Hypertrophic cardiomyopathy (HCM) of cats is the

Transcription

1 J Vet Intern Med 2006;20:65 77 Pulsed Tissue Doppler Imaging in Normal Cats and Cats with Hypertrophic Cardiomyopathy H. Koffas, J. Dukes-McEwan, B.M. Corcoran, C.M. Moran, A. French, V. Sboros, K. Simpson, and W.N. McDicken Myocardial motion was quantified in normal cats (n 5 25) and cats with hypertrophic cardiomyopathy (HCM) (n 5 23) using the pulsed tissue Doppler imaging (TDI) technique. A physiologic nonuniformity was documented in the myocardial motion of normal cats, which was detected as higher early diastolic velocities, acceleration, and deceleration in the interventricular septum compared with the left ventricular free wall (LVFW). HCM cats exhibited lower early diastolic velocities, acceleration, and deceleration and also prolonged isovolumic relaxation time compared with normal cats. These differences were detected mainly along the longitudinal axis of the heart. A cutoff value of E9 in the LVFW along the longitudinal axis.7.2 cm/s discriminated normal from HCM cats with a sensitivity of 92% and a specificity of 87%. The physiologic nonuniformity of myocardial motion during diastole was lost in affected cats. Systolic impairment (decreased late-systolic velocities in most segments along the longitudinal axis and decreased early systolic acceleration in both mitral annular sites) was evident in HCM cats irrespective of the presence of left ventricular outflow tract obstruction and congestive heart failure. Postsystolic thickening was recorded in the LVFW along the longitudinal axis only in affected cats (n 5 6) and was another finding indicative of systolic impairment in the HCM of this species. This study identified both diastolic and systolic impairment in cats with HCM compared with normal cats. The study also documents the normal physiologic nonhomogeneity in myocardial motion in cats and the subsequent loss of this feature in the HCM diseased state. Key words: Diastolic function; Feline; Myocardium; Nonuniform myocardial motion; Systolic function. Hypertrophic cardiomyopathy (HCM) of cats is the most common cardiac disease of this species, and is by convention characterized by a concentrically hypertrophied, nondilated left ventricle, in the absence of other diseases known to cause left ventricular hypertrophy. 1 In certain families of cats, HCM appears to be hereditary and is transmitted as an autosomal dominant trait sharing many morphological characteristics in common with human HCM. 1,2 Diastolic impairment is believed to be the main abnormality of the disease, 1,2 and evidence for this has been provided by both invasive and Doppler echocardiographic studies. 3,4 More recently, tissue Doppler imaging (TDI) has emerged as an alternative tool for the noninvasive quantification of regional and global myocardial function, 5,6 allowing direct quantification of myocardial motion. 5 TDI indices correlate very well with global systolic and diastolic invasive hemodynamic indices, and early diastolic TDI indices have been shown to be independent from changes in preload in the diseased state. 7,8 In the first application of TDI in cats, From the Department of Veterinary Clinical Studies (Koffas, Dukes-McEwan, Corcoran, French, Simpson) and the Department of Medical Physics and Engineering (Moran, Sboros, McDicken), University of Edinburgh, Scotland, UK. Dr Koffas is presently affiliated with the Royal Veterinary College, Hatfield, North Mymms, Hertfordshire, UK. Dr Dukes-McEwan is presently affiliated with the Small Animal Hospital, University of Liverpool, Liverpool, UK. Previously presented in part at the 11th and 12th congresses of the ESVIM in Dublin, Ireland, in September 2001 and in Munich, Germany, in September Reprint requests: H. Koffas, PhD, Royal Veterinary College, Hawkshead Lane, Hatfield, North Mymms, Hertfordshire AL9 7TA, UK; h.koffas@rvc.ac.uk. Submitted August 26, 2004; Revised April 6, 2005; Accepted July 22, Copyright E 2006 by the American College of Veterinary Internal Medicine /06/ /$3.00/0 Gavaghan et al 9 showed that cats with HCM had decreased myocardial diastolic velocities, acceleration, and deceleration and also prolonged isovolumic relaxation time (IVRt). These findings offered further evidence for diastolic impairment in HCM of cats. TDI myocardial velocities from normal nonanesthetized cats have shown to have acceptable reproducibility in sequential measurements suggesting that they could be used for serial examinations for assessing progress of disease or the effect of treatment. 10 The recent wide application of TDI in humans with HCM has also revealed new aspects in the pathophysiology of the disease. 11,12 Apart from the classical abnormalities in diastolic function, such as decreased diastolic velocities and prolonged IVRt, the presence of marked asynchrony in myocardial motion in different parts of the left ventricular (LV) wall has also been detected and is believed to be another significant determinant or result of diastolic impairment in HCM. 13 Furthermore, in contrast to traditional echocardiographic techniques, such as mitral inflow measurements, percentage of fractional shortening (FS%), and the percentage of ejection fraction (EF%), which consider diastolic dysfunction as the main abnormality of the disease, TDI studies have shown that systolic impairment is also evident in human HCM, despite the apparent normal or supernormal contractile state of the left ventricle based on FS% and EF% measurements. 14 In HCM, mutant sarcomeric proteins cause a variety of primary myocyte defects involving diastolic and systolic dysfunction of the individual myocardial cell, which along with disruption and disorganization of the cardiomyocytes can induce the classical pathologic changes seen in the disease Such reports emphasize the necessity for comprehensive evaluation of both systolic and diastolic function in HCM of cats. With a purpose-designed 7.4-MHz transducer equipped to record pulsed TDI, we aimed to quantify myocardial motion in multiple myocardial segments in

2 66 Koffas et al both normal and HCM cats. Diastolic and systolic myocardial indices were determined for all myocardial segments. The differences in myocardial motion between the radial and longitudinal axes of the heart and also the influence of aging, heart rate (HR), weight, sex, and diastolic LV thickness on TDI indices were assessed. Quantification of the right ventricular myocardial properties was attempted by analyzing tricuspid annular velocities in a subgroup of cats. We hoped that this study would establish new TDI echocardiographic indices to aid in the more accurate quantification and early detection of the diseased myocardium. Materials and Methods Study Group None of the normal cats had evidence of cardiovascular disease or other significant abnormalities on clinical examination. All normal cats underwent a complete standard 2D, M-mode, color flow, and spectral Doppler echocardiographic examination and had echocardiographic results within normal limits. 1 All normal cats.7-years of age, and all affected cats had routine CBC and biochemical analyses. Cats with azotemia (defined as creatinine.177 mmol/l), hyperglycemia (defined as.6 mmol/l), or high total thyroxine hormone levels (defined as.48 nmol/l) were excluded. All cats had normal systolic blood pressure (,180 mm Hg) as measured by the Doppler technique. a,20 Affected cats also had a complete standard Doppler echocardiographic examination. Diagnosis of HCM was made on the basis of LV thickness $6 mm on 2D or M-mode echocardiography, in the absence of volume overload (no obvious valvular abnormalities) and systemic diseases known to cause LV hypertrophy. 1 On presentation, all affected cats were in sinus rhythm except 1, which had atrial fibrillation. A 6-lead ECG was performed on each cat. Nineteen cats with HCM were asymptomatic, with 1 cat receiving a b-blocker. Four of the affected cats were being treated for congestive heart failure at the time of evaluation with a combination of diuretics and angiotensin-converting enzyme inhibitors, with or without b-blockers, and all were stable. Medications were not withdrawn before assessment. None of the HCM cats had aortic thromboembolism. Conventional Echocardiography Conventional 2D, M-mode, color flow and Doppler echocardiography was carried out in all cats, using a 7.5-MHz transducer. b All scans were acquired by experienced echocardiographers (Diplomates: JDMcE and AF). Cats were scanned unsedated and manually restrained in lateral recumbency on a purpose-designed table, which allowed placement of the transducer on the dependent part of the thorax. A simultaneous ECG was recorded (lead II) to determine the timing of the phases of the cardiac cycle to guide positioning of the electronic calipers. Measurements were recorded onto S-VHS videotapes and analyzed off-line. The 2D measurements included wall measurements and diastolic aortic and left atrial diameter. Measurement of M-mode LV parameters and calculation of the fractional shortening was done at chordae tendineae level, guided from the right-parasternal short-axis view. The mitral valve M-mode was scrutinized for the presence of systolic anterior motion of the anterior mitral valve leaflet. The left apical 4-chamber view was used to record mitral inflow, pulmonary venous flow, and tricuspid inflow by pulsed wave (PW) spectral Doppler. Peak outflow velocities and atrioventricular E and A velocities were determined. Estimation of the aortic velocity was done from the left 