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The voltage-gated potassium channel Kv4.3 was coexpressed with its beta-subunit Kv channel-interacting protein 2 and the angiotensin type 1 receptor in HEK-293 cells. Proteomic analysis of proteins coimmunoprecipitated with Kv4.3 revealed that Kv4.3 is associated with Rap guanine nucleotide exchange factors MR-GEF and EPAC-1. Previously, we demonstrated that Kv4.3 interacts with the angiotensin type 1 receptor in HE293 cells and cardiac myocytes. On the basis of this, we investigated the angiotensin type 1 receptor signaling to small G-proteins Ras and Rap-1 in the presence and absence of the Kv4.3-Kv channel-interacting protein 2 macromolecular complex. Ras activation was not significantly affected by coexpression of Kv4.3 and Kv channel-interacting protein 2. Ras exhibited a rapid activation-inactivation pattern with maximum activity at 2.5 min after addition of angiotensin II. In contrast, activation of Rap-1 was affected dramatically by coexpression of Kv4.3 and Kv channel-interacting protein 2 with the angiotensin type 1 receptor. In the absence of Kv4.3 and Kv channel-interacting protein 2, stimulation of the angiotensin type 1 receptor resulted in steady activation of Rap-1 that reached a plateau 25 min after addition of angiotensin II. In the presence of Kv4.3 and Kv channel-interacting protein 2, Rap-1 reaches a maximum activity 2.5 min after addition of angiotensin II and then deactivates rapidly, demonstrating a pattern of activation similar to that of Ras. Our findings show that Kv4.3 regulates angiotensin type 1 receptor signaling to the small G-protein Rap-1.

'Cardiac memory' describes an electrocardiographic T wave vector change, recorded during normal sinus rhythm that reflects the QRS complex vector during prior periods of ventricular pacing or arrhythmia. In this brief review we consider the mechanisms responsible for cardiac memory, which offer a unique window for relating molecular determinants of repolarization to their expression in the function of ion channels and in the electrophysiology of the heart. Understanding the steps that translate the molecular mechanisms for memory into clinical expression in this relatively straightforward model facilitates our comprehension of the complex pathways that order normal cardiac repolarization and repolarization changes.

Extract: Gene therapy and stem cells have become buzz words for future medical management. However, to date attempts to apply these technologies therapeutically have met with little success and, in the case of embryonic stem cells, have engendered political and philosophical debate. In this paper, we emphasize progress in one area of gene/stem cell therapy: the use of adult human mesenchymal stem cells (hMSCs, precursor cells for tissues such as skin, bone and muscle that are found in bone marrow) as a platform for delivering genes. These cells are adult hMSCs, and therefore not subject to the restrictions placed by some societies on use of human embryonic stem cells. In addition, they can be loaded with genes using a technique known as electroporation, by which an electrical charge temporarily makes the cell membrane permeable. This technique carries none of the risks that accompany the use of viral vectors, another method of gene delivery. As an example of the utility of hMSCs as platforms for gene delivery, we will discuss the fabrication of biological pacemakers.

