Role of polyunsaturated fatty acids in Japanese patients with coronary spastic angina.

BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) reduce the risk of ischemic heart disease. However, there are few reports of a relationship between n-3 PUFAs and coronary spastic angina (CSA). This study aimed to assess the age-dependent role of serum levels of fatty acid in patients with CSA. METHODS AND RESULTS: We enrolled 406 patients who underwent ergonovine tolerance test (ETT) during coronary angiography for evaluation of CSA. All ETT-positive subjects were diagnosed as having CSA. We categorized the patients by age and results of ETT as follows: (1) young (age ≤ 65 years) CSA-positive (n = 32), (2) young CSA-negative (n = 134), (3) elderly (age > 66 years) CSA-positive (n = 36), and (4) elderly CSA-negative (n = 204) groups. We evaluated the serum levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid, and dihomo-gamma-linolenic acid. In the young groups, the serum levels of EPA (64.3 ±â€¯37.7 µg/mL vs. 49.4 ±â€¯28.8 µg/mL, p = 0.015) and DHA (135.7 ±â€¯47.6 µg/mL vs. 117.4 ±â€¯37.6 µg/mL, p = 0.020) were significantly higher in the CSA-positive group than in the CSA-negative group, respectively. However, this was not the case with elderly groups. In the multivariate analysis in young groups, the serum levels of EPA (p = 0.028) and DHA (p = 0.049) were independently associated with the presence of CSA, respectively. CONCLUSION: Our results suggested that the higher serum levels of EPA and/or DHA might be involved in the pathophysiology of CSA in the young population but not in the elderly population.

Histological validation of atrial structural remodelling in patients with atrial fibrillation.

BACKGROUND AND AIMS: This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation. METHODS AND RESULTS: Patients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (Vbiopsy), global left atrial voltage (VGLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZtotal was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly associated with Vbiopsy (P = .014, P < .001, P < .001, and P = .002, respectively) and VGLA (P = .010, P < .001, P = .001, and P < .001, respectively). The intercellular space was associated with the %Fractionated EGM (P = .001). Fibrosis, intercellular space, and myofibrillar loss were associated with SCZtotal (P = .028, P < .001, and P = .015, respectively). Electron microscopy confirmed plasma components and immature collagen fibrils in the increased intercellular space and myofilament lysis in cardiomyocytes, depending on myofibrillar loss. Among the histological factors, the severity of myofibrillar loss was associated with an increase in macrophage infiltration. CONCLUSION: Histological correlates of atrial structural remodelling were fibrosis, increased intercellular space, myofibrillar loss, and decreased nuclear density. Each histological component was defined using electron microscopy and immunohistochemistry studies.

A traditional herbal medicine rikkunshito prevents angiotensin II-Induced atrial fibrosis and fibrillation.

BACKGROUND: Rikkunshito (RKT), a traditional herbal medicine, has been demonstrated to exert anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in several organs. This study tested the hypothesis that RKT can suppress angiotensin II (AngII)-induced inflammatory atrial fibrosis and ameliorate enhanced vulnerability to atrial fibrillation (AF). METHODS: Eight-week-old male C57BL/6 mice were subcutaneously infused with either vehicle or AngII (2.0 mg/kg/day) for 2 weeks. Water or RKT at a dose of 1000 mg/kg/day were orally administered once daily for 2 weeks. Morphological, histological, and biochemical analyses were performed. AF was induced either by transesophageal burst pacing in vivo or by burst/extrastimuli in isolated perfused hearts using a Langendorff apparatus. RESULTS: RKT at a dose of 1000 mg/kg/day for 2 weeks attenuated atrial interstitial fibrosis and profibrotic and proinflammatory signals induced by continuous infusion of AngII. RKT attenuated AngII-induced enhanced vulnerability to AF in in vivo experiments and in isolated perfused hearts. Atractylodin, an active component of RKT, exhibited antifibrotic activity comparable to that of RKT. RKT reversed AngII-induced suppression of sirtuin 1 (Sirt1) translocation to the nuclei. RKT suppressed AngII-induced phosphorylation of IκB, overexpression of p53, and cellular apoptotic signals and apoptosis. All of the antagonizing effects of RKT against AngII were attenuated by a concomitant treatment with a growth hormone secretagogue receptor (GHSR)-inhibitor. CONCLUSION: Our results demonstrated that RKT prevented atrial fibrosis and attenuated enhanced vulnerability to AF induced by AngII. The results also suggested that potentiating the GHSR-Sirt1 pathway is involved in these processes.

