Valvular Heart Disease

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1 Valvular Heart Disease Low-Flow, Low-Gradient Severe Aortic Stenosis in the Setting of Constrictive Pericarditis Clinical Characteristics, Echocardiographic Features, and Outcomes Michael Y.C. Tsang, MD; Jin-Oh Choi, MD, PhD; Barry A. Borlaug, MD; Kevin L. Greason, MD; Stephen S. Cha, MSc; Rick A. Nishimura, MD; Jae K. Oh, MD Background Low-flow, low-gradient aortic stenosis (AS), associated with a poor prognosis, can be caused by a reduced stroke volume despite a preserved ejection fraction (left ventricular ejection fraction). We hypothesized that impaired ventricular diastolic filling secondary to constrictive pericarditis (CP) could contribute to reduced transaortic gradients in patients with AS+CP. We sought to examine the characteristics and outcomes of this unique cohort. Methods and Results We analyzed 84 patients with different degrees of AS and preserved left ventricular ejection fraction ( 50%): 28 diagnosed with concomitant CP by echocardiography and 56 patients without CP matched by age, sex, and AS severity during 1998 to Prior mediastinal radiation (32.1% versus 5.4%; P=0.0072) and cardiac surgery (50.0% versus 3.6%; P=0.0016) were more common in AS+CP patients than those with AS only. AS+CP patients had lower left ventricular stroke volume index and mean transaortic gradients. Five-year survival was 34.3% for AS+CP patients and 89.1% for those with AS only (P<0.001). In univariate analysis, prior mediastinal radiation (hazard ratio, 8.35; 95% confidence interval, ; P<0.001), reduced left ventricular stroke volume index of <35 ml/m 2 (hazard ratio, 12.52; 95% confidence interval, ; P<0.001), and concomitant CP (hazard ratio, 13.65; 95% confidence interval, ; P<0.001) were highly associated with increased mortality. Conclusions Our findings highlighted the possibility of CP as a pathophysiological mechanism for low-flow, low-gradient AS. Left ventricular stroke volume index and transaortic gradients were commonly reduced in AS in the setting of CP despite a preserved left ventricular ejection fraction, which may result in underestimation of AS severity. Prior mediastinal radiation, lower left ventricular stroke volume index, and concomitant CP were associated with poorer survival in AS patients. (Circ Cardiovasc Imaging. 2015;8:e DOI: /CIRCIMAGING ) Key Words: aortic valve stenosis echocardiography pericarditis, constrictive stroke volume survival Low-flow, low-gradient (LF/LG) severe aortic stenosis (AS) is one of the most challenging conditions encountered in patients with valvular heart disease. Because transaortic gradient depends on stroke volume, it is expected to be lower for a given aortic valve area (AVA) when left ventricular ejection fraction (LVEF) is reduced. However, in a subset of patients with severe AS and normal LVEF, aortic valve gradient is still low as a result of reduced stroke volume. This is related to a reduction in left ventricular cavity size secondary to inward concentric remodeling. Regardless of LVEF, LF/LG AS is associated with poorer prognosis when compared with AS with normal flow and high gradients. 1 3 It has been estimated that LF/LG AS because of depressed LVEF constitutes 5% to 10% of all patients with severe AS. 4,5 A LF/LG state despite a preserved LVEF was observed in 3% of patients with severe AS in a recent study, 6 whereas others have reported a higher prevalence. 3,7,8 See Clinical Perspective Constrictive pericarditis (CP) can coexist with AS, especially in patients with previous mediastinal radiation. One of the main hemodynamic abnormalities observed in CP is impaired ventricular diastolic filling. CP can therefore lead to a reduction in stroke volume and cardiac output. We hypothesized that LF/LG AS could also be seen in patients with combined AS and CP (AS+CP). This association between CP and LF/LG AS has not been described. The present study sought to examine the clinical and echocardiographic characteristics as well as the outcomes of this unique cohort of patients when compared with those with AS but not CP. Received June 29, 2014; accepted June 11, From the Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada (M.Y.C.T.); Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (J.-O.C.); and Division of Cardiovascular Diseases (B.A.B., R.A.N., J.K.O.), Division of Cardiovascular Surgery (K.L.G.), and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (S.S.C.), Mayo Clinic, Rochester, MN. Correspondence to Jae K. Oh, MD, College of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN oh.jae@mayo.edu 2015 American Heart Association, Inc. Circ Cardiovasc Imaging is available at DOI: /CIRCIMAGING

