Abnormalities in serum biomarkers correlate with lower cardiac index in the Fontan population.

BACKGROUND: Fontan survivors have depressed cardiac index that worsens over time. Serum biomarker measurement is minimally invasive, rapid, widely available, and may be useful for serial monitoring. The purpose of this study was to identify biomarkers that correlate with lower cardiac index in Fontan patients. Methods and results This study was a multi-centre case series assessing the correlations between biomarkers and cardiac magnetic resonance-derived cardiac index in Fontan patients ⩾6 years of age with biochemical and haematopoietic biomarkers obtained ±12 months from cardiac magnetic resonance. Medical history and biomarker values were obtained by chart review. Spearman's Rank correlation assessed associations between biomarker z-scores and cardiac index. Biomarkers with significant correlations had receiver operating characteristic curves and area under the curve estimated. In total, 97 cardiac magnetic resonances in 87 patients met inclusion criteria: median age at cardiac magnetic resonance was 15 (6-33) years. Significant correlations were found between cardiac index and total alkaline phosphatase (-0.26, p=0.04), estimated creatinine clearance (0.26, p=0.02), and mean corpuscular volume (-0.32, p<0.01). Area under the curve for the three individual biomarkers was 0.63-0.69. Area under the curve for the three-biomarker panel was 0.75. Comparison of cardiac index above and below the receiver operating characteristic curve-identified cut-off points revealed significant differences for each biomarker (p<0.01) and for the composite panel [median cardiac index for higher-risk group=2.17 L/minute/m2 versus lower-risk group=2.96 L/minute/m2, (p<0.01)]. CONCLUSIONS: Higher total alkaline phosphatase and mean corpuscular volume as well as lower estimated creatinine clearance identify Fontan patients with lower cardiac index. Using biomarkers to monitor haemodynamics and organ-specific effects warrants prospective investigation.

Ultrasonographic imaging of the cervical thoracic duct in children with congenital or acquired heart disease.

Conditions that increase central venous pressure lead to secondary dilation of the thoracic duct and impaired lymphatic circulation. We report the use of ultrasound to directly image the cervical part of the thoracic duct in children without the need for invasive techniques or contrast agents. Systematic evaluation of the thoracic duct may be useful in cardiovascular conditions with congestion of the lymphatic system such as single ventricle following Glenn or Fontan procedures.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive genetic cardiomyopathy characterized by progressive fatty and fibrous replacement of ventricular myocardium. The clinical presentation is marked by ventricular arrhythmias, some fatal. The disease has evolved from a primary electrical/electrophysiological disorder (in the 1980s-1990s) to a diagnostic imaging conundrum (in the 2000s) to the current day understanding of a genetic cardiomyopathy caused by defects in cell-cell adhesion proteins or intracellular signaling components. The pathogenesis, clinical presentation, and the genetics of the disease are discussed in this review.

Disorders of left ventricular trabeculation/compaction or right ventricular wall formation.

Cardiomyopathies are remarkably variable in form. Although hearts may be dilated or hypertrophic, the spectrum of cardiomyopathies includes left ventricular noncompaction/hypertrabeculation and right ventricular wall disorders. These conditions have been increasingly recognized in patients given advances in clinical diagnostics. Here we present information on cardiac pathophysiology, from ventricular wall formation and trabeculae in model organisms to pediatric and adult disease. Many genes to affect the ventricular phenotype, and this has implications for deciphering developmental and disease pathways and for applying testing for clinical care.

Association of Digoxin With Preserved Echocardiographic Indices in the Interstage Period: A Possible Mechanism to Explain Improved Survival?