5-chamber-apical-view, usually with PW Fig 1. Sample volume recording of motion velocity patterns along the longitudinal (4-chamber apical view) (a) and the radial (right parasternal long-axis view) (b) axis. Sample volumes (white circles) were set on the septal (1) and lateral (2) mitral annulus, on the tricuspid annulus (5), on the subendocardial portions of the interventricular septum (3), and the left ventricular free wall (4) at chordae tendineae level on the 4-chamber apical view. Sample volumes were also set on the midwall of the interventricular septum (6) and the left ventricular free wall (7) at chordae tendineae level on the right parasternal long axis view. Doppler. When left ventricular systolic outflow tract obstruction was present, continuous wave (CW) spectral Doppler echocardiography was used to record systolic outflow velocities. PW Doppler was used to record pulmonic outflow from both left and right cranial short-axis views, optimized for the pulmonary artery. Color flow Doppler echocardiography was used to scrutinize for valvular incompetence. If present, velocities of regurgitant jets were recorded with PW or CW Doppler, as appropriate. All conventional echocardiographic indices were calculated from the mean of $6 consecutive cardiac cycles. In the single cat with atrial fibrillation, the mean of 12 cardiac cycles was used. Data from the conventional echocardiographic studies are not the subject of this article, and only the results of findings pertinent to this study are shown. Tissue Doppler Imaging Echocardiography All pulsed TDI recordings were made with a 7.4-MHz phasedarray transducer, c which used prototype TDI software. All scans were acquired by the same experienced echocardiographer (JDMcE). Cats were scanned unsedated and manually restrained in lateral recumbency on a purpose-designed table, as previously described. A simultaneous ECG was recorded (lead II). Off-line analysis of the images was done with a special analysis software. d To investigate myocardial motion along the longitudinal axis of the heart, a 2-dimensional, guided 1-mm sample volume was placed on the subendocardial portions of the interventricular septum (IVS) and the LV free wall (LVFW) at chordae tendineae level in the left 4-chamber apical view (4-ch) (Fig 1a). The septal (sepma) and lateral (latma) corner of the mitral annulus and also the tricuspid annulus (Tr) were sampled using the same echocardiographic view (Fig 1a). To investigate myocardial motion along the radial axis of the heart, the sample volume was placed on the midwall portions of the IVS and the LVFW at chordae tendineae level using the right parasternal long-axis view (rpla) (Fig 1b). No angle correction was used. The Nyquist limit (15 cm/s to 220 m/s) was adjusted to achieve maximum velocity signal while avoiding aliasing. Gain and filter settings were optimized to reduce noise and the maximum sweep rate was used (values obtained every 3 milliseconds). On the basis of myocardial velocity patterns recorded from all myocardial segments, assessment of certain pulsed TDI indices was

3 Pulsed Tissue Doppler Imaging in Cats 67 Fig 2. Pulsed tissue Doppler image (TDI) tracing obtained from the left ventricular free wall (LVFW) along the longitudinal axis of a 7-year-old cat. The y-axis is velocity in cm/s and the x-axis is time in seconds with a simultaneous ECG. Se9, peak early systolic velocity; Sl9, peak late systolic velocity; E9, peak early diastolic velocity; A9, peak late diastolic velocity; IVCa and IVCb, myocardial shifts during the isovolumic contraction period; IVRa and IVRb, myocardial shifts during the isovolumic relaxation period; S9dur, duration of systolic wave; IVRt, isovolumic relaxation period; E9dur, duration of early diastolic wave; A9dur, duration of late diastolic wave; IVCt, isovolumic contraction period; bs9 Sl9, time from beginning of S9 wave to peak latesystolic velocity; Se9acc, the mean acceleration slope of the early systolic peak; tse9acc (not shown on figure), the corresponding time for Se9acc measured from the beginning to the end of this slope; and E9acc and E9dec, the acceleration and deceleration slopes, respectively, of the E9 (early diastolic velocity wave). The durations of these slopes are, respectively, te9acc and te9dec (not shown on figure); the times from the start to peak of the acceleration of E9 and peak E9 velocity to the baseline, respectively. carried out as follows (Fig 2). The velocity wave recorded during LV ejection (from the end of the QRS complex to the end of the T wave of the ECG) was the systolic (S9) component of myocardial motion. Se9 and Sl9 were the peak early and late systolic velocities, respectively. Se9 acc and tse9 acc were the mean early acceleration (measured from the beginning of the S9 wave to Se9) and time of mean acceleration of S9, respectively; bs9 Sl9 was the time from the beginning of S9 to Sl9. E9 and A9 were the peak early and late diastolic velocities (waves) corresponding to early diastolic relaxation phase and atrial contraction, respectively. Mean acceleration (E9 acc) and deceleration (E9dec) of the E9 wave were recorded from the beginning and the end of this wave to its peak, respectively. Acceleration (te9 acc) and deceleration (te9dec) times were the corresponding times of E9acc and E9dec, respectively. When the E9 and A9 waves were partially summated, then only their peak velocities were measured. In cases of full summation, the peak velocity of the summated wave (EA9) was measured. However, EA9 values were excluded from further analysis. When possible, the ratio of E9 to A9 wave (E9 :A9) was calculated from each pulsed TDI tracing. The biphasic, oppositely directed, and brief-duration shifts during the 2 isovolumic periods were the IVCa and IVCb for the isovolumic contraction and IVRa and IVRb for the isovolumic relaxation phases, respectively. Isovolumic contraction period (IVCt) was measured from the end of the A9 wave to the beginning of the S9 wave and isovolumic relaxation period (IVRt) from the end of the S9 wave to the beginning of the E9 wave. The duration of the S9, E9, and A9 waves were also calculated. All TDI indices were calculated from the mean of at least 6 consecutive cardiac cycles. The HR was calculated during each radial and longitudinal TDI examination using the mean R-R interval of the cardiac cycles used. In the single cat with atrial fibrillation, the mean of 12 cardiac cycles was used. Repeatability Study To assess intraobserver variability, 4 normal, unsedated cats were scanned twice with a 1-week interval separation. The same experienced echocardiographer (JDMcE) acquired all the scans for the study. A single observer (HK) analyzed blindly all of the scans in this study. The coefficient of variation (standard deviation of measurements/mean of measurements 3 100) (CV%) was calculated for TDI indices. Repeatability was assessed by calculating the mean difference and the limits of agreement (mean difference standard deviation of the difference) between 2 measurements, according to the Bland-Altman method. 21 The coefficient of repeatability (2 3 standard deviation of the differences) was also calculated. Statistical Analysis Statistical analysis was carried out by using statistical software. e,f Values are expressed as the mean 6 standard deviation (SD). Categorical variables (sex) were checked by means of the Chi-squared test. Analysis of covariance was used to control TDI indices for R-R interval, age, and weight. A t-test was used to compare values between the 2 groups and values from myocardial segments from the same group. Comparisons between the 2 groups were repeated, comparing normal with asymptomatic cats, by excluding from the analysis HCM cats with congestive heart failure (CHF). To avoid the influence of left ventricular outflow tract obstruction on systolic TDI indices, the latter were additionally compared among asymptomatic affected cats with a systolic outflow tract pressure gradient,4 mm Hg and normal cats. Stepwise regression analysis was used to assess the influence of R-R interval, age, weight, sex, and diastolic LV thickness on peak TDI indices. Multiple linear or linear regression analyses were used to assess the association of independent predictors on TDI indices in both groups. A Kolmogorov-Smirnov test was used to assess the distribution of variables. To achieve normality of nonnormally distributed variables, logarithmic transformation was used. A P value of,.05 was considered statistically significant. Results Study Population The study population comprised 25 normal cats, which were pets of staff and students of the University of Edinburgh, and 23 cats with HCM, which were referred to the Cardiopulmonary Service of the Veterinary School for investigation of heart disease. Normal cats of the following breeds were included in the study: 21 domestic short-haired, 1 domestic semilong-haired, 1 Maine-coon, 1 Abyssinian, and 1 Siamese (12 female and 13 male neutered cats). Mean 6 standard deviation of body weight was: kg. All normal cats were in good body condition. The mean age was years (range 10 months to 14 years). The mean HR was beats per minute. The affected group contained the following: 21 domestic short-haired and 2 Persian cats (4 female and 19 male neutered cats). The mean body weight was kg, mean age years (range 1 to 12 years), and mean HR was beats per minute. The groups were found to be age-matched. Although there was a predominance of males in the HCM group, this was not statistically significant (P 5.052).

