Introduction: Stable high‐frequency rotors sustain ventricular fibrillation (VF) in the guinea pig heart. We surmised that rotor stabilization in the left ventricle (LV) and fibrillatory conduction ...toward the right ventricle (RV) result from chamber‐specific differences in functional expression of inward rectifier (Kir2.x) channels and unequal IK1 rectification in LV and RV myocytes. Accordingly, selective blockade of IK1 during VF should terminate VF.
Methods and Results: Relative mRNA levels of Kir2.x channels were measured in LV and RV. In addition, LV
(n = 21)
and RV
(n = 20)
myocytes were superfused with BaCl2 (5–50 μmol/L) to study the effects on IK1. Potentiometric dye‐fluorescence movies of VF were obtained in the presence of Ba2+
(0–50 μmol/L)
in 23 Langendorff‐perfused hearts. Dominant frequencies (DFs) were determined by spectral analysis, and singularity points were counted in phase maps to assess VF organization. mRNA levels for Kir2.1 and Kir2.3 were significantly larger in LV than RV. Concurrently, outward IK1 was significantly larger in LV than RV myocytes. Ba2+ decreased IK1 in a dose‐dependent manner (LV change > RV change). In baseline control VF, the fastest DF domain
(28–40 Hz)
was located on the anterior LV wall and a sharp LV‐to‐RV frequency gradient of
21.2 ± 4.3 Hz
was present. Ba2+ significantly decreased both LV frequency and gradient, and it terminated VF in a dose‐dependent manner. At 50 μmol/L, Ba2+ decreased the average number of wavebreaks (
1.7 ± 0.9
to
0.8 ± 0.6 SP/sec · pixel, P < 0.05
) and then terminated VF.
Conclusion: The results strongly support the hypothesis that IK1 plays an important role in rotor stabilization and VF dynamics. (J Cardiovasc Electrophysiol, Vol. 14, pp. 621‐631, June 2003)
ABSTRACT—Both fixed and dynamic heterogeneities were implicated in the mechanism of wavebreak (WB) generation during ventricular fibrillation (VF). However, their relative roles remain unclear. We ...hypothesized that during ischemic VF, the WBs are produced primarily because of a fixed heterogeneity; namely, the gradient of refractoriness across the ischemic border zone (BZ). Ischemia was induced in 15 isolated blood-perfused hearts by occluding the left anterior descending coronary artery. Simultaneous video imaging (≈32×32 mm) of Di-4-ANEPPS fluorescence in the ischemic zone (IZ), the BZ, and the nonischemic zone (NIZ) was performed. Dominant-frequency maps were constructed to assess gradients of refractoriness during VF. We used singularity points analysis to quantify the incidence of WBs per square centimeter per second. During preischemic VF, the distribution of WBs was relatively uniform. Ischemia caused an increase of WBs in the BZ (from 6.2±2.8 to 10.8±4.0) and a decrease of WBs in the IZ (from 5.8±2.8 to 2.8±1.4), without a significant change in NIZ (from 6.4±2.3 to 4.1±1.7). This finding is fully consistent with the dominant-frequency distribution during ischemic VFthe average dominant frequency was significantly slower in IZ than in NIZ (7.8±0.7 versus 10.1±1.0 Hz), suggesting a large gradient in refractory periods across the BZ. We concluded that acute regional ischemia plays a dual role in the maintenance of VF, decreasing the incidence of WB in the IZ while increasing it in the BZ. This suggests a predominant role of fixed heterogeneities in the formation of WB during VF in acute regional ischemia.
Leptin is a circulating polypeptide hormone produced by an adipocyte-specific gene. It regulates energy balance by binding to receptors in the hypothalamus, leading to alterations in food intake, ...temperature, and energy expenditure. More recent pharmacologic information suggests that this circulating hormone may play an important role in the regulation of body fluid volume and pressures through direct and indirect actions. Although the relevance of the endogenous leptin on cardiovascular and renal function is yet to be clearly determined, it seems to be a potential salt-regulating factor and may function pathophysiologically as a common link to obesity and hypertension.
We tested the hypothesis that left atrial (LA) myocytes are more sensitive to acetylcholine (ACh) than right atrial (RA) myocytes, which results in a greater dose-dependent increase in LA than RA ...rotor frequency, increased LA-to-RA frequency gradient and increased incidence of wavelet formation during atrial fibrillation (AF).
AF was induced in seven Langendorff-perfused sheep hearts in the presence of ACh (0.1-4.0 microM) and studied using optical mapping and bipolar recordings. Dominant frequencies (DFs) were determined in optical and electrical signals and phase movies were used to identify rotors and quantify their dynamics. DFs in both atria increased monotonically with ACh concentration until saturation, but the LA frequency predominated at all concentrations. Rotors were also seen more often in the LA, and although their life span decreased, their frequency and number of rotations increased. Patch-clamp studies demonstrated that ACh-activated potassium current (I(K,ACh)) density was greater in LA than RA sheep myocytes. Additionally, ribonuclease protection assay demonstrated that Kir3.4 and Kir3.1 mRNAs were more abundant in LA than in RA.
A greater abundance of Kir3.x channels and higher I(K,ACh) density in LA than RA myocytes result in greater ACh-induced speeding-up of rotors in the LA than in the RA, which explains the ACh dose-dependent changes in overall AF frequency and wavelet formation.
The inwardly rectifying potassium (Kir) 2.x channels mediate the cardiac inward rectifier potassium current (IK1). In addition to differences in current density, atrial and ventricular IK1 have ...differences in outward current profiles and in extracellular potassium (Ko) dependence. The whole-cell patch-clamp technique was used to study these properties in heterologously expressed Kir2.x channels and atrial and ventricular IK1 in guinea pig and sheep hearts. Kir2.x channels showed distinct rectification profilesKir2.1 and Kir2.2 rectified completely at potentials more depolarized than −30 mV (I≈0 pA). In contrast, rectification was incomplete for Kir2.3 channels. In guinea pig atria, which expressed mainly Kir2.1, IK1 rectified completely. In sheep atria, which predominantly expressed Kir2.3 channels, IK1 did not rectify completely. Single-channel analysis of sheep Kir2.3 channels showed a mean unitary conductance of 13.1±0.1 pS in 15 cells, which corresponded with IK1 in sheep atria (9.9±0.1 pS in 32 cells). Outward Kir2.1 currents were increased in 10 mmol/L Ko, whereas Kir2.3 currents did not increase. Correspondingly, guinea pig (but not sheep) atrial IK1 showed an increase in outward currents in 10 mmol/L Ko. Although the ventricles of both species expressed Kir2.1 and Kir2.3, outward IK1 currents rectified completely and increased in high Ko-displaying Kir2.1-like properties. Likewise, outward current properties of heterologously expressed Kir2.1-Kir2.3 complexes in normal and 10 mmol/L Ko were similar to Kir2.1 but not Kir2.3. Thus, unique properties of individual Kir2.x isoforms, as well as heteromeric Kir2.x complexes, determine regional and species differences of IK1 in the heart.
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