Background For patients with hypoplastic left heart syndrome, digoxin has been associated with reduced interstage mortality after the Norwood operation, but the mechanism of this benefit remains unclear. Preservation of right ventricular (RV) echocardiographic indices has been associated with better outcomes in hypoplastic left heart syndrome. Therefore, we sought to determine whether digoxin use is associated with preservation of the RV indices in the interstage period. Methods and Results We conducted a retrospective cohort study of prospectively collected data using the public use data set from the Pediatric Heart Network Single Ventricle Reconstruction trial, conducted in 15 North American centers between 2005 and 2008. We included all patients who survived the interstage period and had echocardiographic data post-Norwood and pre-Glenn operations. We used multivariable linear regression to compare changes in RV parameters, adjusting for relevant covariates. Of 289 patients, 94 received digoxin at discharge post-Norwood. There were no significant differences in baseline clinical characteristics or post-Norwood echocardiographic RV indices (RV end-diastolic volume indexed, RV end-systolic volume indexed, ejection fraction) in the digoxin versus no-digoxin groups. At the end of the interstage period and after adjustment for relevant covariates, patients on digoxin had better preserved RV indices compared with those not on digoxin for the ΔRV end-diastolic volume (11 versus 15 mL, P=0.026) and the ΔRV end-systolic volume (6 versus 9 mL, P=0.009) with the indexed ΔRV end-systolic volume (11 versus 20 mL/BSA1.3, P=0.034). The change in the RV ejection fraction during the interstage period between the 2 groups did not meet statistical significance (-2 versus -5, P=0.056); however, the trend continued to be favorable for the digoxin group. Conclusions Digoxin use during the interstage period is associated with better preservation of the RV volume and tricuspid valve measurements leading to less adverse remodeling of the single ventricle. These findings suggest a possible mechanism of action explaining digoxin's survival benefit during the interstage period.

Model-Based Comparison of the Normal and Fontan Circulatory Systems-Part III.

BACKGROUND: For patients with the Fontan circulatory arrangement, angiotensin-converting enzyme inhibition, guanylate cyclase activation, phosphodiesterase 5 inhibition, and endothelin receptor antagonism have so far resulted in little or no improvement in [Formula: see text] or peak cardiac index (CI), suggesting that our understanding of the factors that most impact the exercise hemodynamics is incomplete. METHODS: To facilitate comparisons with clinical reports of the exercise performance of preadolescent Fontan patients, we rescaled our previously reported computational models of a two-year-old normal child and similarly aged Fontan patient, extended our Fontan model to capture the nonlinear relationship between flow and resistance quantified from previous computational fluid dynamic analyses of the total cavopulmonary connection (TCPC), and added respiration as well as skeletal muscle contraction. RESULTS: (1) Without respiration, the computational model for both the normal and the Fontan cannot attain the values for CI at peak exercise reported in the clinical literature, (2) because flow through the TCPC is much greater during inspiration than during expiration, the effect on the CI of the dynamic (flow-related) TCPC resistance is much more dramatic during exercise than it is in breath-hold mode at rest, and (3) coupling breathing with skeletal muscle contraction leads to the highest augmentation of cardiac output, that is, the skeletal muscle pump is most effective when the intrathoracic pressure is at a minimum-at peak inspiration. CONCLUSIONS: Novel insights emerge when a Fontan model incorporating dynamic TCPC resistance, full respiration, and skeletal muscle contraction can be compared to the model of the normal.

Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines.

PURPOSE: To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer. PATIENTS AND METHODS: This was a randomized, double-blind, controlled clinical trial comparing enalapril to placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure. RESULTS: There was no difference in the rate of change in MCI per year between enalapril and placebo groups (0.30 v 0.18 L/min/m(2); P =.55). However, during the first year of treatment, the rate of change in LVESWS was greater in the enalapril group than in the placebo group (-8.59 v 1.85 g/cm(2); P =.033) and this difference was maintained over the study period, resulting in a 9% reduction in estimated LVESWS by year 5 in the enalapril group. Six of seven patients removed from random assignment to treatment because of cardiac deterioration were initially treated with placebo (P =.11), and one has died as a result of heart failure. Side effects from enalapril included dizziness or hypotension (22% v 3% in the placebo group; P =.0003) and fatigue (10% v 0%; P =.013). CONCLUSION: Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions.

Using health-related quality of life measures to predict cardiac function in survivors exposed to anthracyclines.

