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1 Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1; and 2 Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Echocardiograms have been assessed only at 56 days in mice overexpressing calcineurin (CN mice). Age-dependent echocardiographic changes were evaluated because the development of sudden death is time dependent. Because cyclosporin A (CsA) reverses hypertrophy in CN mice, its effects on the time course of the development of sudden death and cardiac dysfunction were assessed. In wild-type (WT) mice, the left ventricular (LV) internal end-diastolic dimension (LVIDd) increased and the LV mass index (LVMI) decreased with age. In CN mice, two distinct phases of pathophysiology were found. After 14 days, in CN mice, the LVIDd and LVMI were significantly increased, but sudden death had not occurred. After 28 days, in CN mice, relative dilation of the left ventricle occurred, whereas the LVMI decreased. Sudden death developed during progressive dilation associated with systolic and diastolic dysfunction. CsA treatment reversed hypertrophy in CN mice but did not reverse systolic and diastolic dysfunction and exaggerated sudden death. Sudden cardiac death was associated with systolic and diastolic dysfunction but was not related to isolated cardiac hypertrophy in CN mice.
heart failure; sudden death; ultrasound; hemodynamics; hypertrophy; left ventricular
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MYOCARDIAL
REMODELING is a central feature in the progression of myocardial
failure. Alterations include hypertrophy and cellular apoptosis, changes in the molecular phenotype with reinduction of fetal cardiac genes, and alterations in the quantity and composition of the extracellular matrix (3). Several molecular
pathways have been identified as being instrumental in this progression (16) and have resulted in therapeutic agents such as
vasodilators, angiotensin-converting enzyme inhibitors, and
-adrenergic antagonists that counteract these alterations
(3). Other mechanisms have recently been identified that
have potential therapeutic implications. The calcium-dependent
phosphatase calcineurin causes cardiac hypertrophy (8, 13,
14) and sudden unexpected death in mice (6). However, recent results suggest that calcineurin may not be important in the decompensated phase of cardiac hypertrophy (7).
During the later phase, there may be an uncoupling of hypertrophy and survival. Cardiac hypertrophy (7) has been attenuated with a calcineurin inhibitor without beneficially affecting cardiac function.
Lim et al. (6) reported that calcineurin-overexpressing mice (CN mice) show increases in septal wall thickness (SWT; an index of hypertrophy), increases in end-diastolic dimension (an index of dilation), and decreases in fractional shortening (FS; an index of systolic dysfunction). However, assessment of cardiac function by echocardiography was conducted only at one age (56 days). Histopathological studies indicated that hypertrophy had developed by 14 days, but few mice had died by this time (6). In contrast, ~50% of CN mice had died by 11 wk. The issue addressed herein is to characterize the morphological and functional changes occurring in the period between 2 and 11 wk that contribute to the substrate for unexpected deaths in CN mice. Also, the possibility that diastolic dysfunction may contribute to the late mechanical dysfunction had not been addressed. Previous studies have indicated that long-term in vivo treatment of CN mice with cyclosporin A (CsA), a calcineurin inhibitor, caused resolution of the cardiac hypertrophy but did not reverse the increased left ventricular (LV) dilation or the extent of interstitial fibrosis in CN mice (6). An important related issue is whether CsA reverses the unexpected deaths in CN mice and whether CsA reverses myocardial systolic and diastolic dysfunction. Accordingly, this study assessed the relationship between the LV mass index (LVMI) and LV internal end-diastolic dimension (LVIDd) by echocardiography during the natural history of development of unexpected death in CN mice with and without CsA treatment.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Wild-type (WT) and CN mice (8) were studied. This investigation conforms with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1996). Southern blots were used to separate WT and CN mice (8). Because Molkentin et al. (8) have reported that all of the transgenic lines have the same cardiac phenotype, echocardiographic studies were performed on only one mouse line. Serial measurements were not performed.
Probability of Survival
WT (n = 47), CN (n = 38), CsA-treated WT (WT-CsA; n = 24), and CsA-treated CN (CN-CsA; n = 28) mice were followed for survival for up to 24 wk. CsA (12 mg · kg
1 · day1
sc) was administered starting on day 7 for the duration of
the survival study. Higher doses of CsA caused toxicity in day
7 mice.
