Pulmonary vasodilator therapy in the failing Fontan circulation: rationale and efficacy.

The Fontan operation is the final step of palliation for patients with a functionally single ventricle. Since its introduction in the 1970s, the Fontan surgery has become part of a successful surgical strategy that has improved single ventricle mortality. In recent years, we have become more aware of the limitations and long-term consequences of the Fontan physiology. Pulmonary vascular resistance plays an important role in total cavopulmonary circulation, and has been identified as a potential therapeutic target to mitigate Fontan sequelae. In this review, we will discuss the results of different pulmonary vasodilator trials and the use of pulmonary vasodilators as a treatment strategy for Fontan patients.

Prolonged sinus pauses with hydromorphone in the absence of cardiac conduction disease.

A 49-year-old male had open sigmoid colectomy with colorectal anastomosis for sigmoid diverticulitis. The patient was given patient-controlled analgesia (PCA) hydromorphone and subsequently developed bradycardia with prolonged sinus pauses up to 7.1 seconds. The pauses resolved shortly after the hydromorphone was discontinued. This is the first case report to our knowledge of reversible prolonged sinus pauses associated with the use of hydromorphone. Animal studies support a role for opioid signaling at the sinoatrial (SA) node. Hydromorphone is a potential cause of prolonged sinus pauses and should be taken into consideration when monitoring a patient on hydromorphone for pain control.

Symptomatic bradycardia with oral aripiprazole and oral ziprasidone.

OBJECTIVE: To describe the case of a patient who developed symptomatic bradycardia upon initiation of oral ziprasidone and later with oral aripiprazole, both of which resolved shortly after discontinuation of therapy. CASE SUMMARY: An 18-year-old female with bipolar disorder was started on oral ziprasidone 80 mg at night and the dose was subsequently increased to 120 mg for management of acute mania and delusions. The patient developed symptomatic bradycardia (heart rate 31-35 beats/min), which resolved after ziprasidone was decreased to 80 mg. Three months later, the patient was readmitted for treatment of bipolar mania with psychotic features in the context of medication nonadherence. She was started on oral aripiprazole 15 mg daily (subsequently increased to 20 mg) in conjunction with 600 mg lithium carbonate twice daily. The patient again developed symptomatic bradycardia that resolved after discontinuation of aripiprazole. DISCUSSION: This is the first case report of symptomatic bradycardia associated with the use of ziprasidone or aripiprazole. The Naranjo probability scale suggests that the likelihood of the atypical antipsychotic as the cause of bradycardia is probable for both ziprasidone and aripiprazole. Symptomatic bradycardia with the use of other atypical antipsychotics has been reported in the literature. Little is known about the mechanisms that contribute to the antipsychotic-associated bradycardic response. CONCLUSIONS: Further studies are needed to better determine the relationship between antipsychotics and reflex bradycardia. Although bradycardia remains a relatively uncommon phenomenon seen with the use of these medications, the severity of this potential adverse effect warrants consideration when initiating antipsychotic therapy.

Isl1 expression at the venous pole identifies a novel role for the second heart field in cardiac development.

The right ventricle and outflow tract of the developing heart are derived from mesodermal progenitor cells from the second heart field (SHF). SHF cells have been characterized by expression of the transcription factor Islet-1 (Isl1). Although Isl1 expression has also been reported in the venous pole, the specific contribution of the SHF to this part of the heart is unknown. Here we show that Isl1 is strongly expressed in the dorsal mesenchymal protrusion (DMP), a non-endocardially-derived mesenchymal structure involved in atrioventricular septation. We further demonstrate that abnormal development of the SHF-derived DMP is associated with the pathogenesis of atrioventricular septal defects. These results identify a novel role for the SHF.

Resource Utilization for Prenatally Diagnosed Single-Ventricle Cardiac Defects: A Philadelphia Fetus-to-Fontan Cohort Study.

Background Healthcare resource utilization is substantial for single-ventricle cardiac defects ( SVCD ), with effort commencing at time of fetal diagnosis through staged surgical palliation. We sought to characterize and identify variables that influence resource utilization for SVCD from fetal diagnosis through death, completed staged palliation, or cardiac transplant. Methods and Results Patients with a prenatal diagnosis of SVCD at our institution from 2004 to 2011 were screened. Patients delivered with intent to treat who received cardiac care exclusively at our institution were included. Primary end points included the total days hospitalized and the numbers of echocardiograms and cardiac catheterizations. Subanalysis was performed on survivors of completed staged palliation on the basis of Norwood operation, dominant ventricular morphology, and additional risk factors. Of 202 patients born with intent to treat, 136 patients survived to 6 months after completed staged palliation. The median number of days hospitalized per patient-year was 25.1 days, and the median numbers of echocardiograms and catheterizations per patient-year were 7.2 and 0.7, respectively. Mortality is associated with increased resource utilization. Survivors had a cumulative length of stay of 57 days and underwent a median of 21 echocardiograms and 2 catheterizations through staged palliation. Right-ventricle-dominant lesions requiring Norwood operation are associated with increased resource utilization among survivors of staged palliation. Conclusions For fetuses with SVCD , those with dominant right-ventricular morphology requiring Norwood operation demand increased resource utilization regardless of mortality. Our findings provide insight into care for SVCD , facilitate precise prenatal counseling, and provide information about the resources utilized to successfully manage SVCD .

