Plasma humanin as a prognostic biomarker for canine myxomatous mitral valve disease: a comparison with plasma NT-roBNP.

Myxomatous mitral valve disease (MMVD) is a cardiac condition commonly found in older dogs. The disease process can lead to heart failure (HF). In HF, an increase of reactive oxygen species (ROS) and abnormal mitochondrial activity, as well as apoptosis, have been reported. Humanin (HN) is a polypeptide that has a cardioprotective effect against apoptosis and oxidative stress. The purposes of this study were (1) to investigate the potential role of plasma HN as a cardiac biomarker to predict disease progression of MMVD, and (2) to compare plasma HN concentrations with plasma NT-pro BNP concentrations. Thirty-one dogs were included in the study. The dogs were separated into four groups: Group 1 was healthy dogs (n = 8), Group 2 was MMVD class B (n = 8), Group 3 was MMVD class C (n = 8), and Group 4 was MMVD class D (n = 7). All dogs were given a physical examination, thoracic radiography, echocardiography, and samples of their blood were collected for hematology and blood chemistry analysis. Levels of plasma HN and plasma NT-proBNP were also investigated. The results showed that plasma HN levels were lower in the dogs with MMVD and that lower plasma HN levels were associated with greater severity of MMVD-induced HF. It was possible to observe changes in plasma HN levels at a less severe disease stage than plasma NT-proBNP in dogs with MMVD. These findings sug- gest that a decreased plasma HN level can be used as a biomarker to identify dogs with MMVD-induced HF.

Liraglutide preserves intracellular calcium handling in isolated murine myocytes exposed to oxidative stress.

In ischemic/reperfusion (I/R) injured hearts, severe oxidative stress occurs and is associated with intracellular calcium (Ca(2+)) overload. Glucagon-Like Peptide-1 (GLP-1) analogues have been shown to exert cardioprotection in I/R heart. However, there is little information regarding the effects of GLP-1 analogue on the intracellular Ca(2+) regulation in the presence of oxidative stress. Therefore, we investigated the effects of GLP-1 analogue, (liraglutide, 10 microM) applied before or after hydrogen peroxide (H(2)O(2), 50 microM) treatment on intracellular Ca(2+) regulation in isolated cardiomyocytes. We hypothesized that liraglutide can attenuate intracellular Ca(2+) overload in cardiomyocytes under H(2)O(2)-induced cardiomyocyte injury. Cardiomyocytes were isolated from the hearts of male Wistar rats. Isolated cardiomyocytes were loaded with Fura-2/AM and fluorescence intensity was recorded. Intracellular Ca(2+) transient decay rate, intracellular Ca(2+) transient amplitude and intracellular diastolic Ca(2+) levels were recorded before and after treatment with liraglutide. In H(2)O(2) induced severe oxidative stressed cardiomyocytes (which mimic cardiac I/R) injury, liraglutide given prior to or after H(2)O(2) administration effectively increased both intracellular Ca(2+) transient amplitude and intracellular Ca(2+) transient decay rate, without altering the intracellular diastolic Ca(2+) level. Liraglutide attenuated intracellular Ca(2+) overload in H(2)O(2)-induced cardiomyocyte injury and may be responsible for cardioprotection during cardiac I/R injury by preserving physiological levels of calcium handling during the systolic and diastolic phases of myocyte activation.

Fibroblast growth factor 21 (FGF21) therapy attenuates left ventricular dysfunction and metabolic disturbance by improving FGF21 sensitivity, cardiac mitochondrial redox homoeostasis and structural changes in pre-diabetic rats.

