AIMS:
Despite the latest trials demonstrating beneficial effects of SGLT2-inhibitors on cardiovascular death or hospitalisation in patients with heart failure with preserved ejection fraction (HFpEF), the subgroup of patients with supra-normal left ventricular (LV) ejection fraction (LV-EF) >60% did not show benefits. Distinct characterisation of HFpEF cohorts might offer new insights into the underlying pathophysiology.

METHODS:
HFpEF patients were grouped according to the LV-EF derived from transthoracic echocardiography into LV-EF 50-60% and LV-EF >60% cohort. All patients underwent cardiac magnetic resonance imaging prior to invasive hemodynamic characterisation. Load-independent LV properties were derived from pressure-volume loop analysis during pre-load reduction and handgrip exercise induced after-load challenge. In a sub-cohort, LV myocardial biopsies were collected and fibrosis was histomorphometrically quantified using ImageJ (Version: 2.0.0-rc-15/ 1.49m, Wayne Rasband, NIH, USA).

RESULTS:
A total of 64 patients were included in this analysis and divided up into a healthy control cohort (n=13), HFpEF with LV-EF 50-60% (n=18) and HFpEF with LV-EF >60% (n=33). Clinical presentation of HFpEF patients was similar without any significant differences in age (p=0.121), functional NYHA class (p=0.442), NT-proBNP (p=0.200) and treatment with diuretics (p=0.411). At rest, HFpEF cohort with LV-EF >60% had lower LV indexed end-diastolic volume (EDVi, median 77.9 vs. 67.4 ml/m²; p=0.05) while LV indexed stroke volume (SVi, 39.2 vs. 43.3 ml/m²; p=0.717) and LV end-systolic pressure (ESP, 148 vs. 149 mmHg; p=0.725) were similar. Pressure-volume loop analysis demonstrated higher LV-contractility derived as end-systolic elastance (LV-Ees, 1.34 vs. 1.76 mmHg/ml, p=0.026) in HFpEF with supra-normal LV-EF. During pre-load reduction (p<0.050) and handgrip-induced after-load challenge (p=0.031) LV-SVi was decreased in HFpEF with supra-normal LV-EF. Albeit more advanced increases of ∆LV-Ees (0.60 vs. 2.21 mmHg/ml, p=0.003) and ∆LV-ESP (29 vs. 35 mmHg, p=0.014) as a response to exertion, HFpEF with LV-EF >60% failed to demonstrate a physiological rightward shift (∆LV-EDVi -0.75 ml/m², p=0.319). Moreover, HFpEF cohort with supra-normal LV-EF respond with an upward drift, leaving the physiologic end-diastolic pressure-volume relation. LV end-diastolic pressure at rest (EDP, 16 vs. 18 mmHg, p=0.050) and ∆LV-EDP in exertion (4 vs. 8 mmHg, p=0.018) are significantly elevated in HFpEF with supra-normal LV-EF. Histology revealed significantly higher amount of fibrosis in HFpEF with LV-EF 50-60% (14.2%, n=11) compared to supra-normal LV-EF (9.0%, n=13, p=0.009).

CONCLUSION:
While HFpEF cohort with LV-EF 50-60% resembles hemodynamic characteristics of heart failure with reduced ejection fraction, HFpEF cohort with supra-normal LV-EF is more pre-load dependent and in hyper-contractile state, possibly explaining recent conflicting data of pharmacotherapy in heterogeneous HFpEF cohorts.

Figure 1: Pressure-volume loop analysis in heart failure with preserved ejection fraction cohorts with normal and supra-normal left ventricular ejection fraction during pre-load reduction (A) and after-load challenge (B)