Chronic heart failure with preserved ejection fraction: current understanding of the problem

Full Text

Introduction

Chronic circulatory insufficiency syndrome has a particular significance within the cardiovascular continuum, as it represents the outcome of many circulatory system diseases. In developed countries, approximately 1–2 % of the adult population suffer from established chronic heart failure (CHF), accounting for no fewer than 64.3 million people worldwide [1–4]. In the Russian Federation, according to the "EPOCHA-CHF" study, the prevalence of CHF increased from 6.1 % to 8.2 % over 20 years of observation, with a further rise in this indicator expected [2].

Approximately 50 % of all CHF cases are associated with heart failure with preserved ejection fraction (CHFpEF), and the mortality rate among these patients is comparable to that of individuals with chronic heart failure with reduced ejection fraction (CHFrEF) [3]. Experts estimate that the incidence of CHFpEF increases by approximately 1 % per year and is subject to significant fluctuations due to the influence of demographic trends, the intensity of cardiovascular risk factor modification, and advancements in heart failure diagnostic methods [5–13]. In the Russian Federation, the prevalence of the CHFpEF phenotype among all patients with circulatory insufficiency is strikingly high. According to the "EPOCHA-CHF" epidemiological study, in the majority of hospitalized patients with clinically significant circulatory insufficiency an ejection fraction exceeding 60 % was revealed [5; 6]. This confirms the high incidence of CHFpEF, which has a substantial medical and social significance.

Results and discussion

Experts have determined diagnostic criteria for various CHF phenotypes, which are traditionally classified based on left ventricular ejection fraction, as presented in the table.

 

Characteristics of chronic heart failure depending on left ventricular ejection fraction (LVEF)

Parameter	Characteristic
CHF type	CHFpEF	CHFmrEF	CHFrEF
Criterion 1	Symptoms and/or signsa	Symptoms and/or signsa	Symptoms and/or signsa
Criterion 2	LVEF ≥ 50 %	LVEF 41–49 % c	LVEF ≤ 40 %
Criterion 3	Objective evidence of structural and/or functional cardiac abnormalities consistent with LV diastolic dysfunction / increased LV filling pressure, including increase in natriuretic peptides levelsb	-	-

Note:

CHF – chronic heart failure; CHFpEF – chronic heart failure with preserved ejection fraction; CHFmrEF – chronic heart failure with mildly reduced ejection fraction; CHFrEF – chronic heart failure with reduced ejection fraction; LV – left ventricle; LVEF – left ventricular ejection fraction.

a – Symptoms may be absent in the early stages of heart failure and in patients receiving adequate therapy.

b – Concentric LV hypertrophy (LV mass index ≥ 95 g/m² in female and ≥ 115 g/m² in male; LV relative wall thickness index > 0.42); left atrial enlargement (left atrial volume index > 34 mL/m² in sinus rhythm and > 40 mL/m² in atrial fibrillation; Doppler E/e’ ratio at rest > 9; NT-proBNP/BNP level > 125/35 pg/mL in sinus rhythm or 365/105 pg/mL in atrial fibrillation; systolic pulmonary artery pressure > 35 mm Hg or tricuspid regurgitation velocity > 2.8 m/s).

The more signs are present in the patient, the higher accuracy of CHFpEF diagnosis.

c – In diagnosing HFmrEF, the presence of signs of structural heart damage (left atrial enlargement, left ventricular hypertrophy, or echocardiographic signs of impaired LV filling) makes the diagnosis more likely.

 

One of the key diagnostic criteria for CHFpEF is the presence of a characteristic clinical presentation, which includes typical symptoms such as dyspnea, reduced exercise tolerance, orthopnea, edema, and bendopnea. Typical signs of circulatory insufficiency include elevated jugular venous pressure, "gallop rhythm," leftward displacement of the apical impulse, and hepatojugular reflux. However, these symptoms and signs are nonspecific; some have low sensitivity, may result not only from a cardiovascular pathology but also from other causes, and may be entirely absent in early stages [7; 8].

Echocardiography (EchoCG) plays a pivotal role in assessing structural and functional cardiac changes, as it enables to determine left ventricular ejection fraction, heart chamber dimensions, left ventricular hypertrophy patterns, myocardial wall motion abnormalities, function of the right ventricular and valvular apparatus, pulmonary hypertension, and diastolic dysfunction parameters [7]. However, EchoCG results depend on the operator's expertise and equipment accuracy, and in early stages of the disease, echocardiographic signs of diastolic dysfunction (DD) in some patients may be revealed exclusively on exertion.

