Cardiac resynchronization therapy(CRT) is recommended to reduce mortality and morbidity in chronic heart failure(CHF) patients New York Heart Association(NYHA) class III-IV who are symptomatic despite optimal medical therapy, with a reduced left ventricular(LV) ejection fraction(LVEF) and prolonged complex QRS. CRT improves the prognosis however, despite the improvement, all major trials have demonstrated that one third of the patients are non-responders to CRT. Three months after the CRT implant, the responders have a significant increase in endothelial function(EntF), a decrease in the LV end-systolic volume, and increase in LVEF, 6 minute walk test(6MWT), improvements in NYHA class and quality of life. It is currently unknown if adding an exercise training(ExT) program following CRT provides better clinical outcomes than CRT alone. Prior studies on CRT and ExT have been preliminary in nature, but suggest small improvements in functional capacity(FC). The correction of endothelial dysfunction is associated with a significant improvement in exercise capacity evidenced by a 26%increase in peak oxygen uptake. These findings are important because CHF patients with the greatest sympathetic activation and the most reduced EntF have the poorest prognosis. Our experience with coronary artery disease patients, and most recently data in patients with CHF show that an ExT program that combines aerobic exercise(AE) and resistance exercise training are more effective than an AE program alone, and the aerobic interval training showed better improvements than continuous endurance training. It is unknown how CHF with more severe functional limitations responds to ExT and, more important, the explanation of the physiological mechanism that can explain the improvements as a consequence of ExT. This lack of scientific information is urgent since this is the group of patients that normally is targeted for CRT. The investigators propose to use a stratified randomized longitudinal study to determine the additional effects of a 6 month ExT in addition to CRT in NYHA stage III-IV HF patients. The aims of the study are:1-to determine whether a long-term ExT program follow the CRT provides better clinical outcomes than CRT alone and 2-To identify the mechanisms of the hypothesize improvement. The results of this project will represent an important contribution by understanding the role of ExT after CRT NYHA stage III-IV heart failure(HF) patients, an understudied population with poor clinical outcome. Understanding the potential mechanisms associated with clinical improvement and outcome is essential for the rehabilitative process to develop new innovative therapies in this high risk population. The investigators will use state-of-art methods including an integrated assessment autonomic nervous system(ANS) and arterial function using 123I-MIBG scintigraphy.

