Keywords

ABC HF

ABC: Heart Failure & Cardiomyopathy

ABC Heart Fail Cardiomyop

2764-3107

Sociedade Brasileira de Cardiologia - SBC

abchf.20220058

10.36660/abchf.20220058

Review Article

The Role of Biomarkers in Heart Failure with Preserved Ejection Fraction

0000-0003-1654-4531

Villacorta

Humberto

¹ Conception and design of the research Acquisition of data Writing of the manuscript Analysis and interpretation of the data

0000-0001-7467-0195

Maisel

Alan S.

² Analysis and interpretation of the data Critical revision of the manuscript for important intellectual content 1 Universidade Federal Fluminense Pós-Graduação em Ciência Cardiovascular

Niterói

Brazil Programa de Pós-Graduação em Ciência Cardiovascular, Universidade Federal Fluminense, Niterói, RJ – Brazil 2 Universidade da Califórnia em San Diego Divisão de Medicina Cardiovascular

San Diego

California

USA Divisão de Medicina Cardiovascular, Universidade da Califórnia em San Diego, La Jolla, San Diego – California

Mailing Address: Humberto Villacorta • Universidade Federal Fluminense - Rua Marquês do Paraná, 303. Postal Code 24033-900, Niterói, RJ - Brazil. E-mail: villacortahumberto@gmail.com

Potential Conflict of Interest

Dr. Humberto Villacorta - Speaker honoraria from Roche Diagnostics Dr. Alan S Maisel - Consulting from Abbott

01 12 2022

Jul-Sep 2022

2 3 281 289 15 08 2022 03 09 2022 24 09 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution License

Keywords Heart failure Preserved Ejection Fraction Biomarkers

Introduction

A large proportion of patients with heart failure (HF) have preserved left ventricle (LV) ejection fraction (HFpEF)¹ or slightly reduced systolic function. Although specific cutoff recommendations are constantly evolving, the European Society of Cardiology (ESC) has recently proposed the term HF with mildly reduced ejection fraction (HFmrEF) for values between 40–49% and HFpEF for ejection fraction ≥ 50%.² In the past, different cutoffs were used in studies of HFpEF, ranging from 40% to 55%. Additionally, there is significant overlap between HFpEF and HFmrEF. For these reasons, in this chapter we consider them as a whole.

HFpEF is associated with many comorbidities and has a high rate of morbidity and mortality, both in ambulatory and in-hospital cohorts.^3–5 HFpEF is a heterogeneous syndrome with diverse etiologies and phenotypes and different pathophysiological pathways, which are not fully understood.^6,7 Circulating biomarkers may represent important tools to aid in the diagnosis and prognosis of this condition.^8,9

In this review, we discuss the role of biomarkers that reflect different pathological pathways in HFpEF, with most attention given to myocardial stretch and injury biomarkers such as natriuretic peptides (NP) and troponin. We also provide an overview of biomarkers of inflammation, oxidative stress, fibrosis, and vascular dysfunction.

Natriuretic peptides

NP are endogenous hormones with a variety of hemodynamic, renal, and neurohormonal effects. They are considered the gold standard biomarkers in HF and are secreted almost exclusively by the heart. Although the role of NP has been more extensively demonstrated in patients with reduced ejection fraction (HFrEF), their clinical value has been shown across the whole spectrum of ejection fraction.^10–12 However, the mean concentrations are lower in patients with HFpEF than in those with HFrEF.^13,14 Nevertheless, a specific cutoff does not exist to differentiate HFpEF from HFrEF due to significant overlapping.¹⁴

NP are mainly released in response to myocardial wall stress, leading to an elevation of LV filling pressures (Figure 1). The NP of most clinical importance are B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP). Other NP such as atrial natriuretic peptide (ANP), N-terminal proANP, and C-type NP (CNP), although of importance in terms of pathophysiology, have not been used in clinical practice due to the complex logistics required for their measurement.

Figure 1 Standard cardiac biomarkers in HFpEF: NT-proBNP and hs-cTn. NT-proBNP: N-terminal pro-B-type natriuretic peptide. Diagnosis of HFpEF

The role of NP in the diagnosis of HF, including HFpEF, has been examined in several reports, both in acute and chronic settings.^1,13,15–21 Villacorta et al.¹³ and Maisel et al.¹⁵ (in initial studies in the acute setting with BNP)^13,15 and Januzzi et al. (with NT-proBNP)¹⁶ demonstrated good accuracy for the diagnosis of HF in the entire spectrum of ejection fraction. More recently, Januzzi et al. have confirmed the findings for NT-proBNP in the ICON-RELOADED study.¹⁷ In this study, 41.3% of patients with a diagnosis of acute HF had an LV ejection fraction ≥ 50%. The negative predictive value for NT-proBNP was excellent, close to 98%. In the non-acute setting, Tschöpe et al., in a study with 68 patients with diastolic dysfunction, found that NT-proBNP levels were significantly elevated as compared to those of healthy controls and correlated well with invasive measurements of LV filling pressures.¹⁹ Jorge et al., in a population-based study, found that BNP < 42 pg/mL had a sensitivity of 92% and a negative predictive value of 99% for the diagnosis of HF, regardless of the ejection fraction. In this study, 59% of the population with HF had HFpEF. A recent meta-analysis of 51 studies found that NP have reasonable diagnostic performance in the detection of HFpEF in the non-acute setting, with an area under the curve (AUC) of 80%.²¹ The best utility of these markers was for ruling out diastolic dysfunction or HFpEF, with a negative predictive value of 85%. The specificity and positive predictive value, however, were poor (65% and 60%, respectively).

In all studies mentioned above, patients with HFpEF had lower values of NP than patients with HFrEF. A possible explanation for this could be a stronger association of NP with end-diastolic wall stress, which is lower in HFpEF than in HFrEF.²²

Although NP have been proved to be a good tool for the diagnosis of HFpEF, there are some caveats. NP are influenced by many cardiac and non-cardiac disorders that seem to be even more important in HFpEF. Increased levels of NP are expected in atrial fibrillation, older adults, and those with renal dysfunction. A fivefold increase in NT-proBNP has been reported in patients with HFpEF and atrial fibrillation compared to those in sinus rhythm.²³ In contrast, lower values are observed in obese patients.¹²

All of these characteristics are common in patients with HFpEF, which could explain the unexpected results observed in some studies. For example, Arjan et al. found that 29% of symptomatic outpatients with HFpEF and elevated pulmonary wedge pressures had “normal” BNP values (< 100 pg/mL), suggesting that a normal BNP level may not exclude the diagnosis of HFpEF.²⁴ More recently, Verbrugge et al. observed similar results.²⁵ Using invasive hemodynamics, they retrospectively compared patients with HFpEF and high NT-proBNP values (≥ 125 pg/mL), HFpEF and normal NT-proBNP values (< 125 pg/mL), and a third group of controls with normal hemodynamics. Patients with HFpEF and normal NP (37% of the population with HF) were younger than those in the high NP group, had a higher rate of obesity, and had less structural heart diseases as assessed by echocardiography. The highest event rate was observed in the group with high NP values, but patients with normal NT-proBNP still had a 2.7-fold higher risk for mortality or HF readmission compared with controls. The limitations of the study were its retrospective nature and the fact that it was performed with patients referred to a tertiary center for invasive hemodynamic tests, possibly causing a referral bias.

