Introduction to Heart Failure With Preserved Ejection Fraction
Lewis, in 1933 defined heart failure (HF) as “a condition in which the heart cannot properly discharge its contents” (1). Subsequently, it was concluded that the main characteristic of this syndrome was congestion, promoting a new definition for HF: “an inability of the heart to pump blood to the body at a rate commensurate with its needs, or to do so only at the cost of high filling pressures” (2).
HF is a chronic, progressive clinical syndrome that can present with exacerbations induced by structural and functional cardiac abnormalities, among others. The main terminology used to describe HF is based on the measurement of the left ventricular ejection fraction (LVEF), differentiating patients with reduction <40% (HFrEF), midrange 40-49% (HFmEF), and preserved ≥50%. (HFpEF) ejection fraction. This classification is important due to the different underlying etiologies, pathophysiology, available treatment, and their respective response (3). In this article, we will address the different aspects of HFpEF that we know to date, and we will learn why it represents a challenge that is increasing worldwide.
Epidemiology of Heart Failure With Preserved Ejection Fraction
HF is a global pandemic that is increasing; This is due to the increase in the life expectancy of the population, the improvement in survival after an acute myocardial infarction, and the improvement of the treatment and survival of patients with HF (4).
About 6.5 million adults in the United States have HF. It caused 1 in 8 deaths in 2017. In 2018, it was mentioned on 379,800 death certificates(13,4%) (5).
Approximately half of the 6.5 million adults with HF are considered to have preserved ejection fraction, according to statistics published in 2020 by Heart and Stroke (5). Patients with preserved LVEF were older, more often female, with higher mean arterial pressure, and more often had a history of atrial fibrillation (AF) and hypertension compared with patients with HFrEF (6).
Projections estimate that by 2030 more than 8 million people over 18 years of age will be affected by HF ( 7, 8).
As predisposing pathologies such as diabetes and obesity increase in incidence, so will the incidence of HF, becoming a prolonged and permanent burden for the health system.
Risk Factors of Heart failure with Preserved Ejection Fraction
Historically, HFpEF was exclusively associated with diastolic dysfunction, unlike HFrEF, which was associated with systolic dysfunction. It is currently known that this is not so clear since both types of HF can also present systolic and/or diastolic dysfunction. Different mechanisms are involved in HFpEF. This is believed to be the result of a complex variety of cardiac, vascular, and systemic dysfunctions, with the contribution of various comorbidities (9).
Risk factors such as coronary artery atherosclerosis (CAA), obesity, diabetes, chronic kidney disease, advanced age, and pulmonary hypertension (PH) contribute to HFpEF. These factors promote the release of inflammatory mediators that contribute to the greater severity of PH, the deposition of collagen and other proteins that develop into cardiomyofibrosis and left ventricular hypertrophy (10, 11, 12). This cardiac remodeling predisposes to atrial fibrillation (13), an embolic arrhythmia that requires prompt treatment.
Obesity, in turn, can generate chronic pulmonary vascular remodeling and PH (14, 15), the latter being found in more than 80% of cases and associated with a worse prognosis. Right ventricular dysfunction, with systemic venous congestion, edema, malabsorption, congestive liver disease, cardiorenal syndrome, and cachexia, are also poor prognostic signs (16).
The pathophysiology of the disease is complex, heterogeneous and remains poorly understood. It is known that these patients are generally older, female, with numerous cardiovascular morbidity and non-cardiovascular, thus presenting a great impact on morbidity and mortality (17) and on health systems.
Diastolic dysfunction, when present, results in structural changes such as fibrosis and hypertrophy, microvascular dysfunction, and metabolic abnormalities, with increased stiffness and decreased cardiac compliance. This causes an increase in LV filling pressures and structural and functional changes at the atrial, pulmonary, and right ventricular level due to an increase in upstream pressures. The systolic reserve is also affected, mainly by changes in the ventricular-vascular coupling relationship (9). The ventricular-vascular uncoupling establishes that the acutely increased afterload secondary to ventricular-arterial stiffness leads to increases in blood pressure that worsen diastolic relaxation and to higher filling pressures during stress, resulting in exercise intolerance. By reducing ventricular-arterial stiffness, exercise tolerance improves (18, 19, 20).
Another underlying mechanism in this disorder is chronotropic incompetence, that is, inappropriate heart rate variations due to autonomic nervous system dysfunction secondary to increased serum catecholamines during exercise (9). Electrical and/or mechanical, systolic, and diastolic asynchronies were also observed in some patients (21). Its magnitude is related to the extent of diastolic dysfunction and exercise capacity (9).
