Author + information
- Received May 27, 2015
- Revision received June 23, 2015
- Accepted June 25, 2015
- Published online June 1, 2016.
- Jonathan Grinstein, MDa,
- Eric Kruse, BS, RDCSa,
- Gabriel Sayer, MDa,
- Savitri Fedson, MDa,
- Gene H. Kim, MDa,
- Ulrich P. Jorde, MDb,
- Colleen Juricek, RNa,c,
- Takeyoshi Ota, MD, PhDa,c,
- Valluvan Jeevanandam, MDa,c,
- Roberto M. Lang, MDa and
- Nir Uriel, MDa,∗ ()
- aDepartment of Medicine, University of Chicago Medical Center, Chicago, Illinois
- bDivision of Cardiology, Montefiore Medical Center, New York, New York
- cDepartment of Surgery, University of Chicago Medical Center, Chicago, Illinois
- ↵∗Reprint requests and correspondence:
Dr. Nir Uriel, Transplant and Mechanical Circulatory Support, University of Chicago Medical Center, Cardiovascular Division, 5841 South Maryland Avenue, MC 2016, Chicago, Illinois 60637.
Objectives The aim of this study was to develop a technique to measure regurgitant flow throughout the entire cardiac cycle that would more accurately measure aortic insufficiency (AI) severity in patients with continuous-flow left ventricular assist devices (CF-LVADs).
Background AI is a common problem after CF-LVAD implantation. Current echocardiographic evaluation of AI does not take into account the unique flow properties present in patients with CF-LVADs.
Methods In this prospective study, patients with LVADs who had varying degrees of AI (N = 20) underwent simultaneous right-sided heart catheterization (RHC) and transthoracic echocardiography (TTE). Regurgitant fraction (RF) across the aortic valve was calculated by subtracting the cardiac output obtained using the Fick method from the total systemic flow measured using the sum of the product of the velocity time integral and the cross-sectional area of the LVAD outflow cannula and aortic valve, respectively. The RFs were then compared with the following: 1) traditional TTE grading parameters; and 2) new TTE parameters unique to LVAD physiology, namely the diastolic flow acceleration and the systolic-to-diastolic peak velocity (S/D) ratio of the LVAD outflow cannula.
Results Patients without evidence of AI had an RF approaching zero (2.4 ± 4.6%). Patients with trace and mild AI had an RF of 31.0 ± 5.4%, whereas patients with moderate or severe AI had an RF of 45.8 ± 3.6%. RF correlated better with pulmonary capillary wedge pressure (PCWP) than with vena contracta (correlation coefficient [R] = 0.73 vs. 0.56). The new TTE parameters (S/D ratio and diastolic acceleration) highly correlated with RF (R = 0.91 and 0.94, respectively) and more strongly correlated with PCWP than did vena contracta (R = 0.82 and 0.65 vs. 0.56).
Conclusions RF measured by simultaneous RHC and TTE better correlates with clinical filling pressures than do traditional TTE parameters and may identify significant AI that could be underestimated using conventional measures. Novel TTE parameters, unique to CF-LVAD physiology, better correlate with RF and filling pressures than do our current TTE measurements.
Aortic insufficiency (AI) is a common complication after continuous-flow left ventricular assist device (CF-LVAD) implantation; in approximately 1 in 4 patients, at least mild to moderate AI will develop within 1 year of implantation (1–3). It is hypothesized that AI develops from failure of aortic valve opening during LVAD support that leads to aortic valve commissural fusion and leaflet deterioration (1,2,4). Furthermore, the constant unloading of the left ventricle by the LVAD results in a reversed transaortic valvular pressure gradient that predisposes to progressive worsening of AI from increased shear stress (5). Left untreated, de novo AI after LVAD implantation can lead to clinical heart failure and the need for aortic valve repair, replacement, or closure or urgent cardiac transplantation in up to 50% of patients within 6 months of development of symptomatic moderate or greater AI (1,6,7).