2 2 Tsang et al Aortic Stenosis and Constrictive Pericarditis Methods Patients This study was approved by the Mayo Clinic Institutional Review Board. Consecutive patients aged 18 years who underwent transthoracic echocardiography between January 1, 1998 and December 31, 2013, were enrolled if they met the following criteria: echocardiographic evidence of AS+CP and an LVEF of 50%. Patients with prior aortic valve replacement or more than a moderate degree of valvular stenosis/regurgitation involving other native cardiac valves were excluded. Patients who met our inclusion criteria were matched by age, sex, and severity of AS (based on AVA and indexed AVA) with patients diagnosed with AS but not CP in a 1:2 fashion. These final study cohort consisted of 84 patients, 28 of whom were diagnosed with AS+CP, whereas 56 carried the diagnosis of AS but not CP. Information on demographics, comorbidities, and symptom status was obtained via a review of medical records. Echocardiography Each patient underwent comprehensive 2-dimensional and Doppler echocardiography performed on commercially available ultrasound equipment (Acuson Sequoia, Siemens Medical, Mountain View, CA; Vivid 7, GE Healthcare, Milwaukee, WI; Vivid E9, GE Healthcare, Milwaukee, WI; ie33, Philips Healthcare, Andover, MA). Left ventricular outflow tract diameter was measured from a zoomed view of the aortic valve using the parasternal long-axis window in early systole from the point of aortic cusp insertion into the interventricular septum to the point of aortic cusp insertion into the mitral-aortic intervalvular fibrosa. Left ventricular outflow tract time velocity integral was measured by pulsed-wave Doppler echocardiography with the sample volume placed at the ventricular side of the aortic valve just below the zone of flow convergence in the apical long-axis view. Left ventricular stroke volume was calculated as a product of left ventricular outflow tract area and time velocity integral. At our institution, a nonimaging Doppler transducer was routinely used in multiple positions (apical, suprasternal, right supraclavicular, and right parasternal positions) to ensure that the highest transaortic gradient is obtained for each patient. AVA was calculated by the continuity equation using the time velocity integrals of the left ventricular outflow tract and aortic valve. AVA and left ventricular stroke volume were indexed to the patient s body surface area. AS was graded as severe (AVA <1.0 cm 2 or indexed AVA <0.6 cm 2 /m 2 ), moderate (AVA between 1.0 and 1.5 cm 2 or indexed AVA between 0.60 and 0.85 cm 2 /m 2 ), or mild (AVA >1.5 cm 2 and indexed AVA >0.85 cm 2 /m 2 ). 9 Left ventricular stroke volume index (LVSVI) was classified as reduced if it was <35 ml/m 2. 3,8 Echocardiographic images of the study cohort were reviewed by the investigators, and each AS+CP patient had 2 of the following echocardiographic features of CP: respirophasic ventricular septal motion, exaggerated respirophasic variation in mitral inflow E velocity of >25%, annulus reversus (mitral medial > lateral early diastolic tissue velocity), dilatation of the inferior vena cava (>2.1 cm) or <50% reduction in diameter during inspiration, and diastolic flow reversal during expiration on Doppler interrogation of the hepatic vein. 10 Clinical Outcomes Time zero was defined as the index diagnosis of AS+CP by echocardiography. Subsequent need for AVR (surgical or transcatheter) and surgical pericardiectomy and vital status were determined from a manual review of medical records. The primary end point of interest was all-cause mortality. Patients not known to be deceased were censored at the time of the last known clinical follow-up. Statistical Analysis Data were presented as mean±sd, median (interquartile range), or number (percentage). Distributions of the continuous variables were plotted, and median values were reported for variables that demonstrated appreciable deviation from normality. Conditional logistic regression analyses or Mood median test were performed to compare baseline