HFpEF: Heart Failure with Preserved Ejection Fraction

History

Heart failure is a clinical syndrome that occurs when the heart muscle cannot pump blood effectively.1 Heart failure is further classified based on symptoms and how well the left ventricle functions.2 When the function of the left ventricle is impaired, left ventricular ejection fraction is reduced.2 When left ventricular ejection fraction is less than 40%, this is known as heart failure with reduced ejection fraction (HFrEF).2 When left ventricular ejection fraction is preserved (i.e., greater than 50%), this is known as heart failure with preserved ejection fraction (HFpEF).2

Some patients are also classified as having mildly reduced ejection fraction (HFmrEF) if their ejection fraction is between 41% and 49%.3 Additional classifications include heart failure with improved ejection fraction (HFimpEF), which is reserved for those who have improved ejection fraction greater than 40% after having previously had reduced ejection fraction that was less than 40%.3 The focus of this article is the subclassification of HFpEF. Heart failure with preserved ejection fraction can be caused by a variety of factors, mostly age-related, including hypertension, diabetes, and obesity.

HFpEF Epidemiology

Between 2013 and 2016, there were approximately 6.2 million people in the United States who had heart failure.2 More than 50% of patients who have heart failure are classified as having heart failure with preserved ejection fraction.1 In fact, the incidence of heart failure with preserved ejection fraction (HFpEF) has grown in recent years when compared to the incidence of heart failure with reduced ejection fraction (HFrEF).4 Since 2017, heart failure hospitalization also has increased.3

Heart failure is more common in people who are older.1 Patients who have HFpEF are typically older than patients who have heart failure with reduced ejection fraction (HFrEF).5 Heart failure is also more common in African American patients, with a 25% greater prevalence in African Americans compared with Caucasians.2 Non-Hispanic African American patients also have the highest death rate per capita due to heart failure.3 Although women are less likely to have HFrEF, the risk for HFpEF is similar between men and women.5 Additionally, about half of the patients who have heart failure with preserved ejection fraction (HFpEF) also have five or more major comorbid conditions.5

HFpEF Etiology & HFpEF Risk Factors

Heart failure can occur due to diverse etiologies.1 Common etiologies for heart failure include coronary artery disease, high blood pressure, chronic obstructive pulmonary disease, valvular heart disease, and cardiomyopathies.1 Other possible causes include congenital heart disease, obesity, diabetes mellitus, and infections.1 Risk factors for heart failure with preserved ejection fraction (HFpEF) specifically include hypertension in addition to diabetes, kidney disease, atrial fibrillation (AF), and obesity.1,4,6

HFpEF Prognosis

Patients with HFpEF (heart failure with preserved ejection fraction) have a mortality rate of about 2.9%.1 Mortality is more likely in patients who have more comorbidities.5 Death can occur due to cardiovascular causes or noncardiovascular causes. Noncardiovascular causes are more likely to cause death in patients with heart failure with preserved ejection fraction (HFpEF) when compared with patients with heart failure with reduced ejection fraction (HFrEF).5

HFpEF Diagnosis & Presentation

Some patients with stable heart failure with preserved ejection fraction (HFpEF) may have no clinical signs and symptoms.5 Patients with HFpEF who do have symptoms present with symptoms that are similar to those of patients with heart failure with reduced ejection fraction (HFrEF).1 Common symptoms of both HFrEF and HFpEF include dyspnea, orthopnea, edema, abdominal discomfort, fatigue, anorexia, and weakness.1 If present, these symptoms typically become more severe with exertion.1 Patients who progress to advanced heart failure may present with symptoms such as resting sinus tachycardia, diaphoresis, narrow pulse pressure, and peripheral vasoconstriction.1

Diagnosis is based on multiple sources of data including history, clinical signs and symptoms, laboratory findings, and imaging.1 It is important to note that while findings may be abnormal in patients with HFpEF (heart failure with preserved ejection fraction) who have progressed to decompensated disease, determining the diagnosis is more difficult in patients who are stable or in patients who have only exertional symptoms.5

The clinical composite score H2FPEF may also be used to aid risk stratification and to guide diagnostic workup.3 This score combines patient risk factors, such as obesity, AF, age greater than 60, into a weighted score.3 Patients with a score of less than 2 have low likelihood of having HFpEF, whereas patients with a score greater than 6 have a high likelihood of this disorder.3 A further workup is indicated for patients in the midrange of the score.3

Based on symptoms, laboratory findings, and imaging, the diagnosis of heart failure may be further classified. According to the 2022 ACCF/AHA Guidelines, heart failure may be divided into four stages based on presence of structural changes and presence of symptoms:

  • Stage A: At risk for heart failure; patients at high risk for heart failure but no structural heart disease or symptoms of heart failure
  • Stage B: Pre-heart failure; patients who have asymptomatic left ventricular dysfunction but no symptoms
  • Stage C: Symptomatic heart failure; patients who have heart failure symptoms
  • Stage D: Advanced heart failure; patients with refractory heart failure despite optimized treatment3

Additionally, heart failure is classified into New York Heart Association (NYHA) classes based on how heart failure symptoms affect the patient’s daily physical activities and functioning:

  • Class I: Patients who have asymptomatic left ventricular dysfunction with no limitations on physical activity or symptoms
  • Class II: Patients who have mild symptoms with slight limitation of physical activity
  • Class III: Patients who have moderate symptoms with marked limitation of physical activity
  • Class IV: Patients who have severe symptoms at rest.1

Finally, several established criteria for the diagnosis of heart failure based on clinical symptoms are available.5 One example is the Framingham criteria, which base the diagnosis on the presence of major symptoms (such as, nocturnal dyspnea and orthopnea, among others) as well as minor symptoms (such as, edema of the extremities and exertional dyspnea, among others).5

HFpEF Physical Examination Findings

To assist with diagnosis, a detailed patient history should be collected, and a complete physical exam should be performed.4 However, some individuals with heart failure with preserved ejection fraction (HFpEF) who are stable may not present with clinical signs and symptoms.5

Patients who do present with symptoms may present with nonspecific physical exam findings such as peripheral edema due to fluid retention.7 Orthopnea or bendopnea (shortness of breath when bending forward) may also be present.3

Physical exam should include measurement of patient height and weight, an assessment of the cardiovascular system (including auscultation of heart sounds for irregular rhythm and orthostatic BP measurement), and an assessment of volume status (including peripheral edema, jugular venous distention, and gallop heart sounds).4,7 Patients may report symptoms including breathlessness, exercise intolerance, or fatigue.6,7

Collecting past medical history is important because risk factors such as diabetes, AF, hypertension, and kidney disease increase the probability of a heart failure with preserved ejection fraction or HFpEF diagnosis and are included as part of the clinical composite score H2FPEF.3,4

Finally, family history focused on history of familial cardiomyopathy or other cardiac history can be an important component for those who may have a heart failure with a genetic component.3

HFpEF Diagnostic Workup

Labs

Important components of the diagnostic workup can include complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), serum creatinine, B-type natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP), glucose, fasting lipid profile, lipid function test, thyroid-stimulating hormone (TSH), and iron studies.1,3,6 Elevated natriuretic peptide levels of BNP greater than 35 pg/mL or NT-proBNP greater than 125 pg/mL may indicate heart failure with preserved ejection fraction (HFpEF) in patients who are asymptomatic.6

These values are especially useful for ruling out heart failure during the diagnostic workup process; however, increased values can occur due to other cardiac causes, such as acute coronary syndrome, and noncardiac causes, such as anemia, pneumonia, renal failure.3 Additionally, higher levels are associated with an increased risk of poor outcomes such as hospitalization and death.3 It is important to note that patients who are obese may have reduced levels of these BNP and NT-proBNP biomarkers.3 Additional genetic testing may also be appropriate in patients who are suspected of having cardiomyopathy due to genetic factors based on gathered family history.3

Imaging

An electrocardiogram (ECG) should be performed and rhythm, rate, and QRS morphology and duration noted.1,3 Because atrial fibrillation is a risk factor for HFpEF, identifying AF on ECG may be a useful component of the diagnostic workup and is included as part of the clinical composite score H2FPEF as described above.3,6 Other abnormal ECG findings such as abnormal repolarization are not specific to the diagnosis of HFpEF.6

Other important imaging approaches include chest X-ray and especially the transthoracic echocardiogram (TTE).1 The chest x-ray may be helpful in assessing for pulmonary etiologies or pulmonary congestion, as well as providing information about the size of the heart.3,4 The TTE is considered a very useful component of the diagnostic workup because it provides both diagnostic and prognostic information.3 For example, the results of the TTE are used to determine whether the patient has heart failure with reduced ejection fraction (HFrEF) or HFpEF, and this determines the appropriate management approaches.1,3

Left ventricular ejection fraction, as well as left ventricular diameter, and volume are typically measured.6 Echocardiogram findings, such as a nondilated left ventricle with left ventricular ejection fraction greater than 50%, as well as left ventricular hyperplasia and left atrium enlargement are consistent with heart failure with preserved ejection fraction (HFpEF).6