Whereas in a native heart, AI occurs in diastole, in an LVAD-implanted heart, AI is pancyclic, occurring throughout systole and diastole in response to the constant positive transaortic pressure gradient (1,8–10). Traditional echocardiographic indices of AI severity (i.e., vena contracta, jet width/left ventricular outflow tract [LVOT] diameter, and proximal isovelocity surface area) do not take into consideration the pancyclic nature of AI jets in patients with LVADs and are less reliable with eccentric regurgitant jets, which are commonly encountered in LVAD-associated AI (11,12). Furthermore, the current echocardiographic parameters used for grading AI severity have not been prospectively evaluated in the unique flow patterns that are associated with LVAD implantation.
To our knowledge, this is the first study to evaluate the accuracy of traditional echocardiography measures of AI severity in patients with LVADs. Here, we directly compare the traditional echocardiography parameters of vena contracta and visual estimation with RF measured by right-sided heart catheterization (RHC) and Doppler echocardiography and then correlate these parameters with pulmonary capillary wedge pressure (PCWP). Furthermore, we test the accuracy of 2 new, noninvasive methods for measuring AI in patients with LVADs that were developed to reflect the pancyclic nature and constant volume load of aortic regurgitation more accurately in this unique patient population.
Between September 2014 and February 2015, 20 patients who previously underwent LVAD implantation with either a HeartMate II (Thoratec Corp., Pleasanton, California) or HeartWare HVAD (HeartWare International Inc., Framingham, Massachusetts) and who had varying degrees of AI were prospectively enrolled at the University of Chicago Medical Center in Chicago, Illinois. The Institutional Review Board approved this study, and all patients provided informed consent. Patients were excluded if they had poor echocardiographic windows or known left-to-right or right-to-left shunting. Patients were also excluded if they had known pump malfunction, inlet or outlet cannula malpositioning, or clinical suspicion of thrombosis. Patients’ baseline characteristics were collected and stored.
Right-sided heart catheterization and echocardiographic imaging
All patients underwent simultaneous RHC and transthoracic echocardiography (TTE) in the catheterization laboratory using a 7-F Swan-Ganz Catheter (Edwards Lifesciences, Irvine, California). RHC was performed through the right internal jugular vein or right femoral vein. The following values were measured: central venous pressure, systolic pulmonary artery pressure, diastolic pulmonary artery pressure, mean pulmonary artery pressure, PCWP, and pulmonary artery saturation. Cardiac output and cardiac index were calculated by the indirect Fick equation with estimated oxygen consumption of 125 ml/min/m2. Hemoglobin was measured from venous blood gas, and arterial oxygen saturation was measured by pulse oximetry. In a subset of 5 patients, repeat hemodynamic values were measured during a ramp study. The hemoglobin and arterial oxygen saturation values obtained during the baseline RHC were used for all subsequent Fick calculations during the ramp study.
Data were initially acquired at the patient’s presenting pump speed. From the parasternal window, linear measurements of left ventricular chamber size, aortic valve opening, and traditional AI severity were measured using aortic regurgitation vena contracta width and qualitative estimation of AI severity according to guideline recommendations (11,12) From a modified, right-sided parasternal view, the LVAD outflow cannula diameter and pulse-wave Doppler signal were acquired as previously described (13). The diameter of the LVAD outflow cannula was measured at the point of acquisition of the pulsed Doppler signal. The aortic valve opening was assessed by M-mode echocardiography through the aortic valve from a parasternal short-axis view and averaged over 10 cardiac cycles to determine the fraction of valve opening. Finally, for patients with at least intermittent antegrade flow across the aortic valve, pulse-wave Doppler of the LVOT was measured from the apical window (12). The aortic RF was calculated by subtracting the venous return to the right side of the heart obtained by RHC by the Fick method from the total left-sided systemic flow measured using TTE (Figure 1). Total left-sided systemic flow was calculated by measuring the flow through the LVAD outflow cannula and flow across the aortic valve in those patients with at least intermittent aortic valve opening. Flow across the LVAD outflow cannula was calculated by multiplying the velocity time integral (VTI) across the entirety of the cardiac cycle by the cross-sectional area (CSA) of the LVAD outflow cannula and heart rate (HR). Flow across the aortic valve was calculated by multiplying the VTI during systole in the LVOT by the CSA of the LVOT and HR, as well as the fraction of aortic valve opening according to the equation in Figure 1. The RFs measured with this novel method were compared with traditional indices including vena contracta and qualitative assessment (12). Results were clinically compared with left-sided filling pressures obtained during RHC.