variables between patients with AS and those with AS+CP. Overall survival was estimated by the Kaplan Meier method and compared using the log-rank test. The proportional hazard assumption was assessed by visually checking for the parallel nature of the curves in the plot of log(negative log[survival]) against log(time). The association between baseline characteristics and mortality was analyzed by the univariate Cox proportional hazards model. Statistical analyses were performed using SPSS version 20 (IBM Corp., Armonk, NY) and SAS version 9.3 (Cary, NC), and P values of <0.05 were considered statistically significant. Results Clinical Characteristics There was a higher prevalence of prior mediastinal radiation (32.1% versus 5.4%; P=0.0072) and history of cardiac surgery via a sternotomy (50.0% versus 3.6%; P=0.0016) in AS+CP patients than those with AS only (Table 1). In addition, AS+CP patients were more likely to have a history of coronary artery disease (57.1% versus 21.4%; P=0.0054). AS+CP patients were evaluated by their cardiologists within 6 months of their index diagnosis. Heart failure symptoms (New York Heart Association 2) were reported by 78.6% of patients, and 89.3% of patients demonstrated evidence of volume overload (jugular venous distension or peripheral edema). In contrast, symptomatic heart failure and volume overload were less common among patients without CP (28.6% versus 78.6; P= and 28.6% versus 89.3%; P=0.0010, respectively). Echocardiographic Characteristics At the time of the index diagnosis of AS+CP, a majority of our patients had moderate or severe AS based on echocardiography-derived AVA or indexed AVA: 11 patients (39.3%) with severe AS, 13 (46.4%) with moderate AS, and 4 (14.3%) with mild AS (Table 1). The calculated AVA and indexed AVA were well matched between patients with and without CP: 1.8±0.2 cm 2 (1.0±0.1 cm 2 /m 2 ) versus 1.8±0.3 cm 2 (0.9±0.1 cm 2 /m 2 ; P=0.877), 1.5±0.2 cm 2 (0.7±0.1 cm 2 /m 2 ) versus 1.4±0.2 cm 2 (0.7±0.1 cm 2 /m 2 ; P=0.06), and 1.0±0.2 cm 2 (0.5±0.1 cm 2 /m 2 ) versus 0.9±0.1 cm 2 (0.5±0.1 cm 2 /m 2 ; P=0.09) for patients with mild, moderate, and severe AS, respectively. Despite a similar mean LVEF between the 2 groups, the LVSVI derived by echocardiography was significantly lower in AS+CP patients when compared with those without CP (41.1±8.2 versus 53.2±7.9 ml/m 2 ; P=0.0013). Figure 1 shows a comparison of LVSVI and mean transaortic gradient in different grades of AS between the 2 groups. Patients with moderate or severe AS+CP had significantly lower LVSVI than those with moderate or severe AS but no CP (40.7±7.4 versus 53.3±7.7 ml/m 2 for moderate AS; P<0.001 and 39.3±8.3 versus 52.2±8.4 ml/m 2 for severe AS; P<0.001). A reduced LVSVI (<35 ml/m 2 ) was found in 4 of 11 (36.4%) patients with severe AS and CP and 4 of 13 (30.8%) patients with moderate AS and CP. In contrast, the LVSVI was within normal limits among all patients with AS only. Similarly, patients with moderate or severe AS+CP had significantly lower transaortic gradients than those with a similar grade of AS but no CP (17.0±6.4 versus 30.5±6.6 mm Hg

3 3 Tsang et al Aortic Stenosis and Constrictive Pericarditis Table 1. Baseline Characteristics of Study Population Baseline Characteristics Combined AS and CP (n=28) AS Only (n=56) P Value Age, y 69 (58, 75) 69 (57, 75) Male (%) 19 (67.9) 38 (67.9) Body surface area, m ± ± Medical history (%) Mediastinal radiation 9 (32.1) 3 (5.4) Hypertension 19 (67.9) 34 (60.7) Diabetes mellitus 8 (28.6) 18 (32.1) Hyperlipidemia 16 (57.1) 36 (64.3) CAD 16 (57.1) 12 (21.4) Prior MI 6 (21.4) 3 (5.4) History of cardiac surgery 14 (50.0) 2 (3.6) Prior acute pericarditis 6 (21.4) 0 (0) Prior pericardial effusion requiring drainage 4 (14.3) 0 (0) Tuberculosis 1 (3.6) 0 (0) Rheumatoid arthritis 2 (7.1) 1 (1.8) Echocardiography Severity of AS based on AVA or iava Severe 11 (39.3) 22 (39.3) Moderate 13 (46.4) 26 (46.4) Mild 4 (14.3) 8 (14.3) LV end-diastolic dimension, mm 46.2± ± LVEF (%) 60.4± ± LV stroke volume index, ml/m ± ± Cardiac index, L/min per meter squared 3.0± ± LV mass index, g/m 2 * 88.0 ( ) ( ) Medial E/e * 12.5 ( ) 11.9 ( ) Echo features of pericardial constriction* 3.0 ( ) 0.0 ( ) <0.001 Moderate right ventricular hypokinesis 4 (14.3) 1 (1.8) Right ventricular systolic pressure, mm Hg 44.3± ± Systolic blood pressure (mm Hg) at the time of echocardiography 