The evaluation and diagnosis of a patient suspected of HFpEF remains challenging. Complaints of reduced exercise tolerance and dyspnea on exertion is often attributed to ‘healthy’ aging, and not due to disease, leaving a significant percentage of the HFpEF population under-diagnosed. Secondly, diagnostic criteria of HFpEF, and cut-off values for diastolic function, can be difficult to interpret and remain a topic of debate. The current criteria to diagnose HFpEF include [1] presence of symptoms and/or signs of HF [2]; normal LV ejection fraction (LVEF ≥ 50%) [3]; elevated levels of natriuretic peptides and [4] relevant structural heart disease (LV hypertrophy/LA enlargement) or diastolic dysfunction [15]. Initial assessment of HFpEF therefore includes clinical assessment of symptoms or signs of HF in combination with laboratory measurements and an echocardiography. As previous studies have shown that echocardiographic measures to assess diastolic dysfunction correlate poorly with actual LV filling pressures and lack accuracy, it may be helpful to perform right heart catheterisation to better evaluate left ventricular filling pressures [16, 17]. Additionally, some pathophysiological features of HFpEF may not be evident at rest. Considering that many of the diagnostic echocardiographic parameters used are load dependent and that symptoms principally occur during activity one should consider exercise testing, either stress-echocardiography or, preferably, an invasive assessment of the haemodynamic response to exercise if echocardiography at rest is inconclusive [18].

A central pathophysiologic feature of HFpEF appears to be an increase in the left ventricular end-diastolic pressure (LVEDD). Both vascular and myocardial stiffness may lead to an increase of the LVEDD. Vascular stiffness, caused by ageing and co-morbidities, hinders the diastolic filling [9]. Another important clinical manifestation of vascular stiffness is hypertension, which often goes hand in hand with HFpEF. Due to stiffness of the myocardium, the heart can no longer “relax” in the diastolic phase, thus the LVEDD is relatively high compared to the amount of blood in the ventricle. Factors that contribute to the myocardial stiffness by fibrosis formation are changes in the extracellular matrix, changes in the myocyte intrinsic stiffness, microvascular dysfunction and metabolic abnormalities [19]. Myocardial stiffness is further augmented by the presence of left ventricular hypertrophy, which occurs in response to prolonged hypertension. MRI studies show that the heart not only stiffens due to hypertrophy, but also by the presence of fibrosis [20].

In HFpEF patients, fibrosis is present both in the myocardium as well as in the vessels, which contributes to the deterioration of the diastolic and the systolic function [21, 22]. Fibrosis formation is caused by changes in amount of collagen deposition in the extracellular matrix [22]. Analyses from endomyocardial biopsies demonstrate the collagen synthesis is increased and enzymes that break down collagen are reduced [23, 24]. As a result, we see a pattern of diffuse fibrosis, as opposed to after a myocardial infarction where very localized fibrosis is present. This diffuse fibrosis is caused by, among other things, the activation of TGF-β (transforming growth factor-β) in response to the increased inflammation of the microvascular endothelium [19]. There are sex-specific patterns in regulation of fibrosis in response pressure overload [8]. How this contributes to the predisposition of females to HFpEF remains to be investigated.

Several co-morbidities, which frequently occur in HFpEF, such as diabetes and obesity, cause a chronic low-grade systemic inflammation [25]. This inflammation induces endothelial dysfunction, which is subsequently associated with increased oxidative stress [26]. Although these processes are described both for HFrEF and HFpEF, endothelial dysfunction is more prevalent in HFpEF, even when adjusted for age, sex, the presence of diabetes and hypertension [27]. This suggests that endothelial dysfunction is not merely a result of multiple co-morbidities, but is specifically related to the pathophysiology of HFpEF. Furthermore, endothelial dysfunction is negatively associated with the prognosis of HFpEF [28]. An increased oxidative stress induces diastolic stiffness of the myocyte by an increase in cyclic GMP (guanosinemonofostaat), and ultimately a change in the titin protein, which is a component of the cytoskeleton of the cardiomyocyte [29].

