Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCsh8XQnZYrskPD78mbh8mJBhS0066-782X201900060078410.5935/abc.20190079Review ArticleHeart Failure with Mid-Range Ejection Fraction - State of the Art0000-0002-7452-3870MesquitaEvandro Tinoco0000-0002-4945-7402BarbettaLetícia Mara dos Santos0000-0003-0454-6740CorreiaEduardo Thadeu de OliveiraHospital Universitário Antônio PedroNiteróiRJBrazilHospital Universitário Antônio Pedro, Niterói, RJ - BrazilMailing Address: Letícia Mara dos Santos Barbetta, Hospital Universitário Antônio Pedro - Av. Marquês do Paraná, 303. Postal Code 24033-900, Niterói, RJ - Brazil. E-mail: leticiabarbetta@gmail.com
Author contributions
Conception and design of the research, Analysis and interpretation of the data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Mesquita ET, Barbetta LMS, Correia ETO; Acquisition of data: Barbetta LMS, Correia ETO.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.
150720190620191126784790200820182612201813022019This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedAbstract
In 2016, the European Society of Cardiology (ESC) recognized heart failure (HF) with ejection fraction between 40 and 49% as a new HF phenotype, HF with mid-range ejection fraction (HFmrEF), with the main purpose of encouraging studies on this new category. In 2018, the Brazilian Society of Cardiology adhered to this classification and introduced HFmrEF in Brazil. This paper presents a narrative review of what the literature has described about HFmrEF. The prevalence of patients with HFmrEF ranged from 13 to 24% of patients with HF. Analyzing the clinical characteristics, HFmrEF shows intermediate characteristics or is either similar to HF with preserved ejection fraction (HFpEF) or to HF with reduced fraction (HFrEF). Regarding the prognosis, HFmrEF’s all-cause mortality is similar to HFpEF’s and lower than HFrEF’s. Studies that analyzed cardiac mortality concluded that there was no significant difference between HFmrEF and HFrEF, both of which were lower than HFpEF. Despite the significant increase of publications on HFmrEF, there is a great scarcity of prospective studies and clinical trials that allow delineating specific therapies for this new phenotype. To better treat HFmrEF patients, it is fundamental that cardiologists and internists understand the differences and similarities of this new phenotype.
The classification and characterization of heart failure (HF) by phenotypes has an important relevance in clinical practice, since these phenotypes are currently based on left ventricular ejection fraction (LVEF) and have different characteristics in relation to prognosis and treatment.1
Classically, two main HF phenotypes have been described; the HF with reduced ejection fraction (HFrEF) with LVEF < 40% and the HF with preserved ejection fraction (HFpEF), with LVEF ≥ 50%.2-4 Different guidelines have proposed a new phenotype in the current decade, the HF with mid-range ejection fraction (HFmrEF).
The American College of Cardiology/American Heart Association published a new HF guideline in 2013, in which patients with LVEF between 41% and 50% were classified as “borderline” HFpEF.² In 2016, the ESC recognized HF with LVEF between 40% and 49% as a distinct phenotype; the HFmrEF, mainly intended to stimulate studies that address epidemiology, etiology, characteristics, and prognostics of this new category.³ Finally, the Brazilian Society of Cardiology (BSC) introduced HFmrEF as a new clinical phenotype in its 2018 guideline of acute and chronic HF.5
With the introduction of this new classification, HFmrEF has received great attention and, consequently, has been better studied and characterized. The present review study aims to describe what is currently known about HFmrEF and discuss future perspectives that will contribute to a better approach for this group of patients.
EpidemiologyPrevalence
In the United States, it is estimated that more than 6.5 million people have HF,6 and the percentage of individuals with HFmrEF is between 13% and 24%.7,8 The prevalence of HFmrEF in studies performed with hospitalized patients ranged from 13% to 26%,7,9-12 while the prevalence of HFmrEF in outpatients varied from 9% to 21%.8,13-17
The last census of Brazilian Institute for Geography and Statistics (IBGE) in 2010 census showed an increase in the elderly population in Brazil, and therefore a great potential for the increase of at-risk HF patients. In the DIGITALIS study performed in the city of Niterói, state of Rio de Janeiro, Brazil, a prevalence of 9.3% of HF was identified in patients from the family physician program (59 individuals among 633 volunteers),18 in which 64.2% of these patients were characterized as having HFpEF and 35% as HFrEF.18 Recently, according to unpublished data based on the DIGITALIS study database, the prevalence of HFmrEF patients in Niterói was 22%, HFrEF was 19% and HFpEF was 59%.
Diagnosis
According to the latest acute HF guideline of BSC,5 the diagnosis of HF is based on the combination on medical history findings, physical examination, electrocardiogram and chest x-ray results, as detailed in figure 1. An echocardiogram should be performed for diagnostic confirmation if there is clinical suspicion of HF. In low suspicion cases or if there are diagnostic doubts, the measurement of brain natriuretic peptides (BNP and/or NT-proBNP) and an echocardiogram should be performed, if available. A normal echocardiogram and/or plasma BNP levels < 35 pg/mL and/or NT-proBNP < 125 pg/mL make the HF diagnosis improbable. In the presence of BNP levels > 35 pg/mL and/or NT-proBNP > 125 pg/mL and/or altered echocardiogram results, the HF diagnosis becomes probable. The LVEF echocardiography evaluation contributes to establishing the HF clinical phenotype, since the clinical signs and patients’ symptoms with HFrEF, HFmrEF and HFpEF are similar.3
Diagnostic algorithm in the clinical suspicion of heart failure. Adapted from: Brazilian Guideline for Chronic and Acute Heart Failure of 2018;<sup>5</sup> HFrEF: heart failure with reduced ejection fraction; HFmrEF: heart failure with mid-range ejection fraction; HFpEF: heart failure with preserved ejection fraction; EKG: electrocardiogram; BNP: brain natriuretic peptide; NT-proBNP: amino-terminal fragment of pro-brain natriuretic peptide; LVEF: left ventricular ejection fraction.
A relevant aspect regarding the HFmrEF diagnosis involves methodological aspects related to the cardiac imaging techniques. The LVEF evaluation by echocardiography has been the standard method used to categorize patients with HF; however, it is common that the values obtained are different in relation to other methods, such as cardiac magnetic resonance imaging, radioisotope ventriculography and angiocardiography.19,20 In addition, the ejection fraction evaluation by echocardiography shows considerable intra and inter-observer variability over time, as well as under therapeutic intervention effect.19,20
Clinical-epidemiological characteristics
Previous studies have shown that patients with HFmrEF had clinical characteristics that, although intermediate between the HFrEF and HFpEF groups, were more similar to those of HFpEF.8,9,13,21 Nevertheless, in relation to the presence of ischemic disease, different studies have found that HFmrEF resembles HFrEF, showing a higher prevalence.7,22-24
In the study by Kapoor et al.,7 based on the GWTG-HF (Get With The Guidelines - Heart Failure) registry, patients with HFmrEF were older (mean age of seventy-seven years) and showed a higher percentage of females (48%) when compared to patients with HFrEF, being more similar to HFpEF. Moreover, HFmrEF showed a high prevalence of comorbidities such as DM (50%), atrial fibrillation (AF) (42%), chronic obstructive pulmonary disease (COPD) (36%), anemia (27%) and renal failure (26%), "also similar to HFpEF to HFpEF. However, there was a higher prevalence of ischemic heart disease in up to two thirds of the patients, similar to what as observed with HFrEF.
