Nanotechnology-empowered combination therapy for rheumatoid arthritis: principles, strategies, and challenges.

Rheumatoid arthritis (RA) is an autoimmune disease with multifactorial etiology and intricate pathogenesis. In RA, repeated monotherapy is frequently associated with inadequate efficacy, drug resistance, and severe side effects. Therefore, a shift has occurred in clinical practice toward combination therapy. However, conventional combination therapy encounters several hindrances, including low selectivity to arthritic joints, short half-lives, and varying pharmacokinetics among coupled drugs. Emerging nanotechnology offers an incomparable opportunity for developing advanced combination therapy against RA. First, it allows for co-delivering multiple drugs with augmented physicochemical properties, targeted delivery capabilities, and controlled release profiles. Second, it enables therapeutic nanomaterials development, thereby expanding combination regimens to include multifunctional nanomedicines. Lastly, it facilitates the construction of all-in-one nanoplatforms assembled with multiple modalities, such as phototherapy, sonodynamic therapy, and imaging. Thus, nanotechnology offers a promising solution to the current bottleneck in both RA treatment and diagnosis. This review summarizes the rationale, advantages, and recent advances in nano-empowered combination therapy for RA. It also discusses safety considerations, drug-drug interactions, and the potential for clinical translation. Additionally, it provides design tips and an outlook on future developments in nano-empowered combination therapy. The objective of this review is to achieve a comprehensive understanding of the mechanisms underlying combination therapy for RA and unlock the maximum potential of nanotechnology, thereby facilitating the smooth transition of research findings from the laboratory to clinical practice.

Temporal changes in plaque characteristics after treatment and their relationship with stroke recurrence: a quantitative study using magnetic resonance imaging.

Background: Intracranial atherosclerotic disease (ICAD) is the major cause of ischemic stroke. Despite aggressive medical therapy, around 15% of patients with ICAD experience recurrence. The aim of the present study was to evaluate the temporal changes in intracranial arteriosclerotic plaques after medical treatment based on vessel wall magnetic resonance imaging (VWMRI) and to explore their relationship with stroke recurrence. Methods: A total of 67 symptomatic patients with ICAD who underwent initial and follow-up VWMRI were recruited into this retrospective cohort study. Stroke recurrence was defined as an ipsilateral stroke symptom after the initial attack. The clinical characteristics and plaque features, including stenosis ratio (measured based on luminal diameter or area), plaque thickness, plaque burden (PB), enhancement ratio (ER), and enhancement grade, were evaluated and compared between the initial and follow-up examinations. Changes in plaque characteristics were compared between patients with or without recurrence by univariable analyses. Multivariable regression was performed to investigate imaging markers for recurrent stroke. Results: The median interval between baseline and follow-up VWMRI was 334 days. A total of 13 cases (19.4%) experienced a stroke recurrence. After treatment, significant decreases in the stenosis ratio (area), PB, and ER were observed in cases without recurrence (all P<0.05), while no significant difference in plaque features was found for cases with recurrence. Univariable analyses showed that changes in stenosis ratio (area), plaque thickness, PB, and ER were significantly different between patients with and without recurrence (all P<0.05). Multivariable regression indicated that PB change was the only significant marker associated with stroke recurrence [odds ratio (OR) =1.112 per 1% increase, 95% confidence interval (CI): 1.010 to 1.224, P=0.031]. Conclusions: Patients with arteriosclerotic plaques who benefit from medical treatment show obvious decreases in stenosis (area), PB, and ER. The progression of PB may serve as an independent marker for predicting stroke recurrence.

Hyaluronic acid-cyclodextrin encapsulating paeonol for treatment of atopic dermatitis.

The cyclodextrin (CD) was grafted onto hyaluronic acid (HA) to form a topical delivery carrier (HACD) in which Paeonol was loaded in its CD cavity and self-assemble into the polymeric micelles (HACD-PAE) for the treatment of atopic dermatitis. Fluorescence microscope observed that HACD could fast penetrate into the skin and remain stable within 12 h. In vitro penetration test (IVPT) results showed the PAE retentions of HACD-PAE group in the stratum corneum and dermis were 3.35 and 1.78 times improvement than that of PAE group. ATR-FTIR and H&E staining assays indicated HACD could increase the gap of keratinocytes by interacting with corneum lipids and loosening the keratin. Furthermore, HACD-PAE showed the best therapeutic effect on atopic dermatitis mice. Thus HACD could be a promising skin-specific delivery carrier, not only promoting the drug penetrating but increasing its remaining in the skin and play the skin disease therapy and skin-care role.

