Introduction Chronic heart failure is known to be a complex syndrome, associated to high mortality and disability, involving multiple pathophysiologic mechanisms, neuro-hormonal, endothelial and inflammatory. Besides optimized medication, the nonpharmacologic therapy, like cardiac resynchronization and exercise training, plays a fundamental role. In advanced heart failure, patients with criteria for cardiac resynchronization therapy (CRT) have been studied extensively, though most of the studies were not dedicated to the diversity of effects and involved pathophysiologic mechanisms, in most severely symptomatic patients. In this advanced heart failure population treated with CRT, studies regarding exercise training effects and mechanisms, specifically high intensity interval exercise, are still few and small-sized. 8 Hypothesis Main hypothesis formulated: It is beneficial to associate a high intensity interval training exercise program, long duration, after cardiac resynchronization in advanced Heart Failure Patients. Secondary hypothesis: Several pathophysiologic mechanisms are involved, contributing differently to the exercise training benefit after CRT and to the benefit of CRT without subsequent exercise program in advanced HF patients. Aims The primary aim of this thesis was to determine the effects of a long-term High Intensity Interval Exercise Training (HIIT) program on clinical functional class, quality of life, exercise functional capacity, cardiac function and remodeling, in advanced heart failure patients after cardiac resynchronizer implant. Secondary aim intends to evaluate the potential role of different pathophysiologic mechanisms in the benefits of exercise training after CRT, HIIT, and of CRT without subsequent exercise: endothelial function, autonomic nervous system function, inflammatory process and apoptosis. Methodology A randomized controlled trial was performed to determine the effects of exercise intervention, HIIT, in advanced heart failure patients after CRT. The inclusion criteria considered patients with stable heart failure, class III-IV (NYHA), receiving optimal pharmacologic therapy, assigned to CRT by present guidelines, ischemic and non ischemic etiology, older than 18 years. Exclusion criteria included unstable HF patients, exercise incapacitating orthopedic or muscular disease and geographically long distance living. 9 Patients who fulfilled the inclusion criteria were randomized for long duration high intensity interval exercise training or for control group (EXTG and CG, respectively). Randomization, performed by an independent investigator, was stratified, based on age (1.5 identified more CRT echocardiographic responders (2-fold probability), only in nonischemic. Events at 7 months after CRT, M3, cardiac death or hospital admission or arrhythmia occurred in 14.8% of total population and in 16.2% of nonrandomized patients. Death occurred in 4.9% in total group and in 6% in nonrandomized group. Conclusion In this controlled randomized trial, performed in a sample of advanced HF patients referred to CRT, HIIT exercise after cardiac resynchronizer implant proved to be beneficial and safe, associated to an increased number of clinical and echocardiographic responders and with more significant clinical improvement, suggesting an additional benefit to CRT. The improvement of the peripheral component of heart failure caused by exercise was demonstrated by CPT duration and time to VAT significant increase, associated with more functional responders, along with positive modulation of inflammation, which might have contributed to this effect. No significant effects were demonstrated in endothelial or autonomic nervous system function. Less major events occurred in the HIIT group after the 6 months of training. The additional evaluation of CRT patients in the observational study of the total HF sample, showed a beneficial effect on symptoms severity, quality of life and systolic and diastolic LV function, even excluding those who performed exercise. Central effect of CRT on cardiac remodeling demonstrated to be crucial, with echocardiographic improvement of several variables. Once EXTG patients were excluded, the restant CRT patients did not show significant improvement at 7 months of VO2p, CPT duration or time to VAT, meaning CRT had no effect on HF peripheral component. Autonomic nervous system demonstrated to be a relevant mechanism for CRT response, but only in nonischemic HF. No beneficial effects of CRT were noticed in endothelial function, inflammation or apoptosis. More events were registered in patients who did not exercise. From these thesis results, we may accept, in advanced heart failure patients, exercise (HIIT) as safe and beneficial nonpharmacologic therapy with demonstrated additional benefit, regarding CRT, resulting in fewer patients with CRT nonresponse. This 13 intervention had no deleterious effect on reverse remodeling and some results point out to a potential benefit. The involved mechanism especially regards the peripheral component of HF, manifested by the decrease in clinical symptoms severity, improvement in functional capacity and positive modulation of pathophysiologic inflammatory response.