However, in the meta-analysis published by Lauritsen et al.,25 patients with HFmrEF had entirely intermediate characteristics, and there were significant differences between patients with HFmrEF and HFrEF and between patients with HFmrEF and HFpEF. Patients with HFmrEF were older than those with HFrEF (p < 0.001) but were younger than those with HFpEF (p < 0.001). The proportion of men and the prevalence of ischemic heart disease in patients with HFmrEF were lower than in those with HFpEF (p < 0.001 and p < 0.034, respectively), but higher than in those with HFpEF (p < 0.001 and p < 0.034 respectively). Hypertension was more frequent in patients with HFmrEF than in those with HFrEF (p < 0.001), but less frequent than in patients with HFpEF (p < 0.001). Diabetes mellitus (DM) was significantly less frequent in patients with HFmrEF and HFrEF (p = 0.17) than in those with HFpEF (p = 0.021). AF was more frequent among patients with HFmrEF than among those with HFrEF (p < 0.001), but less frequent than in patients with HFpEF (p < 0.001). The prevalence of COPD was lower in individuals with HFmrEF than in HFpEF (p < 0.001), but higher when compared to patients with HFrEF (p = 0.001). Patients with HFmrEF had significantly better renal function than patients with HFpEF (p < 0.001) but worse than patients with HFrEF (p = 0.001).
In the RICA26 registry, patients with HFmrEF showed mixed characteristics in relation to the other groups. Patients with HFmrEF were similar to patients with HFrEF regarding hypertension rates, and chronic kidney disease (CKD) history, as well as in relation to the presence of higher systolic pressure, higher blood pressure, lower frequency of New York Association (NYHA) classes III-IV, higher prevalence of AF and previous HF.
The study by Bhambhani et al.,22 which analyzed 28,829 without HF participants for an average of 12 years, found that 48% of the patients who developed HFmrEF were females. In addition, participants with HFmrEF shared some similarities with the HFrEF group, including lower body mass index (BMI) in relation to patients with HFpEF, with a lower obesity prevalence, a higher coronary artery disease (CAD) prevalence and lower levels of high density lipoproteins (HDL). Other clinical characteristics of participants with HFmrEF were intermediate between those with HFpEF and HFrEF.
The CHARM27 study found that patients with HFmrEF were similar to HFpEF for most of the characteristics, including age, systolic blood pressure, percentage of women, previous myocardial infarction and AF. HFmrEF was intermediate between HFrEF and HFpEF regarding the history of hypertension, NYHA and BMI class distribution. Some characteristics, such as DM, were simultaneously prevalent in all three categories.27,28
In addition, the study by Wang et al.23 showed no significant differences in gender between HFmrEF, HFpEF and HFrEF. The HFmrEF group was intermediate compared to the other groups regarding characteristics such as age, smoking history, DM and CKD. In contrast, the HFmrEF group was similar to HFpEF regarding the history of ischemic heart disease, with both groups showing significantly higher rates than HFpEF.
In the Swedish Heart Failure24 registry, HFmrEF was intermediate in terms of age, gender, hypertension, AF, valvular and renal disease. However, the presence of ischemic disease was more common in HFrEF and HFmrEF when compared to HFpEF, and the prevalence of DM did not differ between the three groups. The BMI was lower and fewer patients had anemia in HFmrEF.
A summary of the clinical-epidemiological HFmrEF characteristics is shown in figure 2.
Comparisons of the clinical characteristics among the different phenotypes of HF; ? : presence of conflict between studies; CAD: coronary artery disease; DM: diabetes mellitus; HBP: high blood pressure (hypertension); AF: atrial fibrillation; HOSP: hospitalization; HOSP-HF: hospitalization for HF; DEATH: death from all causes; CV-DEATH: cardiovascular death; * Data for constructing the characteristics were taken from references;<xref ref-type="bibr" rid="B7">7</xref><sup>,</sup><xref ref-type="bibr" rid="B22">22</xref><sup>-</sup><xref ref-type="bibr" rid="B27">27</xref><sup>,</sup><xref ref-type="bibr" rid="B32">32</xref> † Data taken from references;<xref ref-type="bibr" rid="B27">27</xref><sup>,</sup><xref ref-type="bibr" rid="B32">32</xref> ‡ Data taken from reference.<xref ref-type="bibr" rid="B32">32</xref>
Biomarkers
Regarding biomarkers, HFmrEF has an intermediate profile, with inflammatory biomarkers being more common in HFpEF and heart distension biomarkers in HFrEF.13 In the study by Bhambhani et al.22 was found that the predictors of HFmrEF were similar to the predictors of other types of HF. However, a higher BMI was a predictor of HFpEF, but not of HFmrEF, and natriuretic peptides were more robust predictors of HFpEF than of HFmrEF.
The Swedish Heart Failure registry24 concluded the median value of NT-pro BNP in HFmrEF was 1,540 pg / mL with an interquartile range of 652-3,317. This value was minimally and not significantly higher than in HFpEF but was significantly higher than in HFrEF (p < 0.001). The study by Moliner et al.29 also concluded that NT-ProBNP levels in HFmrEF were significantly lower than in HFrEF (p = 0.02), but similar to 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 cohorts13,14,31 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
However, the CHARM study showed that the candesartan use improved outcomes for HFmrEF to a degree comparable to improvement for HFrEF. For the HFmrEF group, the incidence rates for the primary outcome (cardiovascular death or HF hospitalization) of candesartan vs. placebo were 7.4 vs. 9.7 per 100 patients per year (HR 0.76, 95% CI, 0.61-0.96, p = 0.02), and the incidence rate of recurrent hospitalization for HF was 0.48 (95 % CI, 0.33-0.70, p <0.001).27,36
The study by Cleland JGF et al.,37 which included 18,637 patients, found that for patients with HF with sinus rhythm and LVEF between 40% and 49%, beta-blockers showed a reduction in cardiovascular death when compared to placebo (HR 0.048, 95% CI, 0.24-0, 97, p = 0.04) and improvement in LV systolic function.37
In the study by Gwag et al.,38 maintenance therapy with β-blocker was seen to be associated with LVEF improvement in patients with HFmrEF (HR 2.021; 95% HF 1.033-3.033; p = 0.04). In addition, maintenance therapy with renin-angiotensin system blockers or aldosterone antagonists were significantly associated with improved survival (HR 0,309; CI 95% 0,162-0,588; p < 0,001; and HR 0,240; CI 95% 0,085 - 0,673; p = 0,01, respectively).
