Echocardiography vs Hemodynamic Assessment of Diastolic Dysfunction

Objectives. Diagnosing diastolic dysfunction (DD) is complex and controversial. The American Society of Echocardiography and the European Association of Cardiovascular Imaging (ASE/EACVI) criteria for diagnosing DD are widely accepted in clinical practice. The study's aim was to evaluate the added value of invasive hemodynamic assessment in patients with unexplained shortness of breath (SOB) undergoing echocardiographic assessment using the most accepted echocardiographic definition of DD.

Methods. A retrospective cohort study included 91 consecutive patients with preserved left-ventricular function who underwent right-heart catheterization with moderate-intensity exercise to evaluate unexplained SOB. Patients were divided into 2 groups: Group 1 without DD (33 patients with resting pulmonary capillary wedge pressure [PCWP] ≤ 15 mm Hg and exercise PCWP < 18), and Group 2 with DD (58 patients with resting PCWP > 15 mm Hg and/or exercise PCWP ≥ 18). Of Group 2, 48 (53%) had a resting PCWP >15 mm Hg and 10 (11%) had exercise-induced PCWP ≥ 18 mm Hg.  

Results. Echocardiographic criteria for DD were compared with invasive PCWP. Mean age was 62 ± 17 years, 66% were women. The ASE/EACVI echocardiographic criteria were positive for DD (3-4/4 criteria) in 12.1% of Group 1 patients and 46.6% of Group 2 patients. Approximately one-half of the patients without echocardiographic evidence (0-1/4 criteria) or with indeterminate echocardiographic findings (2/4 criteria) had invasively proven DD (48.4% and 55.2%, respectively). In patients with echocardiographic evidence of DD (3-4/4 criteria), invasively proven DD was present in 87.1%.

Conclusions: Echocardiographic assessment is insufficiently sensitive for the diagnosis of DD. Invasive hemodynamic assessment can refine the diagnosis of DD in patients with unexplained SOB.

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by the triad of signs and symptoms of heart failure, preserved left ventricular ejection fraction (left ventricular ejection fraction [LVEF] ≥ 50%), and evidence of diastolic dysfunction (DD).^1–3  The diagnosis of DD is established either by echocardiography or by invasive assessment of left ventricular filling pressures. While invasive measurements are considered a hallmark for the diagnosis of DD,^4,5 the echocardiographic criteria for DD are complex and controversial. Numerous position papers and guidelines have been published on this topic with little agreement between them.^1-3,6-9 Specific echocardiographic measures of DD (such as E/e` ratio, mitral inflow, and pulmonary venous flows) are much debated in the literature, and none are sufficiently sensitive nor specific to rule in or rule out DD.³

The American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) echocardiographic criteria combine several parameters for the assessment of DD,¹ which have been widely adopted in clinical practice. The purpose of this study was to evaluate the added value of invasive hemodynamic assessment in patients with unexplained shortness of breath undergoing echocardiographic assessment using the most accepted echocardiographic definition of DD.

Study population. Between 2004 and 2016, 91 consecutive patients underwent right heart catheterization (RHC) with exercise for the evaluation of unexplained shortness of breath. All patients had preserved left-ventricular systolic function (LVEF ≥50%). Decision to perform exercise in the catheterization laboratory was at the operators’ discretion. These patients were retrospectively evaluated for the purpose of this study. Pre-catheterization evaluation included physical examination, electrocardiogram, chest X-ray, echocardiography, pulmonary function test, and lung perfusion scan if indicated. Data collection was approved by the local institutional review committee, and the study approved by the Sheba Medical Center ethics committee and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Patients with significant valvular disease (defined as any degree of aortic or mitral stenosis, and more than mild mitral or aortic regurgitation), left ventricular ejection fraction less than 50% by echocardiography, or significant lung disease by lung function test were excluded. The study population was divided into 2 groups based on the presence of DD as defined by invasively assessed pulmonary capillary wedge pressure (PCWP) at rest or with exercise. The first group included 33 patients without evidence of DD defined as mean resting PCWP less than or equal to 15 mm Hg, and mean exercise PCWP less than 18 mm Hg. The second group included 58 patients with DD defined as a mean resting PCWP greater than 15 mm Hg or mean exercise PCWP greater than or equal to 18 mm Hg.

