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J Vet Intern Med 2006;20:627–634

Tissue Doppler Imaging and Gradient Echo Cardiac Magnetic Resonance Imaging in Normal Cats and Cats with Hypertrophic Cardiomyopathy Kristin A. MacDonald, Mark D. Kittleson, Tanya Garcia-Nolen, Richard F. Larson, and Erik R. Wisner Cats with hypertrophic cardiomyopathy (HCM) often develop diastolic dysfunction, which can lead to development of left congestive heart failure. Tissue Doppler imaging (TDI) echocardiography has emerged as a useful, noninvasive method for assessing diastolic function in cats. Cardiac magnetic resonance imaging (cMRI) has been performed in cats and accurately quantifies left ventricular (LV) mass in normal cats. However, assessment of cardiac function in cats by cMRI has not been performed. Six normal Domestic Shorthair cats and 7 Maine Coon cats with moderate to severe HCM were sedated, and TDI of the lateral mitral annulus was performed. Peak early diastolic velocity (Em) was measured from 5 nonconsecutive beats. Cats were anesthetized with propofol and electrocardiogram-gated gradient echo cMRI was performed during apnea after hyperventilation. Short-axis images of the LV extending from the mitral annulus to the apex were obtained throughout the cardiac cycle. LV mass at end systole and LV volumes throughout the cardiac cycle were quantified according to Simpson’s rule. To assess the possible influence of propofol on diastolic function, TDI was performed on the 7 cats with HCM while sedated and then while anesthetized with propofol. Em was significantly lower in cats with HCM than normal cats (6.7 6 1.3 cm/s versus 11.6 6 1.9 cm/s, P , .001, respectively). There was no difference in the cMRI indices of diastolic function in normal and HCM cats. Propofol did not reduce diastolic function (Em) in cats with HCM but mildly reduced systolic myocardial velocity (S) in Maine Coon cats with HCM that were anesthetized with propofol (P 5 .87 and P 5 .03, respectively). Key words: Diastolic function; Domestic felid.

ypertrophic cardiomyopathy (HCM) is the most common cardiac disease in domestic cats and is characterized by concentric left ventricular (LV) hypertrophy, myocardial fibrosis, and diastolic dysfunction.1–4 LV hypertrophy and fibrosis cause increased myocardial stiffness and increased end diastolic filling pressure. Early diastolic relaxation also is impaired.5 In humans with HCM, the amount of type III collagen significantly correlates with hemodynamic indexes of impaired ventricular relaxation and late diastolic filling, illustrating that myocardial fibrosis is a major determinant of diastolic dysfunction.6 Diastolic dysfunction leads to left atrial enlargement and subsequent congestive heart failure and systemic thromboembolism in some cats. Tissue Doppler imaging (TDI) echocardiography is a technique that is used to quantify myocardial wall motion. It has emerged as one of the most sensitive and specific methods for noninvasive assessment of diastolic function and is relatively unaffected by loading conditions.7 TDI echocardiography enables quantification of myocardial motion during the different phases of the cardiac cycle. Diastolic function is most commonly assessed by measuring the early diastolic velocity of the

H

From the Department of Veterinary Medicine and Epidemiology (MacDonald, Kittleson), School of Veterinary Medicine, Department of Surgical and Radiological Sciences (Garcia-Nolen, Wisner), and Veterinary Medical Teaching Hospital (Larson), University of California, Davis, Davis, CA. Reprint requests: Kristin A MacDonald, DVM, PhD, 2108 Tupper Hall, Department of Medicine and Epidemiology, 1 Shields Avenue, Davis, CA 95616; e-mail: [email protected]. Submitted January 4, 2005; Revised June 21, September 9, 2005 and September 19, 2005; Accepted November 4, 2005. Copyright E 2006 by the American College of Veterinary Internal Medicine 0891-6640/06/2003-0024/$3.00/0

mitral annulus (Em). TDI has been performed on normal cats and cats with HCM.8–10 Em is decreased in cats with HCM (7.9 6 1.7 cm/s) compared with normal cats (12.1 6 2.3 cm/s).8–10 Em velocity also is decreased in people with HCM and is negatively correlated with the time constant of pressure decay during the isovolumic relaxation period (tau).11 TDI indices also are reduced in people with ‘‘preclinical’’ HCM who have a sarcomeric mutation that causes HCM even before development of LV hypertrophy.12,13 Em in people with no phenotypic evidence of HCM is further reduced when they develop LV hypertrophy and is highly negatively correlated with the amount of increase in LV mass.13,14 Reduced Em velocity occurs in other cardiac diseases in which myocardial fibrosis is present and is negatively correlated with the percentage of interstitial fibrosis in people with coronary artery disease and left ventricular dysfunction.15–17 Cardiac magnetic resonance imaging (cMRI) is an accurate noninvasive tool for quantifying LV mass and assessing left and right ventricular function in normal people and people with a wide range of cardiac diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, hypertensive cardiac disease, and aortic stenosis.18–22 cMRI is more accurate for quantifying LV mass in normal people and people with HCM than is echocardiography.23,24 Cine cMRI is more sensitive than traditional Doppler echocardiography in detecting diastolic dysfunction in patients with LV hypertrophy who have normal mitral inflow Doppler indices of diastolic function.18 cMRI also is useful in clinical and research settings to serially measure diastolic function before and during pharmacologic treatment.25,26 cMRI has been used to identify normalization of diastolic function in cardiomyopathic rats with diabetes as well as in humans with LV hypertrophy secondary to systemic hypertension after treatment with an angiotensin-converting enzyme inhibitor.25,26

