Markers of Left Ventricular Systolic Dysfunction when Left Ventricular Ejection Fraction is Normal (2018)

Left ventricular ejection fraction (LVEF) is the most important echo parameter on which therapeutic decisions in heart failure are based today. The latest European Society of Cardiology guidelines on the diagnosis and treatment of acute and chronic heart failure use LVEF as the main discriminator to divide heart failure patients into three groups: heart failure with reduced ejection fraction (HFrEF, LVEF < 40%), heart failure with mid-range ejection fraction (HFmrEF, LVEF 40–49%), and heart failure with preserved ejection fraction (HFpEF, LVEF ≥ 50%).1 There are several reasons why LVEF plays a dominant role. LVEF is very easy to use in clinical practice. Because it is a single number, it can be intuitively understood by other medical professionals and patients. Importantly, LVEF has been a major inclusion criterion in most randomized clinical trials to date. Beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor–neprilysin inhibitors and mineralocorticoid receptor antagonists have all been proven effective in patients with a LVEF < 35–40%. At the same time, no randomized clinical trial of medical therapy has shown benefit in LVEFs > 45%. Because calculation of LVEF is based on end-diastolic volume, reduced LVEF is a metric of eccentric remodelling of the left ventricle.2 As a result, LVEF is a powerful predictor of cardiovascular outcomes, including sudden cardiac death.3 Additionally, LVEF can be used to select heart failure patients who will more likely respond and or benefit from cardiac resynchronization therapy and/or implantable cardioverter defibrillators. Repeated LVEF measurements may also play a role in the surveillance for the cardiotoxic effects of chemotherapy. Notwithstanding the importance and widespread use of LVEF, there are several well-known limitations to its use in heart failure.2, 4-6 First, LVEF fails to directly reflect underlying pathophysiology.7 For instance, a reduced ejection fraction might be caused by ischaemic heart disease, long standing hypertension, or a combination of both. Second, normal values for LVEF are influenced by several factors, e.g. normal values are on average around 1% higher in females and LVEF normally increases with age as well.8 Third, echocardiography, the most widely used modality to determine LVEF, has several important technical limitations. Simpson's biplane method, the recommended method to determine LVEF, is dependent on geometric assumptions and is easily influenced by loading conditions. Endocardial border delineation done either manually or semi-automatically is prone to measurement variation. Foreshortening can be a source of variation as well. These limitations might all contribute to inter- and intra-observer variability. A recent meta-analysis reported Bland–Altman limits of agreement for two-dimensional echocardiography to be ± 13.9%.9 Additionally, a Simpson's biplane LVEF cannot always be obtained: one study of 2006 patients in the STICH trial reported a feasibility of 72.8%.10 Use of three-dimensional echocardiography might result in better accuracy.11 However, the acquisition requires additional time and can be limited by lower frame rate. Administration of contrast media can result in better endocardial border detection, but requires more time as well. Several other echo parameters can be used to assess left ventricular systolic function. First, we might directly estimate cardiac output using the subaortic velocity time integral. Echo-derived cardiac output has shown good correlation with haemodynamic measurements in intensive care unit patients, but has not been extensively investigated in chronic heart failure.12 Use of tissue Doppler, for instance systolic mitral annular velocity (s') has high feasibility, even in acute heart failure patients.13 S' is also an independent predictor of prognosis in chronic heart failure. Other less established echo parameters related to systolic function are mitral annular plane systolic excursion, Tei-index and dP/dT in the presence of mitral regurgitation. In addition, two-dimensional speckle tracking echocardiography (measuring the deformation of the myocardium in longitudinal, circumferential and/or radial directions) has matured over the past decade. There is now a large body of evidence on applications of global longitudinal strain (GLS).14 In heart failure, abnormal GLS offers incremental prognostic information on top of LVEF, both in HFpEF and HFrEF.15 The additive value of GLS is probably largest in those patients with relatively normal ejection fractions. Diminished GLS values are found in up to 60% of patients with preserved ejection fraction.16 Reduced GLS was associated with a higher risk of cardiac death and heart failure hospitalization.17 However, GLS is also load-dependent to a certain degree. Strain rate appears to be less influenced by loading conditions, but normal values have not been established.18 Other deformation-derived parameters hold promise as well. Interestingly, an increase in global circumferential strain might compensate for decreasing longitudinal strain in the first stages of systolic dysfunction.19-21 Left ventricular ejection fraction and strain imaging are fundamentally different parameters: LVEF is based on volume measurements, whereas strain is a measure of deformation. The geometry of the left ventricle influences the relationship between LVEF and deformation.22 Stokke and colleagues mathematically modelled LVEF as a function of wall thickness, end-diastolic volume and global longitudinal and circumferential strain, and then validated their model in real-world patients.20 They found that circumferential strain contributed to LVEF twice as much as longitudinal strain. The model also showed that LVEF can remain constant by increasing wall thickness or reducing left ventricular diameter, despite reductions in longitudinal and circumferential strain. Thus, a patient with a LVEF of 55% with normal left ventricular wall thickness has normal longitudinal and circumferential strain. In contrast, a patient with a LVEF of 55% with increased wall thickness can have diminished GLS, and at the same time have increased circumferential strain, to compensate for impaired left ventricular systolic function, despite a normal LVEF.20 Left ventricular ejection fraction is the most extensively used parameter on which therapeutic decisions in heart failure are based. We have briefly summarized the advantages and disadvantages of LVEF, and listed additional echocardiographic parameters than can be used to assess left ventricular systolic function. Clinicians should be aware that LVEF can be deceptively ‘normal’ despite markedly reduced left ventricular systolic function, for instance in patients with increased wall thickness and a small lumen, as is common in HFpEF. A more comprehensive assessment of left ventricular systolic function is warranted in these patients. In addition to LVEF alone, both anatomic and functional echo parameters should be considered. Morphological parameters of interest are (indexed) left ventricular mass and relative wall thickness, allowing classification of eccentric or concentric hypertrophy. Reduced GLS is an important early marker of reduced left ventricular systolic function. Circumferential deformation increases early in the disease progress as a compensatory mechanism, and diminishes with overt heart failure. An integrated assessment of left ventricular systolic function allows for more precise diagnosis of heart failure. However, establishing cut-off values that separate the diseased from the normal is more challenging with this strategy. Conflict of interest: A.A.V. was a member of the Task Force that wrote the 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, and received consultancy fees and/or research grants from Amgen, Bayer, Boehringer Ingelheim, Merck/MSD, Novartis, Roche Diagnostics, Servier, Trevena, Vifor. All other authors declare no conflicts of interest.