Echocardiography
Echocardiograms in conscious mice. Echocardiograms were obtained to assess systolic function from conscious mice to avoid any cardiodepression induced by anesthesia (17, 21). Echocardiograms were completed on days 14 and 28 in the WT (n = 7) and CN (n = 6) mice. Adult mice were also randomly treated with CsA or placebo for 10 days (12 mg/kg sc, n = 7 WT, 11 CN, 4 WT-CsA, and 5 CN-CsA mice). For the day 14, day 28, adult, and adult CsA-treated groups, the WT mice weighed 8.8 ± 0.9, 14.9 ± 1.4, 33.4 ± 0.6, and 28.6 ± 1.2 g, respectively, whereas the CN mice weighed 9.5 ± 1.0, 12.9 ± 0.3, 28.4 ± 1.6 (P < 0.05, age-matched Student's t-test), and 31.3 ± 3.3 g, respectively. For the adult WT, CN, WT-CsA, and CN-CsA groups, echocardiograms were done at 63 ± 5, 73 ± 11, 53 ± 0, and 78 ± 10 days, respectively.
Conscious mice were restrained in a modified syringe case tubing with an opening for the echocardiographic probe. Mice were allowed to condition for at least 0.5 h before the echocardiogram.Anesthetized mice. Diastolic function could only be assessed in anesthetized mice because transmitral E and A waves fuse at heart rates (HR) >500 beats/min (15). Adult WT (n = 6), CN (n = 9), WT-CsA (n = 4), and CN-CsA (n = 7) mice weighed 27.6 ± 3.1, 28.7 ± 1.8, 28.6 ± 1.2, and 27.4 ± 3.4 g, respectively, and were 50.2 ± 1.3, 56.1 ± 3.8, 53 ± 0, and 60.1 ± 5.7 days old, respectively. CsA (12 mg/kg sc) was administered daily for 10 days before the echocardiographic study.
Mice were anesthetized with xylazine (5 mg/kg) and ketamine (100 mg/kg) intramuscularly. A warming pad was used to maintain normal body temperature. A previous study (12) from our laboratory has reported the methods and measurements used in the echocardiographic imaging.Variability. Mice selected at random from all groups were reanalyzed for LV dimensions, wall thickness, and ejection time (ET) (16 mice) and transmitral Doppler velocities (11 mice) by the same person for intraobserver variability and by a second person for interobserver variability at least 1 wk later. Repeatability was determined by taking several separate scans of the measurements at the time of the initial study. Inter- and intraobserver variability was measured using a standard definition (2).
Statistical Analysis
Survival was assessed by Kaplan-Meier analysis. Data are expressed as means ± SE with statistical significance accepted at the 95% confidence level (P < 0.05). Age-matched mean WT values in conscious day 14 and 28 mice were compared with the values obtained for CN mice by unpaired Student's t-test and the Wilcoxon-Mann-Whitney test. The mean data of adult WT, CN, WT-CsA, and CN-CsA groups were compared with one-way ANOVA and/or Student's t-test with the Bonferroni correction for multiple comparisons.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Survival of Transgenic Mice
Figure 1 shows a plot of survival of CN mice compared with WT mice using Kaplan-Meier analysis. None of the WT mice died during the 24-wk followup, whereas none of the transgenic mice survived beyond 24 wk. The earliest deaths in CN mice occurred at 4 wk. CsA did not alter the probability of survival in WT mice (data not shown). Surprisingly, CN-CsA animals died statistically earlier (P < 0.05) than untreated CN mice.
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Echocardiographic Variability
Intra- and interobserver and repeatability variables are summarized in Table 1. Interobserver variability was higher than intraobserver variability, and the repeatability error was higher for most parameters. The greatest variability was 18% for the E-to-A wave ratio (E/A) repeatability error. All other intra- and interobserver and repeatability variables were <16%. Our measurements of intra- and interobserver variability are comparable with those previously reported (5).
