Patients with chronic heart failure (CHF) underwent to a hospital-based cardiac rehabilitation (CR) program in the Lisbon district Hospitals will be recruited. The participants will be randomized into one of the following exercise groups: A) combined exercise training with more aerobic training and less strength training (CAT); B) combined exercise training with more strength training and less aerobic training (CST). The investigators will test two proportions in combined training, CAT and CST. There hasn't been any data on the so called combined regimes, which include both aerobic exercise with HIIT and ST and the investigators will evaluate the effects of acute and chronic response.

The research project will contribute to a better understanding in several aspects that are unexplained by scientific research.

Literature Review:CHF is the major public health problem in the world[1], highly prevalent in older individuals and a major cause of disability, hospitalizations, morbidity and mortality[2]. Generally, CHF patients have reduced exercise capacity, with main symptoms of effort intolerance, early fatigue and breathlessness[3], also exhibiting increased peripheral and central chemosensitivity, and impaired sympathovagal balance with sympathetic activation(SA) predominance[4].

Understanding the oxidative metabolism and intracellular energy transfer in both skeletal and cardiac muscle, mechanisms of endothelial dysfunction, and the role of SA and inflammatory cytokines provide possible mechanistic explanations of the pathophysiologic factors involved in the development of exercise intolerance[5,6]. It has been shown in CHF patients that increased arterial stiffness is associated with cardiovascular morbidity and mortality[7]. There are evidences that increased arterial stiffness predicts exercise intolerance in CHF patients[8].

Increased carotid IMT is associated with subclinical left ventricular(LV) myocardial dysfunction, suggesting a possible role of carotid IMT in HF risk determination [9]. CHF is associated too with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation(FMD). Since endothelial function is thought to play an important role in coordinating tissue perfusion and modulating arterial compliance, interventions to improve endothelial dysfunction are imperative.

Systemic vasoconstriction and impaired peripheral perfusion are hallmarks in advanced CHF. While a number of factors, including increased sympathetic tone and an activated renin-angiotensin system, have been proposed to be involved in the reduced arterial vasodilatory capacity in HF, the pivotal role of the endothelium in coordinating tissue perfusion has now been recognized.

Several clinical studies have documented endothelial dysfunction of large conduit and small resistance vessels in patients with CHF. Endothelial dysfunction may affect the cardiovascular system in two ways: first, endothelial dysfunction of resistance vessels may impair peripheral perfusion, and, second, endothelial dysfunction of large conduit vessels may limit the increase in blood flow provided by the supplying large vessels and may increase impedance of the failing LV and consequently impair LV ejection fraction(LVEF). An important functional consequence of endothelial dysfunction is the inability to release nitric oxide(NO) in response to physiological stimuli such as increases in flow, reflecting impaired FMD[10]. Conversely, chronically increased blood flow enhances the release of NO in experimental models, by upregulation of NO synthase, the enzyme that uses L-arginine to generate NO. The intermittent increases of blood flow by physical training may increase the capability of the endothelium to release NO and therefore may restore endothelial function in patients with CHF who are usually subjected to a limited degree of physical activity[5]. The dysfunctional endothelium contributes to increased vascular stiffness and impaired arterial distensibility, augmenting myocardial damage[10].

The direct relationship between exercise and vascular health is certain, but the complex set of metabolic pathways, haemodynamic effects of exercise on cardiovascular cells/tissues, and the regulation of genetic expression activated by exercise is still largely undefined[11]. The effects of aerobic and resistance exercise on clinical blood pressure might be different, because they have different mechanical characteristics. Aerobic training(AT) is characterized by the execution of cyclic exercises, carried out with large muscle groups contracting at mild to moderate intensities for a long period of time. On the other hand, strength training(ST) is characterized by the execution of exercises in which muscles from a specific body segment are contracted against a force that opposes the movement[12].

Aerobic capacity is directly related to arterial function, including endothelial function, arterial stiffness and wave reflection. In addition, coupling of arterial and cardiac function is a major determinant of aerobic capacity. Thus, poor resting arterial function likely limits aerobic capacity, but it is also possible that changes in arterial function during acute exercise may play a role. Arterial function is not only associated with aerobic capacity, but is also an independent predictor of mortality[5].

Controlled clinical trials have shown that in HF patients ExT programs improve peripheral and cardiac adaptations and also the aerobic capacity, delay the onset of anaerobic metabolism, and improve the autonomic balance[1,13]. Apart from adaptation in maximal cardiac output, heart contractility, and stroke volume, aerobic ExT is also able to promote amelioration in the peripheral microvascular background by reducing resistance to flow, increasing the compliance of the arteries and endothelial function [13]. Abnormalities in endothelium and FMD are a key phenomenon in the blunted vasodilatory response in CHF patients. ExT enables the improvement of both basal endothelial NO formation and agonist-mediated FMD of the skeletal muscle(SM) vasculature in CHF patients. The correction of endothelial dysfunction is associated with a significant improvement in exercise capacity evidenced by a 26% increase in peak oxygen uptake(VO2peak)[14].

