Sunny S. Po

Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop.

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.The National Heart, Lung, and Blood Institute convened an expert panel April 28-29, 2008 to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiologic and clinical literature about AF, and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: 1) Enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; 2) Improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; 3) Improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural and electrical remodeling markers; 4) Develop additional animal models reflective of the pathophysiology of human AF; 5) Conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and 6) Conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.

Distinct restitution properties in vagally mediated atrial fibrillation and six-hour rapid pacing-induced atrial fibrillation

AIMSnThe atrial potential duration (APD) restitution has been suggested to play an important role in ventricular fibrillation; however, its role in atrial fibrillation (AF) has not been determined. This study sought to investigate the APD restitution properties in two different AF models: vagally mediated AF and 6-h rapid atrial pacing-induced AF.nnnMETHODS AND RESULTSnTwenty anaesthetized open-chest dogs were assigned to Group I, vagally mediated AF (n= 8) or Group II, 6-h rapid atrial pacing-induced AF (n= 12). In both groups, the monophasic APD was subsequently recorded at multiple pulmonary vein and atrial sites. The APD restitution curve was constructed using a dynamic pacing protocol and determined by plotting each APD(90) against the preceding diastolic interval at incremental atrial pacing rates at eight sites. In Group I, vagal stimulation significantly shortened the APD(90), flattened the APD restitution curve (slopes <1), and suppressed the APD alternans at each site, while increasing the AF inducibility and duration (P<0.05 for all). In Group II, 6-h rapid pacing-induced APD shortening steepened the restitution curves (slopes >1), facilitated the APD alternans, and also increased the incidence and duration of AF (P< 0.05 for all). The spatial dispersion of APD restitution was significantly increased in both groups.nnnCONCLUSIONSnThis study showed distinct atrial APD restitution properties in vagally mediated AF and 6-h rapid pacing-induced AF, indicating specific restitution kinetics in different mechanisms of AF.

Electrical Stimulation of Vascular Autonomic Nerves: Effects on Heart Rate, Blood Pressure, and Arrhythmias

Recent clinical studies have shown conflicting results of the efficacy of renal sympathetic denervation (RSD) to mitigate hypertension. In this study, we compared electrical stimulation (ES) of autonomic nerves on the surface of the left pulmonary artery (LPA) and renal arteries (RAs) on heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), and cardiac arrhythmias.

Targeted cellular ionic calcium chelation by oxalates: Implications for the treatment of tumor cells

BackgroundIn malignant melanoma, it has been published that up to 40% of cancer patients will suffer from brain metastasis. The prognosis for these patients is poor, with a life expectancy of 4 to 6 months. Calcium exchange is involved in numerous cell functions. Recently, three types of cellular calcium sequestration have been reported in the medical literature. The first describes a transgenic mouse model in which an increase of aberrant calcium channels triggers hypertrophy and apoptosis. The second provides a protective mechanism whereby astrocytes in the brain inhibit apoptosis of tumor cells by moving ionic calcium out of the tumor cells thru gap junctions. The third is via calcium chelation, which causes cell apoptosis by converting ionic calcium into a calcium salt. This process has been shown to operate in atrial myocardial cells, thus not allowing the intracellular calcium stores to flow through the myocytes intercalated discs. Ideally chemotherapeutic agents would be those that initiate apoptosis in tumor cells.Presentation of the HypothesisWe hypothesize that the recent reported intracellular calcium sequestration by oxalate chelation, due to its chemical process of converting ionic calcium into a calcium salt, may inhibit the protective effect of astrocytes on brain tumor metastasized melanoma cells by not allowing free calcium to leave the metastatic cells, simultaneously apoptosis of tumor and some healthy adjacent cells could occur. This hypothesis could be extended to include other cancerous tumors such as skin cancers amongst others.Testing the hypothesisUsing the experimental model showing the protective mechanism of co-cultured reactive astrocytes and tumor cells treated with oxalates could be used to test this hypothesis in vitro. The calcium specific von Kossa technique could be used to confirm the presence of chelated intracellular calcium architecture of the metastatic cells (which is a sign of apoptosis), and extracellular calcium chelation stores of the Astrocytes (which has been shown to slow neural conduction).Implications of the HypothesisThe life expectancy in patients with metastasized malignant melanoma brain tumors could be significantly prolonged if the chemotherapeutic issue of brain metastasis is overcome. Other cancerous tumors can also be treated by this Targeted Chelation Approach. Ionic calcium sequestration using naturally occurring calcium chelators, viz., oxalates, could accomplish this desired outcome.

