Up to 1/4 of the total! How to recognize the middle value of heart failure in the ejection fraction?

Sources: Ruan Zheng, Huang Jianyu, Jiang Wencai, et al. Median ejection fraction heart failure - how to recognize? [J]. Chinese Journal of General Medicine,2022,25(5):522-529.

Author: Ruan Zheng, Huang Jianyu, Jiang Wencai, Chen Meixiang, Qin Changyu, Xu Lin

Corresponding author: Xu Lin, chief physician, doctoral supervisor

The increasing burden of cardiovascular disease has become a major global public health problem, and its prevention and treatment cannot be delayed. Heart failure is the "final battlefield" of cardiovascular disease management, which has the characteristics of high prevalence, high re-hospitalization rate and high mortality rate, and it is extremely difficult to prevent and treat.

The 2016 European Society of Cardiology (ESC) guidelines formally defined median ejection fraction heart failure (HFmrEF) as left ventricular ejection fraction (LVEF) in 40% to 49% of heart failure, aiming to refine the classification of heart failure and better guide clinical diagnosis and treatment.

However, there are fewer studies on HFmrEF, and there is still a lot of controversy about the pathophysiology and treatment of HFmrEF.

In this paper, the characteristics of HFmrEF patients are elaborated from the aspects of epidemiology, clinical features, pathophysiology, and treatment, in order to deepen the clinicians' understanding and understanding of HFmrEF, so as to better guide clinical treatment.

01

Epidemiological and clinical features of HFmrEF

1. It is estimated that from 2012 to 2030, ≥ 18-year-old heart failure patients in the United States will rise from more than 6 million in 2018 to more than 8 million, while the prevalence will rise from 2.4% in 2012 to 3.0% in 2030, and the prevalence will increase significantly with age.

2. A Chinese hypertension survey analyzed 22,158 participants selected from 2012 to 2015 and found that the prevalence of heart failure in adults aged ≥35 years old was 1.3%, an increase of 44% over 2000; the prevalence of ejection fraction retention heart failure (HFpEF), HFmrEF and Ejection Fraction Reduction Heart Failure (HFrEF) was 0.3%, 0.3% and 0.7%, respectively, and the prevalence of moderate/severe diastolic dysfunction was 2.7%.

3. At present, HFmrEF patients in most of the global studies account for 7.5% to 25.0% of heart failure patients, accounting for a relatively high proportion.

4. The registration study of the China Heart Failure Center and the China-HF study jointly show that the proportion of valvular disease in the causes of heart failure in China has decreased year by year, and the top two causes are coronary heart disease and hypertension.

5. A number of large studies have shown that the overall clinical features of HFmrEF are between HFpEF and HFrEF. However, compared with HFpEF patients, HFmrEF patients are more likely to have ischemic disease, mainly coronary heart disease and patients who have had acute myocardial infarction (AMI) significantly more, which is similar to HFrEF patients, and even more proportions, and compared with HFrEF patients, HFmrEF patients often have atrial arrhythmias (including atrial fibrillation, atrial flutter), old age, more hypertension patients, and characteristics are close to or worse than HFpEF patients.

6. Multiple studies have found that there are more diabetic patients in HFmrEF patients than patients with HFmrEF and HFpEF patients. In addition, the sex characteristics of HFmrEF patients are closer to those of HFREF patients, most of whom are male, and the proportion of patients with hyperlipidemia is high.

7. Some studies have noted the different clinical features shown by HFmrEF patients due to different trends of LVEF, among which the HFmrEF improvement group has a better prognosis than the HFmrEF deterioration group, and it may be that the HFmrEF stable group is the most important "real" HFmrEF patients, but the sample size of the HFmrEF stable group in the study is too small, and more clinical studies are needed to explore the characteristics of patients in the stable group.

02

Relevant pathophysiological mechanisms of HFmrEF

In the existing study, the pathophysiological mechanism of HFmrEF involves mechanisms such as inflammation, metabolism, neuroendocrine activation, etc., and the overall performance is between HFpEF and HFrEF, but it is still not fully defined, and more research is needed to confirm its intrinsic mechanism.

03

Progress in HFmrEF treatment

1. Advances in the treatment of HFmrEF-related drugs

(1) Angiotensin receptor - cerebral lining peptase inhibitor (ARNI)

The PARADIGM-HF trial demonstrated the clear benefits of ARNI in patients with HFrEF.