Digoxin use was evaluated in the study by Abdul-Rahim AH et al.,39 which included 7788 patients, with 1995 patients being classified as HFmrEF. Digoxin reduced cardiovascular death or HF hospitalization (HR: 0.83; 95% CI, 0.66-1.05).39
The study Chang et al.9 showed the comorbidities observed in patients with HFmrEF were more similar to the ones observed in patients with HFpEF, and CAD was associated with greater declines in LVEF in patients with HFpEF.40 Therefore, the management of CAD can help prevent LV systolic dysfunction progression in individuals with HFmrEF.21
Non-cardiac comorbidities, such as hypertension, DM and COPD, are highly prevalent in the HF population and contribute to the general morbidity of these patients.41 In patients with HFmrEF, uncontrolled hypertension was the main precipitant factor of hospitalization for HF compared to the other HF groups.7 In patients with HFmrEF and hypertension, therapy with angiotensin II receptor blockers (ARB) or aldosterone antagonists has shown a reduction in hospitalizations, which suggests that such drugs can be used to control hypertension and reduce the risk of LVEF decline in patients with HFmrEF.7 Regarding the patients with HF undergoing treatment for DM sodium-glucose cotransporter-2 (SGLT2) inhibitors use in patients at high cardiovascular risk showed improvements in the primary outcome, consisting of death from cardiovascular causes, infarction and non-fatal stroke. (HR 0.86; 95% CI, 0.74-0.99; p < 0.001 for noninferiority and p = 0.04 for superiority). In addition, empagliflozin use showed a reduction in cardiovascular death and death from all causes (HR 0.62, 95% CI 0.49-0.77, p < 0.001 and HR 0.68, 95% CI, 0.57-0.82, p < 0.001, respectively), in addition to the reduction in hospitalization for HF (HR 0.65, 95% CI, 0.50-0.85, p = 0.002).42
The current BSC HF guideline5 proposes that initially, the specific treatment of the etiology and comorbidities should be addressed, when possible. Patients with a history of HFrEF who show an improvement of LVEF, which reclassifies them as HFmrEF patients, should be treated by maintaining the therapeutic optimization for HFrEF. For patients with previous HFpEF who show worsening of LVEF and also those with persistent HFmrEF, the use of beta-blocker and angiotensin-convertingenzyme inhibitor (ACEi) or ARB (if ACEi is not tolerated) is recommended. The treatment scheme proposed by the SBC is shown in figure 3.
Algorithm for treatment of HFmrEF according to the Brazilian Guideline for Chronic and Acute Heart Failure of 2018;<sup>5</sup> ACEi: angiotensin-converting-enzyme inhibitor; ARB: angiotensin II receptor blockers; * In the absence of deposit cardiomyopathies, hypertrophic, inflammatory or infectious diseases; † Particularly for coronary heart disease and/or acute myocardial infarction.
Future perspectives
The precision medicine use in the cardiovascular area has advanced, and the identification of HF phenotypes is important for the development of new therapeutic alternatives that offer a better prognosis for the patient with HF.
Although some studies have demonstrated the efficacy of certain therapies in patients with HFmrEF, most publications are retrospective studies that perform a new analysis of previous databases. Therefore, prospective studies and randomized clinical trials including patients with HFmrEF are essential for the creation of therapies with solid evidence-based recommendations.
Conclusion
After the establishment of HFmrEF as a new HF category by national and international guidelines, there was a considerable increase in publications on this type of patients, which allowed a better understanding of their clinical profile, pathophysiological and clinical outcome. However, there is still a great shortage of prospective studies and randomized double-blind clinical trials that allow the specific therapy delineation for this new category of HF. The knowledge of HFmrEF peculiarities by cardiologists and internists is fundamental for the best diagnosis and management of these patients, in addition to the identification of areas of uncertainty regarding the development of basic and clinical researches.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
Ethics approval and consent to participate
This article does not contain any studies with human participants or animals performed by any of the authors.
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Rev Esp Cardiol (Engl Ed). 2017;70(5):338-46.Gómez-OteroIFerrero-GregoriAVarela RománASeijas AmigoJPascual-FigalDAMid-range ejection fraction does not permit risk stratification among patients hospitalized for heart failureRev Esp Cardiol (Engl Ed)201770533834612 Farmakis D, Simitsis P, Bistola V, Triposkiadis F, Ikonomidis I, Katsanos S, et al. Acute heart failure with mid-range left ventricular ejection fraction: clinical profile, in-hospital management, and short-term outcome. Clin Res Cardiol. 2017;106(5):359-68.FarmakisDSimitsisPBistolaVTriposkiadisFIkonomidisIKatsanosSAcute heart failure with mid-range left ventricular ejection fraction: clinical profile, in-hospital management, and short-term outcomeClin Res Cardiol2017106535936813 Rickenbacher P, Kaufmann BA, Maeder MT, Bernheim A, Goetschalckx K, Pfister O, et al. Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF). Eur J Heart Fail. 2017;19(12):1586-96.RickenbacherPKaufmannBAMaederMTBernheimAGoetschalckxKPfisterOHeart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF)Eur J Heart Fail201719121586159614 Vedin O, Lam CSP, Koh AS, Benson L, Teng THK, Tay WT, et al. Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study. Circ Heart Fail. 2017 Jun;10(6):e003875.VedinOLamCSPKohASBensonLTengTHKTayWTSignificance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort studyCirc Heart Fail201706106e00387515 Pascual-Figal DA, Ferrero-Gregori A, Gomez-Otero I, Vazquez R, Delgado-Jimenez J, Alvarez-Garcia J, et al. Mid-range left ventricular ejection fraction: clinical profile and cause of death in ambulatory patients with chronic heart failure. Int J Cardiol. 2017 Aug;240:265-70.Pascual-FigalDAFerrero-GregoriAGomez-OteroIVazquezRDelgado-JimenezJAlvarez-GarciaJMid-range left ventricular ejection fraction: clinical profile and cause of death in ambulatory patients with chronic heart failureInt J Cardiol20170824026527016 Ghio S, Guazzi M, Scardovi AB, Klersy C, Clemenza F, Carluccio E, et al. Different correlates but similar prognostic implications for right ventricular dysfunction in heart failure patients with reduced or preserved ejection fraction. Eur J Heart Fail. 2017;19(7):873-9.GhioSGuazziMScardoviABKlersyCClemenzaFCarluccioEDifferent correlates but similar prognostic implications for right ventricular dysfunction in heart failure patients with reduced or preserved ejection fractionEur J Heart Fail201719787387917 Allen LA, Magid DJ, Gurwitz JH, Smith DH, Goldberg RJ, Saczynski J, et al. Risk factors for adverse outcomes by left ventricular ejection fraction in a contemporary heart failure population. Circ Heart Fail. 2013;6(4):635-46.AllenLAMagidDJGurwitzJHSmithDHGoldbergRJSaczynskiJRisk factors for adverse outcomes by left ventricular ejection fraction in a contemporary heart failure populationCirc Heart Fail20136463564618 Jorge AJ, Rosa ML, Correia DM, Martins WA, Ceron DM, Coelho LC, et al. Evaluation of Quality of Life in Patients with and without Heart Failure in Primary Care. Arq Bras Cardiol. 2017;109(3):248-52.JorgeAJRosaMLCorreiaDMMartinsWACeronDMCoelhoLCEvaluation of Quality of Life in Patients with and without Heart Failure in Primary CareArq Bras Cardiol2017109324825219 Dunlay SM, Roger VL, Weston SA, Jiang R, Redfield MM. Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. Circ Heart Fail. 2012;5(6):720-6.DunlaySMRogerVLWestonSAJiangRRedfieldMMLongitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fractionCirc Heart Fail20125672072620 Clarke CL, Grunwald GK, Allen LA, Barón AE, Peterson PN, Brand DW, et al. Natural history of left ventricular ejection fraction in patients with heart failure. Circ Cardiovasc Qual Outcomes. 