4 68 Koffas et al Table 1. Conventional echocardiographic measurements (mean 6 SD) from normal (n 5 25) and hypertrophic cardiomyopathy (HCM) cats (n 5 23). Normal HCM P IVSd (mm) ,0.001 LVd (mm) ns LVFWd (mm) ,0.001 IVSs (mm) ,0.001 LVs (mm) ns LVFWs (mm) ,0.001 FS (%) ns Ao. vmax (m/s) ,0.01 IVSd, interventricular septal wall thickness (diastole); LVd, left ventricular end-diastolic diameter; LVFWd, left ventricular free wall thickness (diastole); IVSs, interventricular septal wall thickness (systole); LVs, left ventricular end-systolic diameter; LVFWs, left ventricular free wall thickness (systole); FS%, fractional shortening; Ao. vmax, peak aortic velocity; ns, no significant difference between the two groups. The 2D measurements and data from mitral inflow, pulmonary venous flow, tricuspid inflow, and pulmonary outflow are not shown. Conventional Echocardiography Thickness of the IVS and the LVFW at chordae tendineae level were significantly higher in the HCM group than in the normal group (P,.001), which was expected because wall thickness had been used to define the groups (Table 1). In 11 HCM cats the outflow tract pressure gradient was,4 mm Hg (mean aortic velocity 6 SD: m/s), and in 12 affected cats was.4 mm Hg (mean aortic velocity 6 SD: m/s) (reference range for aortic velocity: m/s). Two cats with outflow tract pressure gradient,4 mm Hg were in CHF. Quality of Tracings and Summation Effects The lowest percentage of quantifiable tracings in both normal cats and cats with HCM was from the IVS in the Table 2. Number of cats from which quantifiable pulsed tissue Doppler image (TDI) tracings were obtained. Normal Cats (n 5 25) (% of Total No. of Cats Available) HCM Cats (n 5 23) (% of Total No. of Cats Available) sep MA 25 (100) 23 (100) lat MA 24 (96) 18 (78) 4ch IVS 25 (100) 23 (100) 4ch LVFW 24 (96) 18 (78) rpla IVS 17 (68) 17 (74) rpla LVFW 24 (96) 23 (100) Tr a 8 (100) 12 (100) HCM, hypertrophic cardiomyopathy; sep MA, septal mitral annulus; lat MA, lateral mitral annulus; 4ch, 4-chamber apical view; rpla, right parasternal long axis view; IVS, interventricular septum; LVFW, left ventricular free wall; Tr, tricuspid annulus. a Measurement at the tricuspid annulus (Tr) was only attempted in 8 and 12 cats for the normal and affected groups, respectively, and so constituted 100% of the available cats. Table 3. Number of traces with fully and partially merged (normal cats) E9 and A9 diastolic waves. For the hypertrophic cardiomyopathy (HCM) group the numbers and percentages refer to traces with only fully merged E9 and A9 waves. Normal Cats No. of Tracings (% of Measurable Tracings) HCM Cats No. of Tracings (% of Measurable Tracings sep MA 2 (8) 2 (9) lat MA 1 (4) 3 (16) 4ch IVS 3 (12) 4 (17) 4ch LVFW 3 (12) 3 (17) rpla IVS 2 (12) 3 (18) rpla LVFW 2 (8) 1 (4) Tr 0 (0) 3 (25) sep MA, septal mitral annulus; lat MA, lateral mitral annulus; 4ch, 4-chamber apical view; rpla, right parasternal long axis view; IVS, interventricular septum; LVFW, left ventricular free wall; Tr, tricuspid annulus. radial axis (68 74%, respectively) (Table 2); 100% of the tracings from the septal mitral annulus and the IVS along the longitudinal axis were quantifiable in both groups of cats. There was a relatively low percentage of fully or partially merged E and A diastolic waves ranging from 0 25%, the highest seen in HCM cats (Table 3). Occasionally, fully merged E9 and A9 waves, as well as partially summated waves, occurred in the same individual. Pulsed TDI Indices in Different Myocardial Segments Data for 15 indices were obtained from the septal and lateral mitral annulus, the IVS and LVFW sampled from both the left apical 4-chamber and right parasternal long axis views, and the tricuspid annulus from the 4-chamber apical view. In the following sections, the differences in TDI parameters, for normal and HCM cats, are compared with respect to velocities, acceleration-deceleration, and time intervals (Tables 4, 5). Numerous differences were detected when comparing measurements in the different segments from the same group and were most apparent in the normal group (Table 6). Affected cats also demonstrated differences but to a lesser extent (data not shown). The significant differences are summarized in the following sections. Velocities during the isovolumic phases and also the duration of S9 and A9 waves are not presented because they did not discriminate significantly between the 2 groups. Differences between the Longitudinal and Radial Axis Differences were noted when comparing measurements from the same myocardial segment (IVS and LVFW) obtained from the longitudinal and radial axis (4-ch versus rpla). With respect to the LVFW, the parameters that were significantly greater along the longitudinal axis compared with the radial axis in normal cats were E9, E9 :A9, E9acc, E9dec, and bs9 Sl9 (Table 6). In HCM cats, for the LVFW, the E9 :A9 was

