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Histone Deacetylase 3 Coordinates Heart Development Through Stage-Specific Roles in Cardiac Progenitor CellsDisruptions in cardiac development cause congenital heart disease, the most prevalent and deadly congenital malformation. Genetic and environmental factors are thought to contribute to these defects, however molecular mechanisms remain largely undefined. Recent work highlighted potential roles of chromatin- modifying enzymes in congenital heart disease pathogenesis. Histone deacetylases, a class of chromatin-modifying enzymes, have developmental importance and recognized roles in the mature heart. This thesis aimed to characterize functions of Hdac3 in cardiac development. We found loss of Hdac3 in the primary heart field causes precocious progenitor cell differentiation, resulting in hypoplastic ventricular walls, ventricular septal defect, and mid- gestational lethality. In primary heart field progenitors, Hdac3 interacts with, deacetylates, and functionally suppresses transcription factor Tbx5. Furthermore, a disease-associated Tbx5 mutation disrupts this interaction, rendering Tbx5 hyperacetylated and hyperactive. By contrast, deletion of Hdac3 in second heart field progenitors bypasses these defects, instead causing malformations in the outflow tract and semilunar valves, with lethality prior to birth. Affected semilunar valves and outflow tract vessels exhibit extracellular matrix and EndMT defects and activation of the Tgfβ1 signaling pathway. In normal second heart field development, Hdac3 represses Tgfβ1 transcription, independent of its deacetylase activity, by recruiting the PRC2 methyltransferase complex to methylate the Tgfβ1 promoter. Importantly, knockouts of Hdac3 in differentiated cardiac cells do not fully recapitulate the progenitor-specific knockout phenotypes. These results illustrate spatiotemporal roles of Hdac3, both deacetylase-dependent and deacetylase-independent, in cardiac development, suggesting that dysregulation of Hdac3 in cardiac progenitor cells could be a contributing factor in congenital heart disease pathogenesis.
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Third-degree heart block complicating supraclavicular brachial plexus blockRegional anesthesia is frequently administered to elderly patients and those with known cardiovascular disease in the hope of minimizing the cardiovascular complications associated with general anesthesia. Drug interactions between local anesthetics used in regional techniques and calcium channel blockers have been described. To date, however, potentially life-threatening dysrhythmias associated with brachial plexus blockade using the supraclavicular approach have not been reported. We now describe such a case.
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Coronary artery status of apparently healthy subjects with frequent and complex ventricular ectopyTwenty-five subjects from a cohort of 62 asymptomatic, apparently healthy subjects incidentally discovered to have frequent and complex ventricular ectopy were studied with cardiac catheterization and coronary angiography. Fourteen had normal coronary arteries, five noncritical coronary artery disease (less than 50% luminal narrowing), and six significant coronary artery disease (greater than or equal to 50% luminal narrowing). Slightly elevated left ventricular end diastolic pressures were found in all subject subgroups. Characteristics of the ventricular ectopy detected by maximal exercise testing or 24-hour Holter ambulatory electrocardiography did not differentiate those subjects with coronary artery disease from those with normal coronary arteries. This study documents that a minority of apparently healthy subjects with frequent and complex ventricular arrhythmia have significant coronary artery disease and supports a conservative approach to the management of such patients.