AIMS: Fibroblast growth factor 21 (FGF21) acts as a metabolic regulator and exerts cardioprotective effects. However, the effects of long-term FGF21 administration on the heart under the FGF21-resistant condition in obese, insulin-resistant rats have not been investigated. We hypothesized that long-term FGF21 administration reduces FGF21 resistance and insulin resistance and attenuates cardiac dysfunction in obese, insulin-resistant rats. METHODS: Eighteen rats were fed on either a normal diet (n = 6) or a high-fat diet (HFD; n = 12) for 12 weeks. Then, rats in the HFD group were divided into two subgroups (n = 6 per subgroup) and received either the vehicle (HFV) or recombinant human FGF21 (rhFGF21, 0.1 mg kg(-1)  day(-1) ; HFF) injected intraperitoneally for 28 days. The metabolic parameters, inflammation, malondialdehyde (MDA), heart rate variability (HRV), left ventricular (LV) function, cardiac mitochondrial redox homoeostasis, cardiac mitochondrial fatty acid ß-oxidation (FAO) and anti-apoptotic signalling pathways were determined. RESULTS: HFV rats had increased dyslipidaemia, insulin resistance, plasma FGF21 levels, TNF-α, adiponectin and MDA, depressed HRV, and impaired LV and mitochondrial function. HFV rats also had decreased cardiac Bcl-2, cardiac PGC-1α and CPT-1 protein expression. However, FGF21 restored metabolic parameters, decreased TNF-α and MDA, increased serum adiponectin, and improved HRV, cardiac mitochondrial and LV function in HFF rats. Moreover, HFF rats had increased cardiac Bcl-2, cardiac PGC-1α and CPT-1 protein expression. CONCLUSION: Long-term FGF21 therapy attenuates FGF21 resistance and insulin resistance and exerts cardioprotection by improving cardiometabolic regulation via activating anti-apoptotic and cardiac mitochondrial FAO signalling pathways in obese, insulin-resistant rats.

Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload.

AIM: Iron overload in the heart can lead to iron-overload cardiomyopathy and cardiac arrhythmia. In the past decades, growing evidence has suggested that cardiac mitochondrial dysfunction is associated with the development of cardiac dysfunction and lethal arrhythmias. Despite these facts, the effect of iron overload on cardiac mitochondrial function is still unclear. In this study, we determined the effects of iron overload on the cardiac mitochondrial function and the routes of cardiac mitochondrial iron uptake. We tested the hypothesis that iron overload can lead to cardiac mitochondrial dysfunction and that mitochondrial calcium uniporter (MCU) plays a major role for cardiac mitochondrial iron uptake under iron-overload condition. Cardiac mitochondrial function was assessed via the determination of mitochondrial swelling, mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane potential changes. METHODS: Isolated cardiac mitochondria from male Wistar rats were used in this study. To determine the routes for cardiac mitochondrial iron uptake, isolated mitochondria were exposed to MCU blocker (Ru360), mitochondrial permeability transition pore (mPTP) blocker (cyclosporin A) and an iron chelator (deferoxamine). RESULTS: We found that (i) iron overload caused cardiac mitochondrial dysfunction, indicated by increased ROS production, mitochondrial membrane depolarization and mitochondrial swelling; and (ii) only MCU blocker completely protected cardiac mitochondrial dysfunction caused by iron overload. CONCLUSIONS: These findings strongly suggest that MCU could be the major route for iron uptake into cardiac mitochondria. The inhibition of MCU could be the novel pharmacological intervention for preventing iron-overload cardiomyopathy.

Decreased jaw bone density and osteoblastic insulin signaling in a model of obesity.

Previous studies have demonstrated that decreased bone mass results from either the impairment of osteoblastic insulin signaling or obesity. Our previous study revealed that 12-week high-fat-diet (HFD) consumption caused obesity as well as peripheral and brain insulin resistance. However, the osteoblastic insulin resistance induced by HFD has not been elucidated. Therefore, we hypothesized that 12-week HFD rats exhibited not only peripheral insulin resistance but also osteoblastic insulin resistance, which leads to decreased jawbone quality. We found that the jawbones of rats fed a 12-week HFD exhibited increased osteoporosis. The osteoblastic cells isolated from HFD-fed rats exhibited the impairment of osteoblastic insulin signaling as well as reduction of cell proliferation and survival. In conclusion, this study demonstrated that insulin resistance induced by 12-week HFD impaired osteoblastic insulin signaling, osteoblast proliferation, and osteoblast survival and resulted in osteoporosis in the jawbone.

NaV 1.8, but not NaV 1.9, is upregulated in the inflamed dental pulp tissue of human primary teeth.