Novel measurements of aortic insufficiency
Two new, totally noninvasive indices for grading AI severity in patients with LVADs are proposed: 1) LVAD outflow cannula diastolic acceleration; and 2) the outflow LVAD cannula systolic-to-diastolic peak velocity ratio (S/D ratio) (Figures 2A to 2C). The modified, right-sided parasternal window was used to acquire the pulse-wave Doppler signal of the outflow LVAD cannula. Care was taken to align the LVAD outflow cannula with the transducer at the point of anastomosis with the ascending aorta. The LVAD outflow cannula diastolic acceleration was obtained by measuring the diastolic slope from the onset to the end of diastole (Figures 2A to 2C). The S/D ratio was obtained by dividing the peak systolic velocity by the end diastolic peak velocity of the LVAD outflow cannula (Figures 2A to 2C). The performance of these indices was compared with traditional vena contracta width and aortic regurgitation fraction, measured as described earlier, as well as invasively acquired left-sided filling pressures measured by PCWP at the time of simultaneous heart catheterization.
To assess the performance of these indices at different AI severities induced by different LVAD speeds, parameters were acquired at different stages of a ramp study in a subset of patients (n = 5). We reported our ramp test protocol previously (14); in brief, patients had LVAD speeds increased by 400-rpm increments for the HeartMate II device. Left ventricular linear diastolic dimensions, frequency of aortic valve opening, severity of AI and mitral valvular insufficiency, blood pressure, and LVAD parameters were measured and recorded at each stage.
Data were collected using Excel software (2007 Microsoft Corp., Redmond, Washington) and were analyzed using GraphPad Prism (GraphPad Software Inc., San Diego, California). Continuous variables were evaluated for normality by using the D’Agostino-Pearson test for normal distribution. The Student t test was used to determine differences in normally distributed data. To determine the relationships among the different AI indices, as well as with clinical filling pressures, the Pearson coefficient of correlation was tested with linear regression analysis for each scoring parameter. For RF, patients without AI were excluded from correlation analysis, and for the S/D ratio, patients without AI were excluded from analysis. To assess the reproducibility of the S/D ratio and diastolic slope measurements, all measurements were repeated by a second observer, and interobserver variability was assessed by intraclass correlation measurement. Each patient was analyzed separately and given equal weight throughout all analyses.
Simultaneous RHC and TTE were performed in 20 patients with various degrees of AI ranging from absent to moderately severe AI. Baseline characteristics of the cohort are reported in Table 1. Patients’ ages ranged from 45 to 76 years (mean age 58 years), and 75% of these patients were men. Of these patients, 75% had a HeartMate II device, and 25% had a HeartWare HVAD. The LVAD was implanted as destination therapy in most of the patients (70%).
Performance of regurgitant fraction
RF was calculated in 15 of 20 (75%) patients. In the 5 patients in whom RF could not be calculated, either the LVAD outflow cannula could not be imaged (n = 2) or the Doppler flow recorded was orthogonal to the transducer and was therefore incapable of yielding an accurate Doppler signal. Patients without AI had an RF that was nearly zero (2.4 ± 4.6%). Patients with qualitatively estimated trace or mild AI had an RF of 31.0 ± 5.4%, a value that is well within the lower moderate range for RF, according to American Society of Echocardiography guidelines. The RF of patients with qualitatively estimated moderate or greater AI was higher (45.8 ± 3.6%), falling within the high range of moderate regurgitation fraction for AI (Figure 3A). RF correlated better with PCWP than did vena contracta (correlation coefficient [R] = 0.73 vs. 0.56) in all patients with AI (Figure 3B).
Novel transthoracic echocardiography parameters
The S/D ratio of the LVAD outflow cannula and LVAD outflow cannula diastolic acceleration strongly correlated with RF (R = 0.91 and 0.94, respectively) (Figures 4A and 4B). Both these indices were successfully acquired in 15 of 15 (100%) of patients in whom the LVAD cannula was well visualized. Both the S/D ratio and diastolic acceleration of the LVAD cannula correlated better with PCWP than did the vena contracta (R = 0.82 and 0.65 vs. 0.56) (Figures 4 C and D). The interobserver variability was low for both the S/D ratio and the diastolic slope as represented by a high intraclass correlation coefficient for both variables (r = 0.91 and 0.94, respectively).
