Background— Remodeling occurs in both ventricle and atrium in dilated cardiomyopathy and heart failure. However, the alteration of atrial extracellular matrix components during remodeling and its effect on the electrical remodeling and atrial arrhythmia have never been explored. Methods and Results— Atrial tissue samples of 53 explanted hearts from patients with dilated cardiomyopathy and end-stage heart failure who underwent heart transplantation were examined. Nineteen patients had permanent atrial fibrillation (PmAF), 18 had persistent AF (PsAF), and 16 had no documented AF (NAF). Sixteen donor left atria (LA) were used as controls (CNs). Western Blot analysis revealed a selective downregulation of tissue inhibitor of metalloproteinase (TIMP)-2 in PmAF and PsAF groups compared with the NAF and CN groups and an upregulation of atrial metalloproteinase (MMP)-2 that was most pronounced in the PmAF group followed by the PsAF and NAF groups. Immunofluorescent staining revealed that in the LA, type I collagen volume fraction (CVF-I) increased significantly in the PmAF group followed by the PsAF and NAF groups compared with that in CN. LA CVF-I significantly correlated with LA dimension and TIMP-2 to MMP-2 ratio. In the PsAF group, CVF-I/CVF-III ratio was significantly correlated with AF duration and the frequency of AF recurrence. Conclusions— Atrial extracellular matrix remodeling manifested by the selective downregulation of TIMP-2 along with upregulation of MMP-2 and CVF-I in the atrium is associated with the development of sustained atrial fibrillation in patients with cardiomyopathy and heart failure.

Although there is substantial evidence of abnormal Ca2+ homeostasis in heart cells of the cardiomyopathic Syrian hamster (Bio 14.6 strain), the mechanism by which these myocytes become Ca2'-overloaded is not Ca2+ currents were measured in cardiomyopathic (Bio 14.6 strain) and normal control (FIB) cardiac myocytes.We report here that both L-and T-type Ca> channels were present in ventricular myocytes isolated from 200-to 300-day-old cardiomyopathic and age-matched normal hamsters. The mean current density of T-type Ca>2 channels in cardiomyopathic cells was significantly (more than twofold) higher than in normal cells, whereas the current density through L-type Ca2+ channels was the same in both groups. Thus, Ca2+ entry into myocytes via T-type Ca2+ current may play an important pathogenetic role in this cardiomyopathy. Materials and Methods Cell PreparationIn the present study, we established methods for isolating cardiac myocytes from 8-month-old cardiomyopathic hamsters and age-and sex-matched normal control hamsters. Eightmonth-old Bio 14.6 cardiomyopathic and FIB control hamsters were obtained from Bio-breeders. Normal and cardiomyopathic hamsters were anesthetized with ether, and the hearts were rapidly removed. After cannulation of the aorta, hearts were perfused with oxygenated (37°C) Krebs-Henseleit (K-H) bicarbonate-buffered solution (pH 7.30) containing (mmol/L) NaCl 118, KCl 4.7, CaCl2 0.6, MgSO4 1.20, KH2PO4 1.20, NaHCO3 25, and glucose 15. Hearts were perfused at 5 mL/min for z:=8 minutes until completely cleared of blood.Hearts were then perfused with the same solution but without CaCl2 for 5 minutes. Collagenase (0.03%) was added and recirculated for an additional 25 minutes. The ventricular muscle was removed from the perfusion apparatus, cut into 3-mm3 pieces, and placed in a 10-mL flask with 0.03% collagenase, 0.015% hyaluronidase, 0.0015% trypsin, 0.0015% deoxyribonuclease, and 1 mmol/L CaCl2 in K-H buffer. The

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Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts is efficient and effectively prolongs graft survival. Vectors that would induce long-term expression of such genes may make this approach clinically applicable.