Table of Contents
Year : 2021  |  Volume : 6  |  Issue : 2  |  Page : 88-91

Viewing the future research directions of heart failure from ge's phenotyping of heart failure with preserved ejection fraction

1 Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
2 Department of Cardiology, The First Affiliated Hospital of Harbin Medical University; Institute of Cardiovascular Diseases, Harbin Medical University, Harbin, Heilongjiang Province, China

Date of Submission05-May-2021
Date of Acceptance31-May-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Wei-Min Li
Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Harbin, Heilongjiang Province
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2470-7511.320321

Get Permissions


At present, guideline-directed medical therapy of heart failure (HF) has achieved certain results, but the evidence mostly focuses on HF with reduced ejection fraction, and there are some problems in the research on HF with preserved ejection fraction (HFpEF), such as inconsistent inclusion criteria and unconvincing results. Therefore, it may be more individualized and targeted to perform classification, typing, and treatment of HF from aspects such as pathogenesis, etiology, or pathophysiology, but not ejection fraction, especially HFpEF with strong heterogeneity. Ge's phenotyping of HFpEF is based on etiology and pathology, aiming at improving the outcome of HFpEF and exploring new approaches for the prognosis of HF.

Keywords: Ejection fraction; Heart failure; Etiology; Prognosis

How to cite this article:
Zang YX, Li WM, Lou Q, Wang H, Duan YC. Viewing the future research directions of heart failure from ge's phenotyping of heart failure with preserved ejection fraction. Cardiol Plus 2021;6:88-91

How to cite this URL:
Zang YX, Li WM, Lou Q, Wang H, Duan YC. Viewing the future research directions of heart failure from ge's phenotyping of heart failure with preserved ejection fraction. Cardiol Plus [serial online] 2021 [cited 2021 Oct 16];6:88-91. Available from:

  Introduction Top

At present, ejection fraction as the classification basis of heart failure (HF) has gained global consensus, and HF with recovered ejection fraction has also been put forward in the Universal Definition and Classification of Heart Failure on this basis.[1] However, in clinical practice, patients who have HF with reduced ejection fraction (HFrEF) have greater commonality and better responsiveness to treatment. Left ventricular congestion and decreased left ventricular systolic function of various causes are the main manifestations of HFrEF. Currently, the innovative anti-HF drug - sacubitril/valsartan - can significantly increase the ejection fraction and thereby improve the prognosis. However, the outcomes of HF with mid-range ejection fraction and HF with preserved ejection fraction (HFpEF) are not satisfactory, and improving the ejection fraction is not the aim of HFpEF treatment. Hence, it is necessary to explore targeted treatment strategies for HFpEF.

  Background of Proposing Ge's phenotyping Top

The Prospective comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with angiotensin-receptor blockers (ARBs) on the Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT)-HF study conducted in 2012 was a phase II clinical trial applying ARNIs to patients with HFpEF, which confirmed that sacubitril/valsartan reduced left atrial volume and N-terminal pro-B-type natriuretic peptide level at 12 weeks and improved the New York Heart Association grading of cardiac function at 36 weeks.[2] Based on this preliminary work, the Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) study, a phase III clinical trial in patients with HFpEF, was launched in 2014.[3] This study was a randomized, double-blind, active-comparator trial, which mainly compared the efficacy and safety of sacubitril/valsartan and the active drug valsartan in patients with HFpEF. The primary outcome was a composite of total hospitalizations for HF and death from cardiovascular causes. These innovative composite endpoints can better reflect the influence of ARNI on the disease burden of patients with HFpEF. The PARAGON-HF study showed that compared with valsartan, the incidence rate of primary composite endpoint events in the sacubitril/valsartan group was reduced by 13%, so there was only a very small nonsignificant difference in the reduction. However, the overall evidence of this study revealed that sacubitril/valsartan still had many clinical benefits for patients with HFpEF. Some specific subgroups of patients with HFpEF obtained clinical benefits, including patients with left ventricular ejection fraction (LVEF) ≤57% and female patients, in whom sacubitril/valsartan could significantly reduce the risk of renal events (renal death, end-stage renal disease, or estimated glomerular filtration rate decline ≥50% from baseline). The PARAGON-HF study also confirmed that sacubitril/valsartan had good safety and tolerability, and the incidence of hyperkalemia and proportion of patients with elevated serum creatinine clearance were significantly lower than those in the control group.