AIM: To investigate alterations in Na(V) 1.8 and Na(V) 1.9 expression within inflamed dental pulp tissue of human primary teeth. METHODOLOGY: Dental pulp tissue obtained from both normal and inflamed pulps in primary teeth as well as pulps from normal and inflamed permanent teeth was used. The quantity of Na(V) 1.8 and Na(V) 1.9 expression in the dental pulp tissue was investigated using Western blot analysis. General neuron marker (PGP9.5) was used to quantify for neural density, and an increase in metalloproteinase-9 was used to indicate pulpal inflammation in inflamed teeth. Statistically significant differences for each determined parameter between normal and inflamed teeth of both primary and permanent teeth were tested using the Mann-Whitney rank sum test. RESULTS: There was no significant difference in neural density of normal and inflamed dental pulp tissue, although degrees of inflammation were increased in the inflamed dental pulp of both permanent and primary teeth (P < 0.05). Na(V) 1.8 and Na(V) 1.9 expression in inflamed pulps of permanent teeth increased significantly compared with normal permanent teeth (P < 0.05). However, only Na(V) 1.8 expression was increased significantly in the inflamed dental pulp of primary teeth (P < 0.05). CONCLUSIONS: Na(V) 1.8 alone may be the therapeutic target for treatment of painful pulpitis in primary teeth.

Granulocyte colony-stimulating factor stabilizes cardiac electrophysiology and decreases infarct size during cardiac ischaemic/reperfusion in swine.

AIM: Effects of granulocyte colony-stimulating factor (G-CSF) on cardiac electrophysiology during ischaemic/reperfusion (I/R) period are unclear. We hypothesized that G-CSF stabilizes cardiac electrophysiology during I/R injury by prolonging the effective refractory period (ERP), increasing the ventricular fibrillation threshold (VFT) and decreasing the defibrillation threshold (DFT), and that the cardioprotection of G-CSF is via preventing cardiac mitochondrial dysfunction. METHODS: In intact-heart protocol, pigs were infused with either G-CSF or vehicle (n = 7 each group) without I/R induction. In I/R protocol, pigs were infused with G-CSF (0.33 µg kg(-1 ) min(-1) ) or vehicle (n = 8 each group) for 30 min prior to a 45-min left anterior descending artery occlusion and at reperfusion. Diastolic pacing threshold (DPT), ERP, VFT and DFT were determined in all pigs before and during I/R period. Rat's isolated cardiac mitochondria were used to test the protective effect of G-CSF (100 nm) in H(2) O(2) -induced mitochondrial oxidative damage. RESULTS: Neither G-CSF nor vehicle altered any parameter in intact-heart pigs. During ischaemic period, G-CSF significantly increased the DPT, ERP and VFT without altering the DFT. During reperfusion, G-CSF continued to increase the DPT without altering other parameters. The infarct size was significantly decreased in the G-CSF group, compared to the vehicle. G-CSF could also prevent cardiac mitochondrial swelling, decrease ROS production, and prevent mitochondrial membrane depolarization. CONCLUSION: G-CSF increases the DPT, ERP and VFT and reduces the infarct size, thus stabilizing the myocardial electrophysiology, and preventing fatal arrhythmia during I/R. The protective mechanism could be via its effect in preventing cardiac mitochondrial dysfunction.

Reversal of cardiac iron loading and dysfunction in thalassemic mice by curcuminoids.

