Mitral E‐wave to stroke volume ratio displays stronger diagnostic performance to identify elevated left ventricular filling pressures than mitral E/e’ during passive leg lift: A cross‐sectional study employing simultaneous echocardiography and catheterization

Elevated filling pressure is a hallmark of heart failure (HF) and portends poor prognosis. Accurate diagnosis is challenging, given that patients with normal filling pressure at rest develop disproportionate elevation with sudden preload increase. We aimed to test the accuracy of the ratio between mitral inflow velocity (E) and left ventricular stroke volume (SV) to identify patients with elevated filling pressure with passive leg lifting (PLL) and compare this with other echocardiographic surrogates of filling pressure.


INTRODUCTION
Elevated left ventricular (LV) filling pressure is a hallmark of heart failure (HF) and portends poor prognosis. 1Accurate assessment of LV filling pressure poses a diagnostic challenge irrespective of ejection fraction. 2Furthermore, HF patients with normal filling pressures at rest often display a disproportionate pressure rise when provoked by exertional maneuvers, which include rapid preload increase during passive leg lift (PLL).
In routine clinical practice, right heart catheterization (RHC) is performed to assess intracardiac hemodynamics both at rest and with provocation to identify elevated filling pressure and differentiate pulmonary hypertension (PH) hemodynamic subgroups based on pulmonary capillary wedge pressure (PCWP).Echocardiography is a first-line diagnostic and displays multiple advantages owing to its noninvasive, nonionizing, widely accessible and portable nature.
Echocardiographic variables that rule out elevated LV filling pressure during rest and with provocation are of immense value for screening, effective triage to invasive assessment and subsequent therapy regulation.
Based on a hemodynamic concept and by using pressure-volume loops, the ratio between mitral inflow velocity (E = pressure) and LV stroke volume (SV = volume) could be a method estimating dynamic changes in filling pressures (Figure 1) but its use by during PLL has not been adequately studied.We aimed to compare the accuracy of E/SV with conventional echocardiographic variables to assess elevated LVFP during PLL employing reference standard RHC.Mean right atrial pressure (RAP), systolic and end-diastolic right ventricular pressure (RVEDP), pulmonary artery systolic, mean and diastolic pressures (PASP, PAMP and PADP, respectively) and PCWP were all measured according to guidelines. 3 PCWP pressures were calculated as mean of 10 consecutive beats.Blood samples for estimating oxygen saturation were drawn from the superior canal vein, pulmonary artery and femoral artery, and 8% was considered a significant step up between superior vena cava (SVC) and pulmonary artery.CO was determined by thermodilution technique.Pulmonary vascular resistance (PVR) was calculated using the equation PAMP−PCWP (transpulmonary gradient) divided by CO.PH was defined as mean pulmonary pressures >20 mmHg.

Statistics
Continuous variables were presented as mean ± SD or median (IQR)

RESULTS
Clinical, hemodynamic and echocardiographic characteristics are shown in Table 1.Of the 37 patients, 10 had heart failure with preserved ejection fraction (HFpEF) mainly due to hypertensive disease(n = 9) but one had ATTR cardiac amyloidosis, 11 had rheumatic disease (1 mixed connective disease, 9 had scleroderma and 1 systemic lupus erythematosus (SLE), 6 had chronic thromboembolic pulmonary hypertension (CTEPH), 3 had chronic obstructive pulmonary disease (COPD), 4 had unclear dyspnea and 1 had hypertrophic cardiomyopathy (HCM), 1 had valve prothesis dysfunction and had idiopathic pulmonary arterial hypertension (PAH).No patients had significant (more than mild) valvular disease.

Echocardiography
On echocardiography, patients demonstrated a significant increase

DISCUSSION
In this study, the mitral E-wave to SV ratio displayed a strong ability to identify elevated LV filling pressure with PLL.Further, E/SV > 1 cm/s/mL displayed high sensitivity, specificity and greater accuracy when compared with mitral E/e' as well as resting E/A ratio and catheterization derived resting PCWP.Our findings suggest a role for this novel echocardiographic ratio as a strong adjunct to the assessment of filling pressures during PLL in the setting of suspected HF.

