Clinical material and methods. Clinical Departments of 1 Radiology II and 2 Cardiology, Innsbruck Medical University, Innsbruck, Austria

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1 Aortic Valve Calcification as Quantified with Multislice Computed Tomography Predicts Short-Term Clinical Outcome in Patients with Asymptomatic Aortic Stenosis Gudrun M. Feuchtner 1, Silvana Müller 2, Wilhelm Grander 2, Hannes F. Alber 2, Thomas Bartel 2, Guy J. Friedrich 2, Markus Reinthaler 2, Otmar Pachinger 2, Dieter zur Nedden 1, Wolfgang Dichtl 2 Clinical Departments of 1 Radiology II and 2 Cardiology, Innsbruck Medical University, Innsbruck, Austria Background and aim of the study: Aortic valve calcification may be an independent risk factor for adverse clinical outcome. The study aim was to assess the predictive value of possible risk factors, including the severity of aortic valve calcification as quantified with 16-multislice computed tomography (MSCT) for adverse short-term clinical outcome in patients with asymptomatic, degenerative aortic stenosis (AS). Methods: Possible risk factors for adverse short-term clinical outcome were prospectively tested in 34 consecutive patients with asymptomatic AS as follows: (i) aortic valve calcium (AVC) score as quantified with MSCT; (ii) echocardiographic parameters - aortic valve area (AVA) calculated with continuity equation, mean and maximal transvalvular pressure gradients, end-diastolic septal wall diameter; and (iii) laboratory tests (brain natriuretic peptide (BNP), C-reactive protein (CRP)). Results: Within months of follow up, 11 of 34 patients developed a major adverse clinical outcome. Ten patients suffered from onset of symptoms accompanied by hemodynamic progression, and one patient died from sudden cardiac death. Six of these 10 patients underwent aortic valve replacement, one patient declined surgery, and three patients were not accepted for surgery (one of these died suddenly shortly afterwards). The aortic valve calcium score was the strongest predictor of a major adverse clinical event (p <0.001) among all parameters assessed (1,928 ± 789 versus 5,111 ± 2,409 Agatston units). The plasma level of BNP (p = 0.003), mean transvalvular pressure gradient (p = 0.002) and AVA (p = 0.003) were also risk factors for adverse clinical outcome. Conclusion: The AVC score as quantified with MSCT predicted adverse short-term clinical outcome in patients with asymptomatic AS. In patients with severe aortic valve calcification, close follow up examinations are mandatory, and early elective surgery may be considered even in the absence of symptoms. MSCT provides a comprehensive non-invasive imaging approach for risk stratification in patients with asymptomatic AS. The Journal of Heart Valve Disease 2006;15: Degenerative aortic stenosis is the third most common cardiovascular disease among the elderly, with a prevalence of 2-7% in Western European and North American populations aged over 65 years (1), aside from arterial hypertension and coronary artery disease. Although degenerative aortic stenosis shows a progressive course, the rate of progression and onset of symptoms varies significantly among patients. Therefore, careful clinical evaluation and serial Presented at the European Society of Cardiology (ESC) Annual Meeting, 4th-7th September 2005, Stockholm, Sweden Address for correspondence: Gudrun M. Feuchtner MD, Clinical Department of Radiology II, Innsbruck Medical University, Anichstr. 