No abstract

No abstract

Our recent data show that in cardiac myocytes polyunsaturated fatty acids (PUFAs) are antiarrhythmic. They reduce I Na , shorten the action potential, shift the threshold for excitation to more positive potentials, and prolong the relative refractory period. In this study we use patch-clamp techniques in whole-cell mode and confocal Ca 2؉ imaging to examine the effects of PUFAs on the voltage-gated L-type Ca 2؉ current (I Ca,L ), elementary sarcoplasmic reticulum Ca 2؉ -release events (Ca 2؉ -sparks), and [Ca 2؉ ] i transients in isolated rat ventricular myocytes. Extracellular application of eicosapentaenoic acid (EPA; C20:5 n ؊ 3) produced a prompt and reversible concentration-dependent suppression of I Ca,L . The concentration of EPA to produce 50% inhibition of I Ca was 0.8 M in neonatal rat heart cells and 2.1 M in adult ventricular myocytes. While the EPA induced suppression of I Ca,L , it did not significantly alter the shape of the current-voltage relation but did produce a small, but significant, negative shift of the steady-state inactivation curve. The inhibition of I Ca,L was voltage-and time-dependent, but not use-or frequency-dependent. Other PUFAs, such as docosahexaenoic acid, arachidonic acid, linolenic acid, linoleic acid, conjugated linoleic acid, and eicosatetraynoic acid had similar effects on I Ca,L as EPA. All-trans-retinoic acid, which had been shown to suppress induced arrhythmogenic activity in rat heart cells, also produced a significant inhibition of I Ca,L . The saturated stearic acid and the monounsaturated oleic acid had no effect on I Ca,L . Because both I Ca,L and sarcoplasmic reticulum Ca 2؉ -release underlie many cardiac arrhythmias, we examined the effects of EPA on I Ca,L and Ca 2؉ -sparks. While EPA suppressed both, it did not change the temporal or spatial character of the Ca 2؉ -sparks, nor did it alter the ability of I Ca,L to trigger Ca 2؉ -sparks. We conclude that PUFAs may act as antiarrhythmic agents in vivo in normal and Ca 2؉ -overloaded cells principally because they reduce Ca 2؉ entry by blocking I Ca,L . Furthermore, PUFAs act directly to decrease I Na and I Ca,L , but indirectly to reduce the [Ca 2؉ ] i transients and [Ca 2؉ ] i -activated membrane current. Although a negative inotropic action is associated with application of PUFAs, it is clear that by reducing I Ca,L , I Na and Ca 2؉ -sparks, PUFAs can reduce spontaneous extrasystoles in the heart. The mechanisms by which PUFAs act are discussed.

These results indicate that purified omega-3 fatty acids can prevent ischemia-induced ventricular fibrillation in this dog model of sudden cardiac death.

We have previously reported the cloning, sequencing, and partial characterization of Kid-i, a zinc finger-encoding cDNA from the rat kidney. A limited number of structural motifs have been described for eukaryotic transcription factors. A common motif is the zinc finger structure, which is highly conserved and found in many different species (1). Though the crystal structure of a cocrystal between the three zinc fingers of zif-268 (Egr-i) and their binding site has been elucidated (2), little is known about the interaction between zinc fingers and DNA and how these protein-DNA interactions are involved in the regulation of transcription.Approximately one-third of all zinc finger proteins contain an evolutionarily conserved region of about 75 amino acids at their NH2 terminus-the Krippel-associated box (KRAB), a sequence motif of hitherto unknown function. Similar to regions found in a subset of homeodomain proteins (the paired box and POU domain), the KRAB domain is rich in charged amino acids (3). Because of the potential a-helical structure of KRAB domains, it has been proposed that this domain mediates protein-protein interactions and functions as a transcriptional regulatory domain (3), but this hypothesis has not been previously tested.

Background— The long-chain n-3 fatty acids in fish have been demonstrated to have antiarrhythmic properties in experimental models and to prevent sudden cardiac death in a randomized trial of post–myocardial infarction patients. Therefore, we hypothesized that these n-3 fatty acids might prevent potentially fatal ventricular arrhythmias in high-risk patients. Methods and Results— Four hundred two patients with implanted cardioverter/defibrillators (ICDs) were randomly assigned to double-blind treatment with either a fish oil or an olive oil daily supplement for 12 months. The primary end point, time to first ICD event for ventricular tachycardia or fibrillation (VT or VF) confirmed by stored electrograms or death from any cause, was analyzed by intention to treat. Secondary analyses were performed for “probable” ventricular arrhythmias, “on-treatment” analyses for all subjects who had taken any of their oil supplements, and “on-treatment” analyses only of those subjects who were on treatment for at least 11 months. Compliance with double-blind treatment was similar in the 2 groups; however, the noncompliance rate was high (35% of all enrollees). In the primary analysis, assignment to treatment with the fish oil supplement showed a trend toward a prolonged time to the first ICD event (VT or VF) or of death from any cause (risk reduction of 28%; P =0.057). When therapies for probable episodes of VT or VF were included, the risk reduction became significant at 31%; P =0.033. For those who stayed on protocol for at least 11 months, the antiarrhythmic benefit of fish oil was improved for those with confirmed events (risk reduction of 38%; P =0.034). Conclusions— Although significance was not achieved for the primary end point, this study provides evidence that for individuals at high risk of fatal ventricular arrhythmias, regular daily ingestion of fish oil fatty acids may significantly reduce potentially fatal ventricular arrhythmias.

No abstract

Recent evidence indicates that polyunsaturated long-chain fatty acids (PUFAs) prevent lethal ischemiainduced cardiac arrhythmias in animals and probably in humans. To increase understanding of the mechanism(s) of this phenomenon, the effects of PUFAs on Na+ currents were assessed by the whole-cell patch-clamp technique in cultured neonatal rat ventricular myocytes. Extracellular application of the free 5,8,11,14,17-eicosapentaenoic acid (EPA) produced a concentration-dependent suppression of ventricular, voltage-activated Na+ currents (INa). After cardiac myocytes were treated with 5 or 10 ,iM EPA, the peak INa (elicited by a single-step voltage change with pulses from -80 to -30 mV) was decreased by 51% + 8% (P < 0.01; n = 10) and 64% ± 5% (P < 0.001; n = 21), respectively, within 2 min. Likewise, the same concentrations of 4,7,10,16,19-docosahexaenoic acid produced the same inhibition ofINa. By contrast, 5 and 10 ,uM arachidonic acid (AA) caused less inhibition of INa, but both n -6 and n -3 PUFAs inhibited INa significantly. A monounsaturated fatty acid and a saturated fatty acid did not. After washing out EPA, INa returned to the control level. Raising the concentration of EPA to 40 ,uM completely blocked INa. The IC50 ofEPA was 4.8 ,uM. The inhibition ofthis Na+ channel was found to be dose and time, but not use dependent. Also, the EPAinduced inhibition of INa was voltage dependent, since 10 ,uM EPA produced 83% ± 7% and 29%Yo + 5% inhibition OfINa elicited by pulses from -80 to -30 mV and from -150 to -30 mV, respectively, in single-step voltage changes. A concentration of 10 ,uM EPA shifted the steady-state inactivation curve ofINa by -19 + 3 mV (n = 7; P < 0.01). These effects of PUFAs on INa may be important for their antiarrhythmic effect in vivo.