Key biomarkers used in the diagnosis and prognosis of HFpEF severity and outcomes include natriuretic peptides (NPs) [8]. NPs demonstrate high negative predictive value (up to 97 %); however, approximately 30 % of patients with confirmed HFpEF exhibit NP levels within reference ranges despite presenting typical CHF symptoms, cardiac structural remodeling, echocardiographic evidence of diastolic dysfunction, and elevated left ventricular filling pressure on invasive hemodynamic testing [10].

Compared to CHFpEF patients with elevated NP levels, those with normal NPs tend to be younger, more frequently obese. Obesity may complicate the diagnosis of CHFpEF but effective, combined, and timely therapy results in fewer hospitalizations and improves patient`s quality of life [11; 12]. CHFpEF patients with normal NP levels demonstrate better renal function with lower prevalence of atrial fibrillation. Echocardiography also reveals fewer right-sided cardiac structural and functional abnormalities in such patients. The primary mechanisms of NP levels elevation are volume increase and/or pressure overload and myocardial thickness. CHFpEF patients often exhibit adaptive type of left ventricular myocardial remodeling with hypertrophy, which may blunt NP elevation [9; 14].

A critical challenge of CHFpEF diagnosis remains in female patients, who typically demonstrate more pronounced concentric LV remodeling, smaller chamber dimensions, higher ejection fractions, and greater diastolic dysfunction. An EF of 50–55 % may not represent the normal range for women. So, it determines the need for further study of this problem and development of new diagnostic algorithms for early detection of circulatory insufficiency in women and obese patients – population groups with potentially higher CHFpEF incidence. Recent prognoses suggest an increase of CHF incidence in females by ≥30 % in the coming years [18–20].

The development of simple algorithms for detecting HFpEF and their implementation in clinical practice is extremely important. The HFA-PEFF approach was developed by the researchers of the European Society of Cardiology. The main objective of this algorithm is both to determine the probability of HFpEF and to exclude other causes of symptoms and diastolic dysfunction.

At the first stage the likelihood of CHFpEF in patients with dyspnea of unknown etiology is assessed, as well as their physical endurance. If no non-cardiac causes of dyspnea are identified and risk factors exist, echocardiography is performed at the second stage. This allows verification of CHFpEF criteria established by experts, based on structural and functional cardiac changes and NP levels. The total score suggests the probability of HFpEF, and with 2-4 points, a diastolic stress test (third stage) is performed. This test, whether invasive or noninvasive, enables accurate verification of CHFpEF, including patients with diastolic dysfunction symptoms that manifest only during physical exertion.

It should be noted that the same criteria, depending on various characteristics, may qualify as either major or minor. For example:

• An E/e' value >15 meets a major criterion (2 points)
• While E/e' of 9–14 meets a minor criterion (1 point)

The total score determines the probability of CHFpEF diagnosis:

• 5 points makes CHFpEF probable
• < 2 points excludes CHFpEF
• 2–4 points requires additional testing (invasive or noninvasive stress test)

The invasive stress test involves hemodynamic assessment through cardiac catheterization while exercising with measurement of pulmonary capillary wedge pressure (PCWP). The noninvasive alternative is echocardiography with physical exertion during which diastolic dysfunction parameters are assessed. Thus, stress testing helps to identify CHFpEF in patients who demonstrate diastolic dysfunction symptoms only during exertion [15].

The H2FPEF score for CHFpEF diagnosis was developed at the Mayo Clinic (USA). This method is based on invasive hemodynamic assessment during stress testing, risk factors being determined using points. Evaluation employs clinical and ultrasound criteria to verify CHFpEF.

The scoring works as the following:

• 6–9 points indicate high probability of CHFpEF
• 0–1 points excludes CHFpEF
• 2–5 points requires additional examination with diastolic stress testing on a bicycle ergometer

The discussed scoring systems help to standardize approaches to assessing CHFpEF probability in patients with unexplained dyspnea. However, along with the advantages, these assessment formats have certain limitations. For example, the H2FPEF score cannot classify patients with dyspnea of unclear etiology, while the HFA-PEFF algorithm addresses this issue, though the possibility of using invasive and noninvasive stress tests in clinical practice remains quite low [16].