35, A-6020 Innsbruck, Austria Gudrun.Feuchtner@uibk.ac.at echocardiography to obtain evidence of deteriorating left ventricular function are required. The most critical decision concerns the advisability of surgical treatment. Although the rate of disease progression appears to be most rapid in patients with severe calcifying disease (2), precise echocardiographic quantification of aortic valve calcification is unreliable. The study aim was prospectively to analyze the predictive value of the aortic valve calcium (AVC) score as quantified by multislice computed tomography (MSCT) for short-term clinical outcome. Clinical material and methods Study population Thirty-four patients (20 males, 14 females; mean age 70.5 years; range: 47 to 85 years) with asymptomatic, Copyright by ICR Publishers 2006

2 J Heart Valve Dis Aortic valve calcification and AS 495 degenerative aortic stenosis were examined prospectively between November 2003 and June 2004 with MSCT and transthoracic echocardiography (TTE) on the same day; a blood sample was also taken from each patient. These patients formed a subset of a larger ongoing double-blind, randomized trial investigating the effect of statins on the progression of aortic stenosis. The patients (none of whom had received statin treatment previously) were randomly assigned to 20 mg atorvastatin per day, or to placebo. Exclusion criteria were decreased left ventricular systolic function (ejection fraction <48%), severe aortic regurgitation (> grade 2+), evident rheumatic disease, renal dysfunction, hepatic disease, and evident clinical signs such as angina pectoris, dyspnea or syncope and severe cardiac arrhythmia. After 18 to 24 months, all patients were re-evaluated, and the existence or absence of any major adverse clinical event was noted. The study was approved by the Institutional Review Board, and all patients provided their written, informed consent. MSCT examination technique A 16-multislice CT scanner (Sensation 16; Siemens Medical Systems, Germany) was used. Aortic valve calcification was quantified by performing an unenhanced CT scan with the following scan parameters: collimation mm, table feed 3.8 mm per rotation, gantry rotation 0.5 s, 130 mas, 120 KV, increment 3, effective slice thickness 3 mm, medium convolution kernel B 35 f, and retrospective ECG-gating at 60-80% of RR-interval. Aortic valve calcification and coronary Figure 1: Box-and whisker plot. Patients with asymptomatic aortic stenosis who developed a major adverse clinical event (MACE) within one year had a significantly higher AVC score (Agatston units) than those without MACE (p <0.001). artery calcification were quantified using standard coronary calcium score software in order to calculate the Agatston score on a dedicated computer workstation (Syngo; Leonardo, Siemens, Germany). Transthoracic echocardiography TTE measurements were performed using a standard ultrasonography unit (Acuson Sequoia 256; Acuson-Siemens Medical Systems) equipped with a 3.5/1.75-MHz transducer and operated by an experi- Table I: Predictors of short-term adverse clinical outcome (major adverse clinical event, MACE) within a one-year follow up period. Parameter SI unit MACE * No MACE * p-value (n = 11) (n = 23) AVC Agatston 5,111 ± 2,409 1,928 ± 789 <0.001 P mean mmhg 36 ± 8 26 ± P max mmhg 56 ± 9 42 ± AVA cm ± ± EDD mm 13.7 ± ± NT-proBNP ng/l 1518 ± ± CRP mg/dl 0.70 ± ± Cholesterol mg/dl 198 ± ± LDL mg/dl 123 ± ± HDL mg/dl 60 ± ± CCS Agatston 244 ± ± Triglycerides mg/dl 93 ± ± * Values are mean ± SD. + Inverse correlation AVA: Aortic valve area; AVC: Aortic valve calcium score; CCS: Coronary calcium score; CRP: C-reactive protein; EDD: Enddiastolic septum diameter; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; NT-proBNP: Brain natriuretic peptide; P max : Maximal transvalvular pressure gradient; P mean : Mean transvalvular pressure gradient.

