| Background and purposes:Left ventricular hypertrophy (LVH) is an adaptive response of the heart to an increased workload, caused by a variety of pathological changes, including hypertension and valvular disease. However, if the pressure overload is severe and longstanding, the hypertrophic heart may progress to a pathological state. Although reversal of LVH occurs after aortic valve replacement for aortic stenosis, Ikonomidis has revealed incomplete reversal of pathophysiological changes, such as interstitial fibrosis, ventricular remodeling and dysfunction. Similar phenomenon, no more than a 15% to 20% reduction in left ventricular (LV) mass, has also been observed after optimal blood pressure control in hypertensive patients. The molecular mechanisms that underlie regression of LVH are not yet completely understood.An animal model of LVH regression is important to investigate both disease mechanisms and potential therapies. Animals need undergo a thoracotomy in most of studies on LVH, and endotracheal intubation and mechanical ventilation are usually indispensable. However, several researchers have reported that experiment animals may be predisposed to developing serious tracheal injury and clinically significant sequelae in association with endotracheal intubation. Examination of both progression and regression of LVH in rabbits without endotracheal intubation and mechanical ventilation has not previously been reported but is the subject of this study. Ultimately, this model will facilitate focused study of the mechanisms involved with LVH progression and regression.Methods:1. The experimental animals were randomized 3 times in turn and assigned to 5 groups: sham-operated group (sham group), 8 weeks of aortic banding (AB) group (AB8w group), 16 weeks of AB group (AB16w group), 24 weeks of AB group (AB24w group), early debanding (DB) group (8 weeks of AB followed by 8 weeks of DB), late DB group (16 weeks of AB followed by 8 weeks of DB).2. Without endotracheal intubation and mechanical ventilation, a median sternotomy was performed. To avoid injury the parietal pleura, the median incision was made exactly along the midline of the sternum. Ascending aortic diameter was reduced 50–58% above the aortic valve, which leads to an approximate 75% reduction in crosssectional area. The sham-operated rabbits underwent the same procedures without actual ligation of the aorta. The animals of early DB group and late DB group were subjected to the second operation for removing ligation 8 weeks or 16 weeks after the initial banding surgery, respectively.3. Transthoracic echocardiography was performed before surgery and 2, 4, 8, 10, 12, 16, 18, 20 and 24 weeks after surgery for animals subjected to AB and 2, 4, and 8 weeks for animals subjected to DB.4. Hemodynamic assessment was examined for each group at the last time point.5. At the time of death, body weights and LV weights were obtained after rabbits were sacrificed. And the samples of left ventricular myocardium were obtained for H.E. or Masson's trichrome staining and electron microscopic observation.Results:1. The model of promoting LVH regression in rabbits was successfully developed without the need for endotracheal intubation and mechanical ventilation. The mortality rate was low.2. There was significant difference in LVDD, LVSD, IVS, LVPW, LVMI and FS between AB24w group and sham group since 4 weeks after AB (P<0.01). After band removal, most parameters changed into the direction of baseline during the following 8 weeks period. Reversal of increased LV mass, wall thickness, and LV internal dimension and reversal of decreased FS appeared to be a slower process in the late DB than in the early DB group. There were significant differences in every echocardiographic parameter between early DB and late DB group at each of end time point (P<0.01). All the echocardiographic parameters remained unchanged in the sham group (P>0.05). There was no significant difference in heart rate among the groups over the study period.3. Compared with sham group, LV systolic arterial and +dp/dt max were markedly elevated in AB8w, AB16w and AB24w group (P<0.01). There was significant difference in -dp/dt max between AB16w, AB24w group and sham group (P<0.01). There were significant differences in +dp/dt max and -dp/dt max between AB8w+DB8w vs. AB16w, AB16w+DB8w vs. AB24w, and AB16w+DB8w vs. sham group (P<0.01). Release of pressure overload for 8 weeks resulted in a complete normalization of LVSP, + dp/dt max, and - dp/dt max in early DB, but not late DB, rabbits.4. Compared with sham group, LVW and LVW/BW were markedly elevated in AB8w, AB16w and AB24w group (P<0.01). Releasing pressure overload for 8 wk led to a restoration of increased LV weights. There were statistical differences in LVW and LVW/BW, AB8w+DB8w compared AB16w and AB16w+DB8w compared AB24w (P<0.01). There was significant difference in LVW between early DB and late DB group (P<0.05).5. Histological examination by optical microscope in each AB groups showed myocyte and myofibrillar disarray, hypertrophy, and extensive interstitial fibrosis. After DB surgery, the LVH regressed significantly, and degree of reversal was more conspicuous in early DB than late DB.6. Ultrastructural analysis of AB rabbits by transmission electron microscopy revealed following features: (1) indefinite sarcomeric structure with myofibrillar disarray, (2) disruption of the intercalated discs, (3) a marked enlargement of the sarcoplasmic reticulum, (4) perinuclear vacuoles, (5) a marked increase of mitochondria.Conclusions:These results demonstrate an efficient and reproducible method of promoting LVH regression in rabbits without endotracheal intubation and mechanical ventilation. Ultimately, this model will facilitate the study of independent mechanisms about left ventricular hypertrophy regression that might alter the current paradigm of treatment for patients with hypertensive, ischemic, valvular, and idiopathic cardiomyopathies associated with left ventricular hypertrophy.
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