2013;6(6):680-6.ClarkeCLGrunwaldGKAllenLABarónAEPetersonPNBrandDWNatural history of left ventricular ejection fraction in patients with heart failureCirc Cardiovasc Qual Outcomes20136668068621 Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50(8):768-77.FonarowGCStoughWGAbrahamWTAlbertNMGheorghiadeMGreenbergBHCharacteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF RegistryJ Am Coll Cardiol200750876877722 Bhambhani V, Kizer JR, Lima JA, van der Harst P, Bahrami H, Nayor M, et al. Predictors and outcomes of heart failure with mid-range ejection fraction. Eur J Heart Fail. 2018;20(4):651-9.BhambhaniVKizerJRLimaJAvan der Harst P.Bahrami H.Nayor MPredictors and outcomes of heart failure with mid-range ejection fractionEur J Heart Fail201820465165923 Wang N, Hales S, Barin E, Tofler G. Characteristics and outcome for heart failure patients with mid-range ejection fraction. J Cardiovasc Med (Hagerstown);19(6):297-303.WangNHalesSBarinEToflerGCharacteristics and outcome for heart failure patients with mid-range ejection fractionJ Cardiovasc Med (Hagerstown)19629730324 Savarese G, Orsini N, Hage C, Dahlström U, Vedin O, Rosano GM, et al. Associations with and prognostic and discriminatory role of n-terminal pro-b-type natriuretic peptide in heart failure with preserved versus mid-range versus reduced ejection fraction. J Card Fail. 2018;24(6):365-74.SavareseGOrsiniNHageCDahlströmUVedinORosanoGMAssociations with and prognostic and discriminatory role of n-terminal pro-b-type natriuretic peptide in heart failure with preserved versus mid-range versus reduced ejection fractionJ Card Fail201824636537425 Lauritsen J, Gustafsson F, Abdulla J. Characteristics and long-term prognosis of patients with heart failure and mid-range ejection fraction compared with reduced and preserved ejection fraction: a systematic review and meta-analysis. ESC Heart Fail. 2018;5(4):685-94.LauritsenJGustafssonFAbdullaJCharacteristics and long-term prognosis of patients with heart failure and mid-range ejection fraction compared with reduced and preserved ejection fraction: a systematic review and meta-analysisESC Heart Fail20185468569426 Guisado-Espartero ME, Salamanca-Bautista P, Aramburu-Bodas Ó, Conde-Martel A, Arias-Jiménez JL, Llàcer-Iborra P, et al. Heart failure with mid-range ejection fraction in patients admitted to internal medicine departments: Findings from the RICA Registry. Int J Cardiol. 2018 Mar;255:124-8.Guisado-EsparteroMESalamanca-BautistaPAramburu-BodasÓConde-MartelAArias-JiménezJLLlàcer-IborraPHeart failure with mid-range ejection fraction in patients admitted to internal medicine departments: Findings from the RICA RegistryInt J Cardiol20180325512412827 Lund LH, Claggett B, Liu J, Lam CS, Jhund PS, Rosano GM, et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail. 2018;20(8):1230-9.LundLHClaggettBLiuJLamCSJhundPSRosanoGMHeart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrumEur J Heart Fail20182081230123928 Johansson I, Dahlström U, Edner M, Näsman P, Rydén L, Norhammar A. Type 2 diabetes and heart failure: Characteristics and prognosis in preserved, mid-range and reduced ventricular function. Diab Vasc Dis Res. 2018;15(6):494-503.JohanssonIDahlströmUEdnerMNäsmanPRydénLNorhammarAType 2 diabetes and heart failure: Characteristics and prognosis in preserved, mid-range and reduced ventricular functionDiab Vasc Dis Res201815649450329 Moliner P, Lupón J, Barallat J, de Antonio M, Domingo M, Núñez J, et al. Bio-profiling and bio-prognostication of chronic heart failure with mid-range ejection fraction. Int J Cardiol. 2018 Apr;257:188-92.MolinerPLupónJBarallatJde AntonioMDomingoMNúñezJBio-profiling and bio-prognostication of chronic heart failure with mid-range ejection fractionInt J Cardiol20180425718819230 Rastogi A, Novak E, Platts AE, Mann DL. Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction. Eur J Heart Fail. 2017;19(12):1597-605.RastogiANovakEPlattsAEMannDLEpidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fractionEur J Heart Fail201719121597160531 Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017;19(12):1574-85.ChioncelOLainscakMSeferovicPMAnkerSDCrespo-LeiroMGHarjolaVPEpidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term RegistryEur J Heart Fail201719121574158532 Altaie S, Khalife W. The prognosis of mid-range ejection fraction heart failure: a systematic review and meta-analysis. ESC Heart Fail. 2018;5(6):1008-16.AltaieSKhalifeWThe prognosis of mid-range ejection fraction heart failure: a systematic review and meta-analysisESC Heart Fail2018561008101633 Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J. 2016;37(5):455-62.SolomonSDClaggettBLewisEFDesaiAAnandISweitzerNKInfluence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fractionEur Heart J201637545546234 Xin Y-G, Chen X, Zhao Y-N, Hu J, Sun Y, Hu WY. Outcomes of spironolactone treatment in patients in Northeast China suffering from heart failure with mid-range ejection fraction. Curr Med Res Opin. 2019;35(4):561-8.XinY-GChenXZhaoY-NHuJSunYHuWYOutcomes of spironolactone treatment in patients in Northeast China suffering from heart failure with mid-range ejection fractionCurr Med Res Opin201935456156835 Hernandez AF, Hammill BG, O'Connor CM, Schulman KA, Curtis LH, Fonarow GC. Clinical effectiveness of beta-blockers in heart failure: findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) Registry. J Am Coll Cardiol 2009;53(2):184-92.HernandezAFHammillBGO'ConnorCMSchulmanKACurtisLHFonarowGCClinical effectiveness of beta-blockers in heart failure: findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) RegistryJ Am Coll Cardiol200953218419236 Konstam MA. Seeking therapeutic precision in heart failure: is ejection fraction really the way? Deconstructing the CHARM of heart failure with mid-range ejection fraction. Eur J Heart Fail. 2018;20(8):1240-2.KonstamMASeeking therapeutic precision in heart failure: is ejection fraction really the way? Deconstructing the CHARM of heart failure with mid-range ejection fractionEur J Heart Fail20182081240124237 Cleland JG, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJ, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J. 2018;39(1):26-35.ClelandJGBuntingKVFlatherMDAltmanDGHolmesJCoatsAJBeta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trialsEur Heart J2018391263538 Gwag HB, Lee GY, Choi JO, Lee HY, Kim JJ, Hwang KK, et al. Fate of Acute Heart Failure Patients With Mid-Range Ejection Fraction. Circ J. 2018;82(8):2071-8.GwagHBLeeGYChoiJOLeeHYKimJJHwangKKFate of Acute Heart Failure Patients With Mid-Range Ejection FractionCirc J20188282071207839 Abdul-Rahim AH, Shen L, Rush CJ, Jhund PS, Lees KR, McMurray JJ, et al. Effect of digoxin in patients with heart failure and mid-range (borderline) left ventricular ejection fraction. Eur J Heart Fail. 2018;20(7):1139-45.Abdul-RahimAHShenLRushCJJhundPSLeesKRMcMurrayJJEffect of digoxin in patients with heart failure and mid-range (borderline) left ventricular ejection fractionEur J Heart Fail20182071139114540 Dunlay SM, Roger VL, Weston SA, Jiang R, Redfield MM. Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. Circ Heart Fail. 2012;5(6):720-6.DunlaySMRogerVLWestonSAJiangRRedfieldMMLongitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fractionCirc Heart Fail20125672072641 Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59(11):998-1005.AtherSChanWBozkurtBAguilarDRamasubbuKZachariahAAImpact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fractionJ Am Coll Cardiol20125911998100542 Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 201;373(22):2117-28.ZinmanBWannerCLachinJMFitchettDBluhmkiEHantelSEmpagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 DiabetesN Engl J Med2013732221172128Artigo de RevisãoInsuficiência Cardíaca com Fração de Ejeção Intermediária - Estado da Arte0000-0002-7452-3870MesquitaEvandro Tinoco0000-0002-4945-7402BarbettaLetícia Mara dos Santos0000-0003-0454-6740CorreiaEduardo Thadeu de OliveiraHospital Universitário Antônio Pedro, Niterói, RJ - BrasilCorrespondência: Letícia Mara dos Santos Barbetta, Hospital Universitário Antônio Pedro - Av. Marquês do Paraná, 303. CEP 24033-900, Niterói, RJ - Brasil. E-mail: leticiabarbetta@gmail.com
Contribuição dos autores
Concepção e desenho da pesquisa, Análise e interpretação dos dados, Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Mesquita ET, Barbetta LMS, Correia ETO; Obtenção de dados: Barbetta LMS, Correia ETO.
