Is the combination therapy of IKr-channel blocker and left stellate ganglion block effective for intractable ventricular arrhythmia in a cardiopulmonary arrest patient?

Background: We have previously reported that the defibrillation success rate of intravenous nifekalant hydrochloride (NIF), a pure IKr-channel (IKr: the rapid components of the delayed rectifier potassium current) blocker, was more than 75% for lidocaine-resistant ventricular tachycardia and fibrillation (VT/VF) in patients with out-of-hospital cardiopulmonary arrest (CPA). However, there was no effective treatment for the remaining 25% of patients in whom defibrillation was unsuccessful. We hypothesised that the combination therapy of NIF and left stellate ganglion block (LSGB) was useful for defibrillation in NIF-resistant VT/VF and investigated its efficacy in a retrospective study. Methods and results: We investigated sequentially 272 out-of-hospital CPA patients treated at Tokai University between April and December 2006. VT/VF occurred in 55 patients on arrival or during cardiopulmonary resuscitation (CPR). On the basis of our CPR algorithm, NIF was administered (0.15-0.3 mg/kg, i.v.) after the first direct-current cardioversion. NIF-resistant VT/VFs were observed in 15 out of 55 patients and LSGB was performed on 11 of these with administration of NIF. Sinus rhythm was restored in 7 patients following LSGB (64%) and complete recovery was achieved in 2 patients. In the non-LSGB group, however, all the patients died. Conclusions: The combination therapy of intravenous NIF and LSGB was useful for defibrillation in intractable VT/VF. It is a potential and innovative treatment strategy for IKr-channel blocker resistant VT/VF. (Cardiol J 2007; 14: 355-365

Skuteczność terapii złożonej polegającej na podaniu blokera kanału IKr oraz wykonaniu blokady zwoju gwiaździstego w leczeniu opornych arytmii komorowych u chorych z zatrzymaniem krążenia

Wstęp: W poprzednich doniesieniach autorzy niniejszej pracy dowiedli, że współczynnik skuteczności defibrylacji przy jednoczesnym dożylnym podaniu chlorowodorku nifekalantu (NIF) - selektywnego blokera kanałów szybkiej składowej opóźnionego prostującego prądu potasowego (IKr) wynosił powyżej 75% dla opornego na lignokainę częstoskurczu lub migotania komór (VT/VF) w przebiegu pozaszpitalnego zatrzymania krążenia (CPA). Jednakże dla pozostałych 25% chorych, u których wykonana defibrylacja okazała się nieskuteczna, nie znaleziono efektywnych metod leczenia. Autorzy niniejszej pracy sugerują, że zastosowanie złożonej terapii polegającej na dożylnym podaniu NIF oraz wykonaniu blokady lewego zwoju gwiaździstego (LSGB) jest użyteczne w przypadku defibrylacji VT/VF opornego na działanie NIF. Na podstawie własnych badań retrospektywnych podjęto także próbę oceny skuteczności tej terapii. Metody i wyniki: Do badania włączono kolejnych 272 chorych przyjętych do Kliniki Kardiologii Uniwersytetu Tokai w okresie od kwietnia do grudnia 2006 roku z powodu pozaszpitalnego zatrzymania krążenia. U 55 pacjentów (podczas przyjęcia lub też w przebiegu resuscytacji krążeniowo-oddechowej) stwierdzono VT/VF. Zgodnie z samodzielnie wypracowanymi przez autorów pracy algorytmami prowadzenia resuscytacji krążeniowo-oddechowej NIF (w dawce 0,15-0,3 mg/kg) podawano dożylnie po pierwszej próbie kardiowersji. Oporne na działanie NIF częstoskurcze komorowe/migotania komór wystąpiły u 15 spośród 55 pacjentów. U 11 chorych z powyższej grupy wykonano LSGB oraz podano dożylnie NIF. U 7 osób (64%) po zabiegu LSGB uzyskano powrót rytmu zatokowego. Całkowity powrót do zdrowia zanotowano u 2 chorych. Jednakże w grupie, w której nie wykonano zabiegu blokady lewego zwoju gwiaździstego (grupa nie-LSBG), zmarli wszyscy pacjenci. Wnioski: Terapia złożona polegająca na dożylnym podaniu NIF oraz wykonaniu LSGB okazała się użyteczna w przypadku defibrylacji opornego VT/VF. Jest to potencjalna i innowacyjna strategia leczenia opornego na selektywne blokery kanałów IKr częstoskurczu komorowego/ migotania komór. (Folia Cardiologica Excerpta 2007; 2: 524-536

