Two (or Three) Types of Heart Failure
The most recent guidelines of the European Society of Cardiology1 have a simple algorithm for what is needed to guide the diagnosis of HF (see Table 1). Deceptively simple because it actually indicates two separate diagnoses to be made: HF with reduced EF (HF-REF) and HF with preserved EF (HF-PEF). Unhelpfully the table does not
indicate the definition of these terms, and only in the text is it revealed that HF-REF refers to those who otherwise fit a HF diagnosis, with, in addition, a LVEF of ≤35 %. Can one assume that this value is always known; is stable and reproducible; is an equivalent between different imaging modalities and methods of calculation; or even that by exclusion that cases with a LVEF >35 % must be cases of HF-PEF as they are not by definition HF-REF? Unfortunately none of these assumptions are valid. Often the EF is not known (even more frequently in general practice) and echo-based, magnetic resonance imaging (MRI) and nuclear estimates may differ in the same patient by as much as 10 percentage points, enough to turn a case from true HF-REF into not a case. Interestingly, the HF guidelines do not actually give recommendations for the treatment of HF; mostly they give recommendations for the treatment of HF-REF and give a very much smaller list of statements about what works in HF-PEF. Brief mention is made about a third group, those with all the symptoms and signs of HF, but whose LVEF is in the range of 35–50 %. They are sometimes referred to as the ‘grey zone’, ‘HF with mild systolic dysfunction’ or HF with intermediate EF (HF-IEF). All this is a problem of our making. If we had stuck with a clinical diagnosis we would have a condition of ‘HF’, which we then would have evaluated in clinical trials. Early on we recognised that this condition presented with multiple pathophysiological and aetiological subtypes, as indeed there are for many types of cancer even of one organ. We could have described these subtypes and tested their responses to therapy separately as subgroups in a larger trial of HF. Had we done this we would have tested drugs that might work in all HF and secondarily assessed relative efficacy in major subtypes, and we then would have found that different EF ranges predicted quantitatively, but unlikely qualitatively, different responses. Had we done this we would not have two (or three) diagnoses merely one diagnosis with a pathophysiological parameter (LVEF) that is later shown to be helpful in determining different relative responses to therapy. We would not have dichotomised HF and left many of our patients understudied and undertreated. It is against this background that we review the diagnosis, epidemiology and treatment of HF-PEF. HF-PEF is what is left over when LVEFs below 50 % are excluded. It is not a positive diagnosis at all: it is one of exclusion.
As a result of the lack of an established test, the identification, and therefore the treatment of HF, depends ultimately on the willingness or ability of a physician or medical team to call a particular case HF. As historically most cases of HF that have been enrolled in clinical trials or have been assessed for advanced therapies have been of the type with an enlarged left ventricle and poor systolic function (HR-REF), this particular type is often considered ‘real’ HF. This is of no concern where there is a fair degree of consensus about whether an individual case is or is not HF. Take the case of a younger man with a large MI who survives this initial insult and later presents with global poor LV function and fluid retention. This patient is easily recognised as fitting one of the clinical patterns of what we have for decades called the clinical spectrum of HF. Fortunately, this patient matches the inclusion criteria of any number of landmark clinical trials conducted over the period from the late 1980s to the late 2000s when most of our modern accepted HF therapies were first tested.
Compare this situation to a second patient, who is older, female and has a small thick-walled left ventricle but who presents repeatedly to hospital with pulmonary and peripheral oedema who is limited markedly by exertional dyspnoea and who on echocardiography has a small chambered heart with a stiff, poorly compliant ventricle with incoordinate contraction. This patient in all likelihood has an EF of above 40 % or even 50 % and would not have matched the inclusion criteria of many of the landmark HF trials. She may also have a heightened amount of myocardial fibrosis, her diastolic function may be impaired and she may be at risk of atrial arrhythmias and subendocardial myocardial ischaemia due to vasomotor disturbance and endothelial dysfunction in her coronary vasculature. She has HF, her outlook is poor and she consumes a lot of healthcare resources with her recurrent emergency admissions. Yet she would not have been recruited into the landmark HF mortality and morbidity (M+M) randomised controlled trials (RCTs): CONSENSUS, SOLVD, Copernicus, Rales, Merit-HF, CIBIS-II, Ephesus, etc. As a result, we still do not know if she will respond to the treatments we offer our first patient and she is largely left untreated. This means we are failing approximately half of the patients with HF in the community, those who do not have HF-REF and who have been the subject of remarkably few major M+M RCTs.