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Fig 1. Tissue Doppler imaging (TDI) of a normal cat and a cat with severe hypertrophic cardiomyopathy. A left-sided 4-chamber apical view is used for TDI echocardiography of the lateral mitral annulus (A). The white bars represent the position of the pulsed wave Doppler gate. TDI myocardial velocity of the lateral mitral annulus in a cat with severe hypertrophic cardiomyopathy (B) and a normal cat (C), depicted with different velocity scales. The normal cat had a higher heart rate (HR; 220 beats per minute [bpm] in the normal cat versus HR 115 bpm in the cat with HCM) and fusion of the early (E) and late (A) diastolic waves to form an EA wave. Fusion of the E and A diastolic waves does not affect the peak velocity in normal cats.5,6 Peak diastolic velocity and systolic velocity were greatly reduced in the cat with HCM, and there was E : A reversal, indicating diastolic dysfunction. S, systolic myocardial velocity.

Assessment of diastolic function by cMRI has not been performed in the domestic cat. The hypothesis of this study was that cMRI would be as abnormal in diastole as TDI echocardiography in cats with moderate to severe HCM and would be different when compared with normal cats. The primary aims of the study were to quantify diastolic function by TDI and cMRI and to assess overall cardiac function by cMRI in normal cats and cats with HCM. Because cats evaluated by TDI were sedated and cats evaluated by cMRI were anesthetized with propofol, it was necessary to determine whether cardiac function measured by TDI was different in sedated cats compared with the same cats anesthetized with propofol.

weighed the same as Maine Coon cats (DSH, mean weight 4.93 kg, range 4.1–6 kg; Maine Coon and Maine Coon cross cats, mean weight 4.98 kg, range 4.5–5.9 kg). Cats in both groups were of similar ages with mean age of 3.5 (DSH) and 4.2 years (Maine Coon and Maine Coon cross cats). Cats with HCM were included in the study if the LV free wall (LVFWd) or interventricular septal (IVSd) diastolic thickness was .6 mm, measured by 2-dimensional (2D) echocardiography in the right parasternal short-axis view of the LV.27 No cats with HCM had clinical evidence of congestive heart failure, and 2 of 7 had mild left atrial enlargement, as evidenced by a left atrial to aortic ratio of 1.5–1.7 measured by 2D echocardiography with the right parasternal short-axis view of the heart base. Systolic blood pressure (BP) was measured with a Parks Doppler blood pressure machine, and no cats with HCM had evidence of systemic hypertension (mean BP 130 6 17 mm Hg).

Materials and Methods

Tissue Doppler Imaging Technique

The study population consisted of 6 normal Domestic Shorthair (DSH) cats from 1 research colony and 7 Maine Coon and Maine Coon cross cats with moderate to severe HCM. Cats were cared for according to the principles outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and their use was approved by the Institute for Animal Care and Use Committee at the University of California at Davis. DSH cats

All cats undergoing echocardiography were sedated with 0.1 mg/kg acepromazine and 0.1 mg/kg hydromorphone administered SC. TDI echocardiography was performed 20 minutes after sedation. Heart rate was recorded by ECG. With the use of a 12mHz transducer,a TDI of the lateral mitral annulus was performed from the left apical 4-chamber view, with the gate placed perpendicular to the myocardial movement (Fig 1). Specific TDI

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Fig 2. Epicardial and endocardial tracings from a short-axis view of a normal cat heart at end diastole and end systole with the use of gradient echo cardiac magnetic resonance imaging (CMRI). Endocardial areas were traced on every image obtained in the cardiac cycle, at n P all levels of the left ventricle. Intraventricular volume ~ ½Aslice i Tslice i , where A is the endocardial area (cm2), T is the slice thickness (mm), and n is the slice number. Myocardial volume ~

i~1 n P

½Aslice i Tslice i , where A is the myocardial area (cm2), T is the slice thickness