Non-transferrin bound iron (NTBI) is found in plasma of ß-thalassemia patients and causes oxidative tissue damage. Cardiac siderosis and complications are the secondary cause of death in ß-thalassemia major patients. Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising chelators used to get negative iron balance and improve life quality. DFP has been shown to remove myocardial iron effectively. Curcuminoids (CUR) can chelate plasma NTBI, inhibit lipid peroxidation and alleviate cardiac autonomic imbalance. Effects of CUR on cardiac iron deposition and function were investigated in iron-loaded mice. Wild type ((mu)ß(+/+) WT) and heterozygous ß-knockout ((mu)ß(th-3/+) BKO) mice (C57BL/6) were fed with ferrocene-supplemented diet (Fe diet) and coincidently intervened with CUR and DFP for 2 months. Concentrations of plasma NTBI and malondialdehyde (MDA) were measured using HPLC techniques. Heart iron concentration was determined based on atomic absorption spectrophotometry and Perl's staining methods. Short-term electrocardiogram (ECG) was recorded with AD Instruments Power Lab, and heart rate variability (HRV) was evaluated using MATLAB 7.0 program. Fe diet increased levels of NTBI and MDA in plasma, nonheme iron and iron deposit in heart tissue significantly, and depressed the HRV, which the levels were higher in the BKO mice than the WT mice. CUR and DFP treatments lowered plasma NTBI as well as MDA concentrations (p <0.05), heart iron accumulation effectively, and also improved the HRV in the treated mice. The results imply that CUR would be effective in decreasing plasma NTBI and myocardial iron, alleviating lipid peroxidation and improving cardiac function in iron-loaded thalassemic mice.

Effect of sildenafil citrate on the cardiovascular system.

Sildenafil citrate is a drug commonly used to manage erectile dysfunction. It is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H -pyrazolo[4,3-d]pyrimidin-5-yl)-4 ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate (C22H30N6(O4)S). It is a highly selective inhibitor of cyclic guanine monophosphate-specific phosphodiesterase type 5. In late March through mid-November 1998, the US Food and Drug Administration (FDA) published a report on 130 confirmed deaths among men (mean age, 64 years) who received prescriptions for sildenafil citrate, a period during which >6 million outpatient prescriptions (representing about 50 million tablets) were dispensed. The US FDA recently reported that significant cardiovascular events, including sudden cardiac death, have occurred in men with erectile dysfunction who were taking sildenafil citrate. These reports have raised concerns that sildenafil citrate may increase the risk of cardiovascular events, particularly fatal arrhythmias, in patients with cardiovascular disease. In the past few years, the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively in both animal and clinical studies. According to extensive data available to date, sildenafil citrate has been shown to pose minimal cardiovascular risks to healthy people taking this drug. Some precautions are needed for patients with cardiovascular diseases. However, the only absolute contraindication for sildenafil citrate is the concurrent use of nitrates. This article is intended to review sildenafil citrate's cardiovascular effects, as well as current debates about its arrhythmogenic effects.

Effect of sildenafil citrate on the cardiovascular system

Sildenafil citrate is a drug commonly used to manage erectile dysfunction. It is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H -pyrazolo[4,3-d]pyrimidin-5-yl)-4 ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate (C22H30N6O4 S). It is a highly selective inhibitor of cyclic guanine monophosphate-specific phosphodiesterase type 5. In late March through mid-November 1998, the US Food and Drug Administration (FDA) published a report on 130 confirmed deaths among men (mean age, 64 years) who received prescriptions for sildenafil citrate, a period during which >6 million outpatient prescriptions (representing about 50 million tablets) were dispensed. The US FDA recently reported that significant cardiovascular events, including sudden cardiac death, have occurred in men with erectile dysfunction who were taking sildenafil citrate. These reports have raised concerns that sildenafil citrate may increase the risk of cardiovascular events, particularly fatal arrhythmias, in patients with cardiovascular disease. In the past few years, the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively in both animal and clinical studies. According to extensive data available to date, sildenafil citrate has been shown to pose minimal cardiovascular risks to healthy people taking this drug. Some precautions are needed for patients with cardiovascular diseases. However, the only absolute contraindication for sildenafil citrate is the concurrent use of nitrates. This article is intended to review sildenafil citrate's cardiovascular effects, as well as current debates about its arrhythmogenic effects.

Mechanism of ventricular defibrillation for near-defibrillation threshold shocks: a whole-heart optical mapping study in swine.

