The diagnosis of HF-pEF is more complex than that of other HF phenotypes, particularly in elderly patients with multiple comorbidities who often present normal findings at first examination, with coexisting conditions that can mimic HF-pEF. In addition, the European Society of Cardiology (ESC) criteria,1 based on younger and more stable populations, may have limited applicability in the typical profile seen in internal medicine, especially during acute episodes.34,35

The existence of certain conditions in the clinical history that are well-known risk factors for the development of HF-pEF, such as advanced age, obesity, arterial hypertension, diabetes mellitus, chronic kidney disease and atrial fibrillation increase the likelihood that the clinical condition of the patient is due to the presence of HF-pEF.36

The diagnosis requires the following1:

• a

  Signs and symptoms consistent with clinical HF syndrome (indispensable requirement)

• b

  Left ventricular ejection fraction (LVEF) ≥ 50% (second indispensable requirement) accompanied by

• c

  Evidence of structural or functional LV dysfunction (hypertrophy, left atrial dilatation, or diastolic dysfunction) and/or natriuretic peptide (NP) elevation.

The signs and symptoms are those classical of HF. None alone or in combination are sufficiently specific to be able to establish a clear diagnosis of the HF phenotype according to LVEF.18 The diagnosis of HF will always be more likely in the presence of more specific clinical manifestations (orthopnea, bendopnea, paroxysmal nocturnal dyspnea, jugular vein distension, hepatojugular reflux and/or progressive bilateral edema). However, in elderly people it is not uncommon for the clinical manifestations to be more nonspecific (exertional dyspnea, fatigue, asthenia, loss of appetite, confusional state) and to be entirely or partially secondary to some other non-cardiac condition sharing signs and symptoms with HF (anemia, chronic respiratory disease, renal failure, venous insufficiency, protein malnutrition, immobility, sarcopenia, etc.). All of this requires a careful history and physical examination in an attempt to identify the presence of these clinical confounders, known in the American literature as non-cardiological mimics.18

First of all, patients with suspected HF-pEF should undergo the following:

• •

  Electrocardiogram (ECG): A strictly normal tracing reduces the probability of HF-pEF, but does not rule it out. The presence of hypertrophy or enlargement of the left atrium supports the diagnosis.

• •

  Chest X-ray: The absence of congestion or cardiomegaly suggests against the diagnosis, though without excluding it.

• •

  Basic laboratory tests: These tests can rule out other causes that may explain the symptoms or identify etiological or triggering factors (anemia, renal failure, infection, ischemia).1

If clinical suspicion persists on the basis of the signs and symptoms, together with the ECG findings, the next step is to perform a protocolized transthoracic echocardiogram (TTE), since the ESC definition implies the identification of morphological or functional abnormalities that are difficult to assess in an acute/subacute scenario in non-expert hands or with point-of-care ultrasound (POCUS) devices. If LVEF is ≥ 50%, the structural or functional abnormalities allowing the clinical manifestations of HF to be attributed to the existence of HF-pEF (regardless of the presence or not of non-cardiological mimics) are the following1,36:

• •

  Markers of LV hypertrophy (structural): interventricular septum thickness ≥ 12 mm or a relative LV wall thickness > 0.42. LV mass ≥ 115 g/m2 (in males) or ≥ 95 g/m2 (in females) may also be considered indicative.

• •

  Markers of LV filling abnormality in diastole (functional): E/e’ ratio > 9, e’ < 7 cm/s or left atrial volume index (LAVI) > 34 mL/m2 (for patients with atrial fibrillation [AF]) or 29 mL/m2 (for patients with sinus rhythm).

• •

  Markers of pulmonary hypertension: systolic pulmonary artery pressure > 35 mmHg or tricuspid regurgitation velocity > 2.8 m/s.

The greater the number of abnormalities, the greater the probability that the observed clinical manifestations are secondary to HF-pEF.

On the other hand, TTE can also detect alterations that are not part of this list and which constitute "secondary" HF-pEF, known in the American literature as cardiological mimics (significant valvular disease, right ventricular dysfunction, pericardial disease, hypertrophic cardiomyopathy, hyperdynamic situations, etc.). As with non-cardiological mimics, their presence may be simultaneous with the TTE findings defining “primary” HF-pEF. In fact this situation is not uncommon in elderly patients with multiple potential simultaneous causes of HF (arterial hypertension, cardiac ischemia, valvular disease, pulmonary hypertension, etc.).1

Finally, plasma NP levels should be found to be elevated in HF-pEF, particularly in an acute decompensated scenario. In fact, elevated NP has the same condition as a diagnostic indicator of LV filling abnormality as the E/e’ ratio, e’ value, or LAVI.1 It is very important to emphasize that elevated NP levels are not mandatory to establish the diagnosis: normal NP levels are plausible in relatively young and scarcely symptomatic patients with HF-pEF and obesity.37 However, this is not the usual scenario in internal medicine, and elevated NP levels are thus usually found.