High-resolution compressed sensing time-of-flight MR angiography outperforms CT angiography for evaluating patients with Moyamoya disease after surgical revascularization.

BACKGROUND: To evaluate the utility of high-resolution compressed sensing time-of-fight MR angiography (CS TOF-MRA) for assessing patients with moyamoya disease (MMD) after surgical revascularization, by comparison with computer tomography angiography (CTA). METHODS: Twenty patients with MMD after surgical revascularizations who underwent CS TOF-MRA and CTA were collected. The scan time of CS TOF-MRA was 5 min and 4 s, with a reconstructed resolution of 0.4 × 0.4 × 0.4 mm3. Visualization of superficial temporal artery and middle cerebral artery (STA-MCA) bypass, neovascularization into the brain pial surface and Moyamoya vessels (MMVs) were independently ranked by two neuroradiologists on CS TOF-MRA and CTA, respectively. The patency of anastomosis was assessed as patent or occluded, using digital subtraction angiography and expert's consensus as ground truth. Interobserver agreement was calculated using the weighted kappa statistic. Wilcoxon signed-rank or Chi-square test was performed to investigate diagnostic difference between CS TOF-MRA and CTA. RESULTS: Twenty-two hemispheres from 20 patients were analyzed. The inter-reader agreement for evaluating STA-MCA bypass, neovascularization and anastomosis patency was good to excellent (κCS TOF-MRA, 0.738-1.000; κCTA, 0.743-0.909). The STA-MCA bypass and MMVs were better visualized on CS TOF-MRA than CTA (both P < 0.05). CS TOF-MRA had a higher sensitivity than CTA (94.7% vs. 73.7%) for visualizing anastomoses. Neovascularization was better observed in 13 (59.1%) sides on CS TOF-MRA, in comparison to 7 (31.8%) sides on CTA images (P = 0.005). CONCLUSION: High-resolution CS TOF-MRA outperforms CTA for visualization of STA-MCA bypass, neovascularization and MMVs within a clinically reasonable time in MMD patients after revascularization.

E4BP4 Regulates Hepatic Solute Carrier Family 2 Member 9 and Uric Acid Disposition in Mice.

Solute carrier family 2 member 9 (SLC2A9) is a voltage-driven transporter that mediates cellular uptake and efflux of various substrates such as uric acid. Here, we investigate the role of E4 promoter-binding protein 4 (E4BP4), a transcription factor, in regulating hepatic SLC2A9 in mice. Effects of E4BP4 on hepatic SLC2A9 and other transporters were examined using E4bp4 knockout (E4bp4 -/-) mice. Transporting activity of SLC2A9 was assessed using uric acid as a prototypical substrate. We found that three SLC genes (i.e., Slc2a9, Slc17a1, and Slc22a7) were upregulated in the liver in E4bp4-/- mice with Slc2a9 altered the most. E4bp4 ablation in mice dampened the daily rhythm in hepatic SLC2A9, in addition to increasing its expression. Furthermore, E4bp4-/- mice showed increased hepatic uric acid but reduced uric acid in the plasma and urine. Consistently, allantoin, a metabolite of uric acid generated in the liver, was increased in the liver of E4bp4-/- mice. E4bp4 ablation also protected mice from potassium oxonate-induced hyperuricemia. Moreover, negative effects of E4BP4 on SLC2A9 were validated in Hepa-1c1c7 and primary mouse hepatocytes. Additionally, according to luciferase reporter and chromatin immunoprecipitation assays, E4BP4 repressed Slc2a9 transcription and expression via direct binding to a D-box (-531 bp to -524 bp) in the P2 promoter. In conclusion, E4BP4 was identified as a novel regulator of SLC2A9 and uric acid homeostasis, which might facilitate new therapies for reducing uric acid in various conditions related to hyperuricemia. SIGNIFICANCE STATEMENT: Our findings identify E4BP4 as a novel regulator of SLC2A9 and uric acid homeostasis, which might facilitate new therapies for reducing uric acid in various conditions related to hyperuricemia.