Echocardiography. Two-dimensional transthoracic echocardiographic and Doppler studies were obtained with clinical ultrasound machines equipped with 3.5 MHz transducers using standard views. The studies were digitally stored using McKesson’s Horizon Cardiology Medical Software. Left ventricular function was estimated by the biplane Simpson’s method. Echocardiographic evaluation was in accordance with the ASE Guidelines and Standards.¹

Right heart catheterization. A pulmonary artery catheter was introduced through the right or left femoral vein using the Seldinger technique. The transducer was carefully adjusted to reflect the height of the mid-chest of every patient as previously described.¹⁰ Systolic, diastolic, mean right atrial pressure, right ventricular pressure, pulmonary arterial pressure (PAP), and PCWP were measured directly using a 7.5 French Swan–Ganz catheter (Edwards Life Sciences). Mean PCWP was measured at end-expiration by assessing digitalized and paper tracings. Cardiac output (CO) was measured according to either measured Fick or thermo-dilution methods. Stroke volume was calculated by dividing the CO by the heart rate. The trans-pulmonary gradient (TPG) and the diastolic pressure gradient (DPG) were calculated as previously described.¹¹ As per catheterization laboratory protocol, resting right heart catheterization (RHC) was followed by moderate intensity exercise of the upper extremities, which comprised abduction–adduction movement of the upper limbs while holding 1 kg weights in each arm, until reaching at least a 10% rise in heart rate compared with baseline, or until patient exhaustion. Hemodynamic measurements were repeated at peak exercise.

Statistical analysis. Results are reported as mean ± SD. Categorical data was compared with the use of the Pearson chi-square test or Fisher’s exact test. Continuous data were compared with the use of Student t-test. P for trend was calculated for categorical data with use of Linear-by-Linear Association test, and for continuous data with use of Linear Regression test. Statistical significance was accepted for a 2-sided P <.05. The statistical analyses were performed with SPSS version 25.0 (IBM).

We included 91 patients with unexplained shortness of breath, mean age of 62 ± 17 years, 66% women, and BMI 28.3 ± 6. Diastolic dysfunction, defined as PCWP greater than 15 mm Hg at rest or greater than or equal to 18 mm Hg at peak exercise, was present in 58 patients (64%). Among these, 48 (53%) had a resting PCWP greater than 15 mm Hg, and 10 (11%) had exercise-induced PCWP greater than or equal to 18 mm Hg.

The baseline characteristics of patients with and without DD are shown in Table 1. Patients with DD were numerically older than patients without DD and had significantly higher body mass index. Moreover, patients with DD had significantly greater prevalence of ischemic heart disease, obstructive sleep apnea (OSA), and atrial fibrillation. They had numerically greater prevalence of diabetes and hypertension.

Echocardiographic parameters are shown in Table 2. Patients with DD had significantly greater left ventricular diastolic dimensions, left ventricular mass, and left atrial end-systolic area, greater trans-mitral early diastolic velocity (E wave), and increased ratio of E wave-to-tissue Doppler velocity measured at the septal and lateral walls (E/e`). Left atrial volume index was significantly larger in patients with DD.

Echocardiographic analysis of patients with no evidence for DD on invasively measured PCWP is shown in Figure 1. No echocardiographic evidence of DD (0-1 criterion) was found in 16 patients (48.5%), indeterminate evidence (2 criteria) was found in 13 patients (39.4%), and evidence was falsely positive for DD (3 criteria) in 4 patients (12.1%).

Echocardiographic analysis of patients with DD as defined by invasive measurement of PCWP is shown in Figure 1. A definite echocardiographic diagnosis of DD (3 or 4 positive echocardiographic parameters) was found in 27 patients (46.6%) of patients, indeterminate for DD (2 criteria) in 16 patients (27.6%), and negative for DD (0-1 criterion) in 15 patients (25.9%).

Prevalence of DD as defined by invasively measured PCWP in patients with 0 to 1, 2, and 3 to 4 echocardiographic criteria for DD is shown in Figure 2. In patients with no echocardiographic evidence of DD (0-1 criterion), DD was present in 15 patients (48.4%) (Figure 2A). A similar prevalence of DD (55.2%) was observed in patients with indeterminate findings on echocardiography (2 criteria) (Figure 2B). In patients with echocardiographic evidence of DD (3-4 criteria), DD was present in 27 patients (87.1%) (Figure 2C).

The purpose of our study was to compare echocardiography using the ASE/EACVI echocardiography guidelines for diagnosing DD¹ with invasive hemodynamic assessment and assess whether there is added value in referring symptomatic patients without echocardiographic evidence of DD for invasive assessment.

While there is no "gold standard" for assessing DD, direct measurement of left-ventricular diastolic filling pressures or mean PCWP as a measure of mean left-atrial pressure at rest and with exercise are considered hallmarks of DD.^4,5 The major finding of our study is that, compared with invasive assessment of DD, echocardiography using the current ASE/EACVI criteria have high specificity and low sensitivity for the diagnosis of DD. Indeed, when applying these criteria, only 46.6% of patients with DD were identified, and in almost 26% of patients with DD, the diagnosis was ruled out using the echocardiographic criteria (false negative). Conversely, patients fulfilling the echocardiographic criteria for definite DD were very likely (87%) to have DD on RHC.

