Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome characterized by cardiovascular, metabolic, and pro‐inflammatory diseases associated with advanced age and extracardiac comorbidities. All of these conditions finally lead to impairment of myocardial structure and function. The large phenotypic heterogeneity of HFpEF from pathophysiological underpinnings presents a major hurdle to HFpEF therapy. The new therapeutic approach in HFpEF should be targeted to each HF phenotype, instead of the ‘one‐size‐fits‐all’ approach, which has not been successful in clinical trials. Unless the structural and biological determinants of the failing heart are deeply understood, it will be impossible to appropriately differentiate HFpEF patients, identify subtle myocardial abnormalities, and finally reverse abnormal cardiac function. Based on evidence from endomyocardial biopsies, some of the specific cardiac structural phenotypes to be targeted in HFpEF may be represented by myocyte hypertrophy, interstitial fibrosis, myocardial inflammation associated with oxidative stress, and coronary disease. Once the diagnosis of HFpEF has been established, a potential approach could be to use a panel of biomarkers to identify the main cardiac structural HFpEF phenotypes, guiding towards more appropriate therapeutic strategies. Accordingly, the purpose of this review is to investigate the potential role of biomarkers in identifying different cardiac structural HFpEF phenotypes and to discuss the merits of a biomarker‐guided strategy in HFpEF.

Chronic Heart Failure and Inflammation

“…Interestingly, in this regard, there may be more evidence in humans, where the initial inflammatory/cytokine hypothesis as a mediator of HF was born, and where we will begin our discussion. 8 Similarly, elevated serum proinflammatory cytokines have been observed in HFpEF 22 ; however, we still lack an understanding of how multiple individual risk factors for HFpEF, including hypertension, diabetes mellitus, and coronary artery disease, individually contribute to the inflammatory milieu. Unfortunately, therapeutic interventions aimed at limiting inflammation in the chronic setting have been controversial.…”

Pro‐Inflammatory Biomarkers in Stable Versus Acutely Decompensated Heart Failure With Preserved Ejection Fraction

“…Inflammation, oxidative stress, and extracellular matrix remodeling have been long considered to play a key role in the pathophysiology of heart failure (HF) 1, 2, 3, 4, 5, 6, 7, 8, 9. A number of studies have revealed a significant correlation between elevations in blood levels of pro‐inflammatory biomarkers such as tumor necrosis factor alpha (TNF‐α), C‐reactive protein (CRP),interleukin 6 (IL‐6), and HF severity and prognosis 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.…”

“…It has been proposed that a heightened pro‐inflammatory state may play a role in the progression of HF, including acute decompensations 1, 2, 3, 4, 5, 6, 7, 8, 9. Impairment of nitric oxide bioavailability due to oxidative stress, leading to impaired cyclic guanosine monophosphate‐protein kinase G signaling29 is one potential mechanism underlying the link between inflammation and HF progression.…”

“…Recently, there has been an effort to better characterize biomarkers in HF with preserved EF (HFpEF)2, 9, 31, 32). While inflammation plays a role in both HFpEF and HFrEF,33 there appear to be distinct differences in their pathogenesis 2, 34, 35, 36. We are unaware of any data in regard to whether more intense inflammation plays a role in acutely decompensated HFpEF (AD‐HFpEF).…”

Differentiating heart failure phenotypes using sex‐specific transcriptomic and proteomic biomarker panels

“…Interest in the potential use of ‘‐omic’ biomarker panels as diagnostic, predictive, monitoring and prognostic tools in HF has grown 6, 12, 13. While most initial work in this area have focused on diseased cardiac tissue samples, subsequent studies have demonstrated that informative biomarkers can be found in peripheral blood and that blood and cardiac tissue may show comparable transcriptomic (gene expression) and proteomic profiles 14, 15.…”