ABC | Volume 112, Nº6, June 2019

Review Article Mesquita et al HFmrEF - state of the art Arq Bras Cardiol. 2019; 112(6):784-790 HFpEF levels (p = 0.88). All other biomarkers were similar between HFrEF and HFmrEF. Cystatin-C and ST2 were significantly lower in HFmrEF than in HFpEF (p = 0.01 and p = 0.02, respectively) Galectin-3 and soluble transferrin receptor were relatively lower in HFmrEF when compared to HFpEF, but the difference was not statistically significant. Pathophysiology In the 2016 guideline, the ESC suggested that HFmrEF may have both a mild systolic dysfunction and a diastolic dysfunction contribution.³ A recent study published by Rastogi et al., 30 observed that HFmrEF consists of a heterogeneous group of patients, and consists of at least 3 subgroups based on LVEF, such as: patients with previous LVEF < 40% (recovered HFmrEF), patients with previous LVEF > 50% (impaired HFmrEF) and patients with previous LVEF between 40-50% (unchanged HFmrEF). 30 Most patients in this study were classified as having recovered HFmrEF (73%), while 17% of patients were classified as impaired HFmrEF and only 10% were categorized as unchanged HFmrEF. 30 Also, in this study, the subgroup with recovered HFmrEF had a higher prevalence of male patients and a higher prevalence of patients with CAD, compatible with the characteristics of patients with HFrEF. In contrast, the subgroup with impaired HFmrEF consisted mostly of women with a history of hypertension and AF or flutter, as well as patients with HFpEF. In contrast, the subgroup with impaired HFmrEF consisted mostly of women with a history of hypertension and AF or flutter, as well as patients with HFpEF. Another important observation, in the impaired HFmrEF subgroup, patients had significantly more advanced diastolic dysfunction at the echocardiogram assessment when compared to patients with recovered HFmrEF. 30 A common finding in different cohorts 13,14,31 was that HFmrEF resembled HFrEF in relation to the high prevalence of CAD and a higher risk of new CAD events. In the Swedish Heart Failure register, no difference was observed between the prevalence of CAD between HFmrEF (61%) and HFrEF (60%), while HFpEF was associated with a lower prevalence of the disease (52%). 14 Chioncel et al. 31 based on the long-term HF record of the ESC, found that ischemic etiology was present in 48.6% of patients with HFrEF, 41.8% of patients with HFmrEF, but only in 23.7% % of patients with HFrEF. In the TIME-CHF study, 24 post-hoc analysis, the ischemic etiology was 58.2%, 56.5% and 31.3% for HFrEF, HFmrEF and HFpEF, respectively. Therefore, regarding the etiology, patients with HFmrEF are more similar to those with HFrEF than to the ones with HFpEF. Prognosis Both the CHARM study and the prognosis meta-analysis performed by Altaie et al. 32 concluded that all-cause mortality in HFmrEF patients is significantly lower than in patients with HFrEF (p < 0.001 and RR 0.9; 95% CI 0.85–0.94; p < 0.001, respectively) and statistically similar to patients with (HR 0.98; CI 95% 0.82 – 1.19; p = 0.88 and RR 0.98; 95% CI 0.86–1.12; p = 0.82, respectively). 27,32 Regarding the cardiac mortality, the meta-analysis of Altaie et al. 32 concluded there was no significant difference between HFrEF and HFmrEF (RR 0.89, 95% CI, 0.69-1.15, p = 0.38) while HFpEF showed significantly higher cardiac mortality (RR 1.09, 95% CI, 1.02-1.16, p = 0.001). In the analysis of the prognosis by separating subgroups of HFmrEF, in the study by Rastogi et al., 30 the patient cohort with recovered HFmrEF showed significantly better clinical outcomes compared to patients with HFrEF, after adjusting for age and gender. In contrast, the clinical endpoints of the subgroup with impaired HFmrEF were not significantly different from those with HFpEF after adjusted for the same factors. 30 By observing time to death / transplantation / cardiac hospitalization between the subgroups, the recovered HFmrEF had a significantly better prognosis compared to impaired HFmrEF (p = 0.011), whereas there was no significant difference between the two groups and unchanged HFmrEF. 30 Hospitalization The studies differed regarding hospitalization rates. The meta-analysis of Altaie et al., 32 demonstrated that there was no significant difference in all-cause hospitalization for both HFrEF and HFmrEF, and between HFpEF and HFmrEF (RR 0.91, 95% CI, 0.18-4.59, p = 0.9, and RR 0.95, 95% CI, 0.84-1.07; p = 0.38, respectively). Regarding the HF hospitalization, the meta-analysis also did not show any significant differences between HFrEF and HFmrEF or between HFpEF and HFmrEF (RR 0.92, 95% CI, 0.84-1.01, p = 0.08, and RR 1.05, 95% CI, 0.83-1.33; p = 0.69, respectively.) However, in the CHARM study, all-cause hospitalization was significantly lower in patients with HFmrEF than in the HFpEF phenotype (HR 8.89; 95% CI, 0.81-0.98; p = 0.02). 27 When comparing the different HFmrEF in the Rastogi et al., 30 cohort subgroups, the recovered HFmrEF had a better prognosis compared to HFmrEF (p = 0.029) when observing the time until the first hospitalization for a cardiac event. However, there was no significant difference in relation to the subgroup of unchanged HFmrEF when compared to the other two. Pharmacological treatment and comorbidity management In the TOPCAT study, spironolactone did not present in the primary endpoint (consisting of cardiovascular death, cardiac arrest or HF hospitalization), however, there was a reduction in HF hospitalizations in the treatment group with the greatest benefit observed in patients with LVEF from 45% to 55%. 33 On the other hand, the study by Yan-guo Xin et al., 34 which evaluated spironolactone use in 229 patients with HFmrEF, showed that the drug use reduced the incidence of primiparous death from all causes (21.3% vs. 34.5%, p = 0.014), as well as improving quality of life. However, there was no difference between the groups receiving different doses of medication (21.8 vs 20.7%, p = 0.861.50 mg vs. 25 mg, respectively). The OPTIMIZE-HF study, when evaluating the use of ACE inhibitors and ARBs, showed there was no associated benefit in patients with HFmrEF. 21 Patients with LVEF <40% were compared with those with LVEF ≥ 40%, for long-term outcomes in relation to the use of beta-blockers. 21 In patients with LVEF of 40-50%, as in all patients with LVEF ≥ 40%, there was no significant influence of drug use on the outcomes. 35 787