3 496 Aortic valve calcification and AS J Heart Valve Dis A Figure 2: Linear regression analysis. Moderate correlation between the severity of aortic valve calcification (AVC) and of aortic stenosis as determined by TTE (r = ; p = 0.02). AVA: Aortic valve area. B enced class III observer (S.M.). The aortic valve orifice area (AVA) was derived using the continuity equation approach with Doppler velocity-time integral (VTI). The severity of aortic stenosis was classified according to American College of Cardiology and American Heart Association (ACC/AHA) guidelines (3) as follows: severe, critical at AVA <0.75 cm 2 ; severe, noncritical at AVA cm 2 ; moderate at AVA cm 2 ; and mild at AVA >1.5 cm 2. Mean and maximal transvalvular pressure gradients and the end-diastolic septal wall diameter were also measured. C Laboratory parameters Plasma levels of brain natriuretic peptide (NTproBNP), C-reactive protein (CRP), lipoproteins (HDL, LDL, cholesterol) and triglycerides were determined in all patients. Statistical analysis Statistical analysis was performed using SSPS software (V8.0; SPSS Inc., Chicago, USA). The Mann- Whitney U-test was used to monitor differences between various parametric risk factors (e.g., AVC score, AVA, NT-proBNP) in patients in whom a major adverse clinical event (MACE) was noted and who had an uneventful course. Correlations between the AVC score as measured with MSCT, and AVA as determined by TTE, were determined with linear regression analysis and the Pearson correlation coefficient. A twotailed p-value <0.05 was considered to be statistically significant. Figure 3: Moderate aortic valve calcification. A 48-year-old male with moderate valve calcification (AVC score 3,697.3 Agatston units) and moderate aortic stenosis (AVA 1.1 cm 2 ; LVEF 52%; NT-ProBNP 60.6 ng/l) who had an uneventful course within one year. The AVC score progressed slightly to 3,911.8 Agatston units after 1 year. A) Left coronal oblique view of the left ventricle and ascending aorta. The arrow denotes aortic valve calcifications. B) The cross-sectional transverse plane reveals a bicuspid aortic valve by applying multiplanar reformation and volume-rendering technique (C).

4 J Heart Valve Dis Aortic valve calcification and AS 497 Figure 4: Severe aortic valve calcification. A 67-year-old male with severe valve calcification (AVC score 10,107.2) and severe, asymptomatic aortic stenosis (AVA 0.6 cm 2 ; LVEF 55%; NT-ProBNP 1079 ng/l baseline) in whom aortic valve replacement was indicated due to severe hemodynamic progression and onset of symptoms. NT- ProBNP had increased distinctively to 3,661 ng/l prior to valve surgery. Cross-sectional transverse plane showing the aortic valve closed during diastole (left) and opened during systole (* indicates AVA) (right). The arrows indicate regions of heavy valve calcification. Results The AVC score predicts short-term clinical outcome During a follow up period of months, 11 patients (eight males, three females; five receiving atorvastatin, six assigned to placebo) (Table I) developed a MACE. Ten of 11 patients suffered from onset of symptoms accompanied by hemodynamic progression, and one patient died from sudden cardiac death. Six of these 10 patients underwent aortic valve replacement, one patient declined surgery, and three were not accepted for surgery (one of these patients died suddenly shortly afterwards). Patients who developed a MACE within months had a significantly higher AVC score compared to those without a MACE (Fig. 1; Table I). The AVC score was the strongest predictor of adverse clinical outcome when compared to other risk factors (Table I). Other risk factors for adverse clinical outcome were hemodynamic parameters as determined with TTE (mean and peak systolic transvalvular pressure gradients) and plasma levels of NT-proBNP. Overall, among the 34 patients, 19 were receiving statin treatment and 15 were assigned to placebo. AVC score by MSCT versus AVA The AVC score correlated moderately and inversely to the AVA, as determined by TTE (r = -0,39; p = 0.02; Pearson coefficient) (Fig. 2). Coronary calcium score The coronary calcium score did not correlate with any MACE (non-mace 441 ± 752 versus MACE 244 ± 241; p = 0.9). Discussion The results of the present study showed that the AVC score, as determined with MSCT, predicted short-term clinical outcome in patients with degenerative aortic stenosis. Compared to other laboratory investigations (e.g., lipid levels) and echocardiographic parameters, the AVC score was the strongest predictor of adverse clinical outcome (see Table I). Although all patients were completely asymptomatic when entering the study, 32% developed a MACE within 24 months, which reflected the overall poor prognosis in patients with asymptomatic aortic stenosis (4). These data clearly support the concept that patients