PURPOSE: As the number of pediatric cancer survivors increases, so does the number of survivors previously exposed to anthracyclines as part of their cancer therapy. Because screening is costly, some have suggested that health-related quality of life (HRQL) measures might be useful in focusing screening tests on those patients with cases most likely to display positive findings. This study reports on the predictive ability of HRQL measures to detect patients with abnormalities on serial cardiac testing. METHODS: Using 127 patients from the ACE-Inhibitor after Anthracycline (AAA) Trial, this study compared serial measures of the Short Form-36 (SF-36; for ages > 13 years) and Child Health Questionnaire-Child Form 87 (CHQ-CF87; for ages < or = 13 years) to serial cardiac performance tests including echocardiographic shortening fraction, left ventricular end systolic wall stress (LVESWS), LVESWS-index, and maximal cardiac index (MCI; a measure of cardiac output at peak exercise). RESULTS: Generally, there was no clinically or statistically significant correlation between any HRQL measure and any cardiac function measure except between MCI and vitality and physical functioning. For each of these measures, the correlation between MCI was statistically significant (P < .006), but each HRQL subscale could explain no more than 7% of the variation in MCI. HRQL measures were not predictive of any other cardiac function measure. CONCLUSION: HRQL measures should not be used in isolation as a screen for cardiac function abnormalities in patients exposed to anthracylines who already have a mild degree of ventricular dysfunction. Patient history appears to be no substitute for cardiac testing in this cohort.

Model-Based Comparison of the Normal and Fontan Circulatory Systems-Part II: Major Differences in Performance Characteristics.

BACKGROUND: In the absence of an accessible chronic animal model of the Fontan circulation, computational modeling can provide insights into this unique circulatory arrangement, especially how differently it behaves from the normal mammalian circulation. Many groups have focused on refining a single element of the entire Fontan circulation-the total cavopulmonary connection (TCPC). Yet, only modest improvements in transplant-free survival have resulted. From an engineering perspective, optimizing the performance of a complex, multiparameter system requires an understanding of how the performance is affected by the full set of system parameters. METHODS: We evaluated the hemodynamic impact of nine physiological perturbations in the two-year-old (yo) patient with hypoplastic left heart syndrome having a Fontan rearrangement (using our previously described lumped-parameter multicompartment model of both pulmonary and systemic circulations). In cases where comparison is appropriate, we evaluated the hemodynamic impact of analogous pathophysiologies in the normal two-year-olds. We operated the model in open-loop mode in order to expose the magnitude of the impact of uncompensated physiological perturbations. RESULTS: Without the benefit of compensatory mechanisms, a valvar regurgitant fraction of 50% is sufficient to drop the cardiac index (CI) to 2.0 L/min/m(2) or less. Aortopulmonary collateral flow of 0.6 L/min (1.1 L/min/m(2)) or 0.5 L/min (0.9 L/min/m(2)), sufficient to raise the ratio of pulmonary flow to systemic flow (Qp/Qs) to no higher than 1.2 or 1.5 (fenestration present or absent, respectively), is the maximum which could be tolerated (CI = 2.0 L/min/m(2)) without the help of compensatory mechanisms. Ventricular end-diastolic elastance (stiffness) changes have dramatic effects on CI in a Fontan circulatory arrangement. CONCLUSIONS: Several components of the Fontan circulation other than the TCPC actually have equal, or greater, impact on CI under certain conditions.

Cloning and characterization of zebrafish tbx1.

Tbx1 is one of the genes within the DiGeorge Critical Region (DGCR) and has been recently identified as the critical gene for the cardiovascular anomalies in the DiGeorge mouse models. We have cloned, sequenced and analyzed the zebrafish (Danio rerio) tbx1 cDNA. It encodes a protein of 460 amino acids that shares 64% identity and 67% similarity with the human TBX1 orthologue at the amino acid level. Although maternal expression was detected by RT-PCR, only zygotic expression could be detected by whole-mount in situ hybridization. Expression of zebrafish tbx1 by whole-mount in situ hybridization was first detected at 40% epiboly, 5.0 hours post fertilization (hpf) in the dorsal blastoderm margin. Through the stage of embryonic shield formation, tbx1 expression is restricted to the hypoblast, in the region of cells fated to become head and lateral plate mesoderm and pharyngeal endoderm. At 18 hpf, when the heart tube is beginning to assemble, three domains of tbx1 expression can be seen: cardiac precursors, pharyngeal arch precursors and otic vesicle. These three domains will remain the sites of tbx1 expression to varying degrees through at least 72 hpf. By 51 hpf, tbx1 expression can be seen in the cardiac outflow tract, the ventricle and the atrium, although by 72 hpf cardiac expression is strongest in the cardiac outflow tract. This newly identified tbx1 expression pattern in cardiac regions other than the cardiac outflow tract offers a new insight into the role of the tbx1 transcription factor in cardiac development.