5 Pulsed Tissue Doppler Imaging in Cats 69 Table 4. Mean values (standard deviation) of tissue Doppler myocardial indices from normal cats and cats with hypertrophic cardiomyopathy (HCM). Comparisons were made after values were controlled for heart rate, age, and weight by analysis of covariance (ANCOVA). sep MA lat MA 4ch IVS 4ch LVFW rpla IVS rpla LVFW Tr Normal HCM Normal HCM Normal HCM Normal HCM Normal HCM Normal HCM Normal HCM E9 (cm/s) 6.42 *** (1.83) 4.12 (0.85) 8.39 *** (2.58) 5.24 (1.22) 6.8 *** (1.9) 5.12 (1.96) 9.28 *** (2.14) 5.87 (1.39) 5.2 (1.69) 4.93 (1.55) 5.6 (1.58) 5.04 (1.99) 9.78 ** (2.27) 7.08 (1.24) A9 (cm/s) 6.57 (2.4) 6.55 (2.09) 6.2 (2.43) 6.05 (1.89) 6.16 (1.61) 7.26 (3.12) 5.37 (1.92) 5.98 (2.42) 5.34 (2.22) 7.08 (2.74) 5.58 (1.78) 7.27 (2.28) 10.3 ** (3.59) 16.3 (4.7) E9 :A ** (0.25) 0.74 (0.47) 1.47 *** (0.59) 0.92 (0.2) 1.15 ** (0.38) 0.79 (0.44) 1.87 *** (0.59) 1.12 (0.48) 1.15 *** (0.64) 0.77 (0.27) 1.07 *** (0.37) 0.74 (0.29) 1.04 *** (0.37) 0.46 (0.09) Se9 (cm/s) 7 (1.8) 6.26 (1.72) 7.1 * (2.34) 5.77 (2.22) 6.17 (1.5) 6.46 (2.18) 6.34 (1.85) 5.37 (1.72) 5.65 (1.26) 6.1 (1.11) 6.16 (1.26) 6.05 (1.48) 12.2 (6.08) 10.5 (3.31) Sl9 (cm/s) 4.65 *** (1.26) 3.31 (0.63) 4.2 * (1) 3.18 (0.78) 4.79 ** (1.41) 3.78 (1.02) 3.8 (1.02) 3.56 (0.94) 3.17 (0.72) 3.42 (0.68) 3.98 (1.35) 3.52 (1.52) 6.64 (2.17) 6.57 (1.7) sep MA, septal mitral annulus; lat MA, lateral mitral annulus; 4ch, 4-chamber apical view; 4ch IVS, interventricular septum sampled from the 4ch; 4ch LVFW, left ventricular free wall sampled from the 4ch; rpla, right parasternal long axis view; rpla IVS, interventricular septum sampled from the rpla; rpla LVFW, left ventricular free wall sampled from the rpla; Tr, tricuspid annulus sampled from the 4ch; E9, early diastolic peak; A9, late diastolic peak; E9 : A, ratio of early to late diastolic wave; Se9, early systolic peak; Sl9, late systolic peak. * P,.05; ** P,.01; *** P,.001, difference in values obtained from the same myocardial segment (same projection) between the 2 groups. Table 5. Mean values (standard deviation) of tissue Doppler myocardial indices from normal cats and cats with hypertrophic cardiomyopathy (HCM). Comparisons were made after values were controlled for heart rate, age, and weight by analysis of covariance (ANCOVA). sep MA lat MA 4ch IVS 4ch LVFW rpla IVS rpla LVFW Tr Normal HCM Normal HCM Normal HCM Normal HCM Normal HCM Normal HCM Normal HCM E9acc (cm/s 2 ) 179 *** (58) 94 (33) 240 *** (75) 120 (73) 206 ** (78) 150 (80) 317 *** (82) 165 (73) 147 (59) 128 (30) 186 * (63) 122 (49) 203 (63) 157 (37) te9acc (ms) 38 ** (8) 47 (12) 36 * (6) 47 (10) 36 (8) 37 (10) 31 ** (6) 43 (14) 48 (18) 43 (10) 34 * (9) 41 (11) 50 (9) 47 (7) E9dec (cm/s 2 ) 128 * (41) 96 (52) 190 *** (88) 88 (35) 169 *** (68) 98 (36) 192 *** (66) 118 (58) 147 (63) 99 (26) 135 * (47) 84 (36) 140 (44) 110 (32) te9dec (ms) 51 (7) 55 (23) 48 * (12) 68 (19) 44 (11) 55 (15) 54 (19) 60 (18) 43 (11) 54 (8) 47 * (16) 64 (27) 72 (18) 68 (17) E9dur (ms) 88 (11) 104 (29) 84 *** (16) 114 (26) 78 (14) 92 (22) 81 * (13) 105 (28) 87 (28) 96 (15) 80 *** (20) 108 (38) 122 (20) 120 (20) Se9acc (cm/s 2 ) 290 * (110) 219 (58) 310 * (128) 191 (80) 225 (78) 207 (74) 256 * (68) 181 (60) 207 (75) 221 (100) 216 (67) 195 (81) 303 (102) 335 (103) tse9acc (ms) 27 (5) 30 (4) 24 ** (4) 33 (9) 29 * (5) 33 (7) 27 * (9) 33 (8) 30 (8) 33 (11) 31 (8) 36 (12) 35 (5) 33 (4) bs9 Sl9 (ms) 77 (13) 88 (9) 81 * (9) 102 (30) 87 (12) 92 (14) 99 (30) 94 (22) 89 * (17) 99 (16) 92 (25) 96 (22) 95 (10) 94 (33) IVRt (ms) 61 * (13) 75 (22) 54 * (11) 72 (32) 61 *** (15) 81 (33) 57 ** (10) 75 (25) 67 (25) 71 (22) 61 (16) 62 (21) 53 (19) 66 (21) IVCt (ms) 36 (14) 34 (10) 49 (17) 53 (16) 36 (13) 34 (11) 46 (19) 49 (14) 39 (24) 36 (19) 50 (15) 47 (16) 28 (6) 39 (11) Sep MA, septal mitral annulus; lat MA, lateral mitral annulus; 4ch, 4-chamber apical view; 4ch IVS, interventricular septum sampled from the 4ch; 4ch LVFW, left ventricular free wall sampled from the 4ch; rpla, right parasternal long-axis view; rpla IVS, interventricular septum sampled from the rpla; rpla LVFW, left ventricular free wall sampled from the rpla; Tr, tricuspid annulus sampled from the 4ch; E9acc, acceleration of the E9 wave; te9acc, acceleration time of the E9 wave; E9dec, deceleration of the E9 wave; te9dec, deceleration time of the E9 wave; E9dur, duration of the E9 wave; Se9acc, acceleration of the systolic wave; tse9acc, acceleration time of the systolic wave; Sl9, late systolic peak; bs9 Sl9, time from onset of the S9 wave to the Sl9; IVRt, isovolumic relaxation period; IVCt, isovolumic contraction period. * P,.05; ** P,.01; *** P,.001, difference in values obtained from the same myocardial segment (same projection) between the 2 groups.

