonary angiography was used to define the central branch pulmonary arteries and MAPCA. Patients were a median age of 4 months at the first operation. RESULTS There was one operative death (4%) in this cohort of 25 patients, and complete repair was achieved in the 24 survivors (96%). There were two distinct subgroups of patients: 11 demonstrated cyanosis in the neonatal timeframe and underwent an initial procedure to augment pulmonary blood flow (+PBF). The remaining 14 patients formed the second group (-PBF). The median age at the first operation was 0.8 months in the +PBF group and 5.2 months in the -PBF group (p<0.005). Complete repair was achieved in 91% of patients in the +PBF group and in 100% in the -PBF group; however, the average number of procedures to achieve complete repair was 2.8 in the +PBF group vs 1.0 in the -PBF group (p<0.005). CONCLUSIONS Outcomes for PS/VSD/MAPCAs as a whole were excellent, with a low surgical mortality and high rate of complete repair. There were two identifiable subgroups with distinctive differences required in their surgical management. These results provide a prognostic outlook for patients with PS/VSD/MAPCAs that can be compared and contrasted with PA/VSD/MAPCAs.

Late repair of the native pulmonary valve in patients with pulmonary insufficiency after surgery for tetralogy of Fallot.

Pulmonary regurgitation developing late after tetralogy of Fallot repair is now recognized as a serious threat to the long-term welfare of these patients. This article summarizes our experience with 5 patients who underwent reoperations for treatment of severe pulmonary regurgitation after transannular patch repair of tetralogy of Fallot. In each case, the intraoperative findings revealed anatomy favorable for valve repair and enabled preservation of the native pulmonary valves.

Case Report: Rhabdomyolysis Induced by Mibefradil in a Patient Treated with Cyclosporine and Simvastatin

R ecently, sev eral new classes of drugs with unique mecha nisms of action have been approved. Most atten tion is paid to their great prom ise to improve thera peu tics. How ever, as Bates points out, these new drug classes have a doubleedged sword of bene fits ver sus risks, and more atten tion should be directed to the risk side of this equa tion. Poten tial unknown risks include direct adverse effects of the new drug and adverse inter ac tions with other drugs. Although sub jects in phase I, II, and III clini cal tri als are moni tored for adverse drug effects, seri ous but infre quent effects may not be detected. Also, these trial popu la tions usu ally exclude patients with other com pli cated con comi tant dis eases and their needed medi ca tions. Once approved, these pre vi ously excluded patients may be pre scribed the new drug. The recent approval of mibe fra dil and its sub se quent removal from the mar ket prove a case in point of the first drug in a new class with sig nifi cant clini cal poten tial but car ry ing the bag gage of seri ous, unex pected adverse drug inter ac tions. Mibe fra dil (Posi cor), approved by the FDA on June 20, 1997, is the first mem ber of a new class of cal cium channelblocking agents indi cated for the treat ment of hyper ten sion as well as chronic angina pec to ris. Unlike the other chan nel block ers, mibe fra dil has greater selec tiv ity for the T-type chan nel than the L-type chan nel. On June 8, 1998, Roche Labo ra to ries vol un tar ily with drew mibe fra dil due to increas ing infor ma tion con cern ing poten tial drug inter ac tions. Mibe fra dil is metabo lized by hepatic esterases and by the cyto chrome P450, CYP 3A4, to inac tive metabo lites of which 75% are excreted into the bile. The pri mary bile excre tion route is desir able for the treat ment of patients with chronic renal insuf fi ciency. Drug inter ac tions asso ci ated with mibe fra dil are related to the inhi bi tion of the CYP 3A4 enzyme sys tem. This raises con cern in patients treated with cyclo spor ine and sim vas ta tin ther apy because both are metabo lized by this enzyme sys tem. Sim vas ta tin, an HMGCoA reduc tase inhibi tor, has been reported to cause rhab do my oly sis. Cyclo spor ine has been shown to directly raise the plasma con cen tra tion of sim vas ta tin through com pe ti tion for CYP 3A4. Ele vated sim vas ta tin con cen tra tions have resulted in rhab do my oly sis and acute renal fail ure. In this case report, we pres ent an exam ple of mibe fradil’s influ ence on cyclo spor ine and sim vas ta tin plasma con cen tra tion in a renal trans plant patient who devel oped rhab do my oly sis and acute renal fail ure.

Insights into dyssynchrony in Hypoplastic Left Heart Syndrome

BACKGROUND Cardiac resynchronization therapy has been proposed for treatment of hypoplastic left heart syndrome (HLHS) patients with right ventricular (RV) failure. The role of dyssynchrony, however, is poorly understood in this population. OBJECTIVE The purpose of this study was to better understand the relationship between electrical and mechanical dyssynchrony in HLHS using 3-dimensional electrical mapping, tissue Doppler indices of wall motion, and vector velocity imaging. METHODS Eleven HLHS subjects with normal RV function and ten normal subjects (age 3-18 years) were studied. Electrical and mechanical activation times and dyssynchrony indices (electrical dyssynchrony index, mechanical dyssynchrony index) were calculated using 3-dimensional electrical mapping, tissue Doppler indices, and vector velocity imaging. RESULTS No differences in measures of electrical dyssynchrony were seen when comparing HLHS patients and normal patients (electrical activation time 63.3 ± 22.8 ms vs 56.2 ± 11.2 ms, P = .38; electrical dyssynchrony index 13.7 ± 6.3 ms vs 11.6 ± 3.0 ms, P = .34). However, measures of mechanical dyssynchrony were markedly abnormal in HLHS patients despite normal RV function (mechanical activation time 16 ± 11.3 ms vs 0.9±1.9 ms, P = .01; mechanical dyssynchrony index 7.5 ± 5.5 vs 0.4 ± 0.8, P<.01). CONCLUSION Patients with HLHS and preserved RV systolic function have normal electrical activation when compared to patients with normal right and left ventricles. In contrast, these patients demonstrate mechanical dyssynchrony compared to patients with normal right and left ventricles. This finding raises important questions about the indications for cardiac resynchronization therapy in this patient population.