Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure with normal or near-normal ejection fraction and objective evidence of diastolic dysfunction.
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Terminology
Heart failure with preserved ejection fraction was initially termed ‘diastolic heart failure' and was replaced with the current name 1.
Epidemiology
Heart failure with preserved ejection fraction makes up for more than half of heart failure patients. The condition affects mainly older people, affecting 4.9% of the population aged above 60 years 2. It seems to be more common in females and the frequency is expected to increase as people live longer 2-7.
Risk factors
Risk factors for heart failure with preserved ejection fraction include the following conditions 1-5:
- advanced age
- obesity
- diabetes mellitus
- metabolic syndrome
- hypertension
- atrial fibrillation
- physical inactivity
- smoking (doubles risk) 14
Associations
Heart failure with preserved ejection fraction is associated with the following conditions 1,6,8:
- systemic inflammation
- microvascular dysfunction
- myocardial fibrosis
- hypertensive heart disease
- infiltrative cardiomyopathies such as cardiac ATTR (transthyretin) amyloidosis (in up to 13-19%)
- renal artery stenosis
- chronic kidney disease
- sleep disorders
- ventricular dyssynchrony
- pulmonary hypertension
Diagnosis
Diagnostic criteria
There is an ongoing diagnostic uncertainty with several varying diagnostic criteria proposed by societies and clinical trials 3,4. A simplified approach recommended by the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure were the following criteria 3:
- clinical symptoms and signs of heart failure
- preserved left ventricular ejection fraction of ≥50%*
- objective evidence of structural, functional and serological cardiac abnormalities in keeping with diastolic dysfunction and increased left ventricular filling pressures
* A history of reduced left ventricular ejection fraction <40% with later recovery should be considered as such 3 and a left ventricular ejection fraction of 40-49% is considered as a grey area or as ‘mildly reduced’ 3,4.
Clinical presentation
Typical presenting symptoms are that of heart failure including fatigue, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, nocturia etc. 4.
ECG might demonstrate atrial fibrillation or features of left ventricular hypertrophy.
Serologically circulating natriuretic peptides as NT-proBNP or BNP (brain natriuretic peptide) will be typically elevated 1. The following values can be considered as abnormal 3,5:
- NT-proBNP >125 pg/mL in sinus rhythm or >365 pg/mL in atrial fibrillation
- BNP >35 pg/mL in sinus rhythm or >105 pg/mL in atrial fibrillation
Complications
Untreated heart failure with preserved ejection fraction might progress to heart failure with reduced ejection fraction. Further complications include arrhythmias and cardiac arrest.
Pathology
The main problem in heart failure with preserved ejection fraction is ventricular diastolic dysfunction characterized by an abnormally increased diastolic pressure-volume relationship due to impaired ventricular relaxation and increased stiffness of the myocardium 4,6. Hereby, the ventricle is filled with lower end-diastolic preload volumes at higher pressures due to a prolonged pressure decay during isovolumetric relaxation in early diastole 6.
Under stress, when the heart rate increases, the left ventricle is not able to enhance relaxation appropriately, which contributes to an increase in left ventricular and left atrial pressures and leads to an insufficient rise of ejection fraction 4,6.
Other factors contributing to the limitation of systolic reserve capacity and increase in filling pressures, and thus diastolic and systolic dysfunction, include left atrial dysfunction, chronotropic incompetence, atrial fibrillation, autonomic imbalance, arterial stiffening, endothelial dysfunction, and peripheral impairments in skeletal muscle and body composition 6.
Etiology
In most cases, the cause of heart failure with preserved ejection fraction is thought to evolve from a combination of risk factors and associations or comorbidities mentioned above.
Specific etiologies are not much different from other types of heart failure and include abnormalities of the myocardium and abnormal loading conditions, such as 1,2:
- ischemic heart disease (e.g. myocardial scarring, myocardial stunning, microvascular dysfunction)
- toxins (e.g. alcohol, heavy metals, medications, radiation etc.)
- immune or inflammatory heart disease (e.g. myocarditis, rheumatoid arthritis)
- infiltrative cardiomyopathies (e.g. cardiac amyloidosis, cardiac sarcoidosis, storage disorders)
- metabolic conditions (e.g. thyroid disease, thiamine deficiency etc.)
- genetic conditions (e.g. hypertrophic cardiomyopathy, muscular dystrophy)
- endocardial disease (e.g. endocardial fibroelastosis)
- hypertensive heart disease
- valvular and structural heart disease
- high output states (e.g. anemia, sepsis, thyrotoxicosis)
- volume overload (e.g. renal failure)
- cardiac arrhythmias
Radiographic features
Plain radiograph
Chest x-ray might show non-specific findings of heart failure including pulmonary venous congestion, cephalisation of pulmonary veins, pulmonary interstitial or alveolar edema.
Echocardiography
Echocardiography typically shows preserved left ventricular ejection fraction with findings of diminished left ventricular distensibility and increased left ventricular filling pressures and includes an assessment of the following parameters 2,3:
- left ventricular mass index and relative wall thickness
- left atrial volume index
- E/e’ or E/A ratios at rest
- tricuspid regurgitation velocity
Left ventricular long-axis function might be abnormal and can be assessed using mitral annular plane systolic excursion, systolic velocities or left ventricular global longitudinal strain 2.
CT
Coronary CTA might be used to rule out coronary artery disease.
MRI
Cardiac MRI can reliably assess cardiac function, including cardiac volumes and measurements and ventricular wall thickness. However, its main task in the setting of heart failure with preserved ejection fraction is the etiological workup, the detection of myocardial fibrosis, and the identification of infiltrative cardiomyopathies or inflammatory conditions such as cardiac amyloidosis, Fabry disease, cardiac sarcoidosis or myocarditis 2,9.
Nuclear medicine
Scintigraphy with a technetium pyrophosphate scan can be helpful in the setting of ATTR amyloidosis 4.
Coronary angiography
Coronary angiography might be performed in the setting of suspected coronary artery disease 4.
Radiology report
The radiological report should include a description of the following features:
- cardiac volumes and measurements
- cardiac wall motion abnormalities
- potential etiologies, such as:
- myocardial fibrosis
- myocarditis
- infiltrative cardiomyopathies
- endocardial fibroelastosis
Treatment and prognosis
Treatment has been non-specific for many decades, including diuretics and control of comorbid conditions with restrained success and prognosis 1,3-7. Outcomes are better than in patients who have reduced ejection fraction according to clinical trial populations, even if they are close to the latter in observational studies 4.
Recently, the EMPEROR-Preserved trial showed a significant reduction of the combined risk of cardiovascular death and hospitalization for heart failure by 21% after administration of empagliflozin 10, a sodium glucose co-transporter-2 (SGLT-2) inhibitor in the renal proximal tubules, in patients with a left ventricular ejection fraction of more than 40%. Similarly positive findings were found in the DELIVER trial of dapagliflozin 15.
History and etymology
Heart failure with preserved ejection fraction was recognized in the second half of the 20th century by cardiovascular physiologists and clinical investigators as Robin and Burwell in 1957 11.
Brutsaert et al. established a more precise definition of ‘diastolic heart failure’ in 1993 before the name was replaced by ‘heart failure with preserved ejection fraction’ 12.
Differential diagnosis
Conditions that must be considered in the presence of heart failure with preserved ejection fraction include 2-4:
- pericardial disease
- hypertrophic cardiomyopathy
- infiltrative cardiomyopathies
- coronary artery disease
- valvular heart disease
- cardiac arrhythmias
- anemia
- deconditioning
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