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Measures of Cardiac Hypertrophy
Significant cardiac hypertrophy was observed in CN mice by 14 days as shown in Table 2. Comparison of WT with CN mice for SWT (0.6 ± 0.03 vs. 0.7 ± 0.02 mm), posterior wall thickness (PWT; 0.5 ± 0.02 vs. 0.7 ± 0.02 mm), and LV mass (34 ± 5 vs. 66 ± 8 mg) showed significant increases in CN mice. During further development to adulthood, further exaggeration of wall thickness and LV mass was observed in CN mice. The SWT, PWT, and LV mass did not differ in adult WT and WT-CsA mice (Table 2). In CN mice, CsA significantly reversed the hypertrophic indexes (LV mass and LVMI). However, only partial reversal was achieved because the values remained significantly elevated from WT mice.
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Progression of Hypertrophy
As shown in Table 2, during normal WT development from 14 to 28 days to adult, a progressive increase in the LV mass was observed (34 ± 5, 52 ± 3, and 72 ± 1 mg, respectively). However, LV mass normalized to body weight (LVMI) significantly decreased with age (4.2 ± 1.0, 3.1 ± 0.5, and 2.2 ± 0.1 mg/g, respectively). By 14 days, CN mice manifested a significant increase in the LVMI compared with WT mice (7 ± 0.5 vs. 4 ± 1 mg/g) and failed to demonstrate a progressive decrease in the LVMI thereafter. The LVMI at 28 days and 10 wk were 8 ± 0.5 and 6 ± 0.5 mg/g, respectively (Table 2).The relationship between LVMI and LVIDd is illustrated in Fig.
2. A fundamental difference in cardiac
development was observed when comparing WT with CN mice. In WT mice, as
LVIDd progressively increased with normal growth and development from
14 to 28 days to adult, there was a progressive and significant
decrease in the LVMI. It should be noted that changes are expressed in
relation to day 14 WT data (LVIDd and LVMI = 100%). In
day 14 CN mice, both LVIDd and LVMI significantly increased
compared with day 14 WT mice. During development from 14 to
28 days, LVMI and LVIDd both increased; however, from 28 days old to
adult, in CN mice, the LVMI decreased, whereas the LVIDd continued to
increase. These data indicate two distinct phases in the
pathophysiology of cardiac hypertrophy in CN mice: 1) up to
28 days, the LVMI increased to an extent greater than expected with
normal growth and development; and 2) thereafter, relative
dilation of the left ventricle occurred.
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Figure 2 further illustrates the substantial effect of CsA on reversal of the hypertrophic indexes of LVMI and LVIDd. Both LVMI and LVIDd were effectively reduced in CN-CsA mice. Absolute values are shown in Table 2.
Natural History of Systolic Function in CN Mice
Whereas hypertrophy was manifested by 14 days in CN mice (Table 2), no significant decrease in the parameters of systolic function [circumferential fiber shortening velocity (Vcf) or FS] was observed in CN mice compared with WT mice (Table 2). Statistically significant decreases in systolic function were observed by 28 days and progressively decreased in adult CN mice. When adult CN mice were compared with WT mice, Vcf was 7 ± 0.8 vs. 15 ± 0.4 circumferences/s and FS was 32 ± 2% vs. 61 ± 2% (Table 2), respectively.Diastolic function in CN Mice
Figure 3 shows representative examples of transmitral Doppler velocities in adult WT, CN, and CN-CsA mice. Adult CN mice show substantial diastolic dysfunction compared with WT mice (Table 3). Peak A wave mitral inflow velocity was significantly decreased (0.40 ± 0.04 vs. 0.27 ± 0.03 m/s). Furthermore, the peak E/A was significantly increased from 2.9 ± 0.3 in WT mice to 5.0 ± 0.6 in CN mice.