The search for highly sensitive and specific biomarkers that could verify HFpEF at early stages is particularly important. There is an approach of a simultaneous determination of multiple myocardial stress markers, enabling earlier diagnosis while considering the disease's pathogenetic features.

Pro-inflammatory cytokines, including growth differentiation factor 15, tumor necrosis factor receptors 1, vascular endothelial growth factor A, interleukins 6 and 8, as well as ST2 and galectin-3, show significant correlation with the severity of circulatory insufficiency and possess prognostic value. These findings confirm the inflammatory theory of the disease pathogenesis [21].

The treatment of CHFpEF patients is not less challenging. Previous clinical guidelines adopted an etiological approach for this patient cohort, as the evidence base for therapeutic strategies in CHFpEF remains less convincing than for the patients with reduced EF [17].

For CHFpEF patients with congestive symptoms, diuretics may be recommended to alleviate heart failure symptoms and signs [22]. Limited evidence exists regarding angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) in reducing symptoms and improving functional status in patients with circulatory insufficiency [23]. These medications, along with aldosterone antagonists, may be prescribed to reduce HF-related hospitalization risk [24].

The use of angiotensin receptor-neprilysin inhibitors (ARNIs) should be considered in order to decrease the risk of circulatory insufficiency-related hospitalizations and mortality [25]. The PARAGON-HF trial demonstrated a trend toward reduced cardiovascular death and heart failure hospitalizations in patients treated with ARNI [26].

For HFpEF patients, SGLT-2 inhibitors are recommended with the highest evidence level to reduce HF decompensation-related hospitalizations and mortality, as clearly demonstrated by the EMPEROR-Preserved and DELIVER trials. A meta-analysis of combined data from both studies confirmed a 20% reduction in the composite endpoint of cardiovascular death or first HF hospitalization, justifying the inclusion of SGLT-2 inhibitors in circulatory insufficiency treatment regimens. The reduction in primary endpoint was observed across the entire spectrum of LVEF values [23], consistent with all recommendations in the ESC HF 2021 guidelines. However, questions concerning optimal timing for initiating this therapy relative to other recommended HF medications still remain.

Conclusions

Current approaches to the diagnosis and treatment of patients with CHFpEF are studied in this review. In conclusion, the authors note the following: CHFpEF is a common phenotype of heart failure, but new protocols must be developed for its verification. Modern echocardiographic criteria, the use of stress tests, and expert-level ultrasound equipment complicate the verification of circulatory failure at early stages. The level of atrial natriuretic peptides does not always exceed previously established diagnostic thresholds, even in clinically significant CHFpEF. Therefore, additional examinations and the implementation of a multimarker diagnostic approach are required.

Taking into account the limited availability of these diagnostic methods in the primary healthcare institutions of the Russian Federation, the development of a two-stage routing system for patients with suspected CHFpEF and the establishment of diagnostic centers with the capability to verify this condition are necessary.

Current randomized clinical trial data demonstrate a positive impact of SGLT2 inhibitors on clinical outcomes in patients with CHFpEF. This strongly supports the inclusion of a new class of drugs–SGLT2 inhibitors–into HFpEF therapy regimens. Nevertheless, the study results do not allow to identify the benefits and safety of SGLT2 inhibitors in CHFpEF. Moreover, questions regarding the optimal timing for initiating this therapy in the context of prescribing other recommended medications for heart failure treatment still remain.

About the authors

O. A. Ponomareva

Ye.A. Vagner Perm State Medical University

Author for correspondence.
Email: sovpel_olga@bk.ru
ORCID iD: 0009-0009-4835-2666

Postgraduate Student, Assistant of the Department of Faculty Therapy no. 1

Russian Federation, Perm

V. Е. Vladimirsky

Ye.A. Vagner Perm State Medical University

Email: sovpel_olga@bk.ru
ORCID iD: 0000-0001-6451-9045

DSc (Medicine), Head of the Department of Faculty Therapy no. 1

Russian Federation, Perm

I. V. Petukhova

Ye.A. Vagner Perm State Medical University

Email: sovpel_olga@bk.ru
ORCID iD: 0009-0005-7328-7537

PhD (Medicine), Associate Professor of the Department of Faculty Thera­py no. 1

Russian Federation, Perm

References

Supplementary files