Reshma Biniwale

Novel techniques of mechanical circulatory support for the right heart and Fontan circulation

BACKGROUND Currently available ventricular assist devices are designed primarily for use in patients with left sided heart failure. This study evaluated the efficacy of the Jarvik 2000 ventricular assist device (VAD) as a pulmonary pump to power a Fontan circuit in a large animal model. METHODS Without the use of cardiopulmonary bypass, Fontan circulations were surgically created in 4 pigs (50 kg) using synthetic grafts from the inferior and superior vena cavas to the main pulmonary artery. Subsequently, the VAD was implanted within the common Fontan graft to provide a pulmonary pump. Direct chamber pressures and epicardial Doppler images were taken during the various phases of the experiment. Heart rate, femoral artery blood pressure, oxygen saturation, and aortic flow rate were continuously recorded. The outflow cannula of the VAD was then partially banded by 50% and then 75% to mimic increased afterload. RESULTS Fontan and VAD implantation was successfully performed in all 4 animals. Arterial pressure and aortic flow decreased dramatically with institution of the Fontan but were restored to baseline upon activation of the VAD. The pressure within the systemic venous circulation rose precipitously with institution of the Fontan circulation and improved appropriately with activation of the VAD. Adequate perfusion was maintained during increased afterload. CONCLUSIONS An axial flow VAD can restore normal hemodynamics and cardiac output when used as a pulmonary pump in a Fontan circulation. A VAD can rescue a failing Fontan as a bridge to transplant or recovery, even in the setting of high pulmonary resistance.

Lung Transplant Outcomes in Systemic Sclerosis with Significant Esophageal Dysfunction. A Comprehensive Single-Center Experience

RATIONALE Consideration of lung transplantation in patients with systemic sclerosis (SSc) remains guarded, often due to the concern for esophageal dysfunction and the associated potential for allograft injury and suboptimal post-lung transplantation outcomes. OBJECTIVES The purpose of this study was to systematically report our single-center experience regarding lung transplantation in the setting of SSc, with a particular focus on esophageal dysfunction. METHODS We retrospectively reviewed all lung transplants at our center from January 1, 2000 through August 31, 2012 (n = 562), comparing the SSc group (n = 35) to the following lung transplant diagnostic subsets: all non-SSc (n = 527), non-SSc diffuse fibrotic lung disease (n = 264), and a non-SSc matched group (n = 109). We evaluated post-lung transplant outcomes, including survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates. In addition, we defined severe esophageal dysfunction using esophageal manometry and esophageal morphometry criteria on the basis of chest computed tomography images. For patients with SSc referred for lung transplant but subsequently denied (n = 36), we queried the reason(s) for denial with respect to the concern for esophageal dysfunction. MEASUREMENTS AND MAIN RESULTS The 1-, 3-, and 5-year post-lung transplant survival for SSc was 94, 77, and 70%, respectively, and similar to the other groups. The remaining post-lung transplant outcomes evaluated were also similar between SSc and the other groups. Approximately 60% of the SSc group had severe esophageal dysfunction. Pre-lung transplant chest computed tomography imaging demonstrated significantly abnormal esophageal morphometry for SSc when compared with the matched group. Importantly, esophageal dysfunction was the sole reason for lung transplant denial in a single case. CONCLUSIONS Relative to other lung transplant indications, our SSc group experienced comparable survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates, despite the high prevalence of severe esophageal dysfunction. Esophageal dysfunction rarely precluded active listing for lung transplantation.

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm

BACKGROUND Neuronal remodeling in human heart disease is not well understood. METHODS Stellate ganglia from patients with cardiomyopathy (CMY) and refractory ventricular arrhythmias undergoing cardiac sympathetic denervation (n = 8), and from organ donors with normal hearts (n = 8) collected at the time of organ procurement were compared. Clinical data on all subjects were reviewed. Electron microscopy (EM), histologic, and immunohistochemical assessments of neurotransmitter profiles, glial activation and distribution, and lipofuscin deposition, a marker of oxidative stress, were quantified. RESULTS In CMY specimens, lipofuscin deposits were larger, and present in more neurons (26.3% ± 6.3% vs. 16.7% ± 7.6%, P < 0.043), than age-matched controls. EM analysis revealed extensive mitochondrial degeneration in CMY specimens. T cell (CD3+) infiltration was identified in 60% of the CMY samples, with one case having large inflammatory nodules, while none were identified in controls. Myeloperoxidase-immunoreactive neutrophils were also identified at parenchymal sites distinct from inflammatory foci in CMY ganglia, but not in controls. The adrenergic phenotype of pathologic samples revealed a decrease in tyrosine hydroxylase staining intensity compared with controls. Evaluation of cholinergic phenotype by staining for the vesicular acetylcholine transporter revealed a low but comparable number of cholinergic neurons in ganglia from both groups and demonstrated that preganglionic cholinergic innervation was maintained in CMY ganglia. S100 staining (a glial cell marker) demonstrated no differences in glial distribution and relationship to neurons; however, glial activation demonstrated by glial fibrillary acidic protein (GFAP) staining was substantially increased in pathologic specimens compared with controls. CONCLUSIONS Stellate ganglia from patients with CMY and arrhythmias demonstrate inflammation, neurochemical remodeling, oxidative stress, and satellite glial cell activation. These changes likely contribute to excessive and dysfunctional efferent sympathetic tone, and provide a rationale for sympathectomy as a treatment for arrhythmias in this population. FUNDING This work was made possible by support from NIH grants HL125730 to OAA, GM107949 to DBH, and HL084261 and OT2OD023848 to KS.

Decoding the Long Noncoding RNA during Cardiac Maturation: A Roadmap for Functional Discovery

Background—Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated. Methods and Results—From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes. Conclusions—The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects.