Due to the reduced performance of biomarkers in some subgroups of patients (the ones mentioned above), some authors have used machine learning techniques, combining clinical variables with biomarkers as a continuous variable in an effort to improve diagnostic accuracy. This strategy has been successfully used for the diagnosis of acute myocardial infarction using high-sensitivity troponins²⁶ and for the diagnosis of pulmonary embolism using D-dimer.²⁷ Recently, Lee et al. developed a model named CoDE-HF, which used machine learning techniques to overcome the barriers observed in some subgroups due to the influence of clinical variables on the diagnostic performance of NT-proBNP.²⁸ They combined the biomarker with ten clinical variables. This tool ruled in and ruled out acute heart failure more accurately than did any approach using NT-proBNP thresholds alone and performed consistently across all subgroups.

HFpEF is a complex disease whose pathophysiology is poorly understood, and its diagnosis is difficult to establish. To simplify the diagnostic approach for the clinician, clinical scores were created. The two most used are the H2FPEF score,²⁹ developed by the Mayo Clinic, and the HFA-PEFF score, created by the ESC.³⁰ An important difference between these two scores is that the H2FPEF score does not include biomarkers. In contrast, the HFA-PEFF score incorporates NP. Both scores are recommended by the main HF guidelines, with no preference of one over the other.^2,31,32 In the external validation of H2FPEF,³³ the score had a poor performance in patients presenting with dyspnea. On the contrary, HFA-PEFF demonstrated good accuracy in the validation cohort.³⁴ Of note, the biomarker domain performed almost as well as the whole score (AUC 89% vs 90%, respectively). However, 3 out of 11 patients classified in the low-probability category still had HFpEF, underscoring the relatively low sensitivity of the score. A prospective head-to-head comparison between the two scores is lacking. In this regard, only one case-control study has been carried out.³⁵ In this investigation, both scores discriminated patients with HFpEF from controls, but the H2FPEF score had a greater AUC (84% vs 71%). Specificity was robust for both scores, but sensitivity was poorer for HFA-PEFF (false-negative rate of 55% for low-probability scores compared with 25% for H2FPEF). However, these results should be interpreted with caution due to the retrospective nature of the study.

Prognosis of HFpEF

The usefulness of NP goes beyond their diagnostic role. The higher the values, the higher the event rates. In the acute setting, NT-proBNP is considered a strong independent predictor of all-cause mortality, as described in the study by Lopuszynski et al. performed in a cohort hospitalized with HFpEF.³⁶ Admission and discharge levels and relative changes during hospitalization confer the same relative risk information for HFpEF as in HFrEF.³⁷

In chronic HF, several studies have shown that NP provide strong and independent prognostic information.^38–41 In the I-PRESERVE Study, NT-proBNP emerged as one of the strongest predictors of all-cause mortality or cardiovascular hospitalization.³⁹ There was a continuous linear increase in the incidence of the primary endpoint from the lowest to the highest quartiles of NT-proBNP.⁴⁰ A recent unsupervised cluster analysis based on a wide range of biomarkers found that higher levels of NT-proBNP identify a subgroup of HFpEF patients (who also have higher levels of cardiac troponins) who are at the highest risk of death or HF hospitalization.⁴¹

Guiding Therapy in HFpEF

Although there is a suggestion that NP may be helpful in guiding therapy in patients with HFrEF, few studies have examined this issue in patients with HFpEF. Maeder et al.⁴² studied 123 patients with HFpEF (ejection fraction > 45%) who were randomized to standard medical therapy, titrated to reduce symptoms to NYHA class ≤ II or also to reduce NT-proBNP below the inclusion threshold (400 or 800 pg/mL, depending on age). Differently from patients with HFrEF, patients with HFpEF did not benefit from this strategy. In fact, NP-guided therapy tended to worsen 18-month outcomes in patients with HFpEF. This finding was later confirmed in a meta-analysis performed by Brunner-La Roca et al.⁴³ In contrast, patients with the so-called “mid-range” ejection fraction, now referred to as mildly reduced ejection fraction, seemed to have the same benefits with NP-guided therapy as patients with HFrEF. Rickenbach et al.,⁴⁴ using data from the TIME-CHF trial, demonstrated a benefit of NT-proBNP-guided therapy regarding survival free of HF hospitalization in HFrEF and HFmrEF, but not in HFpEF.

High-sensitivity cardiac troponins

Traditionally used in the diagnosis of acute myocardial infarction, cardiac troponins are now being increasingly detected in HF due to improvements in assay sensitivity. This is referred to as myocardial injury (acute or chronic).¹¹ Values of cardiac troponins in HF may be elevated in the whole spectrum of ejection fraction but are higher in HFrEF compared to HFpEF.⁴⁵ Elevated high-sensitivity cardiac troponin (hs-cTn) discriminates a subgroup of patients with HFpEF who have ongoing myocardial damage, higher wall stress, or impaired microcirculation, as evidenced in a mechanistic study performed by Obokata et al.⁴⁶. They compared 38 patients with HFpEF with 20 control patients. Those with HFpEF had higher troponin levels at rest, which correlated with higher pulmonary capillary wedge pressure and worse systolic and diastolic tissue Doppler velocities. Additionally, troponins correlated with a greater degree of oxygen supply-demand mismatch.

Baseline hs-cTn has been shown to predict HFpEF in older adults, especially in those without LV hypertrophy at baseline.⁴⁷ There was a 2.4-fold increase in the incidence of HFpEF in patients in the third tertile of troponin compared with patients in the first tertile. In the acute setting, several studies have shown a prognostic role of hs-cTn measured at admission or discharge in patients hospitalized with decompensated HFpEF.^48–50

Both hs-cTn T and I are elevated in chronic HFpEF and are independently associated with poorer outcomes.^11,12,51 In the study by Gohar et al.⁵¹, the hs-cTn T assay provided the greatest additional prognostic value in HFpEF in comparison with hs-cTn I and NT-proBNP. However, hs-cTn I was more strongly associated with composite events in men with HFpEF.

Serial measurements of hs-cTn in patients with HFpEF have also been studied. In a substudy of the PARAGON-HF trial, investigators demonstrated that hs-cTn T was reduced by sacubitril/valsartan therapy compared to valsartan and that patients with a decrease in hs-cTn T (from randomization to 16 weeks to a value at or below the median value of 17 ng/L) subsequently had a lower risk of the composite outcome than those who had persistently elevated hs-cTn T values.⁵² Thus, both baseline and serial measurements of hs-cTn seem to be useful to predict events in patients with HFpEF. Figure 1 illustrates the stimulus for hs-cTn release and its role in clinical practice in HFpEF.

Other biomarkers

NP and hs-cTn are standard and established cardiac biomarkers. Their accuracy in the diagnosis and prognosis of cardiovascular conditions in great part results from the fact that they are secreted almost exclusively by the heart. However, heart diseases have systemic repercussions and are influenced by systemic conditions as well. In this regard, there is a potential role for systemic biomarkers in HFpEF, which are driven by different pathways (Figure 2). These markers are not useful for diagnosis, since they are not specific for the heart, but are important prognostic markers.