The mean S/D ratio and diastolic acceleration stratified by RF along with proposed thresholds for moderate and severe AI stratified at the 30% and 50% RF thresholds, respectively, are reported in Table 2.
In a subset of 5 patients, the S/D ratio and diastolic acceleration of the LVAD cannula was measured at each stage of a ramp test (Figures 5A and 5B). One patient had no AI, 2 patients had mild AI, and 2 patients had moderate to severe AI. An average of 6 data points was obtained (range 5 to 9) in each patient. Given the augmented pressure gradient between the ascending aorta and the left ventricle at faster LVAD speeds, it would be expected that the degree of AI would increase at faster LVAD speeds. In keeping with this concept, in all patients the S/D ratio decreased and the diastolic slope of the LVAD outflow cannula increased at the augmented ramp test speeds, findings supporting the performance of these TTE parameters across a variety of LVAD settings (Figures 5A and 5B).
In the current study we evaluated the traditional echocardiographic methods of assessing the severity of AI and compared them with a novel, semi-invasive method of acquiring RF in patients with LVADs. Furthermore, we described 2 new noninvasive indices to assess pancyclic AI. The main findings of this study are as follows: 1) traditional echocardiographic methods used to assess AI in patients with LVAD underestimate the severity of AI compared with RF; 2) vena contracta fails to correlate accurately with left-sided filling pressures; and 3) the LVAD outflow cannula diastolic acceleration and the LVAD outflow cannula S/D ratio correlated well with RF and left-sided filling pressures.
It is now well established that de novo AI is a common complication after CF-LVAD implantation (1,2,15). The AI tends to be progressive and can lead to worsening heart failure and end-organ hypoperfusion with adverse effects on long-term survival (3,16). Initial management often involves adjusting LVAD speeds. Reduction of the LVAD speed decreases the transaortic pressure gradient and thus decreases AI severity, which often occurs at the expense of an elevation of left-sided filling pressures and worsening end-organ perfusion (5). Alternatively, LVAD speeds can be augmented to partially overcome the regurgitant flow and improve end-organ perfusion while simultaneously reducing clinical congestion (1). However, the increased pump speed further accelerates the destructive forces responsible for the AI. An invasive ramp study using combined real-time hemodynamics and echocardiographic structural assessment can help determine the optimal LVAD speed setting to temporize the disease (14,17). Ultimately, definitive management with valve repair, replacement, or closure or, alternatively, urgent transplantation is required for symptomatic AI. To date, there are no guidelines to assess the severity of AI in patients with LVADs, and instead, most centers continue to use American Society of Echocardiography guidelines that were described for patients with normal cardiac physiology and pulsatility.
Echocardiography has been shown to be useful in evaluating LVAD pump function, ventricular function, and hemodynamics in patients with CF-LVADs (14,18,19). Based on the continuity equation, total left-sided systemic flow must equal right-sided cardiac flow unless a shunt or AI is present. Using this principle, investigators have proposed that pump flow can be estimated by subtracting TTE-derived flow across the LVOT from flow across the right ventricular outflow tract (RVOT) (17,20). Similarly, Estep et al. (18) have suggested that a drop in flow across the RVOT as measured by TTE with preservation of cannula inflow or outflow Doppler profiles may indicate significant AI (18). In this study, we report for the first time a novel method that combines RHC and Doppler echocardiography to quantify AI severity based on the continuity of flow principle. After excluding patients with known shunts, we demonstrate that AI RF can be measured by subtracting right-sided cardiac output measured by RHC from left-sided total systemic cardiac output (flow across the LVAD added to flow across the aortic valve when present) measured by echocardiography.