Novel techniques in the use of bivalirudin for cardiopulmonary bypass anticoagulation in a child with heparin-induced thrombocytopenia:

Heparin-induced thrombocytopenia (HIT) occurs in both the pediatric and adult populations after exposure to heparin. Bivalirudin has been used as an alternative to heparin for adults undergoing cardiac surgery and cardiopulmonary bypass, but has only been used minimally in children for this purpose. We report the successful use of bivalirudin for anticoagulation during cardiopulmonary bypass in a small child with HIT, using novel techniques not previously described.

Incidence and outcome of infective endocarditis following percutaneous versus surgical pulmonary valve replacement

To provide a comparison of the outcome of infective endocarditis (IE) in patients undergoing transcatheter pulmonary valve replacement (TPVR) versus surgical pulmonary valve replacement (SPVR).

Lung transplantation and concomitant cardiac surgery: Is it justified?

OBJECTIVE Increasing numbers of lung transplant candidates have cardiac conditions that affect their survival after transplantation. Our objective was to determine if patients who undergo concomitant cardiac surgery (CCS) during the lung transplant procedure have similar outcomes, as a cohort of isolated lung transplant recipients. METHODS This was a retrospective, observational, matched-cohort analysis. The records of lung transplant recipients who underwent CCS from August 2000 to August 2013 were reviewed. A cohort of isolated lung transplant recipients, matched on the basis of age, lung allocation score, diagnosis, type of procedure, and era, was identified. The primary endpoint of this trial was 5-year survival. The secondary endpoints were primary graft dysfunction, grade III, at 72 hours, intensive care unit and hospital length of stay, and 5-year major adverse cardiac event rates. RESULTS A total of 120 patients underwent lung transplantation and CCS. Compared with the isolated lung transplant group, the donor, recipient, and operation characteristics were similar. No difference was found in the survival of the 2 groups for up to 5 years, or in the incidence of primary graft dysfunction Grade III at 72 hours, intensive care unit length of stay, invasive ventilation, hospital length of stay, or incidence of 5-year major adverse cardiac events. CONCLUSIONS Lung transplant recipients undergoing CCS have early and midterm clinical outcomes similar to those of isolated lung transplant recipients. Given that this report is the largest published experience, offering cardiac surgery at the time of lung transplantation, to selected patients, remains justified.

Wnt11 regulates cardiac chamber development and disease during perinatal maturation

Ventricular chamber growth and development during perinatal circulatory transition is critical for functional adaptation of the heart. However, the chamber-specific programs of neonatal heart growth are poorly understood. We used integrated systems genomic and functional biology analyses of the perinatal chamber specific transcriptome and we identified Wnt11 as a prominent regulator of chamber-specific proliferation. Importantly, downregulation of Wnt11 expression was associated with cyanotic congenital heart defect (CHD) phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Perinatal hypoxia treatment in mice suppressed Wnt11 expression and induced myocyte proliferation more robustly in the right ventricle, modulating Rb1 protein activity. Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse hearts and reduced Rb1 protein and phosphorylation in neonatal cardiomyocytes. Finally, downregulated Wnt11 in hypoxemic TOF infantile hearts was associated with Rb1 suppression and induction of proliferation markers. This study revealed a previously uncharacterized function of Wnt11-mediated signaling as an important player in programming the chamber-specific growth of the neonatal heart. This function influences the chamber-specific development and pathogenesis in response to hypoxia and cyanotic CHDs. Defining the underlying regulatory mechanism may yield chamber-specific therapies for infants born with CHDs.

CREATION OF A SURGICAL FONTAN ANIMAL MODEL AND THE USE OF A VENTRICULAR ASSIST DEVICE TO RESTORE CARDIAC OUTPUT

Current ventricular assist devices are not designed for use in patients with failing Fontans. This study evaluated the efficacy of the Jarvik 2000 ventricular assist device (VAD) as a pulmonary pump to power a Fontan circuit in a large animal model. Without the use of cardiopulmonary bypass, Fontan

Ventricular arrhythmia burden after transcatheter versus surgical pulmonary valve replacement

Objective Comparative ventricular arrhythmia (VA) outcomes following transcatheter (TC-PVR) or surgical pulmonary valve replacement (S-PVR) have not been evaluated. We sought to compare differences in VAs among patients with congenital heart disease (CHD) following TC-PVR or S-PVR. Methods Patients with repaired CHD who underwent TC-PVR or S-PVR at the UCLA Medical Center from 2010 to 2016 were analysed retrospectively. Patients who underwent hybrid TC-PVR or had a diagnosis of congenitally corrected transposition of the great arteries were excluded. Patients were screened for a composite of non-intraoperative VA (the primary outcome variable), defined as symptomatic/recurrent non-sustained ventricular tachycardia (VT) requiring therapy, sustained VT or ventricular fibrillation. VA epochs were classified as 0–1 month (short-term), 1–12 months (mid-term) and ≥1 year (late-term). Results Three hundred and two patients (TC-PVR, n=172 and S-PVR, n=130) were included. TC-PVR relative to S-PVR was associated with fewer clinically significant VAs in the first 30 days after valve implant (adjusted HR 0.20, p=0.002), but similar mid-term and late-term risks (adjusted HR 0.72, p=0.62 and adjusted HR 0.47, p=0.26, respectively). In propensity-adjusted models, S-PVR, patient age at PVR and native right ventricular outflow tract (RVOT) (vs bioprosthetic/conduit outflow tract) were independent predictors of early VA after pulmonary valve implantation (p<0.05 for all). Conclusion Compared with S-PVR, TC-PVR was associated with reduced short-term but comparable mid-term and late-term VA burdens. Risk factors for VA after PVR included a surgical approach, valve implantation into a native RVOT and older age at PVR.