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Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator-activated receptor-γ coactivator 1α, a key regulator of fatty acid metabolism, and that proliferator-activated receptor-γ coactivator 1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice., Conclusions: Decreased proliferator-activated receptor-γ coactivator 1α expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart. (Hepatology 2017;65:189-201)., (© 2016 by the American Association for the Study of Liver Diseases.)

Objectives: Sudden death is common in patients with hypoplastic left heart syndrome and comparable lesions with parallel systemic and pulmonary circulation from a common ventricular chamber. It is hypothesized that unforeseen acute deterioration is preceded by subtle changes in physiologic dynamics before overt clinical extremis. Our objective was to develop a computer algorithm to automatically recognize precursors to deterioration in real-time, providing an early warning to care staff., Methods: Continuous high-resolution physiologic recordings were obtained from 25 children with parallel systemic and pulmonary circulation who were admitted to the cardiovascular intensive care unit of Texas Children's Hospital between their early neonatal palliation and stage 2 surgical palliation. Instances of cardiorespiratory deterioration (defined as the need for cardiopulmonary resuscitation or endotracheal intubation) were found via a chart review. A classification algorithm was applied to both primary and derived parameters that were significantly associated with deterioration. The algorithm was optimized to discriminate predeterioration physiology from stable physiology., Results: Twenty cardiorespiratory deterioration events were identified in 13 of the 25 infants. The resulting algorithm was both sensitive and specific for detecting impending events, 1 to 2 hours in advance of overt extremis (receiver operating characteristic area = 0.91, 95% confidence interval = 0.88-0.94)., Conclusions: Automated, intelligent analysis of standard physiologic data in real-time can detect signs of clinical deterioration too subtle for the clinician to observe without the aid of a computer. This metric may serve as an early warning indicator of critical deterioration in patients with parallel systemic and pulmonary circulation., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

While exercise stress testing (EST) is an important tool, little is known about its use for determining ischemia in patients with hypoplastic left heart syndrome (HLHS) and Fontan palliation. We sought to determine the frequency of ST segment changes during EST in HLHS patients after Fontan and examine results of further testing performed in response to ST changes. A single-center chart review of HLHS patients post-Fontan from January 1995 to December 2012 was performed. Data collected included demographics, indications for EST, resting electrocardiogram findings, EST and echocardiogram results and outcomes. ESTs were evaluated for ST segment changes concerning for ischemia. Results of additional testing performed based on concerning EST findings were collected. Twenty-seven patients underwent 64 ESTs (mean 2.4 ESTs/patient). Median age at first EST was 9.6 years (range 6.2-16.4). EST was concerning for ischemia in 13 patients (48 %) on 25 (39 %) ESTs. Based on EST results, two patients had stress sestamibi testing, two underwent coronary angiography, and one had both. No reversible perfusion defects or coronary artery obstructions were demonstrated. No patient who underwent EST has died. ST segment depression was not associated with ventricular dysfunction prior to EST or at the end of follow-up (p > 0.05). In patients with HLHS post-Fontan palliation, ST segment depression on EST is common. In patients who underwent further testing, no evidence of ischemia or coronary abnormalities was found. Additional testing may not be necessary in all patients.

Clinically significant cardiovascular malformations (CVMs) occur in 5-8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs.

Objective: Barth syndrome is an X-linked recessive disorder characterized by dilated cardiomyopathy, neutropenia, 3-methylglutaconic aciduria, abnormal mitochondria, variably expressed skeletal myopathy, and growth delay. The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28. We report a novel exonic splicing mutation in the TAZ gene in a patient with atypical Barth syndrome., Patient & Methods: The 4-month-old proband presented with respiratory distress, neutropenia, and dilated cardiomyopathy with reduced ejection fraction of 10%. No 3-methylglutaconic aciduria was detected on repeated urine organic acid analyses. Family history indicated that his maternal uncle died of endocardial fibroelastosis and dilated cardiomyopathy at 26 months. TAZ DNA sequencing, mRNA analysis, and cardiolipin analysis were performed., Results: A novel nucleotide substitution c.553A>G in exon 7 of the TAZ gene was identified in the proband, predicting an amino acid substitution p.Met185Val. However, this mutation created a new splice donor signal within exon 7 causing mis-splicing of the message, producing two messages that only differ in the presence/absence of exon 5; these retain intron 6 and have only 11 bases of exon 7. Cardiolipin analysis confirmed the loss of tafazzin activity. The proband's mother, maternal aunt, and grandmother carry the same mutation., Conclusions: The identification of a TAZ gene mutation, mRNA analysis, and monolysocardiolipin/cardiolipin ratio determination were important for the diagnosis and genetic counseling in this family with atypical Barth syndrome that was not found to be associated with 3-methylglutaconic aciduria.