Figure 2 Systemic biomarkers involved in HFpEF, addressing the relationship of systemic processes and the heart. CRP: C-reactive protein; FABP4: fatty acid-binding protein 4; GDF-15: growth differentiation factor 15; IL: interleukin; ST2: suppression of tumorigenicity 2; TNF: tumor necrosis factor. GDF-15

Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-^β cytokine superfamily associated with inflammation and oxidative stress.⁵³ It has emerged as a useful marker in many cardiovascular conditions, such as coronary artery disease, atrial fibrillation, and HF, and also in non-cardiac disorders such as obesity and COVID-19.⁵³ GDF-15 is elevated in patients with HFpEF and provides additional prognostic information over clinical variables and traditional biomarkers.^54,55 Izumiya et al.⁵⁴ demonstrated a positive association of GDF-15 with NYHA class and BNP, and GDF-15 strongly predicted cardiovascular events. Interesting findings were also observed by Santhanakrishnan et al.⁵⁵. They compared different biomarkers in HFrEF vs HFpEF and their relation to each other. GDF-15 strongly differentiated HFpEF cases from healthy controls and the NT-proBNP/GDF-15 ratio distinguished between HFrEF and HFpEF. This finding is consistent with the important role of inflammation in HFpEF.

Many patients with HFpEF have atrial fibrillation and an important role of GDF-15 in this scenario has been demonstrated.^56–58 GDF-15 is the strongest predictor of bleeding in patients with atrial fibrillation taking anticoagulants.⁵⁶ The ABC (age, biomarker, clinical history) score is a biomarker-based risk score developed for the prediction of stroke and bleeding in patients with atrial fibrillation. The ABC bleeding score⁵⁶ incorporates GDF-15 and hs-cTn, and the ABC stroke score⁵⁷ incorporates NP and hs-cTn. Both ABC scores outperformed the traditional risk scores in atrial fibrillation (ABC bleeding and HAS-BLED, AUC 0.69 vs 0.62, respectively; ABC stroke and CHADSVASC, AUC 0.67 vs 0.59, respectively).⁵⁸

Thus, GDF-15 is a promising biomarker in HFpEF. In addition to the prognostic role, it may contribute to elucidating the pathophysiology of HFpEF and identifying specific target therapies.

ST2

ST2 is a member of the interleukin 1 receptor family, also known as interleukin 1 receptor-like 1 (IL1RL-1).⁵⁹ ST2 stands for “suppression of tumorigenicity 2”. ST2 is the receptor for interleukin-33 (IL-33), which exerts its effects by binding to the transmembrane receptor ST2L isoform, anchored in the myocyte membrane. The interaction of IL-33 and ST2L has been proven to be cardioprotective in experimental models, reducing myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis and improving myocardial function. However, the soluble ST2 receptor (sST2) works as a decoy receptor, which inhibits ST2L binding to IL-33. For this reason, sST2 has been proposed as a marker of cardiac hypertrophy, fibrosis, and remodeling.⁵⁹

In HFpEF, ST2 release may be related to myocardial stress and an elevated LV filling pressure, as demonstrated by the direct correlation of ST2 levels with the diastolic load measured on the basis of the LV end diastolic pressure.^60,61 The TIME-CHF study measured circulating levels of different biomarkers and sST2 levels were higher in patients with HFpEF compared to those with HfrEF.⁴⁵ In patients presenting with acute dyspnea and normal LV systolic function, ST2 was the only biomarker predicting mortality.⁶² These results were also observed in the study by Manzano-Fernandes et al. in acutely decompensated HF, where the prognostic value of ST2 in HFpEF was comparable to that in HFrEF.⁶³ These findings suggest that ST2 may be a useful prognostic marker in HFpEF, especially in the acute setting.

Galectin-3

Galectin-3 (Gal-3) has also been mechanistically involved in cardiovascular inflammation and fibrosis.¹¹ In the PARAMOUNT trial, Gal-3 correlated with disease severity as evidenced by the positive correlation with NT-proBNP and the E/E’ ratio in patients with HFpEF.⁶⁴ In a study with 592 patients, Gal-3 was a stronger predictor of mortality in patients with HFpEF compared to those with HFrEF.⁶⁵ In addition, serial measurements of GAL-3 seem to be valuable. In the ALDO-DHF trial, increases in Gal-3 over time were associated with all-cause mortality.⁶⁶ Finally, Gal-3 can predict the development of HFpEF in patients with comorbidities (de Boer 2013).⁶⁷

Inflammatory markers

Elevated levels of inflammatory cytokines such as TNF-^α, IL1, IL6, IL8, and CRP are often observed in patients with HFpEF.¹⁰ Circulating levels of TNF-^α receptors (TNFR1 and TNFR2) are associated with the severity of diastolic dysfunction and symptoms.¹⁰ Nevertheless, scarce evidence on their prognostic role is currently available.

Fatty acid-binding protein 4

Fatty acid-binding proteins (FABPs) are intracellular lipid chaperones.¹² FABP4—also known as adipocyte FABP or aP2—plays an important role in the development of obesity, insulin resistance, diabetes, and atherosclerosis and has been associated with cardiac remodeling and left and right ventricular dysfunction.^68,69 In a substudy of the TOPCAT trial, FAPB4 was associated with the risk of death or HF admission in HFpEF, independently of the MAGGIC risk score.⁷⁰ Recently, Harada et al. reported that event-free survival was significantly decreased in patients with HFpEF and FABP4 ≥ 43.5 ng/mL.⁶⁹

Cystatin C

Cystatin C is secreted by nucleated cells at a constant rate, filtered and reabsorbed by the glomeruli, and then completely decomposed by intact renal tubules; it provides a more accurate method for estimated glomerular filtration rate (eGFR) measurement.¹² Excess cystatin C may promote myocardial fibrosis and ventricular hypertrophy and increase atrial volume.¹² It is a strong risk factor for new-onset HFpEF⁷¹ and is associated with worse NYHA classification, even after adjustments for eGFR.⁷² Furthermore, it is an independent predictor of unfavorable outcome in patients admitted with HFpEF.⁷³ In chronic HFpEF, data are less compelling. In one study, there was a trend for predicting death or HF admission, but without significance in multivariate analysis.¹² Table 1 provides a summary on the role of important biomarkers in HFpEF.

Table 1 Summary of the pathophysiology and potential role of different biomarkers in HFpEF

Biomarker	Mechanism of action	Role in HFpEF
Natriuretic peptides	Myocardial stretch; marker of hemodynamic load	Diagnosis and prognosis
hs-cTn	Released by cardiac ischemia or myocardial stress or injury	Predictor of mortality and incidence of HFpEF; adds prognostic value to NP
GDF-15	Inflammation, oxidative stress; secreted by cytokines	HF phenotyping; predictor of mortality; NT-proBNP/GDF-15 ratio differentiates HFpEF from HFrEF
ST2	High levels block the favorable effects of IL-33 by limiting activation of the cascade triggered by the IL-33/ST2L interaction	High levels associated with cardiac fibrosis and remodeling and worse outcomes
Galectin-3	Marker of inflammation, deposits type-1 collagen leading to fibrosis, inflammation, and cardiac remodeling	HFpEF phenotyping and risk stratification; predicts the development of HFpEF in patients with comorbidities
Inflammatory markers (TNF-α, IL1, IL6, IL8, and CRP)	Inflammation	Levels of TNF-α receptors are associated with the severity of diastolic dysfunction and symptoms;
FABP4	Development of obesity, insulin resistance, diabetes, and atherosclerosis	Predictor of death or heart failure admission
Cystatin C	Renal function marker; excess cystatin promotes myocardial fibrosis and hypertrophy	Strong risk factor for new-onset HFpEF; predicts outcomes, especially in acute HFpEF

CRP: C-reactive protein; FABP4: fatty-acid-binding protein 4; GDF-15: growth differentiation factor 15; HFpEF: heart failure with preserved ejection fraction; hs-cTn high-sensitivity cardiac troponin; IL: interleukin; NP: natriuretic peptides; NT-proBNP: N-terminal pro-B-type natriuretic peptide; ST2: suppression of tumorigenicity 2; TNF: tumor necrosis factor.