PPAR-γ integrates obesity and adipocyte clock through epigenetic regulation of Bmal1.

While growing evidence suggests that circadian clock and obesity are intertwined, the underlying mechanism is poorly understood. Here, we investigate how circadian clock is linked to obesity. Methods: Metabolomics profiling of WAT (white adipose tissue) samples was performed to identify the metabolites altered in obese model. mRNA levels were analyzed by qPCR assays. Proteins were detected by immunoblotting, immunofluorescence and ELISA. ChIP and luciferase reporter assays were used to investigate epigenetic and transcriptional regulation. Results: Obesity causes perturbance of circadian clock in WAT in mice and humans, particularly, BMAL1 is markedly reduced. Metabolomic analysis reveals reduced glutamine and methionine in obese WAT. Glutamine metabolism contributes to production of acetyl-CoA, whereas methionine metabolism generates S-adenosyl methionine (SAM). Acetyl-CoA and SAM are the substrates for histone acetylation and methylation, respectively. Reduced glutamine and methionine in obese WAT are associated with decreased H3K27ac and H3K4me3 at Bmal1 promoter. Consistently, glutamine or methionine administration in vitro and in vivo increases H3K27ac or H3K4me3, promoting Bmal1 transcription and expression. A screen of transport and metabolic genes identifies downregulation of the uptake transporter SLC1A5 as a cause of reduced glutamine or methionine in obese WAT. Moreover, we observe impaired expression of PPAR-γ in obese WAT. PPAR-γ trans-activates Slc1a5 via direct binding to a response element in promoter. Conclusion: Impaired PPAR-γ in obesity provokes downregulation of SLC1A5 and reductions in adipocyte uptake of glutamine and methionine (two epigenetic modulators), leading to disruption of Bmal1. Therefore, PPAR-γ integrates obesity and adipocyte clock, promoting a vicious cycle between circadian disruption and obesity development.

Acupoint nanocomposite hydrogel for simulation of acupuncture and targeted delivery of triptolide against rheumatoid arthritis.

BACKGROUND: Attenuating inflammatory response and relieving pain are two therapeutic therapeutical goals for rheumatoid arthritis (RA). Anti-inflammatory and analgesic drugs are often associated with many adverse effects due to nonspecific distribution. New drug delivery systems with practical targeting ability and other complementary strategies urgently need to be explored. To achieve this goal, an acupoint drug delivery system that can target deliver anti-inflammatory drugs and simulate acupuncture in relieving pain was constructed, which can co-deliver triptolide (TP) and 2-chloro-N (6)-cyclopentyl adenosine (CCPA). RESULTS: We have successfully demonstrated that acupoint nanocomposite hydrogel composed of TP-Human serum album nanoparticles (TP@HSA NPs) and CCPA could effectively treat RA. The result shows that CCPA-Gel can enhance analgesic effects specifically at the acupoint, while the mechanical and thermal pain threshold was 4.9 and 1.6 times compared with non-acupoint, respectively, and the nanocomposite gel further enhanced. Otherwise, the combination of acupoint and nanocomposite hydrogel exerted synergetic improvement of inflammation, bone erosion, and reduction of systemic toxicity. Furthermore, it could regulate inflammatory factors and restore the balance of Th17/Treg cells, which provided a novel and effective treatment strategy for RA. Interestingly, acupoint administration could improve the accumulation of the designed nanomedicine in arthritic paws (13.5% higher than those in non-acupoint at 48 h), which may explain the better therapeutic efficiency and low toxicity. CONCLUSION: This novel therapeutic approach-acupoint nanocomposite hydrogel, builds a bridge between acupuncture and drugs which sheds light on the combination of traditional and modern medicine.

mmu-miR-199a-5p regulates CYP2B10 through repression of E4BP4 in mouse AML-12 hepatocytes.

