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1 Left Ventricular Diastolic Dysfunction in Chronic Aortic Dissection Yasushige Shingu, MD, Norihiko Shiiya, MD, PhD, Taisei Mikami, MD, PhD, Kenji Matsuzaki, MD, Takashi Kunihara, MD, PhD, and Yoshiro Matsui, MD, PhD Department of Cardiovascular Surgery, Hokkaido University Hospital, and Department of Medical Technology, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan Background. In chronic aortic dissection, compression of the true lumen by the expanded false lumen may be a cause of left ventricular afterload elevation, which may result in diastolic dysfunction. We compared the left ventricular diastolic function by echocardiography between those patients who had double-barrel descending aortic dissection and those who did not. Methods. Twelve patients (mean age, years) with chronic type B aortic dissection were enrolled in this study. Patients in group I had double-barrel aortic dissection that had expanded the patent false lumen and narrowed the true lumen (n 7, 58.3%), and patients in group II had a wider-caliber true lumen with a thrombosed false lumen (n 5, 41.7%). We evaluated the left ventricular diastolic function with the transmitral flow pattern (E and A waves) with the pulsed Doppler method and flow propagation velocity (FPV) with color M-mode Doppler images, and classified its severity into grade I (abnormal relaxation), grade II (pseudonormalization) and grade III (restriction). Results. All patients in group II had grade I diastolic dysfunction, with an E/A of less than 1.0. By contrast, 4 of the 7 patients in group I had grade II diastolic dysfunction, with an FPV/E of less than 0.6 and a pseudonormalized (> 1.0) E/A ratio (p 0.081). Consequently, the E/A ratio was higher in group I than in group II ( versus ; p < 0.05). Conclusions. It is suggested that left ventricular diastolic function is severely reduced in the patients having aortic dissection with a double-barrel and narrowed true lumen. (Ann Thorac Surg 2007;83: ) 2007 by The Society of Thoracic Surgeons In patients with aortic dissection, expansion of the false lumen sometimes results in narrowing of the true lumen, which may be a cause of left ventricular (LV) afterload elevation. Although recent experimental and clinical studies have shown that elevated afterload is a cause of LV diastolic dysfunction [1 4], little is known about the effect of a narrowed true lumen on LV function. Transthoracic echocardiography, which incorporates several Doppler techniques, has become an established tool for the noninvasive assessment of LV systolic and diastolic function. Using this tool, we assessed LV systolic and diastolic function in patients with chronic type B aortic dissection to elucidate the effect of a narrowed true lumen on LV function. Material and Methods Patients Twelve patients, who underwent elective operations for chronic type B aortic dissection from May 2001 to December 2005 at our institution, were enrolled in this study. The patients ages ranged from 36 to 76 years (mean age, ). Five were female (41.7%). The mean period from the onset of dissection to the operation was years. We included 1 patient after an ascending aorta and aortic arch operation, but excluded patients after valve Accepted for publication Oct 27, Address correspondence to Dr Shingu, , Nishi 3 chome, Kita 18 jo, Kitaku, Sapporo, Hokkaido , Japan; infoweb.ne.jp. replacement, including Bentall operation. Cases with atrial fibrillation, mitral stenosis, an ejection fraction less than 50%, and severe aortic or mitral regurgitation were not present in this series. The study population was divided into two groups. Patients in group I had double-barrel aortic dissection with an enlarged patent false lumen and narrowed true lumen (n 7, 58.3%), whereas those in group II had a wider-caliber true lumen with a thrombosed false lumen (n 5, 41.7%). Operative indication was aneurysmal