121.2± ± Atrial fibrillation at the time of presentation (%) 5 (17.9) 3 (5.4) NYHA class at the time of presentation I 6 (21.4) 40 (71.4) II 10 (35.7) 10 (17.9) III 7 (25.0) 5 (8.9) IV 5 (17.9) 1 (1.8) Evidence of volume overload (jugular venous distension or 25 (89.3) 16 (28.6) peripheral edema; %) Subsequent aortic valve replacement (%) 11 (39.3) 33 (58.9) Subsequent pericardiectomy (%) 11 (39.3) 0 (0) Subsequent AVR and pericardiectomy (%) 8 (28.6) 0 (0) AS indicates aortic stenosis; AVA, aortic valve area; AVR, aortic valve replacement; CAD, coronary artery disease; CP, constrictive pericarditis; iava, indexed aortic valve area; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; and NYHA, New York Heart Association. *Median (interquartile range). for moderate AS; P<0.001 and 27.2±6.1 versus 51.1±10.5 mm Hg for severe AS; P<0.001). The mean transaortic gradients in those with moderate or severe AS+CP were lower than expected (20 40 mm Hg for moderate AS and >40 mm Hg for severe AS) for the corresponding grade of AS severity given a preserved LVEF. 9 In the 11 patients classified as having severe AS+CP, none had a mean transaortic gradient of >40 mm Hg. AS+CP patients had smaller LV end-diastolic dimensions (46.2±5.9 versus 49.7±4.5 mm; P=0.0104) and lower echocardiography-derived cardiac index (3.0±0.7 versus 3.6±0.6 L/

4 4 Tsang et al Aortic Stenosis and Constrictive Pericarditis A Left ventricular stroke volume index (ml/m 2 ) B Mean transaortic gradient (mmhg) Mild Moderate Severe Severity of aortic stenosis Mild Moderate Severe Severity of aortic stenosis min per meter squared; P=0.0033) when compared with those with AS only. Requirement for Surgical Intervention for AS and CP Median follow-up was 55.5 months (interquartile range, months). Among the 28 AS+CP patients, 8 subsequently underwent both AVR and pericardiectomy, 3 received an isolated AVR, and 3 underwent a pericardiectomy only (Figure 2). All patients who subsequently underwent both AVR and surgical pericardiectomy had moderate AS at the time of surgery. AS was graded as severe at the time of surgery for all of those with AS+CP who subsequently received an isolated AVR. Among the 11 patients diagnosed with severe AS+CP, 4 subsequently underwent both AVR and pericardiectomy (median, 27 days [range, 3 78 days] after the index diagnosis of severe AS+CP), whereas 3 received an isolated AVR (median, 52 days [range, days] after the index diagnosis; Figure 2). One of these 3 patients had a history of tuberculous pericarditis and a prior surgical creation of an aortopulmonary window. At the time of his AVR, dense pericardial adhesions were observed, and lysis of adhesions was performed. In the Figure 1. Mean left ventricular stroke volume index (A) and mean transaortic gradient (B) in different grades of aortic stenosis (AS) in patients with and without constrictive pericarditis (CP). Patients with moderate or severe aortic stenosis and concomitant constrictive pericarditis had significantly lower left ventricular stroke volume index and transaortic gradients than those with moderate or severe aortic stenosis but no constrictive pericarditis. second patient, no significant pericardial thickening was found during AVR despite echocardiographic evidence of pericardial constriction, and pericardiectomy was therefore not performed. The third patient underwent a transcatheter AVR because the risk of a conventional AVR and pericardiectomy was deemed prohibitively high. One patient received a pericardiectomy but not AVR 8 months after the initial diagnosis. AVR and pericardiectomy were recommended but not performed in 1 patient because of prohibitive surgical risk. In those patients with moderate AS+CP, 3 subsequently underwent concomitant AVR and pericardiectomy (median, 2 days [range, days] after the index diagnosis), whereas 1 patient received a pericardiectomy followed by an AVR 8 days and 9 months, respectively, after the initial diagnosis (Figure 2). One other patient underwent a pericardiectomy alone 6 days after the index diagnosis. Pericardiectomy was recommended but not performed for 2 patients because of a recent stroke in 1 and patient s refusal in the other. Among the 4 patients who were diagnosed with mild AS+CP, 1 patient underwent a pericardiectomy 51 months after the index diagnosis (Table 2). None of these patients received an AVR during follow-up.