Future Biomarkers Circulating microRNAs (miRNAs)

They offer attractive potential as epigenetic disease biomarkers due to their biological stability and ready accessibility in liquid biopsies.¹² Numerous clinical cohort studies have revealed unique miRNA profiles in different disease settings, suggesting their utility as markers with diagnostic and prognostic applications. In one study, a panel of eight HFpEF-related miRNAs was reported as valuable in identifying HFpEF.⁷⁴ However, there is no consensus on which specific miRNA might better serve as a HFpEF biomarker. Further research is needed to understand their role in HFpEF (Figure 3).

Figure 3 Novel biomarkers in HFpEF. The role of these new biomarkers in clinical practice still needs to be validated, but they may be useful in phenotyping HFpEF in the future. HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction. Metabolomics

Patients with HFpEF have a specific metabolic profile as compared to those with HFrEF. In an exploratory study,⁷⁵ patients with new-onset HFpEF had a diverging metabolite pattern compared to that of patients with HFrEF, reflecting potential differences in pathophysiological mechanisms. Patients with HFpEF displayed elevated hydroxyproline, reflecting fibrosis; elevated symmetrical dimethylarginine, indicating oxidative stress; and elevated alanine, cystine, and kynurenine, reflecting a state of increased inflammation compared with patients with HFrEF. Patients with HFpEF also had lower levels of cGMP and cyclic adenosine monophosphate, suggesting impaired cell signaling. Finally, serine and arginine were lower in patients with HFpEF than in those with HFrEF, reflecting endothelial dysfunction.

Proteomics

An analysis of 92 proteins from the Olink Cardiovascular II Panel and their association with obese HFpEF has been recently reported in the LIFE-Heart study.¹² Obese patients with HFpEF exhibited higher circulating biomarkers of volume expansion (adrenomedullin), myocardial fibrosis (thrombospondin-2), and systemic inflammation (galectin-9, CD4) compared to obese non-HFpEF or lean HFpEF patients.

In the setting of HFpEF and diabetes, Hanff et al., using SomaScan assays and proteomic analyses of plasma from participants in the TOPCAT trial and the Penn Heart Failure Study, identified 10 proteins with differential expression in patients with HFpEF and diabetes. These proteins included fatty acid-binding protein, alpha-1-microglobulin/bikunin precursor, trafficking protein particle complex subunit 3, pigment epithelium-derived factor, tumor necrosis factor ligand superfamily member 15, ubiquitin-conjugating enzyme E2 G2, reticulon-4 receptor, insulin, cartilage intermediate layer protein 2, and apolipoprotein M. Of these, apolipoprotein M was found to mediate 72% of the association between diabetes and risk of cardiovascular death, aborted cardiac arrest, and HF hospitalization.⁷⁶ In addition, the use of SomaScan technology has shown that HFrEF, HFmrEF and HFpEF have unique patterns of circulating proteins.⁷⁷ Thus, it may be possible to use proteomic assays to more accurately predict the phenotype of patients with HF. Further research is needed to validate and translate proteomic data into clinical practice.

Conclusions

HFpEF is a complex disease whose pathophysiology is not completely understood. Biomarkers are useful tools in the management of HFpEF. NP are the gold standard biomarker for the diagnosis of HF in the whole spectrum of ejection fraction. However, their diagnostic performance in HFpEF is inferior to that observed in HFrEF, especially in obese patients.

For prognostic purposes, it seems reasonable that the use of multiple markers reflecting the activation of different pathophysiological pathways may more accurately identify high-risk individuals. NP and hs-cTn are useful cardiac prognostic markers and many non-cardiac biomarkers reflecting inflammation, fibrosis, and oxidative stress, among other pathways, may provide additional information.

The pathophysiological basis for identifying and classifying HFpEF based on a multimarker strategy seems logical and deserves further research. The information on non-cardiac components of HFpEF may increase our understanding of the disease and may be useful in determining HFpEF phenotypes that may guide therapy and clinical trials.

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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Artigo de Revisão

O Papel dos Biomarcadores na Insuficiência Cardíaca com Fração de Ejeção Preservada

0000-0003-1654-4531

Villacorta

Humberto

¹ Concepção e desenho da pesquisa Obtenção de dados Redação do manuscrito Análise e interpretação dos dados

0000-0001-7467-0195

Maisel

Alan S.

² Análise e interpretação dos dados Revisão crítica do manuscrito quanto ao conteúdo intelectual importante 1

Niterói

Brasil Programa de Pós-Graduação em Ciência Cardiovascular, Universidade Federal Fluminense, Niterói, RJ – Brasil 2

San Diego

Califórnia

USA Divisão de Medicina Cardiovascular, Universidade da Califórnia em San Diego, La Jolla, San Diego – Califórnia

Correspondência: Humberto Villacorta • Universidade Federal Fluminense - Rua Marquês do Paraná, 303. CEP 24033-900, Niterói, RJ - Brasil E-mail: villacortahumberto@gmail.com

Potencial conflito de interesse

Dr. Humberto Villacorta - palestrante da Roche Diagnostics

Dr. Alan S Maisel - consultor da Abbott

Palavras-chave Insuficiência Cardíaca Fração de Ejeção Preservada Biomarcadores

Introdução

Um grande número de pacientes com insuficiência cardíaca (IC) apresenta fração de ejeção preservada (FEp) do ventrículo esquerdo (VE)¹ ou função sistólica ligeiramente reduzida. Embora recomendações específicas de corte estejam em constante evolução, a Sociedade Europeia de Cardiologia (ESC) propôs recentemente o termo IC com fração de ejeção levemente reduzida (ICFElr) para valores entre 40%-49% e ICFEp para FE ≥50%.² Anteriormente, utilizavam-se diferentes cortes nos estudos de ICFEp, variando de 40% a 55%. Além disso, há uma sobreposição significativa entre ICFEp e ICFElr. Portanto, consideramo-las conjuntamente neste capítulo.

A ICFEp está associada a muitas comorbidades e apresenta alta taxa de morbidade e mortalidade, tanto em coortes ambulatórias quanto em coortes hospitalares.^3–5 A ICFEp é uma síndrome heterogênea com diversas etiologias e fenótipos, e diferentes vias fisiopatológicas, que não são bem compreendidas.^6,7 Os biomarcadores circulantes podem representar ferramentas importantes para auxiliar no diagnóstico e prognóstico dessa condição.^8,9

Nesta revisão, discutimos o papel dos biomarcadores que refletem diferentes vias patológicas na ICFEp, dedicando-se maior atenção aos biomarcadores de estiramento e lesão miocárdica, tais como os peptídeos natriuréticos (PNs) e a troponina. Adicionalmente, abordamos o papel de biomarcadores de inflamação, estresse oxidativo, fibrose e disfunção vascular.