The PARAGON-HF study is of great significance in the field of HF treatment. First, there is no clear HFpEF management scheme at present. This study allows us to gain a new understanding of HFpEF and consider the rationale behind classifying patients with HF only by the LVEF value. HFpEF is a highly heterogeneous clinical syndrome, the disease progression of which is related to the dynamic changes in heart structure and function. The conclusion of classification only based on LVEF may be inaccurate, which also provides an important lesson for us to analyze clinical research. Second, the PARAGON-HF study for the first time revealed that sacubitril/valsartan has very significant clinical benefits for patients with low LVEF (≤57%) and female patients.[4] This is an essential breakthrough for HFpEF management.

In the population of HFrEF, homogenous response to treatment shows in a way that several pharmacological and nonpharmacological interventions with established benefit on cardiovascular death and HF hospitalizations,[5] and that means one size fits all approach. On the contrary, the heterogeneous population of HFpEF did not get the same benefits as HFrEF did. Therefore, we need to analyze the causes of differences in clinical research results of HFpEF. The substantial reason may come from the heterogeneity of HFpEF, which can greatly vary in pathology, pathophysiology, and etiology. The best basis for classification or phenotyping of HFpEF is a point to be further explored.

  Introduction to Ge's Phenotyping Top

Ge's phenotyping of HFpEF[6] divides HFpEF into five categories [Table 1] according to etiology and pathology:[6] (1) HFpEF-1 (HFpEF related to vascular diseases), including hypertension, coronary artery disease, and coronary microcirculation disturbance; (2) HFpEF-2 (cardiomyopathy-related HFpEF), including HFpEF resulting from hypertrophic cardiomyopathy and infiltrative cardiomyopathies (amyloidosis, Fabry disease, etc.); (3) HFpEF-3 (HFpEF related to the right heart and pulmonary), which often refers to pulmonary hypertension with or without right heart dysfunction; (4) HFpEF-4 (HFpEF related to valves and rhythm), which mainly refers to HFpEF resulting from valve diseases and atrial fibrillation (AF); and (5) HFpEF-5 (HFpEF related to extracardiac diseases, which mainly includes metabolic diseases such as diabetes and obesity, high output-related diseases such as anemia, liver diseases, hyperthyroidism, arteriovenous fistula, and other diseases such as chronic kidney disease and tumor after radiotherapy. Ge's phenotyping is expected to guide the clinical treatment of HFpEF.
Table 1: Ge's phenotypic coding for heart failure with preserved ejection fraction

Click here to view

  Clinical Thinking of Ge's Phenotyping Top

Although Ge's phenotyping of HFpEF is based on heterogeneity, according to the latest published 2020 China Report on Medical Care Quality Control of Heart Failure,[7] HF tends to be heterogeneous overall, rather than only in HFpEF. Based on the above report, the main etiologies of HF include hypertension (56.3%) and coronary heart disease (48.3%), followed by valvular heart disease (18.7%) and dilated cardiomyopathy (16.3%). The complications of HF are mainly diabetes and AF (or atrial flutter). Subgroup analysis based on ejection fraction showed that hypertension and coronary heart disease are the main etiologies of HF, so any etiology-oriented typing should be extended to all types of HF if it benefits HFpEF.

In addition, other phenotypes caused by a single etiology are different in the development and progression of HF. HFrEF is mainly due to impaired LVEF, while HFpEF is more associated with inflammation, fibrosis, or cardiac metabolism, among other conditions. Blood vessels are used as the etiological basis for Ge's phenotyping of HFpEF-1, but there exist significant differences in the treatment of hypertension, obstructive coronary disease, and coronary microvascular dysfunction. Further research is needed on whether elimination of the primary disease can intervene in the long-term prognosis. Some scholars divided the mechanisms of HFpEF into three hemodynamic mechanisms (volume overload, pulmonary vascular disease/right ventricular dysfunction, and left ventricular congestion/diastolic dysfunction/left atrial hypertension) as well as three cellular/molecular level mechanisms (microvascular inflammation, abnormal cardiac metabolism, and changes in cellular or extracellular structures),[8] among which there are many drug therapies for the hemodynamic mechanisms, but so far, there is no clear clinical benefit of drug therapies at the cellular level.