Potencial conflito de interesses
Declaro não haver conflito de interesses pertinentes.
Resumo
Em 2016, a Sociedade Europeia de Cardiologia (ESC) reconheceu a insuficiência cardíaca (IC) com fração de ejeção do ventrículo esquerdo entre 40% e 49% como um novo fenótipo de IC, a IC com fração de ejeção intermediária (ICFEI), tendo como principal intuito, incentivar estudos sobre essa nova categoria.
Em 2018, a Sociedade Brasileira de Cardiologia aderiu a essa classificação e introduziu a ICFEI no Brasil. O presente trabalho traz uma revisão narrativa sobre o que a literatura descreve até o momento sobre ICFEI. A prevalência de pacientes com ICFEI variou de 13-24% dos pacientes com IC. Quando avaliadas as características clínicas, a ICFEI apresenta um caráter intermediário ou se assemelha algumas vezes com a IC de fração de ejeção preservada (ICFEP) e outras com a IC de fração reduzida (ICFER). Quanto ao prognóstico, a ICFEI apresenta mortalidade por todas as causas semelhante a ICFEP e menor que a ICFER. Os estudos que analisaram a mortalidade por causa cardíaca concluíram que não houve diferença significativa entre ICFEI e ICFER, sendo ambas menores que a ICFEP. Apesar do considerável aumento de publicações sobre a ICFEI, ainda existe uma grande carência de estudos prospectivos e ensaios clínicos que possibilitem delinear terapias específicas para esse novo fenótipo. O conhecimento das particularidades da ICFEI por cardiologistas e internistas é fundamental para o melhor manejo desses pacientes.
Palavras-chaveInsuficiência Cardíaca/fisiopatologiaFração de Ejeção VentricularPeptídeos NatriuréticosDiagnóstico por ImagemEletrocardiografiaEcocardiografiaImagem por Ressonância MagnéticaIntrodução
A classificação e caracterização dos fenótipos de insuficiência cardíaca (IC) são de grande relevância na prática clínica, visto que esses fenótipos atualmente são baseados na fração de ejeção do ventrículo esquerdo (FEVE) e possuem diferentes características entre si em relação ao prognóstico e tratamento.1
Classicamente têm sido descritos 2 principais modelos de IC, a IC de fração reduzida (ICFER) com FEVE < 40% e a IC de fração de ejeção preservada (ICFEP) com FEVE ≥ 50%.2-4 Na atual década diferentes diretrizes têm proposto um novo fenótipo, a IC com fração de ejeção intermediária (ICFEI).
Em 2013 a American College of Cardiology/American Heart Association publicou uma nova diretriz de IC, na qual pacientes com FEVE entre 41% e 50% foram classificados como ICFEP “Borderline”.2 Em 2016, a Sociedade Europeia de Cardiologia (ESC) reconheceu a IC com FEVE entre 40% e 49% como um fenótipo distinto, a ICFEI, principalmente com o intuito de estimular estudos que abordem a epidemiologia, etiologia, características, prognóstico e tratamento dessa nova categoria.3 Por fim, em 2018, a Sociedade Brasileira de Cardiologia (SBC) em sua nova diretriz sobre IC aguda e crônica, introduziu a ICFEI como um novo fenótipo clínico.5
Com a introdução desse novo modelo, a ICFEI tem recebido grande atenção, sendo melhor estudada e caracterizada. A presente revisão narrativa tem como objetivo descrever o que é conhecido sobre a ICFEI atualmente e discutir perspectivas futuras que contribuirão para uma melhor abordagem desse grupo de pacientes.
EpidemiologiaPrevalência
Nos Estados Unidos é estimado que mais de 6,5 milhões de pessoas possuam IC,6 sendo a porcentagem de indivíduos com ICFEI entre 13 e 24% desses pacientes.7,8 A prevalência de ICFEI em estudos realizados com pacientes hospitalizados variou de 13% a 26%,7,9-12 enquanto a prevalência de ICFEI em pacientes ambulatoriais variou entre 9% a 21%.8,13-17
No último censo do IBGE, no ano de 2010, observou-se crescimento da população idosa no Brasil e, com isso, um grande potencial de crescimento de pacientes em risco ou portadores de IC. No estudo DIGITALIS, realizado na cidade de Niterói, foi identificada uma prevalência de 9,3% de IC em pacientes do programa médico de família (59 indivíduos entre 633 voluntários),18 sendo que 64,2% desses pacientes foram caracterizados como portadores de ICFEP e 35,8% de ICFER.18 Recentemente, em dados ainda não publicados, baseados no banco de dados do estudo DIGITALIS, a prevalência de pacientes com ICFEI em Niterói foi de 22%, de ICFER 19% e ICFEP 59%.
Diagnóstico
De acordo com a última diretriz de IC aguda e crônica da SBC,5 o diagnóstico de IC está embasado na combinação de achados da história clínica, exame físico, eletrocardiograma e raio X de tórax, conforme está detalhado na Figura 1. Caso ocorra suspeita clínica de IC deve-se realizar um ecocardiograma para confirmação diagnóstica. Em casos de baixa suspeita ou de dúvidas sobre diagnóstico, deve ser realizada, desde que disponível, a dosagem de peptídeos natriuréticos (BNP e/ou NT-proBNP), além do ecocardiograma. Um ecocardiograma normal e/ou concentrações plasmáticas de BNP < 35 pg/mL e/ou NT-proBNP < 125 pg/mL tornam o diagnóstico de IC improvável. Na presença de concentrações plasmáticas de BNP > 35 pg/mL e/ou NT-proBNP > 125 pg/mL e/ou na presença de um ecocardiograma alterado, o diagnóstico de IC se torna provável. A avaliação da FEVE pela ecocardiografia contribui para discernimento do fenótipo clínico da IC, já que os sinais e sintomas clínicos de pacientes com ICFER, ICFEI e ICFEP são semelhantes.3
Algoritmo diagnóstico na suspeita clínica de insuficiência cardíaca. Adaptado de: Diretriz Brasileira de Insuficiência Cardíaca Crônica e Aguda de 2018;<sup>5</sup> ICFER: insuficiência cardíaca com fração de ejeção reduzida; ICFEI: insuficiência cardíaca com fração de ejeção intermediária; ICFEP: insuficiência cardíaca com fração de ejeção preservada; ECG: eletrocardiograma; BNP: peptídeo natriurético do tipo B; NT-proBNP: fração N-terminal do peptídeo natriurético do tipo B; FEVE: fração de ejeção do ventrículo esquerdo.