5 5 Tsang et al Aortic Stenosis and Constrictive Pericarditis Combined AS and CP (n=28) Mild AS (n=4) Moderate AS (n=13) Complete pericardiectomy only (n=1) 51 months AVR and complete pericardiectomy (n=3) Median 2 days (range days) Complete pericardiectomy and subsequent AVR (n=1) (8 days and 9 months respectively) Complete pericardiectomy only (n=1) 6 days AVR and pericardiectomy recommended but not performed (n=2) Severe AS (n=11) AVR and complete pericardiectomy (n=4) Median 27 days (range 3-78 days) AVR only (n=3) Median 52 days (range days) Complete pericardiectomy only (n=1) 8 months Figure 2. Requirement for aortic valve replacement and complete pericardiectomy in the study population. AS indicates aortic stenosis; AVR, aortic valve replacement; CP, constrictive pericarditis; and IQR, interquartile range. AS (n=56) Mild AS (n=8) Moderate AS (n=26) Severe AS (n=22) In patients diagnosed with AS only, 17 of the 22 patients with severe AS subsequently underwent AVR (median, 1.0 month [interquartile range, months] after the index diagnosis of severe AS), whereas 16 of the 26 patients with moderate AS subsequently received an AVR (median, 46.5 months [interquartile range, months] after the index diagnosis of moderate AS). Survival Figure 3 shows a comparison of overall survival between AS+CP patients and those with AS only. Among the 28 patients with AS+CP, there were 16 mortalities during followup, 3 of which occurred within the first 30 days of AVR and pericardiectomy. Two of these patients had undergone simultaneous AVR and pericardiectomy, whereas remaining patient had received a transcatheter AVR only because of prohibitively high surgical risk. In contrast, there were 5 mortalities in 56 patients with AS only, none of which occurred in the early postoperative period. The 5-year survival for AS+CP patients was 34.3%, whereas those with AS only had a 5-year survival of 89.1% (P<0.001). Univariate Cox proportional hazards model identified prior mediastinal radiation (hazard ratio [HR], 8.35; 95% confidence interval [CI], ; P<0.001), a reduced LVSVI (HR, 12.52; 95% CI, ; P<0.001), and the presence of AS+CP (HR, 13.65; 95% CI, ; P<0.001) to be highly associated with increased all-cause mortality (Table 2). In addition, a few other clinical or echocardiographic variables were also significantly associated with poorer long-term survival but with a smaller HR, such as a history of coronary artery disease (HR, 2.79; 95% CI, AVR and pericardiectomy recommended but not performed (n=1) No AVR (n=8) Median follow-up 79.5 months (IQR months) AVR (n=16) Median 46.5 months (IQR months) AVR (n=17) Median 1.0 month (IQR months) ; P=0.019), prior cardiac surgery (HR, 3.02; 95% CI, ; P=0.018), right ventricular systolic pressure (HR, 1.74 per every 10 mm Hg increase; 95% CI, ; P=0.004), and symptomatic heart failure at the time of presentation (HR, 4.06; 95% CI, ; P=0.004). Discussion This is the first report in the literature to describe the clinical characteristics, echocardiographic features, and outcomes of a unique cohort of AS+CP patients when compared with AS patients matched by age, sex, and AS severity in the absence of CP. The current study has revealed several important findings and highlights the possibility of CP or pericardial constriction as one of the underlying pathophysiological mechanisms for LG AS, especially in patients with prior mediastinal radiation. Grading of AS Severity The severity of AS is typically classified by numeric measures of AVA and mean transaortic gradient. However, transaortic gradient is a function of flow rate, which in turn is determined by the stroke volume. A reduction in flow rate may result in an important decrease in the transaortic gradient despite a severely stenotic aortic valve. 8 This discordance between AVA and transaortic gradient has important clinical implications because it may lead to an underestimation of AS severity and unnecessary delay in follow-up and AVR. A flow-gradient classification has been recently proposed to better characterize the hemodynamic features of severe AS into normal-flow (SVI 35 ml/m 2 ) or LF (SVI <35 ml/m 2 ), and low (<40 mm Hg) or high transaortic gradient ( 40 mm Hg). 3,8 LF/LG AS can

