Reconstituted high-density lipoprotein shortens cardiac repolarization.

OBJECTIVES: We hypothesize that increasing high-density lipoprotein cholesterol (HDL-C) shortens cardiac repolarization. BACKGROUND: HDL-C is inversely associated with sudden death. The relation between HDL-C and repolarization of the heart is unexplored. METHODS: HDL-C was elevated with reconstituted high-density lipoprotein (rHDL). Cardiac repolarization was studied by recording cardiac transmembrane potentials with the patch clamp technique from isolated rabbit cardiomyocytes that were superfused with rHDL. Infusions with rHDL (40 mg/kg body weight) were performed in dyslipidemic patients and healthy volunteers. Electrocardiograms were recorded to assess cardiac repolarization before and 24 h after infusion with rHDL. RESULTS: rHDL as well as purified human apolipoprotein AI shortened repolarization of isolated rabbit cardiomyocytes by ∼25% (p < 0.05). rHDL infusion shortened the heart rate-corrected QT interval on surface electrocardiograms in all participants (p < 0.001). CONCLUSIONS: rHDL shortens cardiac repolarization. These data provide evidence for a novel mechanism of HDL infusion that may contribute to reduction of sudden cardiac death.

Cilostazol attenuates ventricular arrhythmia induction and improves defibrillation efficacy in swine.

Previous reports demonstrated that cilostazol, a phosphodiesterase 3 inhibitor, affected cellular electrophysiology and reduced episodes of ventricular fibrillation (VF) in patients with Brugada syndrome. However, its effects on VF induction and defibrillation efficacy have never been investigated. We tested the hypothesis that cilostazol increases the VF threshold (VFT) and decreases the upper limit of vulnerability (ULV) and the defibrillation threshold (DFT). A total of 48 pigs were randomly assigned to defibrillation and VF induction studies. The diastolic pacing threshold (DPT), VFT, ULV, DFT, and effective refractory period were determined before and after the infusion of cilostazol at 6 mg/kg, 3 mg/kg, or vehicle. The DPT was significantly increased after administration of 3 and 6 mg/kg cilostazol. The ULV and DFT were significantly decreased after administration of 6 mg/kg cilostazol only. The ULV in the 6 mg/kg group had 12% lower peak voltage and 25% lower total energy, and the DFT had 13% lower peak voltage and 25% lower total energy. The VFT was not altered in any experimental group. This study shows that cilostazol administration significantly increased the DPT, which was associated with significantly reduced DFT and ULV.

Sildenafil citrate on the inducibility of ventricular fibrillation and upper limit of vulnerability in swine.

BACKGROUND: Sildenafil citrate at supratherapeutic levels has been reported to decrease defibrillation efficacy. However, its effects on ventricular fibrillation induction and the upper limit of vulnerability (ULV) have not been investigated. We tested the hypothesis that sildenafil citrate reduces the ventricular fibrillation threshold (VFT) and increases the ULV. MATERIAL/METHODS: Twenty-one pigs (25-30 kg) were randomly assigned into 3 groups of 7 pigs each. A solution containing 100 mg (group 100) or 50 mg (group 50) sildenafil citrate or 100 cc saline (group control) was infused intravenously in each pig. A train of 10 S1s was delivered from an RV electrode, and an S2 stimulus was delivered at the peak of the T wave of the last S1 activation to determine the VFT and ULV, before and after drug administration. RESULTS: The 100 mg sildenafil citrate significantly (P<0.03) decreased VFT, accounting for approximately 36% by peak voltage and approximately 52% by total energy, and significantly (P<0.009) increased ULV, accounting for approximately 28% by peak voltage, and approximately 56% by total energy. CONCLUSIONS: Supratherapeutic concentrations of sildenafil citrate significantly decreased the VFT and increased the ULV, resulting in an expansion of the VF induction window during the vulnerable period.

Effects of garlic on the induction of ventricular fibrillation.

OBJECTIVE: Previous studies have shown that oral and intravenous administrations of garlic provide a significant antiarrhythmic effect and improve defibrillation efficacy. We tested the hypothesis that garlic could decrease the inducibility of ventricular arrhythmia. METHODS: Twenty-one pigs (25-30 kg) were divided into three groups. In each group, the ventricular fibrillation threshold (VFT) and the upper limit of vulnerability (ULV) were determined. After the control VFT and ULV values were obtained, solutions containing 20 mg/kg (group 1, n = 7) and 40 mg/kg (group 2, n = 7) of garlic (1.3% allicin) were administered intravenously. The VFT and ULV were determined again at the end of garlic infusion. In group 3 (n = 7), 100 mL of normal saline was administered instead of garlic. RESULTS: The VFT values in groups 1 and 2 were not different from the control VFT. The ULV in group 1 was not different from the control ULV. However, the ULV in group 2 (328 +/- 58 V, 8 +/- 3 J) was significantly lower than the control ULV (415 +/- 24 V, 13 +/- 2 J), thus accounting for the reduction of approximately 21% by peak voltage and approximately 38% by energy. The effective refractory period and diastolic pacing threshold were not altered after garlic infusion. Saline did not alter VFT or ULV. CONCLUSION: Garlic cannot alter the VFT, but it significantly decreases the ULV in a dose-dependent pattern, indicating that it can reduce the range of the stimulation strength between the VFT and ULV (vulnerability window) during the vulnerable period of a cardiac cycle.