Previous studies in HF have been showing that 16.4% of 171 patients had cachexia, and the mortality at 18 months of follow up was as high as 50% in the subset of patients with cachexia compared with 17% in those without cachexia. Cardiac cachexia is defined as an advanced stage of HF associated with involuntary loss of at least 5% of non-oedematous body weight. And muscle wasting, also known as sarcopenia, is the loss of muscle mass(MM) and strength, whereas cachexia describes loss of weight. Distinction of the two clinical conditions might also be challenging, because cachexia and muscle wasting can co-exist in the same patient. Indeed, cachexia might lead to muscle wasting and vice versa, although muscle wasting can occur earlier in the course of the disease[15].

SM strength, in upper and lower limbs, are parameters that independently predict survival[16,17,18]. This alternative treatment should focus on increasing MM, strength and power in the limbs to improve functionality and performance[19]. SM dysfunction includes reduced cardiac contractile performance that contributes to changes in SM physiology, muscle atrophy, weakness and reduced oxidative capacity [20]. Muscle function is also enhanced in response to ST in CHF patients, including myofilament function and whole muscle[21] as well as SM oxidative capacity[21].

It's crucial that the ExT in such patients should be train the peripheral muscles effectively without producing great cardiovascular stress. An alternative treatment approach should focus on the application of specific resistance exercise program to improve body composition[22], increase the cross-sectional area, muscle fiber[23], all of which counteract muscle wasting and may be cornerstone in the prevention of sarcopenia and cardiac cachexia in CHF patients[24].

ExT is a major component of rehabilitation/secondary prevention interventions, inducing significant beneficial changes in mechanisms of pathophysiology, exercise tolerance, functional capacity and QoL, while a positive impact on hospitalization and mortality reduction. There has been growing interest in the characteristics and modalities of exercise training able to induce optimal benefits. High intensity and interval mode have been shown to induce greater benefits than moderate intensity and continuous mode regimes. Considering the current body of evidence of high-intensity interval training(HIIT) in CHF, HIIT demonstrated to be more efficient, resulting in long-term adherence, which be an important practical aspect to consider during the ExT and consequently optimized improvements in central and peripheral adaptations[25]. More studies are needed to proof their safety and benefits on this type of patients.

Additionally, there has been sound rationale for the inclusion of ST to the HIIT, which has been also shown able to yield benefits in terms of exercise capacity and QoL. It is well known that combined AT and ST is the preferred exercise intervention to reverse or attenuate the loss of MM and improve exercise and functional capacity, muscle strength in this individuals[19]. But there are underlying mechanisms from the ST in the CHF patient's peripheral capacity that remains unidentified. And isn't known what is the benefits of combine different proportions of AT and ST.

For that reason, the investigators will test two proportions in combined training, CAT and CST. There hasn't been any data on the so called combined regimes, which include both aerobic exercise with HIIT and ST and the investigators will evaluate the effects of acute and chronic response.

Purpose:The research project will contribute to a better understanding in several aspects that are unexplained by scientific research. The purpose of this research project are:

1. To determine the effectiveness of an ExT programme with different proportions of CAT and CST in promoting cumulative effects in acute and chronic adaptations in CHF patients;
2. To identify the mechanisms of the potential improvement in effectiveness promoted by ST; This research project is going to employ state of the art methods focusing peripheral adaptations analysis in both groups namely in echocardiography variables, cardiopulmonary exercise testing, arterial stiffness, functional physical fitness, QoL and body composition in 2 distinguished moments: M1)baseline and M2)3 month.

Plan and Methods:This project will assess the acute and chronic effects in central and peripheral adaptations of a combined training to patients with CHF would address a number of important breaches in scientific knowledge with potential clinical benefits.

Study Design: A longitudinal randomized control trial (RCT) research design using two distinct ExT prescriptions (CAT and CST) will be applied in CHF patients. All the same assessments will be done in two moments: M0 - baseline and M1 - 3 months after starting the ExT. The patients will be randomized into either one of the two ExT group.

Recruitment and screening will last 9 months(October 2017 to June 2018) and the patient assessment will last until August 2018. It is expected to finish the project with peer-review redaction submitted and/or accepted in December 2018.

The following assessments on the 4 moments will be performed at the host Hospital, FMH-UL: Echocardiogram(Echo); cardiopulmonary exercise test(CPET); arterial stiffness - Complior Analyse; Intima-media thickness - ultrasound; body composition - dual-energy radiographic absorptiometry; functional physical fitness - Fullerton Functional Fitness Test; isometric strength - portable hand dynamometer JAMAR plus digital; maximal strength - 1RM and QoL questionnaire.

All assessment moments will be done in 4 days:

Day 1-The CPET, Echo will be performed at the host Hospital; Day 2 and 3-during one day and time of the ExT session at the host hospital, the patient will perform the functional physical fitness tests; maximal strength; isometric strength and QoL questionnaire. In another day the investigators will perform the arterial stiffness and the IMT before the session in rest and after the ExT; Day 4-In FMH, and dual-energy radiographic absorptiometry(DXA) exam. Individual reports will be sent by email or delivered on paper. During the 1-year project the multidisciplinary team will have bimonthly meetings to update the study information and discuss the patient's progress.

Inclusion Criteria:

• CHF patients; 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 heart failure (HF), no change in medication, and no change in New York Heart Association (NYHA) functional class.

Exclusion Criteria:

• If they are younger than 18 years or are unable to sign informed consent; unstable angina pectoris; and orthopedic or neurological limitations to exercise.