6 70 Koffas et al Table 6. Mean values (standard deviation) of tissue Doppler myocardial indices from normal cats. sep MA lat MA 4ch IVS 4ch LVFW rpla IVS rpla LVFW Tr E9 (cm/s) 6.42 a,d (1.83) 8.39 a,d (2.58) 6.8 a (1.9) 9.28 a,b (2.14) 5.2 (1.69) 5.6 b (1.58) 9.78 d (2.27) E9dur (ms) 88 d (11) 84 d (16) 78 (14) 81 (13) 87 (28) 80 (20) 122 d (20) E9acc (cm/s 2 ) 179 a (58) 240 a,c (75) 206 a,b (78) 317 a c (82) 147 a,b (59) 186 a,b (63) 203 (63) te9acc (ms) 38 d (8) 36 c,d (6) 36 a,b (8) 31 a,c (6) 48 a,b (18) 34 a (9) 50 d (9) E9dec (cm/s 2 ) 128 a,c (41) 190 a (88) 169 c (68) 192 b (66) 147 (63) 135 b (47) 140 (44) te9dec (ms) 51 (7) 48 (12) 44 (11) 54 (19) 43 (11) 47 (16) 72 (18) A9 (cm/s) 6.57 d (2.4) 6.2 d (2.43) 6.16 (1.61) 5.37 (1.92) 5.34 (2.22) 5.58 (1.78) d (3.59) E9 :A a (0.25) 1.47 a (0.59) 1.15 a (0.38) 1.87 a,b (0.59) 1.15 (0.64) 1.07 b (0.37) 1.04 (0.37) Se9 (cm/s) 7 d (1.8) 7.1 d (2.34) 6.17 (1.5) 6.34 (1.85) 5.65 (1.26) 6.16 (1.26) d (6.08) Se9acc (cm/s 2 ) 290 c (110) 310 c (128) 225 c (78) 256 c (68) 207 (75) 216 (67) 303 (102) tse9acc (ms) 27 (5) 24 d (4) 29 (5) 27 b (9) 30 (8) 31 b (8) 35 (5) Sl9 (cm/s) 4.65 (1.26) 4.2 (1) 4.79 a,b (1.41) 3.8 a (1.02) 3.17 b (0.72) 3.98 (1.35) 6.64 (2.17) bs9 Sl9 (ms) 77 (13) 81 c (9) 87 a (12) 99 a,b,c (30) 89 (17) 92 b (25) 95 (10) IVRt (ms) 61 (13) 54 (11) 61 (15) 57 (10) 67 (25) 61 (16) 53 (19) IVCt (ms) 36 a (14) 49 a,d (17) 36 a (13) 46 a (19) 39 (24) 50 (15) 28 (6) sep MA, septal mitral annulus; lat MA, lateral mitral annulus; 4ch, 4-chamber apical view; 4ch IVS, interventricular septum sampled from the 4ch; 4ch LVFW, left ventricular free wall sampled from the 4ch; rpla, right parasternal long axis view; rpla IVS, interventricular septum sampled from the rpla; rpla LVFW, left ventricular free wall sampled from the rpla; Tr, tricuspid annulus sampled from the 4ch; E9, early diastolic peak; E9acc, acceleration of the E9 wave; te9acc, acceleration time of the E9 wave; E9dec, deceleration of the E9 wave; te9dec, deceleration time of the E9 wave; E9dur, duration of the E9 wave; A9, late diastolic peak; E9 : A, ratio of early to late diastolic wave; Se9, early systolic peak; Se9acc, acceleration of the systolic wave; tse9acc, acceleration time of the systolic wave; Sl9, late systolic peak; bs9 Sl9, time from onset of the S9 wave to the Sl9; IVRt, isovolumic relaxation period; IVCt, isovolumic contraction period. a P,.05 difference in values between sep MA and lat MA, between 4ch IVS and 4ch LVFW and between rpla IVS and rpla LVFW. b P,.05 difference between 4ch LVFW and rpla LVFW and between 4ch IVS and rpla IVS. c P,.05 difference between lat MA and 4ch LVFW and between sep MA and 4ch IVS. d P, 0.05 difference between sep MA or lat MA and tricuspid annulus (Tr). greater along the longitudinal axis (data not shown). With respect to the IVS, E9acc and Sl9 were greater along the longitudinal axis in normal cats. For some parameters, in normal cats, the measurements in the radial axis were significantly longer than in the longitudinal axis, and these included for the LVFW: tse9acc, and for the IVS: te9acc (Table 6). Differences along the Longitudinal Axis Significant differences were also noted when comparing measurements at different sites (LVFW versus lateral mitral annulus, and IVS versus septal mitral annulus) along the longitudinal axis. These differences, again, were predominantly found in normal cats. In HCM cats, the only differences were in the E9acc (IVS. sepma) and in the te9acc (IVS, sepma). For normal cats, the parameters that showed significant difference between separate sites were te9acc (LVFW, latma), E9acc (LVFW. latma), E9dec (IVS. sepma), Se9acc (sepma. IVS, and latma. LVFW) and bs9 Sl9 (latma, LVFW). Differences between IVS and LVFW Additionally, significant differences in parameter values were found when comparing the IVS and the LVFW in both the longitudinal and radial axes. Again, most differences were detected in the normal cats (Table 6). When the lateral mitral annulus and the LVFW were compared to the septal mitral annulus and the IVS, respectively, in the longitudinal axis in normal cats, significantly greater values were obtained from the former for E9, E9 :A9, E9acc, IVCt, E9dec (latma. sepma), and bs9 Sl9 (4ch-LVFW. 4ch-IVS). When comparing the LVFW with the IVS along the radial axis, significantly greater values were found from the former for E9acc in normal cats. The septal side in normal cats had a significantly greater value for Sl9 and te9acc (4ch- IVS. 4ch LVFW) in the longitudinal axis, and only te9acc was longer in the radial axis. HCM cats had a significantly greater E9 :A9 when comparing the LVFW with the IVS in the longitudinal axis, a finding that was shared with the normal cats. The only other differences in HCM cats were for the IVCt (4ch LVFW. 4ch IVS) and the bs9 Sl9 (sepma, latma). Differences between Mitral and Tricuspid Annular Sites Pulsed TDI values for the Tr were only obtained in small numbers of cats. However, statistically significant differences were also detected between the mitral and tricuspid annular sites for several of the measured parameters and indices. A very common finding was that Tr measurements were higher than those from latma and sepma. In addition, a roughly equal number of differences were found for both the normal and affected cats. Both groups of cats had significantly greater tricuspid E9, A9, and Se9 velocities compared with both the lateral and septal mitral annulus. Similarly, normal cats had greater tricuspid values compared with both mitral sites for te9acc and E9dur. The Tr E9acc in HCM cats was significantly greater only when compared with that from the sepma. The latma

7 Pulsed Tissue Doppler Imaging in Cats 71 Fig 3. Box plots and ROC figure from TDI indices from normal cats and cats with HCM. had greater values than the tricuspid valve annulus for IVCt in the normal cats and for bs9 Sl9 in HCM cats. Differences between the Two Groups Distinct differences were found between the normal and affected cats for a large number of TDI parameters and indices. In particular, there were obvious significant differences in indices of both diastolic and systolic function between the 2 groups (Figs 3, 4). HCM cats had significantly lower values for the following parameters (Tables 4, 5): E9 (all myocardial segments along the longitudinal axis); E9 :A9 (all myocardial segments along Fig 4. Myocardial velocities recorded from the interventricular septum (IVS) along the longitudinal axis of a normal cat (upper panel) and a cat with hypertrophic cardiomyopathy (HCM) (bottom panel). The normal cat exhibits a normal velocity diastolic pattern with the early diastolic velocity (E9) exceeding the late diastolic velocity (A9). The HCM cat presents an abnormal relaxation pattern with a very low early diastolic velocity and an increased late diastolic component. Se9, early systolic velocity; Sl9, late systolic velocity. both axes); Se9 (latma); Sl9 (sepma, latma, and IVS along the longitudinal axis); E9acc and E9dec (all segments along the longitudinal axis and in the LVFW along the radial axis); and Se9acc (sepma, latma, and LVFW along the longitudinal axis). A cutoff value of E9 in the LVFW along the longitudinal axis.7.2 cm/s could discriminate normal from affected cats with a sensitivity of 92% and a specificity of 87% (Fig 3b). Timing for many of these diastolic and systolic parameters were prolonged in the HCM cats compared with the normal cats and included te9acc (both annular sites and LVFW along both axes); te9dec (latma and LVFW along the radial axis); tse9acc (all segments along the longitudinal axis except for the sepma); E9dur (latma and LVFW along both axes); and bs9 Sl9 (latma and IVS along the radial axis). Lastly, IVRt (all segments along the longitudinal axis) was prolonged in the HCM cats. For the tricuspid valve annulus in HCM cats, the E9 was reduced whereas the A9 was increased significantly compared with that in normal cats. Influence of Heart Failure on TDI Indices Se9 of the lateral mitral annulus was not statistically different between the 2 groups when only asymptomatic HCM and normal cats were compared. A9 of the IVS along both axes of the heart was significantly higher in asymptomatic than in normal cats (P,.05). Differences in Systolic TDI Indices between Asymptomatic Cats without Left Ventricular Outflow Tract Obstruction and Normal Cats Asymptomatic HCM cats with systolic LV outflow pressure gradient,4 mm Hg had lower values for the following parameters: Sl9 (sepma, latma, and IVS along the longitudinal axis) and Se9acc (sepma, latma,