Impact of the extent of low-voltage zone on outcomes after voltage-based catheter ablation for persistent atrial fibrillation.

BACKGROUND: Low-voltage zones (LVZs), as measured by electroanatomic mapping, are thought to be associated with fibrosis. We reported the efficacy of atrial fibrillation (AF) ablation aiming to homogenize left atrial (LA) LVZ. The purpose of this study was to evaluate the impact of LVZ extension outcomes after LVZ homogenization in patients with nonparoxysmal AF. METHODS: This prospective observational cohort study included 172 patients with nonparoxysmal AF undergoing their initial ablation. LVZ was defined as an area with bipolar electrograms <0.5mV during sinus rhythm. LVZ extent was calculated as the percentage of LA surface area, and subsequently, LVZ was categorized into stages I (<5%), II (≥5% to <20%), III (≥20% to <30%), and IV (≥30%). Patients with LVZs underwent LVZ ablation aimed at homogenization of ≥80% of LVZs following pulmonary vein isolation. The primary endpoint was atrial tachyarrhythmia recurrence-free survival after a single procedure at 18 months off antiarrhythmic drugs. The association of %LVZ with recurrence-free survival was examined using Cox proportional hazard models. RESULTS: The survival rates were 76%, 74%, 57%, and 28% in patients with stages I, II, III, and IV LVZ, respectively. The difference was significant between stages I and IV (log-rank, p<0.001), while not significant between stages I vs. II and I vs. III (p=0.843, p=0.073, respectively). Cox proportional hazard model revealed that %LVZ was an independent predictor of recurrence-free survival (hazard ratio, 1.025 per 1% increase, p<0.001; unadjusted model). The results were similar after demographic and clinical covariate adjustments and after excluding 12 patients who did not achieve homogenization of ≥80% of LVZ. CONCLUSIONS: The extent of LVZ is an independent predictor for recurrence even after LVZ homogenization.

Early repolarization is involved in ventricular fibrillation in patients with variant angina.

BACKGROUND: Variant angina (VA) is caused by reversible coronary artery spasm, which is characterized by chest pain with ST segment elevations on a standard 12-lead electrocardiogram (ECG) at rest. VA attack often causes lethal ventricular arrhythmia. The early repolarization (ER) pattern is associated with ventricular fibrillation (VF). However, whether the ER pattern is involved in VF in patients with VA is not known. We investigated the association between the ER pattern and VF in patients with VA. METHODS: Fifty patients underwent induction of ST elevation on 12-lead ECGs with total or nearly total occlusion by provocation test (VA patients). Twelve of these patients underwent induction of VF or had documented VF before hospital admission (VF occurrence group). The J-wave morphology was characterized as exhibiting notching or slurring. The amplitude of each J wave was measured manually with amplified waveforms. RESULTS: ER patterns were observed significantly more often in the VF occurrence group than in the non-VF occurrence group (P = 0.007). The J-wave amplitude was significantly higher in the VF occurrence group compared with the non-VF occurrence group (P = 0.02). Univariate analyses suggested that age, smoking, and ER patterns were associated with VF. Upon multivariate analyses, age (odds ratio [OR] = 0.880; 95% confidence interval [CI]: 0.794-0.975; P = 0.014) and ER patterns (OR = 8.937; 95% CI:1.661-48.06; P = 0.011) predicted VF independently. CONCLUSIONS: These data suggest that an ER pattern in VA patients is a risk factor for VF. The ER pattern may be one of the useful factors for adaptation of implantation of implantable cardioverter-defibrillator in patients with coronary spasm-induced VF.