Peptídeos natriuréticos

Os PNs são hormônios endógenos com diversos efeitos hemodinâmicos, renais e neuro-hormonais. Eles são considerados biomarcadores padrão-ouro na IC e são secretados quase que exclusivamente pelo coração. Embora o papel dos PNs tenha sido mais amplamente demonstrado em pacientes com fração de ejeção reduzida (ICFEr), seu valor clínico foi demonstrado em todo o espectro da FE.^10–12 Entretanto, as concentrações são, em média, menores em pacientes com ICFEp do que naqueles com ICFFEr.^13,14 Não obstante, não existe um corte específico para diferenciar ICFEp de ICFEr, em virtude de considerável sobreposição.¹⁴

A liberação de PNs deve-se principalmente ao estresse da parede miocárdica, levando à elevação da pressão de enchimento do VE (Figura 1). Os PNs de maior importância clínica são o PN tipo B (BNP) e o fragmento N-terminal do pró-hormônio do BNP (NT-proBNP). Outros PNs, como o PN atrial (ANP), o fragmento N-terminal do pró-hormônio do ANP e o PN tipo C (CNP), embora de importância em termos de fisiopatologia, não têm sido utilizados na prática clínica devido à complexa logística para realizar suas medições.

Figura 1 Biomarcadores cardíacos padrão na ICFEp: NT-proBNP e troponinas cardíacas de alta sensibilidade. NT-proBNP: fragmento N-terminal do pró-hormônio dos peptídeos natriuréticos tipo B Diagnóstico da ICFEp

O papel dos PNs no diagnóstico de IC, incluindo a ICFEp, foi analisado em vários relatos, tanto em cenário agudo como crônico.^1,13,15–21 Villacorta et al.¹³ e Maisel et al.,¹⁵ em estudos iniciais em cenários agudos com BNP,^13,15 e Januzzi et al., com NT-proBNP,¹⁶ demonstraram boa precisão no diagnóstico da IC em todo o espectro da FE. Mais recentemente, Januzzi et al. confirmaram os resultados para o NT-proBNP no estudo ICON-RELOADED.¹⁷ Nesse estudo, 41,3% dos pacientes com diagnóstico de IC aguda apresentavam FE do VE 50%. O valor preditivo negativo para o NT-proBNP foi excelente, próximo a 98%. No cenário não agudo, Tschöpe et al., em um estudo com 68 pacientes com disfunção diastólica, constataram que os níveis do NT-proBNP eram significativamente elevados em comparação aos dos controles saudáveis e se correlacionavam bem com as medições invasivas das pressões de enchimento do VE.¹⁹ Jorge et al., em um estudo populacional, descobriram que níveis de BNP <42 pg/mL apresentavam sensibilidade de 92% e valor preditivo negativo de 99% para o diagnóstico de IC, independentemente da FE. Nesse estudo, 59% da população com IC apresentava ICFEp. Uma metanálise recente de 51 estudos constatou que os PNs têm um desempenho diagnóstico razoável na detecção da ICFEp em cenários não agudos, com área sob a curva (ASC) de 80%.²¹ A melhor utilidade desses marcadores foi excluir a disfunção diastólica ou a ICFEp, com um valor preditivo negativo de 85%. A especificidade e o valor preditivo positivo, no entanto, eram baixos (65% e 60%, respectivamente).

Em todos os estudos mencionados anteriormente, os pacientes com ICFEp apresentavam valores mais baixos que os pacientes com ICFEr. Uma possível explicação poderia ser uma associação mais consistente de PNs com o estresse da parede diastólica final, que é menor na ICFEp que na ICFEr.²²

Embora esteja comprovado que os PNs sejam uma boa ferramenta para o diagnóstico de ICFEp, há ressalvas. Os PNs são influenciados por muitos distúrbios cardíacos e não cardíacos, que parecem ser ainda mais importantes na ICFEp. Espera-se um aumento dos níveis de PNs na fibrilação atrial, em indivíduos idosos e naqueles com disfunção renal. Relata-se um aumento de 5 vezes do NT-proBNP em pacientes com ICFEp e fibrilação atrial, em comparação com aqueles em ritmo sinusal.²³ Em contrapartida, observam-se valores mais baixos em pacientes obesos.¹²

Todas essas características são comuns em pacientes com ICFEp, o que poderia explicar alguns resultados inesperados observados em alguns estudos. Por exemplo, Anjan et al. descobriram que 29% dos pacientes ambulatoriais sintomáticos com ICFEp e pressão capilar pulmonar elevada apresentavam valores “normais” de BNP (<100 pg/mL), sugerindo que um nível de BNP normal pode não excluir o diagnóstico de ICFEp.²⁴ Mais recentemente, Verbrugge et al. observaram resultados semelhantes.²⁵ Recorrendo à hemodinâmica invasiva, compararam retrospectivamente pacientes com ICFEp e valores elevados de NT-proBNP (≥125 pg/mL), ICFEp e NT-proBNP normal (<125 pg/mL) e um terceiro grupo controle com hemodinâmica normal. Os pacientes com ICFEp com níveis normais de PNs (37% da população com IC) comparados com o grupo com níveis elevados de PNs eram mais jovens, mais obesos e tinham menos doença cardíaca estrutural avaliada por ecocardiografia. A maior taxa de eventos foi observada no grupo com valores elevados de PNs, porém os pacientes com NT-proBNP normal ainda tinham um risco 2,7 vezes maior de mortalidade ou readmissão por IC em comparação com os controles. As limitações desse estudo foram a natureza retrospectiva e o fato de incluir pacientes encaminhados a um centro terciário para testes hemodinâmicos invasivos, possivelmente levando a um viés de referência.

Devido ao desempenho reduzido dos biomarcadores nos subgrupos de pacientes supracitados, alguns autores utilizam técnicas de aprendizagem de máquina, combinando variáveis clínicas com biomarcadores como variável contínua, no esforço de melhorar a precisão diagnóstica. Essa estratégia tem sido usada com sucesso no diagnóstico de infarto agudo do miocárdio usando troponinas de alta sensibilidade²⁶ e no diagnóstico de embolia pulmonar usando D-dímero.²⁷ Recentemente, Lee et al. desenvolveram um modelo chamado CoDE-HF que utiliza técnicas de aprendizagem de máquina para superar as barreiras observadas em alguns subgrupos, devido à influência de variáveis clínicas no desempenho diagnóstico do NT-proBNP.²⁸ Eles combinaram o biomarcador com 10 variáveis clínicas. Esse instrumento incluiu e descartou a IC aguda com mais precisão do que qualquer abordagem que utilizasse somente os valores limite do NT-proBNP, tendo obtido resultados consistentes em todos os subgrupos.

A ICFEp é uma doença complexa cuja patofisiologia é mal compreendida, sendo difícil estabelecer seu diagnóstico. Foram criados escores clínicos para simplificar a abordagem diagnóstica para o clínico. Os 2 escores mais utilizados são o H2FPEF,²⁹ desenvolvido pela Clínica Mayo, e o HFA-PEFF, criado pela ESC.³⁰ Uma diferença importante entre esses 2 escores é que o H2FPEF não inclui biomarcadores. Em contrapartida, o HFA-PEFF inclui PNs. Ambos são recomendados pelas principais diretrizes de IC, sem preferência de um em detrimento do outro.^2,31,32 Na validação externa do H2FPEF,³³ o escore teve desempenho inferior em pacientes que apresentavam dispneia. Diferentemente, o HFA-PEFF demonstrou boa precisão na coorte de validação.³⁴ Destaca-se que o domínio do biomarcador teve desempenho quase tão bom quanto o escore total (ASC 89% vs 90%, respectivamente). Entretanto, 3 dos 11 pacientes classificados na categoria de baixa probabilidade ainda apresentavam ICFEp, evidenciando a sensibilidade relativamente baixa do escore. Ainda não há comparação prospectiva entre os 2 escores. Neste sentido, foi realizado um único estudo caso-controle.³⁵ Nesse estudo, ambos os escores discriminaram os pacientes com ICFEp dos controles, mas o escore H2FPEF apresentou ASC maior (84% vs 71%). A especificidade foi robusta para ambos os escores, mas a sensibilidade foi menor para o HFA-PEFF (taxa falso-negativo de 55% para escores de baixa probabilidade em comparação com 25% para o H2FPEF). Entretanto, esses resultados devem ser interpretados com cautela, devido à natureza retrospectiva do estudo.