8 72 Koffas et al Table 7. Relationship among peak TDI velocities and independent predictors in normal cats and cats with hypertrophic cardiomyopathy (HCM). Linear and Multiple Linear Regression Equations R R 2 P Normal sep MA E9 :A9 E9 :A ( age) ,.01 lat MA E9 :A9 E9 :A ( LVFWd) 2 ( age) ,.001 ( weight) + ( R-R) 4ch IVS E9 :A9 E9 :A ( age) ,.001 4ch LVFW E9 :A9 E9 :A ( age) ,.01 E9 E ( age) ,.001 HCM sepma A9 A ( IVSd) + ( sex) ,.05 lat MA E9 E ( LVFWd) ,.01 A9 A ( LVFWd) + ( weight) ,.01 4ch LVFW E9 E ( weight) 2 ( R-R) ,.05 A9 A ( R-R) ,.05 Sl9 Sl ( R-R) ,.05 rpla IVS A9 A ( IVSd) ,.01 Se9 Se ( R-R) ,.01 sep MA, septal mitral annulus; lat MA, lateral mitral annulus; 4ch, 4-chamber apical view; 4ch IVS, interventricular septum sampled from the 4ch; 4ch LVFW, left ventricular free wall sampled from the 4ch; rpla, right parasternal long axis view; rpla IVS, interventricular septum sampled from the rpla; E9, early diastolic peak; A9, late diastolic peak; E9 : A, ratio of early to late diastolic wave; Se9, early systolic peak; Sl9, late systolic peak. and LVFW along the longitudinal axis) when compared with normal cats. Influence of Independent Predictors on TDI Indices The E9 :A9 ratio in all myocardial segments along the longitudinal axis was negatively influenced by age in normal cats (Table 7). LVFW diastolic thickness was negatively associated with the E9 :A9 ratio in the lateral mitral annulus in normal cats. Weight and R-R interval were a significant positive predictor for the E9 :A9 ratio of the lateral mitral annulus in normal cats. E9 of the LVFW along the longitudinal axis was inversely associated with age in normal cats (R , P,.001). A negative association was found between LVFW diastolic thickness and E9 in the lateral mitral annulus of HCM cats (R , P,.01). Weight was a significant positive predictor for E9 in the LVFW along the longitudinal axis and also for A9 in the lateral mitral annulus in affected cats. The R-R interval was a negative predictor for E9 in the LVFW along the longitudinal axis in the affected group. An inverse association was found between LVFW diastolic thickness and A9 in the lateral mitral annulus and between IVS diastolic thickness and A9 of the IVS along the radial axis in HCM cats. A positive association was found between sex and the A9 wave in the septal mitral annulus of affected cats. However, no statistical significant difference was found between male and female cats for this TDI index. Se9 showed an inverse association with the R-R interval in the IVS along the radial axis in HCM cats (R , P,.01). There was a similar relationship between the A9 and the Sl9 in the LVPW along the longitudinal axis and R-R in the affected group (R , P,.05 and R 2 5.4, P,.05, respectively). Repeatability Study Results of the repeatability study are shown in Table 8. The early diastolic myocardial velocities showed a CV%, which was usually,20% and quite often,10%. Less frequently, the CV% for E9 was between 20 30% or.30%. The LVFW along the radial axis and the IVS along the longitudinal axis had the narrower limits of agreement for E9. The CV% for A9 was generally,20% and, more frequently,,10% than it was for the early diastolic velocity. The variability of the E9 :A9 ratio followed the trends described for the early and late diastolic myocardial velocities. The lower variability and narrower limits of agreement for the E9 :A9 ratio were found in the LVFW along both axes. Early systolic myocardial velocities were the most reproducible among the pulsed TDI indices. The CV% for the Se9 was,10% in the septal mitral annulus and the LVFW along the radial axis in all animals. The Sl9 velocities were less reproducible than Se9 in the corresponding myocardial segments. Acceleration and deceleration of E9 and acceleration of Se9 were, in general, less reproducible than peak myocardial velocities. Although on many occasions, E9acc, E9dec, and Se9acc showed a CV% of,10%, quite often, they had a CV%.30%. The acceleration of E9 and Se9 waves showed a lower CV% than the deceleration of E9 in most instances. Discussion In this study, we have demonstrated that diastolic dysfunction in HCM of cats is expressed as decreased early diastolic velocities, acceleration, and deceleration and also as loss of the physiologic nonuniformity of myocardial motion. Systolic dysfunction was evident in

9 Pulsed Tissue Doppler Imaging in Cats 73 Table 8. Results of intraobserver variability of pulsed tissue Doppler imaging (TDI) indices. sep MA lat MA 4ch IVS 4ch LVFW a rpla IVS rpla LVFW Tr E9 (cm/s) (2.1) (1.97) (1.34) (1.22) (1.62) (0.38) (1.62) (2.34 to 26.06) (3.53 to 24.36) (2.04 to 23.34) (1.34 to 23.55) (2.68 to 23.78) (0.19 to 21.32) (2.68 to 23.78) 16, 31, 18, 40 12, 7, 12, 20 32, 6, 13, 4 18, 12, 16, 9 25, 5, 15, 24 13, 1, 12, 11 25, 5, 15, 24 E9acc (cm/s 2 ) 274 (83) 285 (94) 228 (34) 8 (7) 244 (88) () 244 (88) (93 to 2243) (103 to 2273) (40 to 296) (21 to 25) (132 to 2220) () (132 to 2220) 52, 5, 35 22, 8, 24, 42 26, 1, 13 3, 0, 9 6, 0, , 0, 53 E9dec (cm/s 2 ) 246 (21) 16 (48) 260 (49) 250 (56) 256 (75) () 256 (75) (24 to288) (111 to 280) (38 to 21.58) (62 to 2161) (94 to 2205) () (94 to 2205) 17, 26, 32 4, 2, 39, 6 50, 4, 34 41, 26, 14 10, 6, , 6, 51 A9 (cm/s) (0.6) (2.95) 0.25 (0.88) (0.55) (0.61) (1.1) (0.61) (0.08 to 22.33) (5.65 to 26.14) (2.01 to 21.52) (0.49 to 21.71) (0.73 to 21.7) (1.52 to 22.89) (0.73 to 21.7) 17, 20, 7, 15 29, 35, 21, 47 2, 12, 7, 17 4, 19, 12, 1 1, 9, 26, 2 22, 6, 5 1, 9, 26, 2 E9 :A (0.4) 0.13 (0.65) (0.43) (0.19) 0.04 (0.8) (0.16) 0.04 (0.8) (0.63 to 20.98) (1.42 to 21.17) (0.78 to 20.93) (0.36 to 20.4) (1.64 to 21.56) (0.29 to 20.36) (1.64 to 21.56) 33, 11, 11, 26 17, 29, 9, 29 34, 6, 20, 21 14, 7, 4, 10 25, 15, 40, 26 9, 5, 15 25, 15, 40, 26 Se9 (cm/s) (0.7) 0.7 (1.01) 0.35 (1.76) (1.9) 0.5 (1.68) (0.45) 0.5 (1.68) (1.19 to 21.61) (2.71 to 21.31) (3.88 to 23.18) (3.16 to 24.45) (3.87 to 22.87) (0.86 to 20.94) (3.87 to 22.87) 6, 7, 7, 10 21, 17, 6, 6 22, 23, 13, 9 7, 27,17, 26 27, 21, 24, 1 8, 4, 1, 3 27, 21, 24, 1 Se9acc (cm/s 2 ) 3 (38) 15 (80) 8 (103) 224 (55) 4 (66) 17 (14) 4 (66) (80 to 274) (175 to 2144) (215 to 2199) (86 to 2134) (136 to 2127) (44 to 211) (136 to 2127) 8, 3, 4, 14 18, 2, 39, 21 12, 41, 3, 32 24, 2, 8 25, 2, 26 6, 12, 2 25, 2, 26 Sl9 (cm/s) (0.35) (1.11) 0.84 (0.82) (0.42) 0.24 (1.11) 21 (1.24) 0.24 (1.11) (20.27 to 21.69) (1.44 to 22.99) (2.48 to 20.79) (0.23 to 21.43) (2.47 to 21.98) (1.48 to 23.47) (2.47 to 21.98) 9, 22, 20 27, 7, 1, 30 41, 4, 14, 6, 15, 24, 6 17, 4, 37 2, 40, 18 17, 4, 37 sep MA, septal mitral annulus; lat MA, lateral mitral annulus; 4ch, 4-chamber apical view; 4ch IVS, interventricular septum sampled from the 4ch; 4ch LVFW, left ventricular free wall sampled from the 4ch; rpla, right parasternal long axis view; rpla IVS, interventricular septum sampled from the rpla; rpla LVFW, left ventricular free wall sampled from the rpla; Tr, tricuspid annulus