Interestingly, when traditional AI indices were compared with RF measured by the proposed method, traditional indices appeared to underestimate AI severity, particularly among patients with less than moderate regurgitation. Similarly, RF correlated better with left-sided filling pressures than did tradition indices. Because AI increases the volume load of the left ventricle, left-sided filling pressures serve as a strong clinical correlate of AI severity. Accordingly, it appears that traditional indices may lead to underestimation of hemodynamically significant AI and to diagnosis in advanced clinical presentations. Unfortunately, with more advanced AI and clinical disease, patients are deemed high-surgical risk candidates and therefore frequently undergo high-risk aortic valve surgical procedures or, alternatively, undergo percutaneous aortic valve closure with less favorable long-term outcomes (21). It is hoped that more timely recognition of more severe AI may allow for disease modification or surgical intervention with improved outcomes. However, there are no published data to prove that early repair of AI will change the course of the disease and result in better outcomes.
Over the course of our study, we gained valuable insight and experience with imaging the LVAD outflow cannula. It became apparent during this study that the LVAD outflow cannula area was more variable than initially appreciated. Although the outflow cannula has a predefined ex vivo diameter as defined by the respective manufacturer (1.4 cm for the HeartMate II and 1.0 cm for the HeartWare HVAD), in vivo several cannulas had considerably smaller diameters at the point of Doppler signal acquisition related to the angle of anastomosis to the aorta, the degree of sewing at the anastomosis, kinking of the outflow cannula, or possible external compression of the pliable cannula. Outflow cannula obstruction can impair the efficiency of the LVAD and can predispose the patient to clinical signs of heart failure. Additional imaging studies focusing on distortion of LVAD outflow cannula anatomy are needed to define the scope of this problem more clearly.
We also describe 2 novel, completely noninvasive techniques to assess AI severity using Doppler echocardiography that correlate more favorably with RF and left-sided filling pressures than vena contracta does. We demonstrated that LVAD outflow cannula diastolic acceleration and LVAD outflow cannula S/D ratio can be acquired in the majority of patients with LVADs, although such indices may be difficult to measure in patients with poor acoustic windows or tachycardia. These new indices strongly correlate with RF and better correlate with PCWP than does vena contracta. Flow through the LVAD outflow cannula is directly proportional to preload in the left ventricle and is inversely proportional to afterload in the ascending aorta. During systole, afterload in the ascending aorta augments from enhanced flow either through the LVAD or across the aortic valve (in patients who have some degree of aortic valve opening) (Figure 6A). During diastole, regurgitant flow into the left ventricle across the aortic valve coupled with forward downstream flow into the aortic arch and ascending aorta leads to progressive reduction in afterload in the ascending aorta (Figure 6B). Furthermore, the regurgitant flow across the aortic valve adds to the left ventricular preload. Thus, with increasing AI severity, an acceleration of diastolic outflow cannula flow is expected. Similarly, the flow ratio through the LVAD cannula from peak systole (when afterload is the highest and preload is the lowest) to end-diastole (when afterload is the lowest and preload the highest) is expected to decrease as AI severity worsens.
In this study, an excellent correlation between LVAD outflow cannula diastolic flow acceleration and RF is demonstrated, thus supporting the use of these indices as sensitive markers of AI severity in patients with LVADs. We also demonstrate a high inverse correlation between peak S/D ratios and AI RF. An elevated S/D ratio has also been previously shown to predict LVAD thrombosis in patients with intravascular hemolysis (22). Both the diastolic acceleration of the LVAD outflow cannula and the peak S/D ratio performed well across a variety of LVAD settings as demonstrated during ramp testing. AI severity would be expected to increase at higher LVAD speeds given the enhanced gradient between the aorta and the left ventricle with increased LVAD speed. Accordingly, the S/D ratio decreased and the diastolic acceleration of the LVAD outflow cannula increased in all patients during ramp testing.
Our study demonstrates that traditional echocardiographic methods underestimate the severity of AI and do not correlate as highly with left-sided filling pressures compared with RF. As such, the true severity of aortic regurgitation as a contributor to worsening heart failure may be underappreciated in these patients. We describe 2 additional novel noninvasive methods that correlate well with RF and PCWP. These indices may further help us understand the physiology and progression of the disease and allow us better to study the clinical consequences of AI in patients with LVADs. Given the lack of a true gold standard for measuring AI in patents with LVADs, the enhanced correlation with left-sided filling pressures that was observed with the novel parameters suggests that these parameters may be more clinically relevant. Accordingly, the novel parameters may allow us better to evaluate the epidemiology of AI in this patient population.