i~1

(mm), and n is the slice number. LV mass was obtained by multiplying by the myocardial volume by the density of muscle (1.05 g/mL). settings included Nyquist limit 10–15 cm/s, sweep speed 100 cm/s, gate width 0.11 cm, and filter 50 Hz. Five nonconsecutive measurements of peak diastolic velocity (Em) were recorded and averaged. The chosen tracings had the highest velocities and minimal artifact. Peak diastolic velocity included measurements of either early diastolic mitral annular velocity or summated early and late diastolic mitral annular velocity. To assess the possible influence of propofol on diastolic function, TDI was performed on the 7 Maine Coon cats with moderate to severe HCM during sedation (same as previous TDI sedation protocol) and immediately after anesthesia with propofol according to the same protocol used for cMRI. Em, heart rate (HR), and systolic mitral annular velocity (S) were measured from 5 nonconsecutive beats. Because Em has been shown to be correlated with heart rate in other TDI studies, normal lateral mitral annular Em velocity was determined from 20 normal DSH cats, and 64 measurements of Em were recorded at different heart rates with an Acuson 128-XP machine.8 These measurements were obtained for another study on an earlier date by a different investigator.8 Because Em is positively correlated with heart rate, 95% prediction intervals were constructed to determine the upper and lower limits of normal Em, depending on the heart rate, with the following formulas, vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi u u  Þ2 ðX { X 1 SIND ~ SY :X u P 2 t1 z n z P ð Xi Þ Xi2 { n Prediction interval ~ Yc + tSIND ¯ is where Y is the predicted individual value of Em, X is heart rate, X the mean heart rate, n is the sample number, SIND is the square root of the variance of Y, and t is the t multiple determined for n – 2 degrees of freedom.

Cardiac Magnetic Resonance Technique b

cMRI was not performed on the same day as the TDI procedure. Cats were given acepromazine and hydromorphone (0.1 mg/kg SC each), and anesthesia was induced with up to 2 mg/

kg propofol administered IV in 1/4 dose increments alternating with midazolam administered 0.1 mg/kg IV twice. A light anesthetic plane was maintained with propofol at a continuous rate infusion of 0.15 mg kg21 min21. Cats were positioned in dorsal recumbency, intubated with a cuffed endotracheal tube, and maintained with positive pressure ventilation on 100% oxygen with a peak inspired pressure of 8–12 mm Hg at a respiratory rate of 8–15 breaths/min, a tidal volume of 15 ml/kg, and end tidal CO2 between 35 and 42 mm Hg. To maintain HR between 85 and 120 beats per minute (bpm), atropine was administered at 0.01 mg/kg IV as a bolus if heart rate was ,90 bpm. Intravenous fluids (0.9% saline) were administered at a rate of 3 ml kg21 h21. The ventral surface of the cat was shaved, and MRI-compatible ECG electrodesc were placed at the level of the heart and on the caudal ventral abdomen. Two 3-inch-diameter phased array surface coils were placed in parallel as close together as possible on either side of the thorax at the level of the heart. T1-weighted cMRI images were acquired during multiple phases of the cardiac cycle with the use of a gradient echo sequence with the following parameters: field of view (FOV) 5 12 cm2; echo time (TE) 5 5.2 ms; repetition time (TR) 5 12.1 ms; flip angle 5 30u; NEX 5 1; matrix 5 256 3 128 pixels. Cardiac gating was triggered from the R wave of the ECG. Initially, 3-plane localizer images were used to prescribe an imaging plane to obtain a 4-chamber long-axis image. The long-axis view was used to obtain 3-mm-thick contiguous short-axis images perpendicular to the long axis of the LV, extending from the annulus to the apex (Fig 2). Short-axis images of each LV slice were obtained during hyperventilation- induced apnea. For each LV slice, multiple images were acquired throughout the cardiac cycle. LV mass was obtained by Simpson’s rule (ie, method of discs). LV endocardial and epicardial areas were traced at each slice at end systole, and their difference was myocardial area (Fig 2). Total myocardial volume was calculated with the equation ROI Vmyocardium ~

n P

½Aslice i Tslice i 

i~1

ROI where Vmyocardium is the region of interest of estimated myocardial volume (cm3), Aslice i is myocardial area (cm2), Tslice i is the slice