Um aspecto relevante em relação ao diagnóstico de ICFEI envolve aspectos metodológicos em relação às técnicas de cardioimagem. A avaliação da FEVE pela ecocardiografia, tem sido o método padrão utilizado para categorizar pacientes com IC. No entanto, é comum que os valores obtidos sejam diferentes em relação a outros métodos, como ressonância cardíaca, ventriculografia radioisotópica e angiocardiografia.19,20 Além disso, a avaliação da fração de ejeção pelo ecocardiograma apresenta variabilidade considerável intra e inter-observador, ao longo do tempo e também sob o efeito das intervenções terapêuticas.19,20
Características clínico-epidemiológicos
Estudos anteriores demonstraram que pacientes com ICFEI apresentaram características clínicas que, embora intermediárias entre os grupos ICFER e ICFEP, foram mais semelhantes a ICFEP.8,9,13,21 Contudo, em relação a presença de doença isquêmica, diferentes estudos encontraram que a ICFEI assemelha-se a ICFER, apresentando maior prevalência.7,22-24
No estudo de Kapoor et al.,7 com base no registro GWTG-HF (Get With The Guidelines - Heart Failure), pacientes com ICFEI foram mais velhos (idade média de 77 anos) e com maior porcentagem feminina (49%) quando comparados com pacientes com ICFER, sendo mais similar à ICFEP. Além disso, a ICFEI apresentou alta prevalência de comorbidades como diabetes mellitus (DM) (50%), fibrilação atrial (FA) (42%), doença pulmonar obstrutiva crônica (DPOC) (36%), anemia (27%) e insuficiência renal (26%), achados também mais semelhantes à ICFEP. Contudo, houve maior prevalência de doença isquêmica cardíaca em até dois terços dos pacientes, característica similar à ICFER.
Já na metanálise publicada por Lauritsen et al.,25 pacientes com ICFEI apresentaram características totalmente intermediárias, existindo diferenças significativas entre pacientes com ICFEI e ICFER, e entre pacientes com ICFEI e ICFEP. Pacientes com ICFEI eram mais velhos que aqueles com ICFER (p < 0,001), mas eram mais jovens que aqueles com ICFEP (p < 0,001). A proporção de homens e prevalência de doença isquêmica do coração em pacientes com ICFEI foram menores que aqueles com ICFER (p < 0,001 e p < 0,034 respectivamente), mas maior que aqueles com ICFEP (p < 0,001 e p < 0,001 respectivamente). A hipertensão foi mais frequente em pacientes com ICFEI que naqueles com ICFER (p < 0,001), mas menos frequente que nos pacientes com ICFEP (p < 0,001). O DM foi significativamente menos frequente na ICFEI e ICFER (p = 0,17) que na ICFEP (p = 0,021). A FA foi mais frequente entre os pacientes com ICFEI que entre aqueles com ICFER (p < 0,001), mas menos frequente que em pacientes com ICFEP (p < 0,001). A prevalência de DPOC foi menor em indivíduos com ICFEI em relação a ICFEP (p < 0,001), mas maior quando comparados a pacientes com ICFER (p = 0,001). Os pacientes com ICFEI tiveram função renal significativamente melhor que os pacientes com ICFEP (p < 0,001), mas pior em relação a pacientes com ICFER (p = 0,001).
A partir do registro RICA26 observou-se que pacientes com ICFEI apresentaram características mistas em relação aos outros grupos. Pacientes com ICFEI foram semelhantes aos pacientes com ICFER em termos de taxas de hipertensão e história de doença renal crônica (DRC). Entretanto, em outros aspectos foram similares a pacientes com ICFEP, como em relação a presença de maior pressão sistólica, maior pressão arterial, menor frequência das classes III-IV da New York Heart Association (NYHA), maior prevalência de FA e IC prévia.
No estudo de Bhambhani et al.,22 que analisou 28.820 participantes livres de IC por uma média de 12 anos, foi encontrado que 48% dos pacientes que desenvolveram ICFEI eram do sexo feminino. Além disso, participantes com ICFEI compartilharam algumas semelhanças com o grupo de ICFER, incluindo menor índice de massa corporal (IMC) em relação a ICFEP, com menor prevalência de obesidade, maior prevalência de doença arterial coronariana (DAC) e menores níveis de HDL. Demais características clínicas dos participantes com ICFEI foram intermediárias entre aqueles com ICFEP e ICFER.
O estudo CHARM27 observou que pacientes com ICFEI foram similares a ICFEP em relação à maioria das características, incluindo idade, pressão arterial sistólica, porcentagem de mulheres, infarto do miocárdio prévio e FA. A ICFEI foi intermediária entre ICFER e ICFEP em relação à história de hipertensão, distribuição da classe NYHA e IMC. Algumas características, como DM foram similarmente prevalentes em todas as três categorias.27,28
Já no estudo de Wang et al.,23 não houve diferenças significativas no sexo entre ICFEI, ICFEP e ICFER. O grupo com ICFEI foi intermediário aos demais grupos em características como idade, histórico de tabagismo, DM e DRC. Em contraste, o grupo ICFEI foi semelhante ao ICFER na história da doença cardíaca isquêmica, com ambos os grupos apresentando taxas significativamente mais altas que a ICFEP.
No registro Swedish Heart Failure,24 a ICFEI foi intermediária em relação à idade, sexo, hipertensão, FA, doença valvar e renal. Entretanto, a presença de doença isquêmica foi mais comum na ICFER e ICFEI quando comparadas com a ICFEP, e a prevalência de DM não diferiu entre os três grupos. O IMC foi menor e menos pacientes apresentaram anemia na ICFEI.
Um resumo das características clínico-epidemiológicas da ICFEI está retratado na Figura 2.
Comparações das características clínicas entre os diferentes fenótipos de insuficiência cardíaca (IC). ?: presença de conflito entre estudos; Sexo M: sexo masculino; DAC: doença arterial coronariana; DM: diabetes mellitus; HAS: hipertensão arterial sistêmica; FA: fibrilação atrial; INTERN: internação; INTERN‑IC: internação por IC; MORTE: morte por todas as causas; MORTE CV: morte por causa cardiovascular. * Os dados para a construção das características.<xref ref-type="bibr" rid="B7">7</xref><sup>,</sup><xref ref-type="bibr" rid="B22">22</xref><sup>-</sup><xref ref-type="bibr" rid="B27">27</xref><sup>,</sup><xref ref-type="bibr" rid="B32">32</xref> † Dados retirados das referências;<xref ref-type="bibr" rid="B27">27</xref><sup>,</sup><xref ref-type="bibr" rid="B32">32</xref> ‡ Dados retirados da referência.<xref ref-type="bibr" rid="B32">32</xref>
Biomarcadores
Em relação a biomarcadores, a ICFEI apresenta um perfil intermediário, sendo os biomarcadores de inflamação mais presentes na ICFEP e os biomarcadores de distensão cardíaca na ICFER.13 No estudo de Bhambhani et al.,22 foi encontrada uma sobreposição clínica e bioquímica de preditores de incidência de ICFEI com outros subtipos de IC. Entretanto, um maior IMC foi um preditor de ICFEP, mas não de ICFEI, e peptídeos natriuréticos foram preditores mais robustos de ICFER do que de ICFEI.