In 2014, Shah et al.[9] proposed that HFpEF should be classified into various classifications, including pathophysiologic classification, clinical/etiologic classification, classification of HFpEF based on clinical presentation, and phenomics (“phenomapping”) of HFpEF. The above did not propose a fixed method for treatment but a series of directions that can be classified. Ge's classification is mainly based on etiology to further summarize, which is helpful to strengthen the intervention of etiology on the basis of general treatment and improve the treatment effect.

  The Future of Heart Failure with Preserved Ejection Fraction Top

Ge's phenotyping of HFpEF is a new way of thinking about HFpEF developed by Chinese scholar, which guides the new typing of HF in China. Based on Ge's phenotyping and the current status of treatment, we have to explore the effects of new therapy of HF, such as ARNIs, sodium-dependent glucose transporter 2 (SGLT2) inhibitors, and soluble guanylate cyclase (sGC) stimulators, on specific types of HFpEF. For example, whether SGLT2 inhibitors or sGC stimulators are suitable for HFpEF with cardiac metabolic disorder and whether HFpEF caused by hemodynamics will benefit more from sacubitril/valsartan are the research directions of classification and treatment of HFpEF in the future. Many scholars in Europe believe that it is too simple to classify HF by LVEF, and the targeting of therapies is insufficient.[10] The patients with HFrEF benefit more from guideline-directed medical therapy in various studies, but those with HFpEF, accounting for approximately 50% of all cases of HF, are not. Ge's phenotyping of HFpEF represents Chinese wisdom in the typing and treatment of HF, and future research should be based on a large Chinese patient population to improve the cure rate and reduce the burden of HF.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Bozkurt B, Coats AJS, Tsutsui H, Abdelhamid CM, Adamopoulos S, Albert N, et al. Universal definition and classification of heart failure: A report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail 2021;23:352-80. doi: 10.1002/ejhf.2115.  Back to cited text no. 1
Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: A phase 2 double-blind randomised controlled trial. Lancet 2012;380:1387-95. doi: 10.1016/S0140-6736(12)61227-6.  Back to cited text no. 2
Solomon SD, McMurray JJ, Anand IS, Ge J, Lam CS, Maggioni AP, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609-20. doi: 10.1056/NEJMoa1908655.  Back to cited text no. 3
McMurray JJ, Jackson AM, Lam CS, Redfield MM, Anand IS, Ge J, et al. Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction: Insights from PARAGON-HF. Circulation 2020;141:338-51. doi: 10.1161/CIRCULATIONAHA.119.044491.  Back to cited text no. 4
Del Buono MG, Iannaccone G, Scacciavillani R, Carbone S, Camilli M, Niccoli G, et al. Heart failure with preserved ejection fraction diagnosis and treatment: An updated review of the evidence. Prog Cardiovasc Dis 2020;63:570-84. doi: 10.1016/j.pcad.2020.04.011.  Back to cited text no. 5
Ge J. Coding proposal on phenotyping heart failure with preserved ejection fraction: A practical tool for facilitating etiology-oriented therapy. Cardiol J 2020;27:97-8. doi: 10.5603/CJ.2020.0023.  Back to cited text no. 6
Working Group on Heart Failure, National Center for Cardiovascular Quality Improvement. 2020 Clinical Performance and Quality Measures for Heart Failure in China. Chin J Heart Fail & Cardiomyopathy 2020;04:237-49. doi: 10.3760/cma.j.cn101460-20201217-00123.  Back to cited text no. 7
Lam CS, Voors AA, de Boer RA, Solomon SD, van Veldhuisen DJ. Heart failure with preserved ejection fraction: From mechanisms to therapies. Eur Heart J 2018;39:2780-92. doi: 10.1093/eurheartj/ehy301.  Back to cited text no. 8
Shah SJ, Katz DH, Deo RC. Phenotypic spectrum of heart failure with preserved ejection fraction. Heart Fail Clin 2014;10:407-18. doi: 10.1016/j.hfc.2014.04.008.  Back to cited text no. 9
Triposkiadis F, Butler J, Abboud FM, Armstrong PW, Adamopoulos S, Atherton JJ, et al. The continuous heart failure spectrum: Moving beyond an ejection fraction classification. Eur Heart J 2019;40:2155-63. doi: 10.1093/eurheartj/ehz158.  Back to cited text no. 10


  [Table 1]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Background of Pr...
Introduction to ...
Clinical Thinkin...
The Future of He...
Article Tables

 Article Access Statistics
    PDF Downloaded91    
    Comments [Add]    

Recommend this journal