Model-Based Comparison of the Normal and Fontan Circulatory Systems: Part I: Development of a General Purpose, Interactive Cardiovascular Model.

BACKGROUND: Every year, approximately 1,000 Fontan operations are performed in the United States. Transplant-free, 30-year survival is only 50%. Although some performance characteristics may be universal among Fontan survivors, others may be patient specific and tunable; in either case, a quantitatively rigorous understanding of the Fontan circulatory arrangement would facilitate improvements in patient surveillance and management. METHODS: To create a computational model of a normal two-year-old and a two-year-old patient with hypoplastic left heart syndrome (HLHS) following staged surgical palliations, we extensively modified the lumped parameter model developed by Clark, a multicompartment model of both pulmonary and systemic circulations. RESULTS: With appropriately scaled parameter values, we achieved a maximum relative error (against target values for clinically realistic hemodynamic variables for the normal two-year-old) of 2.8% and an average relative error of 0.9%. Employing the model of a Fontan operation, we achieved a maximum relative error of 2.0% and the average relative error of 0.8%. CONCLUSIONS: Even with >200 model parameters, once we identified an acceptable set of values for the normal, only 12 required modification in order to attain clinically plausible hemodynamics in the HLHS after Fontan. When placed within the broad context of our extensive model, the impact on cardiac output of the resistance of the total cavopulmonary connection is found to be significantly affected by ventricular elastance and to be much lower in the two-year-old than in patients with markedly lower end-diastolic elastance (higher end-diastolic compliance).

How insights from cardiovascular developmental biology have impacted the care of infants and children with congenital heart disease.

To illustrate the impact developmental biology and genetics have already had on the clinical management of the million infants born worldwide each year with CHD, we have chosen three stories which have had particular relevance for pediatric cardiologists, cardiothoracic surgeons, cardiac anesthesiologists, and cardiac nurses. First, we show how Margaret Kirby's finding of the unexpected contribution of an ectodermal cell population - the cranial neural crest - to the aortic arch arteries and arterial pole of the embryonic avian heart provided a key impetus to the field of cardiovascular patterning. Recognition that a majority of patients affected by the neurocristopathy DiGeorge syndrome have a chromosome 22q11 deletion, have also spurred tremendous efforts to characterize the molecular mechanisms contributing to this pathology, assigning a major role to the transcription factor Tbx1. Second, synthesizing the work of the last two decades by many laboratories on a wide gamut of metazoans (invertebrates, tunicates, agnathans, teleosts, lungfish, amphibians, and amniotes), we review the >20 major modifications and additions to the ancient circulatory arrangement composed solely of a unicameral (one-chambered), contractile myocardial tube and a short proximal aorta. Two changes will be discussed in detail - the interposition of a second cardiac chamber in the circulation and the septation of the cardiac ventricle. By comparing the developmental genetic data of several model organisms, we can better understand the origin of the various components of the multicameral (multi-chambered) heart seen in humans. Third, Martina Brueckner's discovery that a faulty axonemal dynein was responsible for the phenotype of the iv/iv mouse (the first mammalian model of human heterotaxy) focused attention on the biology of cilia. We discuss how even the care of the complex cardiac and non-cardiac anomalies seen in heterotaxy syndrome, which have long seemed impervious to advancements in surgical and medical intensive care, may yet yield to strategies grounded in a better understanding of the cilium. The fact that all cardiac defects seen in patients with full-blown heterotaxy can also be seen in patients without obvious laterality defects hints at important roles for ciliary function not only in left-right axis specification but also in cardiovascular morphogenesis. These three developmental biology stories illustrate how the remaining unexplained mortality and morbidity of congenital heart disease can be solved.

Insights after 40 years of the fontan operation.

