ABC | Volume 114, Nº1, January 2019

Review Article Fernandes et al. Heart Failure with Preserved Ejection Fraction Arq Bras Cardiol. 2020; 114(1):120-129 10. Ranolazine It is known that both HF and ischemic heart disease show increased late sodium current on intracellular calcium cycling, compromising cardiac relaxation. By inhibiting the late sodium channels with ranolazine, an improvement in the diastolic function would theoretically be expected. 6 The RAnoLazIne for the Treatment of Diastolic Heart Failure in Patients With Preserved Ejection Fraction, the “ RALI-DHF” trial 29 was an exploratory study that evaluated the drug in patients with HFpEF. Despite hemodynamic improvements after 24 hours, there were no significant changes in diastolic function after 14 days of treatment. Another Direction The failure of clinical trials in testing proven effective drugs in HFrEF, has led to a new direction in the treatment of patients with HFpEF. Attempts were made to better understand the pathophysiological mechanism of the disease and act on those different pathways (Figure 2). New drugs have been tested and new approaches are under research. (Table 1-B) 11. Albuterol Given the frequent lung involvement in these patients, drugs acting at this level are being tested. This is the case of albuterol, an inhaled bronchodilator. The Inhaled Beta‑adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF, the “ BEAT – HFpEF” trial, 30 aims to assess the impact of this drug on symptoms, through its effect on pulmonary vascular resistance at rest and during exercise. 12. Interatrial septal shunt It is known that the atrial volume and pressure overload not only contributes to the development of symptoms and exercise intolerance, but it is also a major determinant of morbimortality. Pulmonary capillary wedge pressure (PCWP) is an invasive hemodynamic parameter with prognostic value, which reflects the pressure in the LA and pulmonary veins. Based on these hemodynamic changes and in view of the limited success of pharmacological management of patients with HFpEF, an interatrial communication device was developed, which is used to reduce LA pressure. The prospective, non-randomized, open‑label study, called “ A Transcatheter Intracardiac Shunt Device for Heart Failure with Preserved Ejection Fraction “REDUCE LAP-HF” 31 evaluated the performance and safety of this device in 64 patients with HFpEF and elevated PCWP. Preliminary analyses demonstrated clinical and hemodynamic benefits at 6 months. Pressure reductions in LA resulted in improved functional capacity, at the expense of a slight increase in the right cardiac pressure and output. These benefits persisted in a long-term evaluation with sustained improvement of the hemodynamic profile, NYHA functional class, quality of life and exercise capacity at the end of one year, with no evidence of complications. 32 Subsequently, a randomized controlled phase II trial was performed with PCWP evaluation during exercise, one month after the implantation of the interatrial septal shunt device vs . sham procedure. It showed to be safe and effective, with a reduction of PCWP and without a significant increase in pulmonary artery pressure (PAP) or pulmonary vascular resistance, which are possible consequences of right cardiac overload. 33 It remains unclear whether this hemodynamic effect will lead to sustained clinical improvements. 13. Monitoring Congestive symptoms are present in the majority of patients hospitalized for decompensatedHF regardless of LVEF. Changes in body volume and cardiac filling pressures are predictive of adverse events. A strategy of hemodynamic monitoring, with consequent targeted and early therapeutic intervention, may reduce the risk of hospitalization for HF. The Wireless pulmonary artery haemodynamic monitoring in chronic heart failure , the “CHAMPION” trial, 34 tested this hypothesis by using a microelectromechanical system pressure sensor permanently implanted during right cardiac catheterization. Through daily assessment of PAP and active reduction of filling pressures with diuretics and vasodilators, significant reductions were demonstrated in hospital admissions. The benefits persisted in the subgroup of patients with HFpEF, with reductions of 50% in HF hospitalizations after 17 months. 35 14. Exercise Physical exercise is beneficial in certain conditions strictly related to HFpEF, such as hypertension and metabolic syndrome. The effect of structured and supervised training on exercise capacity, diastolic function and quality of life was evaluated. The Exercise Training Improves Exercise Capacity and Diastolic Function in Patients With Heart Failure With Preserved Ejection Fraction, the “ EX DHF” trial, 36 showed that a short-term supervised endurance/resistance training is achievable, safe, and effective in patients with HFpEF. The programmaintenance in the long term and the involvement of elderly patients, at advanced stages of the disease and with multiple comorbidities, are possible limitations. Nevertheless, it seems a promising strategy with potential synergism with other pharmacological and non-pharmacological approaches. It is important to define the regimen approach, improve long-term adherence and expand availability. 37 15. Comorbidities Another of the proposed pathophysiological mechanisms involves the existence of a systemic proinflammatory state induced by multiple comorbidities, resulting in endothelial dysfunction, cardiac remodeling and dysfunction. It was hypothesized that by screening and treating comorbidities in a targeted manner, the overall prognosis of these patients could be improved. The Optimizing the Management of Heart Failure with Preserved Ejection Fraction in the Elderly by Targeting Comorbidities, the “OPTIMIZE-HFpEF” trial, 38 proposes a systematic screening and optimized treatment of comorbidities as a pathophysiological mechanism of HF, rather than the simple treatment of previously diagnosed concomitant pathologies. Although it lacks sufficient power to assess cost-effectiveness, it is a good starting point to test a new promising approach. 126