1. IntroductionHeart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome that is currently subject to intense debate regarding the pathophysiological mechanisms underlying its generation and progression [1,2]. These mechanisms are crucial to finding therapeutic options that can modify the natural history of the disease since approximately 50% of new diagnoses of heart failure correspond to patients with non-reduced ejection fraction (EF) [3,4]. Likewise, morbidity and mortality in this patient group are comparable to patients with reduced ejection fraction (HFrEF) [5,6]. Although cardiovascular events cause most mortal events in HFpEF, a great proportion is due to comorbidities in this syndrome, unlike HFrEF [7].

At present, few pharmacological therapeutics for the management of HFpEF patients have proven to reduce morbidity and mortality. All of them have been extensively reviewed. This review aims to present a summary in diagnosis and management in HFpEF focused on new targets such cardiac fibrosis, alterations in calcium handling, NO pathway, and systemic inflammation, among others. Comprehending these interventions will enable understanding of the most promising methods to prevent adverse outcomes of this silent pandemic.

3. Clinical Presentation and DiagnosisHF is suspected in a patient with cardiovascular risk factors (CVRF). Hypertension and obesity are highly present in patients with HFpEF [11]. Other CVRF include diabetes mellitus, chronic kidney disease, alcohol consumption, and a family history of cardiomyopathy or sudden death, as well as specific etiologies that can directly impair cardiac structure and/or function such as a history of a congenital heart disease, a previous myocardial infarction (MI), cardiotoxic chemotherapy, or valve disease [9]. If symptomatic, patients generally present with signs and symptoms of clinical congestion, that result from elevated cardiac filling pressures. Typical HF symptoms include dyspnea, which can be classified according to the New York Heart Association (NYHA) functional classification, and reduced exercise tolerance, which is a canonical symptom in HFpEF [12]. Other symptoms that may be present are orthopnea, paroxysmal nocturnal dyspnea, fatigue, tiredness, and leg edema, while specific signs include the presence of jugular vein distention, hepatojugular reflux, third heart sound, and laterally displaced apical impulse. Nonetheless, they lack sufficient accuracy to be used alone to make the diagnosis of HF [9]. For an initial assessment, the European Society of Cardiology and the American Heart Association recommend an electrocardiogram (ECG), which will seldom be normal, often presenting abnormalities such as atrial fibrillation (AF), Q waves, LV hypertrophy, and a widened QRS complex [10]. Furthermore, an initial laboratory evaluation should include a complete blood count, urinalysis, serum electrolytes, blood urea nitrogen, serum creatinine, glucose, fasting lipid profile, liver function tests, iron studies, and thyroid-stimulating hormone levels [9]. A chest X-ray is also recommended to investigate differential diagnosis, and because it can show findings that support the presence of HF [10].For diagnostic confirmation an echocardiography is mandatory, since it may determine LVEF, as well as providing information about heart structure and function [10]. Most relevant measurements that may be present in HFpEF are an elevated E/e’ ratio (early mitral inflow velocity and mitral annular early diastolic velocity) and an increase in the pulmonary artery systolic pressure [13]. Assessment of natriuretic peptides (NPs) is recommended, if available, considering that low levels may help exclude the presence of HF because of their high negative predictive values, while higher levels have a high positive predictive value for HF [10], although this must be interpreted with caution since patients with HFpEF have NP levels that are lower than those of patients with HFrEF, and may even be normal especially considering the high prevalence of obesity in this group of patients [11], moreover, there are other sources for elevated NPs such as renal or liver dysfunction [9,10].Integrated diagnostic approaches have recently gained increasing importance. These are the H2FPEF [13] and the HFA-PEFF [14] scores. Both tools assign patients to a group with low, intermediate, or high likelihood of HFpEF, allowing further diagnostic methods only for those with an intermediate score. The former uses a composite evidence-based approach, while the latter involves a systematic step-by-step algorithm based on an expert consensus. They have shown, independently, a good discriminatory capacity [15,16], but discordant results when applied to the general population [17]. Finally, screening for etiologies is the last step, looking for cardiovascular and non-cardiovascular comorbidities that impair myocardium function, for example, ischemic disease, toxic (medications, radiation, substance abuse, heavy metals), infiltrative, immune, or inflammatory pathology. Or alterations in loading conditions, i.e., hypertension, acquired or congenital valvular disease, volume overload (renal failure), and cardiac rhythm disturbances, among others [14].

In conclusion, although numerous diagnostic approaches and tools have been proposed, HFpEF diagnosis still needs to be improved for clinicians and researchers, and a unifying criterion is still required.