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Fig 3. Cardiac magnetic resonance imaging assessment of cardiac function in a normal cat. Left ventricular intracardiac volume was quantified at all levels of the left ventricle throughout the cardiac cycle and plotted versus time in the cardiac cycle (Fig 2A). End systolic and end diastolic volumes were calculated. The 1st derivative of volume versus time was determined and was plotted as dV/dt (Fig 2B), which was used to obtain peak diastolic filling rate, mean diastolic filling rate, early diastolic filling rate (EFR), and late diastolic filling rate (AFR). thickness (mm), and n is the slice number. LV mass was the product of total myocardial volume and myocardial density (1.05 g/mL). LV mass was indexed (LVMI) to body weight (kg). LV volume was determined at multiple phases of the cardiac cycle depending on HR. Left ventricular volume versus time in cardiac cycle was plotted (Fig 3). The plot was interpolated between time points, oversampled by 4 times the original data points, and then smoothed with a Butterworth filter to create a volume versus time plot.d End systolic and end diastolic volumes (ESV and EDV, respectively) were defined by the smallest and largest volumes on the plot, respectively. Stroke volume (SV) was calculated by subtracting ESV from EDV, and cardiac output (CO) was calculated as the product of SV and HR. Cardiac index was calculated as CO/body surface area (m2). The 1st derivative of the left ventricular volume per time unit was calculated, which produced the graph dV/dt (Fig 3). From this plot, cMRI indices of diastolic function were obtained and included peak early filling rate within the 1st half of diastole (mL/s), peak late filling rate within the last half of diastole, peak filling rate, average filling rate, early filling percentage (volume increase from end systole to midpoint of diastole/SV 3 100), time to peak early filling, and early to late filling rate ratio.

Statistical Analysis Because of the small number of cats in each group, nonparametric tests were used. The exact Mann-Whitney test was used to compare TDI variables Em and HR and cMRI variables between normal DSH cats and Maine Coon cats with HCM.e A Wilcoxon signed rank test for paired data was used to compare HR, Em, and S in Maine Coon cats with HCM that were sedated versus anesthetized with propofol to determine whether TDI variables changed with anesthesia.f Spearman’s rank correlation was used to assess whether Em was correlated with HR, LV mass, and LVMI of all cats. A significant difference was defined as P , .05.

Results cMRI was successfully performed on all cats, with an average scanning time of 55 minutes. Cats with HCM had a higher LV mass and LVMI than normal DSH cats (P 5 .001 for LV mass and for LVMI; HCM cats:

median LV mass 14.82 g, range 13.5–21.8 g; median LVMI 3.2 g/kg, range 2.7–4.4 g/kg; DSH cats: median LV mass 7.7 g, range 6.7–11.1 g; median LVMI 1.6 g/ kg, range 1.6–1.9 g/kg; Table 1). The number of cMRI images acquired per cardiac cycle varied depending on heart rate and ranged from 17 to 27, with a mean of 22 phases. The number of LV slices per study varied depending on LV length and ranged from 9 to 15, with a mean of 11 slices. An average of 242 images was used to calculate cardiac function in each study. Global systolic cardiac function measurements by cMRI were not different when comparing cats with HCM and normal cats (ie, SV, ESV, ejection fraction; Table 1). Median EDVcMRI was larger in cats with HCM than in normal cats (5.0 ml versus 4.0 ml, respectively; P 5 .01; Table 1). Mean dV/dT values for 2 cats with HCM were censored because they were obvious outliers with extremely high values (15 mL/s2 and 13.6 mL/s2). Excluding the 2 outliers, mean dV/dT was not different between cats with HCM and normal cats (P 5 .18; Table 1). Maximum dV/dT, peak early filling rate, and time to peak early filling were not different between normal cats and cats with HCM. Because the atrial component of diastolic filling was not obtained from several of the gradient echo cMRI studies, late filling rate and E : A filling rate ratio were not analyzed. Heart rate during cMRI was not different between groups. EmTDI was lower in cats with HCM (median 6.7 cm/s; range 4.6–8.1 cm/s) than in normal DSH cats (11.6 cm/s; range 9.7–14.7 cm/s; P 5 .001; Table 1). EA summation occurred in 4 of 7 Maine Coon cats with HCM and in all 6 normal DSH cats. Heart rate during TDI was higher in normal cats than in cats with HCM (P 5 .05; normal cats: median 204 bpm, range 143– 260 bpm; HCM cats: 157 bpm, range 115–176 bpm). With 95% prediction intervals for HR-dependent Em from the historical normal cats, all normal DSH cats had normal Em and all Maine Coon cats with HCM had reduced Em (Fig 4).

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Table 1. Cardiac magnetic resonance imaging and tissue Doppler imaging measurements in normal cats (n 5 6) and cats with hypertrophic cardiomyopathy (n 5 7). Parameter LVMI (g/kg) LV mass (g) ESV (mL) EDV (mL) SV (mL) CI (mL/m2) Early filling rate (mL/s) Maximum filling rate (mL/s) Mean filling rate (mL/s) Early filling (%) Em (cm/s) E/Em HRTDI (bpm)

Normal Median (Range) 1.6 7.7 1.4 4.0 2.6 75.0 22.0 23.3 7.0 85.0 11.6 6.9 203.5

HCM Median (Range)

(1.6–1.9) (6.7–11.1) (1.1–2.1) (3.4–4.9) (2.3–3.3) (58–87) (19.6–30) (19.6–28.5) (5.4–8.7) (67.7–92.4) (9.7–14.7) (6–8.8) (143–260)