Prognóstico de ICFEp

A vantagem dos PNs vai além de seu papel diagnóstico. Quanto maiores forem os valores, maiores serão as taxas de eventos. No cenário agudo, o NT-proBNP é considerado um forte preditor independente de mortalidade por todas as causas, como descrito no estudo de Lopuszynski et al., realizado em coorte hospitalizada com ICFEp.³⁶ Internação, alta e alterações relativas durante a internação conferem as mesmas informações de risco relativo tanto para ICFEp quanto para ICFEr.³⁷

Com relação à IC crônica, vários estudos mostraram que os PNs fornecem informações prognósticas robustas e independentes.^38–41 No Estudo I-PRESERVE, o NT-proBNP surgiu como um dos mais fortes preditores de mortalidade por todas as causas ou hospitalização cardiovascular.³⁹ Houve um aumento linear contínuo na incidência do desfecho primário dos quartis mais baixos para os mais altos de NT-proBNP.⁴⁰ Uma recente análise de agrupamento não supervisionada baseada em uma ampla gama de biomarcadores descobriu que níveis mais altos de NT-proBNP identificam um subgrupo de pacientes com ICFEp (que também apresentam níveis mais elevados de troponinas cardíacas), que estão em maior risco de morte ou hospitalização por IC.⁴¹

Terapia guiada por peptídeos natriuréticos na ICFEp

Embora sugira-se que os PNs possam ser úteis na orientação da terapia em pacientes com ICFEr, poucos estudos abordaram essa questão em pacientes com ICFEp. Maeder et al.⁴² estudaram 123 pacientes com ICFEp (FE >45%), que foram sorteados para terapia médica padrão, foram titulados para reduzir os sintomas da classe II da NYHA ou também para reduzir o NT-proBNP abaixo do limiar de inclusão (400 ou 800 pg/mL, dependendo da idade). Diferentemente dos pacientes com ICFEr, os pacientes com ICFEp não se beneficiaram dessa estratégia. De fato, a terapia orientada por PNs tendeu a piorar os resultados aos 18 meses em pacientes com ICFEp. Brunner-La Roca et al.⁴³ confirmaram essa descoberta mais tarde em uma metanálise. Por outro lado, pacientes com a chamada FE “média”, agora denominada FElr, parecem ter os mesmos benefícios com a terapia orientada por PNs que pacientes com ICFEr. Rickenbach et al.,⁴⁴ utilizando-se de dados do ensaio TIME-CHF, demonstraram um benefício da terapia orientada por NT-proBNP em relação à sobrevida sem internação por IC na ICFEr e na ICFElr, mas não na ICFEp.

Troponinas cardíacas de alta sensibilidade

Tradicionalmente utilizadas no diagnóstico de infarto agudo do miocárdio, as troponinas cardíacas estão sendo cada vez mais detectadas na IC devido a melhorias na sensibilidade do diagnóstico. É conhecida como lesão miocárdica (aguda ou crônica).¹¹ Os valores de troponinas cardíacas na IC podem ser elevados em todo o espectro da FE, porém são mais altos na ICFEr em comparação com a ICFEp.⁴⁵ O aumento da troponina cardíaca de alta sensibilidade (hs-cTn) discrimina um subgrupo de pacientes com ICFEp com dano miocárdico contínuo, maior estresse da parede ou microcirculação prejudicada, como evidenciado em estudo mecanicista realizado por Obokata et al.⁴⁶ Eles compararam 38 pacientes com ICFEp com 20 pacientes controle. Os pacientes com ICFEp tinham níveis mais altos de troponina em repouso, o que se correlacionou com maior pressão capilar pulmonar e piores velocidades de Doppler do tecido sistólico e diastólico. Além disso, as troponinas se correlacionaram com um maior grau de desajuste entre a oferta e a demanda de oxigênio.

A hs-cTn basal demonstrou predizer a ICFEp em indivíduos idosos, especialmente naqueles sem hipertrofia do VE basal.⁴⁷ Houve aumento de 2,4 vezes da incidência de ICFEp em pacientes no terceiro tercil de troponina em comparação com pacientes no primeiro tercil. No cenário agudo, vários estudos mostraram papel prognóstico da hs-cTn medida na admissão ou na alta em pacientes internados com ICFEp descompensada.^48–50

Tanto a hs-cTn T como a hs-cTn I são elevadas na ICFEp crônica e estão independentemente associadas a desfechos menos favoráveis.^11,12,51 No estudo de Gohar et al.,⁵¹ o exame de hs-cTn T forneceu maior valor prognóstico adicional na ICFEp em comparação com a hs-cTn I e o NT-proBNP. Entretanto, a hs-cTn I estava mais estreitamente associada a desfechos compostos em homens com ICFEp.

Também foram estudadas as medições sucessivas de hs-cTn em pacientes com ICFEp. Em um subestudo do ensaio PARAGON-HF, os investigadores demonstraram redução da hs-cTn T com terapia sacubitril/valsartan em comparação com valsartan e, ainda, descobriram que os pacientes com diminuição da hs-cTn T da amostragem até 16 semanas, a um valor igual ou inferior ao valor mediano de 17 ng/L, posteriormente apresentavam menor risco do desfecho composto do que aqueles que apresentavam valores de hs-cTn T persistentemente elevados.⁵² Portanto, tanto as medições basais quanto as sucessivas medições de hs-cTn parecem ser úteis para prever eventos em pacientes com ICFEp. A figura 1 ilustra o estímulo à liberação de hs-cTn e seu papel na prática clínica da ICFEp.

Outros biomarcadores

Os PNs e as hs-cTns são biomarcadores cardíacos padrão e estabelecidos. Sua precisão no diagnóstico e prognóstico das condições cardiovasculares resulta, em grande parte, do fato de serem secretados quase que exclusivamente pelo coração. Entretanto, as doenças cardíacas têm repercussões sistêmicas e também são influenciadas pelas condições sistêmicas. Neste sentido, os biomarcadores sistêmicos têm um papel promissor na ICFEp, que são motivados por diferentes vias (Figura 2). Esses marcadores não são úteis para o diagnóstico, pois não são específicos para o coração, embora sejam importantes marcadores de prognóstico.