The standard drug therapy for HF such as beta-blockers, ACE inhibitors/angiotensin receptor antagonists (ARBs) or mineralocorticoid antagonists have not shown any beneficial effect in patients with HFpEF [15]. These drugs have been extensively studied in several clinical trials, and provide no improvement in survival, exercise tolerance, functional class or quality of life. Diuretics are recommended if fluid retention is present, and although they may reduce symptoms, the prognosis is not altered [15]. The reasons for these negative results remain unclear. As described earlier in this chapter, it remains a challenge to diagnose HFpEF and consequently the various studies have used different inclusion and exclusion criteria. This results in a very large variety of different types and degrees of HFpEF [30]. One of the reasons for the negative results lies therefore, at least partly, in the fact that HFpEF is not a uniform disease. Due to the presence of numerous co-morbidities, the HFpEF population represents a very heterogeneous group, wherein it is not unlikely that specific sub-groups may still benefit from certain HF medications [31]. In the future, a better characterization of the different subgroups of HFpEF patients will also provide valuable information for more effective treatment. This should result in a personalized treatment, based on the specific characteristics of the disease, instead of the current one-size-fits-all approach.

Because of the negative and neutral findings of recent trials, the emphasis of treatment in HFpEF is currently focused on treatment of the various co-morbidities, such as optimal regulation of blood pressure and strict regulation of glucose levels. Most drugs that are used in patients with HFrEF are safe for HFpEF patients, and most of the drugs that should be avoided in HFrEF, should also be avoided in HFpEF, with the exception of verapamil and diltiazem [15]. These calcium blockers can be given safely to HFpEF patients.

Besides medical therapy, exercise training is an important part of the treatment of heart failure, also in HFpEF. Various studies in HFpEF patients report an improvement in exercise tolerance after exercise training; for instance the multi-centre Ex-DHF-P study, which included HFpEF patients with NYHA class 2-3, showed that 32 sessions in which a combined aerobic and strength training improved exercise tolerance, diastolic function and quality of life [32]. Whether there is an impact on survival or the number of hospitalizations is unknown yet.

Spironolacton has shown to decrease mortality in HFrEF and could be a promising therapy for HFpEF [33]. Spironolactone exerts its effect by a competitive antagonism with the intracellular aldosterone receptor. Aldosterone plays a role in hypertension, endothelial dysfunction and myocardial fibrosis, which are all processes involved in the onset of HFpEF. Intervention in this system therefore seems attractive. Previous studies already showed that patients with hypertension develop less LV hypertrophy when treated with spironolactone [34, 35]. However the TOPCAT study, a large international randomized, placebo-controlled trial, failed to show beneficial effect of spironolactone treatment on the combined endpoint of mortality and hospitalization in patients with HFpEF [36]. However, the results are somewhat more complex as there was a large difference in event rates in the placebo group among the different geographical areas. A post-hoc analysis showed that when patients from Russia and Georgia (approximately 45% of all patients) were excluded from the analysis, there was a positive effect with regard to fewer hospital admissions for heart failure [37]. It was therefore suspected that these countries enrolled too many ‘unreal’ HFpEF patients and that spironolactone may still need to get a place in the treatment of HFpEF.

Phosphodiesterase-5 inhibitors (PDE-5) intervene in the sGC NO-cGMP-signaling pathway (see figure). Increased cGMP activates cGMP-dependent protein kinases, which work favourably on ventricular hypertrophy, diastolic relaxation and stiffness. Inhibition of PDE 5 leads to an accumulation of intracellular cGMP, and therefore could work beneficial. Animal studies show that sildenafil, a PDE-5 inhibitor, affects the cardiomyocyte remodelling. Sildenafil reduced progression of ventricular remodelling and dysfunction and suppressed fibrosis formation and left ventricular hypertrophy [38, 39]. Additionally, in a small, randomized trial of 44 patients with HFpEF and (slightly) increased right ventricular pressures, sildenafil improved hemodynamics, RV function, and also quality of life compared to placebo [40]. However, a multi-centre randomized study with 216 HFpEF patients, showed no difference in exercise tolerance or clinical status after 24 weeks of treatment with sildenafil or placebo [41]. Further investigation to evaluate the role of this drug is needed.