Spontaneous Echocardiographic Contrast in the Left Atrium During Transcatheter Aortic Valve Replacement is Associated With Worse Outcomes

Transcatheter aortic valve replacement (TAVR) has dramatically changed the management of patients with severe aortic stenosis AS.^1,2 However, these patients remain at high risk for future adverse events because of their underlying comorbidities. Recently, spontaneous echocardiographic contrast (SEC) was shown to be a poor prognostic factor in a wide range of cardiac diseases.³ Although SEC has been associated with increased risk of stroke in patients with atrial fibrillation (AF) and mitral stenosis,^4,5 there is scarce information about the impact of SEC on the prognosis of patients undergoing TAVR. 

Spontaneous echocardiographic contrast has been reported frequently in patients with rheumatic mitral stenosis and atrial fibrillation.⁶ However, Lenders et al recently reported that SEC was observed in 47% of severe AS patients referred for TAVR.⁷ In severe AS, all (reservoir, conduit, and active) of left atrial (LA) function was impaired.⁸ In addition, severe AS is frequently associated with left ventricular (LV) diastolic dysfunction and increased LV filling pressures.⁹ Therefore, LA diastolic dysfunction in severe AS may contribute to the pathophysiology of SEC formation in the LA. The impact of SEC on patient outcomes after they have undergone TAVR has not been examined. Therefore, this study was designed to assess the impact of SEC on the outcomes of severe AS patients who have received TAVR.

Methods

Study design, patient population, and procedures. This was a retrospectively designed study. Patient demographics, comorbidities, Society of Thoracic Surgeons (STS) scores, and echocardiographic parameters were obtained from electronic medical records. Ninety-three patients who underwent TAVR at a single center between June 2012 and March 2015 were screened for inclusion. Patients who experienced major procedure-related complications that resulted in conversion to open-heart surgery or death were excluded. Baseline clinical data that were collected included New York Heart Association functional class, history of arterial hypertension (>140/90 mm Hg or on antihypertensive medication), dyslipidemia (on lipid-lowering therapy), diabetes mellitus (receiving oral antihyperglycemic medications, insulin, or a hemoglobin A1c ≥6.5%), chronic kidney disease (estimated glomerular filtration rate <60 mL/min/m²), peripheral artery disease, cerebrovascular disease, coronary artery bypass graft, myocardial infarction, and permanent pacemaker implantation. All procedures were performed in a hybrid operating room under general anesthesia. Patients underwent implantation of either an Edwards Sapien valve (Edwards Lifesciences) prosthesis or a CoreValve (Medtronic, Inc). Heparin was administered to achieve a goal activated clotting time >250 seconds throughout the procedure. The study had approval from the institutional review board of Montefiore Medical Center and Albert Einstein College of Medicine.    

Transthoracic echocardiography (TTE). All patients were evaluated by standard TTE (Philips IE33; Philips Medical) before TAVR. Echocardiographic images were recorded with the subjects in the left lateral recumbent position. All parameters were obtained according to the American Society of Echocardiography guidelines.¹⁰ LV ejection fraction was calculated using the biplane Simpson’s method. LV diameter and left atrial (LA) anteroposterior diameter were measured on the parasternal long-axis view at the end diastolic and systolic phase, respectively. Aortic valve area was calculated using the continuity equation and indexed to body surface area. Mean aortic pressure gradient was calculated from the modified Bernoulli equation. Doppler flow was placed in parallel to the LV outflow tract in the apical 5-chamber or 3-chamber view, or right parasternal or suprasternal notch view, to obtain accurate continuous-wave velocity. The degrees of mitral insufficiency, mitral stenosis, and AS severity were quantified based on the current practice guidelines.¹¹

Evaluation of spontaneous echocardiographic contrast. TAVR was performed under the guidance of TEE using a Philips IE33 system X7 TEE transducer (Philip Medical System). Mid-esophageal 2-chamber or 4-chamber images were recorded before and after the procedure. The entire LA cavity and LA appendage were observed under optimal depth, focus settings, gain settings, and room light. TEE images were obtained throughout the procedure to assist guidewire delivery, monitor for valve and cardiac function, and optimize the prosthetic valve positioning. SEC was evaluated by intraprocedural TEE and by two independent readers blind to clinical events. The presence of SEC was assessed visually and consensus was reached in case there was a disagreement regarding the presence of SEC. 

Primary endpoints. The primary composite endpoint was defined as all-cause mortality, a cardioembolic event, or admission for heart failure exacerbation within 3 months of TAVR. Cardioembolic events were considered if magnetic resonance imaging findings were indicative of embolic in origin (multiple small strokes or stroke in accordance with major artery distribution) or if there was an acute end-organ ischemic event from thromboembolism. Definitions for complications were made according to the Valve Academic Research Consortium (VARC) 2 criteria.¹² Heart failure exacerbation was determined by the physician based on the history, physical examination, laboratory, and imaging results on admission. When more than two events (eg, stroke and death) occurred in the same patient, the first event was counted as the primary event and only one event was counted.