6 6 Tsang et al Aortic Stenosis and Constrictive Pericarditis Table 2. Univariate Predictors of All-Cause Mortality Parameter Univariate Hazard Ratio P Value Age, y 1.01 ( ) Male sex 1.22 ( ) Body surface area, m ( ) Medical history Mediastinal radiation 8.35 ( ) <0.001 Diabetes mellitus 0.89 ( ) Hypertension 0.78 ( ) Hyperlipidemia 0.61 ( ) Coronary artery disease 2.79 ( ) Myocardial infarction 2.19 ( ) Prior cardiac surgery 3.02 ( ) Prior acute pericarditis 2.57 ( ) Prior pericardial effusion requiring drainage 1.04 ( ) Echocardiography Severe AS based on aortic valve area or indexed 1.65 ( ) aortic valve area LV ejection fraction (%) 0.96 ( ) LV stroke volume index (per 10 ml/m 2 increase) 0.29 ( ) <0.001 LV stroke volume index <35 ml/m ( ) <0.001 Cardiac index, L/min per meter squared 0.55 ( ) Combined AS and CP (AS as reference) ( ) <0.001 Moderate right ventricular systolic dysfunction 3.02 ( ) RVSP (per 10 mm Hg increase) 1.74 ( ) Systolic blood pressure at the time of echocardiography 0.97 ( ) Atrial fibrillation at the time of presentation 2.06 ( ) Symptomatic heart failure (NYHA 2) at the time of presentation 4.06 ( ) AS indicates aortic stenosis; CP, constrictive pericarditis; LV, left ventricular; NYHA, New York Heart Association; and RVSP, right ventricular systolic pressure. occur in conjunction with an impaired LVEF. More recently, paradoxical LF/LG AS has received much attention and represents a LF state in which the stroke volume is reduced despite a preserved LVEF. This is typically associated with exaggerated myocardial concentric remodeling, small left ventricular cavity, and reduced left ventricular filling. 3,7 Cumulative survival (%) Log-rank p<0.001 Figure 3. Comparison of overall survival between patients with combined aortic stenosis (AS) and constrictive pericarditis (CP) and those with aortic stenosis only. Patients with AS and concomitant CP had significantly worse overall survival than those with aortic stenosis only. Number at risk Years AS + CP AS

7 7 Tsang et al Aortic Stenosis and Constrictive Pericarditis LVSVI and Transaortic Gradient in the Setting of CP CP leads to impaired ventricular diastolic filling and a LF state, but this has not been previously reported as a potential underlying mechanism for LF/LG AS. The current study demonstrated that AS+CP patients had disproportionately low transaortic gradients relative to the corresponding grade of AS. In addition, among the 11 patients with severe AS+CP, none had a mean transaortic gradient of >40 mm Hg, which is the usual range of gradients observed in severe AS. To account for the discrepancy in transaortic gradients between patients with AS only and those with AS+CP, we also compared the LVSVI between patients with and without CP. Our findings indicated that transaortic gradients were commonly reduced in the setting of CP despite a preserved LVEF, and this could at least be partially explained by a reduction in LVSVI. Discordance between AVA and transaortic gradient has also been reported in prior studies where 36% to 43% of patients with an AVA of <1.0 cm 2 had a mean transaortic gradient of <40 mm Hg, and a reduced stroke volume was speculated to account for the low gradients. 11,12 This discordance may have important implications for the management of AS patients. Physicians may underestimate the severity of AS because the gradients are lower than expected in the setting of CP, which can lead to delay in surgical treatment. To further complicate this issue, CP is often a diagnostic challenge based on clinical and echocardiographic examination. 13 Impact of Hemodynamic and Clinical Factors on Outcomes In the current study, a lower LVSVI, a history of mediastinal radiation, and a diagnosis of AS+CP were strongly associated with poorer long-term survival. Previous studies examining the prognostic impact of different flow-gradient patterns in patients with severe AS reported results similar to ours. In a study by Lancellotti et al, 14 cardiac event-free survival at 2 years was significantly worse in those with LF/LG severe AS and preserved LVEF than in patients with normal-flow, low-gradient severe AS (27±13% versus 83±6%). 