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Effects of CsA on Cardiac Function
In CN mice treated with CsA (Fig. 3C and Table 2), the LVMI (3.4 ± 0.4 mg/g) was decreased compared with untreated CN mice (6.3 ± 0.5 mg/g). The LVIDd was also decreased from 4.6 ± 0.2 to 3.8 ± 0.1 mm in CN-CsA mice without a significant increase in FS from 32.3 ± 2.2% in adult CN mice to 39.6 ± 3.6% after CsA. Diastolic dysfunction, as assessed by E/A, was not altered by CsA in CN mice (Table 3). In CN mice, although CsA dramatically reversed the hypertrophic changes, no improvement in reduced systolic and diastolic function was observed.In WT mice treated with CsA (Table 2), FS was decreased by CsA treatment (61.0 ± 1.6% vs. 52.5 ± 1.2%), but Vcf remained unchanged (14.5 ± 0.4 vs. 13.0 ± 0.9 circumferences/s). Whereas CsA treatment of WT mice significantly increased the LVMI compared with adult WT mice, the LV mass was not significantly different. The difference in the LVMI exists only because of a significant difference in body weight when comparing adult WT with WT-CsA mice (P = 0.003).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our data indicate that there are two distinct phases in the development of cardiac pathophysiology in CN mice: an initial hypertrophy stage, followed by a stage of cardiac dilation (Fig. 2). Concomitantly, systolic performance progressively deteriorated (Table 2). By adulthood, CN mice showed marked systolic (Table 2) and diastolic LV dysfunction (Table 3). Whereas CsA dramatically reversed the cardiac hypertrophy and dilation in CN mice, the systolic and diastolic dysfunction was not reversed. Importantly, CsA exaggerated the incidence of sudden death associated with overexpression of calcineurin in transgenic mice (Fig. 1).
Similar to the findings of the present study (Fig. 2), the natural progression of decreasing LVMI and increasing LVIDd in control mice has previously been reported using MRI (19). In contrast, CN mice have early hypertrophy and dilation (increased LVMI and LVIDd), followed by progressive dilation.
Our measurements of systolic performance (FS and Vcf) in WT mice in this study are similar to those observed in other WT strains in our laboratory (12). Our findings of hypertrophy and reduced FS (Table 2) are consistent with those of Lim et al. (6); however, their echocardiography measurements of LV dimensions and FS were obtained only at 56 days. Our findings extend the understanding of the time course of development of the various aspects of heart disease associated with calcineurin overexpression. Lim et al. (6) also found substantial reversal of hypertrophy and minimal reversal of FS with CsA treatment and suggested that the failure to completely restore FS to control WT values may have been due, in part, to incomplete reversal of fibrosis in the CN hearts (6).
Previous studies have used abnormal E/A as an index of diastolic dysfunction in mutant mice (5, 9). Our measurements of E and A peak velocities and E/A are similar to values obtained in other strains of WT mice in our laboratory (12). However, the restrictive filling pattern observed in the CN mice in this study contrasts with the abnormal relaxation pattern observed in db/db mice studied in our laboratory. A restrictive E/A pattern of filling of the left ventricle has been reported to be associated with severe heart failure (10) and is in keeping with previously reported findings of several parameters indicative of heart failure (8, 22). Molkentin et al. (8) reported LV dilation and deposits of collagen and fibrosis of the ventricular wall. Yatani et al. (22) reported that overexpression of calcineurin results in an increase in the density of the L-type Ca2+ channel current (ICa,L) associated with accelerated inactivation, which is reversed by ryanodine treatment. These data suggest that the increase in ICa,L is associated with exaggerated calcium release from the sarcoplasmic reticulum. We speculate that increased sarcoplasmic reticulum calcium release could contribute to the diastolic dysfunction (increased E/A) seen in CN mice. Furthermore, Lim et al. (6) also reported that CsA consistently reversed myofiber hypertrophy and dilation, whereas interstitial fibrosis was a more permanent condition. Thus the lack of reversal of echocardiographic diastolic dysfunction with CsA treatment is consistent with previously reported histological analyses (6).
Although the lack of reversal of fibrosis with CsA treatment may explain the lack of reversal of both systolic and diastolic dysfunction despite substantial reduction of hypertrophy, additional factors may also be important. Long-term CsA treatment in rats induces a negative inotropic effect on peak myocardial contractility likely caused by enhancement of spontaneous Ca2+ release from the sarcoplasmic reticulum during the interstimulus interval, which results in a net reduction in sarcoplasmic reticulum Ca2+ content (1). Average diastolic intracellular Ca2+ concentration would also likely be increased, affecting diastolic function as well. Chronic changes in Ca2+, specifically Ca2+ overload, are known to be detrimental and result in heart failure (18) and arrhythmias. Furthermore, the reduction of LV hypertrophy may decompensate the heart to failure more readily (7). Thus a reduction in LV hypertrophy may represent a double-edged sword, as shown in other models of hypertrophy (7), because hypertrophy is associated with detrimental molecular and structural reorganization (6, 8) yet is an important initial compensatory mechanism.