O registro Swedish Heart Failure24 concluiu que o valor mediano do NT-proBNP na ICFEI foi de 1.540 pg/ml com variação interquartil de 652 - 3.317. Esse valor foi minimamente e não significativamente maior que na ICFEP, mas foi significativamente menor que na ICFER (p < 0,001). O estudo de Moliner et al.,29 também concluiu que os níveis de NT-proBNP na ICFEI foram significativamente menores que na ICFER (p = 0,02), mas semelhantes aos níveis na ICFEP (p = 0,88). Todos os demais biomarcadores foram semelhantes entre ICFER e ICFEI. Cistatina-C e ST2 foram significativamente menores na ICFEI que na ICFEP (p = 0,01 e p = 0,02, respectivamente). Galectina-3 e receptor solúvel de transferrina foram relativamente menores na ICFEI que na ICFEP, mas a diferença não foi estatisticamente significativa.
Fisiopatologia
Na diretriz de 2016, a ESC sugeriu que a ICFEI pode ter tanto uma contribuição leve da disfunção sistólica, quanto uma contribuição da disfunção diastólica.3 Um estudo recente publicado por Rastogi et al.,30 observou que a ICFEI é composta por um grupo heterogêneo de pacientes, sendo constituído por pelo menos 3 subgrupos baseados na FEVE, sendo eles: pacientes com uma FEVE anterior < 40% (ICFEI recuperada), pacientes com FEVE anterior > 50% (ICFEI deteriorada) e pacientes com FEVE anterior entre 40-50% (ICFEI inalterada).30 A maioria dos pacientes deste estudo foram classificados como ICFEI recuperada (73%), enquanto 17% dos pacientes foram classificados como ICFEI deteriorada e apenas 10% foram categorizados como ICFEI inalterada.30
Ainda nesse estudo, o subgrupo com ICFEI recuperada teve maior prevalência de pacientes do sexo masculino e maior prevalência de pacientes com DAC, compatível com as características de pacientes com ICFER. Em contraste, o subgrupo com ICFEI deteriorada era composto mais por mulheres com história de hipertensão e fibrilação ou flutter atrial, assim como pacientes com ICFEP. Outra observação importante foi que no subgrupo com ICFEI deteriorada, os pacientes apresentavam uma disfunção diastólica significativamente mais avançada pelo ecocardiograma quando comparado com pacientes com ICFEI recuperada.30 Um achado comum em diferentes coortes13,14,31 foi que a ICFEI se assemelhou a ICFER em relação a alta prevalência de DAC e a um maior risco de novos eventos de DAC. No registro Swedish Heart Failure não foi observada diferença entre as prevalências de DAC entre ICFEI (61%) e ICFER (60%), enquanto a ICFEP foi associada a uma menor prevalência (52%).14 Chioncel et al.,31 com base no registro de longa duração para IC da ESC, constataram que a etiologia isquêmica foi presente em 48,6% dos pacientes com ICFER, 41,8% dos pacientes com ICFEI, mas apenas em 23,7% dos pacientes com ICFEP. Na análise post-hoc do estudo TIME-CHF,24 a etiologia isquêmica foi de 58,2%, 56,5% e 31,3% para ICFER, ICFEI e ICFEP, respectivamente. Portanto, em termos de etiologia, os pacientes com ICFEI são mais semelhantes aos de ICFER que aos de ICFEP.
Prognóstico
Tanto o estudo CHARM, quanto a metanálise de prognóstico realizada por Altaie et al.,32 concluíram que a mortalidade por todas as causas em pacientes com ICFEI é significativamente menor que nos pacientes com ICFER (p < 0,001 e RR 0,9; 95% IC 0,85-0,94; p < 0,001, respectivamente) e estatisticamente semelhante aos pacientes com ICFEP (HR 0,98; IC 95% 0,82-1,19; p = 0,88 e RR 0,98; 95% IC 0,86-1,12; p = 0,82, respectivamente).27,32
Quanto a mortalidade por causa cardíaca, a metanálise de Altaie et al.,32 concluiu que não houve diferença significativa entre a ICFER e ICFEI (RR 0,89; 95% IC; 0,69-1,15; p = 0,38), enquanto a ICFEP apresentou mortalidade por causa cardíaca significativamente maior (RR 1,09; 95% IC 1,02-1,16; p = 0,001).
Na análise do prognóstico separando os subgrupos de ICFEI, no estudo de Rastogi et al.,30 a coorte de pacientes com ICFEI recuperada mostrou desfechos clínicos significativamente melhores em relação a pacientes com ICFER, ajustando para idade e gênero. Em contraste, os desfechos clínicos do subgrupo com ICFEI deteriorada não foram significativamente diferentes em relação a pacientes com ICFEP, quando ajustados para os mesmos fatores.30 Ao observar o tempo até a morte/transplante/hospitalização cardíaca entre os subgrupos, a ICFEI recuperada teve significativamente um melhor prognóstico em comparação com a ICFEI deteriorada (p = 0,011), enquanto não houve uma diferença significativa entre os dois grupos e a ICFEI inalterada.30
Hospitalização
Quanto a hospitalização os estudos diferiram. A metanálise de Altaie et al.,32 demonstrou que não houve diferença significativa na hospitalização por todas as causas tanto entre ICFER e ICFEI, quanto entre ICFEP e ICFEI (RR 0,91; IC 95% 0,18-4,59; p = 0,9; e RR 0,95; IC 95% 0,84-1,07; p = 0,38, respectivamente). Quanto à hospitalização por IC, a metanálise também não demonstrou diferenças significativas entre ICFER e ICFEI ou entre ICFEP e ICFEI (RR 0,92; IC 95% 0,84-1,01; p = 0,08; e RR 1,05; 95% IC 0,83-1,33; p = 0,69, respectivamente). Entretanto, no estudo CHARM a hospitalização por todas as causas foi significativamente menor em pacientes com ICFEI quando comparado ao fenótipo de ICFEP (HR 0,89; IC 95% 0,81-0,98; p = 0,02).27 Ao comparar os diferentes subgrupos de ICFEI da coorte de Rastogi et al.,30 a ICFEI recuperada apresentou um melhor prognóstico em comparação com a ICFEI deteriorada (p = 0,029) ao observar o tempo até a primeira hospitalização por evento cardíaco. Entretanto, não houve diferença significativa em relação ao subgrupo de ICFEI inalterada em relação aos outros dois.
Tratamento farmacológico e manejo de comorbidades
No estudo TOPCAT a espironolactona não apresentou efeito no desfecho primário (composto por morte cardiovascular, parada cardíaca ou hospitalização por IC), contudo, houve redução nas hospitalizações por IC no grupo de tratamento com maior benefício observado em pacientes com FEVE de 45% a 50%.33
Já o estudo de Yan-guo Xin et al.,34 que avaliou o uso da espironolactona em 229 pacientes com diagnóstico ICFEI, mostrou que o uso do medicamento reduziu a incidência dos desfechos primários de morte por todas as causas (21,3% vs. 34,5%, p = 0,014), além de apresentar melhoria na qualidade de vida. No entanto, não houve diferença entre os grupos que receberam diferentes doses de medicamento (21,8% vs. 20,7%, p = 0,861, 50 mg vs. 25mg, respectivamente).