dilatation in all cases, and patients with rupture or ischemic complications related to dissection were not included. Use of the clinical records for research was approved by the Institutional Ethics Review Board. Our committee waived the need for patient consent. Echocardiography and Doppler Studies Echocardiographic studies were performed a few days before operations in all cases using a SONOS 5500 ultrasound system (Phillips Medical Systems, Tokyo, Japan) with a 3S transducer (3 to 5 MHz), a Vivid Seven system (GE/Vingmed, Milwaukee, Wisconsin) with an M3S (2.5 to 3.5 MHz) transducer, or an Aplio system (Toshiba Medical Systems, Tokyo, Japan) with a 2.5-MHz transducer by experienced examiners. The following basic variables were measured from parasternal long-axis and short-axis views: LV end-diastolic and end-systolic dimensions (mm); the ejection fraction (%) by the Teichholz method; the left atrial dimension (mm); the interventricular septal thickness; and the LV posterior wall thickness (mm) [5]. The LV mass index, estimated by LV cavity dimension and wall thickness 2007 by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg SHINGU ET AL 2007;83: DIASTOLIC FUNCTION IN AORTIC DISSECTION 1357 at end-diastole, was also calculated according to the report by Devereux and colleagues [6]. On an apical long-axis color Doppler flow image, a sample pulsed-doppler volume was located at the tip of the mitral valve leaflets to obtain the transmitral flow velocity. Peak early and late transmitral flow velocities (E and A, respectively [cm/s]), the ratio of early to late peak velocities (E/A), and deceleration time (DT [ms]) of early transmitral flow velocity were measured. Furthermore, isovolumic relaxation time (IRT [ms]) was measured as the period from the end of aortic flow to the onset of mitral inflow using continuous-wave Doppler echocardiography from the same echo window. A color M-mode Doppler image of LV filling flow in early diastole was also recorded using the apical approach. The ultrasound beam was interrogated from the apex of the heart toward the center of the mitral orifice as close to parallel as possible to the filling flow. The propagation velocity of early diastolic flow (FPV [cm/s]) was measured as the slope of the peak velocity of early diastolic filling flow on the color M-mode Doppler image, as we reported previously [7, 8]. The FPV/E ratio was also calculated to correct the influence of preload on FPV [7]. Five different cardiac cycles were analyzed, and mean values were used for each measurement. The severity of diastolic dysfunction was classified into three grades, based on the report by Nishimura and colleagues [9]. Grade I diastolic dysfunction (abnormal relaxation) was defined as an E/A ratio of less than 1.0 with prolonged IRT ( 90) and DT ( 240). In grade II diastolic dysfunction, increased filling pressure results in pseudonormalization of the E/A ratio ( 1.0). In this setting, IRT and DT may also be pseudonormalized. Patients with grade III diastolic dysfunction have a restrictive filling pattern on the mitral flow. The E/A ratio becomes more than 2.0 [5, 9, 10]. The FPV/E decreases parallel to the progression of diastolic dysfunction [11]. Significant LV relaxation abnormality (grade I or more) was considered to be present when FPV was less than 50 cm/s or FPV/E was less than 0.6 (Fig 1) [11 14]. Cardiac Catheterization Data At the time of operation, a pulmonary artery catheter (Swan-Ganz) was inserted through the internal jugular vein after the induction of anesthesia in all cases. The baseline data of central venous pressure and pulmonary artery pressure were obtained after hemodynamic stabilization after induction of anesthesia. At the same time, the cardiac index (L min 1 m 2 ) and mixed venous oxygen saturation (%) were calculated by a Vigilance Monitor (Baxter Healthcare, Edwards Critical Care Division, Irvine, California). Statistical Analysis All