Beschreibung: The number of patients surviving with congenital heart disease (CHD) has soared over the last 3 decades. Adults constitute the fastest-growing segment of the CHD population, now outnumbering children. Research to date on the heart-brain intersection in this population has been focused largely on neurodevelopmental outcomes in childhood and adolescence. Mutations in genes that are highly expressed in heart and brain may cause cerebral dysgenesis. Together with altered cerebral perfusion in utero, these factors are associated with abnormalities of brain structure and brain immaturity in a significant portion of neonates with critical CHD even before they undergo cardiac surgery. In infancy and childhood, the brain may be affected by risk factors related to heart disease itself or to its interventional treatments. As children with CHD become adults, they increasingly develop heart failure, atrial fibrillation, hypertension, diabetes mellitus, and coronary disease. These acquired cardiovascular comorbidities can be expected to have effects similar to those in the general population on cerebral blood flow, brain volumes, and dementia. In both children and adults, cardiovascular disease may have adverse effects on achievement, executive function, memory, language, social interactions, and quality of life. Against the backdrop of shifting demographics, risk factors for brain injury in the CHD population are cumulative and synergistic. As neurodevelopmental sequelae in children with CHD evolve to cognitive decline or dementia during adulthood, a growing population of CHD can be expected to require support services. We highlight evidence gaps and future research directions.

Beschreibung: Rationale: Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. After myocardial infarction, phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes. The molecular mechanisms of efferocytosis of cardiomyocytes and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function. Objective: We set out to identify mechanisms of dying cardiomyocyte engulfment by phagocytes and, for the first time, to assess the causal significance of disrupting efferocytosis during myocardial infarction. Methods and Results: In contrast to other apoptotic cell receptors, macrophage myeloid-epithelial-reproductive tyrosine kinase was necessary and sufficient for efferocytosis of cardiomyocytes ex vivo. In mice, Mertk was specifically induced in Ly6c LO myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic cardiomyocytes, independently of changes in noncardiomyocytes, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk ; reciprocal transplantation of Mertk +/+ marrow into Mertk –/– mice corrected systolic dysfunction. Interestingly, an inactivated form of myeloid-epithelial-reproductive tyrosine kinase, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of myeloid-epithelial-reproductive tyrosine kinase inactivation after myocardial infarction. Conclusions: These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.

Beschreibung: Background— Multiple echocardiographic methods are used to measure left ventricular size and function. Clinical management is based on individual evaluations and longitudinal trends. The Pediatric Heart Network VVV study (Ventricular Volume Variability) in pediatric patients with dilated cardiomyopathy has reported reproducibility of several of these measures, and how disease state and number of beats impact their reproducibility. In this study, we investigated the impact of observer and sonographer variation on reproducibility of dimension, area, and volume methods to determine the best method for both individual and sequential evaluations. Methods and Results— In 8 centers, echocardiograms were obtained on 169 patients prospectively. During the same visit, 2 different sonographers acquired the same imaging protocol on each patient. Each acquisition was analyzed by 2 different observers; first observer analyzed the first acquisition twice. Intraobserver, interobserver, interacquisition, and interobserver-acquisition (different observers and different acquisition) reproducibility were assessed on measurements of left ventricular end-diastolic dimension, area, and volume. Left ventricular shortening fraction, ejection fraction, mass, and fractional area change were calculated. Percent difference was calculated as (interobservation difference/mean) x 100. Interobserver reproducibility for both acquisitions was better for both volume and dimension measurements ( P ≤0.002) compared with area measurements, whereas intraobserver, interacquisition (for both observers), and interobserver-acquisition reproducibilities (for both observer-acquisition sets) were best for volume measurements ( P ≤0.01). Overall, interobserver-acquisition percent differences were significantly higher than interobserver and interacquisition percent differences ( P 〈0.001). Conclusions— In pediatric patients with dilated cardiomyopathy, compared with dimension and area methods, left ventricular measurements by volume method have the best reproducibility in settings where assessment is not performed by the same personnel. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00123071.

Beschreibung: Background— Fetal hypoxia has been implicated in the abnormal brain development seen in newborns with congenital heart disease (CHD). New magnetic resonance imaging technology now offers the potential to investigate the relationship between fetal hemodynamics and brain dysmaturation. Methods and Results— We measured fetal brain size, oxygen saturation, and blood flow in the major vessels of the fetal circulation in 30 late-gestation fetuses with CHD and 30 normal controls using phase-contrast magnetic resonance imaging and T2 mapping. Fetal hemodynamic parameters were calculated from a combination of magnetic resonance imaging flow and oximetry data and fetal hemoglobin concentrations estimated from population averages. In fetuses with CHD, reductions in umbilical vein oxygen content ( P 〈0.001) and failure of the normal streaming of oxygenated blood from the placenta to the ascending aorta were associated with a mean reduction in ascending aortic saturation of 10% ( P 〈0.001), whereas cerebral blood flow and cerebral oxygen extraction were no different from those in controls. This accounted for the mean 15% reduction in cerebral oxygen delivery ( P =0.08) and 32% reduction cerebral V o 2 in CHD fetuses ( P 〈0.001), which were associated with a 13% reduction in fetal brain volume ( P 〈0.001). Fetal brain size correlated with ascending aortic oxygen saturation and cerebral V o 2 ( r =0.37, P =0.004). Conclusions— This study supports a direct link between reduced cerebral oxygenation and impaired brain growth in fetuses with CHD and raises the possibility that in utero brain development could be improved with maternal oxygen therapy.