6. General Pathophysiology in HFpEFIn the past, the main feature associated with HFpEF was diastolic dysfunction. For this reason, both terms were used as synonyms twenty years ago [35]. Nevertheless, we find diastolic dysfunction in preserved and EF is reduced. Non-cardiac abnormalities appear in this manner, from the molecular to the systemic level, as presented in Figure 1. Hence, the advance in molecular mechanisms in basic cardiology research and new concepts enable a greater understanding of more targets in this syndrome.At the molecular level, chronic inflammation is a leading cause of HFpEF due to dysregulation in the humoral immune system. High levels of cytokines such as interleukine-1, -6 (IL-1, IL-6) and tumor necrosis factor-α (TNF-α) in blood samples, cell adhesion molecules, and other mediators can infiltrate the myocardium, leading to chronic damage [36]. In the same way, cardiac fibrosis plays a central role in fibroblast replacement in the heart due to activation gene expression of myofibroblast through some profibrotic factors (TGFb, IL-11, AngII) [37]. Another well-known pathway is nitric oxide (NO), which is becoming a potential new target because cGMP levels are decreased in HFpEF related to oxidative stress, endothelial dysfunction, and inflammation. NO is a promissory treatment since it corrects cardiac fibrosis, immune dysregulation, and gap junction remodeling [38]. At this level, reactive oxygen species (ROS) lead to mitochondrial damage [39], with insufficient ATP production activating downstream pathways associated with cardiac fibrosis, inflammation, and diastolic dysfunction. Lastly, calcium is broadly studied due to calcium handling in cardiomyocytes being finely regulated related to the calcium-induced calcium release mechanism, best known as the calcium transient that drives muscle contraction. However, diastolic dysfunction could appear to be comorbidity-dependent in HFpEF [40].At the cellular level, endothelial progenitor cells (EPCs) are necessary for endothelial repair, and EPCs can be recognized by their CD34+ receptor on the surface. HFpEF patients have lower and impaired circulating levels of CD34+ cells [41]. The reduced EPCs are related to NO imbalance, elevated ROS production, and a systemic proinflammatory state [42]. Finally, at the systemic level, neurohumoral and mechanical properties of cardiac function are impaired. Endothelin and adrenomedullin pathways are activated in this syndrome associated with pulmonary hypertension, resulting in worse right ventricular diastolic reserve and oxygen consumption dysregulation in a patient with reduced cardiac output and elevated left ventricular (LV) filling pressure [43].

These mechanisms will be exhaustively addressed at diverse levels, focusing on their preliminary results in pre-clinical and different-phase clinical trials.

7. The First Choice Drug: DiureticsThe ESC 2021 guideline has a low-grade recommendation in the use of a diuretic within HFpEF [44]. This is mainly based on a summary of studies from randomized controlled trials for diuretics in patients with congestive heart failure with no distinction of LV ejection fraction [45].Even though acute decompensation is one of the most common causes of hospitalization in heart failure, congested patients have some significant differences in hemodynamic features [46]. A small study showed differences in volume overload across HFpEF. Measuring total blood volume with labeled albumin and red blood cell mass, revealed an increase excess of volume in HFrEF compared to HFpEF evidenced by less intravascular volume expansion but more interstitial fluid congestion [47].In the same line, the diuretic response may differ between both diseases. Despite the wide use of diuretics, there is still a lack of a standardized protocol for depletive therapy and no differences have been reported between bolus or continuous infusion in acute heart failure management [48]. A recent study compared the high-dose with the low-dose diuretic strategy separately in HFrEF and HFpEF, revealing a higher net fluid loss and weight change in HFrEF at 72 h with the high-dose strategy, and with no differences in HFpEF on efficacy of intensive therapy. Interestingly, higher doses of diuretics were associated with impaired renal function in HFpEF, with a higher proportion compared with HFrEF [49]. Similarly, high doses of diuretics were associated with lower mortality rates in HFrEF but with no significant differences in HFpEF.

Taken together, there is a need for more individualized therapy considering phenotypes of presentation at admission. Further research is needed to improve the accuracy of congestion in a multiparameter approach with clinical and laboratory findings to lead depletion therapy in HFpEF and HFrEF.