Serial TTE may be used to assess patient progress, including any changes to the structures of the heart and changes to the ejection fraction. Repeat imaging is recommended only if the patient experiences new clinical signs and symptoms or to guide management decisions.3 Other imaging modalities that may be performed if more information is needed after the TTE include cardiac MRI, CT, PET.3

Additional Tests & Procedures

Exercise stress testing may be useful for unmasking heart failure symptoms in patients with heart failure with preserved ejection fraction (HFpEF) who are otherwise asymptomatic and can help identify the common comorbidity of coronary artery disease.6 Additionally, exercise testing can help assess the functional impact of heart failure, which can aid with heart failure classification.3 Tests that may be used include the cardiopulmonary exercise test (CPET) and the 6-minute walk test.3 Invasive exercise stress testing is also available.4

Cardiac catheterization or coronary angiography may also be performed if more information is needed after noninvasive testing.1 Cardiac catheterization or coronary angiography may also be appropriate for the assessment of heart failure; catheterization for hemodynamic monitoring can be used within the context of acute events such as acute respiratory distress or cardiogenic shock.3

HFpEF Differential Diagnosis

The differential diagnosis for heart failure is broad and spans many body systems. They may include:

  • Pulmonary disease: Such as respiratory failure and pulmonary embolism
  • Renal disease: Such as acute kidney injury and nephrotic syndrome
  • Liver disease: Such as cirrhosis
  • Cardiac disease: Such as myocardial infarction
  • Infection1

Identifying the specific etiology is important because treatment can vary based on underlying disease.3

HFpEF Management (Nonpharmacotherapy and Pharmacotherapy)

Patients with heart failure are typically managed by an interdisciplinary team that includes cardiologists, nurses, dieticians, and social workers.3

Nonpharmacotherapy

All patients with heart failure should be advised regarding the nonpharmacotherapy approach of lifestyle changes, including behavioral, dietary modifications, and regular exercise.1,4 This approach lowers the risk of developing heart failure in those at risk, and also includes smoking cessation and maintaining normal weight, blood pressure (BP), and blood glucose levels.3

While sodium restriction has typically been included in dietary recommendations, there are concerns about the impact of sodium restriction on dietary quality.3 The Dietary Approaches to Stop Hypertension (DASH) diet can help patients restrict sodium while still maintaining appropriate nutrient intake.3

Pharmacotherapy

Whereas many pharmacologic approaches are described for treatment for heart failure in patients with HFrEF, there are no known disease-modifying therapies that improve the outcomes of patients with heart failure with preserved ejection fraction (HFpEF).1

Because hypertension is one of the main risk factors for HFpEF, controlling blood pressure is the focus of treatment; however, there are no known optimal antihypertensive regimens specifically for patients with HFpEF.1,3 Therefore, to control BP, medications such as beta blockers, angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), angiotensin receptor–neprilysin inhibitors (ARNi), or mineralocorticoid receptor agonists (MRAs) may be used.1

Typically, beta blockers may be preferred in patients with a history of myocardial infarction, symptomatic coronary artery disease, or atrial fibrillation with a rapid ventricular response.3 Treatment of symptoms such as fluid overload may include the use of diuretics.1

The specific medications which have been studied in patients with HFpEF are the mineralocorticoid antagonist spironolactone and the ARNi sacubitril/valsartan.4 Spironolactone, a potassium-sparing diuretic, was shown to improve diastolic function in patients with HFpEF, while sacubitril/valsartan was shown to lower NT-proBNP levels.3

Because patients with HFpEF may have other comorbidities, such as coronary artery disease or AF, pharmacologic management of these conditions via medications such as statins and anticoagulants are also part of the management plan.4 Digoxin may be appropriate for rate control of comorbid AF in patients with HFpEF.3

Patients with comorbid diabetes, medications such as the sodium–glucose transport protein 2 (SGLT2) inhibitor dapagliflozin or empaglifozin may be used.4 However, these medications may also be useful for reducing heart failure hospitalization in all patients with HFpEF, including those who do not have diabetes mellitus.3

While nitrates and phosphodiesterase-5 inhibitors are often used in the management of patients with heart failure with reduced ejection fraction (HFrEF), these medications have not been shown to be beneficial in patients with HFpEF.3

Implantable Devices

Some patients with heart failure may be candidates for implantable devices such as cardiac resynchronization therapy (CRT) or implantable cardioverter-defibrillator (ICD).3 For patients with associated coronary artery disease, revascularization procedures may be advised.3