Preliminary study of a dual CCD based ratiometric optical mapping system

A customized dual CCD based optical mapping system is designed and constructed for the purpose of applying ratiometry to the study of cardiac arrhythmia mechanisms. The system offers 490 frames per second data acquisition speed, 128 by 128 detector elements and 12 bits digitization. Each CCD camera is dedicated to imaging a specific region of the di-4-ANEPPS emission spectrum, through the use of appropriate filtering, the red region (635 ∓ 27.5nm) and the green region (532nm ∓ 19nm). The resulting two dimensional images collected from each spectrum region behaved consistently with the spectrum shift characteristics of di-4-ANEPPS, with the fluorescence intensity of the red region decreasing during action potential and the fluorescence intensity of the green region increasing during action potential. By taking the ratio of the two images, a ratiometric signal is constructed that offered improved uniformity in fluorescence intensity distribution, compared to the individual regional images.

Feasibility studies of a high spatial resolution cardiac optical mapping system

Optical mapping, based on voltage sensitive dyes, has become a prominent technique in the study of electrical activities within cardiac tissues. The technique is best carried out with devices that can gather optical signals with both high spatial frequency and temporal frequency. Currently, two devices dominate the field, Charge Coupled Devices (CCD) and Photo Diode Arrays (PDA). Both optical mapping techniques possess advantages and disadvantages in their performance. The objective of this investigation is to design an optical mapping system with a high spatial resolution CCD as its main component. In this feasibility study, a wavelength selective optical mapping experimental setup was designed and implemented in accordance with the fluorescence characteristics of one of the most common dyes used in cardiac mapping, di-4-ANEPPS. To test the capabilities of the optical system setup, a high resolution (512 pixels by 512 pixels, 12 bit dynamic range) CCD camera with approximately 33 ms temporal resolution is chosen as the fluorescence signal acquisition device. Experiments with di- 4-ANEPPS stained canine cardiac tissues with stimulated action potentials through external electrodes resulted in successful mapping of the distribution and propagation of the action potential wave front. A new CCD based optical mapping system was also built. It offers a 128 by 128 pixel resolution, 12 bits digitization and a temporal resolution of approximately 2 ms.

Learning Without Burning: Emerging Knowledge of the Autonomic Innervation of the Heart

The advent of radiofrequency catheter ablation for termination of atrioventricular reentrant tachycardia (AVRT) in patients with preexcitation syndromes marked the beginning of a new era in clinical electrophysiology.1 With a pea-sized burn applied to a culprit accessory pathway, a cure could be achieved with a 90% or greater success rate. Early recurrences could be treated with a repeat procedure and late recurrences were rare.2 Very quickly catheter ablation was applied in cases with atrioventricular junctional reentrant tachycardia (AVJRT) and atrial flutter (AFL) with similar success and relatively few radiofrequency applications. It is generally agreed that the impetus for the use of catheter ablation for atrial fibrillation (AF) resulted from the seminal finding of Jais et al.3 and Haissaguerre et al.4 that those patients whose AF was resistant to standard antiarrhythmic drugs manifested ectopic firing arising from the myocardium within the pulmonary veins (PVs). The prevailing procedure for catheter ablation now consists of some or all of the following steps: (1) circumferential lesions for PV isolation of the four PVs from the left atrium; (2) a lesion line connecting the circumferential lines at the atrial roof; (3) a lesion line from the inferior cicumferential lesion to the mitral annulus; (4) ablation of complex fractionated electrograms; and (5) if necessary, ablations within the coronary sinus.5 Lesion sets 2 and 3 are instituted to treat iatrogenically induced macroreentrant tachycardias. Notwithstanding these modifications, the pulmonary vein isolation (PVI) procedure remains the foundation of the strategy for the treatment of drug-resistant AF.

Magnetic Targeting of Therapeutics

Multiple formulations of nano-sized particles, capsules, dendrimers, lipids, ceramics and genetic materials are being investigated in multiple labs for delivery of therapeutic moieties to targeted tissues. Interest is driven by reducing health care costs while increasing therapeutic efficacy and cost of treatment. One technology, magnetic targeting, incorporates iron oxide nanoparticles, to target nanomedicine payloads, down the gradients of external magnetic fields. When iron oxide crystal domains are less than ∼20–40 nm, particles become superparamagnetic (SPION), that is exhibit no remanent induction but very high magnetic susceptibility in the presence of an external magnetic field. Thus, targeting can be vectored by magnetic lines of flux. Particles can be pulled out of the microcirculation and across membranes into tissues. Two target organs that can employ magnetic targeting are the heart (epicardium) and inner ear (cochlea).Copyright