13. Device-Based Therapies 13.1. Can a Device Ameliorate Impaired Mechanisms in HFpEF? The structural alterations determine a small LV when compared to those patients with HFrEF [163] and impaired LV filling function, raising LV end-diastolic pressure, which can be transmitted retrograde to the left atrium (LA), generating atrial remodeling, then to the pulmonary circulation, which produces the symptoms of pulmonary congestion and remodeling [164]. Using devices to treat patients with HFpEF aims to reduce pressure in the LA to normalize hemodynamics would prevent this process. The devices used in clinical and pre-clinical studies are interatrial shunt devices (IASDs), which work by forming a shunt between the LA and another cavity to reduce LA pressure and, consequently, retrograde pressure towards the pulmonary circulation [164]; second, LV expander devices, that assist early ventricular filling by optimizing elastic energy during systole and releasing during diastole [165]; third, mechanical circulatory support devices, predominantly the continuous flow rotodynamic blood pumps (RBPs) [166,167] that aim to decompress the left atrium and restore arterial pulsatility and cardiac output; and finally, neurohumoral devices are used to control the autonomic nervous system response in these patients. All these devices and a summary of their ongoing trials are presented in Figure 3. 13.2. Interatrial Shunt DevicesIn one of the first studies of interatrial shunt devices, the investigators recruited eleven patients with EF greater than 45%, PCWP equal to or greater than 15 mmHg at rest or than 25 mmHg while exercising; and at least one hospitalization for heart failure in the last 12 months, or functional capacity III/IV NYHA dyspnea for at least three months. After 30 days, PCWP decreased by an average of 28%, and the pressure in the right atrium and the systolic pressure of the pulmonary artery did not change. In addition, there was a decrease in RV filling pressure of 5.5 mmHg, and dyspnea improved by two classes in two patients and one class in five patients. In this trial, two serious adverse effects occurred: heart failure requiring re-hospitalization and a malpositioned device [168].Subsequently, REDUCE LAP-HF, a prospective multicenter phase 1 trial, where 68 patients with similar criteria to the last study were recruited with a 6-month follow-up, shows an improvement in functional capacity (NYHA), better perception of quality of life, and best distance performance in 6 MWT. Structural changes were measured by echocardiography, which shows a decrease in the LV diastolic volume index, an increase in the RV diastolic volume index, an increase in the RA volume, and a slight increase in the LA volume. These structural changes do not affect pro-BNP levels or the adjustment of furosemide therapy [164].REDUCE LAP-HF I [169], a multicenter phase 2 study and the first to be randomized (to IASD versus a sham procedure) and double-blind, included patients with class III or IV NYHA functional capacity, EF ≥ 40%, PCWP in exercise ≥ 25 mmHg, and PCWP/right atrial pressure gradient ≥ 5 mmHg. Forty-four patients participated, twenty-two for the IASD arm and the control group. In the first month, there was a more significant reduction in PCWP in the intervention group compared to the control group, in all stages of exercise, without a decrease in maximum PCWP. At one year of follow-up [170], a better functional capacity was demonstrated by improved quality of life and the distance walked in 6 MWT. Regarding the structural changes, it was described that at six months, there was already an increase in the RV size in the IASD group versus the control group.REDUCE LAP-HF II [171] is an ongoing multicenter, randomized, double-blind trial. This study used the same inclusion and exclusion criteria as the previous one, recruiting 608 patients. The primary endpoint was a composite that included cardiovascular mortality or stroke within 12 months, hospitalizations for heart failure or need for intravenous diuretics within 24 months, and changes in the Kansas City Cardiomyopathy Questionnaire from enrollment to 12-month follow-up. Follow-up will be carried out by echocardiography at 6, 12, and 24 months to evaluate the shunt, size, and functionality of cardiac cavities, with a total of 5 years of follow-up. There has yet to be a definitive results publication (NCT03088033). 13.3. V-Wave ShuntV-Wave shunts are devices that allow a unidirectional flow from the LA to the RA when the pressure gradient exceeds 5 mmHg. They are installed percutaneously, similarly to IASDs. The feasibility and operation of the device have been reported in pre-clinical and clinical studies, demonstrating functional and hemodynamic improvements in animal models and humans with HFrEF [172,173].In a prospective, multicenter study with thirty-eight patients, eight had HFpEF, with a mean follow-up of 28 months, showing an improvement in NYHA functional class up to I and II in 60% of the patients, along with improvements in the quality-of-life questionnaires and 6 MWT. In addition, an adverse event related to the device and three general adverse events with two deaths were described, highlighting a 36% occlusion of the shunts at 12 months of follow-up [174]. 13.4. Atrial Flow Regulator (AFR)The AFR is a self-expanding device that allows a variable opening diameter of 6 to 10 mm with an interatrial flow that can be bidirectional, and its installation is percutaneous. The first AFR was implanted in a patient with severe pulmonary hypertension, with improvement in clinical outcomes such as 6 MWT, O2 saturation at rest, and symptom relief within six weeks [175].In the PRELIEVE trial, the safety and effectiveness of AFR were evaluated in HFrEF and HFpEF patients, demonstrating an average decrease of 5 mmHg in PCWP at rest at three months of follow-up [176], this decrease being more significant in patients with HFpEF. Without significant changes in functional capacity, distance walked in 6 MWT, or quality of life, in addition to two major adverse events.

