IJCS | Volume 31, Nº6, November / December 2018

656 Figure 1 - Phenogroups of heart failure with preserved ejection fraction. SAH: systemic arterial hypertension; COPD: chronic obstructive pulmonary disease; CKD: chronic kidney disease; PH: pulmonary hypertension; AF: atrial fibrillation . GROUP 2 GROUP 1 GROUP 3 OBESITY DIABETES SLEEP APNEA SAH AGING COPD CKD PH AF Mesquita et al. HFPEF phenotypes Int J Cardiovasc Sci. 2018;31(6)652-661 Review Article For hypertension phenotype, anti-hypertensive are the most recommended treatment, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers and calcium channel blockers, highlighting the importance of this treatment to HF prevention, to vascular conditions not related toHF (such as stroke and myocardial infarction) and to improve the quality of life of HFPEF patients. The CHARM- Preserved, PEP-CHF and TOPCAT studies demonstrated a reduction in hospitalization rates of patients with HFPEF by blockage of the renin-angiotensin-aldosterone system. These studies used, respectively, an angiotensin II receptor blocker, ACE inhibitors and an aldosterone antagonist (spironolactone). 36-38 Inhibition of the renin- angiotensin-aldosterone system would be of benefit to the patients due to the association of neurohormonal activation with hypertension and volume retention. 39,40 Control of heart rate is mediated by activation of the sympathetic system, which has a direct effect on adverse outcomes in patients with HFPEF. A study derived from the I-Preserve study showed an association between increased heart rate and higher incidence of death for cardiovascular causes and hospitalizations in patients in sinus rhythm. 41 Therefore, heart rate control would be an effective treatment target. In patients with pulmonary hypertension, the use of dobutamine improved pulmonary vascular function, and studies on new pulmonary vasodilators targeting GMPc, endothelin and nitric oxide (NO) 32 have also been developed (Table 1). In patients with kidney dysfunction, sildenafil had no significant effects in the RELAX clinical trial. 42 Due to the high prevalence of patients with HFPEF andpulmonary hypertension, and its intrinsic relationship with morbidity and mortality, pulmonary vasodilation is paramount in the treatment of these patients. 43 Based on the studies reviewed, we conclude that phenotype mapping in HFPEF has enabled the development of a new generation of clinical trials aimed at new therapeutic approaches (Figure 2). HFPEF accounts for nearly half of HF patients on treatment and its prevalence has increased. Cardiovascular disease phenotypes are complex, with many influencing factors. Systemic inflammatory reaction andmicrovascular endothelial dysfunction lead to ventricular remodeling and dysfunction. Specific therapeutic interventions should be multifaceted and focused on stages of these signaling cascades. New therapeutic approaches should encompassmetabolic control, modulation of inflammatory response, control of pulmonary hypertension, prevention of muscle weakness, and reduction of sodium and water retention. Due to the wide range of interventions, phenotype mapping becomes an essential tool for future investigations and clinical trials (to confirm the results). Possibly, there will be more significant changes as new genetic, cellular, molecular and immunologic biomarkers are incorporated and used to discriminate treatment groups in a clear and objective manner. Cardiacdiseases that simulateHFPEF–Phenocopies The term “phenocopies” was first used in the study of hypertrophic cardiomyopathies, in which a subgroup of