miR-199a-5p is an important regulator of many biological processes. However, whether and how CYP enzymes are regulated by miR-199a-5p are unknown. Here, we aimed to investigate the potential role of mmu-miR-199a-5p in regulating CYP2 enzymes.Regulatory effects of mmu-miR-199a-5p on CYP expression were assessed in mouse AML-12 hepatocytes. The metabolic activity of CYP2B10 was probed using cyclophosphamide (CPA) as a specific substrate. The regulatory mechanism was investigated using combined luciferase reporter assays and chromatin immunoprecipitation.Of several important drug-metabolizing CYPs, mmu-miR-199a-5p significantly increased the mRNA levels of Cyp2a10, Cyp2c29, and Cyp2j5 in AML-12 cells with Cyp2a10 altered the most. Consistently, mmu-miR-199a-5p enhanced the expression of CYP2B10 protein and cellular metabolism of CPA. Based on database analysis, Cyp2b10 was not a direct target gene of mmu-miR-199a-5p. Thus, a mediator is necessary for the miRNA regulation of CYP2B10. We found that E4BP4 repressed Cyp2b10 transcription and expression through specific binding to a D-box element in the gene promoter. Moreover, mmu-miR-199a-5p inhibited the expression of E4bp4 at the posttranscriptional level by directly targeting the 59-65 nt segment in its 3'-UTR.In conclusion, mmu-miR-199a-5p positively regulates CYP2B10 expression through inhibiting its repressor E4BP4. Our findings may provide an increased understanding of the complex regulatory pathways for CYP2B10.

Pharmacokinetics-Based Chronoefficacy of Semen Strychni and Tripterygium Glycoside Tablet Against Rheumatoid Arthritis.

Rheumatoid arthritis is a systemic autoimmune disease characterized by synovial inflammation and bone destruction. Identifying drugs with time-varying efficacy and toxicity, and elucidating the mechanisms would help to improve treatment efficacy and reduce adverse effects. Here, we aimed to determine the chronoefficacy of semen strychni (SS) and tripterygium glycoside tablet (TGT) against rheumatoid arthritis in mice, and to investigate a potential role of circadian pharmacokinetics in generating chronoefficacy. SS extract and TGT suspension were prepared with ultrasonication. Effects of SS and TGT on collagen-induced arthritis (CIA) were evaluated by measuring TNF-α and IL-6 levels. SS dosed at ZT18 was more effective in protecting against CIA than drug dosed at ZT6 (i.e., lower levels of key inflammatory factors at ZT18 than at ZT6). This was accompanied by higher systemic exposure levels of strychnine and brucine (two main putative active ingredients of SS) in ZT18-treated than in ZT6-treated CIA mice. TGT dosing at ZT2 showed a better efficacy against CIA as compared to herb doing at ZT14. Consistently, ZT2 dosing generated a higher exposure of triptolide (a main putative active ingredient of TGT) as compared to ZT14 dosing in CIA mice. Moreover, strychnine, brucine, and triptolide significantly inhibited the proliferation of fibroblast-like synoviocytes, and reduced the production of TNF-α and IL-6 and the mRNAs of TNF-α, IL-6, COX-2, and iNOS, suggesting that they possessed an anti-arthritis activity. In conclusion, SS and TGT display chronoefficacy against rheumatoid arthritis in mice, that is attributed to circadian pharmacokinetics of main active ingredients. Our findings have implications for improving treatment outcomes of SS and TGT via timed delivery.

An injectable peptide hydrogel with excellent self-healing ability to continuously release salvianolic acid B for myocardial infarction.