Literature Review Generally CHF patients have reduced exercise capacity, with main symptoms of effort intolerance, early fatigue and breathlessness.They also exhibit increased peripheral and central chemosensitivity, impaired sympathovagal balance with sympathetic activity (SA) predominance, and depressed baroreflex n control. Compared with myocardium of healthy controls, the myocardium of patients with chronic LV dysfunction is characterized by a significant reduction of pre-synaptic norepinephrine (NE) uptake and post-synaptic beta adrenoceptor density.There is generalized increased SA in the heart of patients with CHF that might contribute to the remodeling process of the LV. This concept is consistent with the finding that down-regulation of myocardial beta-adrenoceptor density, measured using positron emission tomography with 11C-CGP-12177, soon after acute myocardial infarction (MI) is predictive of the occurrence of LV dilatation at follow-up. Myocardial beta-adrenoceptor density appears reduced in patients with HF due to dilated cardiomyopathy and down-regulation of myocardial beta-adrenoceptor is more pronounced in patients with hypertrophic cardiomyopathy who proceed to LV dilation and HF. Therefore, myocardial beta-adrenoceptor down-regulation may be a general nonspecific response to stress and could be due to a locally increased amount of NE in the synaptic cleft. The sustained hyperactivity of the SA observed in HF is the consequence of several mechanisms including increased central sympathetic outflow, altered neuronal NE reuptake, and facilitation of cardiovascular response to sympathetic stimulation by angiotensin II. CRT is an accepted treatment for patients with moderate-to-severe CHF and intraventricular conduction delay. Intraventricular conduction delays, identified by a QRS interval of 120 msec or more on a 12-lead electrocardiogram (ECG), occur in up to a third of patients with severe systolic HF and are associated with dyssynchronous contraction of the LV, leading to impaired emptying and, in some patients, mitral regurgitation. Abnormal atrioventricular coupling (identified by a prolonged PR interval) and interventricular dyssynchrony, identified on an echocardiogram, may also occur. CRT with atrialsynchronized biventricular pacing often improves cardiac performance immediately, by increasing stroke volume (SV) and reducing mitral regurgitation. Randomized trials involving patients with severe HF showed that CRT resulted in a reduction in symptoms and improved FC, a reduction in the number of hospitalizations for worsening HF, and increased survival. ExT in CHF produce meaningful improvements in peak oxygen consumption (VO2peak) with an expected average improvement of 17%. This is particularly important since improvement in FC is related to the improvement in neurohormonal activation, peripheral abnormalities and ventilatory function. Submaximal exercise capacity (SubMaxExC) is also improved, as assessed by a significant increase in the ventilatory anaerobic threshold (VAT) and in 6-MWT. The improvement in SubMaxExC of CHF patients (NYHA II-III) was probably due to peripheral training adaptations in skeletal muscle mass (SMM). Theoretically, by improving SMM strength, a lower % of maximal contraction would be used to do a similar amount of work following training. A lower relative muscle contraction would be expected to produce less blood lactate, thereby decreasing the need for carbon dioxide (CO2) elimination, thus increasing the VAT. The improvement in VAT is important as it would allows patients to exercise longer and harder without negative alterations in ventricular dynamics associated with the VAT and could possibly delay the onset of the ischemic threshold. To severe CHF patients, the truly meaning of improvement SubMaxExC as effect of ExT is related to QOL since the engagement in daily activities does not demand VO2peak. All the previous studies were done with low to moderate risk patients but high risk patients probably have a greater need in order to lead a normal, independent life. Results from previous studies with CHF showed that ExT reduces NE levels at rest and during exercise, decreases central sympathetic nerve outflow as measured by microneurography. ExT also enhances vagal control with a shift away from sympathetic activity, and improves heart rate (HR) variability and HR recovery with a return to a better sympathetic-vagal balance. Moreover, ExT produces significant reduction in the local expression of cytokines such as interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) in the SMM of CHF patients and has a beneficial effect on peripheral inflammatory markers reflecting monocyte/macrophage-endothelial cell interaction. These local anti inflammatory effects of ExT may attenuate the catabolic wasting process associated with the progression of CHF. This can be an important issue since inflammatory responses plays a pathogenic role in the development and progression of CHF. Probably the impaired availability of nitric oxide (NO) is responsible for the impaired endothelium dependent relaxation of peripheral resistance and conduit arteries and may contribute to the reduced FC in CHF and other severe symptoms. Also endothelium-independent vasodilatation abnormalities may relate to a combination of impaired smooth muscle responsiveness to NO, impaired of NO diffusion to the smooth muscle or structural alterations in arterial compliance associated with CHF. The combination of ExT in CRT is not been well-investigated. One small-scale pilot study (not randomized ) suggested that functional capacity improved. More recently, Patwala et al. reported improvements in quality of life (QOL) and VO2peak through improved SMM performance with the addition of a 3-month ExT 3-month after the CRT. In this study, all the patients were in class III of NYHA and an ExT only 3 months in duration. Little is known about ExT for elderly severe CHF patients.

