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.

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.

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).

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.

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.

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.

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.