3.17 14.8 1.9 5.0 3.3 95.0 28.5 32.0 7.7 78.4 6.7 8.8 157

(2.7–4.4) (13.5–21.8) (1.3–2.9) (4.7–6.0) (2.5–4.1) (64–104) (15.9–33.9) (15.9–34.4) (6.7–8.8) (25.1–93.7) (4.6–8.1) (6.7–14.1) (112–176)

P value P 5 .001 P 5 .001 P 5 .01

P 5 .001 P 5 .05

LVMI, left ventricular mass index; ESV, end systolic volume; EDV, end diastolic volume; SV, stroke volume; CI, cardiac index; Em, peak diastolic mitral annular Tissue Doppler imaging (TDI) velocity; E/Em, ratio of early mitral inflow velocity to peak diastolic mitral annular TDI velocity; HR, heart rate; bpm, beats per minute.

Fig 4. Prediction intervals (95%) for peak diastolic mitral annular velocity depending on heart rate in 20 normal Domestic Shorthair cats and reduced Em velocity in 7 Maine Coon cats with moderate to severe hypertrophic cardiomyopathy (HCM). Peak diastolic velocity of the lateral mitral annulus (Em) was previously measured in 20 normal Domestic Shorthair cats several times at different heart rates (n 5 64 measurements, depicted as circles).5 The 95% prediction intervals were constructed for this study to determine the upper and lower limits of normal Em for a given heart rate (dark lines). The lower limit of the 95% prediction interval of Em for a given heart rate was used to identify HCM cats with decreased Em and diastolic dysfunction. Em was lower in all Maine Coon cats with moderate to severe HCM (depicted as triangles) when compared with 6 normal Domestic Shorthair cats in this study (P , .0001). With the use of the lower limit of the 95% prediction intervals, all 7 cats with HCM had reduced Em and all 6 normal Domestic Shorthair cats had normal Em. These cats subsequently underwent cardiac magnetic resonance imaging for quantification of diastolic function.

Propofol anesthesia did not change diastolic function in Maine Coon cats with HCM (median Emsedated 6.8 6 2.2 cm/s; median Emanesthetized 5.8 6 2.3 cm/s; P 5 .87) and mildly decreased systolic mitral annular velocity (median Ssedated 5.3 6 2.5 cm/s; median Sanesthetized 4.5 6 1.0 cm/s; P 5 .03; Table 2). HRTDI was the same in the sedated and anesthetized states (median HRsedated 186 6 32 bpm; HRanesthetized 151 6 12 bpm; P 5 .06). With the use of data from the normal DSH cats and the Maine Coon cats with HCM, peak diastolic mitral annular velocity (EmTDI) was negatively correlated with LVMIcMRI (R 5 .85, P 5 .003), LV masscMRI (R 5 .83, P 5 .004), and positively correlated with HRTDI (R 5 .65, P 5 .02).

Discussion This study confirmed that diastolic mitral annular velocity as measured by TDI echocardiography is decreased in Maine Coon cats with moderate to severe HCM when compared with normal DSH cats. TDI has been shown to be an excellent method for noninvasive assessment of diastolic function because it is less sensitive to preload than is traditional pulsed wave (PW) Doppler measurement of mitral inflow.7,28 In an experimental model of altered LV relaxation in dogs, early diastolic mitral annular velocity dependence on preload was more prominent in the normal physiologic state, but dependence was markedly diminished with

Table 2. Tissue Doppler imaging assessment of diastolic and systolic function in Maine Coon cats with moderate to severe hypertrophic cardiomyopathy under sedation (n 5 7) and under propofol anesthesia (n 5 7). TDI Measured Parameter

Sedation Median (Range)

S (cm/s) Em (cm/s) HR (bpm)

5.3 (3.5–10.6) 6.8 (3.6–9.7) 186 (130–211)

Propofol Anesthesia Median (Range) 4.5 (3.3–6.3) 5.8 (3.7–10.9) 151 (133–161)

P value P 5 .03 P 5 .87 P 5 .06

TDI, tissue Doppler imaging; S, systolic lateral mitral annulus velocity; Em, peak diastolic mitral annular velocity; HR, heart rate.

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diastolic dysfunction.29 Mitral annular motion is determined by the sum of the motion of the longitudinally oriented myocardial fibers and allows assessment of global LV relaxation.30 EmTDI is related to both LV relaxation and the elastic recoil of the LV and is highly correlated with tau (a load-independent measure of active relaxation).7 In an experimental model of altered LV relaxation in dogs, EmTDI dependence on preload was more prominent in the normal physiologic state, but dependence was markedly diminished with diastolic dysfunction.29 TDI has been used to diagnose diastolic dysfunction in humans and in animals with various types of cardiac diseases, including HCM, endomyocardial fibrosis, hypertensive heart disease, restrictive cardiomyopathy, ischemic heart disease, and dilated cardiomyopathy.11,31– 34 TDI also has been useful to detect diastolic dysfunction in cats with HCM and cardiomyopathy in a transgenic rabbit model of human HCM and in juvenile Golden Retrievers with preclinical muscular dystrophy.8,35,36 TDI measurement of Em accurately discriminates patients with HCM from athletes with physiologic hypertrophy and from patients with hypertensive heart disease with high sensitivity (87%) and specificity (97%).37 Diastolic dysfunction in HCM could occur from changes in intrinsic relaxation properties as a result of myofiber disarray and hypertrophy and is also caused by myocardial fibrosis.6 Impaired relaxation occurs in HCM, in which there is a shift in LV filling toward end diastole.5 Delayed relaxation can be caused by abnormal calcium handling in HCM. Abnormal calcium handling because of impaired sarcolemmal calcium channel regulation and impaired sarcoplasmic reticulum calcium uptake led to increased intracellular calcium concentrations and impaired active relaxation in a study of isolated ventricular muscle from people with HCM.38 Delayed or incomplete relaxation not only negatively affects early diastole, but the continuing interaction of contractile elements and persistent myocardial tension increases myocardial stiffness.39 Interstitial fibrosis, myocyte hypertrophy, and myocyte disarray all contribute to diastolic dysfunction, but myocyte disarray was found to be the most important factor related to diastolic dysfunction in people with HCM.40 Myofiber disarray is commonly seen in Maine Coon cats with severe HCM and is variably seen (30–62%) in other cats with HCM.1,2,41 In people with HCM, the greatest impairment of diastolic function (lowest Em) occurs in the regions with the greatest amount of hypertrophy, but other nonhypertrophied regions also have impaired diastolic function.11 Diastolic dysfunction also has been identified by TDI in humans and rabbits with a genetic sarcomeric mutation for HCM before phenotypic expression of LV hypertrophy.12,35 Pulsewave (PW) TDI is advantageous because specialized postprocessing software is not necessary for measurement of diastolic and systolic velocities, and peak velocities can be immediately measured at the time of examination. Limitations include inability to simultaneously assess velocities in more than 1 region of the

myocardium and inability to obtain endocardial-toepicardial velocity gradients. Given the translational movement of the heart within the chest from breathing and intrinsic cardiac forces, stable PW TDI tracings often are not possible, and amplitudes of myocardial velocities can vary. In addition, this study and other studies have demonstrated that Em TDI is positively correlated with heart rate in cats.5,9 This study indicates that gradient echo cMRI is not useful for identifying diastolic dysfunction in cats with moderate to severe HCM when compared with normal cats. cMRI might not be sensitive enough to identify diastolic dysfunction in Maine Coon cats with moderate to severe HCM in the absence of congestive heart failure. Only 2 studies have evaluated cine cMRI for assessment of diastolic function in humans with HCM.19,42 One study examined 24 patients and 10 normal volunteers and identified regional early diastolic dysfunction in people with HCM, with greater diastolic impairment in patients with greater LV mass.19 In contrast, in an earlier study of 7 patients with hypertrophic obstructive cardiomyopathy and 10 normal volunteers, early diastolic filling fraction by cMRI was not significantly reduced in patients compared with normal volunteers and there was marked individual variability.42 In addition to studies evaluating people with HCM, cine cMRI also has been used to identify diastolic dysfunction in people with LV hypertrophy secondary to systemic hypertension or valvular aortic stenosis.18,22,26 One disadvantage of the gradient echo sequence used for cMRI is that it employs prospective ECG gating, in which no images are acquired during the brief trigger delay at the R wave and a short trigger window preceding the R wave. Prospective gating might cause a void of early systolic and late diastolic images, which could affect functional analysis. Because only the terminal part of diastole would be affected, only the early to mid-diastolic indices were analyzed in this study. Velocity-encoded cine (VEC) cMRI is an attractive alternative to gradient echo cMRI for cardiac function studies.21,22 VEC employs retrospective ECG gating, and images are acquired throughout the entire cardiac cycle. The amount of time required for image analysis also is decreased because images are only acquired from 1 slice placed below the mitral annulus. One limitation of VEC in cats is the disruption of the ECG during image acquisition, which prevents successful cardiac gating in some studies. In one portion of this study, TDI was performed during sedation with acepromazine and hydromorphone, and then during propofol anesthesia in Maine Coon cats with moderate to severe HCM. The purpose was to identify whether propofol-induced diastolic dysfunction could partially explain why cMRI-derived diastolic indices were not different between normal cats and cats with HCM. Propofol did not reduce the TDI measure of diastolic function (Em) but mildly impaired the TDI measure of systolic function. Similarly, in humans, propofol was found to cause negative inotropic effects but had no effect on diastolic function.43

Tissue Doppler Imaging and Cardiac MRI

Limitations of cMRI include the need for general anesthesia, the cost and availability of the equipment, the steep learning curve to obtain and analyze the images, and the time necessary to manually trace endocardial borders if semiautomated analysis is not available. Currently, it appears that gradient echo cMRI is not useful for measuring diastolic function in cats. The easier, faster method of TDI appears to be a more accurate, less expensive, and safer for noninvasive assessment of diastolic function in cats. A limitation of this study is the small number of normal cats and cats with HCM evaluated. Intraobserver and interobserver errors were not assessed for either TDI or cMRI. Other studies have measured observer error in TDI, but results cannot be extrapolated to this study. In one study, within-day and between-day coefficients of variation were 6.5 and 13.6%, respectively, for measuring Em by color TDI in normal cats, which would not impair ability to identify diastolic dysfunction.6 TDI, but not gradient echo cMRI, was effective in detecting diastolic dysfunction in cats with moderate to severe HCM compared with normal cats. Propofol did not alter diastolic function but did impair systolic function in Maine Coon cats with moderate to severe HCM.

Footnotes a

Hewlett Packard Sonos 5500, Philips Medical Systems, 3000 Minuteman Road, Andover, MA 01810-1099 b General Electric Signa 1.5 Tesla MRI, 8.3 operating system software, GE Medical Systems, PO Box 414, Milwaukee, WI 53201 c Quatrode, In Vivo Research, Inc, 12601 Research Parkway, Orlando, FL 32826 d Matlab, The MathWorks Inc, 3 Apple Hill Drive, Natick, MA 01760-2098 e StatXact, version 6, Cytel Software Corporation, Cambridge, MA f Statview, SAS Institute, SAS Campus Drive, Cary, NC 27513

Acknowledgments Supported by grants from Winn Feline Foundation, University of California at Davis Center for Companion Animal Health, and Intervet Pharma R&D.

References 1. Kittleson MD, Meur KM, Munro MJ, et al. Familial hypertrophic cardiomyopathy in Maine Coon cats: An animal model of human disease. Circulation 1999;99:3172–3180. 2. Fox PR, Liu SK, Maron BJ. Echocardiographic assessment of spontaneously occurring feline hypertrophic cardiomyopathy. An animal model of human disease. Circulation 1995;92:2645– 2651. 3. Liu SK, Maron BJ, Tilley LP. Feline hypertrophic cardiomyopathy: Gross anatomic and quantitative histologic features. Am J Pathol 1981;102:388–395. 4. Bright JM, Herrtage ME. Pulsed Doppler assessment of left ventricular diastolic function in normal and cardiomyopathic cats.

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Proceedings of the Fifteenth Annual Veterinary Medical Forum, Denver, CO, American College of Veterinary Internal Medicine, 1997. 5. Golden AL, Bright JM. Use of relaxation half-time as an index of ventricular relaxation in clinically normal cats and cats with hypertrophic cardiomyopathy. Am J Vet Res 1990;51: 1352–1356. 6. Kitamura M, Shimizu M, Ino H, et al. Collagen remodeling and cardiac dysfunction in patients with hypertrophic cardiomyopathy: The significance of type III and VI collagens. Clin Cardiol 2001;24:325–329. 7. Sohn DW, Chai IH, Lee DJ, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30: 474–480. 8. Gavaghan BJ, Kittleson MD, Fisher KJ, et al. Quantification of left ventricular diastolic wall motion by Doppler tissue imaging in healthy cats and cats with cardiomyopathy. Am J Vet Res 1999;60:1478–1486. 9. Chetboul V, Athanassiadis N, Carlos C, et al. Quantification, repeatability, and reproducibility of feline radial and longitudinal left ventricular velocities by tissue Doppler imaging. Am J Vet Res 2004;65:566–572. 10. Koffas H, Dukes-McEwan J, et al. Peak mean myocardial velocities and velocity gradients measured by color M-mode tissue Doppler imaging in healthy cats. J Vet Intern Med 2003;17: 510–524. 11. Oki T, Mishiro Y, Yamada H, et al. Detection of left ventricular regional relaxation abnormalities and asynchrony in patients with hypertrophic cardiomyopathy with the use of tissue Doppler imaging. Am Heart J 2000;139:497–502. 12. Nagueh SF, Bachinski LL, Meyer D, et al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation 2001;104:128–130. 13. Ho CY, Sweitzer NK, McDonough B, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105: 2992–2997. 14. Nagueh SF, McFalls J, Meyer D, et al. Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation 2003;108:395–398. 15. Shan K, Bick RJ, Poindexter BJ, et al. Relation of tissue Doppler derived myocardial velocities to myocardial structure and beta-adrenergic receptor density in humans. J Am Coll Cardiol 2000;36:891–896. 16. Patel R, Nagueh SF, Tsybouleva N, et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 2001;104:317–324. 17. Slama M, Susic D, Varagic J, Frohlich ED. Diastolic dysfunction in hypertension. Curr Opin Cardiol 2002;17:368–373. 18. Kudelka AM, Turner DA, Liebson PR, et al. Comparison of cine magnetic resonance imaging and Doppler echocardiography for evaluation of left ventricular diastolic function. Am J Cardiol 1997;80:384–386. 19. Yamanari H, Morita H, Nakamura K, et al. Assessment of regional early diastolic function using cine magnetic resonance imaging in patients with hypertrophic cardiomyopathy. Jpn Circ J 1996;60:917–924. 20. Natale L, Meduri A, Caltavuturo C, et al. MRI assessment of ventricular function. Rays 2001;26:35–44. 21. Paelinck BP, Lamb HJ, Bax JJ, et al. Assessment of diastolic function by cardiovascular magnetic resonance. Am Heart J 2002;144:198–205.

634

MacDonald et al

22. Hartiala JJ, Foster E, Fujita N, et al. Evaluation of left atrial contribution to left ventricular filling in aortic stenosis by velocity-encoded cine MRI. Am Heart J 1994;127:593–600. 23. Devlin AM, Moore NR, Ostman-Smith I. A comparison of MRI and echocardiography in hypertrophic cardiomyopathy. Br J Radiol 1999;72:258–264. 24. Grothues F, Smith GC, Moon JC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29–34. 25. Al-Shafei AI, Wise RG, Gresham GA, et al. Magnetic resonance imaging analysis of cardiac cycle events in diabetic rats: The effect of angiotensin-converting enzyme inhibition. J Physiol 2002;538:555–572. 26. Hoffmann U, Globits S, Stefenelli T, et al. The effects of ACE inhibitor therapy on left ventricular myocardial mass and diastolic filling in previously untreated hypertensive patients: A cine MRI study. J Magn Reson Imaging 2001;14:16–22. 27. Kittleson MD, Kienle R. Small Animal Cardiovascular Medicine. St Louis: Mosby; 1998:357. 28. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533. 29. Firstenberg MS, Greenberg NL, Main ML, et al. Determinants of diastolic myocardial tissue Doppler velocities: Influences of relaxation and preload. J Appl Physiol 2001;90:299–307. 30. De Boeck BW, Cramer MJ, Oh JK, et al. Spectral pulsed tissue Doppler imaging in diastole: A tool to increase our insight in and assessment of diastolic relaxation of the left ventricle. Am Heart J 2003;146:411–419. 31. Rodriguez L, Garcia M, Ares M, et al. Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral Doppler inflow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 1996;131:982–987. 32. Garcia MJ, Rodriguez L, Ares M, et al. Differentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108–114. 33. Mishiro Y, Oki T, Yamada H, et al. Evaluation of left ventricular contraction abnormalities in patients with dilated

cardiomyopathy with the use of pulsed tissue Doppler imaging. J Am Soc Echocardiogr 1999;12:913–920. 34. Alam M, Wardell J, Andersson E, et al. Effects of first myocardial infarction on left ventricular systolic and diastolic function with the use of mitral annular velocity determined by pulsed wave Doppler tissue imaging. J Am Soc Echocardiogr 2000;13:343–352. 35. Nagueh SF, Kopelen HA, Lim DS, et al. Tissue Doppler imaging consistently detects myocardial contraction and relaxation abnormalities, irrespective of cardiac hypertrophy, in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 2000;102:1346–1350. 36. Chetboul V, Escriou C, Tessier D, et al. Tissue Doppler imaging detects early asymptomatic myocardial abnormalities in a dog model of Duchenne’s cardiomyopathy. Eur Heart J 2004;25:1934–1939. 37. Vinereanu D, Florescu N, Sculthorpe N, et al. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001;88:53–58. 38. Gwathmey JK, Warren SE, Briggs GM, et al. Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole. J Clin Invest 1991;87:1023–1031. 39. Grossman W, Barry WH. Diastolic pressure-volume relations in the diseased heart. Fed Proc 1980;39:148–155. 40. Ohsato K, Shimizu M, Sugihara N, et al. Histopathological factors related to diastolic function in myocardial hypertrophy. Jpn Circ J 1992;56:325–333. 41. Liu SK, Roberts WC, Maron BJ. Comparison of morphologic findings in spontaneously occurring hypertrophic cardiomyopathy in humans, cats and dogs. Am J Cardiol 1993;72:944– 951. 42. Schwammenthal E, Wichter T, Joachimsen K, et al. Detection of regional left ventricular asynchrony in obstructive hypertrophic cardiomyopathy by magnetic resonance imaging. Am Heart J 1994;127:600–606. 43. Gare M, Parail A, Milosavljevic D, et al. Conscious sedation with midazolam or propofol does not alter left ventricular diastolic performance in patients with preexisting diastolic dysfunction: A transmitral and tissue Doppler transthoracic echocardiography study. Anesth Analg 2001;93:865–871.