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1. It has been shown that in experimental rickets the well known changes in the epiphysial cartilage which so seriously affect growth are accompanied by severe interference with the progress of the metaphysial vessels into the growth cartilage. 2. Further evidence has been found that, by the repeated increase in their number, the cartilage cells occupying the more distal part of the proliferative segment become more and more affected by their remoteness from the epiphysial vessels, which supply the transudates to these cells. At a given distance these cells are affected and change, becoming hypertrophic, with increasingly large vacuolae, and are rich in glycogen and alkaline phosphatase. 3. The hypertrophic cells alter the nature of the intercellular substance they deposit and this becomes calcifiable. Provided that the metaphysial vessels are situated at an appropriate distance–about three cell capsules away–and that the blood has its necessary components, calcification occurs. 4. Calcification produces the advancing, rigid multitubular structure within which the progressing metaphysial vessels are protected. 5. The interruption of calcification by the withdrawal of fat-soluble vitamins breaks down the whole mechanism of growth and stops the vessels growing into their proper position. The administration of the required vitamins re-establishes the normal sequence of events and allows the vessels to play their decisive role in osteogenesis. 6. Any mechanism which causes the interruption of the vascular progression, whether from metaphysial ischaemia (Trueta and Amato 1960), from severe pressure (Trueta and Trias 1961) or from lack of calcification by withdrawing the fat-soluble vitamins, equally interrupts growth.

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Rationale: Recently, we provided a technique of chronic high-frequency electric stimulation (HFES) of the right inferior ganglionated plexus for ventricular rate control during atrial fibrillation in dogs and humans. In these experiments, we observed a decrease of the intrinsic ventricular rate during the first 4 to 5 months when HFES was intermittently shut off.Objective: We thus hypothesized that HFES might elicit trophic effects on cardiac neurons, which in turn increase baseline parasympathetic tone of the atrioventricular node. Methods and Results:In mongrel dogs atrial fibrillation was induced by rapid atrial pacing. Endocardial HFES of the right inferior ganglionated plexus, which contains abundant fibers to the atrioventricular node, was performed for 2 years. Sham-operated nonstimulated dogs served as control. In chronic neurostimulated dogs, we found an increased neuronal cell size accompanied by an increase of choline acetyltransferase and unchanged tyrosine hydroxylase protein expression as compared with unstimulated dogs. Moreover, ␤-nerve growth factor (NGF) and neurotrophin (NT)-3 were upregulated in chronically neurostimulated dogs. In vitro, HFES of cultured neurons of interatrial ganglionated plexus from adult rats increased neuronal growth accompanied by upregulation of NGF, NT-3, glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) expression. NGF was identified as the main growth-inducing factor, whereas NT-3 did not affect HFES-induced growth. However, NT-3 could be identified as an important acetylcholine-upregulating factor. Key Words: atrial fibrillation Ⅲ tachyarrhythmias Ⅲ acetylcholine Ⅲ nervous system D uring the last 10 years, techniques have been developed to directly and selectively interfere with the intrinsic cardiac neural system via electric stimulation catheters or leads in animals and patients. [1][2][3][4][5] The baseline observation for these applications was that depolarization of intracardiac neural fibers by high-frequency electric stimulation (HFES) delivers neurotransmitters that subsequently act locally on cardiac structures (eg, stimulation of sympathetic fibers along the coronary sinus selectively increases left ventricle inotropy). 5 Furthermore, acute, short-term endocardial HFES of the right inferior ganglionated plexus (RIGP) elicits selective negative dromotropic effects in awake patients and slows atrioventricular (AV) conduction during atrial fibrillation. 3 The RIGP is located between the inferior caval vein, the left atrium and the ostium of the coronary sinus. It contains abundant parasympathetic fibers that affect AV node conduction. 6,7 After proof of concept in humans, we and others developed a technique for chronic endocardial 8,9 and epicardial 10 neurostimulation of the RIGP for ventricular rate control during atrial fibrillation (AF) in dogs. Of note, the negative dromotropic effect during endocardial HFES could be maintained throughout the entire neurostimulation period of 2 year...