Figura 2 Biomarcadores sistêmicos envolvidos na ICFEp, tratando da relação entre os processos sistêmicos e o coração. PCR: proteína C-reativa; FABP4: proteína 4 ligante de ácidos graxos; GDF-15: fator de crescimento e diferenciação celular-15; ICFEp: insuficiência cardíaca com fração de ejeção preservada; IL: interleucina; ST2: supressão de tumorigenicidade 2; TNF: fator de necrose tumoral. GDF-15

O fator de crescimento e diferenciação celular-15 (GDF-15) é um membro da superfamília de citocinas do fator de crescimento transformador ^β, associado à inflamação e ao estresse oxidativo.⁵³ Tornou-se um marcador útil em muitas condições cardiovasculares, como doença arterial coronariana, fibrilação atrial e IC, além de doenças não cardiovasculares, como obesidade e COVID-19.⁵³ O GDF-15 é elevado em pacientes com ICFEp e fornece informações prognósticas adicionais sobre variáveis clínicas e biomarcadores tradicionais.^54,55 Izumiya et al.⁵⁴ demonstraram uma associação positiva do GDF-15 com a classificação NYHA, e o BNP e GDF-15 prognosticaram eventos cardiovasculares consistentemente. Santhanakrishnan et al. também observaram resultados interessantes.⁵⁵ Eles compararam diferentes biomarcadores na ICFEr vs ICFEp e a relação entre si. O GDF-15 diferenciou claramente os casos de ICFEp dos controles saudáveis e a relação NT-proBNP/GDF-15 distinguiu entre ICFEr e ICFEp. Essa constatação é consistente com o importante papel da inflamação na ICFEp.

Muitos pacientes com ICFEp têm fibrilação atrial e demonstrou-se um papel importante do GDF-15 nesse cenário.^56–58 O GDF-15 é o preditor mais contundente de hemorragia em pacientes com fibrilação atrial que tomam anticoagulantes.⁵⁶ O escore ABC (idade, biomarcador, histórico clínico) é um escore de risco baseado em biomarcador, desenvolvido para a previsão de AVC e hemorragia em pacientes com fibrilação atrial. O escore de hemorragia ABC⁵⁶ incorpora o GDF-15 e hs-cTns e o escore de AVC ABC⁵⁷ inclui PNs e hs-cTns. Ambos os escores ABC superaram os escores de risco tradicionais para fibrilação atrial (escore de hemorragia ABC e HAS-BLED, ASC 0,69 vs 0,62, respectivamente; escore de AVC ABC e CHADSVASC, ASC 0,67 vs 0,59, respectivamente).⁵⁸

Assim, o GDF-15 é um biomarcador promissor na ICFEp. Além do papel prognóstico, ele pode contribuir para a elucidação da fisiopatologia da ICFEp e para a identificação de terapias alvo específicas.

ST2

O receptor supressão de tumorigenicidade 2 (ST2) integra a família de receptores da interleucina 1 (IL-1), também conhecida como receptor tipo 1 semelhante à interleucina 1 (IL-1RL-1).⁵⁹ O ST2 é o receptor da interleucina-33 (IL-33), que exerce seus efeitos ao ligar-se ao receptor transmembrana ST2L isoforma, ancorado na membrana do miócito. A interação da IL-33 com o ST2L foi comprovada como cardioprotetora em modelos experimentais, reduzindo a fibrose miocárdica, a hipertrofia cardiomiocitária e a apoptose, além de melhorar a função miocárdica. Entretanto, o receptor ST2 solúvel (sST2) funciona como um receptor chamariz, o qual inibe a ligação do ST2L à IL-33. Por esta razão, o sST2 foi proposto como um marcador de hipertrofia cardíaca, fibrose e remodelação.⁵⁹

Na ICFEp, a liberação de ST2 pode estar relacionada ao estresse miocárdico e à pressão elevada de enchimento do VE, como demonstrado pela correlação direta dos níveis de ST2 com a carga diastólica medida com base na pressão diastólica final do VE.^60,61 No estudo TIME-CHF foram medidos os níveis circulantes de diferentes biomarcadores e os níveis sST2 foram maiores em pacientes com ICFEp em comparação com pacientes com ICFEr.⁴⁵ Em pacientes com dispneia aguda com função sistólica do VE normal, o ST2 foi o único biomarcador a prever mortalidade.⁶² Esses resultados também foram observados no estudo de Manzano-Fernandes et al. na IC descompensada aguda, em que o valor prognóstico de ST2 na ICFEp foi comparável ao da ICFEr.⁶³ Esses achados sugerem que o ST2 pode ser um marcador de prognóstico válido na ICFEp, especialmente em cenário agudo.

Galectina-3

A Galectina-3 (Gal-3) também tem estado mecanisticamente envolvida no processo de inflamação cardiovascular e na fibrose.¹¹ No ensaio PARAMOUNT, a Gal-3 correlacionou-se com a gravidade da doença, como evidenciado pela correlação positiva com o NT-proBNP e a relação E/E’ em pacientes com ICFEp.⁶⁴ Em um estudo com 592 pacientes, a Gal-3 foi um preditor mais categórico de mortalidade em pacientes com ICFEp em comparação com a ICFEr.⁶⁵ Além disso, as medições sucessivas de Gal-3 parecem ser valiosas. No ensaio ALDO-DHF, os incrementos de Gal-3 ao longo do tempo foram associados à mortalidade por todas as causas.⁶⁶ Finalmente, a Gal-3 pode prever o desenvolvimento de ICFEp em pacientes com comorbidades (de Boer 2013).⁶⁷

Marcadores inflamatórios

Níveis elevados de citocinas inflamatórias, como o TNF-^α, IL-1, IL-6, IL-8 e PCR, são frequentemente observados em pacientes com ICFEp.¹⁰ Os níveis circulantes de receptores de TNF-^α (TNFR1 e TNFR2) estão associados à gravidade da disfunção diastólica e dos sintomas.¹⁰ Não obstante, atualmente há poucas evidências sobre seu papel prognóstico.

Proteína 4 ligante de ácidos graxos

As proteínas ligantes de ácidos graxos (FABPs) são chaperonas intracelulares de lipídios.¹² A FABP4, também conhecida como FABP adipócito ou aP2, desempenha um papel importante no desenvolvimento da obesidade, na resistência à insulina, no diabetes e na aterosclerose, e é associada à remodelação cardíaca e disfunção ventricular esquerda e direita.^68,69 Em um subestudo do ensaio TOPCAT, associou-se a FAPB4 ao risco de morte ou à admissão por IC na ICFEp, independentemente do escore de risco MAGGIC.⁷⁰ Recentemente, Harada et al. relataram que a sobrevida sem eventos foi significativamente reduzida em pacientes com ICFEp e FABP4 ≥43,5 ng/mL.⁶⁹

Cistatina C

A cistatina C é secretada por células nucleadas a uma taxa constante, é filtrada e reabsorvida pelos glomérulos, posteriormente é completamente decomposta por túbulos renais intactos e fornece um método mais preciso para a medição da taxa de filtração glomerular estimada (TFGe).¹² O excesso de cistatina C pode promover fibrose miocárdica e hipertrofia ventricular e aumentar o volume atrial.¹² É um forte fator de risco para a ICFEp⁷¹ recém-estabelecida e está associada à classificação desfavorável da NYHA, mesmo após ajustes da TFGe.⁷² Além disso, é um preditor independente de desfecho desfavorável em pacientes admitidos com ICFEp.⁷³ Na ICFEp crônica, os dados são menos contundentes. Em um estudo, verificou-se tendência para prever a morte ou admissão por IC, porém não significativa na análise multivariada.¹² A Tabela 1 fornece um resumo sobre o papel de biomarcadores importantes na ICFEp.