Two studies focused on AFR in patients with HFpEF are currently recruiting: the AFteR registry (NCT04405583) and FROST-HF (NCT03751748).

13.5. Trans-Catheter Atrial Shunt Systems

These devices create a left–right interatrial shunt reducing LA pressure. This short-circuit creates an increase in the pressures and volumes of the right cavities. Against this, a device that generates a short circuit from the LA to the coronary sinus is under development without involving the right cavities and avoids the risk of atrial arrhythmias and thromboembolic phenomena.

Initially, eleven patients were recruited to undergo percutaneous atriotomy via the internal jugular vein to generate a shunt from the coronary sinus to the LA. This study included seven patients with HFpEF and four with HFrEF. The 201-day follow-up shows seven patients decreased hospital admissions, improved functional capacity, quality of life, and the 6 WMT. Regarding structural changes, left ventricular function remained unchanged, with a decrease in LA volume, without changes in dimensions, function, or systolic pressure of the right ventricle, and without changes in right atrial pressure, as well as in the mean pressure of the pulmonary artery [177].

Two studies evaluating the Edwards atrial shunt system are currently underway (NCT04965623 and NCT03523416). Participants have already been recruited, and the results will be published early next year.

13.6. Left Ventricle Expanders (LVEs)LVEs are spring-like devices that apply an eccentric force, improving the LV filling capacity. During systole, these devices store elastic energy and transfer it to the LV during diastole, assisting during the early filling phase of the cardiac cycle [178]. There are currently two devices: the ImCardia and the CORolla transapical approach device (CORolla TAA), which were designed to be implanted at the level of the pericardium and endocardium, respectively.The ImCardia is a self-expanding elastic device that decreases the LV diastolic pressure curve. In addition, animal studies have demonstrated effectiveness in improving filling function [179]. Concerning these findings, a prospective non-randomized study has been developed in nineteen patients with HFpEF, candidates for aortic valve replacement due to aortic stenosis. There were no changes in the LV ejection fraction in the intervention group, but there was a decrease in the LV myocardial mass. The study stopped due to the complexity of installing the device (NCT01347125).The CORolla TAA stands out over the ImCardia due to its minimally invasive installation through an intercostal incision. In a pre-clinical study, this device resulted in a significant decrease in EF at six months, two mitral regurgitation events, and one rupture of the semi-tendinous chordae. In the histopathological study, the presence of active thrombi was evidenced at 3 and 6 months of follow-up. However, with double platelet anti-aggregation, active thrombi were not documented at follow-ups of 12 and 24 months [179].

The first study with CORolla TAA in HFpEF patients was carried out to evaluate the procedure’s safety, feasibility, and effectiveness in ten patients with a follow-up of 24 months (NCT02499601). Preliminary results in one patient have shown a decrease in LV mass index, left atrial volume, LV end-diastolic volume, functional capacity class, perception of quality of life, and 6 MWT. However, at the 24-month follow-up, these changes tended to decrease.

13.7. Mechanical Circulatory Support Devices (MCS)

MCSs provide hemodynamic support to the underperforming left or right ventricles to improve the quality of life of patients with HFrEF in the terminal phase; however, there are no clinical studies to evaluate their efficacy and safety in HFpEF. Examples of these devices are left atrial decompression pumps (Synergy pump, heartware), valveless pulsatile pumps (CoPulse), and the left atrial assist device (LAAD).

13.7.1. Left Atrial Decompression PumpsPre-clinical studies have incorporated a pump with the pressure-flow characteristics of the Synergy continuous-flow micropump (HeartWare). Synergy’s blood flow could come from the left atrium or the left ventricle and be ejected directly into the proximal aorta. This study concluded that for HFpEF, this mechanical circulatory support significantly increases cardiac output, provides a modest increase in systolic blood pressure, and markedly reduces left atrial and pulmonary pressures [166]. 13.7.2. CoPulse

The valveless pulsatile pump (CoPulse) consists of a device implanted in the apex of the heart that is made up of a blood chamber and an air chamber divided by a flexible polyurethane membrane. Blood flow enters the chamber during diastole and is expelled by displacement of the separating membrane during systole.