BACKGROUND: To study the mechanism by which shocks succeed (SDF) or fail (FDF) to defibrillate, global cardiac activation and recovery and their relationship to defibrillation outcome were investigated for shock strengths with approximately equal SDF and FDF outcomes (DFT(50)). METHODS AND RESULTS: In 6 isolated pig hearts, dual-camera video imaging was used to record optically from approximately 8000 sites on the anterior and posterior ventricular surfaces before and after 10 DFT(50) biphasic shocks. The interval between the shock and the last ventricular fibrillation activation preceding the shock (coupling interval, CI) and the time from shock onset to 90% repolarization of the immediate postshock action potential (RT(90)) were determined at all sites. Of 60 shocks, 31 were SDF. The CI (59+/-7 versus 52+/-6 ms) and RT(90) (108+/-19 versus 88+/-8 ms) were significantly longer for SDF than FDF episodes. Spatial dispersions of CI (36+/-5 versus 34+/-3 ms) and RT(90) (40+/-16 versus 40+/-8 ms) were not significantly different for SDF versus FDF episodes. The first global activation cycle appeared focally on the left ventricular apical epicardium 78+/-32 ms after the shock. CONCLUSIONS: For near-threshold shocks, defibrillation outcome correlates with the electrical state of the heart at the time of the shock and on RT. Global dispersion of RT was similar in both SDF and FDF episodes, suggesting that it is not crucial in determining defibrillation outcome after DFT(50) shocks.

Reduction in atrial defibrillation threshold by a single linear ablation lesion.

INTRODUCTION: This study investigated a hybrid approach to reduce the atrial defibrillation threshold (ADFT) by determining the effect of a single linear radiofrequency ablation (RFA) lesion on both the ADFT and activation patterns during atrial fibrillation (AF). METHODS AND RESULTS: In 18 open chest sheep (45 to 57 kg), coil defibrillation electrodes were placed in a superior vena cava/right ventricular configuration. AF was induced by burst pacing and maintained with acetyl beta-methylcholine (2 to 42 microL/min). ADFTs were obtained before and after a linear RFA lesion was created in the left atrium (LAL; n = 6), right atrium (RAL; n = 6), or neither atrium as a control (n = 6). In animals receiving an LAL, a 504-unipolar-electrode plaque was sutured to the LA. For animals receiving an RAL, two 504-electrode plaques were placed, one each on the LA and RA. From each plaque, activations were recorded before and after ADFT shocks, and organizational characteristics of activations were analyzed using algorithms that track individual wavefronts. In sham-treated controls, the ADFT did not change. In contrast, LAL reduced ADFT energy 29%, from 4.5 +/- 2.3 J to 3.2 +/- 2.0 J (P < 0.05). RAL reduced ADFT energy 25%, from 2.0 +/- 0.9 J to 1.5 +/- 0.7 J (P < 0.05). AF activation was substantially more organized after RFA than before RFA for both the RAL- and LAL-treated animals. CONCLUSION: A single RFA lesion in either the RA or LA reduces the ADFT in this sheep model. This decrease is associated with an increase in fibrillatory organization.

Prediction of defibrillation outcome by epicardial activation patterns following shocks near the defibrillation threshold.

INTRODUCTION: Ventricular defibrillation is probabilistic and shock strength dependent. We investigated the relationship between defibrillation outcome and postshock activation patterns for shocks of the same strength (approximately 50% probability of success for defibrillation [ED50] to yield an equal number of successful and failed shocks). METHODS AND RESULTS: In five pigs, 10 shocks of approximately ED50 strength (right ventricle-superior vena cava, biphasic, 6/4 msec) were delivered after 10 seconds of ventricular fibrillation (VF). Epicardial activation sequences following shocks were mapped with a 504-electrode shock and analyzed by animating dV/dt of the electrograms. Intercycle interval (ICI, time between the onset of successive postshock cycles), wavefront conduction time (WCT, time between the earliest and latest activation of a cycle), and overlapping index (WCT of cycle[n]/ICI of cycle[n+1]) were determined for the first five postshock cycles. An overlapping index >1 indicates overlap between successive cycles. Of 50 defibrillation attempts, 25 were successes. There was no difference between successful and failed episodes for both ICI (68 +/- 9 msec vs 62 +/- 10 msec) and WCT (97 +/- 24 msec vs 100 +/- 14 msec) of cycle 1. However, starting at cycle 2, the ICI was longer, and the WCT was shorter for successful than failed episodes (P < 0.01). Overlapping cycles (index > 1) were found during the transition from cycles 2 through 5 in all failed (index >1) and in no successful episodes. CONCLUSIONS: (1) Defibrillation outcome cannot be determined during the first postshock cycle. (2) At least three rapid successive cycles with overlap of cycles 2 and 3 are present in all failed and in no successful episodes. (3) The overlapping index is a marker to predict defibrillation outcome.