Drug-loaded hydrogels can improve blood supply and inhibit extracellular matrix degradation after myocardial infarction. However, due to the continual dynamic motion of cardiac tissue, the hydrogel structure cannot be reconstructed in time, causing accelerated degradation and drug burst release. Here, a novel, superior, self-healing elastin-mimic peptide hydrogel (EMH) was fabricated for the local delivery of salvianolic acid B (SaB). The self-healing ability of EMH is enhanced by SaB-loaded polydopamine nanoparticles (SaB-PDA). In vitro, the pre-hydrogel (SaB-PDA/pre-EMH) is endowed with excellent biocompatibility and a low viscosity, making it suitable for intramyocardial injection. Once injected into the myocardial infarction (MI) region, SaB-PDA/pre-EMH can form SaB-PDA/EMH with great mechanical strength under the action of upregulated transglutaminase (TGase) in heart tissue post-MI. The superior self-healing ability of SaB-PDA/EMH allows for an increase in retention time in the beating ventricular wall. Therefore, with long-term release of SaB, SaB-PDA/EMH can inhibit ventricular remodeling and promote angiogenesis for MI treatment.

Oscillating lncRNA Platr4 regulates NLRP3 inflammasome to ameliorate nonalcoholic steatohepatitis in mice.

Background: Understanding the molecular events and mechanisms underlying development and progression of nonalcoholic steatohepatitis is essential in an attempt to formulating a specific treatment. Here, we uncover Platr4 as an oscillating and NF-κB driven lncRNA that is critical to the pathological conditions in experimental steatohepatitis Methods: RNA-sequencing of liver samples was used to identify differentially expressed lncRNAs. RNA levels were analyzed by qPCR and FISH assays. Proteins were detected by immunoblotting and ELISA. Luciferase reporter, ChIP-sequencing and ChIP assays were used to investigate transcriptional gene regulation. Protein interactions were evaluated by Co-IP experiments. The protein-RNA interactions were studied using FISH, RNA pull-down and RNA immunoprecipitation analyses Results: Cyclic expression of Platr4 is generated by the core clock component Rev-erbα via two RevRE elements (i.e., -1354/-1345 and -462/-453 bp). NF-κB transcriptionally drives Platr4 through direct binding to two κB sites (i.e., -1066/-1056 and -526/-516 bp), potentially accounting for up-regulation of Platr4 in experimental steatohepatitis. Intriguingly, Platr4 serves as a circadian repressor of Nlrp3 inflammasome pathway by inhibiting NF-κB-dependent transcription of the inflammasome components Nlrp3 and Asc. Loss of Platr4 down-regulates Nlrp3 inflammasome activity in the liver, blunts its diurnal rhythm, and sensitizes mice to experimental steatohepatitis, whereas overexpression of Platr4 ameliorates the pathological conditions in an Nlrp3-dependent manner. Mechanistically, Platr4 prevents binding of the NF-κB/Rxrα complex to the κB sites via a physical interaction, thereby inhibiting the transactivation of Nlrp3 and Asc by NF-κB. Conclusions:Platr4 functions to inactivate Nlrp3 inflammasome via intercepting NF-κB signaling. This lncRNA might be an attractive target that can be modulated to ameliorate the pathological conditions of steatohepatitis.

Morphological transformation enhances Tumor Retention by Regulating the Self-assembly of Doxorubicin-peptide Conjugates.

Rationale: Both spatial accuracy and temporal persistence are crucial in drug delivery, especially for anti-tumor intravenous nanomedicines, which have limited persistence due to their small particle sizes and easy removal from tumors. The present study takes advantage of morphological transformation strategy to regulate intravenous nanomedicines to display different sizes in different areas, achieving high efficient enrichment and long retention in lesions. Methods: We designed and synthesized functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) consisting of self-assembled doxorubicin-peptide conjugates (DPCs) and an acidic-responsive shielding layer named the functional polylysine graft (FPG), which can regulate the assembly morphology of the DPCs from spherical DPC nanoparticles (DPC-NPs) to DPC-nanofibers (DPC-NFs) by preventing the assembly force from π-π stacking and hydrogen bond between the DPC-NPs. The morphology transformation and particle changes of FDPC-NPs in different environments were determined with DLS, TEM and SEM. We used FRET to explore the enhanced retention effect of FDPC-NPs in tumor site in vivo. HPLC-MS/MS analytical method was established to analyze the biodistribution of FDPC-NPs in H22 hepatoma xenograft mouse model. Finally, the antitumor effect and safety of FDPC-NPs was evaluated. Results: The FDPC-NPs were stable in blood circulation and responsively self-assembled into DPC-NFs when the FDPC-NPs underwent the acid-sensitive separation of the shielding layer in a mildly acidic microenvironment. The FDPC-NPs maintained a uniform spherical size of 80 nm and exhibited good morphological stability in neutral aqueous solution (pH 7.4) but aggregated into a long necklace-like chain structure or a crosslinked fiber structure over time in a weakly acidic solution (pH 6.5). These acidity-triggered transformable FDPC-NPs prolonged the accumulation in tumor tissue for more than 5 days after a single injection and improved the relative uptake rate of doxorubicin in tumors 31-fold. As a result, FDPC-NPs exhibited a preferable anti-tumor efficacy and a reduced side effect in vivo compared with free DOX solution and DOX liposomes. Conclusions: Morphology-transformable FDPC-NPs represent a promising therapeutic approach for prolonging the residence time of drugs at the target site to reduce side effect and enhance therapeutic efficacy. Our studies provide a new and simple idea for the design of long-term delivery systems for intravenous chemotherapeutic drugs.