Biological Features Associated With Sudden Cardiac Death
Overexpression of calcineurin is associated with the development of cardiac hypertrophy, followed by dilation, interstitial fibrosis, and systolic and diastolic dysfunction. Cardiac hypertrophy alone is not associated with the time course of the development of sudden cardiac death. Death begins to occur (Fig. 1) during the phase of the biology wherein there is a decreased LVMI associated with both systolic and diastolic dysfunction. This study does not define which of these pathological entities is the substrate for sudden death, but hypertrophy alone does not appear to be sufficient. Long-term studies are required to address whether congestive heart failure or arrhythmias are responsible for the sudden deaths.Importantly, CsA treatment partially reverses hypertrophy and dilation but does not reverse the incidence of sudden cardiac death and diastolic dysfunction. In fact, survival is significantly worsened. These data suggest that the pathophysiological features associated with systolic and diastolic dysfunction appear to contribute to the propensity for sudden cardiac death.
Methodological Considerations
In mice, FS is dependent on preload and afterload; Vcf is relatively independent of preload but dependent on HR and afterload (20). Because the diastolic LV internal dimension, a direct measure of preload, was increased in CN mice at all ages (Table 2), the decreased systolic function observed in CN mice may potentially be even greater when adjusted for preload (Frank-Starling Law) (11). The force-frequency relation in mice has been shown to be minimal when normalized for changes in preload (4). Because a modest positive relation was observed only at lower HR, the low HR in the day 28 CN mice (Table 2) may have contributed to the depressed systolic function. The contribution of afterload to systolic function remains to be investigated.With a restrictive filling pattern (10), increased LV end-diastolic pressure and decreased ventricular compliance minimizes ventricular filling due to atrial contraction, so that the peak A wave decreases, with a resultant increase in the E/A. In control mice, the peak A wave and the E/A are dependent on HR (15). Because the E/A is linearly and inversely related to HR (15) and the end-diastolic volume (preload) decreases with an increased HR in mice (4), a change in the E/A due to HR alone must be considered. Indeed, as the diastolic LV internal dimension increased, HR decreased and the E/A increased in CN mice (Table 3). Although Taffet et al. (15) indicate that the E/A was linear down to ~180 beats/min, the mean HR in our CN mice was lower (150 beats/min). Accordingly, our measurements of the E/A may be altered in part due to changes in HR. However, a change in the E/A (~20%) based on similar HR changes (15) is not great enough to account for the gross difference in the E/A between the WT and CN mice (76% increase). Thus the E/A likely reflects a true change in ventricular compliance. Unfortunately, due to fusion of the E/A at higher HR (15), diastolic function can only be measured in anesthetized mice, and the anesthetic may also influence results.
The current study does not provide evidence to discriminate whether CsA reversed hypertrophy or just inhibited its development in CN mice. Furthermore, when CsA is administered early in life, it is possible that its direct immunosuppressive actions or its effects on renal function could contribute to the worsened survival in CN mice.
In conclusion, progressive propensity to sudden death in these transgenic mice is associated with dilation of the left ventricle with both systolic and diastolic dysfunction. CsA partially reverses hypertrophy and dilation but does not reverse systolic and diastolic dysfunction and exaggerates the propensity to sudden death.
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ACKNOWLEDGEMENTS |
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We thank Agilent Technologies for donated use of the Hewlett-Packard Sonus 4500 machine.
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FOOTNOTES |
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H. J. Duff is an Alberta Heritage Medical Scientist. This study was funded by the Canadian Institutes of Health Research and the Andrew Family Professorship. L. M. Semeniuk held a Studentship Grant from the Alberta Heritage Foundation for Medical Research.
Address for reprint requests and other correspondence: H. J. Duff, Dept. of Medicine, Univ. of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 (E-mail: hduff{at}ucalgary.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00546.2002
Received 2 July 2002; accepted in final form 28 September 2002.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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, n = 38) died earlier than the
wild-type (WT) mice (
, n = 47) mice.
Cyclosporin A (CsA) further reduced the probability of survival in the
CN mice (CN-CsA mice; 
, n = 28).