O estudo OPTIMIZE-HF ao avaliar o uso de inibidor da enzima conversora de angiotensina (IECA) e bloqueador do receptor da angiotensina (BRA) mostrou que em pacientes com ICFEI não houve nenhum benefício associado.21 Pacientes com FEVE < 40% foram comparados com aqueles com FEVE ≥ 40% para desfechos em longo prazo em relação ao uso de betabloqueadores.21 Em pacientes com FEVE de 40 - 50%, assim como em todos com FEVE ≥ 40%, não foi encontrada influência significativa do uso dos medicamentos nos desfechos.35
Contudo, o estudo CHARM, mostrou que o uso de candesartana melhorou os desfechos para a ICFEI com um grau comparável a melhora para ICFER. Para o grupo de ICFEI as taxas de incidência para o desfecho primário (morte cardiovascular ou hospitalização por IC) do candesartana vs. placebo foram de 7,4 vs. 9,7 por 100 pacientes-ano (HR 0,76, IC 95% 0,61-0,96; p = 0,02), e a taxa de incidência de hospitalização recorrente por IC foi de 0,48 (IC 95% 0,33-0,70; p < 0,001).27,36
O estudo de Cleland et al.,37 que incluiu 18.637 pacientes, observou que para pacientes com IC com ritmo sinusal e FEVE entre 40% e 49% os betabloqueadores apresentaram redução da morte cardiovascular quando comparados a placebo (HR 0,048; IC 95% 0,24-0,97; p = 0,04) e melhora da função sistólica do VE.37
No estudo de Gwag et al.,38 foi visto que a terapia de manutenção com β-bloqueador estava associada à melhora da FEVE em pacientes com ICFEI (HR 2.021; IC 95% 1.033-3.959; p = 0,04). Além disso, a terapia de manutenção com bloqueadores do sistema renina-angiotensina ou antagonistas da aldosterona foram significativamente associados a uma melhor sobrevida (HR 0,309; IC 95% 0,162 - 0,588; p < 0,001; e HR 0,240; IC 95% 0,085 - 0,673; p = 0,01, respectivamente).
O uso de digoxina foi avaliado no estudo de Abdul-Rahim AH et al.,39 que incluiu 7.788 pacientes, sendo 1.195 pacientes com ICFEI. A digoxina reduziu a morte cardiovascular ou hospitalização por IC (HR: 0,83; IC 95% 0,66-1,05).39
O estudo de Chang et al.9 mostrou que as comorbidades observadas em pacientes com ICFEI se assemelham mais com as comorbidades presentes em pacientes com ICFEP, sendo a DAC associada a maiores declínios na FEVE em pacientes com ICFEP.40 Dessa forma, o manejo da DAC pode ajudar a prevenir a progressão da disfunção sistólica do VE em indivíduos com ICFEI.21
Comorbidades não-cardíacas, como por exemplo, hipertensão, DM e DPOC, são altamente prevalentes na população com IC e contribuem para a morbidade geral desses pacientes.41 Em pacientes com ICFEI, a hipertensão não controlada foi o principal fator precipitante da hospitalização por IC em comparação com os outros grupos com IC.7 Em pacientes com ICFEP e hipertensos, a terapia com BRA ou antagonistas de aldosterona apresentou redução nas hospitalizações, o que nos faz pensar que tais medicamentos podem ser utilizados para controlar a hipertensão e reduzir o risco de declínio da FEVE em pacientes com ICFEI.7 Já em relação ao tratamento da DM em pacientes com IC, o uso de inibidores do co-transportador de sódio 2 em pacientes de alto risco cardiovascular apresentou melhoras no desfecho primário, composto por morte por causas cardiovasculares, infarto e acidente vascular encefálico não fatal (HR 0,86; IC 95% 0,74 - 0,99; p < 0,001 para não inferioridade e p = 0,04 para superioridade). Além disso, o empagliflozin apresentou redução da morte cardiovascular e morte por todas as causas (HR 0,62; 95% IC 0,49 - 0,77; p < 0,001; e HR 0,68; IC 95% 0,57 - 0,82; p < 0,001, respectivamente), além da redução da hospitalização por IC (HR 0,65; IC 95% 0,50 - 0,85; p = 0,002).42
A atual diretriz de IC da SBC5 propõe que inicialmente, deve-se abordar o tratamento específico da etiologia e comorbidades, quando possível. Pacientes com histórico de ICFER em que houve melhora da FEVE, os reclassificando como portadores de ICFEI, devem ser tratados com manutenção da optimização terapêutica para ICFER. Pacientes com ICFEP prévia em que houve piora da FEVE e também para aqueles com ICFEI persistente, é recomendado o uso de betabloqueador e IECA ou BRA (se IECA não for tolerado). O esquema de tratamento proposto pela SBC está representado na Figura 3.
Algoritmo para tratamento da ICFEI de acordo com a Diretriz Brasileira de Insuficiência Cardíaca Crônica e Aguda de 2018;<sup>5</sup> * Na ausência de miocardiopatias de depósito, doença hipertrófica, inflamatória ou infecciosa; † Particularmente por doença coronariana e ou infarto agudo do miocárdio. ICFEI: insuficiência cardíaca com fração de ejeção intermediária; ICFER: insuficiência cardíaca com fração de ejeção reduzida; FEVE: fração de ejeção do ventrículo esquerdo; IECA: inibidor da enzima conversora de angiotensina; BRA: bloqueador do receptor da angiotensina.
Perspectivas futuras
O emprego da medicina de precisão na área cardiovascular tem avançado, sendo a identificação dos fenótipos de IC importante para o desenvolvimento de novas alternativas terapêuticas que ofereçam um melhor prognóstico para o portador de IC. Apesar de alguns estudos terem demonstrado a eficácia de certas terapias nos pacientes com ICFEI, a maioria das publicações são estudos retrospectivos que promovem uma nova análise de grandes bancos de estudos. Dessa forma, a realização de estudos prospectivos e ensaios clínicos randomizados que incluam os pacientes com ICFEI é imprescindível para construirmos terapias com sólidas recomendações baseadas em evidências.
Conclusão
Após o estabelecimento da ICFEI como uma nova categoria de IC pelas diretrizes nacional e internacionais, houve um considerável aumento de publicações sobre essa categoria de pacientes, o que possibilitou uma melhor compreensão sobre o seu perfil clínico, fisiopatologia e desfecho clínico. No entanto, ainda existe uma grande escassez de estudos prospectivos e ensaios clínicos randomizados duplo-cego que possibilitem delinear terapias específicas para essa nova categoria de IC. O conhecimento das particularidades da ICFEI por cardiologistas e internistas é fundamental para o melhor diagnóstico e manejo desses pacientes, além da identificação de áreas de incerteza para desenvolvimento de pesquisas básicas e clínicas.
Fontes de financiamento
O presente estudo não teve fontes de financiamento externas.
Vinculação acadêmica
Não há vinculação deste estudo a programas de pós-graduação.
Aprovação ética e consentimento informado
Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.