Previous studies of individual echocardiographic measures of DD did not demonstrate significant results. For example, E/e` was normal in about 30% of stable outpatients with unexplained dyspnea and invasively proven DD,<sup>12</sup> and was not able to reflect changes in PCWP during alterations in loading conditions<sup>.13</sup> Thus, it would seem that E/e` is not sensitive enough to detect HFpEF in early stages of the disease and does not rule out the presence of DD.⁶ Other echocardiographic measures have similar limitations. For example, enlargement of left atrial volume can occur following chronically increased left ventricular filling pressures, and so its presence supports the presence of DD.¹  However, there is overlap between normal individuals and patients with DD and, furthermore, elite athletes have been shown to have enlarged LA volumes^.14 The poor performance of individual echocardiographic parameters of DD was the driving force behind the ASE/EACVI guidelines, which attempt to achieve greater diagnostic accuracy by combining several parameters of ventricular relaxation, left atrial size, and TR velocity as measures of pulmonary arterial pressure.

Only 1 previous study has assessed the performance of the ASE/EACVI guidelines. This excellent study by Obokata et al performed simultaneous stress echo and stress RHC in 74 patients. Using hemodynamically defined DD as the “gold standard,” the ASE/EACVI guidelines for resting echocardiography achieved a specificity of 83%, almost identical to the 85% found in our study. However, and again like the specificity rate of 48% found in our study, the specificity of the ASE/EACVI guidelines was only 34%.⁵  Interestingly, exercise echocardiography only nominally improved diagnosis of DD. This was related largely to the complexity and reduced feasibility for obtaining complete data during exercise. In this study, addition of exercise E/e′ alone was useful to rule out DD if it was completely normal. However, the false-positive rate also increased with addition of exercise E/e′, suggesting that confirmatory invasive testing may still be required if exercise E/e′ is abnormal in this population.

While the findings of the study by Obokata et al regarding the sensitivity and specificity of the ASE/EACVI guidelines are remarkably similar to ours, there are some notable methodological differences. Firstly, the exercise PCWP cutoff for defining DD was lower in our study (≥18 mm Hg compared with >25 mm Hg in Obokata’s study). Secondly, and most importantly, the Obokata exercise protocol was part of a prospective study protocol that utilized jugular access and graded bicycle ergometry, which are not available in most catheterization laboratories and are both complex to perform and time consuming. Our study utilized a simple hand exercise that is used in clinical practice at our laboratory and that can be easily replicated without the introduction of special equipment. The protocol involves arm adduction and abduction until a modest increase in pulse (10% compared with rest) or patient exhaustion occurs. Despite these differences, the findings of the 2 studies were remarkably similar, suggesting that a simplified approach to performing the invasive stress study is clinically sound.

Limitations: Our study has a number of limitations. Echocardiograms and hemodynamic stress tests were performed within a clinical framework and not as part of a study protocol and were not performed simultaneously, but rather within a 3-month time frame. While this is a weakness, it does reflect how we assess patients in real life, and it is unlikely that a more contemporaneous echocardiogram would show different measures of DD. Also, we have no data on stress echocardiography and how this might have impacted the diagnosis in this population. However, the meticulous data collected by Obokata et al⁵ suggest that while exercise echocardiography using E/e` was useful in ruling out DD if completely normal, the high false-positive rate suggests that confirmatory invasive testing may still be required if exercise E/e′ is abnormal. In addition, the technical complexity of performing exercise echocardiography in this population is significant given the patients’ physical limitations and inability to obtain significant rise in pulse, as well as the difficulty in obtaining high-fidelity echocardiographic images related to the high prevalence of overweight and obesity in this population. We had no available data regarding brain natriuretic peptides, which constitute a diagnostic criterion for the definition of HFpEF.³ However, compared with HFrEF, biomarker levels are lower in HFpEF patients.¹² Indeed, almost 1 in 5 patients with invasively proven DD display completely normal NT-proBNP (<125 pg/mL)⁵ and hemodynamic proof of DD is present in a substantial number of patients with normal NT-proBNP levels, either when assessed at rest¹⁵ or during exercise.⁸

The diagnosis of DD among patients with unexplained shortness of breath remains challenging. The current ASE/EACVI echocardiographic criteria, while fairly specific for ruling in DD, are not sensitive and do not allow for the ruling-out of significant DD in symptomatic patients with normal echocardiographic indices of diastolic function. Stress echocardiography and brain natriuretic peptides have also been shown to have limited utility in this clinical setting. Based on our findings, hemodynamic assessment can further refine the diagnosis of DD in symptomatic patients with no obvious alternative explanation and no echocardiographic evidence of DD. We have demonstrated the utility of using a simplified hand exercise, which can be integrated into standard catheterization laboratory protocols. Further research is needed to refine non-invasive modalities for the assessment of DD. Until then, invasive RHC with exercise will remain an important tool in the assessment of these patients.     

From the ¹Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; ²Arrow Project, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; ³Department of Medicine B, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Disclosures: The authors report no financial relationships or conflicts of interest regarding the content herein.

Address for correspondence: Lior Fisher, MD, Leviev Heart Center, Sheba Medical Center, Tel Hashomer 5265601, Israel. Email: Lior.Fisher@sheba.health.gov.il