Plan and Methods The purpose of this research project is to determine the effects of adding ExT to CRT on clinical status, ANS function, in ischemic and nonischemic cardiomyopathy patients with moderate to severe CHF. The investigators will evaluate the following specific aims: 1- To determine the effects of a long-term ExT program following CRT provides on clinical outcome; 2-Identify the mechanisms of the hypothesized improvements in clinical status. The primary end points for aim 1 are the clinical status, namely NYHA functional class, all-cause mortality, hospitalization rate, cardiac function and maximal and SubMax FC. For aim 2 the SA, HRV, HRR and blood endothelin-1, brain natriuretic peptide (BNP), IL-6, tumor necrosis factor (TNF)-a and C reactive protein (CRP). As secondary end points the investigators will analyze neuromuscular function(NMF), body composition(BC) and QOL. Relevance: Due to increased prevalence of CHF and consequent implications for mortality and morbidity rates, the prognosis of HF has improved in the past 20 years, but it remains a serious condition with a markedly increased risk of death in the early period after onset of the syndrome. In population studies, there is 10% mortality by 30 days. For those who survive this early high-risk period, the 5-year mortality is 54% in men and 40% in women. In clinical trials of CHF therapy, 50% of deaths are due to sudden death and progressive HF accounts for around 30% of deaths, this latter proportion increasing as symptomatic severity increases.In population studies including patients with new-onset HF, progressive HF appears to be the single most common cause of death (52%), with sudden death accounting for only 22% of deaths within the first 6 months of diagnosis.ExT has been shown to be effective in CHF patients NYHA II-III, as it improves autonomic control by enhancing vagal tone and reducing sympathetic activation, improves exercise FC, QOL, SMM, vasodilator capacity, endothelial dysfunction and decrease oxidative stress, hospitalization and mortality%. No information is available in more severe patients and they are the patients that are in most need and their treatment will also significantly impact heath care costs. Moreover, scientific research is absent on the effects of ExT after CRT on severe CHF patients and there is no information on the effects of both therapies on ANS. Thus, the proposed project will address a number of important gaps in scientific knowledge with potentially large clinical benefits. Methods: The investigators will use a controlled stratified experimental design, using a longitudinal approach with 3 assessment time points: baseline, before the cardiac implant (CI) (M1); at 3 (M2) and 6-month (M3) after the experimental therapy (ET). It will be a continuum of recruitment during the 24 month but the study protocol it will be the same for all patients. The study will employ state of the art methods for ANS analysis, namely the Scintigraphy with 123I-meta-iodobenzylguanidine (123I-MIBG). The investigators will evaluate both clinical, physiological and QOL outcomes. The assessment of cardiac sympathetic neuronal activity with 123I-MIBG, a radio-labelled analogue of NE, will improve the understanding of the mechanisms responsible for increased sympathetic activity in HF, and how sympathetic overactivity exerts its deleterious actions. This technique offers a huge advantage in order to understand what happens in the heart, compared to the more commonly used technique of Muscle Sympathetic Nerve Activity. The inclusion of a M2 assessment will allow us to update the exercise intensity and also to conduct initial data analysis. Also the technique chosen in our project for group assignment (stratified by age and etiology randomization), provides the best opportunity to evaluate if the expected changes will be related with ET since patients with different age and etiology responded differently to ExT. The ExT design was done based on Wisloff's results. The AE will be developed with an AIT since previous results showed better results but due to the clinical status of our patients and longer intervention duration we will employ a different (slower) exercise prescription progression. We will begin with shorter aerobic intervals and only at the end of the 2nd month the investigators will use the same protocol as Wisloff et al. Compared with continuous exercise training methods, this method allows patients with HF to complete short periods of exercise at high intensity (which stress the heart's ability) but without deleterious effects of undue stress and fatigue. Another difference in the ExT program is the incorporation of resistive and sensoriomotor exercises (SME). These types of exercises will improve the lack of SMM of the CHF patients producing positive consequences in activities of daily life and QOL, and will enhance muscle performance of muscles not involved in the aerobic mode of exercise. This project can provide evidence for a useful and powerful treatment to reduce the high sympathetic activation (SA) that leads to an endothelial dysfunction contributing to both central and peripheral impairments in patients with severe CHF. In CHF patients, SA is initially increased as a compensatory mechanism; however, chronically elevated stimulation of the adrenergic system is associated with sustaining the process of myocardial remodeling. Another consequence is endothelial dysfunction manifested as impaired endothelium-dependent relaxation of peripheral resistance and conduit arteries, most probably due to impaired availability of NO. Besides the expected changes from the CRT we hypothesize that adding an ExT protocol that use the AIT and inclusion of endurance and SME to these patients will maximize both clinical and physiological outcomes. Our project will be the first to provide evidence for sympathetic and parasympathetic ANS action on the heart itself, and how these may be altered over 6 month of ET in patients with severe CHF. The combination of the selected assessment techniques will allow an overview of the expected adaptations and the underlying mechanisms. To our knowledge this project will be the first to address with precise and valid methods the benefits of a 6- month ExT program just after CRT on the ANS of moderate-to-severe CHF patients. Linking these results with NMF, BC, QOF and clinical status improvements will contribute to further understand the impact of ExT on overall health status of these patients. Also, the longer period of the ExT program and the inclusion of the M2 assessment will allow a more accurate analysis of the change process. Expected results: This study will firstly contribute to a better understanding of the implications of a combined therapy in CHF patients. This study can provide an extensive characterization of changes in ANS both central and peripheral, which will be of great value for stabilization or regression of the disease with direct impact in patient's daily life. It is expected that the ExT group compared with the control group will improve all the physiological variables included in the project as was observed in previous studies with less severe CHF patients and this will lead to improvements in clinical status. The investigators also expect that ExT group show a better improvement in the clinical outcomes and in health related QOL leading to a decrease in overall health care costs.

Inclusion Criteria:

• Patients with chronic heart failure (CHF), classified in NYHA functional class III or IV;
• Receiving optimal medical therapy for CHF (including an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and a beta-blocker unless a contraindication is evident) with a stable condition for more than 1 month (no hospitalization for HF, no change in medication, and no change in NYHA functional class);
• Left ventricular ejection fraction (LVEF) < 35%;
• QRS duration ≥ 120 ms.

Exclusion Criteria:

• If they are younger than 18 years or are unable to sign informed consent;
• Patients who had been treated with an intravenous inotropic agent within the 30 days prior to implantation (these medications affect endothelial function after they are discontinued);
• Unstable angina pectoris;
• Orthopedic or neurological limitations to exercise.