Tabela 1 Resumo da fisiopatologia e possível papel dos diferentes biomarcadores na ICFEp

Biomarcadores	Mecanismo de ação	Papel na ICFEp
Peptídeos natriuréticos	Estiramento miocárdico; marcador de carga hemodinâmica	Diagnóstico e prognóstico
Troponinas cardíacas de alta sensibilidade	Liberadas por isquemia cardíaca ou estresse ou lesão miocárdica	Preditor de mortalidade e incidência de ICFEp; agrega valor prognóstico aos PNs
GDF-15	Inflamação, estresse oxidativo; secretado pelas citocinas	Fenotipagem de IC; é um preditor de mortalidade; a relação NT-proBNP/GDF-15 diferencia a ICFEp da ICFEr
ST2	Níveis elevados bloqueiam os efeitos favoráveis da IL-33, ao limitar a ativação da cascata desencadeada pela interação da IL-33/ST2L	Níveis elevados associados à fibrose cardíaca e remodelação e desfechos mais desfavoráveis
Galectina-3	Marcador de inflamação, deposita colágeno tipo 1 levando à fibrose, inflamação e remodelação cardíaca	Fenotipagem da ICFEp e estratificação de risco; prevê o desenvolvimento de ICFEp em pacientes com comorbidades
Marcadores inflamatórios (TNF-α, IL-1, IL-6, IL-8 e PCR)	Inflamação	Os níveis dos receptores do TNF-α estão associados à gravidade da disfunção diastólica e dos sintomas
FABP4	Desenvolvimento da obesidade, resistência à insulina, diabetes e aterosclerose	Preditor de morte ou de admissão por IC
Cistatina C	Marcador da função renal; o excesso de cistatina promove fibrose e hipertrofia miocárdica	Grande fator de risco para ICFEp recém-estabelecida; prevê desfechos, especialmente na ICFEp aguda

ICFEp: insuficiência cardíaca com fração de ejeção preservada; PNs: peptídeos natriuréticos; GDF-15: fator de crescimento e diferenciação celular-15; NT-proBNP: fragmento N-terminal do pró-hormônio dos peptídeos natriuréticos tipo B; ICFEr: insuficiência cardíaca com fração de ejeção reduzida; IL: interleucina; ST2: supressão de tumorigenicidade 2; TNF: fator de necrose tumoral; PCR: proteína C-reativa; FABP4: proteína 4 ligante de ácidos graxos.

Futuros biomarcadores MicroRNAs (miRNAs) circulantes

Oferecem um potencial atrativo como biomarcadores epigenéticos de doenças devido a sua estabilidade biológica e pronto acesso em biópsias líquidas.¹² Numerosos estudos clínicos de coorte revelaram perfis únicos de miRNAs em diferentes cenários de doenças, sugerindo sua utilidade como marcadores com aplicações diagnósticas e prognósticas. Em um estudo, um painel de 8 miRNAs relacionados à ICFEp foi indicado como valioso para a identificação de ICFEp.⁷⁴ Entretanto, não há consenso sobre quais miRNAs específicos poderiam servir melhor como biomarcadores da ICFEp. É necessário realizar mais pesquisas para entender seu papel na ICFEp (Figura 3).

Figura 3 Novos Biomarcadores na ICFEp. O papel desses novos biomarcadores na prática clínica ainda precisa ser validado, mas eles podem ser úteis na fenotipagem da ICFEp no futuro. ICFEp: insuficiência cardíaca com fração de ejeção preservada; ICFEr: insuficiência cardíaca com fração de ejeção reduzida. Metabolômica

Pacientes com ICFEp têm um perfil metabólico específico em comparação com a ICFEr. Em um estudo exploratório,⁷⁵ pacientes com ICFEp recém-estabelecida tinham um padrão metabólico diverso em comparação com o de pacientes com ICFEr, refletindo possíveis diferenças nos mecanismos fisiopatológicos. Pacientes com ICFEp apresentavam elevada hidroxiprolina, refletindo fibrose, dimetilarginina simétrica elevada, indicando estresse oxidativo, e alanina, cistina e cinurenina elevadas, refletindo um estado de inflamação aumentado em comparação com pacientes com ICFEr. Pacientes com ICFEp também tinham níveis mais baixos de monofosfato de guanosina cíclico e monofosfato de adenosina cíclico, sugerindo uma sinalização celular deficiente. Finalmente, a serina e a arginina eram menores na ICFEp do que na ICFEr, refletindo disfunção endotelial.

Proteômica

A análise de 92 proteínas do painel Olink cardiovascular II e sua associação com a ICFEp em obesos foi relatada recentemente no estudo LIFE-Heart.¹² Pacientes obesos com ICFEp apresentaram níveis mais elevados de biomarcadores circulantes de expansão volêmica (adrenomedulina), fibrose miocárdica (trombospondina-2) e inflamação sistêmica (galectina-9, CD4) em comparação com pacientes obesos sem ICFEp ou pacientes magros com ICFEp.

No cenário da ICFEp e diabetes, Hanff et al., utilizando ensaios SomaScan e análise proteômica do plasma dos participantes do ensaio TOPCAT e do Penn Heart Failure Study, identificaram 10 proteínas com expressão diferencial em pacientes com ICFEp e diabetes. Essas proteínas incluíam a FABP, precursor da ^α-1 microglobulina/bicunina, subunidade 3 do complexo de partículas proteicas de tráfego, fator derivado do epitélio pigmentado, membro da superfamília 15 do fator de necrose tumoral, E2 G2 enzima conjugante de ubiquitina, receptor de reticulon-4, insulina, proteína 2 da camada intermediária de cartilagem e apolipoproteína M. Desses, descobriu-se que a apolipoproteína M serve de mediador em 72% da associação entre diabetes e risco de morte cardiovascular, parada cardíaca abortada e admissão por IC.⁷⁶ Além disso, o uso da tecnologia SomaScan mostrou que a ICFEr, ICFElr e ICFEp têm um padrão único de proteínas circulantes.⁷⁷ Assim, pode-se utilizar ensaios proteômicos para prever com maior precisão o fenótipo de pacientes com IC. Mais pesquisas são necessárias para validar e traduzir os dados proteômicos em prática clínica.

Conclusões

A ICFEp é uma doença complexa cuja patofisiologia não é completamente compreendida. Os biomarcadores são ferramentas úteis no manejo da ICFEp. Os PNs são o biomarcadores padrão-ouro para o diagnóstico de IC em todo o espectro da FE. Entretanto, o desempenho do diagnóstico na ICFEp é inferior ao observado na ICFEr, especialmente em pacientes obesos.

Para fins de prognóstico, parece razoável que o uso de múltiplos marcadores que reflitam a ativação de diferentes vias fisiopatológicas permita identificar de forma mais precisa os sujeitos de alto risco. Os PNs e as hs-cTns são marcadores de prognóstico cardíaco úteis. Muitos biomarcadores não cardíacos, que indicam inflamação, fibrose e estresse oxidativo, entre outras vias, podem fornecer informações adicionais.

A base fisiopatológica para identificar e classificar a ICFEp com base em uma estratégia de multimarcadores parece lógica e merece ser mais pesquisada. As informações sobre componentes não cardíacos da ICFEp podem aumentar nossa compreensão da doença e podem ser úteis na determinação dos fenótipos da ICFEp, que podem orientar a terapia e os ensaios clínicos.

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Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.