Effects of combined sildenafil-nitric oxide donor on defibrillation efficacy.

BACKGROUND: A previous study demonstrated that supra-therapeutic concentration of sildenafil citrate attenuates defibrillation efficacy. However, the effect of combined sildenafil and NTG administration on defibrillation efficacy is not known. OBJECTIVE: The present study investigated whether sildenafil administration at the therapeutic level increases the defibrillation threshold (DFT) when combined with NTG. MATERIAL AND METHOD: Twenty-four pigs (20-25 kg) were randomized into four groups. After the control DFT was obtained, a stock solution of 50-mg (group 1, therapeutic concentration) and 100-mg (group 2, supratherapeutic concentration) of sildenafil, and 100-mL of saline (groups 3 and 4) were infused at 2 mL/min. Then, NTG was administered in groups 1-3 at 5 microg/min, with an increment of 5 microg/min every 5 min. The DFT was determined again after NTG was infused for 20 minutes. RESULTS: In group 1, the DFT (402 +/- 33V, 11 +/- 2J) was not different from the control (404 +/- 28V, 11 +/- 2J). In group 2, the DFT (521 +/- 18V, 19 +/- 1J) was higher (p < 0.004) than that in the control group (444 +/- 31V, 14 +/- 2J). Saline did not alter the DFT either individually or in combination with NTG. CONCLUSION: Supratherapeutic dose of sildenafil-NTG combination significantly increased the DFT (17% of peak voltage, 37% of total energy). This effect on DFT appears to be driven by sildenafil and not NTG.

Effects of sildenafil citrate on defibrillation efficacy.

INTRODUCTION: Although fatal arrhythmia and sudden death have been reported in patients taking sildenafil citrate, its effect on defibrillation efficacy has not been investigated. The aim of this study was to test the hypothesis that sildenafil citrate increases the shock strength required to successfully defibrillate during ventricular fibrillation (VF). METHODS AND RESULTS: A total of 26 pigs (20-25 kg) were randomly assigned into three groups. In each group, the defibrillation threshold (DFT) was determined at the beginning of the study using a three-reversal up/down protocol. Each shock (RV-SVC, biphasic) was delivered after 10 seconds of VF. Group 1 (n = 10) received 50 mg and group 2 (n = 10) received 100 mg of sildenafil citrate intravenously at a rate of 2 mL/minute for 50 minutes. Group 3 (n = 6) received 100 mL of saline intravenously at the same rate as in group 1. The DFT was determined again after the drug (drug-DFT) and saline (saline-DFT) administration. For 100-mg sildenafil citrate infusion, the DFT (483 +/- 39 V, 18 +/- 3 J) was significantly (P < 0.003 and P < 0.01, respectively) higher than the control-DFT (407 +/- 123 V, 13 +/- 7 J). This sildenafil citrate infusion increased the DFT approximately 19% by voltage, and approximately 38% by total energy. After 50-mg sildenafil citrate infusion, the DFT (454 +/- 28 V, 15 +/- 2 J) was not different than the control DFT (449 +/- 28 V, 15 +/- 2 J). Saline infusion (391 +/- 18 V, 12 +/- 1 J) did not alter the control DFT (399 +/- 22 V, 12 +/- 1 J). CONCLUSION: The 100-mg sildenafil citrate infusion, representing a supra-therapeutic plasma level, significantly increased the DFT. This finding indicates that VF occurring during supra-therapeutic sildenafil citrate treatment would require a stronger shock to successfully defibrillate.

Effects of n-3 polyunsaturated fatty acid on upper limit of vulnerability shocks.

BACKGROUND: Ventricular fibrillation (VF) can be induced when a strong shock is delivered during the vulnerable period of a cardiac cycle. VF, however, cannot be induced if the shock strength is increased to the "upper limit of vulnerability" (ULV) level. Docosahexaenoic acid (DHA) has been shown to prevent the occurrence of VF after coronary occlusion. However, its effects on the ULV have not been verified. We tested the hypothesis that ULV shock strength is decreased after DHA administration. METHODS: In 10 pigs, 10 S1s (square, 5-ms) were delivered from the RV apex electrode at 300 ms cycle length. Shocks (S2, biphasic) were delivered from the RV-SVC electrodes after the last S1. The ULV was determined using an up/down protocol. In group 1 (n = 5), after the control ULV was determined at the beginning of the study, a solution containing 1.0 gm of DHA was infused intravenously within 90 min. The ULV (DHA-ULV) was determined again after the end of infusion. In group 2 (n = 5), the vehicle for DHA was infused instead of DHA to confirm that the vehicle did not have an effect on the ULV. RESULTS: DHA-ULV (412 +/- 58 V, 12 +/- 3 J) was significantly decreased (P < 0.04) compared to the control ULV (478 +/- 32 V, 16 +/- 3 J). The ULV before (483 +/- 28 V, 16 +/- 1 J) and after (463 +/- 28 V, 15 +/- 2 J) the vehicle infusion was not different (P = 0.4). There was no change in the systolic blood pressure as well as heart rate in both groups. CONCLUSION: DHA significantly decreases the ULV (13% by voltage and 25% by energy), suggesting that DHA can help to prevent VF induced by a strong stimulus delivered during the vulnerable period.