Monitoring Side Effects, Adverse Events, Drug-Drug Interactions

Beta Blockers

Beta-blocker common side effects include bradycardia, hypotension, fatigue, dizziness, nausea, constipation, and sexual dysfunction.8 Bronchospasm is another possible side effect, and patients with a history of respiratory disease such as asthma should be monitored carefully.8 Beta blockers may also exacerbate the symptoms associated with Raynaud disease.8 Because beta blockers affect heart rate and blood pressure, these parameters should be monitored closely.8 There is also a risk of heart block.8

ACE Inhibitors

ACE inhibitors may have side effects including dry cough, dizziness, hypotension, increased BUN and creatinine, syncope, and hyperkalemia.9 Less commonly, angioedema can occur and is potentially life-threatening, so patients should be educated and monitored appropriately and the ACE inhibitor discontinued if angioedema occurs.9 Patients should also be monitored for cough, because this side effect can decrease medication adherence.9

There are multiple contraindications to the use of ACE inhibitors, including absolute contraindications (hypersensitivity reaction with previous ACE inhibitor use, pregnancy) and relative contraindications (patients with abnormal renal function, aortic valve stenosis, or hypovolemia).9 Monitoring BP, potassium, and BUN and creatinine may be indicated due to these possible side effects.9 Because diuretics can also lead to hypotension, these medications can be discontinued prior to initiating ACE inhibitor therapy to avoid additive effects.9

ARBs

ARBs rates of side effects are low.10 While cough and angioedema are possible side effects, the rate of these are much lower with ARBs than with ACE inhibitors.10 These medications are also contraindicated in pregnancy, as well as in patients who have bilateral renal artery stenosis or hypotension due to heart failure.10

Using ARBs in combination with an ACE inhibitor leads to additive effects with regard to hypotension, hyperkalemia, and renal impairment, and patients should be monitored closely when ACE inhibitors and ARBs are given simultaneously.10 Additionally, because these medications lower blood pressure, BP should be monitored.10

ARNI in HFpEF: Sacubitril/Valsartan

ARNI sacubitril/valsartan is in a different class but is typically used in place of ACE inhibitors or ARBs in patients who have previously tolerated ACE inhibitors or ARBs.11 Side effects are similar to the side effects of ACE inhibitors and ARBs and include hypotension, hyperkalemia, renal impairment, cough, and angioedema.11 Symptomatic hypotension may occur more often with the use of an ARNI than with the use of ACE inhibitors or ARBs.3

Valsartan Contraindications

Sacubitril/valsartan is also contraindicated in patients who are pregnant, those who are hypersensitive to sacubitril/valsartan, or those who have experienced angioedema with ACE inhibitor or ARB administration.11 This medication should not be given to patients with diabetes who take aliskiren.11 Monitoring BP, potassium, and renal function is also important.11 This medication inhibits the breakdown of BNP, so NT-proBNP levels should be monitored.11

MRA Spironolactone in HFpEF

Common side effects of MRA spironolactone include hyperkalemia and the non-electrolyte hormonal effects such as gynecomastia in men and menstrual irregularities in women.12 Liver toxicity as evidenced by elevated ALT and AST is a rare side effect, and the medication should be discontinued if this occurs.12

Due to the possible side effect of hyperkalemia, this medication is contraindicated in patients who have hyperkalemia, patients who are at an increased risk of developing hyperkalemia, or patients with renal impairment.12 Monitoring potassium and renal function is important, especially in patients who are also taking ACE inhibitors or ARBs, due to the additive effects of these medications.12

SGLT-2 Inhibitors for HFpEF

SGLT-2 inhibitors that may be used especially within the context of comorbid diabetes mellitus (DM), common side effects include genital mycotic infections, nasopharyngitis, urinary tract infections, back pain, influenza, dyslipidemia, constipation, discomfort during urination, and pain in an extremity.13 There is the rare side effect of necrotizing fasciitis of the perineum. If this occurs, the patient will be managed with broad-spectrum antibiotics and surgical debridement and the medication should be discontinued.13

Contraindications include concurrent use with another SGLT-2 inhibitor or hypersensitivity reaction to the medication.13 Because this medication is given within the context of comorbid DM, blood glucose and hemoglobin A1c should be monitored.13 Additionally, volume status, renal function, and symptoms of hypoglycemia should be assessed.13