Pacing following shocks stronger than the defibrillation threshold: impact on defibrillation outcome.

INTRODUCTION: A recent study of shocks near defibrillation threshold (DFT) strength demonstrated that at least three rapid cycles always occur after failed shocks but not after successful shocks, suggesting that the number and rapidity of postshock cycles are important in determining defibrillation success. To test this hypothesis, rapid pacing was performed following a shock stronger than the DFT that by itself did not induce rapid cycles and ventricular fibrillation (VF). METHODS AND RESULTS: Epicardial activation was mapped in six pigs using a 504-electrode sock. The DFT was determined by an up/down protocol with S1 shocks (right ventricle-superior vena cava, biphasic). Ten shocks that were 100 to 200 V above the DFT (aDFT) were delivered after 10 seconds of VF to confirm they always defibrillated. Then, S2, S3, etc., pacing at 5 to 10 times diastolic threshold was performed from the left ventricular apex after aDFT shocks during VF. First, the postshock interval after aDFT shocks was scanned with an S2 stimulus to find the shortest S1-S2 coupling interval (CI) that captured. This was repeated for S3, S4, etc., until VF was induced. To induce VF after aDFT shocks, three pacing stimuli (S2, S3, S4) with progressively shorter CIs were always required; S2 or S2,S3 never induced VF. For the S2-S4 cycles, the intercycle interval was shorter (P < 0.01), and the wavefront conduction time was longer (P < 0.01) for episodes in which VF was induced (n = 57) than for episodes in which it was not (n = 60). Following the S4 cycle that induced VF, two types of spontaneous activation patterns appeared: focal (88%) and reentrant (12%). CONCLUSION: VF induction after aDFT shocks always required at least three rapid successive paced-induced cycles. Thus, the number and rapidity of the first several postshock cycles rather than just the first postshock cycle may be determining factors for defibrillation outcome.

Left ventricular apex ablation decreases the upper limit of vulnerability.

BACKGROUND: After shocks with an approximately 50% probability of success for the upper limit of vulnerability (ULV(50)) of strength, the first few activations appear focally on the epicardium at almost the same site at the left ventricular (LV) apex in both successful and failed induction of ventricular fibrillation (VF). We tested the hypothesis that subendocardial ablation at this early site would decrease the shock strength required for the ULV(50). METHODS AND RESULTS: Ten S1 stimuli were delivered from the right ventricular apex at a 300-ms coupling interval in 5 pigs. Biphasic shocks were delivered from right ventricular-superior vena cava electrodes after the last S1 stimulus. The ULV(50) was determined using an up/down protocol with T-wave scanning. Radiofrequency ablation was performed endocardially at the apical LV. The ULV(50) was determined again 30 minutes after ablation. To determine the importance of the ablation region, this protocol was repeated in another 5 pigs with ablation at the LV base. Delivered voltage (401+/-60 versus 323+/-50 V) and energy (11+/-3 versus 7+/-2 J) for the ULV(50) were significantly decreased after LV apex ablation by 19% and 34%, respectively. However, no difference existed in ULV(50) before and after LV base ablation. Lesions at both the LV apex and base were subendocardial and ranged from 0.8 to 1.1 cm in diameter. CONCLUSIONS: Subendocardial ablation at the apical LV markedly decreases ULV(50), which suggests that the activation originating from this postshock early site is responsible for VF initiation and that interventions to electrically silence this site can influence the outcome of VF induction by ULV shocks.

Influence of postshock epicardial activation patterns on initiation of ventricular fibrillation by upper limit of vulnerability shocks.