Neurohormonal alterations, such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system (RAAS), are also important mechanisms involved (9).
Clinical Presentation of Heart Failure with Preserved Ejection Fraction
As a consequence of diastolic dysfunction, left atrial filling pressures increase to compensate for and maintain a stable end-diastolic volume. At first, this mechanism is sufficient, however, the retrograde increase in pressure affects the pulmonary circulation and the right cavities (22, 23). For this reason, these patients can develop PH concomitant with right ventricular dysfunction, which translates into congestive symptoms, decreased exercise tolerance, and chronotropic failure (24).
The ECG detects signs of ventricular hypertrophy and atrial fibrillation (25). Chest X-ray may show cardiomegaly and signs of pulmonary venous hypertension such as vascular redistribution and pleural effusion. In acute pulmonary edema, the image “on butterfly wings” can be observed.
Transthoracic echocardiography frequently diagnoses the etiology and provides useful data for prognosis. It detects structural anomalies and determines the LVEF, which makes it the most useful noninvasive tool for the approach to these patients (26, 27).
Natriuretic peptides in HFpEF have lower values than in HFrEF patients (28), although it is accepted that values above 100 pg/ml for brain natriuretic peptide (BNP) or an N-terminal brain natriuretic peptide greater than 300 pg /ml are associated with adverse cardiovascular outcomes (29), without forgetting that lower values do not rule out the presence of the syndrome (27).
Left heart catheterization demonstrating ventricular filling resting pressure > 16 mmHg confirms the diagnosis of HFpEF, as does a mean wedge pressure at rest > 15 mmHg (27).
Treatment of Heart Failure with Preserved Ejection Fraction
The variability in the etiology and associated comorbidities poses a challenge for each individual (9). No effective treatments were found to decrease morbidity and mortality or improve the prognosis in these patients, even with therapies that have this impact on HFrEF and HFmFr (9).
Current guidelines are based on symptom relief, detection, and treatment of associated diseases (3). Diuretics are recommended in case of congestion for symptom relief regardless of LVEF (3). Loop diuretics, such as furosemide, are widely used, although there are no specific recommendations on which diuretic treatment should be followed (30).
Let’s move on to analyze some useful drugs for this disorder:
- Furosemide. This potent loop diuretic is mainly indicated in HF when there are congestive symptoms. It also has a vasodilator effect that makes it very useful in acute pulmonary edema. It has the particularity that it eliminates a lot of potassium, so it must be associated with a potassium sparer drug such as spironolactone or eplerenone (31).
- Beta-blockers (BB). These drugs decrease both heart rate and contractility, so myocardial oxygen demands are lower. This is useful when HF is accompanied by CAA. In addition, by reducing the rate and increasing relaxation during diastole, it improves myocardial perfusion. On the other hand, they also exert an antihypertensive effect by reducing peripheral vascular resistance (32). It was suggested that carvedilol, a nonselective BB, would have pleiotropic effects, such as increased insulin sensitivity, a vasodilator effect with decreased preload, antioxidant, and antiarrhythmic effects, which could give it superiority over other drugs in the same group; however, nebivolol, a recent beta-blocker with pleiotropic effects, has also been considered as another option (33). Currently suggests that the advanced LV diastolic dysfunction, indicated by left atrial dilation, worsens the prognosis of HFpEF and that the standard dose of carvedilol exerts a significant reduction in the incidence of clinical outcomes in patients with HFpEF with advanced diastolic dysfunction (34).
It is noteworthy that there are contradictory findings regarding the reduction of mortality and the use of BB in HF with preserved ejection fraction. While several studies show that this pharmacological group does not modify mortality, others show contrary findings. In a study, they evaluated the post-discharge mortality of patients hospitalized for HF functional class III-IV and the use of carvedilol, from metoprolol, bisoprolol, and nebivolol, resulting in a decrease in mortality. This study further suggests that this benefit is dose-related (6).
At the start of treatment with these drugs, they should be given in small doses and slowly increase so as not to worsen HF due to their negative inotropic effects; therefore, they should be given in a situation of euvolemia.