sampled from the 4ch; E9, early diastolic peak; E9acc, acceleration of the E9 wave; E9dec, deceleration of the E9 wave; A9, late diastolic peak; E9 : A, ratio of early to late diastolic wave; Se9, early systolic peak; Se9acc, acceleration of the systolic wave; Sl9, late systolic peak. a Mean of the difference; Standard deviation of the difference; Limits of agreement; and Coefficient of variation (CV%) for 2 sets of measurements obtained from each individual cat. a number of TDI indices suggesting that systolic impairment may be an inherent component in HCM of this species. TDI has evolved as a very useful and sensitive tool in the noninvasive assessment of regional and global myocardial function. The use of TDI has allowed the simultaneous quantification of myocardial motion during all phases of the cardiac cycle, and more specifically, assessment of motion of the differently oriented fiber types. This is feasible by using different echocardiographic projections such as, right parasternal short- and long-axis views for quantifying motion of the radially oriented fibers, and apical views for assessing the longitudinally arranged fibers. Moreover, TDI indices, such as peak early diastolic and systolic myocardial velocities, correlate strongly with invasive hemodynamic variables, such as the time constant of pressure decay in isovolumetric relaxation (t) and the peak positive and negative rate of pressure development (dp : dt), suggesting that they could be used as alternative tools in the noninvasive assessment of global diastolic and systolic function. 8,22,23 Peak early diastolic myocardial velocity has been proven to be preload-independent and, therefore, capable of unmasking pseudonormal mitral inflow patterns in patients with high left atrial pressures. 24 Additionally, the ratio of early mitral inflow to early mitral annular diastolic velocity (E : E9) has predicted with relatively high accuracy LV filling pressures in various cardiac settings. 22,25 In a recent study, Schober et al 26 revealed that in anesthetized normal cats, most peak mitral annular systolic and diastolic TDI indices were increased with increased preload induced by saline infusion. These results reconfirm the observations of studies in normal humans and experimental animals and show that the preload independence of some TDI indices and their sensitivity in predicting LV pressures are enhanced in the diseased state. 27 TDI studies have detected age-related changes in the diastolic and systolic performance of the normal human myocardium. 28 In our group of normal cats, changes associated with aging were found mainly in diastolic TDI indices and were reflected as a significant decrease in early diastolic velocities and E9 :A9 ratio along both axes with increasing age. Changes in the active state of myocardial fibers and in viscoelasticity are induced because of aging, and it has been shown to affect the diastolic properties of the myocardium. 29 A major finding of TDI has been the demonstration of a physiologic nonuniformity in the myocardial motion of normal humans and experimental animals. This has been described during both phases of the cardiac cycle, and it is believed to be, along with load and activation-inactivation mechanisms, one of the main

10 74 Koffas et al determinants of optimal myocardial performance under normal circumstances. 30 Investigation of myocardial motion with TDI along both axes has shown that, with the exception of the E9 wave of the LVFW along the radial axis, myocardial motion along the longitudinal axis in normal humans is more prominent than it is along the radial axis during all phases of the cardiac cycle. 31 In our group of normal cats, myocardial motion along the longitudinal axis during early diastole (E9) was more marked than along the radial axis. This was reflected in the higher velocities and accelerations recorded during early diastole in almost all myocardial segments along the longitudinal axis. During systole, myocardial motion was more uniform among the different myocardial segments along both axes. This study demonstrates that differences in myocardial motion between the IVS and LVFW of the normal myocardium of cats are mainly along the longitudinal axis in which the LVFW exhibited higher early diastolic velocities, acceleration, and E9 : A9 when compared with that of the IVS. Our findings indicate higher compliance of the LVFW in the normal cat myocardium and are in agreement with previous observations in normal humans. 32 With respect to diastolic dysfunction in cats with HCM, diastolic impairment was evident in a number of TDI indices including decreased early diastolic velocities and early diastolic acceleration and deceleration. Diastole lasted longer at both annular sites and in the LVFW along both axes in HCM cats compared with that in normal cats. Peak early diastolic velocity in most myocardial segments tended to occur later (te9acc) in the HCM group compared with that in normal cats. Decreased early diastolic deceleration was also recorded in the lateral mitral annulus and the LVFW along the radial axis. The prolonged IVRt recorded in many myocardial segments in the affected group was further evidence of diastolic impairment in feline HCM. Numerous TDI studies have shown that humans with HCM exhibit decreased early myocardial velocities and prolonged early diastolic deceleration and isovolumic relaxation times. 31 Cats with HCM have previously been reported to have decreased diastolic velocities, acceleration, and deceleration and also prolonged IVRt. 9 These findings are in general agreement with the results reported in the current study. However, the previous study 9 had technical limitations in that they could not identify the late diastolic A9 wave but mostly the E9 or combined EA9 waves. In this analysis, we did not include summated E9 and A9 waves. Although it has been shown that the ratio of the combined mitral inflow EA to the combined myocardial EA9 can be used to predict, with relatively high accuracy, pulmonary capillary wedge pressure (PCWP), 25 we believe that diastolic velocities (early, late, or summated early and late diastolic velocities) cannot be used interchangeably in assessing diastolic myocardial properties in cats and that a combined interpretation of their characteristics is required to do so. This is supported by the fact that early and late diastolic velocities have different physiologic and hemodynamic determinants, and hence, to a certain extent, they reflect different physiological processes. Affected asymptomatic animals can exhibit very low early diastolic velocities, suggesting impaired active relaxation properties and decreased elastic recoil or, on the other hand, prominent late diastolic velocities reflecting preserved or enhanced LA contractility. Under these circumstances, in the presence of relatively high heart rates, asymptomatic animals can present with high amplitude EA9 waves because of the increased contribution of LA contraction (A9 wave) in the genesis of the summated velocity wave, despite impaired ventricular early diastolic properties. Decreased summated EA9 waves are most likely to occur in animals with CHF, in which both early and late diastolic myocardial velocity components are decreased. Interestingly, affected cats tended to have summated EA9 waves at lower heart rates than in the normal cats, suggesting that summation may be an indicator of diastolic impairment. The comparison of a relatively large number of EA9 waves obtained from the same myocardial segment, between normal and HCM cats would help to clarify the utility of summated EA9 waves in the assessment of diastolic myocardial properties of cats. Marked temporal and spatial nonuniformity is another common finding in human HCM and is believed to be a significant determinant of diastolic impairment in this condition. 