the descriptive data are given as mean SD. Statistical analysis was performed with the SPSS version 10.0 software (SPSS, Chicago, Illinois). The Student t test was used for comparing the continuous variables, and the 2 test or Fisher s exact test was used to compare frequencies between the groups. A p value of less than 0.05 was considered statistically significant. Fig 1. Diagram of a proposed grading system for diastolic dysfunction based on the progression of disease. Below the variation curves of FPV/E, E/A, DT, and IRT is a schematic representation of the mitral flow velocity curve. Normal FPV/E is defined as being greater than 0.6. (A A wave; DT deceleration time; E E wave; FPV flow propagation velocity; grade diastolic dysfunction grade; IRT isovolumic relaxation time.) Results Patients Characteristics There was no significant difference between the groups in age, number of females, and Marfan syndrome, previous proximal aortic operations, and atherosclerotic risk factors such as smoking, hypertension, diabetes mellitus, or hyperlipidemia. Coronary angiography or stress cardiac scintigraphy was performed for all patients preoperatively. One patient in each group had ischemic heart disease, and there was only 1 case with renal failure (serum creatinine 2.0) in group II. Furthermore, ascending and total arch replacement for type A aortic dissection had been performed for 1 case in group II. There was no history of proximal aortic dissection present in any of the other subjects. The short-axis minimum dimension of the true lumen calculated by computed tomography scanning at the level of the right pulmonary artery was mm and mm in group I and group II, respectively (p 0.002). The preoperative antihypertensive medications were also similar and the systolic and diastolic blood pressures were not significantly different. The ankle brachial pressure index was normal in both groups (Table 1). Echocardiographic Findings All the patients exhibited a normal ejection fraction, and none had an LV wall motion abnormality. Furthermore, there was no significant difference observed between groups I and II with respect to LV end-diastolic and end-systolic dimensions, ejection fraction, left atrial dimensions, interventricular septal thickness, or LV mass index. The E/A ratio was, however, significantly higher in group I than in group II: E was significantly greater in group I than in group II (Table 2). There was no significant difference in A-wave, deceleration time, and IRT between groups I and II. Color

3 1358 SHINGU ET AL Ann Thorac Surg DIASTOLIC FUNCTION IN AORTIC DISSECTION 2007;83: Table 1. Patients Characteristics Group I (n 7) Group II (n 5) p Value Female/male 2/5 3/ Age (years) Previous proximal aortic opereation Marfan syndrome Hypertension Diabetes mellitus Hyperlipidemia Smoking Coronary artery disease Antihypertensive drugs Diuretics Angiotensin-converting enzyme inhibitor Angiotensin receptor blocker Alpha-blocker Beta-blocker Calcium-channel blocker Number of medications Dimension of true lumen (range, mm) (8 14) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Ankle brachial pressure index Right Left Table 2. Echocardiographic and Cardiac Catheterization Data Group I (n 7) Group II (n 5) p Value LVDd (mm) LVDs (mm) EF (%) LAD (mm) IVST (mm) LVPWT (mm) LV mass index (g/m 1 ) Transmitral flow E (cm/s) A (cm/s) E/A Deceleration time (ms) IRT (ms) Intraoperative data Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Systolic pulmonary artery pressure (mm Hg) Diastolic pulmonary artery pressure (mm Hg) Central vein pressure (mm Hg) Cardiac index (L min 1 m 2 ) Mixed venous saturation (%) A atrial wave; E early wave; EF ejection fraction; IRT isovolemic relaxation time; IVST interventricular septal thickness; LAD left atrial dimension; LVDd left ventricular end-diastolic dimension; LVDs left ventricular end-systolic dimension; LVPWT left ventricular posterior wall thickness.

