Falcão-Pires I, Leite-Moreira AF, Lourenço AP. Spectral transfer function analysis of respiratory hemodynamic fluctuations predicts end-diastolic stiffness in preserved ejection fraction heart failure. Am J Physiol Heart Circ Physiol 310: H4 -H13, 2016. First published October 16, 2015 doi:10.1152/ajpheart.00399.2015.-Preserved ejection fraction heart failure (HFpEF) diagnosis remains controversial, and invasive left ventricular (LV) hemodynamic evaluation and/or exercise testing is advocated by many. The stiffer HFpEF myocardium may show impaired stroke volume (SV) variation induced by fluctuating LV filling pressure during ventilation. Our aim was to investigate spectral transfer function (STF) gain from end-diastolic pressure (EDP) to indexed SV (SV i) in experimental HFpEF. Eighteen-weekold Wistar-Kyoto (WKY) and ZSF1 lean (ZSF1 Ln) and obese rats (ZSF1 Ob) randomly underwent LV open-chest (OC, n ϭ 8 each group) or closed-chest hemodynamic evaluation (CC, n ϭ 6 each group) under halogenate anesthesia and positive-pressure ventilation at constant inspiratory pressure. Beat-to-beat fluctuations in hemodynamic parameters during ventilation were assessed by STF. Enddiastolic stiffness ( i) and end-systolic elastance (Eesi) for indexed volumes were obtained by inferior vena cava occlusion in OC (multibeat) or single-beat method estimates in CC. ZSF1 Ob showed higher EDP spectrum (P Ͻ 0.001), higher STF gain between enddiastolic volume and EDP, and impaired STF gain between EDP and SV i compared with both hypertensive ZSF1 Ln and normotensive WKY controls (P Ͻ 0.001). Likewise  i was only higher in ZSF1 Ob while Eesi was raised in both ZSF1 groups. On multivariate analysis  i and not Eesi correlated with impaired STF gain from EDP to SVi (P Ͻ 0.001), and receiver-operating characteristics analysis showed an area under curve of 0.89 for higher i prediction (P Ͻ 0.001).Results support further clinical testing of STF analysis from right heart catheterization-derived EDP surrogates to noninvasively determined SV as screening/diagnostic tool to assess myocardial stiffness in HFpEF.heart failure with preserved ejection fraction; spectral analysis; spectral transfer function; myocardial stiffness HEART FAILURE (HF) with preserved ejection fraction (HFpEF) accounts for a rising proportion of over 50% of HF cases (25) and remains one of the unmet cardiovascular research challenges. Although it may constitute a heterogeneous disorder with complex determinants (32), most experts believe abnormalities in myocardial relaxation and compliance that develop under the influence of aging and comorbidities are the main underlying pathophysiological mechanisms (12). Diagnosis remains challenging and controversial. Biomarkers and noninvasive echocardiographic indexes would be desirable (26) but many question their accuracy and sensitivity based on invasively derived left ventricular (LV) hemodynamic evaluation and exercise testing in asymptomatic patients (27). In a small proof-of-concept study carried out in HFpEF patients and a...