Longitudinal Assessment of Outcome From Prenatal Diagnosis Through Fontan Operation for Over 500 Fetuses With Single Ventricle-Type Congenital Heart Disease: The Philadelphia Fetus-to-Fontan Cohort Study.

Background Prenatal diagnosis of single ventricle-type congenital heart disease is associated with improved clinical courses. Prenatal counseling allows for optimal delivery preparations and opportunity for prenatal intervention. Expectant parents frequently ask what the likelihood of survival through staged palliation is and the factors that influence outcome. Our goal was specifically to quantify peri- and postnatal outcomes in this population. Methods and Results We identified all patients with a prenatal diagnosis of single ventricle-type congenital heart disease presenting between July 2004 and December 2011 at our institution. Maternal data, fetal characteristics, and data from the postnatal clinical course were collected for each patient. Kaplan-Meier curves and multivariate analysis with logistic regression were used to evaluate variables associated with decreased transplant-free survival. Five hundred two patients were identified, consisting of 381 (76%) right ventricle- and 121 left ventricle-dominant lesions. After prenatal diagnosis, 42 patients did not follow up at our center; 79 (16%) chose termination of pregnancy, and 11 had intrauterine demise with 370 (74%) surviving to birth. Twenty-two (6%) underwent palliative care at birth. Among 348 surviving to birth with intention to treat, 234 (67%) survived to at least 6 months post-Fontan palliation. Presence of fetal hydrops, right ventricle dominance, presence of extracardiac anomalies, and low birthweight were significantly associated with decreased transplant-free survival. Conclusions In patients with a prenatal diagnosis of single ventricle-type congenital heart disease and intention to treat, 67% survive transplant-free to at least 6 months beyond Fontan operation. An additional 5% survive to 4 years of age without transplant or Fontan completion. Fetuses with right ventricle-dominant lesions, extracardiac anomalies, hydrops, or low birthweights have decreased transplant-free survival.

The Parasternal Short-Axis View Improves Diagnostic Accuracy for Inferior Sinus Venosus Type of Atrial Septal Defects by Transthoracic Echocardiography.

BACKGROUND: Sinus venosus defects (SVD) of the inferior vena cava (IVC) type, or inferior SVDs, are an uncommon form of atrial communication located outside the confines of the fossa ovalis and involve override of the IVC. Despite numerous studies describing the anatomical and echocardiographic features of the inferior SVD, distinguishing this defect from a large secundum atrial septal defect (ASD) by echocardiography is often challenging. Accurate diagnosis of an inferior SVD and correct differentiation from a secundum ASD is essential for appropriate presurgical planning. Absence of the posterior rim in the parasternal short-axis views may serve as a useful clue in diagnosing inferior SVDs. We sought to determine the utility of using the presence or absence of a posterior atrial rim in the parasternal short-axis view to help distinguish an inferior SVD from a secundum ASD. This sign may help clinch the diagnosis when subcostal imaging is suboptimal. METHODS: We retrospectively reviewed transthoracic echocardiograms from 15 patients with a known surgical diagnosis of an inferior SVD between 2004 and 2015. The presence or absence of a posterior rim in the parasternal short-axis view was determined by two primary investigators. The posterior rim was also evaluated in 14 patients with a secundum ASD repair as controls. Echocardiograms were then reviewed blindly by attending-level echocardiographers and cardiology fellows in training. Diagnostic accuracy was assessed both with and without the use of the posterior rim criterion. Statistical analysis was used to determine the effect of using the rim criterion on inferior SVD diagnosis. We also reviewed all surgically diagnosed secundum ASDs that were incorrectly diagnosed as inferior SVD by preoperative imaging and determined whether use of the posterior rim criterion would have resulted in the correct diagnosis. RESULTS: The posterior rim was absent in all 15 patients with a surgical diagnosis of inferior SVD and present in all 14 patients with a secundum ASD. For all observers, there was a statistically significant increase in diagnostic accuracy of inferior SVDs with the use of the rim criterion (P < .0001). We noted that secundum ASDs with inferior extension also have persistent posterior rims. The rim criterion correctly classified all large secundum ASDs with inferior extension that were previously misdiagnosed by echocardiogram preoperatively. CONCLUSIONS: Absence of the posterior rim ("bald" posterior wall) is a consistent finding in patients with an inferior SVD and distinguishes an inferior SVD from a large secundum ASD with inferior extension. Parasternal short-axis evaluation of the posterior atrial rim is a helpful tool for all levels of physician training in improving diagnostic accuracy for detecting inferior SVDs and in distinguishing them from secundum ASDs.