4 Ann Thorac Surg SHINGU ET AL 2007;83: DIASTOLIC FUNCTION IN AORTIC DISSECTION 1359 Table 3. Transmitral Flow Properties and Diastolic Dysfunction Grade Case E/A DT (ms) IRT (ms) FPV (cm/s) FPV/E Grade Group I I I II II I II II Group II I I I I I DT deceleration time; E/A ratio of early to late peak velocities; FPV flow propagation velocity; FPV/E ratio of flow propagation velocity and transmitral E wave velocity; IRT isovolumic relaxation time. M-mode Doppler evaluation was performed for the patients with an E/A ratio greater than 0.9 in group I to differentiate the pseudonormal transmitral flow pattern from the normal one. In all the 4 patients, the FPV was less than 50 cm/s and the FPV/E was less than 0.6, indicating that the E/A ratio was pseudonormalized in these 4 patients (Table 3). No patient in group II had the E/A ratio greater than 1.0. Therefore, in group I, 3 patients had grade I and 4 patients had grade II diastolic dysfunction, whereas in group II, all 5 patients had grade I diastolic dysfunction (p 0.081). Cardiac Catheterization Data Central venous pressure, systolic pulmonary artery pressure, cardiac index, and mixed venous saturation were not significantly different between the groups. Pulmonary wedge pressure was not available for every patient. Diastolic pulmonary artery pressure in group I was significantly higher than that in group II (Table 2). Table 4. Perioperative and Postoperative Characteristics Variables Group I (n 7) Group II (n 5) Operative procedures Thoracoabdominal aortic replacement 3 1 Descending aortic replacement 1 3 Arch replacement with or without ET 3 1 Hospital mortality 0 0 ICU stay 3 days 1 2 Postoperative brain infarction 1 1 Postoperative pericardial effusion 2 0 ET elephant trunk; ICU intensive care unit. Operative Results The perioperative and postoperative data are shown in Table 4. Thoracoabdominal aortic replacement was performed in 4 patients (33.4%), descending aortic replacement in 4 (33.3%), and arch replacement with or without a frozen elephant trunk in 4 (33.4%). There was no hospital mortality. One patient in group I who underwent total arch replacement and the elephant trunk (ET) procedure suffered from pulmonary hypertension, severe tricuspid regurgitation, and dyspnea with normal systolic function 7 days after operation. Before operation, he had grade II diastolic dysfunction, and his E/A of transmitral flow was Ten days after the operation, the E/A was 2.25, which gradually went down to the baseline in 6 weeks, and his symptoms disappeared. Comment The association between arterial disease and LV systolic dysfunction has been well characterized. However, the clinical significance of diastolic LV dysfunction has not been highlighted until recently, and little is known about the association between the aortic pathology and diastolic LV dysfunction. We evaluated the diastolic filling pattern in the patients of chronic double-barrel aortic dissection by echocardiography. The results suggested that they had left ventricular diastolic dysfunction. This report is the first to imply the possibility of left ventricular diastolic dysfunction in chronic aortic dissection. Echocardiographic Evaluation Pulsed Dopper measurement of transmitral flow such as DT, IRT, and E/A has been widely used to assess the left ventricular relaxation abnormality. However, pulsed Doppler-derived indexes are affected by several factors, such as alterations of loading conditions. The abnormality of left ventricular relaxation is concealed in patients with more severe diastolic dysfunction because the transmitral flow pattern is pseudonormalized by an increased atrioventricular pressure gradient (grade II). In these patients, pulsed Doppler-derived indexes show poor correlations with invasive variables of left ventricular diastolic properties [7].

5 1360 SHINGU ET AL Ann Thorac Surg DIASTOLIC FUNCTION IN AORTIC DISSECTION 2007;83: Recently, FPV measured by color M-mode Doppler echocardiography has been used as an index of ventricular relaxation [7, 12, 13]. The FPV strongly correlates with left ventricular peak negative dp/dt and minimal pressure. Furthermore, the ratio of component velocity E over the FPV during early filling, by correcting for the effect of left ventricular relaxation, provides a better estimate of pulmonary wedge pressure or left ventricular end-diastolic pressure than does standard transmitral Doppler flow properties. In this study, we evaluated the FPV and FPV/E to differentiate grade II diastolic dysfunction from the normal relaxation pattern. Because we routinely use the FPV/E, but not the E/FPV based on the clinical experience, we applied the former in this study [7]. Aortic Morphology We divided the study population into two groups according to the presence of a patent false lumen. In the double-barrel aorta, the true lumen is compressed by an expanded false lumen. Therefore, we hypothesized that the left ventricular afterload is higher in group I than group II, although we did not prove it by direct measurement of central aortic