Although some studies suggest that in the HF-pEF population, the NP values are somewhat lower than those found in patients with HF and a mildly reduced ejection fraction (HF-mrEF) or HF-rEF,38 the guidelines do not recommend differential cut-off values suggestive of one phenotype or another. Overall, the plasma NP levels that reinforce the clinical suspicion of HF are more demanding in prototypical elderly patients seen in internal medicine.39 In addition, a wide range of alternative causes are usually present in this population that may (even if only partially) account for the increase in NP levels (Supplementary Table 1).1 Thus, the contribution of NP levels as an aid to the diagnostic process is not as relevant as the combination of compatible clinical manifestations, together with objective TTE findings.

The NT-proBNP cut-off values suggestive of HF are1,36,40:

• •

  Acute HF (widespread use, values independent of LVEF, but increasing according to age): > 450 pg/mL (< 50 years), > 900 pg/mL (50–75 years), > 1800 pg/mL (> 75 years).

• •

  HF-pEF in the stable patient: variable values of non-widespread use, which according to the ESC consensus range from > 125 pg/mL (in patients with sinus rhythm) to > 660 pg/mL (in patients with AF).

The European guidelines of 2021 established as treatment recommendations for patients with HF-pEF the screening and treatment of the causes and comorbidities (cardiovascular and non-cardiovascular), as well as the diuretic treatment of patients with congestion in order to alleviate the symptoms and signs of HF-pEF.1 In 2023, following clinical trials with the sodium-glucose cotransporter-2 inhibitors (SGLT2i) empagliflozin and dapagliflozin,52,53 the ESC updated the guidelines, including these drugs as first-line treatment for patients with HF-pEF.14 Since then, new evidence has been published with other drug classes that have demonstrated clinical benefit in this patient population, mainly sacubitril-valsartan, finerenone, semaglutide, and tirzepatide, which offer the potential to expand the therapeutic options in certain patients.54–57

Diuretics are the treatment of choice for congestion, particularly loop diuretics. In acute decompensation, it is usually necessary to administer diuretics intravenously and at high doses, and they can be combined with hydrochlorothiazide during the acute phase - especially in patients who receive baseline treatment with 80 mg or more of furosemide every 24 h.58 Resistance to treatment with diuretics is defined as a decreased response to these drugs, which prevents adequate elimination of sodium and water, causing the persistence of congestion despite the administration of high doses. In this case, treatment strategies include dose escalation, the combination of different types of diuretics (e.g., loop diuretics and thiazides), or the administration of hypertonic saline in conjunction with furosemide to enhance its action.59

During the stability phase, loop diuretics should be used at the lowest possible dose, even considering their discontinuation in situations of euvolemia, or switching to hydrochlorothiazide in the case of arterial hypertension.11

SGLT2i represent the first drug class to be shown to reduce the risk of events in patients with HF-pEF. In this regard, the EMPEROR-Preserve (empagliflozin) and DELIVER (dapagliflozin) studies achieved significant reductions in the primary endpoint (cardiovascular mortality or hospitalization due to HF in the first study, and cardiovascular mortality or worsening of HF in the second study), of 21% and 18%, respectively. These findings were mainly due to a marked decrease in hospitalizations due to HF, with a trend towards a reduction in cardiovascular mortality (Supplementary Table 4).52,53 Thus, the guidelines consider SGLT2i to be the cornerstone treatment for patients with HF-pEF, with grade IA recommendation.10,14