Fontan's visionary operation and its modifications over the ensuing decades have re-established nonturbulent flow and substantially reduced cyanosis for patients with severe hypoplasia of one ventricle. However, a long list of largely unexpected sequelae has emerged over the last 40 years. Although it is not difficult to understand how care providers could become discouraged, a number of myths have arisen, which we will attempt to dispel with real-world counterexamples as well as with lessons learned from other disciplines: evolutionary, developmental, and computational biology. We argue that distinctive biochemical abnormalities pointing to dysfunction in multiple organs, including the largest organ system in the body, the endothelium, occur long before grossly observable changes in cardiac imaging can be recognized. With a rational redesign of both our surveillance scheme and our wellness strategies, we hope that Fontan survivors and their families, as well as physicians, nurses, and therapists, will see why Fontan's principle remains just as vibrant today as it was in 1971.

Serum alkaline phosphatase reflects post-Fontan hemodynamics in children.

Although survivors of Fontan palliation for a single ventricle are known to have lower cardiac index than patients with two-ventricle surgical reconstructions, it is unclear whether two frequently observed sequelae, short stature and protein-losing enteropathy (PLE), have hemodynamic origins. A serum marker that reflects hemodynamic status would be a tremendous asset in the long-term management of children with these sequelae. The authors recently noted severely reduced total alkaline phosphatase (TALP) levels in two children with early-onset PLE after Fontan operations, both of whom had low cardiac output at cardiac catheterization. Catheter-based or surgical interventions that rapidly increased cardiac output in these two patients resulted not only in relief of PLE but also in a prompt TALP rise. To examine whether the apparent correlation of low TALP with impaired cardiac output also is seen in Fontan patients without PLE, this study retrospectively examined the TALP data from two other Fontan patients who underwent cardiac catheterization specifically to assess the potential benefit of vasodilator therapy. The TALP levels were abnormally low in both cases but increased after up-titration of angiotensin-converting enzyme inhibition. Serum TALP activity, an indicator of osteoblastic function particularly in pre-adolescence, may be a marker of low cardiac output after a Fontan operation.

Developmental regulation and expression of the zebrafish connexin43 gene.

We cloned and sequenced the zebrafish (Danio rerio) connexin43 (Cx43alpha1) gene. The predicted protein sequence shows a high degree of sequence conservation. Transcript analyses revealed multiple transcription start sites and a potential alternative transcript encoding a N-terminally truncated Cx43alpha1 protein. Maternal Cx43alpha1 transcripts were detected, with zygotic expression initiated before gastrulation. In situ hybridization revealed many Cx43alpha1 expression domains, including the notochord and brain, heart and vasculature, many resembling patterns seen in mammalian embryos. Of interest, a reporter construct under control of the mouse Cx43alpha1 promoter was observed to drive green fluorescent protein expression in zebrafish embryos in domains mimicking the native Cx43alpha1 expression pattern in fish and mice. Sequence comparison between the mouse and zebrafish Cx43alpha1 promoter sequences showed the conservation of several transcription factor motifs, which otherwise shared little overall sequence homology. The conservation of protein sequence and developmental gene regulation would suggest that Cx43alpha1 gap junctions are likely to have conserved roles in vertebrate embryonic development.

T-box genes and cardiac development.

BACKGROUND: T-box genes play roles in vertebrate gastrulation and in later organogenesis. Their existence in all metazoans examined so far indicates that this is an evolutionarily ancient gene family. Drosophila melanogaster has eight T-box genes, whereas Caenorhabditis elegans has 22. Mammals appear to have at least 18 T-box genes, comprising five subfamilies. METHODS: A full range of cytological, developmental, molecular and genetic methodologies have recently been applied to the study of T-box genes. RESULTS: Over the last 5 years, mutations in TBX1 and TBX5 have been implicated in two human disorders with haplo-insufficient cardiovascular phenotypes, DiGeorge/velocardiofacial syndrome and Holt-Oram ("heart-hand") syndrome. Interestingly, the number of T-box gene family members discovered to have cardiac or pharyngeal arch expression domains during vertebrate embryonic development has steadily grown. In addition, various Tbx5 loss-of-function models in organisms as distant as the mouse and zebrafish do indeed phenocopy Holt-Oram syndrome. Finally, the intriguing discovery earlier this year that a T-box gene is expressed in a subset of cardioblasts in D. melanogaster suggests that members of this gene family may have fundamental, conserved roles in cardiovascular pattern formation. CONCLUSIONS: These developments prompted us to review the current understanding of the contribution of T-box genes to cardiovascular morphogenesis.