Heart failure (HF) is a chronic condition characterised by a number of signs and symptoms, e.g. elevated jugular venous pulse (JVP), peripheral oedema and breathlessness and fatigue, respectively. Diagnosis is based on presence of signs and/or symptoms of HF and echocardiographic findings evidencing cardiac dysfunction. Further classification involves measurement of left ventricular ejection fraction (LVEF). Ejection fraction (EF) values vary slightly depending on guidelines, but it is generally accepted that HF with reduced ejection fraction (HFrEF) is defined as HF with an EF of less than or equal to 40%. Patients with an ejection fraction between 41% and 49% have HF with mildly reduced ejection fraction (HFmrEF). HF with preserved ejection fraction (HFpEF) is accepted as being a challenging diagnosis. Therefore, the European Society of Cardiology (ESC) recommends a simplified approach to diagnosis: signs and symptoms of HF, an LVEF of more than or equal to 50%, and objective evidence of cardiac structural and/or functional abnormalities consistent with presence of left ventricular (LV) diastolic dysfunction/raised LV filling pressures (such as LV hypertrophy, left atrial enlargement or raised natriuretic peptides) [1, 2]. Diagnosis involves the use of history, clinical examination, natriuretic peptide levels and echocardiography. However, some patients with HFpEF will get symptoms only on exertion, but do not have clinical signs at rest and therefore the aforementioned diagnostic testing may be inconclusive; this is where other investigations such as exercise stress testing, cardiopulmonary exercise testing and invasive haemodynamic testing can also be used to diagnose HFpEF or else confirm or exclude other diagnoses too. Patients with HFpEF tend to be older, female and are more likely to have comorbidities such as hypertension, atrial fibrillation, diabetes mellitus (DM), chronic lung disease, chronic kidney disease and anaemia .
Disease burden is an increasing issue. Studies have found the prevalence of HFpEF is increasing, and that up to 50% of patients with the clinical syndrome of HF have HFpEF [2, 4, 5]. There appears to be general agreement that the incidence of HFpEF is increasing and is more prevalent in women than men, when compared with HFrEF [2, 6]. This, perhaps, reflects the increased recognition of the diagnosis of HFpEF, or perhaps is a reflection of an increasingly comorbid population. HF is thought to affect around 26 million people worldwide .
HF has long been a researched and clinically interesting diagnosis. There are a multitude of causes such as coronary artery disease, alcohol misuse, cardiotoxic chemotherapy, valvular disease, hypertension, infiltrative disease (such as amyloidosis and sarcoidosis), congenital heart disease and many more. However, many of the causes of HF are more associated with HFrEF than HFpEF. Risk factors for HFpEF appear to stem from comorbidities such as hypertension, obesity and diabetes, as well as being more prevalent with increasing age and in female individuals . The recognition of LV diastolic dysfunction and a normal ejection fraction with the clinical syndrome of HF has been around for decades, although the underlying pathophysiology in HFpEF is perhaps poorly understood when compared with HFrEF . Essentially, systolic function is normal in HFpEF (with the exception of some findings of reduced systolic function during stress) as the heart is able to contract normally, but there is an inability of the LV to relax normally to allow adequate ventricular filling. This therefore results in an increased left ventricular end diastolic pressure (LVEDP) .
“Diastolic dysfunction” was the term used to describe HFpEF in the past; however, this was adjusted as diastolic dysfunction can also be observed in HFrEF and is not specific to HFpEF. Indeed, some of the understood pathophysiology is about diastolic dysfunction, including the knowledge of myocardial stiffness being a cause. The amount and type of collagen in the extracellular matrix as well as actions of cardiomyocytes lead to this increased myocardial stiffness . Increased degradation of collagen type 1 (leading to a build-up in the extracellular matrix) is also seen in arterial hypertension—which is a known risk factor for HFpEF . Slow LV relaxation is seen in HFpEF, especially at higher heart rates, which, along with myocardial stiffness and impaired ventricular-arterial coupling all leading to reduced stroke volume, may explain the abnormal systolic function seen in patients under stress in HFpEF despite normal systolic function at rest [2, 8]. Vascular stiffening (e.g. reduced aortic distensibility) is also a key factor in HFpEF, and is also seen in the common associated conditions of hypertension, diabetes and old age . The processes aforementioned can lead to pulmonary hypertension and limited systolic reserve during stress . The general understanding of late is that HFpEF is caused by the presence of co-existing inflammatory conditions (e.g. diabetes) causing systemic microvascular endothelial inflammation and vascular dysfunction, along with reduction in nitric oxide and cyclic guanosine monophosphate levels which can then lead to hypertrophy and exacerbated cardiomyocyte stiffness as well as fibrosis . Contributing factors include chronotropic incompetence, left atrial dysfunction and atrial fibrillation .
HFpEF is becoming a growing problem in people with diabetes, and DM is associated with increased morbidity and mortality in HFpEF. Approximately 30–40% of patients with HFpEF suffer with DM , and people with type 2 diabetes mellitus (T2DM) have up to three times higher risk of developing cardiovascular disease, particularly HFpEF . HFpEF and DM share some of the same inflammatory processes such as endothelial dysfunction, interstitial and perivascular fibrosis, advanced glycated end products deposition and hypertrophy ; additionally impaired insulin signalling is also thought to contribute to HFpEF . Other shared pathological processes include sodium retention, release of proinflammatory cytokines and impaired skeletal muscle function , in addition to the shared risk factors of obesity and hypertension. With links already seen between HF and DM many decades ago, e.g. in the Framingham Heart Study , it is no wonder that treatments for diabetes may have some effect on HF outcomes (Fig. 1).
Prognoses in HFrEF and HFpEF appear to be equally limited; 5-year mortality for HFrEF and HFpEF has been found to be 75.3% and 75.7%, respectively . However, treatments for HFpEF are particularly limited and concentrate on symptom management, when compared to treatment options for HFrEF.