Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery that occurs in up to 60% of patients. POAF is associated with increased risk of cardiovascular mortality, stroke and other arrhythmias that can impact on early and long term clinical outcomes and health economics. Many factors such as disease-induced cardiac remodelling, operative trauma, changes in atrial pressure and chemical stimulation and reflex sympathetic/parasympathetic activation have been implicated in the development of POAF. There is mounting evidence to support a major role for inflammation and oxidative stress in the pathogenesis of POAF. Both are consequences of using cardiopulmonary bypass and reperfusion following ischaemic cardioplegic arrest. Subsequently, several anti-inflammatory and antioxidant drugs have been tested in an attempt to reduce the incidence of POAF. However, prevention remains suboptimal and thus far none of the tested drugs has provided sufficient efficacy to be widely introduced in clinical practice. A better understanding of the cellular and molecular mechanisms responsible for the onset and persistence of POAF is needed to develop more effective prediction and interventions.

Although hypertension is the most prevalent risk factor for atrial fibrillation, there is currently no information available from animal models of hypertension regarding the development of atrial remodeling or increased susceptibility to atrial tachyarrhythmia. Therefore, we examined the susceptibility to atrial tachyarrhythmia and the development of atrial remodeling in excised perfused hearts from male spontaneously hypertensive rats in comparison with age-matched male Wistar–Kyoto normotensive controls at age 3 and 11 months, corresponding with early hypertension and pre-heart failure stages, respectively. The incidence and duration of left atrial tachyarrhythmia induced by burst pacing was greater in hearts from 11-month–old hypertensive animals than either in age-matched controls or in 3-month–old hypertensive rats, although there was no difference between hypertensive and normotensive hearts at 3 months. Thus, hypertension was associated with the development of an arrhythmic substrate. Atrial effective refractory period and the duration of monophasic action potentials recorded from the left atrium were not altered with either hypertension or age, although there were changes in the whole-cell Ca ²⁺ current density of isolated left atrial myocytes. On the other hand, Masson’s trichrome staining of wax-embedded sections of left atrium revealed markedly greater interstitial fibrosis in 11-month–old hypertensive rats compared with controls. These data constitute the first experimental evidence that hypertension is associated with the development of a substrate for atrial tachyarrhythmia involving left atrial fibrosis without changes in the atrial effective refractory period and demonstrate that the spontaneously hypertensive rat represents a suitable model for investigating hypertension-associated atrial remodeling.

Objective— Vascular endothelial growth factor (VEGF) exerts many of its effects by stimulating endothelial calcium influx, but little is known about channels mediating VEGF-induced cation entry. The aim of this study was to measure and characterize for the first time the VEGF-activated cation current in human microvascular endothelial cells (HMVECs). Methods and Results— Whole-cell patch-clamp recordings were made from HMVECs. During applied voltage ramps, VEGF activated a current that reversed at 0 mV, was sensitive to gadolinium, and required extracellular cations. Noise analysis yielded a single-channel conductance of 27 pS. The current was not dependent on intracellular calcium stores, and was not blocked by inositol triphosphate (IP ₃ ) receptor or serine/threonine kinase inhibition but was partially inhibited by flufenamic acid. A similar current was activated by 1-oleoyl-2-acetyl- sn -glycerol (OAG), a membrane-permeant analog of diacylglycerol (DAG). To determine whether VEGF could activate recombinant ion channels with similar properties, we investigated the effect of VEGF on Chinese hamster ovary cells cotransfected with VEGFR2 and the canonical transient receptor potential (TRPC) channels, TRPC3 or TRPC6. VEGF induced a similar current to that described above in VEGFR2-TRPC3 and VEGFR2-TRPC6 cells but not in cells transfected with either cDNA alone. Conclusions— VEGF activates a receptor-operated cation current in HMVECs and OAG can activate directly a similar current in these cells. VEGF is also able to activate heterologously expressed TRPC3/6 channels through VEGFR2.

Background—: Although arterial hypertension and left ventricular hypertrophy are considered good epidemiological indicators of the risk of atrial fibrillation (AF) in patients, the link between elevated afterload and AF remains unclear. We investigated atrial remodeling and the substrate for arrhythmia in a surgical model of elevated afterload in rats. Methods and Results—: Male Wistar rats (aged 3–4 weeks) were anesthetized and subjected to either partial stenosis of the ascending aorta (AoB) or sham operation (Sham). Experiments were performed on excised hearts 8, 14, and 20 weeks after surgery. Unipolar electrograms were recorded from the left atrial epicardial surface of perfused hearts using a 5×5 electrode array. Cryosections of left atrial tissue were retained for histological and immunocytochemical analyses. Compared to Sham, AoB hearts showed marked left atrial hypertrophy and fibrosis at 14 and 20 weeks postsurgery. The incidence and duration of pacing-induced AF was increased in hearts from AoB rats at 20 weeks postsurgery. The substrate for arrhythmia was associated with reduced vectorial conduction velocity and greater inhomogeneity in conduction but without changes in effective refractory period. Left atrial expression of the gap junction protein, connexin43, was markedly reduced in AoB compared with Sham hearts. Conclusions—: Using a small-animal model, we demonstrate that elevated afterload in the absence of systemic hypertension results in increased inducibility of AF and left atrial remodeling involving fibrosis, altered atrial connexin43 expression, and marked conduction abnormalities.