14 Patients with LF/LG severe AS also had higher brain natriuretic peptide level and more pronounced impairment of LV longitudinal myocardial function, indicating more advanced disease. Another recent study by Eleid et al 6 demonstrated that a LF/ LG pattern was the strongest predictor of mortality in patients with severe AS and preserved LVEF. This subgroup was characterized by a higher prevalence of atrial fibrillation and heart failure. The prevalence of CP, however, was not documented in either of these 2 studies. It is speculated that patients with a low LVSVI in the current study may represent a group with more severe or long-standing CP. Prolonged pericardial constriction can result in myocardial atrophy, which may further impair myocardial compliance. 15 This may have contributed to the observed association between a low LVSVI and poorer survival in our cohort. Implications of Radiation-Induced Heart Disease Radiation-induced pericardial disease is a well-established cardiovascular complication associated with mediastinal radiation. The incidence of radiation-induced CP depends on the cumulative dose of radiation and implementation of proper shielding. 16 In our study, a history of mediastinal radiation was found to be highly associated with poorer survival. Other studies have also demonstrated an association between mediastinal radiation and increased long-term mortality. 15,17 In a cohort of 135 patients with CP confirmed at surgery or autopsy, previous radiation therapy was the most powerful predictor of worse survival despite surgical pericardiectomy. 17 Several factors may explain the poorer outcome in patients with a prior history of mediastinal radiation. First, patients who previously received radiation therapy may have residual systemic or pleuropulmonary disease that can increase the risk of noncardiac death. Second, patients with a history of mediastinal radiation may have more severe pericardial constriction and greater impairment in ventricular diastolic filling than individuals with CP caused by other pathogeneses. Third, patients with prior mediastinal radiation may also experience other cardiovascular sequelae, such as more rapid progression of coronary artery disease, myocardial fibrosis, and valvular heart disease It is easier to recognize and diagnose AS than CP because AS is more common and has well-recognized echocardiography findings and physical examination features. Therefore, it is possible that CP may not be readily detected when it coexists with AS. When aortic valve velocity and mean transaortic gradient are lower than expected for a given severity of AS, echocardiographic parameters for CP (ventricular septal motion, mitral inflow velocity, mitral annulus tissue velocity, and hepatic vein expiratory diastolic flow reversal) 10 should be carefully evaluated, especially when there is a history of mediastinal radiation therapy or cardiac surgery. Similarly, among patients presenting with symptomatic CP and valvular heart disease as complications of previous radiation therapy, a meticulous echocardiographic assessment of AS should be performed to ensure that AS severity is not underestimated in the presence of a low transaortic gradient and to determine the need for an AVR at the time of pericardiectomy. Limitations Our analyses were limited by the small sample size and its retrospective nature. However, this is the first report in the literature to characterize this unique cohort with AS+CP. LF/ LG AS in the setting of CP has not been described before, and our study has provided important insights into this novel underlying pathophysiological mechanism for low-gradient AS. The presence of CP in our study cohort was established by echocardiography. Anatomic confirmation by inspection of the pericardium was possible only in those who subsequently underwent a surgical pericardiectomy. Nevertheless, patients who were included in this study all met echocardiographic diagnostic criteria for CP, and 16 of the 28 patients also had supportive evidence of CP based on cardiac computed tomography, MRI, or right heart catheterization. In this study, grading of AS severity was based on the calculated AVA and indexed AVA on echocardiography. As aforementioned, AS+CP patients had disproportionately low transaortic gradients relative to the corresponding grade of AS when compared with individuals with AS only. Dobutamine