Photoluminescent polymer hydrogels with stimuli-responsiveness constructed from Eu-containing polyoxometalate and imidazolium zwitterions.

Inorganic-organic co-assembly of anionic polyoxometalates (POMs) with zwitterions provides a facile way to fabricate functional soft materials. In this paper, a translucent, photoluminescent polymer hydrogel was fabricated from Weakley-type POM Na9EuW10O36 (EuW10) and polymerizable imidazole-type zwitterion 3-(1-vinyl-3-imidazolio)propanesulfonate (VIPS) via a one-step synthesis method. Detailed characterization indicated that the polymerization of double bonds in VIPS and electrostatic interactions between EuW10 and VIPS play important roles in the formation of the hydrogels. Additionally, the introduction of non-polymerizable zwitterions 3-(1-methyl-3-imidazolio)propanesulfonate (MIPS) or 3-(1-decyl-3-imidazolio)propanesulfonate (C10IPS) can improve the mechanical and luminous performances of the hydrogels. Especially, C10IPS with a long alkyl chain would more significantly alter the coordination environment of EuW10, and consequently resulted in a more efficient energy transfer process. Further investigations revealed that the chemical environment around the Eu3+ can be highly influenced by organic solvents with stronger coordination abilities than water molecules, such as acetone. The translucency and luminescence intensity of the hydrogels can be reversibly transformed after alternately immersing in acetone or H2O for several minutes. Our results provided a useful strategy for the fabrication of luminescent hydrogels by regulating the noncovalent interactions between POMs and zwitterions.

Chirality transfer based on dynamic covalent chemistry: from small chiral molecules to supramolecules.

Single-tailed and gemini-type supra-gelators were facilely fabricated via the conjugation of the d- or l-enantiomeric dihydrazide TDH with single-tailed achiral aldehyde C12BAD through dynamic acylhydrazone bonding. Chirality transfer from small molecules to supramolecules was successfully achieved via the spontaneous assembly of the formed supra-gelators into supramolecular chiral hydrogels.

Smart low molecular weight hydrogels with dynamic covalent skeletons.

We report a new strategy for fabricating a smart low molecular weight hydrogel based on dynamic covalent chemistry from a bola-type supra-gelator, which was facilely fabricated in situ from two non-assembling building blocks, (3-(2-(4-formylphenoxy) ethyl)-1-methyl imidazolium bromide, MA) and (3,3'-dithiobis (propionohydrazide), DSPDZ), through dynamic acylhydrazone bonding. The obtained low molecular weight hydrogels exhibited redox-responsive and controllable self-healing properties. The role of dynamic covalent bonding in the formation of smart hydrogels is revealed in this study, which provides a simple and bottom-up method for constructing smart low molecular weight hydrogels.

The effects of acute amiodarone on short- and long-duration ventricular defibrillation threshold in canines.

