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Transplantation of cardiotrophin-1–expressing myoblasts to the left ventricular wall alleviates the transition from compensatory hypertrophy to congestive heart failure in Dahl salt-sensitive hypertensive rats

Ryuji Toh, MD^*, Seinosuke Kawashima, MD, PhD^*,*, Miki Kawai, MD, PhD^*, Tsuyoshi Sakoda, MD, PhD, Tomomi Ueyama, MD, PhD^*, Seimi Satomi-Kobayashi, MD^*, Sonoko Hirayama, MD, PhD^* and Mitsuhiro Yokoyama, MD, PhD^*

^* Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
Department of Internal Medicine, Cardiovascular Division, Hyogo College of Medicine, Nishinomiya, Japan

Manuscript received October 23, 2003; revised manuscript received December 30, 2003, accepted February 3, 2004.

^* Reprint requests and correspondence: Dr. Seinosuke Kawashima, Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
kawashim{at}med.kobe-u.ac.jp

OBJECTIVES: We investigated whether autologous transplantation of skeletal myoblasts (MB) transferred with cardiotrophin-1 (CT-1) gene could retard the transition to heart failure (HF) in Dahl salt-sensitive (DS) hypertensive rats.

BACKGROUND: Although MB is a therapeutic candidate for chronic HF, little is known about the efficiency of this strategy when applied in nonischemic HF. Cardiotrophin-1 has potent hypertrophic and survival effects on cardiac myocytes. We hypothesized that transplantation of CT-1–expressing myoblasts could provide cardioprotective effects against ventricular remodeling in DS hypertensive rats.

METHODS: The DS rats were fed a high salt diet for 6 weeks and developed left ventricular (LV) hypertrophy at 11 weeks. At this stage, animals underwent MB to the myocardium with skeletal myoblasts transferred with CT-1 gene using retrovirus (transplantation of CT-1–expressing myoblasts [MB + CT], n = 31) or myoblasts alone (MB, n = 31). The sham group rats were injected with phosphate-buffered saline (n = 24).

RESULTS: At 17 weeks, MB and MB + CT groups showed a significant alleviation of LV dilation and contractile dysfunction compared with the sham group. The degree of alleviation was significantly greater in the MB + CT group than the MB group (LV end-diastolic dimension: sham 7.06 ± 0.14 mm, MB 6.51 ± 0.16 mm, MB + CT 6.24 ± 0.07 mm; fractional shortening: sham 32.1 ± 1.4%, MB 38.5 ± 1.5%, MB + CT 43.2 ± 0.8%). Histological examination revealed that the myocyte size was 20% larger in the MB + CT group at 17 weeks than in the age-matched sham group. Upregulation of renin-angiotensin and endothelin systems during the transition to HF was attenuated by myoblast transplantation, and this effect was enhanced in the MB + CT group.

CONCLUSIONS: Transplantation of skeletal myoblasts combined with CT-1-gene transfer could be a useful therapeutic strategy for HF.

Abbreviations and Acronyms   Ang II = angiotensin II   CT-1 = cardiotrophin-1   DS = Dahl salt-sensitive   EDD = end-diastolic dimension   ET-1 = endothelin-1   %FS = percent fractional shortening   HF = heart failure   LV = left ventricle or left ventricular   MB = transplantation of skeletal myoblasts alone   MB + CT = transplantation of cardiotrophin-1–expressing myoblasts   PWT = posterior wall thickness

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