BACKGROUND: Shocks of identical strength and timing sometimes induce ventricular fibrillation (VFI) and other times do not (NoVFI). To investigate this probabilistic behavior, a shock strength near the upper limit of vulnerability, ULV(50), was delivered to yield equal numbers of VFI and NoVFI episodes. METHODS AND RESULTS: In 6 pigs, a 504-electrode sock was pulled over the ventricles. ULV(50) was determined by scanning the T wave. S(1) pacing was from the right ventricular apex. Ten S(2) shocks of approximate ULV(50) strength were delivered at the same S(1)-S(2) coupling interval. Intercycle interval (ICI) and wave front conduction time (WCT) were determined for the first 5 postshock cycles. ICI and the WCT of cycle 1 were not different for VFI versus NoVFI episodes (P=0.3). Beginning at cycle 2, ICI was shorter and WCT was longer for VFI than NoVFI episodes (P<0.05). CONCLUSIONS: The first cycle after shocks of the same strength (ULV(50)) delivered at the same time has the same activation pattern regardless of shock outcome. During successive cycles, however, a progressive decrease in ICI and increase in WCT occur during VFI but not NoVFI episodes. These findings suggest shock outcome is (1) deterministic but exquisitely sensitive to differences in electrophysiological state at the time of the shock that are too small to detect or (2) probabilistic and not determined until after the first postshock cycle.

Pacing after shocks stronger than the upper limit of vulnerability: impact on fibrillation induction.

BACKGROUND: After upper-limit-of-vulnerability (ULV) shocks of the same strength and coupling interval (CI) during the T wave, (1) the epicardial activation pattern (EAP) for the first postshock cycle is indistinguishable between shocks that do (VF) and do not (NoVF) induce ventricular fibrillation (VF) and (2) >/=3 cycles in rapid succession always occur during VF but not during NoVF episodes. To study the role of these rapid cycles, rapid pacing was performed after a shock stronger than the ULV that by itself did not induce rapid cycles and VF. METHODS AND RESULTS: A 504-electrode sock was sutured to the heart in 6 pigs to map EAPs. The S2 shock strength and S1-S2 CI at the ULV were determined by T-wave scanning with an up/down protocol. Ten shocks 50 to 100 V above the ULV (aULV) were delivered at the same S1-S2 CI to confirm that VF was not induced. Then, the postshock interval after aULV shocks was scanned with an S3 pacing stimulus from the LV apex until the shortest S2-S3 CI that captured was reached. This was repeated for S4, S5, etc, until VF was induced. To induce VF, 3 pacing stimuli (S3-S5) with progressively shorter CIs were required; S3 or S3, S4 never induced VF. After cycle S5, which induced VF, 2 EAP types occurred: focal (74%) and reentrant (26%). CONCLUSIONS: At least 3 cycles with short CIs are necessary for VF induction after aULV shocks. Cycles S3-S4 may create the substrate for cycle S5 to initiate VF.

Effect of altering the left ventricular pressure on epicardial activation time in dogs with and without pacing-induced heart failure.

BACKGROUND: The influence of an increased left ventricular end-diastolic pressure (LVEDP) on the development of lethal arrhythmias in chronic heart failure is unclear. We investigated the effect of chronic and acute LVEDP increase on the epicardial activation time of sinus (SB) and paced (PB) beats. METHODS: Six dogs underwent rapid ventricular pacing at 220-280[emsp4 ]beats/min for 6-14 weeks for induction of heart failure. On the study day, baseline (ba) LVEDP was determined for the surviving heart failure animals (HF-ba), and for seven control animals (C-ba). The epicardial activation time (EAT, time between the earliest and latest epicardial activation) for five consecutive SB and five ventricular PB during the baseline hemodynamic state were recorded using a 504 electrode mapping-sock. In the control animals a 2-litre volume (vl) was infused over 10[emsp4 ]min to acutely increase the LVEDP (C-vl) to a level comparable to the chronic increased LVEDP of the HF-ba. The same volume challenge was performed in two HF animals (HF-vl) and the EAT for SB and PB was redetermined. RESULTS: Three of six HF animals died during induction of heart failure. In the three remaining HF animals, chronic LVEDP increased from 6+/-1 to 17+/-10.8[emsp4 ]mmHg (P=0.07), EAT for SB increased by 68 % compared to control animals (HF-ba vs. C-ba, P<0.05). In contrast, in the control animals the acute rise in LVEDP from 6.8+/-4.5 to 14.7+/-6.2 mmHg P<0.05), shortened the EAT for SB (C-ba vs. C-vl, P<0.05). A similar decrease in EAT for SB caused by acute volume load was seen in the HF animals, but did not reach significance due to the small sample size (one of the three remaining HF animals died of spontaneous ventricular fibrillation before the volume load). Chronic LVEDP elevation significantly prolonged the EAT for PB from 72+/-11 to 120+/-31[emsp4 ]ms (C-ba vs. HF-ba) while acute LVEDP increase had no significant effect on EAT for PB. CONCLUSION: Chronic HF increases LVEDP and prolongs EAT, while an acute increase in LVEDP shortens the EAT for sinus beats. A prolongation of EAT in heart failure may make the heart more susceptible to ventricular arrhythmias and electromechanical dissociation.