Another drug class that has shown clinical benefit in the subgroup of patients with HF-pEF and obesity has been the GLP1 receptor agonists, particularly semaglutide 2.4 mg via the subcutaneous (s.c.) route. In the STEP-HF-pEF study, compared with placebo, weekly semaglutide s.c. improved patient quality of life and exercise tolerance, and reduced inflammation and body weight in individuals with obesity-associated HF-pEF.63 In the STEP-HF-pEF DM study, which included patients with HF-pEF, obesity and type 2 diabetes, semaglutide 2.4 mg s.c. produced, as in patients without DM, improvement of the HF symptoms and physical limitations (improved quality of life), as well as significant reduction of body weight, after one year of treatment.64 In the pre-specified pooled analysis of both studies, not only were these results confirmed, but the use of semaglutide 2.4 mg s.c. was also associated as a tertiary objective with a significant reduction in time to the first HF event and time to the first HF event or cardiovascular death.65 In the recent pooled analysis of patients with HF-pEF in the SELECT (individuals with atherosclerotic cardiovascular disease and who are overweight or obese), FLOW (subjects with type 2 diabetes and chronic kidney disease), STEP-HF-pEF and STEP-HF-pEF DM studies, treatment with semaglutide s.c. was associated with significant 31% reductions in the risk of cardiovascular death or HF events (HR 0.69; 95%CI 0.53−0.89) and 41% reductions in the risk of worsening HF events (HR 0.59; 95%CI 0.41−0.82) (Supplementary Table 4).56

The last drug class to show benefits in patients with HF-pEF and obesity are the dual G1P/GLP1 agonists, particularly tirzepatide. Thus, in the SUMMIT study, in patients presenting HF with LVEF ≥ 50%, and body mass index (BMI) ≥ 30 kg/m2, compared to placebo, tirzepatide (up to 15 mg s.c. weekly) reduced the risk of the primary endpoint (first event worsening HF or cardiovascular death) by 38% (HR 0.62; 95%CI 0.41−0.95), as well as the risk of HF worsening events by 46% (HR 0.54; 95%CI 0.34−0.85), in addition to improving health status and quality of life (Supplementary Table 4).57

Different clinical trials have analyzed the role of renin-angiotensin system inhibitors in patients with HF-pEF, with discrete results. Thus, neither the CHARM (candesartan) nor the I-PRESERVE (irbesartan) study reported any significant reduction in the primary endpoint, although candesartan was associated with a 16% lowering of the incidence of the secondary objective HF hospitalizations.66,67 Similarly, in the PEP-CHF study, perindopril 4 mg/day was not able to reduce the primary endpoint of the study, although it was associated with a lower risk of hospitalization due to HF.68 Therefore, renin-angiotensin system inhibitors would be indicated in patients with HF-pEF, particularly in the treatment of comorbidities such as high blood pressure.11

As regards beta-blockers (BB), clinical trials conducted with nebivolol or carvedilol have shown no benefit in terms of mortality or hospitalizations due to HF, although the SENIORS study reported a favorable trend in the subgroup of patients with LVEF > 35%.72,73 It is important to note that BB may cause chronotropic incompetence in patients with HF-pEF.74 Therefore, the indication of BB in patients with HF-pEF would be reserved for those subjects with specific conditions such as ischemic heart disease, AF or an inappropriately high heart rate.10,11,14

On the other hand, it is expected that in the future we will have evidence of new approaches helping to further complete the pharmacological treatment of patients with HF-pEF. In this regard, the efficacy of the aldosterone synthase inhibitor vicadrostat combined with empagliflozin versus empagliflozin in patients with HF-pEF (NCT06424288) is currently being investigated.

In short, in the light of all this evidence, including the most recent data, the management of patients with HF-pEF has changed substantially, as now there are different drugs that have been shown to be able to modify the course of the disease, and which make it necessary to update the treatment algorithm. To summarize, the background treatment which these patients should receive is expanded, specifically diuretics in the case of water retention, SGLT2i (empagliflozin or dapagliflozin) and finerenone, which would be indicated in all patients. Likewise, in the case of obese individuals, tirzepatide 15 mg or semaglutide 2.4 mg weekly (both via the s.c. route) could be used (Fig. 2). Given the clinical benefits of these drugs, and whenever possible, combined early initiation is important, depending on the patient characteristics.75,76

Figure 2.

Pharmacological therapeutic approach recommended in patients with chronic HF-pEF.

* Except type 1 DM, history of diabetic ketoacidosis or eGFR < 20 mL/min/1.73 m2 for empagliflozin and < 25 mL/min/1.73 m2 for dapagliflozin, according to the EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) trials.

** Acute phase evidence in CLOROTIC trial with dose adjusted according to estimated glomerular filtration rate. Monitor renal function and ions early.

*** If symptoms persist and LVEF ≤ 60%, based on pooled analysis of PARAGON-HF and PARAGLIDE-HF.

^ Except if potassium > 5 mmol/l and/or eGFR < 25 mL/min/1.73 m2. Dose for diabetic kidney disease, in HF-pEF or HF-mrEF. Consider spironolactone if symptoms persist and finerenone is not possible.

# No approved indication for HF-pEF.

ARAII: angiotensin II receptor antagonist; GLP1-RA: GLP1 receptor agonist; GLP1-RA/GIP: dual agonists of the GLP1 receptor and gastric inhibitory polypeptide; MRA: mineralocorticoid receptor antagonist; nsMRA: non-steroidal mineralocorticoid receptor antagonist; ARNI: angiotensin receptor-neprilysin inhibitor; CV: cardiovascular; DM: diabetes mellitus; DM2: type 2 diabetes mellitus; eGFR: estimated glomerular filtration rate; LVEF: left ventricular ejection fraction; HF-pEF: heart failure with preserved ejection fraction; HF-mrEF: heart failure with mildly reduced ejection fraction; SGLT2i: sodium-glucose cotransporter-2 (SGLT2) inhibitor; s.c.: subcutaneous.

In the acute phase, in addition to diuretics for the treatment of congestive symptoms, we have evidence to support the use of SGLT2i, since empagliflozin has shown benefit in the EMPULSE study and dapagliflozin has shown safety in the DAPA-ACT study. For the rest of drugs, evidence on the treatment of HF-pEF comes mainly from stabilized patients without fluid overload. Thus, recommendations on their use are mainly focused on this patient population, although we advocate the early initiation of disease-modifying drugs once the patient is stabilized.

Non-pharmacological measures are a fundamental part of the management of patients with HF-pEF. It is important to ensure adequate calorie and protein intake in this group of patients, avoiding excess salt in the diet and controlling fluid intake. In addition, in cases of malnutrition or sarcopenia, nutritional supplements play an essential role. Physical exercise (aerobic and strength) should be encouraged, adapted to the patient characteristics (age, frailty, mobility, etc.) and implemented on a gradual basis (Supplemental Table 5).10,11,13–17,44,77,78 Further details on these recommendations can be found in Appendix 1 of the Supplementary material.

One of the key aspects in the management of patients with HF-pEF is the approach to their comorbidities. These not only increase the overall disease burden, but also promote polypharmacy and thus the risk of drug interactions, adverse effects, and relevant clinical events (such as falls, functional impairment, sarcopenia, readmissions, and mortality). The most common comorbidities in HF-pEF include diabetes mellitus, high blood pressure, obesity, chronic obstructive pulmonary disease, obstructive sleep apnea, chronic kidney disease, ischemic heart disease, iron deficiency, anemia, and AF. 10,11,13–15,17,44,77,79–83 The main recommendations for the management of each of these conditions in patients with HF-pEF are summarized in Table 2.

Despite the demonstrated benefits of disease-modifying therapies, their use remains limited in frail patients, contributing to poorer clinical outcomes. Given the high burden of complications in this group of patients, it is essential to reinforce the implementation of evidence-based therapies that improve their prognosis and quality of life.84

Patients with HF-pEF are often older and have multiple associated comorbidities, which means that management should be performed from a holistic approach, considering all aspects in a global manner. The best approach is represented by the multidisciplinary HF units, particularly the Comprehensive Management Units for Patients with Heart Failure (Unidades de Continuidad Asistencial [UMIPIC]) and the Continuity of Care Units (Unidades de Continuidad Asistencial [UCAS]), where all aspects required by complex patients with HF-pEF can be addressed. In fact, several experiences with the success of multidisciplinary units in Spain led by Internal Medicine have been published, with significant reductions in cardiovascular and non-cardiovascular complications, including decreased mortality and HF admissions. Nursing staff play an essential part in these units, given their central role in the organization of the unit, educational work, and patient follow-up.85–87 Telemonitoring allows remote monitoring of patients with HF, collecting key data such as body weight, blood pressure and heart rate to prevent decompensations and reduce hospitalizations. The devices send this information to the hospital, where the staff can proactively adopt therapeutic measures. Given the clinical usefulness of telemonitoring, its use should also be extended in the HF-pEF population.88 As part of the strategies aimed at reducing readmissions, it is important to identify those patients who will potentially benefit from adequate palliative care. In this regard, the EPICTER scale has demonstrated its clinical utility.89

HF-pEF not only requires a multidisciplinary approach within the hospital; an adequate transition from the time of discharge, ensuring continuity of care with primary care, also play a central role in the effective and efficient care of these patients. The primary care physician is essential to the initial approach, starting with diagnostic suspicion, in addition to outpatient follow-up of chronic patients, stabilizing them, the early detection of decompensation, checking of adequate treatment adherence, or the detection of potential treatment-related complications, among others. Thus, it is necessary to implement locally consensus-based protocols, as well as to ensure adequate training of all the professionals involved in the care of these patients.90,91