We validated a multi-scale model of a left-dominant coronary circulation using high fidelity pressure and flow data acquired in adult sheep and newborn lambs. The model incorporated a one-dimensional representation of the major left conduit coronary arteries, allowing for the study of wave propagation effects. The coronary microvasculature was represented by regional instances of a lumped parameter model consisting of three transmural layers, each with two serial compartments accounting for compliance, resistance and intramyocardial pressure effects. Model inputs comprised measured aortic pressure/flow and ventricular pressure. Minimal data fitting was employed, with only measured mean coronary flow used to iteratively adjust total coronary resistance. The model was adapted to different heart sizes via allometric scaling. Excellent agreement was observed between model and experimental flow waveforms in the proximal circumflex artery, both in terms of the degree of systolic flow impediment and transient waveform features. The proposed multi-scale modelling approach is likely to be useful for studying phasic features of the coronary flow waveform, including coronary waves in different coronary anatomies and throughout development.

Separating pressure, flow/velocity and wave intensity signals into forward and backward components provide insights about arterial wave propagation and reflection. A linear wave separation is normally used, but ignores the pressure-dependence of wave speed. While a non-linear separation could incorporate this pressure-dependence, no such method exists for wave intensity decomposition. Moreover, although linear separation errors for pressure (5-10 %) have been quantified previously, errors for velocity and wave intensity have not. Accordingly, we describe a non-linear wave separation technique based on the method of characteristics. Data from a computer model suggest that the percentage linear separation errors for velocity and wave intensity are approximately one-half and twice that for pressure, respectively. Although comparable to measurement uncertainty in many instances, linear separation errors may become more significant: (1) if wave speed varies substantially over the cardiac cycle, e.g. if pulse pressure or vessel compliance is high, (2) if the degree of wave reflection in the arterial system is large, or (3) if the constant wave speed used for the linear separation is closer to the minimum or maximum pressure-dependent value rather than the mean. Consideration of linear separation errors may therefore be important in some physiological settings.

Arterial wave speed estimated invasively from pressure (P) and velocity (U) measurements using the P-U loop method, or non-invasively from diameter (D) and U measurements using the lnD-U loop method, assume that during early systole 1) backward-running waves are absent and 2) wave speed is constant. These assumptions also form the basis of a method for correcting time lags between P (or lnD) and U in which the R(2) of the early-systolic linear regression is maximized. However, neither of the two assumptions are strictly valid in vivo, where the diastolic pressure decay from the previous beat may give rise to some non-zero backward-running P, U and wave intensity (WI) components, and the pressure-dependency of wave speed may lead to curvilinearity in the early-systolic P-U and lnD-U relations. Accordingly, this study assessed the robustness of three phase correction algorithms, (including two that are not dependent on the two assumptions stated above, i.e., aligning the times of the peak 2nd derivative or peak signal curvature) and of the P-U and lnD-U loop wave speed estimation methods under a range of diastolic decay rates and degrees of vessel wall non-linearity. Results from a simple computer model of the arterial circulation suggested that although an apparent phase lag may be introduced by assuming linearity, the magnitude of this phase lag is likely to be small considering the sample intervals normally used in experimental studies; however, under highly non-linear flow conditions, the apparent lag may be comparable to hardware-related lags. Predicted errors in estimated wave speed using the P-U loop method were generally less than 10%, while somewhat higher errors were found in the lnD-U loop method (up to 15-20%). In both, higher diastolic pressure decay rates were associated with higher wave speed errors, although this effect was eliminated by subtracting the extrapolated diastolic pressure curve from the measured pressure. Overall, each of the time lag correction algorithms and wave speed estimation methods were generally satisfactory, although further experimental work is required to assess the curvature-based phase correction method and pressure adjustment in vivo.