Origin and fate of cardiac mesenchyme.

The development of the embryonic heart is dependent upon the generation and incorporation of different mesenchymal subpopulations that derive from intra- and extra-cardiac sources, including the endocardium, epicardium, neural crest, and second heart field. Each of these populations plays a crucial role in cardiovascular development, in particular in the formation of the valvuloseptal apparatus. Notwithstanding shared mechanisms by which these cells are generated, their fate and function differ profoundly by their originating source. While most of our early insights into the origin and fate of the cardiac mesenchyme has come from experimental studies in avian model systems, recent advances in transgenic mouse technology has enhanced our ability to study these cell populations in the mammalian heart. In this article, we will review the current understanding of the role of cardiac mesenchyme in cardiac morphogenesis and discuss several new paradigms based on recent studies in the mouse.

A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development.

The mesenchymal tissues involved in cardiac septation are derived from different sources. In addition to endocardial-derived mesenchyme, the heart also receives contributions from the neural crest, the proepicardium, and the dorsal mesenchymal protrusion (DMP). Whereas the contributions of the neural crest and proepicardium have been thoroughly studied, the DMP has received little attention. Here, we present the results of a comprehensive spatiotemporal study of the DMP in cardiac development. Using the Tie2-Cre mouse, immunohistochemistry, and AMIRA reconstructions, we show that the DMP, in combination with the mesenchymal cap on the primary atrial septum, fuse with the major atrioventricular cushions to close the primary atrial foramen and to form the atrioventricular mesenchymal complex. In this complex, the DMP constitutes a discrete prominent mesenchymal component, wedged in between the major cushions. This new model for atrioventricular septation may provide novel insights into understanding the etiology of congenital cardiac malformations.

Cartilage link protein 1 (Crtl1), an extracellular matrix component playing an important role in heart development.

To expand our insight into cardiac development, a comparative DNA microarray analysis was performed using tissues from the atrioventricular junction (AVJ) and ventricular chambers of mouse hearts at embryonic day (ED) 10.5-11.0. This comparison revealed differential expression of approximately 200 genes, including cartilage link protein 1 (Crtl1). Crtl1 stabilizes the interaction between hyaluronan (HA) and versican, two extracellular matrix components essential for cardiac development. Immunohistochemical studies showed that, initially, Crtl1, versican, and HA are co-expressed in the endocardial lining of the heart, and in the endocardially derived mesenchyme of the AVJ and outflow tract (OFT). At later stages, this co-expression becomes restricted to discrete populations of endocardially derived mesenchyme. Histological analysis of the Crtl1-deficient mouse revealed a spectrum of cardiac malformations, including AV septal and myocardial defects, while expression studies showed a significant reduction in versican levels. Subsequent analysis of the hdf mouse, which carries an insertional mutation in the versican gene (CSPG2), demonstrated that haploinsufficient versican mice display septal defects resembling those seen in Crtl1(-/-) embryos, suggesting that reduced versican expression may contribute to a subset of the cardiac abnormalities observed in the Crtl1(-/-) mouse. Combined, these findings establish an important role for Crtl1 in heart development.

Polaris and Polycystin-2 in dorsal forerunner cells and Kupffer's vesicle are required for specification of the zebrafish left-right axis.

Recently, it has become clear that motile cilia play a central role in initiating a left-sided signaling cascade important in establishing the LR axis during mouse and zebrafish embryogenesis. Two genes proposed to be important in this cilia-mediated signaling cascade are polaris and polycystin-2 (pkd2). Polaris is involved in ciliary assembly, while Pkd2 is proposed to function as a Ca(2+)-permeable cation channel. We have cloned zebrafish homologues of polaris and pkd2. Both genes are expressed in dorsal forerunner cells (DFCs) from gastrulation to early somite stages when these cells form a ciliated Kupffer's vesicle (KV). Morpholino-mediated knockdown of Polaris or Pkd2 in zebrafish results in misexpression of left-side-specific genes, including southpaw, lefty1 and lefty2, and randomization of heart and gut looping. By targeting morpholinos to DFCs/KV, we show that polaris and pkd2 are required in DFCs/KV for normal LR development. Polaris morphants have defects in KV cilia, suggesting that the laterality phenotype is due to problems in cilia function per se. We further show that expression of polaris and pkd2 is dependent on the T-box transcription factors no tail and spadetail, respectively, suggesting that these genes have a previously unrecognized role in regulating ciliary structure and function. Our data suggest that the functions of polaris and pkd2 in LR patterning are conserved between zebrafish and mice and that Kupffer's vesicle functions as a ciliated organ of asymmetry.