This study was a single-center, prospective study with a small cohort size and thus prone to bias related to our own institution’s surgical techniques and TTE image acquisition. However, the physiologic nature of the study together with the strong correlations described overcome the size limitation. In our study, cardiac output was measured by the indirect Fick method using calculated oxygen consumption and indirect arterial oxygen saturation using pulse oximetry. We opted to use a physiologic calculation of right-sided flow instead of calculating right-sided flow using the RVOT VTI. In a subset of patients, we were able to show a linear increase in AI severity as measured both by RF and by S/D ratio and diastolic acceleration of the LVAD cannula during a RAMP study. During the ramp, each patient acts as his or her own control, thereby effectively limiting bias related to cannula anatomy, operator experience, and oxygen consumption assumptions. Furthermore, our study analyzed the limitations of vena contracta and visual estimation. We did not analyze alternative traditional parameters including jet width/LVOT diameter and proximal isovelocity surface area, and therefore the accuracy of these methods is still unclear. Additionally, the validity of any noninvasive parameter, be it traditional or novel, is limited by the lack of a universally agreed on, quantifiable, direct measurement of AI severity to serve as the gold standard.
Traditional echocardiographic methods underestimate the severity of AI in LVAD patients compared with RF and do not correlate as strongly with left-sided filling pressures. The LVAD outflow cannula diastolic acceleration and the LVAD outflow cannula S/D ratio had excellent correlations with RF and left-sided filling pressures and should be used to assess AI severity in these patients.
COMPETENCY IN MEDICAL KNOWLEDGE: The new TTE parameters, diastolic acceleration of the LVAD outflow cannula and S/D ratio of the LVAD outflow cannula, allow for reliable and easily reproducible evaluation of AI severity in patients with CF-LVADs. These novel parameters better correlated with intracardiac filling pressures and may detect clinically meaningful regurgitant flow across the aortic valve sooner than currently used TTE parameters.
TRANSLATIONAL OUTLOOK: The clinical consequence of AI in patients with CF-LVADs remains uncertain, and future studies are needed to evaluate the prognostic performance of the S/D ratio and diastolic acceleration of the LVAD outflow cannula. Furthermore, clinical studies evaluating the efficacy of aortic valve interventions including valve closure and replacement are needed to define more clearly when such interventions are warranted.
Dr. Uriel is a consultant to HeartWare and Thoratec. Dr. Jeevanandam is a scientific advisor to Thoratec, HeartWare, and Reliant Heart. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- aortic insufficiency
- continuous-flow left ventricular assist device
- cross-sectional area
- left ventricular assist device
- pulmonary capillary wedge pressure
- regurgitant fraction
- right-sided heart catheterization
- S/D ratio
- systolic-to-diastolic peak velocity ratio
- transthoracic echocardiography
- velocity time integral
- Received May 27, 2015.
- Revision received June 23, 2015.
- Accepted June 25, 2015.
- American College of Cardiology Foundation
- Jorde U.P.,
- Uriel N.,
- Nahumi N.,
- et al.
- Mano A.,
- Gorcsan J.,
- Teuteberg J.J.,
- et al.
- Martina J.,
- de Jonge N.,
- Sukkel E.,
- Lahpor J.
- Kato T.S.,
- Maurer M.S.,
- Sera F.,
- Homma S.,
- Mancini D.
- Siontis K.C.,
- Nkomo V.T.,
- Pislaru C.,
- Enriquez-Sarano M.,
- Pellikka P.A.,
- Pislaru S.V.
- Lang R.M.,
- Bierig M.,
- Devereux R.B.,
- et al.
- Horton S.C.,
- Khodaverdian R.,
- Chatelain P.,
- et al.
- Uriel N.,
- Morrison K.A.,
- Garan A.R.,
- et al.
- Estep J.D.,
- Stainback R.F.,
- Little S.H.,
- Torre G.,
- Zoghbi W.A.
- Estep J.D.,
- Vivo R.P.,
- Krim S.R.,
- et al.
- Retzer E.,
- Tabit C.E.,
- Estrada J.R.,
- et al.
- Fine N.M.,
- Topilsky Y.,
- Oh J.K.,
- et al.