Estimation of left ventricular filling pressures at rest using Doppler
Echocardiography is recommended as a part of clinical HF examinations but has its limitations. 6,7hocardiographic algorithms take into consideration mitral E wave, mitral e' velocity, TR velocity and indexed left atrial volume (LAVI).
We have recently demonstrated that adding left atrial strain to the diagnostic algorithm improves its accuracy in the setting of preserved EF. 8 Additional studies suggest a role for alternative algorithms and exercise echocardiography in LV filling pressure assessment.We suggest that the E/SV ratio may demonstrate value to identify patients with elevated PCWP under PLL.Earlier studies show a lack of increase in SV during PLL both in patients with PH 14 and in HFpEF. 15We demonstrate similar findings, suggesting that the inability to augment SV may be owing to the LV operating on the plateau limb of the Frank-Starling curve.In this setting, preload reserve is likely exhausted, leading to an increase in LV filling pressure to preserve CO.Obokata and colleagues also showed that mitral E wave velocity increases both in HFpEF and in hypertensive controls without signs of HF during PLL. 15Increase in transmitral flow in HFpEF can be attributed to a rise in filling pressure, while in controls, this may be owing to LV suction.The utilization of RHC as an invasive reference in our study further corroborates these findings.
Another striking finding in our results were the number of patients which needed reclassification to a different PH group during PLL. 16 rest 62% had precapillary PH which reduced to 32 % at PLL.None had isolated post capillary PH which increased to 5% at PLL. Twentytwo percent normal hemodynamics which reduced to 14% during PLL.
Finally, 16% had combined pre and post capillary PH which increased to 46% at PLL.Thus, more patients were found having PH at PLL and Therefore, performing PLL and Doppler echocardiography simultaneously might be an important diagnostic method to evaluate patients with stress induced increase in LV filling pressures.

Limitations
Our study cohort comprised patients with precapillary PH and HF, and patient heterogeneity may be considered a major limitation in this study.However, a heterogeneous population permitted closer inspection of the transition of hemodynamic subgroups with PLL, which suggests that hemodynamic classifications at rest are misleading.We believe that this finding is of scientific interest and may not have been showcased if we had strictly defined populations.Additionally, the larger representation of heart failure with reduced ejection fraction (HFrEF) in those having elevated PCWP with PLL may limit the interpretation of our results.Finally, the relatively small number of patients in this cohort where echocardiography and catheterization were simultaneously performed is a limitation in this study.The novelty of these findings would, hence, need to be validated in larger groups.

CONCLUSION
The novel E/SV ratio identifies patients with elevated PCWP during PLL and displays stronger diagnostic performance than routinely utilized echocardiographic measures such as E/e' in addition to resting invasive PCWP.However, its use in clinical practice needs to be validated in larger cohorts.

Echocardiography.
Echocardiographic examination was performed simultaneously with RHC using a Vivid 9 system (GE Medical Systems, Horten, Norway) equipped with an adult 1⋅5−4⋅3 MHz phased array transducer.Standard views from the parasternal long axis, short axis and apical four-chamber views were used.LA volume was measured from the apical four-chamber view using area-length method and was further adjusted for body surface area (BSA) (LAVI).Flow velocities were obtained using Pulse-Wave (PW) and Continuous-Wave (CW) Doppler techniques as proposed by the American Society of Echocardiography and European Association of Cardiovascular Imaging. 4,5All Doppler recordings were made at a sweep speed of 50−100 mm s −1 with a superimposed ECG (lead II).Offline echocar-F I G U R E 1 Hemodynamic pressure/volume and Doppler aspects on resting and leg raise in normal and patients(abnormal) with elevation in PLL filling pressures.PLL, passive leg lifting.
Clinical data, resting and PLL echocardiographic data in patient subgroups with or without increased PCWP during PLL.
17 B L E 2 Abbreviations: BSA, body surface area; CO, cardiac output; CPH, capillary pulmonary pressure; E and e' , early diastolic blood and myocardial velocity; RV, right ventricle; RA, right atrial; SV, stroke volume; CO, cardiac output.GLS, global longitudinal strain; LAVI, left atrial volume index; mPAP, mean pulmonary artery pressures; PALS, peak atrial longitudinal strain; RHC, right heart catheterization.F I G U R E 2 Scatterplott of the relationship between E/SV during PLL and PCWP during PLL.Circles are patients and cross are controls.Vertical line is 1.05 and horizontal line 15 mmHg.E, pressure PCWP, pulmonary capillary wedge pressures; PLL, passive leg lifting; SV, stroke volume.F I G U R E 3In all patients (n = 37) E/SV PLL identified patients with PCWP > 15 mmHg during PLL with an AUC of .94.AUC for E/e' PLL was .81,AUCforMF E/A rest was .76,AUCforresting PCWP and PCWPv .84 and .81.E/SV PLL > 1.0 had a sensitivity of 8% and a specificity of 76% identifying patients with a PCWP during PLL > 15 mmHg.AUC, area under the curve; E, pressure PCWP, pulmonary capillary wedge pressures; PLL, passive leg lifting; SV, stroke volume.17However,an accurate measure for elevated filling pressures at cardiac stress is important as many patients with HF have normal filling pressures during rest which demasks during stress.Passive leg lifting (PLL) is a quick and easily performed maneuver which increases preload and tests the cardiac compliance.