Background: Blockade of oxidative phosphorylation may activate ATP sensitive mitochondrial potassium (mitoK(ATP)) channels. We examined whether both metabolic inhibition and mitoK(ATP) channel openers protect both the whole organ and isolated cells from ischemia., Methods and Results: Using a Langendorff preparation, one group of isolated rabbit hearts were exposed to ischemic preconditioning (IPC) via 2 episodes of flow interruption. The second group of hearts was preconditioned with 2 episodes of either the metabolic inhibitor, sodium cyanide (NaCN), or the mitoK(ATP) channel opener, diazoxide. The third group of hearts was exposed to the mitoK(ATP) channel inhibitor, 5-hydroxydecanoic acid (5-HD) prior to preconditioning with NaCN, diazoxide or IPC. Controls had no drug infused. Then, ischemia was induced in all hearts by left anterior descending coronary artery occlusion and infarct size was determined. Compared with controls (40+/-3%), infarct size was significantly reduced in hearts preconditioned with NaCN, diazoxide or IPC (18+/-3%, 26+/-3%, 21+/-2%, respectively; P<0.05 versus control). These reductions were reversed by 5-HD (36+/-3%, 33+/-2%, 37+/-2%; NaCN, diazoxide, IPC, respectively). Secondly, whole cell patch clamped isolated guinea pig ventricular myocytes were preconditioned with 2 episodes of either NaCN or diazoxide followed by Tyrodes perfusion with membrane potential set to -70 mV. Control cells were exposed to Tyrodes solution. All cells were then clamped to -20 mV and exposed to NaCN, which caused induction of an outward potassium current. Compared with controls, the average time to induction of the outward current was significantly reduced in cells preconditioned with either brief application of NaCN (11.6+/-1.8 versus 5.1+/-1.0 minutes, control versus NaCN, P<0.05) or diazoxide (5.5+/-1.4 versus 2.0+/-0.8 minutes, control versus diazoxide, P<0.05)., Conclusions: Preconditioning protects the heart through mitoK(ATP). This protection also alters a surface membrane current, which may be important in myocardial protection.

Background: Mental stress (MS) is an important provocateur of myocardial ischemia in many patients with chronic coronary artery disease. The majority of laboratory assessments of ischemia in response to MS have included measurements of either myocardial perfusion or function alone. We performed this study to determine the relationship between alterations in perfusion and ventricular function during MS. Methods and results Twenty-eight patients with reversible perfusion defects on exercise or pharmacologic stress myocardial perfusion imaging (MPI) underwent simultaneous technetium 99m sestamibi single photon emission computed tomography (SPECT) MPI and transthoracic echocardiography at rest and during MS according to a mental arithmetic protocol. In all cases the MS study was performed within 4 weeks of the initial exercise or pharmacologic MPI that demonstrated ischemia. SPECT studies were analyzed visually with the use of a 13-segment model and quantitatively by semiautomated circumferential profile analysis. Echocardiograms were graded on a segmental model for regional wall motion on a 4-point scale. Of 28 patients, 18 (64%) had perfusion defects and/or left ventricular dysfunction develop during MS: 9 (32%) had myocardial perfusion defects develop, 6 (21%) had regional or global left ventricular dysfunction develop, and 3 (11%) had both perfusion defects and left ventricular dysfunction develop. The overall concordance between perfusion and function criteria for ischemia during MS was only 46%. Among 9 patients with MS-induced left ventricular dysfunction, 5 had new regional wall motion abnormalities and 4 had a global decrement in function. In patients with MS-induced ischemia by SPECT, the number of reversible perfusion defects was similar during both MS and exercise/pharmacologic stress (2.8 +/- 2.0 vs 3.5 +/- 1.8, P =.41). Hemodynamic changes during MS were similar whether patients were divided on the basis of perfusion defects or left ventricular dysfunction during MS., Conclusions: These data indicate the feasibility of simultaneous assessment of perfusion and function responses during MS. Flow and function responses to MS are frequently not concordant. These data suggest that MS-induced changes in perfusion may represent a different phenomenon than MS-induced changes in left ventricular function (either globally or regionally).

From the time of its introduction as a clinical tool in the early 1970s, efforts have been made to use echocardiography to characterize the atrium and its function as these relate to attempted cardioversion and embolic risk. M-mode and 2-D echo studies suggest left atrial size is not a definitive determinant of the potential for successful cardioversion. Doppler studies show that atrial function can take weeks to recover postcardioversion, accounting in part for the delayed embolic risk. TEE is particularly effective at detecting atrial thrombi and shows that slow velocities in the atrium and appendage are an important risk factor for embolism and clot. All are associated with the finding of spontaneous echo contrast and atrial stunning postcardioversion. The ultimate role of TEE in management is not yet fully defined. The insights these and other studies provide to our understanding of atrial physiology and the appropriate management of atrial fibrillation are reviewed.