Statistical analysis. Continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as percentage or number. The Student’s t-test and Mann-Whitney U-test were utilized as appropriate to evaluate continuous variables. The Chi-square test and Fisher’s exact test were used to evaluate categorical variables as appropriate. Multivariate logistic regression analysis was used to determine independent risk factors for the presence of SEC and the primary endpoints. Univariate analysis was performed to screen for candidate variables. Variables were included in the multivariable analysis if the P-value was <.10. Because of the relationship between AF and SEC, we included AF in the multivariate analysis and Cox proportional hazards regression model even though it did not reach statistical significance in univariate analysis. We assessed the event-free survival using Kaplan-Meier analysis and log-rank test between group 1 (SEC) and group 2 (no SEC).  Variables were screened with the log-rank test to identify variables to be incorporated into the Cox proportional hazards regression model. Receiver operating characteristic (ROC) analysis was used to calculate the optimal cut-off value to predict SEC. Cox proportional hazards model was used to calculate the hazard ratio for each variable. Backward stepwise analysis was used for both multivariate logistic regression and Cox proportional hazards regression. A P-value <.05 was considered statistically significant. All data analysis was performed by EZR version 1.27.¹³  

Results

\The study cohort consisted of 90 TAVR patients (3 patients were excluded because of major procedural complications). The mean age was 81.3 ± 8.1 years and 50% were male. The mean STS score was 7.9 ± 4.9. Forty-nine patients (54%) underwent transfemoral approach, 46 patients (51%) underwent transapical approach, and 5 patients (6%) underwent a transaortic approach. Patients underwent implantation of 84 Sapien valves (93%) and 6 CoreValves (7%). Six patients (7%) were on hemodialysis for end-stage renal failure. Twelve patients were found to have SEC and made up group 1. Seventy-eight patients without intraprocedure SEC comprised group 2.

\Overall, the groups were well-matched (Tables 1 and 2). There was a trend toward higher rates of cerebrovascular disease (33% vs 12%; P=.09) and persistent atrial fibrillation (50% vs 13%; P=.01) in group 1, whereas diabetes mellitus (17% vs 53%; P=.03) was more frequently observed in group 2. Mean LV ejection fraction, LV diastolic diameter, LA diameter, transvalvular gradient, and aortic valve area index were 59 ± 13%, 4.8 ± 0.7 cm, 4.4 ± 0.6 cm, 40.5 ± 14.0 mm Hg, and 0.37 ± 0.10 cm²/m², respectively. No patient had significant mitral stenosis. Group 1 had significantly lower mean aortic gradient (P<.01). 

Predictors of SEC. Atrial fibrillation, diabetes mellitus, hypertension, EF ≤50%, mean aortic gradient ≤40 mm Hg, indexed aortic valve area ≤0.40 cm²/m², and more than moderate mitral insufficiency were screened with univariate analysis. Atrial fibrillation, diabetes mellitus, and mean aortic gradient ≤40 mm Hg (odds ratio, 5.14; 95% confidence interval [CI], 1.29-20.5; P=.02) and mean aortic gradient ≤40 mm Hg (odds ratio, 9.77; 95% CI, 1.17-81.9; P=.04) were independently associated with the presence of SEC. On ROC analysis, the mean transvalvular aortic gradient was a good predictor of the presence of SEC (Figure 2). 

Primary endpoints, independent risk factors, and prognosis. A total of 22 patients (24%) experienced the composite endpoint during the 3-month follow-up period. There were 5 deaths (6%: 1 unknown cause, 4 non-cardiac deaths), 4 cardioembolic events (4%: 3 cerebrovascular in which cardioembolic etiology was suspected and 1 acute lower-limb ischemia), and 13 admissions for heart failure (14%). Figure 1 shows the prevalence of endpoints that occurred according to group. SEC was a risk factor for the combined endpoints (Table 3). After adjusting for gender, AF, and STS ≥15, the presence of SEC remained the only independent predictor for the primary endpoint (odds ratio, 5.88; 95% CI, 1.64-21.1; P<.01) 

Log-rank test identified SEC (P<.01), sex (P=.045), and STS ≥15 (P=.01) as univariate predictors of the composite endpoint. Cox proportional hazards regression showed an STS score ≥15 points (hazard ratio [HR], 6.37; 95% CI, 2.02-20.1; P=.01) and SEC (HR, 5.02; 95% CI, 1.96-12.9; P<.001) to be independent predictors for the composite endpoint. On survival analysis, group 1 had decreased event-free survival compared with group 2 (Figure 3).