pressures or the augmentation index. Mottram and associates [1] reported that arterial compliance is an independent predictor of diastolic dysfunction in patients with hypertensive heart disease and should be considered a potential target for intervention in diastolic heart failure. Similarly, if we can correct the diastolic dysfunction by surgical intervention to enlarge the true lumen, diastolic heart failure can be an operative indication for type B dissection. It is well established that LV relaxation is often abnormal in the hypertensives with or without LV hypertrophy, suggesting that abnormal relaxation may be an early response to cardiac overload caused by hypertension [15]. In an experimental study using pressure-overloaded rats, Kuwahara and coworkers [16] found that transforming growth factor- played a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation after pressure overload. The fibrosis began even before the cardiomyocyte grew in diameter [16]. In our study population, diastolic dysfunction was observed without an increase of LV wall thickness. Our result is in accordance with the report by Kuwahara and associates, suggesting that diastolic dysfunction may precede clinical LV hypertrophy. Study Limitations Tissue Doppler imaging of the mitral annulus, which has recently been proposed as a method to evaluate diastolic LV function [17] and is reported as effective as flow propagation velocity to estimate LV filling pressure [18], was not used. This is not a prospective study, and the patients background may not be uniform. Because the number of patients is small and we do not have the predissection or postoperative echocardiographic data, we do not know whether LV dysfunction is induced by dissection or is merely an epiphenomenon, nor do we know whether it is reversible. Further study with a larger volume of patients is thus required. In conclusion, left ventricular diastolic function can be severely reduced in patients with type B chronic aortic dissection that has a double barrel and a narrowed true lumen. References 1. Mottram PM, Haluska BA, Leano R, Carlier S, Case C, Marwick TH. Relation of arterial stiffness to diastolic dysfunction in hypertensive heart disease. Heart 2005;91: Ikonomidis I, Lekakis J, Stamatelopoulos K, Markomihelakis N, Kaklamanis PG, Mavrikakis M. Aortic elastic properties and left ventricular diastolic function in patients with Adamantiades-Behcet s disease. J Am Coll Cardiol 2004;43: Oyama R, Murata K, Tanaka N, et al. Is the ratio of transmitral peak E-wave velocity to color flow propagation velocity useful for evaluating the severity of heart failure in atrial fibrillation? Circ J 2004;68: Ikonomidis I, Tsoukas A, Parthenakis F, et al. Four-year follow-up of aortic valve replacement for isolated aortic stenosis: a link between reduction in pressure overload, regression of left ventricular hypertrophy, and diastolic function. Heart 2001;86: Fujita M. Text of echocaridiography. Tokyo: Ishiyaku Publishers, 2001: Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57: Takatsuji H, Mikami T, Urasawa K, et al. A new approach for evaluation of left ventricular diastolic function: spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 1996;27: Nishihara K, Mikami T, Takatsuji H, et al. Usefulness of early diastolic flow propagation velocity measured by color M- mode Doppler technique for the assessment of left ventricular diastolic function in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2000;13: Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician s Rosetta Stone. J Am Coll Cardiol 1997;30: Oh JK, Seward JB, Tajik JA. The echo manual. 2nd ed. Baltimore: Lippincott Williams & Wilkins, Mikami T. How to diagnose left ventricular diastolic dysfunction. Shineko 2004;5: Garcia MJ, Ares MA, Asher C, Rodriguez L, Vandervoort P, Thomas JD. An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29: Schwammenthal E, Popescu BA, Popescu AC, et al. Association of left ventricular filling parameters assessed by pulsed wave Doppler and color M-mode Doppler echocardiography with left ventricular pathology, pulmonary congestion, and left ventricular end-diastolic pressure. Am J Cardiol 2004;94: Arques S, Ambrosi P, Roux E, Habib G. Potentials and limitations of color M-Mode and tissue Doppler indexes in identifying pseudonormal mitral filling pattern in patients with acute symptoms of heart failure and preserved left ventricular systolic function. Am J Cardiol 2004;93: Wachtell K, Smith G, Gerdts E, et al. Left ventricular filling patterns in patients with systemic hypertension and left ventricular hypertrophy (the LIFE study). Am J Cardiol 2000;85: Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 2002;106: Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quiñones MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30: Nagueh SF, Lakkis NM, Middleton KJ, et al. Changes in left ventricular diastolic function 6 months after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 1999;99:344 7.

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