Escher et al. [180] demonstrated in a porcine heart model that this device reduced left atrial pressure and increased cardiac output in vitro. 13.7.3. Left Atrial Assist Device (LAAD)The LAAD consists of a continuous pump implanted in the mitral valve, transferring blood flow from the left atrium to the left ventricle and was the first MCS device for HFpEF tested in animals. In a pre-clinical study, the LAAD was inserted in four healthy animals through an incision in the left atrium at the level of the mitral valve, resulting in increased cardiac output and mean aortic pressure, with a corresponding decrease in left atrial pressure. In turn, left ventricular end-diastolic pressure, central venous pressure, and heart rate remained stable, and echocardiography did not show left ventricular outflow tract obstruction [181]. 13.8. Autonomic RegulationIn HFpEF patients, an autonomic imbalance occurs with increased sympathetic activity and decreased vagal control over the heart rate, these changes are responsible for chronic symptoms, such as exercise intolerance, which is a strong determinant of the prognosis and quality of life of these patients [182].There is significant heterogeneity in sympathetic neural control, such as higher heart rate and sympathetic tone in patients with HFpEF compared to healthy volunteers [183] and increases in muscle sympathetic activity with age in a non-linear way, without significant differences in sex in individuals older than 50 years [182]. In addition, univariate analyses have found a significant correlation between the concentration of arterial norepinephrine with systolic blood pressure and pulmonary capillary pressure, suggesting that the autonomic imbalance could be associated with hemodynamic factors determining the development of this condition [183].

Despite the above, different clinical trials focused on this potential therapeutic target, have failed to demonstrate efficacy in this subgroup of patients.

13.8.1. BAROSTIM NEO and BAROSTIM BATOne of the therapeutic targets with the most potential is a device for baroreceptor reflex activation. The BAROSTIM NEO System is a neuromodulation system that targets the decreased baroreceptor sensitivity observed in HFpEF patients by activating the baroreceptors in the carotid artery wall. This system aims to stimulate the afferent and efferent pathways of the autonomic nervous system, increasing parasympathetic tone and decreasing sympathetic stimuli. This subcutaneous device is implanted by ultrasound-guided incision next to the carotid artery, with an electrode linked to a pulse generator in a subcutaneous pocket, and is secure and effective in HFrEF [184]. Furthermore, the BAROSTIM BAT system has been developed to allow an ultrasound-guided suture-less procedure without cutting down to the carotid artery [185,186].

With a 6-month follow-up in the prospective cohort of the BAROSTIM THERAPY study recruiting HFpEF patients with hypertension resistant to maximally tolerated pharmacological treatment with a diuretic and two other antihypertensive medications, this study will assess changes in systolic blood pressure, as well as LV and LA mass indices, NYHA functional class, and re-hospitalization for HF (NCT02876042).

13.8.2. Cardiac Contractility Modulation (CCM)This strategy focused on delivering high-voltage non-excitatory biphasic electrical signals in the right ventricular septum during the absolute refractory period of the action potential. Thus, increasing calcium influx into the cardiomyocytes, leading to a sustained increase in contractility without increasing myocardial oxygen consumption. In the long term, it causes changes in gene expression in managing calcium, improving myocardial contractility [187].

Recent studies show a significant benefit in HFpEF patients, improving exercise tolerance and quality of life and decreasing hospitalizations. In light of these results, implantation of the CCM device has recently received FDA approval in HF patients ineligible for CRT, with the Optimizer Smart CE being the only FDA-approved CCM therapy device.

CCM-HFpEF was a prospective multicenter study designed to evaluate the efficacy and safety of CCM therapy in heart failure patients with LVEF ≥ 50% and NYHA class II or III despite 24 weeks of optimal medical therapy. In 47 patients, an improvement was observed in the Kansas City Cardiomyopathy questionnaire and a 67% reduction in the number of hospitalizations for heart failure at one year of follow-up (NCT02895048).

13.8.3. Cardiac Resynchronization Therapy (CRT)Broadly studied for HFrEF, in a subgroup analysis of the PROSPECT (Predictors of Response to CRT) trial initially designed to test the performance of CRT in patients with HFrEF, revealed similar improvement in patients with LVEF > 35% compared with LVEF 188]. This finding promoted other studies, investigating CRT efficacy in patients with LVEF ≥ 40%, such as the PREFECTUS prospective cohort trial that aimed to evaluate CRT effects on chronotropic incompetence in patients with HFpEF (NCT03338374).

Finally, other clinical studies are ongoing, such as the PACE HFpEF trial (NCT04546555). In this trial, the effects of personalized pacing on atrial fibrillation and hospitalization rates will be evaluated, as well as on left atrial and ventricular pressures in patients with HFpEF.