Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study

Abstract

Background: Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging and relies largely on demonstration of elevated cardiac filling pressures (pulmonary capillary wedge pressure). Current guidelines recommend use of natriuretic peptides (N-terminal pro-B type natriuretic peptide) and rest/exercise echocardiography (E/e' ratio) to make this determination. Data to support this practice are conflicting.

Methods: Simultaneous echocardiographic-catheterization studies were prospectively conducted at rest and during exercise in subjects with invasively proven HFpEF (n=50) and participants with dyspnea but no identifiable cardiac pathology (n=24).

Results: N-Terminal pro-B type natriuretic peptide levels were below the level considered to exclude disease (≤125 pg/mL) in 18% of subjects with HFpEF. E/e' ratio was correlated with directly measured pulmonary capillary wedge pressure at rest (r=0.63, P<0.0001) and during exercise (r=0.57, P<0.0001). Although specific, current guidelines were poorly sensitive, identifying only 34% to 60% of subjects with invasively proven HFpEF on the basis of resting echocardiographic data alone. Addition of exercise echocardiographic data (E/e' ratio>14) improved sensitivity (to 90%) and thus negative predictive value, but decreased specificity (71%).

Conclusions: Currently proposed HFpEF diagnostic guidelines on the basis of resting data are poorly sensitive. Adding exercise E/e' data improves sensitivity and negative predictive value but compromises specificity, suggesting that exercise echocardiography may help rule out HFpEF. These results question the accuracy of current approaches to exclude HFpEF on the basis of resting data alone and reinforce the value of exercise testing using invasive and noninvasive hemodynamic assessments to definitively confirm or refute the diagnosis of HFpEF.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01418248.

Keywords: diagnosis; exercise; exercise test; heart failure.

Figure 1. Baseline echocardiographic parameters shown in heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnea (NCD)

(A) medial E/e’ ratio, (B) mitral E velocity, (C) medial e’ velocity, (D) deceleration time, (E) tricuspid regurgitant (TR) velocity, and (F) left atrial (LA) volume index. Notably, there was substantial overlap in these rest echocardiographic parameters.

Figure 2. Correlations between Invasive Filling pressures and Echocardiographic Estimates

Amongst subjects with obtainable data, medial and lateral E/e’ ratios were modestly correlated with directly measured pulmonary capillary wedge pressure (PCWP) at rest, submaximal (20W) and peak exercise. The feasibility of obtaining diagnostic quality echocardiographic measurements decreased during exercise.

Figure 3. Echocardiographic hemodynamic and Ventricular function indices during Exercise

(A–C) Compared to NCD, medial E/e’ was higher, medial e’ velocity was lower, and TR velocity was higher in HFpEF patients during submaximal (20W) and (D–F) peak exercise. However, there was still substantial overlap between HFpEF and NCD in these echocardiographic markers during exercise, with the E/e’ ratio showing the best separation between the groups. Abbreviations as in Figure 1.

Figure 4. Relationships between invasive and noninvasive estimated filling pressures during exercise

(A) Compared to rest, exercise E/e’ underestimated PCWP during exercise. 95% CI on regression lines are for the best-fit mean line. Interaction p value reflects the difference in slopes in the regression between E/e’ and PCWP at rest and during exercise. (B) Absolute values of PCWP and medial E/e’ during exercise for HFpEF and NCD. Error bars indicate SEM. P values at the top reflect a 1-way repeated measures ANOVA testing whether PCWP or E/e’ changes during exercise stages in HFpEF and NCD. †p<0.05 vs at rest; #p<0.05 vs 20 W exercise. (C) Absolute unit increases (i.e. changes from baseline, Δ) in both medial and lateral E/e’ were much lower than unit changes in PCWP in both HFpEF and NCD at 20W (left) and peak exercise (right). Error bars indicate SD. *p<0.05 vs PCWP. (D) Compared to HFpEF with elevated resting PCWP, changes with exercise (Δ) in medial E/e’ were greater in HFpEF with normal rest filling pressures both submaximal (20W) and peak exercise. Error bars indicate SD. ‡p<0.05 vs. HFpEF with rest PCWP >15mmHg. Abbreviations as in Figures 1 and 2.

Figure 5. Proportion of subjects with HFpEF and NCD identified according to the different guideline recommended algorithms

Dark blue indicates subjects diagnosed with true HFpEF (A) or true NCD (B) diagnosed as having HFpEF (dark blue) or NCD (light blue) using the different schemes. ASE/EACVI indicates the American Society of Echocardiography/ European Association of Cardiovascular Imaging algorithm; Cath, catheterization; Echo, echocardiography; ESC, the European Society of Cardiology criteria; Ex, exercise; and other abbreviations as in Figure 1.

Figure 6. Proposed diagnostic approach for HFpEF

In a patient with normal EF suspected of HFpEF, assessment of pretest probability is performed based upon clinical characteristics, physical exam, natriuretic peptide levels, and rest imaging. Patients with very few or most of these characteristics are very unlikely or very likely (respectively) to have HFpEF, and the diagnosis can be made with reasonable confidence in these groups without further testing. If diagnosis is needed with certainty in this cohort, then the gold standard of invasive exercise testing should be performed because exercise echo results may not sufficiently change the post test probability if discordant with the pretest likelihood. Rest Doppler echocardiography (E/e’) has reasonable specificity but poor sensitivity for the diagnosis of HFpEF. For patients with intermediate pretest probability, exercise echocardiography focused on E/e’ should be considered. If this is normal, the likelihood of HFpEF is low and further testing is not likely required. However, a positive exercise echo should prompt consideration for exercise cath to confirm the diagnosis because of the higher false positive rate. An equivocal or nondiagnostic exercise echo should also prompt consideration of invasive diastolic stress testing to clarify the diagnosis. Invasive testing at rest has poor sensitivity and all patients with suspected HFpEF referred for cardiac catheterization should undergo invasive exercise testing if the PCWP at rest is normal. ECG indicates electrocardiogram; LV, left ventricular; NT-proBNP, N-terminal pro-B type natriuretic peptide; and other abbreviations as in Figures 1 and 5.