- Angiotensin Converting Enzyme Inhibitor (ACEI)/Angiotensin Receptor Blocker (ARB). The benefit in patients with HFpEF is limited. Being arterial and venous vasodilators, they decrease preload and afterload, favoring cardiac output in the failing heart. Candesartan demonstrated a reduction in hospital admissions with no impact on cardiovascular mortality in patients with HF and LVEF greater than 40% (35). Perindopril did not show a statistical benefit on long-term mortality but improved HF symptoms and hospitalization (36). Irbesartan did not show benefits in terms of mortality, hospitalizations, or quality of life in this population (37). Enalapril also failed to show improvement in exercise tolerance, aortic compliance, or quality of life (38).
- Mineralocorticoids/aldosterone receptor antagonists (MRAs). Activation of mineralocorticoid receptors contributes to the pathophysiology of HF through sodium and water retention, potassium loss, endothelial dysfunction, inflammation, fibrosis, and hypertrophy (39). Blockage of these receptors could be beneficial in this syndrome. Spironolactone showed long-term benefits for left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life (39). This study was unable to assess the effect of spironolactone on HF hospitalizations or mortality. Clinical benefits and reduction of hospitalizations in patients with high BPN have also been established (40). For this reason, it is currently added to the US guidelines (41).
A frequent side effect is hyperkalemia caused by the retention of this ion, in addition to the fact that its diuretic potency is lower compared to other groups, its combination with loop or thiazide diuretics is common. A frequent reason for abandoning this drug is breast tenderness or gynecomastia caused by the activation of androgen receptors (42). Eplerenone is an alternative to prevent these effects.
- Angiotensin receptor neprilysin inhibitor (ARNI). Neprilysin is an enzyme that is responsible for the degradation of vasoactive peptides such as natriuretic peptides (NP). Sacubitril/valsartan is a crystalline compound composed of the angiotensin receptor blocker valsartan and the prodrug neprilysin inhibitor sacubitril. It dissociates into its components after ingestion. The increase in plasmatic NP improves myocardial relaxation with reduction of fibrosis and favors vasodilation and natriuresis with improvement of cardiac symptoms (43).
Another study evaluated NT-proBNP levels in patients receiving sacubitril/valsartan vs valsartan. The result was significantly better in the first group at 12 weeks of treatment, at 36 weeks a reduction in left atrial volume and an improvement in functional class were found (44).
- Ivabradine. The sinoatrial node is responsible for controlling HR. It may be overstimulated in these pathologies such as HF, having a poor prognosis and increasing mortality. Drugs such as ivabradine that act by selectively inhibiting this nodule can be of great help by prolonging diastole (45). However, it did not show benefit on exercise capacity and plasma NT-proBNP concentrations at 8-month follow-up. This effect on exercise was demonstrated at the start of treatment (46).
- Digoxin. Digoxin increases myocardial contractility while reducing systole. It also produces an increase in vagal tone, inhibition of central and peripheral sympathetic tone, and cardiac electrophysiology, being useful in patients with atrial fibrillation or flutter. It did not show any effect on mortality or HF hospitalizations (47).
- Nitrates and Nitrites. The hemodynamic effects of nitrates could attenuate exertional pulmonary congestion and improve exercise capacity in heart failure with preserved ejection fraction (48). Even so, it was shown that it did not improve submaximal exercise capacity, perception of quality of life, or NT-proBNP levels in these patients, in addition to causing an increase in HF symptoms (48). Its use is limited by its frequent side effects, such as excessive hypotension. Beneficial findings were found with inorganic nitrates, but it is necessary to expand studies (49).
- Sildenafil. It is proposed that sildenafil reverses cardiac remodeling in patients with HFpEF and improves vascular function with symptomatic benefits in pulmonary arterial hypertension, improvement in diastolic function, and exercise capacity. On the other hand, it negatively affects renal function and NT-proBNP levels (50).
Numerous studies are currently being developed, and more are required in the future on pharmacological treatment in HFpEF and thus be able to optimize the results. Many drugs have shown a reduction in mortality in patients with HFrEF but without the same benefit in HFpEF. Its frequent correlation with PH represents a new therapeutic objective involving trials with new drugs.
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Dyspnea Due to Respiratory Causes
Elena Diaz, MD
Elena Diaz is a physician graduated from the National University of Cordoba, Argentina. She works as a professor at the same university where she earned her degree and has participated in various scientific conferences, where she has lectured on her works in clinical research. Her beginnings in research were on addictions, which has led her to obtain a Diploma from the Provincial University of Cordoba. Currently, she has changed her focus to continue researching and training in cardiovascular medicine.