The PARAGON-HF trial found that patients with ejection fractions below the median 57% (45%, 57%) benefited more, reducing the likelihood of the main combined outcome of cardiovascular death and hospitalization for heart failure by 22%, including some HFmrEF patients.

A single-center study in China found that sakubatrivosartan sodium compared with benazepril hydrochloride could further reduce the risk of re-hospitalization of heart failure and the risk of endpoint events in patients with HFmrEF, reverse ventricular remodeling, improve cardiac function, and be more effective in women aged > 65 years, women and obese (BMI>24 kg/m2).

At present, sakubatri valsartan sodium has been officially approved as an indication for hypertension and has become the sixth class of antihypertensive drugs, and the application of ARNI in heart failure, hypertension or other fields is still worth looking forward to.

(2) Sodium-glucose synergistic transporter 2 inhibitor (SGLT-2i)

Multiple studies suggest that SGLT-2i can provide cardiovascular benefits, but there are fewer studies specifically targeting SGLT-2i in patients with HFmrEF.

A prospective study in China found that in HFmrEF patients with type 2 diabetes mellitus, the dapagliflozin group decreased significantly compared with the control group NT-proBNP, hypersensitive C-reactive protein (hs-CRP), soluble growth-stimulating factor gene expression of 2 protein (ST2), and the walking distance was significantly improved at 6 min, but there was no significant effect on the left ventricular diastolic inner diameter and LVEF in the short-term (observation period of the study was 6 months).

A prospective study in Japan found that dapagliflozin can improve the global longitudinal response (GLS) of heart failure patients through cardiac ultrasound, especially in HFpEF patients, followed by HFmrEF patients who also improved, while HFrEF patients did not significantly improve, but declined, which may be related to small sample size.

Studies related to aegliflozin have also demonstrated its benefits for cardiovascular disease.

SGLT-2i has already demonstrated its superiority in the field of heart failure, and more related research will be carried out in the future, which will surely be pushed to a new height.

(3) Soluble guanylate cyclase agonist (SGC)

The results of the SOCRATES-REDUCED study first published by the SGC for the drug Vericcique in 2015, which proposed to clarify Vericcique and found that the higher the oral dose of Velicique from 2.5 mg/d titration to 10 mg/day, the more pronounced the NT-proBNP decline, and the more pronounced the LVEF increase after 12 months.

The SOCRATES-PRESERVED study of 45% of HFpEF patients with LVEF ≥ found no difference in changes in NT-proBNP and left atrial volume (LAV) after 12 weeks compared with the placebo group, but self-assessment scores found significant improvements in the quality of life of patients in the trial group, suggesting that a larger sample and longer follow-up time were needed to explore the effects of Vericcique in patients with heart failure.

Then, a larger VICTORIA study was published, for LVEF

Some HFmrEF patients were included in the above studies, and although there is currently a lack of SGC specifically for HFmrEF studies, the benefits of SGC in patients with HFmrEF have been derived from related studies.

(4) Myocardial myoglobulin agonist (OM)

The GALATIC-HF study found that at an average of 22 months of follow-up, patients with HFrEF had a 2.1 percent lower absolute risk of cardiovascular death and heart failure readmission than placebo, an 8 percent relative risk reduction, and that patients with lower LVEF benefited more from OM.

OM has shown good application prospects in the field of heart failure, and whether it can benefit HFmrEF and HFpEF patients later needs more research to verify.

2. Room septal shunt

(1) Principle: On the basis of not significantly reducing the amount of cardiac blood flow affecting the blood supply to the whole body, proper shunting can reduce the pressure on the left atrium (LAP).

(2) Studies have suggested that patients implanted with atrial septal shunts may also have severe atrial arrhythmias.

(3) At present, the atrial spacer shunt has shown its advantages in HFmrEF and HFpEF patients, and future studies will be carried out in HFrEF patients.

04

brief summary

The exploration of HFmrEF has never stopped, combined with the current research progress, HFmrEF is more like a transitional stage of HFpEF and HFrEF, rather than a unique phenotype, its pathophysiology has not yet been fully understood; the current 4 new drugs in the field of heart failure and the atrial septal shunt device have shown broad application prospects in the treatment of HFmrEF patients. In the future, more subgroup studies of HFmrEF patients, especially based on different indicators (e.g. LVEF itself, trends) are needed to unveil their mysteries.

Image source: 123RF

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