8 8 Tsang et al Aortic Stenosis and Constrictive Pericarditis stress testing in conjunction with echocardiography or cardiac catheterization is commonly used to differentiate true and pseudosevere AS in patients with LF/LG AS. This is particularly challenging in AS+CP patients because the stroke volume is primarily limited by reduced ventricular diastolic filling rather than LV systolic dysfunction. Dobutamine infusion is therefore unlikely to effectively increase the cardiac output or stroke volume to allow a reliable differentiation between true and pseudosevere AS. In the recent decade, emerging data have suggested that aortic valve calcification measured by cardiac computed tomography correlates well with AS severity and provides independent prognostic information. 22,23 Unfortunately, this imaging modality was not commonly used during the study period of the current investigation, but it is anticipated that this excellent diagnostic tool will enhance the evaluation of AS severity in patients with AS+CP in the future. The impact of AVR and pericardiectomy on survival of AS+CP patients was not specifically examined in the current study for 2 reasons. First, we were not able to accurately establish the chronicity of the patients CP, which might have undermined the potential benefit of subsequent surgery if performed earlier. Second, the small sample size limited us from drawing any definitive conclusions on the impact of and the appropriate timing for AVR and pericardiectomy in our cohort. In this study, all-cause mortality was the primary outcome of interest in our Cox proportional hazards analyses, and we elected not to examine the factors that predicted the need for cardiac surgery. Our institution serves as a quaternary referral center for patients with valvular or pericardial disease, and some patients may undergo cardiovascular surgeries soon after their index diagnoses. The analysis of this outcome, therefore, may not add much to the aforementioned findings of this study. In addition, a univariate Cox proportional hazards model was used to identify factors associated with increased all-cause mortality in the current study, whereas a multivariate analysis was not performed because of the small sample size and number of outcomes. Clinical Implications and Conclusions AS coupled with CP is a rare entity, and this is the first study to characterize this unique population. Our observations have highlighted the possibility of CP as one of the underlying pathophysiological mechanisms for LF/LG AS. AS+CP patients had lower LVSVI and mean transaortic gradients despite a preserved LVEF than those with similar AS severity but no CP. Prior mediastinal radiation, lower LVSVI, and a concomitant diagnosis of CP were strongly associated with poorer long-term survival. Our findings argue for a careful evaluation of AS patients to rule out a concomitant diagnosis of CP when there is discordance between AVA and transaortic gradient. This is particularly important among patients with a prior history of mediastinal radiation or other risk factors for the development of CP. Similarly, in patients presenting with symptomatic CP and valvular heart disease related to previous radiation therapy, a meticulous assessment of AS severity is essential before a pericardiectomy to ensure that AS severity is not underestimated in the presence of a low transaortic gradient and to determine the need for AVR at the time of pericardiectomy. None. Disclosures References 1. Monin JL, Monchi M, Gest V, Duval-Moulin AM, Dubois-Rande JL, Gueret P. Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients: risk stratification by low-dose dobutamine echocardiography. J Am Coll Cardiol. 2001;37: Pereira JJ, Lauer MS, Bashir M, Afridi I, Blackstone EH, Stewart WJ, McCarthy PM, Thomas JD, Asher CR. Survival after aortic valve replacement for severe aortic stenosis with low transvalvular gradients and severe left ventricular dysfunction. J Am Coll Cardiol. 2002;39: Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. 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10 Low-Flow, Low-Gradient Severe Aortic Stenosis in the Setting of Constrictive Pericarditis: Clinical Characteristics, Echocardiographic Features, and Outcomes Michael Y.C. Tsang, Jin-Oh Choi, Barry A. Borlaug, Kevin L. Greason, Stephen S. Cha, Rick A. Nishimura and Jae K. Oh Circ Cardiovasc Imaging. 2015;8: doi: /CIRCIMAGING Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2015 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Imaging can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation: Cardiovascular Imaging is online at: