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Department Introduction

Department Introduction

Ischemia Heart Disease Group

(10) Arrhythmia/Basic

Research on Arrhythmogenic Mechanism in Non-uniform Contraction

It has been reported that cardiac resynchronization therapy reduces not only death from cardiac failure but also death from arrhythmia. Arrhythmia during cardiac failure is thought to occur as a mechanism of delayed afterdepolarization in half the ischemic disease cases and in most of the non-ischemic disease cases, but the affect on the onset of delayed afterdepolarization of myocardial contraction heterogeneity seen in pathologic myocardium and of recovery via cardiac resynchronization therapy are not known. When an non-uniform contraction test model was created through local perfusion using drugs that reverse the myocardial characteristics of the trabeculae local area, which is a multicellular ventricular myocardium preparation, a calcium wave appeared during local perfusion (Figure 1) and arrhythmia occurred. Since the arrhythmia disappeared when the perfusion was stopped (Figure 2), this indicates that the non-uniform contraction due to the local perfusion contributed to the onset of arrhythmia. The Department is currently conducting fundamental research based on the hypothesis that disassociated calcium from contractile protein contributes to the onset of arrhythmia.

Fig. 1 (Left): Calcium wave caused by local perfusion Fig. 2 (Right): Onset of Arrhythmia Due to Local Perfusion
Fig. 1 (Left): Calcium wave caused by local perfusion
Local perfusion using caffeine (CF), BDM, and low calcium (LC) generated a calcium wave between the boundary between the perfusion area and non-perfusion area.

Fig. 2 (Right): Onset of Arrhythmia Due to Local Perfusion
Arrhythmia occurs after aftercontraction during BDM local perfusion and disappears when perfusion is stopped.
Publications (since 2000)
  1. Miura M, Wakayama Y, Endoh H, Nakano M, Sugai Y, Hirose M, ter Keurs HEDJ, Shimokawa H. Spatial non-uniformity of excitation-contraction coupling can enhance arrhythmogenic delayed afterdepolarizations in rat cardiac muscle. Cardiovasc Res. 2008 (in press).
  2. Endo H, Miura M, Hirose M, Takahashi J, Nakano M, Wakayama Y, Sugai Y, Kagaya Y, Watanabe J, Shirato K, Shimokawa H. Reduced inotropic effect of nifekalant in failing hearts in rats. J Pharmacol Exp Ther. 2006;318:1102-7.
  3. Wakayama Y, Miura M, Stuyvers BD, Boyden PA, ter Keurs HEDJ. Spatial nonuniformity of excitation-contraction coupling causes arrhythmogenic Ca2+ waves in rat cardiac muscle. Circ Res. 2005;96:1266-1273.
  4. Hirose M, Miura M, Wakayama Y, Endo H, Sugai Y, Stuyvers BDMY, Kagaya Y, Watanabe J, ter Keurs HEDJ, Shirato K. Effect of nifekalant, a class Ⅲ antiarrhythmic agent, on Ca2+ waves in rat intact trabeculae. Circ J. 2005;69:739-745.
  5. Wakayama Y, Miura M, Sugai Y, Kagaya Y, Watanabe J, ter Keurs HEDJ, Shirato K. Stretch and quick release of rat cardiac trabeculae accelerates Ca2+ waves and triggered propagated contractions. Am J Physiol . 2001;281:H2133-42.

( Text by Masato Miura )

Molecular Pathological Explanation of cardiomyopathy

In recent years many of the genes responsible for various familial disorders have been identified using molecular genetic techniques. Familial occurrence is thought of as a special type of disorder, but these disorders provide important hints for deeply understanding general disorders. The genes causing hypertrophic cardiomyopathy and dilated cardiomyopathy have also been identified as being implicit in myocardial disease. We seek to understand the pathology on the genetic level and cellular level using molecular genetic techniques with actual patients to explain in a broad sense the pathology of myocardial disease that causes unexplained lethal ventricular arrhythmia and stimulus conducting system diseases, such as atrioventricular block. It has been previously shown that for hypertrophic cardiomyopathy the change in the regulatory molecule of the contractile protein that is the cause of this disease accentuates the intracellular calcium sensitivity, and for familial cases with preexcitation syndrome it has been reported that there is a change in the gene that contributes to metabolic regulation in myocardial cells. An analysis of Japanese familial myocardial disease cases with advanced atrioventricular block was conducted and a nuclear protein lamin A/C genetic mutation was found in several family lines showing a high occurrence rate in this clinical type (See figure). For family lines with this type of clinical type, preclinical diagnosis can be made through gene analysis and preventative treatment given.
The Department is currently researching the genetic factors of naturally occurring myocardial disease that leads to lethal ventricular arrhythmia such as Brugada's syndrome. Understanding the disease pathology from the molecular level in this manner makes it possible to develop specific permanent cure treatments for individual cases.

Fig. 1

Fig. 1: One family line with familiar myocardial disease comprising multiple arrhythmias antecedent to advanced atrioventricular block (FDCM-CD3B)Fig. 1: One family line with familiar myocardial disease comprising multiple arrhythmias antecedent to advanced atrioventricular block (FDCM-CD3B)

Fig. 2

Fig. 2: Results of Lamin A/C gene analysis of the proband of the FDCM-CD3 family line
An IVS3-10A<G mutation was found in intron 3 where a splicing error introduced 9 new bases and 3 new amino acids.

Fig. 3

Fig. 3: Mutation and position positional relationship found in the Lamin A/C gene
The LMNA mutation was found in 5 family lines of the 8 family lines where advanced atrioventricular block coexists with familial myocardial disease.

Publications (since 2000)
  1. Otomo J, Kure S, Shiba T, Karibe A, Shinozaki T, Yagi T, Naganuma H, Tezuka F, Miura M, Ito M, Watanabe J, Matsubara Y, Shirato K. Electrophysiological and histopathological characteristics of progressive atrioventricular block accompanied by familial dilated cardiomyopathy caused by a novel mutation of lamin A/C gene. J Cardiovasc Electrophysiol. 2005;16:137-45.
  2. Li D, Czernuszewicz GZ, Gonzalez O, Tapscott T, Karibe A, Durand JB, Brugada R, Hill R, Gregoritch JM, Anderson JL, Quinones M, Bachinski LL, Roberts R. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation. 2001;104:2188-93.
  3. Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan AS, Ahmad F, Lozado R, Shah G, Fananapazir L, Bachinski LL, Roberts R. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 2001;344:1823-31.
  4. Karibe A, Tobacman LS, Strand J, Butters C, Back N, Bachinski LL, Arai AE, Ortiz A, Roberts R, Homsher E, Fananapazir L. Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis. Circulation. 2001;103:65-71.
  5. Li D, Ahmad F, Gardner MJ, Weilbaecher D, Hill R, Karibe A, Gonzalez O, Tapscott T, Sharratt GP, Bachinski LL, Roberts R. The locus of a novel gene responsible for arrhythmogenic right-ventricular dysplasia characterized by early onset and high penetrance maps to chromosome 10p12-p14. Am J Hum Genet. 2000;66:148-56.

( Text by Akihiko Karibe )

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