Digoxin

Digoxin, which may be used for rate control of comorbid AF, include side effects of nausea, vomiting, anorexia, and visual changes.14 Digoxin toxicity can also occur when serum concentration is greater than 2 ng/ml.14 Arrhythmias can occur within the context of digoxin toxicity.14 Many contraindications exist for the use of digoxin, including acute myocardial infarction, ventricular fibrillation, hypersensitivity to the medication.14

Digoxin should also be used with caution in patients with renal impairment, AV block, and thyroid disease.14 Digoxin also interacts with many medications, such as macrolide antibiotics, azole antifungals, loop diuretics, so careful analysis of drug-drug interactions should occur.14 Due to the potential for toxicity, digoxin levels should be monitored with medication changes or changes in clinical status.14

Statins

Common side effects of statin medications, used to address comorbid hyperlipidemia, include myopathy, rhabdomyolysis, and hepatotoxicity.15 Statins are contraindicated in pregnancy and in patients who have liver disease or increased liver enzymes.15 Some statins are substrates of CYP3A4 and drug-drug interactions can occur with medications that inhibit this enzyme, so the potential for drug-drug interactions should be assessed carefully.15 Baseline liver function should be assessed, but regular monitoring of liver function is no longer recommended unless there are clinical signs or symptoms of liver toxicity.15 Typically, lipid panels are performed at baseline and then again in 6 to 12 weeks to assess for efficacy of the statin.15

Anticoagulants

In anticoagulants, bleeding is the main risk.16 There are also absolute contraindications (active bleeding, coagulopathy, major trauma) and relative contraindications (gastrointestinal bleeding, low-risk surgery).16 Monitoring requirements vary based on medication, but routine monitoring is not typically required for direct oral anticoagulants that may be used within the context of atrial fibrillation management.16 If bleeding is suspected, testing such as CBC and aPTT, may be performed.16 Reversal agents vary based on medication and may be used in cases of toxicity.16

Complications of HFpEF

A variety of complications affecting multiple body systems can occur due to heart failure.17 These heart failure complications include arrhythmias (especially AF), thromboembolism (including stroke, pulmonary embolism, or deep venous embolism), gastrointestinal complications such as hepatic dysfunction due to congestion, musculoskeletal complications such as muscle wasting, and respiratory complications such as pulmonary congestion.17

Cardiovascular complications that occur specifically as heart failure with preserved ejection fraction (HFpEF) progresses include changes to cardiac reserve and rhythm, stiffening of the ventricles, and endothelial dysfunction, among others.18 Pulmonary complications of HFpEF include pulmonary hypertension. Pulmonary hypertension is associated with high mortality and morbidity.19

HFpEF Guidelines

For more information, please see the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

References

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  3. Heidenreich P, Bozkurt B, Aguilar D, al. e. AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022:e263–e421. https://doi.org/10.1016/j.jacc.2021.12.012
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  5. Dunlay S, Roger V, Redfield M. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017:591-602.
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  10. Hill R, Vaidya P. Angiotensin II receptor blockers (ARBs). In: StatPearls. NCBI Bookshelf version: 2022. Accessed September 14, 2022.
  11. Nicolas D, Kerndt C, Reed M. Sacubitril/valsartan. In: StatPearls. NCBI Bookshelf version: 2022. Accessed September 14, 2022.
  12. Patibandla S, Heaton J, Kyaw H. Spironolactone. In: StatPearls. NCBI Bookshelf version: 2022. Accessed September 14, 2022.
  13. Padda I, Mahtani A, Parmar M. Sodium-glucose transport protein 2 (SGLT2) inhibitors. In: StatPearls. NCBI Bookshelf version: 2022. Accessed September 14, 2022.
  14. David M, Shetty M. Digoxin. In: StatPearls. NCBI Bookshelf version: 2022. Accessed September 21, 2022.
  15. Sizar O, Khare S, Jamil R, et al. Statin medications. In: StatPearls. NCBI Bookshelf version: 2022. Accessed September 14, 2022.
  16. Umerah C, II M. Anticoagulation. In: StatPearls. NCBI Bookshelf version: 2022. Accessed September 14, 2022.
  17. Watson R, Gibbs C, Lip G. ABC of heart failure. Clinical features and complications. BMJ. 2000:236-239. doi: https://doi.org/10.1136/sbmj.000358
  18. Borlaug B. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2014:507-515.
  19. Lai Y, Wang L, Gladwin M. Insights into the pulmonary vascular complications of heart failure with preserved ejection fraction. J Physiol. 2019:1143-1156. doi: 10.1113/JP275858

Author Bio

Anna Courant is a medical writer and nurse practitioner.