Discussion

In this study, we found that 13% of patients undergoing TAVR have SEC in the LA. SEC serves as an independent risk factor for adverse events in patients who undergo TAVR. Our study is one of the first to identify SEC as a predictor of adverse outcomes in patients undergoing TAVR. 

Spontaneous echocardiographic contrast and severe aortic stenosis. SEC is a phenomenon often described as a “smoke-like pattern” seen on echocardiography.¹⁴ The fundamental pathogenesis of SEC is considered the aggregation of red blood cells by fibrinogen.¹⁵ In addition, an underlying inflammatory process is thought to be present.^16,17 In a series by Lenders et al, the incidence of SEC in patients referred for TAVR was 47%.⁷ The higher incidence of SEC compared with our report may be attributable to the higher incidence of AF in their series (36% vs 18% in the current study). 

Previously described risk factors for developing SEC include low-flow states such as mitral stenosis, AF, depressed LV function, diastolic dysfunction, and LA enlargement.^7,18-20 We speculate that patients with severe AS – particularly the low gradient type – may develop SEC because severe AS leads to low cardiac output, increased LV and LA pressures, and blood pooling in the LA, creating a substrate for SEC. The SEC resolves once the stenotic aortic valve, the source of increased afterload, is replaced. Our study showed that in addition to previous risk factors for SEC, low transvalvular gradient was also a risk factor for SEC. Larger LA size has also been reported as an independent risk factor for SEC.⁷ LA dilation is a sequela in severe AS patients due to increased LA pressure.^21,22 This may implicate intracardiac hemodynamic changes and LA structural remodeling in the formation of SEC. This hypothesis is supported by the observation by Slovut et al that SEC disappeared quickly after aortic valve prosthesis deployment and removal of a key source of afterload.²³ This may suggest that stasis of blood in the LA contributes to SEC formation. Additional study with a larger cohort will be necessary to confirm this observation.  

Spontaneous echocardiographic contrast and prognosis. Our study demonstrated that SEC was an independent risk factor for adverse events in severe AS patients in the 3 months following TAVR. The prognostic impact of SEC has been studied in several cardiac conditions. Leung et al reported that SEC was detected in 59% by TTE in patients with AF and was the only predictor of future cerebrovascular events.²⁴ Shen et al demonstrated that in patients with dilated cardiomyopathy, SEC conferred an increase in mortality during an average follow-up of 20 ± 13 months.²⁵ Kupczynska et al recently reported SEC detected by harmonic imaging in patients referred for various clinical reasons. They found that SEC in the LA was related to increased risk of mortality, stroke, or transient ischemic attack.³

Because stroke is one of the major complications associated with TAVR, there have been recent reports for novel prevention methods.^26-28 Our study may help to further risk stratify patients who would benefit, if future larger studies verify our results. 

Lender et al were the first to report SEC prevalence and its independent risk factors in patients referred for TAVR.⁷ The present study expanded its impact to short-term adverse events in AS patients undergoing TAVR. One could argue that it may be the AF that was the driver of poor outcomes in group 1. However, AF did not emerge as an independent risk factor in univariate or multivariate analyses and therefore was unlikely to be the major cause of higher endpoints in group 1. 

Study limitations. This study has several limitations. First, the study carries with it the drawbacks associated with retrospective cohort studies. Second, the grading of SEC was subjective and there may be discrepancies in terms of tendency to report mild SEC vs non-SEC. Third, patients with SEC had mixed severity of SEC. The impact of different severity of SEC on outcomes was not assessed. Fourth, in our study, the cohort size was relatively small, with only up to 3 months of follow-up. Therefore, the long-term impact of SEC remains to be determined. 

Conclusion

SEC was seen in 13% of the patients undergoing TAVR and was an independent risk factor for adverse events. Larger studies are warranted to more accurately assess the impact of SEC in severe AS patients undergoing TAVR. Because these patients remain at high risk for morbidity and mortality even after TAVR, the further exploration of measures to decrease the risk in these patients is warranted. Whether this specific patient population would benefit from anticoagulation warrants further study in the future.

Acknowledgment. The authors would like to thank the Montefiore heart valve team for their dedication to patient care. 

References

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_________________________________________________

From the ¹Department of Internal Medicine, Mount Sinai Beth Israel; Icahn School of Medicine at Mount Sinai, New York, New York; and ²Division of Cardiology, ³Department of Cardiothoracic and Vascular Surgery, Montefiore Medical Center; Albert Einstein College of Medicine, Bronx, New York.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted October 5, 2015, provisional acceptance given December 8, 2015, final version accepted February 8, 2016.

Address for correspondence: Tomo Ando, MD, 1st avenue and 16th Street, New York, NY 10003. Email: tando@chpnet.org