A CCTA-based strategy for low-to-intermediate-risk patients presenting with a possible acute coronary syndrome appears to allow the safe, expedited discharge from the emergency department of many patients who would otherwise be admitted. (Funded by the Commonwealth of Pennsylvania Department of Health and the American College of Radiology Imaging Network Foundation; ClinicalTrials.gov number, NCT00933400.).
Background-We tested the hypothesis that increased cardiac myocyte adenylyl cyclase (AC) content increases cardiac function and response to catecholamines in cardiomyopathy. Methods and Results-Transgenic mice with cardiac-directed expression of AC type VI (AC VI ) were crossbred with mice with cardiomyopathy induced by cardiac-directed G q expression. G q mice had dilated left ventricles, reduced heart function, decreased cardiac responsiveness to catecholamine stimulation, and impaired -adrenergic receptor (AR)-dependent and AC-dependent cAMP production. G q /AC mice showed improved basal cardiac function in vivo (Pϭ0.01) and ex vivo (PϽ0.0005). When stimulated through the AR, cardiac responsiveness was increased (Pϭ0.02), and cardiac myocytes showed increased cAMP production in response to isoproterenol (Pϭ0.03) and forskolin (PϽ0.0001). Key Words: receptors, adrenergic, beta Ⅲ gene therapy A hallmark of dilated cardiomyopathy is decreased generation of cAMP by cardiac myocytes in response to -adrenergic receptor (AR) stimulation. However, treatments for clinical heart failure that increase myocardial cAMP content with pharmacological agents that stimulate the AR or decrease the breakdown of cAMP generally have failed, perhaps because of deleterious consequences of unrelenting stimulation of the AR. Indeed, overexpression of cardiac ARs in transgenic mice caused increased basal heart rate, function, and cAMP generation, 1 and mice overexpressing cardiac G s␣ developed cardiomyopathy due to sustained AR stimulation. 2 Cardiac-directed overexpression of ARs failed to improve heart function and increased mortality in murine dilated cardiomyopathy. 3 We recently showed that cardiac myocytes with increased expression of adenylyl cyclase (AC) produce more cAMP when stimulated through the AR or AC. 4 Cardiac-directed expression of AC type VI (AC VI ) results in a phenotypically normal heart with normal basal function and cAMP levels but supranormal responses to catecholamine stimulation. 5 Thus, receptor/G-protein overexpression and standard inotropic therapy yield continuous AR activation and detrimental consequences, whereas overexpression of cardiac AC VI alters transmembrane signaling only when receptors are activated.
Conclusions-IncreasingThis could provide increased cAMP generation in heart failure in a manner that circumvents the deleterious consequences of sustained activation.Cardiac-directed expression of G q results in reduced left ventricular (LV) function, decreased cardiac responsiveness to catecholamines, and impaired AR-dependent and ACdependent cAMP production. 6 The exact mechanism for dilation is unknown, but G q is coupled to endothelin, angiotensin II, and ␣ 1 -adrenergic receptors, pathways that influence cardiac myocyte growth and remodeling. This model provides an opportunity to test the hypothesis that cardiacdirected AC expression can increase cAMP generation and restore heart function and response to catecholamines in dilated cardiomyopathy.
Methods
AnimalsAnimal use followed...
Compressive sensing (CS)-based interior tomography is a state-of-the-art method for accurate image reconstruction from only locally truncated projections. Here, we report our preliminary interior tomography results reconstructed from raw projections of a patient acquired on a GE Discovery CT750 HD scanner. This is the first clinical application of the CS-based interior reconstruction techniques, and the results show an excellent match with those reconstructed from global projections.
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