13 In this study, the physiologic heterogeneity and asynchrony seen in the myocardial motion of normal cats was lost rather than increased in HCM cats. This was evident in the loss of differences in peak early diastolic velocities between the LVFW and septal side of the heart, mainly along the longitudinal axis and also between the 2 axes in the LVFW. Differences in the early diastolic acceleration and deceleration between the 2 groups followed a similar pattern. We suggest that the loss of physiologic heterogeneity in the disease state is an extra contributing factor in the deterioration of diastolic function of the myocardium with potential negative hemodynamic effects. A9 wave was significantly higher along both axes of the heart in the IVS and the Tr in asymptomatic animals compared with that in normal cats. This finding reflects increased atrial response to the high LA pressures and it is indicative of preserved atrial contractility in the early stages of the disease. 27 With respect to the tricuspid valve annulus, the decreased early diastolic velocities recorded in the tricuspid annulus of affected cats indicates right ventricular involvement in the myopathic process. 33 A number of findings in this study provided evidence for systolic dysfunction in cats with HCM. For example, this was reflected in the decreased late systolic velocities recorded along the longitudinal axis, the reduced peak systolic acceleration of both annular sites, and of the LVFW along the longitudinal axis in the HCM group compared with that in normal cats (Fig 3d). Peak late systolic velocity occurred later (bs9 Sl9) in both the lateral mitral annulus and the IVS along the radial axis in affected than in normal cats. None of the differences in the above systolic TDI indices between the 2 groups were attributable to CHF or to LV outflow tract

11 Pulsed Tissue Doppler Imaging in Cats 75 obstruction. Although peak early systolic velocity of the lateral mitral annulus appeared to be lower in HCM than in normal cats, this difference was lost when only asymptomatic animals were considered in the analysis. All cats in CHF had very low systolic mitral annular velocities (3 of them,3 cm/s and 1,5 cm/s). Low early systolic velocities were recorded in almost all myocardial segments in animals with CHF. These findings suggest that deterioration of systolic dysfunction in cats with HCM may play an important role in the development of CHF. However, a larger number of cats with end-stage disease would be required to confirm this hypothesis. In the present study, decreased contractility was detected in a number of systolic TDI indices in cats with HCM, despite having similar FS% to that recorded in normal cats. These observations are in partial agreement with previous findings in humans and experimental animals with HCM and shows that traditional methods of assessment of global systolic function are less sensitive in accurately reflecting LV systolic properties. However, the reduction in systolic TDI indices documented in the current group of HCM cats was not of the magnitude reported in some TDI studies in humans with HCM. Quantification of myocardial motion was easier in the septal side of the heart along the longitudinal axis and in the LVFW along the radial axis. This was reflected in the higher number of quantifiable tracings acquired from these regions. Quantification of motion of the IVS at chordae tendineae level along the radial axis often provided erratic velocity signals. Two-dimensional color TDI studies have revealed that, even in the normal human myocardium, the IVS during systole exhibits a paradoxical movement with its upper-basal part moving anteriorly whereas the lower-apical part moves posteriorly. 34 Although qualitative assessment of motion of the IVS with 2-dimensional TDI was not performed in this study, we believe that a similar pattern of motion in the IVS of cats is a possible cause of the erratic velocity signals obtained from this region along the radial axis. The motion of the IVS is influenced by ventricular interdependence and right ventricular filling. 35 That motion is also influenced more from overall heart motion than other parts of the myocardium, especially along the radial axis of the heart. 31 These factors make it more difficult to quantify its motion with routine echocardiographic methods. Quantification of the LVFW along the longitudinal axis was quite often unsuccessful and provided an unidentifiable sequence of velocity signals, especially in affected cats. In 6 affected animals, the LVFW along the longitudinal axis exhibited very prominent positive velocities during the second phase of the IVR period, which were substantially higher (. twice) than the preceding systolic velocities (Fig 5). A similar velocity pattern, called postsystolic thickening (PST), has been documented in several clinical conditions, such as myocardial ischemia and stunning, left bundle branch block and syndrome X in human patients and various explanations have been given so far for its genesis Postsystolic thickening has also been reported in experimental cats, during both Fig 5. Postsystolic thickening (PST) recorded in the LVFW along the longitudinal axis from a HCM cat. The y-axis is velocity in cm/s and the x-axis is time in seconds, with the simultaneous ECG. Note that the systolic velocity (Se9) is substantially lower from that recorded just before the onset of early diastole. E9 and A9 are peak early and late diastolic velocities. ischemia following coronary artery ligation, and reperfusion. 40 Whether myocardial infarction is related to the reduced systolic velocities and the augmented PST recorded in the LVFW along the longitudinal axis in some cats with HCM remains uncertain. Combining TDI and histopathologic data would help to elucidate the mechanisms of this phenomenon in HCM cats. However, irrespective of the underlying causative mechanism, the presence of PST is indicative of impaired systolic function. The fact that erratic, unidentifiable velocity signals and PST were recorded in the LVFW of cats only along the longitudinal axis and not along the radial axis suggests the more profound impairment of longitudinally arranged fibers in this myocardial wall of cats with HCM. Assessing reproducibility in acquiring and analyzing echocardiographic data and also knowing the level of natural or random variability occurring in these measurements is crucial for assessing whether changes in sequentially acquired data are genuinely the result of disease progress or are in response to treatment. 41,42 TDI velocities have shown adequate reproducibility in both cats and dogs. 10,43 Interpretation of the results from this study reveal that the LVFW along the radial axis and the IVS along the longitudinal axis had the narrower limits of agreement for E9, presumably because it was easy to quantify them, and they provided consistently quantifiable tracings. The variability for A9 was larger in the lateral mitral annulus, a finding that probably reflects the general difficulty in acquiring late diastolic myocardial signals from this particular myocardial segment. In general, pulsed TDI indices from all myocardial segments from the normal animals used in the repeatability study had real values, which overlapped with the corresponding values from the affected group. This indicates that interpretation of pulsed TDI indices from individual animals should be done cautiously. When the reproducibility in acquiring serial echocardiographic measurements in cats is examined, the existence of natural variability, due to respiratory and especially to heart rate variability, needs to be