Heart failure is an important cause of morbidity and mortality in individuals of all ages. The many-faceted nature of the clinical heart failure syndrome has historically frustrated attempts to develop an overarching explanative theory. However, much useful information has been gained by basic and clinical investigation, even though a comprehensive understanding of heart failure has been elusive. Heart failure is a growing problem, in both adult and pediatric populations, for which standard medical therapy, as of 2010, can have positive effects, but these are usually limited and progressively diminish with time in most patients. If we want curative or near-curative therapy that will return patients to a normal state of health at a feasible cost, much better diagnostic and therapeutic technologies need to be developed. This review addresses the vexing group of heart failure etiologies that include cardiomyopathies and other ventricular dysfunctions of various types, for which current therapy is only modestly effective. Although there are many unique aspects to heart failure in patients with pediatric and congenital heart disease, many of the innovative approaches that are being developed for the care of adults with heart failure will be applicable to heart failure in childhood., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Specific features of hemodynamic signals are invaluable for elucidating ventricular and vascular function. A semi-automatic algorithm is presented that enables accurate detection of any feature in any hemodynamic signal, using feature extraction from local maxima and minima in signal curvature. A particular feature is selected manually in the first beat and then detected automatically in subsequent beats.

Objective: We sought to assess the effects of insulin-like growth factor 1 on the balance between systemic oxygen consumption and oxygen delivery after cardiopulmonary bypass in piglets., Methods: Twelve piglets weighing 4.5 to 8.3 kg undergoing hypothermic (28 degrees C) cardiopulmonary bypass for 70 to 120 minutes with 40 minutes of aortic crossclamping were studied before and during the first 6 hours after cardiopulmonary bypass. Oxygen consumption was continuously measured by an indirect calorimeter, Deltatrac II MBM-200 Metabolic Monitor (Datex Division Instrumentarium, Helsinki, Finland). Oxygen delivery and cardiac output were calculated from oxygen consumption and the arterial and mixed venous oxygen contents sampled before and every 30 minutes after cardiopulmonary bypass. Oxygen extraction ratio was derived by the ratio of oxygen consumption to oxygen delivery. Arterial blood lactate was measured before and every 30 minutes after cardiopulmonary bypass. Six animals were randomly assigned to receive an intravenous infusion of insulinlike growth factor 1 at 1.2 mg/h from 1 to 6 hours after cardiopulmonary bypass; the remaining 6 served as a control group., Results: Relative to the control group, intravenous infusion of insulin-like growth factor 1 significantly reduced oxygen consumption (P =.02) and increased cardiac output (P =.016) and oxygen delivery (P =.049) during the first 6 hours after surgery with hypothermic cardiopulmonary bypass. As a result, oxygen extraction was significantly decreased (P =.012)., Conclusions: Intravenous infusion of insulin-like growth factor 1 improved oxygen transport by reducing oxygen consumption as well as increasing cardiac output and oxygen delivery during the first 6 hours after cardiopulmonary bypass in piglets. This may have important clinical implications for the care of critically ill children after surgery with cardiopulmonary bypass.

It is unknown if nitric oxide (NO) modulates the balance between systemic or myocardial O2 delivery ( DO2) and consumption VO2 during inotropic stimulation with the beta-adrenergic agonist dobutamine. Accordingly, we measured systemic and left ventricular (LV) DO2 and during dobutamine infusion to a peak of 10 microg .kg-1 .min-1, before and after inhibition of NO synthesis with i.v. N(omega)-nitro- L-arginine ( L-NNA, 25 mg.kg-1) in 11 anesthetized ewes instrumented with aortic, pulmonary arterial and coronary sinus catheters, an ultrasonic coronary artery flow probe and a pulmonary arterial thermistor to measure cardiac output. L-NNA reduced systemic DO2 by 19% (2.1+/-0.5 ml.min-1.kg-1, P<0.005) but increased systemic by 13% (0.4+/-0.1 ml.in-1.g-1, P<0.05), whereas LV DO2 and rose by 44% (4.3+/-1.3 ml.min-1).100 g-1, P<0.005) and 47% (3.1+/-0.9.min-1.100 g-1, P<0.025) respectively. Dobutamine increased systemic DO2 by 61% (5.3+/-0.9 ml.min-1.kg-1, P<0.001) and systemic by 10% (0.32+/-0.12 ml.min-1.kg-1, P<0.01), with no effect of L-NNA on either response ( P>0.9). As a result, while was 0.5 ml.min(-1).kg-1 higher at any given level of DO2 ( P<0.001), the slope of the systemic DO2- relation was unchanged after L-NNA. By contrast, LV DO2 increased by 152% (15.6+/-2.2 ml.min-1.100 g-1, P<0.001) and by 184% (12.7+/-1.9 ml.min-1.100 g-1, P<0.001), but because the slope of both dose-response curves was reduced by 48% after L-NNA ( P<0.001), the LV DO2- relationship was unaffected by inhibition of NO synthesis. These results suggest that NO modulated the baseline balance between systemic, but not myocardial, DO2 and. However, NO did not additionally alter dobutamine-related changes in either systemic or myocardial DO2 and balance.