INTRODUCTION: Some studies have shown that the defibrillation threshold (DFT) differs between short-duration ventricular fibrillation (SDVF, <1 minute) and long-duration ventricular fibrillation (LDVF > 1 minute). The goal of this study is to evaluate the effects of acute intravenous amiodarone on SDVF-DFT and LDVF-DFT and its possible mechanism as well. METHODS: Twelve open-chest dogs were randomly divided into 2 groups (control group, normal saline, 10 mL·kg·h maintenance, n = 6; amiodarone group, loading dose 10 mg/kg over 10 minutes, maintenance dose 5 mg·kg·h, n = 6). VF was electrically induced and recorded with a 12 × 12 unipolar electrode plaque (2-mm spacing) sutured on the left ventricular epicardium and a plunge needle (6 unipolar electrode) inserted in the left ventricular apex. The DFTs of SDVF and LDVF were determined 20 seconds and 3 minutes after VF induction, respectively. Restitution was estimated from activation recovery intervals during pacing from the plaque and plunge needle electrodes. The activation rate was estimated by Fast Fourier Transform analysis of VF at same electrodes. The VF cycle length was defined as the reciprocal of the activation rate. The epicardial and transmural dispersion of the maximal slope of the restitution curve and VF cycle length of SDVF and LDVF were calculated, respectively. RESULTS: : In controls, LDVF-DFT was higher than SDVF-DFT (645 ± 61 vs. 520 ± 63 V, P < 0.01). Amiodarone did not significantly alter SDVF-DFTs (496 ± 49 vs. 552 ± 69 V, P > 0.05) but decreased LDVF-DFT by 31% (P < 0.01). Compared with control, amiodarone significantly reduced the maximum slope of the restitution curve (1.12 ± 0.35 vs. 0.81 ± 0.25, P = 0.03) and its epicardial dispersion (0.32 ± 0.07 vs. 0.24 ± 0.04,coefficient of variation, P = 0.017). Amiodarone significantly increased the SDVF-CL (92 ± 8 vs. 99 ± 10 milliseconds, P < 0.01) and epicardial dispersion 0.14 ± 0.06 vs. 0.18 ± 0.05, P < 0.01. Amiodarone did not change the LDVF-CL (228 ± 12 vs. 226 ± 10 milliseconds, P > 0.05) or epicardial dispersion (0.17 ± 0.03 vs. 0.15 ± 0.02, P > 0.05) compared with control. However, the drug significantly decreased the transmural dispersion of LDVF-CL (68 ± 28 vs. 39 ± 14 milliseconds, P < 0.01) without changing the transmural dispersion of SDVF-CL (29 ± 22 vs. 32 ± 30 milliseconds, P > 0.05). CONCLUSIONS: Acute amiodarone significantly decreased the LDVF-DFT. The decreased transmural dispersion of LDVF-CL by amiodarone might contribute to the decreased LDVF-DFT.

High-energy defibrillation increases the dispersion of regional ventricular repolarization.

PURPOSE: This study evaluated the effects of shock energy on the dispersion of regional ventricular repolarization (DRVR), post-shock rhythm and sinus recovery time (SRT), and the relationship between DRVR and post-shock ventricular arrhythmias. MATERIALS AND METHODS: Ten open-chest dogs were anesthetized. Ventricular fibrillation (VF) was electrically induced and recorded from a 6 × 6 unipolar electrode plaque (4 mm spacing) sutured on the left ventricular epicardium. Defibrillation threshold (DFT) was determined after 20 s of VF. DRVR was measured before VF, during the earliest post-shock sinus rhythm, and during sinus rhythm 30 s following shocks. Post-shock rhythm and SRT were evaluated after energies of 100% DFT, 125% DFT, 175% DFT, and 250% DFT. RESULTS: In the100% DFT group, the DRVR of the earliest sinus rhythm and 30 s after successful defibrillation was not significantly different than that before VF. But the DRVRs were significantly increased in 125% DFT, 175% DFT, and 250% DFT group. DRVR after defibrillation in the 250% DFT group was higher than those in the 100% DFT and 125% DFT groups. SRT in the 250% DFT group was significantly longer than that in the other groups .The incidence of post-shock ventricular tachycardia was increased when a high-shock energy was applied (P = 0.041). CONCLUSION: DRVR was increased by application of high-energy defibrillation associated with SRT prolongation. The increased DRVR may play an important role in the onset of post-shock ventricular tachycardia.