Relationship between oversizing of self-expanding stents and late loss index in carotid stenting.

Stenting of the internal carotid artery is facilitated by stenting across the carotid bifurcation and sizing the diameter of a self-expanding stent to the large common carotid segment. This usually results in marked oversizing of the self-expanding stent in the internal carotid segment. This study was done to determine the relationship between stent oversizing and late luminal loss index after stenting of the internal carotid artery. Between September 1995 and March 1997, there were 165 patients (189 vessels) who underwent successful carotid stenting with self-expanding stents. Fifty-nine patients (63 vessels) had six-month follow-up carotid angiograms and on-line quantitative angiographic analysis. The mean reference diameter of the internal carotid arteries was 4.93+/-1.31 mm. Nominal stent size was 5 mm in 4 patients, 6 mm in 6 patients, 8 mm in 106 patients, 10 mm in 77 patients, and 12 mm in 1 patient. The average stent/patient was 1.03+/-0.16. There were three patients who had more than 50% diameter renarrowing at follow-up. The mean late loss index was 0.25+/-0.41. By linear regression analysis, there was no clear linear relationship between stent oversizing and late loss index after stenting (correlation coefficient = -0.21, P = 0.09). When analysis of variance with linear contrast was used to analyze six groups of different stent/artery ratios (from 1.4 to > or = 2), late loss indexes are significantly lower in the groups of high stent/artery ratio than the groups of low stent/artery ratio (P = 0.01). The process of oversizing of self-expanding stents deployed in the internal carotid artery does not appear to be associated with late restenosis and high stent/artery ratio seems to be associated with low late loss index.

Locally propagated activation immediately after internal defibrillation.

BACKGROUND: Electrical mapping studies indicate an interval of 40 to 100 ms between a defibrillation shock and the earliest activation that propagates globally over the ventricles (globally propagated activation, GPA). This study determined whether activation occurs during this interval but propagates only locally before being blocked (locally propagated activation, LPA). METHODS AND RESULTS: In five anesthetized pigs, the heart was exposed and a 504-electrode sock with 4-mm interelectrode spacing was pulled over the ventricles. Ten biphasic shocks of a strength near the defibrillation threshold (DFT) were delivered via intracardiac catheter electrodes, and epicardial activation sequences were mapped before and after attempted defibrillation. Local activation was defined as dV/dt < or =-0.5 V/s. Postshock activation times and wave-front interaction patterns were determined with an animated display of dV/dt at each electrode in a computer representation of the ventricular epicardium. LPAs were observed after 40 of the 50 shocks. A total of 173 LPA regions were observed, each of which involved 2+/-2 (mean+/-SD) electrodes. LPAs were observed after both successful and failed shocks but occurred earlier (P<.0001) after failed (35+/-8 ms) than successful (41+/-16 ms) shocks, although the times at which the GPA appeared were not significantly different. On reaching the LPA region, the GPA front either propagated through it (n=135) or was blocked (n=38). The time from the onset of the LPA until the GPA front propagated to reach the LPA region was shorter (P<.01) when the GPA front was blocked (32+/-12 ms) than when it propagated through the LPA region (63+/-20 ms). CONCLUSIONS: LPAs exist after successful and failed shocks near the DFT. Thus, the time from the shock to the GPA is not totally electrically silent.