A case of Wolff-Parkinson-White syndrome presenting spontaneous mutual frequent transition between atrioventricular reciprocating tachycardia and atrioventricular nodal re-entrant tachycardia.

Atrioventricular reciprocating tachycardia (AVRT) and atrioventricular nodal re-entrant tachycardia (AVNRT) can coexist and present unidirectional transition (from AVRT to AVNRT, or from AVNRT to AVRT) in a single patient. Actually, such cases have already been reported previously. However, a case with spontaneous bidirectional transition of both tachycardias during supraventricular tachycardia has never been reported. This article describes a case with spontaneous, mutual, and frequent transition between AVRT and AVNRT.

Efficacy of Left Atrial Voltage-Based Catheter Ablation of Persistent Atrial Fibrillation.

BACKGROUND: Low-voltage zones (LVZs) represent fibrotic tissue and are substrates for atrial fibrillation (AF). We hypothesized that LVZ-based substrate modification along with pulmonary vein isolation (PVI) would improve outcomes in persistent AF (PeAF) patients with LVZs, whereas PVI alone would work in patients without LVZs. METHODS AND RESULTS: Voltage mapping of the left atrium (LA) was performed during sinus rhythm in 101 PeAF patients in whom LVZ was defined as an area with bipolar electrograms <0.5 mV. Thirty-nine patients had LVZs and underwent ablation of the entire LVZ area after PVI (LVZabl group). In the remaining 62 patients without LVZs, PVI alone was performed with no further substrate modifications (PVI group). An additional group of 16 consecutive PeAF patients with LVZ did not undergo any substrate modification after PVI and were used as a comparison group (LVZnon-abl group) despite having similar size of LVZs to that in the LVZabl group. After a single session, 28 (72%) patients in the LVZabl group had no recurrence, whereas 49 (79%) patients in the PVI group had no recurrence during 18 ± 7 months of follow-up (log-rank, P = 0.400). In the LVZnon-abl group, only 6 patients (38%) had no recurrence during 32 ± 7 months of follow-up, even after a mean number of sessions of 1.8 (log-rank, P < 0.001, compared with the LVZabl group). CONCLUSIONS: Additional LVZ-based substrate modification after PVI improved the outcome in PeAF patients with LVZs, whereas PVI alone worked in patients without LVZs, even in those with PeAF.

Long-term results of pulmonary vein antrum isolation in patients with atrial fibrillation: an analysis in regards to substrates and pulmonary vein reconnections.

AIMS: To examine the impact of left atrial (LA) low-voltage zones (LVZs) on atrial fibrillation (AF) recurrence after pulmonary vein antrum isolation (PVAI) without LA substrate modification. METHODS AND RESULTS: Seventy-six patients with AF (paroxysmal/persistent 65/11) were prospectively enroled. Left atrial voltage maps were constructed during sinus rhythm using NavX to identify LVZs (<0.5 mV), and PVAI without any LA substrate modification was performed using an open-irrigation catheter. After PVAI, 20 mg of adenosine triphosphate (ATP) was injected. Adenosine triphosphate-induced PV reconnections were eliminated by touch-up ablation when unmasked. Voltage maps revealed LVZs in 24 patients (32%) and no LVZs in 52 (68%). During 24 ± 7 months of follow-up, 15 patients (63%) with LVZs and 10 (19%) without had AF recurrences off antiarrhythmic drugs (log-rank P < 0.001). A multivariate logistic regression analysis revealed that LVZ areas [odds ratio (OR): 1.12 per 1 cm(2), 95% confidence interval (CI): 1.04-1.23, P = 0.001] and ATP-induced reconnection (OR: 2.08, 95% CI: 1.01-4.91, P = 0.046) were significant predictors of recurrence. In those with LVZs, the LVZ area was strongly correlated with the LA body volume (r = 0.81, P < 0.001) and a unique predictor of recurrence (OR: 1.17 per 1 cm(2), 95% CI: 1.01-1.55, P = 0.031), while in those without an LVZ, ATP-induced PV reconnection was a unique predictor (OR: 3.24, 95% CI: 1.15-15.39, P = 0.025). CONCLUSION: The LVZ area was an independent predictor of recurrence after PVAI without any LA substrate modification. Adenosine triphosphate-induced PV reconnection was also an independent predictor, especially in those without LVZs.

Candesartan restored cardiac Hsp72 expression and tolerance against reperfusion injury in hereditary insulin-resistant rats.

AIMS: We tested the hypothesis that candesartan, an angiotensin II (AII) type 1 receptor antagonist, would restore the depressed phosphatidylinositol 3 (PI3) kinase-dependent Akt phosphorylation, an essential signal to induce heat-shock protein 72 (Hsp72) in response to hyperthermia, in Otsuka Long-Evans Tokushima fatty (OLETF) rats. METHODS AND RESULTS: At 14 weeks of age, male OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats were treated with candesartan (0.25 mg/kg/day) for 2 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. We observed the following: (i) Candesartan did not improve insulin sensitivity in OLETF rats. (ii) Candesartan restored depressed PI3 kinase-dependent Akt phosphorylation and Hsp72 expression in OLETF rat hearts. (iii) Cardiac ventricular tissue contents of AII were greater in OLETF rats, which were suppressed by candesartan. (iv) Cardiac levels of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphorylation were greater in OLETF rats, which were suppressed by candesartan. In cultured cardiomyocytes, application of AII induced PTEN phosphorylation, which was suppressed by candesartan. (v) In high-fat diet insulin-resistant rats, similar results were observed with respect to Hsp72 expression, Akt phosphorylation and PTEN phosphorylation. (vi) In isolated, perfused heart experiments, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by candesartan. CONCLUSION: Our results suggest that the depression of PI3 kinase-dependent Akt activation in response to hyperthermia in OLETF rats can be restored by candesartan. Substantial activation of the renin-angiotensin system, represented by increased myocardial AII content and subsequent PTEN phosphorylation, may underlie the pathogenesis which is ameliorated by candesartan.

A new method of a pulmonary vein map to identify a conduction gap on the pulmonary vein antrum ablation line.

BACKGROUND: Electrical isolation of the pulmonary veins (PV) is crucial for atrial fibrillation (AF) ablation. Conduction gaps on the circumferential PV antrum ablation (CPVA) line sometimes remain, which are sometimes difficult to identify. METHODS AND RESULTS: CPVA of the ipsilateral superior and inferior PVs was performed during sinus rhythm or coronary sinus pacing using the NavX system in 22 AF patients, in whom 1 round of CPVA failed to disconnect 26 individual PVs (30%) in 18 patients. In these patients, a local activation map within the CPVA line (PV map) was created by a 20-pole circular mapping catheter with the use of the NavX, with 71 ± 37 sampling points per PV antrum. The conduction gap was defined as a site on the CPVA line, from which the activation proceeded toward the entire PV. The mapped PV antra were comprised of the left superior PV in 11, right superior PV in 10, left inferior PV in 3, right inferior PV in 1 and a left common PV in 1 PV(s). The conduction gaps were identified at 1.4 ± 0.7 sites per PV antrum, with an electrogram amplitude of 0.8 ± 0.7 mV. A point ablation at the gap completely isolated 24 out of 26 PV antra (92%) with 1.9 ± 1.3 applications. CONCLUSIONS: The PV map was useful for quickly and accurately identifying the conduction gap(s) after 1 round of CPVA.

New lipoic acid derivative drug sodium zinc dihydrolipoylhistidinate prevents cardiac dysfunction in an isolated perfused rat heart model.

OBJECTIVE: Myocardial ischemia/reperfusion injury is a life-limiting condition. Reactive oxygen species are released upon reperfusion, resulting in damage to myocardial cells. Accordingly, antioxidant drugs have been shown to protect the myocardium against ischemia/reperfusion injury. The purpose of the present study was to determine the cardioprotective effects of the new lipoic acid-derivative drug sodium zinc dihydrolipoylhistidinate in a global ischemia isolated perfused rat heart model. DESIGN: Animals were randomly divided into five groups: 1) normal group, 2) control ischemia/reperfusion group, 3) high-dose sodium zinc dihydrolipoylhistidinate (1 ng/mL) plus ischemia/reperfusion group, 4) medium-dose sodium zinc dihydrolipoylhistidinate (0.1 ng/mL) plus ischemia/reperfusion group, or 5) low-dose sodium zinc dihydrolipoylhistidinate (0.01 ng/mL) plus ischemia/reperfusion group. SETTING: University medical center research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 250-300 g. MEASUREMENTS AND MAIN RESULTS: Hearts underwent ischemia/reperfusion after isolation with or without sodium zinc dihydrolipoylhistidinate treatment. We then conducted cardiac histopathology and transmission electron microscopy analyses and assessed cardiac function. In addition, we examined the effects of sodium zinc dihydrolipoylhistidinate on ischemia/reperfusion-induced mitochondrial dysfunction. We found that cardiac dysfunction and mitochondrial damage were significantly reduced after reperfusion by sodium zinc dihydrolipoylhistidinate treatment. However, only rats treated with high-dose sodium zinc dihydrolipoylhistidinate showed improved cardiac function. Furthermore, treatment with sodium zinc dihydrolipoylhistidinate significantly improved mitochondrial function in vitro. CONCLUSIONS: These findings suggest that sodium zinc dihydrolipoylhistidinate attenuates ischemia/reperfusion-induced myocardial dysfunction in rats. Furthermore, sodium zinc dihydrolipoylhistidinate exerted cardioprotective effects via preservation of mitochondrial function. Taken together, our results strongly support the potential therapeutic role of sodium zinc dihydrolipoylhistidinate in the treatment of ischemia/reperfusion injury.

Characterization of non-pulmonary vein foci with an EnSite array in patients with paroxysmal atrial fibrillation.

AIMS: Non-pulmonary vein (PV) foci are sometimes difficult to identify and eliminate. The EnSite array (EA) reveals the detailed beat-to-beat virtual activation. This study aimed to characterize non-PV foci using the EA. METHODS AND RESULTS: Sixty-five patients with paroxysmal atrial fibrillation (AF) were included. All had ectopy initiating AF and/or focal atrial tachycardia analysed using the EA. All patients underwent PV isolation (PVI) and additional ablation of non-PV foci if present. The EA revealed 59 PV foci in 48 patients (Group P) and 19 non-PV foci in 17 patients (Group N). In Group N, 12 patients (71%) also had 17 PV foci. The non-PV foci were frequently distributed in the left atrial (LA) roof (n = 5) and superior vena cava (n = 5). Pulmonary vein isolation during on-going AF terminated AF in 34 of 37 in Group P (92%) and 4 of 14 in Group N (29%) patients (P < 0.0001). All non-PV foci were eliminated by an EA-guided ablation. During a 23 ± 10 month follow-up, 11 patients (17%) had AF recurrences, mainly due to LA-PV reconnection. CONCLUSION: Non-PV foci are prevalent in the LA roof and SVC sites, but can originate from other sites as well. When non-PV foci are observed, PVI may be insufficient and should be supplemented with non-PV foci ablation.

Radiofrequency catheter ablation of ventricular tachyarrhythmia under navigation using EnSite array.

BACKGROUND: EnSite array (EA) provides virtual activation of ventricular tachycardia (VT) and premature ventricular contraction (PVC) on a beat-to-beat basis. METHODS AND RESULTS: Fifty-five consecutive patients (age 52+/-16 years) with 79 VTs/PVCs undergoing EA-guided radiofrequency catheter ablation (RFA) were studied, of whom 7 patients had organic heart diseases. A virtual activation map showed that 66 VTs/PVCs originated from the right ventricle (RV), including the RV outflow tract in 57, lateral wall of RV in 4, His bundle region in 3 and tricuspid annulus in 2. Ten VTs/PVCs originated from the left ventricle (LV), including the LV endocardium in 7 and aortic sinus cusp in 3. The origins of 3 PVCs, one each in 3 patients, were not identified. Six of 38 VTs were sustained and the remaining 32 VTs were non-sustained. RFA eliminated all but 3 focal PVCs, and all macroreentrant VTs at a critical conducting pathway, which was identified by the combined use of contact voltage and virtual activation maps. There were 11+/-9 applications, and the radiofrequency energy and fluoroscopy time were 11,354+/-13,360 J and 30+/-21 min, respectively. All patients with acute success were free of any symptoms during a follow up of 21+/-11 months. CONCLUSIONS: EA-guided RFA is safe and effective for VT/PVC, irrespective of its origin, mechanism, sustainability, hemodynamic condition, and underlying heart disease.

Characterization of bipolar electrograms during sinus rhythm for complex fractionated atrial electrograms recorded in patients with paroxysmal and persistent atrial fibrillation.

AIMS: Complex fractionated atrial electrogram (CFAE) has been reported to relate to maintain atrial fibrillation (AF). The aims of this study were to investigate the relationship between CFAE and background conditions during sinus rhythm (SR). METHODS AND RESULTS: Electroanatomical mapping using an EnSite Array was performed in 20 patients (paroxysmal AF:persistent AF = 16:4) who underwent pulmonary vein antrum isolation (PVAI). Contact bipolar electrograms were recorded before PVAI, during SR, and subsequently during induced AF. Peak-to-peak voltages and morphologies of the electrograms during SR were compared between sites with and without CFAE during AF. Among 1947 points obtained during SR, 974 (50%) were included in CFAE sites and 973 (50%) in non-CFAE sites. Electrogram amplitude during SR was higher at the CFAE sites than at the non-CFAE sites (2.4 +/- 1.7 vs. 1.9 +/- 1.9 mV; P < 0.0001), whereas fractionated or double electrograms were found in a similar range between the two areas (2 vs. 3%; P = 0.21). When analysed further in terms of AF termination by PVAI followed by confirmation of non-inducibility, the voltage of electrograms at the CFAE sites was lower (2.1 +/- 1.7 vs. 2.6 +/- 1.8 mV; P = 0.0001) and the morphology was more complex in patients without AF termination compared with those with AF termination. CONCLUSION: Our results suggest that in paroxysmal and persistent AF with minimally damaged LA, the CFAE sites in patients with AF termination by PVAI alone represent healthy atrial tissue with rapid electrical activity in response to an AF driver located in the pulmonary vein. However, in patients without AF termination, they represent more damaged tissue responsible for maintaining AF.

Real-time 3-dimensional imaging of the esophagus and left atrium with a noncontact mapping system.

BACKGROUND: Recognizing the relative location of the esophagus to the left atrial posterior wall (LAPW) is required to avoid esophageal injury during atrial fibrillation ablation. METHODS AND RESULTS: The 24 patients undergoing circumferential pulmonary vein isolation (CPVI) each had the geometry of their left atrium (LA) and esophagus constructed by a noncontact mapping system with EnSite version 6.0J. The esophageal course relative to the LAPW was found to be to the left in 12, middle in 8, right in 2, and obliquely left-to-right in 2 patients, and in 13 patients (54%) it was located on or near either the left or right CPVI line. The mean distance between the esophagus and LAPW was shorter at the bottom line of the LAPW connecting both inferior pulmonary veins (3 +/- 3 mm) than at the LA roof line connecting both superior pulmonary veins (6 +/- 6 mm, P<0.01). CONCLUSIONS: The location of the esophagus relative to the LAPW varies with the patient, but a close location to either CPVI line was found in approximately 50% and a close location between the esophagus and LAPW was found in the inferior and middle locations in most patients.

Gender differences in the effect of auditory stimuli on ventricular repolarization in healthy subjects.

INTRODUCTION: Gender differences in the incidence of ventricular arrhythmias have been reported and torsade de pointes associated with long-QT syndrome (LQTS) is more common in women than men. Although auditory stimulation has been recognized as an important trigger of torsade de pointes in LQT2 patients, the normal response and gender differences in ventricular repolarization induced by auditory stimuli remained to be evaluated systematically. METHODS: Holter ECGs were recorded in 30 healthy volunteers (14 men aged 25 +/- 4 years and 16 women aged 23 +/- 2 years). They were awakened by an alarm clock at 5:00 am. The RR and QT (QTc) intervals and the T-wave amplitude were measured before and after alarm ringing. RESULTS: The morphology of the T-wave changed dynamically and transiently during awakening. The RR interval significantly decreased just after sounding of the alarm in both sexes (P < 0.0001). The QT interval changed little after the alarm ringing and was significantly longer in women than men (P < 0.0001). The QTc intervals were significantly prolonged just after alarm ringing in both sexes (P < 0.0001); QTc prolongation was significantly longer and more sustained in women than men (P < 0.0001). The T-wave amplitude decreased after the alarm and was significantly lower in women than men (P = 0.0001). CONCLUSION: Auditory stimulation abruptly and abnormally modulated the dynamics of ventricular repolarization in healthy subjects; the effect was more pronounced in women than men. This gender difference may partially account for the increased susceptibility of women with electrically unstable hearts to arrhythmogenesis.

Hyperthermia-induced cardioprotection is potentiated by ischemic postconditioning in rats.

We tested the hypothesis that the protective effects of hyperthermia (HT) could be augmented by ischemic postconditioning (PostC) via enhancement of reperfusion-induced Akt phosphorylation. The role of the mitoKATP channel as an effecter to protect hearts against ischemia/reperfusion injury was also investigated. In isolated perfused heart experiments using a Langendorff apparatus, 30 min of no-flow global ischemia was followed by 120 min of reperfusion. Ischemic PostC, 5 cycles of 10-sec reperfusion/10-sec ischemia, was achieved at the initial moment of reperfusion. Hyperthermia (HT, 43 degrees C for 20 min) was applied 24 hr before ischemia onset. Ischemic PostC alone did not show significant protection, but HT did. The HT-induced protection in terms of infarct size, recovery of left ventricular performance, amount of released creatine kinase and apoptosis were enhanced by ischemic PostC. These protective effects were consistent with the levels of Akt phosphorylation 7 min after reperfusion and were completely blocked by the pretreatment with the phosphatidylinositol 3-kinase inhibitor wortmannin. HT-induced protection was also completely abolished by concomitant perfusion with 5-hydroxydecanoate (5HD, 100 microM), an inhibitor of the mitochondrial ATP-sensitive potassium (mitoKATP) channel. However, the potentiated protection by ischemic PostC remained, even in the presence of 5HD. In conclusion, ischemic PostC could potentiate the protective effects of HT possibly via enhancement of reperfusion-induced Akt phosphorylation. Although the opening of the mitoKATP channel is predominantly involved as an effecter in HT-induced protection, potentiated protection by ischemic PostC may involve mechanisms other than the mitoKATP channel.

Adrenomedullin improves cardiac expression of heat-shock protein 72 and tolerance against ischemia/reperfusion injury in insulin-resistant rats.

We recently reported that long-term treatment with pioglitazone restored cardiac Akt phosphorylation in response to hyperthermia (HT) and subsequent cardiac heat-shock protein 72 (HSP72) expression, in heredity insulin resistance rats via improvement of insulin sensitivity. Because adrenomedullin (AM) promotes Akt phosphorylation and attenuates myocardial ischemia/reperfusion injury, we tested the hypothesis that pretreatment with AM before HT could restore depressed Akt activation and cardiac HSP72 expression, thereby enhancing protection against ischemia/reperfusion injury in this model. At 16 wk of age, male insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were treated with AM (0.05 microg/kg . /min iv) or vehicle for 60 min. Thereafter, HT (43 C for 20 min) or normothermia (NT; 37 C for 20 min) was applied. The heart was isolated 1 and 24 h after HT. 1) Either AM or HT induced myocardial Akt phosphorylation in a phosphatidylinositol 3-kinase-dependent manner, which was augmented by their combination. 2) Akt phosphorylation induced by HT, or a combination of HT and AM, was attenuated in insulin-resistant OLETF rat hearts. 3) The levels of Akt phosphorylation in response to AM and/or HT correlated with reperfusion-induced left ventricular functional recovery and amount of released creatine kinase during reperfusion. 4) AM protected the hearts of OLETF rats and LETO rats. Our results suggest that AM pretreatment could enhance HT-induced myocardial Akt phosphorylation and subsequent HSP72 expression in a phosphatidylinositol 3-kinase-dependent manner, in association with tolerance against ischemia/reperfusion injury. This intervention was effective even in insulin-resistant hearts.

Hyperthermia treatment prevents angiotensin II-mediated atrial fibrosis and fibrillation via induction of heat-shock protein 72.

We tested the hypothesis that atrial fibrosis and atrial fibrillation (AF) evoked by angiotensin II (AII) could be prevented by the induction of heat-shock protein 72 (HSP72) by hyperthermia (HT). In cultured atrial fibroblasts isolated from male Sprague-Dawley rats, HT (42 degrees C) was applied for 30 min. AII (100 nmol/L) was added to the medium 8 h later. HT induced the expression of HSP72, which was associated with the attenuation of AII-induced extracellular signal-regulated kinase (ERK1/ERK2) phosphorylation, alpha-smooth muscle actin (alpha-SMA) expression, transforming growth factor-beta(1) secretion, collagen synthesis, and expression of collagen type I and tissue inhibitor of metalloproteinases-1. A small interfering RNA targeting HSP72 abolished these anti-fibrotic effects of HT. In male Sprague-Dawley rats in vivo, an osmotic mini-pump was subcutaneously implanted for continuous infusion of AII (400 ng/kg/min). Whole-body HT (43 degrees C, 20 min) was applied 24 h before and 7, 14, and 21 days after the start of the AII infusion. Repeated HT led to the induction of HSP72 expression, which resulted in an attenuation of AII-induced left atrial fibrosis. In an electrophysiological study using isolated perfused heart, continuous AII caused slowing of interatrial conduction without affecting atrial refractoriness. In AII-treated hearts, extrastimuli from the right atrial appendage resulted in a high incidence of repetitive atrial responses, which were suppressed by treatment with HT. Our results suggest that HT treatment is effective in suppressing AII-mediated atrial fibrosis and AF via induction of HSP72 at least in parts, and is thus expected to be a novel strategy for prevention of AF.

Gender differences in autonomic modulation of ventricular repolarization in humans.

BACKGROUND: Gender differences in the incidence of ventricular arrhythmias have been reported and torsades de pointes associated with long QT syndrome are more common in women than men. Although increased sympathetic tone has an important role in vulnerability to arrhythmia, little is currently known regarding gender differences in the dynamic electrophysiological response to sympathetic stimulation. Therefore, we investigated whether there is a gender difference in humans with respect to the dynamic response of ventricular repolarization to beta-adrenergic stimulation and to autonomic blockade. METHODS: Twelve-lead ECGs were continuously recorded during isoproterenol infusion (protocol 1) and autonomic blockade with propranolol and atropine infusion (protocol 2) in 24 healthy volunteers (12 men, 23 +/- 2 years; 12 women, 23 +/- 5 years). QT (QTc) intervals were measured at the baseline and at a heart rate of 75, 100, and 120 beats/min. RESULTS: (1) The morphology of the T wave dynamically and transiently changed to bifid or biphasic during the acute phase of isoproterenol infusion. The incidence of these morphologic changes was higher in women than men (P < 0.05). (2) The QTc interval was initially prolonged and then shortened in both men and women during isoproterenol administration. However, QTc prolongation was significantly greater in women (0.44 +/- 0.02 to 0.55 +/- 0.03 sec) than men (0.42 +/- 0.03 to 0.51 +/- 0.04 sec; P < 0.05). (3) The QTc interval was significantly prolonged under autonomic blockade and the intrinsic QTc interval was longer in women than men (P < 0.05). CONCLUSION: While sympathetic stimulation and autonomic blockade modulated the dynamics of ventricular repolarization in both sexes, it was more pronounced in women. This gender difference may partially account for the susceptibility of women to arrhythmogenesis.