Heavy ion radiation up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction

OBJECTIVE: Radiation has been shown to enhance intercellular communication in the skin and lungs through an increase of connexin43 (Cx43) expression. If analogous Cx43 up-regulation is induced in the diseased heart, it would provide a new perspective in radiation therapy for arrhythmias. The aim of the present study is to test this hypothesis. METHODS: Non-transmural myocardial infarction (MI) was created in 24 rabbits by microsphere injection into the coronary arteries. Twenty-four rabbits without MI were used as controls. Targeted external heavy ion beam irradiation (THIR; 15 Gy) was applied 2 weeks after MI with an accelerator (HIMAC, Chiba, Japan). RESULTS: The THIR was associated with an increase of Cx43 mRNA and protein levels in the left ventricle in control as well as in MI rabbits. THIR also increased lateralization of Cx43, which was no longer colocalized with cadherins. In MI hearts, immunoreactive Cx43 signals were reduced in the peri-infarct zone, and the reduction was reversed by THIR. In-vivo epicardial potential mapping on the free wall (64 unipolar electrodes to cover 7 x 7 mm) in MI hearts revealed reduced conduction velocity, whereas dispersion of the activation-recovery interval (ARI) was increased compared with controls, and these changes were reversed by THIR. The vulnerability for ventricular tachyarrhythmias (VT/VF), which was estimated by programmed stimulation, was increased in MI hearts, and this increased vulnerability to arrhythmias was reversed by THIR. CONCLUSIONS: THIR increases Cx43 expression, improves the conductivity, decreases the spatial heterogeneity of repolarization, and reduces the vulnerability of rabbit hearts to ventricular arrhythmias after MI. THIR could have an antiarrhythmic potential through an improvement of electrical coupling

Year-long upregulation of connexin43 in rabbit hearts by heavy ion irradiation

A previous study from our laboratory has shown that a single targeted heavy ion irradiation (THIR; 15 Gy) to rabbit hearts increases connexin43 (Cx43) expression for 2 wk in association with an improvement of conduction, a decrease of the spatial inhomogeneity of repolarization, and a reduction of vulnerability to ventricular arrhythmias after myocardial infarction. This study investigated the time- and dose- dependent effects of THIR (5–15 Gy) on Cx43 expression in normal rabbit hearts (n 􏰈 45). Five rabbits without THIR were used as controls. A significant upregulation of Cx43 protein and mRNA in the ventricular myocardium was recognized by immunohistochemistry, Western blotting, and real-time PCR from 2 wk up to 1 yr after a single THIR at 15 Gy. THIR 􏰊10 Gy caused a significant dose- dependent increase of Cx43 protein and mRNA 2 wk after THIR. Anterior, lateral, and posterior free wall of the left ventricle, inter- ventricular septum, and right ventricular free wall were affected similarly by THIR in terms of Cx43 upregulation. The radiation- induced increase of immunolabeled Cx43 was observed not only at the intercalated disk region but also at the lateral surface of ventricular myocytes. The increase of immunoreactive Cx43 protein was predom- inant in the membrane fraction insoluble in Triton X-100, that is the Cx43 in the sarcolemma. In vivo examinations of the rabbits 1 yr after THIR (15 Gy) revealed no significant changes in ECGs and echocar- diograms (left ventricular dimensions, contractility, and diastolic function), indicating no apparent late radiation injury. A single appli- cation of THIR causes upregulation and altered cellular distribution of Cx43 in the ventricles lasting for at least 1 yr. This long-lasting remodeling effect on gap junctions may open the pathway to novel therapy against life threatening ventricular arrhythmias in structural heart disease

The Potential Application of Heavy Ion Beams in the Treatment of Arrhythmia: The Role of Radiation-Induced Modulation of Connexin43 and the Sympathetic Nervous System.

It has been known that heart disease—such as myocardial infarction (MI), cardiac hypertrophy, or heart failure—alters the molecular structure and function of the gap junction, which can lead to an abnormal heart rhythm. Radiation has been shown to modulate intercellular communication in the skin and lungs by increasing connexin43 (Cx43) expression. Understanding how Cx43 upregulation is induced in a diseased heart can help provide a new perspective to radiation therapy for arrhythmias. In a recent study with rabbits after MI, carbon ions were accelerated to 290 MeV/u and extracted in the air; a biologically (cell kill) uniform 6-cm spread-out Bragg peak beam was generated, and beam tissue depth was set to 30 mm with energy degraders to the depth position. Targeted heavy ion irradiation (THIR) with 15 Gy to the left ventricle increased Cx43 expression, improved conductivity, decreased the spatial heterogeneity of repolarization, and reduced the vulnerability of rabbit hearts to ventricular arrhythmias after MI. In clinically normal rabbits, THIR (>10 Gy) caused a significant dose-dependent increase of Cx43 protein and messenger RNA 2 weeks after irradiation. The left (irradiated) and right (non-irradiated) ventricles exhibited circumferential upregulation of Cx43 lasting for at least 1 year. There were no significant changes in electrocardiograms and echocardiograms, indicating no apparent injury for 1 year. A single exposure of 135 MeV/u THIR with 15 Gy to a dog heart attenuated vulnerability to ventricular arrhythmia after the induction of MI for at least 1 year through the modulation of Cx43 expression. This long-lasting remodeling effect on gap junctions may lay the groundwork to novel therapies against life-threatening ventricular arrhythmias in structural heart disease. To date, there have been few investigations into the effects of carbon-ion irradiation on electrophysiological properties in the human heart. Patients with mediastinum cancer were investigated for 5 years after treatment that included irradiation to the heart, and investigators found that carbon-ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction. Its practical application in non–cancer treatment, such as in arrhythmia treatment, is highly anticipated

Arrhythmia Treatment Using Carbon Ion Beams

We found that carbon beam irradiation to a part of heart induces Cx43 protein in the whole heart, and antiarrhythmic effect by improve stimulating conduction. Arrhythmia reduced to be 1 from 4 cases in 5 myocardial infarction rabbits after the irradiation, and the expression of Cx43 in mRNA, Immunostaining, and Western Blotting continued for one year. Myocardial infarction dogs also showed increased expression of Cx43 and decreased arrhythmia, and no myocardial injury was observed at one year later the irradiation. Electrophysiological heart studies were conducted in 8 mediastinum cancer patients treated with carbon and follow-up for 5 years. Tendency of arrhythmia observed in 5 cases decreased in 4 cases but 1 case was unchanged, and no side-effects were observed.International Symposium on Ion Therapy 201

Utility and limitations of coherent mapping algorithm utilizing vectors and global propagation patterns in atrial tachycardia

Background: A novel mapping algorithm utilizing vectors and global patterns of propagation (Coherent™, Biosense Webster) has been developed to help identify the mechanism of atrial tachycardia (AT). We aimed to determine the diagnostic accuracy of coherent mapping compared with that of ripple mapping. Methods and results: This study included 41 consecutive patients with 84 ATs (47 reentrant and 37 focal ATs). Two independent electrophysiologists confirmed the diagnoses using coherent mapping before the ripple map-guided ablation. AT termination was achieved in 75 of 84 ATs (89%) at first ablation lesion set. Four of the remaining nine ATs, which were terminated before an index radiofrequency (RF) application, were non-inducible after RF delivery at the first lesion set, whereas the other five ATs were terminated at the second lesion set. Diagnostic agreement between coherent and ripple maps was achieved in 51 of 84 ATs (61%): 28 of the 47 macroreentrant ATs (60%) and 23 of the 37 focal ATs (62%; P = 0.826). In typical macroreentrant ATs, including left atrial roof, perimitral, and cavotricuspid isthmus-dependent ATs, coherent maps achieved diagnostic agreement in 23 of 29 ATs (79%), which was higher than that in other ATs (51%, P = 0.018): 13 of 26 macroreentrant ATs (50%) and 15 of 29 focal ATs (52%, P = 1.000). Conclusion: Ripple map-guided AT ablation achieved a high termination rate in the first lesion set. Coherent mapping yielded a favorable diagnostic accuracy for typical macroreentrant ATs, though its value for diagnosing other ATs was limited