with severe calcification require close follow up examinations, and early elective surgery may be considered, even in the absence of symptoms (2). The MSCT images shown in Figures 3 and 4 provide a visual impression of different valve calcification patterns in two patients. The patient shown in Figure 3 had moderate valve calcification and followed an uneventful course. In contrast, the patient shown in Figure 4 was asymptomatic but had severe valve calcification, with aortic surgery being indicated at a one-year follow up. Other risk factors included well-established parameters such as the AVA, the mean transvalvular pressure gradient, and plasma levels of NT-proBNP (5). In addition, the present data showed that the severity of valve calcification was associated with the severity of aortic valve disease. These findings were in accordance with the details of a recently published investigation which showed the AVC score to correlate strongly with the severity of aortic stenosis, and to have a high diagnostic value in the detection of severe aortic stenosis (6). Moreover, MSCT was shown to provide good reproducibility for the quantification of aortic valve calcium (7), similar to that achieved with electron beam CT (6,8). Potential further clinical applications of MSCT Multislice CT coronary angiography may be performed quickly and easily in patients referred for MSCT calcium score scanning. MSCT coronary angiography has been shown to be highly accurate in the detection of significant coronary artery stenosis >50% (9-12). However, patients with severe aortic stenosis require surgical intervention, including a preoperative evaluation of concomitant coronary artery disease (3), which is currently routinely performed by using invasive coronary angiography. Thus, MSCT coronary angiography may have the potential to replace cardiac catheterization in selected patients prior to valve surgery. It should be noted that the coronary arteries are prone to calcify in patients with severe calcific aortic valve disease, and severe coro-

5 498 Aortic valve calcification and AS nary calcification might adversely affect visualization of the coronary artery lumen due to beam-hardening and partial volume artifacts; it may also cause an overestimation of the degree of stenosis. Therefore, results obtained from currently ongoing clinical trials on the diagnostic performance of MSCT coronary angiography in patients with degenerative aortic stenosis are awaited. In conclusion, TTE remains the clear examination of choice for diagnosis and risk stratification in patients with degenerative aortic stenosis. Calculation of the AVA by TTE remains by far the most important parameter guiding clinical management, besides the onset of symptoms. However, MSCT provides a promising, comprehensive non-invasive imaging approach for risk stratification in patients with asymptomatic aortic stenosis. The severity of aortic valve calcification as quantified with MSCT may provide additional information for the optimal management of asymptomatic patients with degenerative aortic stenosis. References 1. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors with calcific aortic valve disease. J Am Coll Cardiol 1997;29: Rosenhek R, Binder T, Porenta G, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343: Bonow R, Carabello B. Guidelines for the management of patients with valvular heart disease. ACC/AHA guidelines. Circulation 1998;98: Rosenhek R, Klaar U, Schemper M, et al. Mild and J Heart Valve Dis moderate aortic stenosis. Natural history and risk stratification by echocardiography. Eur Heart J 2004;25: Bergler-Klein J, Klaar U, Heger M, et al. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation 2004;109: Messika-Zeitoun D, Aubry MC, Detaint D, et al. Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography. Circulation 2004;110: Morgan-Hughes GJ, Owens PE, Roobottom CA, Marshall AJ. Three-dimensional volume quantification of aortic valve calcification using multislice computed tomography. Heart 2003;89: Budoff MJ, Mao S, Takasu J, Shavelle DM, Zhao XQ, O Brien KD. Reproducibility of electron-beam CT measures of aortic valve calcification. Acad Radiol 2002;9: Hoffmann MH, Shi H, Schmitz BL, et al. Non-invasive coronary angiography with multislice computed tomography. JAMA 2005;293: Nieman K, Cademartiri F, Lemos PA, Raaijmakers R, Pattynama PM, de Feyter PJ. Reliable non-invasive coronary angiography using sub-millimeter multislice spiral CT. Circulation 2002;106: Kuettner A, Kopp A, Schroeder S, et al. Diagnostic accuracy of multidetector computed angiography in patients with angiographically proven coronary artery disease. J Am Coll Cardiol 2004;43: Mollet NR, Cademartiri F, Krestin GP, et al. Improved diagnostic accuracy with 16-row multislice computed tomography coronary angiography. J Am Coll Cardiol 2005;45: