(Hypertension. 1996;28:609-614.)
© 1996 American Heart Association, Inc.
Articles |
Myocyte Remodeling During the Progression to Failure in Rats With Hypertension
the Department of Anatomy and Structural Biology, University of South Dakota, College of Medicine, Vermillion, and the Department of Food Science and Technology, Ohio State University, Columbus (S.A.M.).
Correspondence A. Martin Gerdes, PhD, Department of Anatomy and Structural Biology, University of South Dakota, College of Medicine, 414 E Clark St, Vermillion, SD 57069. E-mail mgerdes@sundance.usd.edu.
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Abstract |
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Regional changes in cardiac myocyte shape during the progression to failure with hypertension have not been clearly established. To address this issue, we examined left and right ventricular myocytes from lean, female spontaneously hypertensive/heart failure rats with compensated hypertrophy (approximately 12 months of age) and congestive heart failure (approximately 24 months of age). During this period, body weight did not change, but heart weight increased 59% and lung weight increased 93%. Left ventricular function declined with the onset of failure. Left ventricular myocyte volume increased 27% exclusively because of myocyte lengthening (29% increase). The onset of left ventricular failure resulted in a 72% increase in right ventricular myocyte volume. Right ventricular myocyte growth, however, was proportional, with a 23% increase in myocyte length and 18% increase in myocyte width. Changes in left ventricular myocyte shape were virtually identical to data collected previously from patients with similar disease, suggesting that this is a relevant animal model. Evidence suggests that left ventricular myocyte transverse growth is defective because dilation and failure were associated with cell lengthening, without a change in myocyte diameter. Although severe hypertrophy was present in the right ventricle as a result of left ventricular failure, myocyte growth was proportional, suggesting that cell shape was properly regulated in this chamber.
Key Words: heart failure, congestive • ventricular function • cell size
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Introduction |
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Chronic cardiovascular diseases, such as hypertension and ischemic heart disease, may lead to congestive heart failure and death. As a diseased heart progresses to failure, characteristic gross anatomic changes occur. The ventricular chamber dilates without a concomitant change in wall thickness.1 2 3 This increase in the ratio of chamber diameter to wall thickness is associated with elevated wall stress and ventricular dysfunction.4 5 Recent data from patients with heart failure caused by ischemic cardiomyopathy and idiopathic dilated cardiomyopathy indicate that chamber dilation may be largely due to excessive myocyte lengthening.6 7 These human data suggest that inadequate myocyte transverse growth may be responsible for the apparent absence of an appropriate wall thickening response in failure. Because of many factors, such as the difficulty in acquiring adequate fresh myocardial tissue from healthy humans and insufficient human data defining the extent of genetic heterogeneity of various cellular parameters, the cellular and molecular bases for myocyte remodeling in heart failure could be examined better in an animal model that mimics the gross physiological and anatomic changes occurring in humans.
Recent data from animals with pacing-induced tachycardia indicate that myocyte length-width ratio increased and ventricular function deteriorated during pacing, whereas heart mass remained unchanged.8 Ventricular function improved and myocyte hypertrophy was detected after pacing was discontinued. Thus, the experimental pacing model is quite different from the usual situation in humans in which overloaded hearts hypertrophy, reach a state of stable hyperfunction, and subsequently progress to failure. LV myocyte length-width ratio may also be increased because of mitral regurgitation.9 Under these particular loading conditions, however, myocyte shape may reflect a normal, rather than abnormal, cellular response to reduced afterload and increased preload. This does not seem to be the case in patients with ischemic and dilated cardiomyopathy, in which the cell shape change does not match the loading conditions.6 7
We used an animal model of chronic hypertension that progresses to congestive heart failure in these experiments.10 11 12 This model mimics a common disease process in humans. Furthermore, changes in left ventricular (LV) myocyte shape associated with failure are virtually indistinguishable from data collected from humans with comparable disease.13 Changes in right ventricular (RV) myocyte shape as a consequence of LV failure due to systemic hypertension are reported for the first time. The RV data are of particular interest because it appears that myocyte shape is being properly regulated despite the presence of severe hypertrophy. Results from these experiments suggest that this is a relevant animal model of human disease and will be useful in defining the mechanism of ventricular dilation in heart failure caused by hypertension.
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Methods |
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Animal Model
SHHF/Mcc-facp (abbreviated SHHF) rats were obtained from a colony maintained by Dr Sylvia McCune at Ohio State University, Columbus. SHHF indicates selective breeding for spontaneous hypertension and heart failure, and facp indicates that the fa and cp obesity genes are allelic.10 11 12 All SHHF rats used in this study were lean females although it was not known if they were homozygous lean (+/+) or heterozygous lean (+/facp) because a genetic marker is currently unavailable. Irrespective of the presence or absence of the obesity gene, all SHHF rats develop congestive heart failure. It has been well characterized that the onset of LV failure in these rats is associated with the following: LV dysfunction (as assessed by in vivo and in vitro methods), the presence of myocardial fibrosis, elevated plasma atrial natriuretic peptide levels, pulmonary congestion, hepatic congestion, electrocardiographic alterations typically seen in failure, mechanical alternans, increased chamber diameter–wall thickness ratio, dyspnea, orthopnea, cyanosis, ascites, and RV hypertrophy after the development of LV failure.10 11 12 14 15 SHHF rats were divided into two experimental groups: compensated hypertrophy (approximately 12 months of age, n=8) and failure (approximately 23 to 26 months of age, n=8). Additional control rats were not used because this was a progression study. All procedures were approved by the University of South Dakota Animal Care and Use Committee and followed institutional guidelines for animal care.
Hemodynamic Measurements
Rats were anesthetized with ketamine (30 mg/kg IM) and xylazine (5 mg/kg IM). After tracheotomy, a cannula was placed into the trachea through which the rats breathed spontaneously. The left ventricle was catheterized via the right common carotid artery with an ultraminiature catheter pressure transducer (model SPC-33A, Millar Instruments). After 5 minutes of stabilization, LV pressure and dP/dt were recorded.
Isolation of Myocytes
After hemodynamic data were collected, heparin (3000 U/kg, Sigma Chemical Co) was injected into an atrial appendage. The hearts were removed, blotted, weighed, and cannulated through the aorta for retrograde perfusion. The aorta was perfused with calcium-free Joklik medium (Sigma) containing 0.01 mmol/L EGTA (Sigma) followed by Joklik medium plus collagenase (Worthington Biochemical Co, 200 U activity/mL). Softened tissue was minced and poured through 250-µm nylon mesh for collection of myocytes. Isolated myocytes readily passed through the mesh, and incompletely digested clumps of tissue remained in the mesh. Freshly isolated cardiac myocytes were fixed immediately in a manner that does not alter cell volume.16 The isolated cell suspensions were centrifuged through a Ficoll gradient for removal of capillaries, blood cells, and other unwanted debris.17 With this procedure, the heavier myocytes tend to settle to the bottom of the centrifuge tube, and unwanted debris (capillaries, damaged cells, etc) tends to become more concentrated in the supernatant, which is discarded. To ensure that Ficoll treatment did not alter cell sampling, we measured mean cell length from samples before and after this procedure.
Myocyte Morphometry
Myocyte dimensions were determined in the following manner. With a microscope, the maximal myocyte length parallel to the long axis was measured from 40 cells from each sample. On the basis of a standard equation for sample size,18 40 cell length measurements reduced the sampling error to less than 3% for all samples.
Cell volume was measured with a Channelyzer (model C256, Coulter Electronics, Inc) interfaced to a Coulter Counter (model ZM). The Coulter system determines cell volume by measuring the change in electrical resistance caused by displacement of electrolytes as cells move through the aperture. The Coulter instruments were calibrated with 42-µm-diameter microspheres (Coulter Size Standards No. 6601329) with the use of a standard procedure outlined by the manufacturer. We have found that it is important to calibrate the instrument with microsphere standards within the approximate range of particles to be examined (eg, the mean volume of 42-µm-diameter microspheres used here is 38 800 µm3). Based on work by Hurley,19 a shape factor of 1.05 representing a myocyte length-width ratio of approximately 7 was used. Since the Coulter Channelyzer software incorporates a shape factor for spheres (1.5) in the denominator of the equation, we multiplied cell volume measurements by 1.43 to adjust the shape factor to 1.05 (eg, 1.5/1.05=1.43). Cell volume histograms for both rat groups displayed a gaussian distribution, but cells from 24-month-old rats had a slightly broader distribution. Median values for cell volume were used for statistical analyses. The validity of this approach for sizing cardiac myocytes has been extensively documented17 and confirmed by other researchers.20 Additionally, Burres and Cass21 have demonstrated that the Coulter Channelyzer system can be used to obtain reliable volume measurements of irregularly shaped cells.
Myocyte cross-sectional area was calculated from cell volume and length (Cross-sectional Area=Volume/Length). Therefore, calculations represent average values for myocyte cross-sectional area along the entire length of the cell. Myocyte diameter was also calculated from cross-sectional area with the formula for a circle (Area=
r2; Diameter=2r).
Statistical Analyses
Student's t test was used for comparison of data between the two rat groups. Mean (or median in the case of Coulter volume data) values from individual rats were used for statistical analyses that assessed interanimal variability between the two groups.
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Results |
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Rats were examined at approximately 12 and 24 months of age. At 12 months of age, rats demonstrated normal behavior and appeared healthy. Clinical signs of congestive failure became apparent at approximately 24 months of age. At that time, rats developed dyspnea, cyanosis, and orthopnea and were poorly groomed. Although fluid amounts were not measured, visual inspection revealed ascites and pleural effusion in all rats showing signs of failure. These changes were not seen in 12-month-old rats.
Changes in body and organ weights are summarized in Table 1
. Body weight was not different between the two rat groups examined. Heart weight increased 59%, and heart weight–body weight ratio increased 62% during the 12-month interval. Liver weight increased 28%, and lung weight increased 93%.
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Hemodynamic alterations are summarized in Table 2. With progression to failure, LV systolic pressure declined 38%, +dP/dt declined 48%, and -dP/dt declined 57%. LV end-diastolic pressure was not different between the two groups (data not shown).
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Regional values for cardiac myocyte dimensions are listed in Table 3. Cell length measurements before and after Ficoll treatment were the same, indicating that this procedure did not alter cell sampling (data not shown). LV myocyte volume was 27% greater in 24-month-old rats with congestive heart failure than in those with compensated hypertrophy (12 months old). This was exclusively due to an increase in myocyte length (29% increase) rather than myocyte cross-sectional area (P=NS) or width (P=NS). Consequently, changes in myocyte length and width resulted in a 31% increase in myocyte length-width ratio. Sarcomere length was the same in both rat groups (1.88±0.01 µm for LV myocytes from 12-month-old SHHF; 1.88±0.01 µm for LV myocytes from 24-month-old SHHF).
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LV failure was associated with dramatic alterations in RV myocyte dimensions (Table 3
). Cell volume increased 72% because of a 23% increase in myocyte length and 40% increase in myocyte cross-sectional area (18% increase in myocyte width). These changes reflected a proportional increase in myocyte dimensions because myocyte length-width ratio was unchanged (P=NS).
It should be noted that RV myocyte size data from two nonfailing hearts were excluded because of poor quality (eg, <50% rod cells). Optimal collagenase perfusion time for the left and right ventricles may vary slightly. The smaller right ventricle may often become overdigested when collagenase perfusion time is adjusted to obtain optimal quality and yield of LV myocytes. Perhaps because of the pronounced RV hypertrophy in the SHHF rats with heart failure, cell quality was good in both ventricles of all rats with heart failure.
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Discussion |
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Regional changes in cardiac myocyte shape were examined in the SHHF rat, a genetic model of hypertension and heart failure. Compared with 12-month-old rats, 24-month-old rats displayed classic symptoms of congestive heart failure: dyspnea, orthopnea, ventricular dilation, ascites, pleural effusion, and depressed LV hemodynamic function. In the left ventricle, myocyte volume increased significantly during the progression from compensated hypertrophy to failure. LV dilation and failure were associated with cell lengthening alone because myocyte cross-sectional area was unchanged. Thus, LV myocyte remodeling resulted in a dramatic increase in myocyte length-width ratio. RV myocyte volume increased dramatically as a result of LV failure. Presumably, this change was largely due to increased pulmonary resistance (eg, afterload), which is known to occur after LV failure. Unlike the growth response of LV myocytes, however, RV myocyte hypertrophy was due to a proportional increase in cell length and width (cross-sectional area).
The rats used in this study were obtained from a colony in which all rats develop spontaneous hypertension, leading to congestive heart failure. The heart failure trait has been maintained through at least 25 generations.12 14 Approximately 25% of the rats in the colony are obese. The effects of obesity and male sex predispose rats to an earlier onset of heart failure. For instance, obese males develop heart failure at approximately 10 to 12 months of age, whereas heart failure occurs at approximately 14 to 18 months in obese females and lean males.10
It should be pointed out that there is not general agreement on a definition of heart failure.22 The 24-month-old SHHF rats used in the present study displayed some but not all of the signs and symptoms associated with congestive heart failure. It could be argued that these rats were not in failure because pulmonary edema was not detected and LV end-diastolic pressure was not significantly elevated. It is clear, however, that 24-month-old rats had severe heart disease and were near death. We believe that these rats should be classified as having severe congestive heart failure but recognize that other researchers may have some reservations about this diagnosis.
We used lean females in this study to eliminate the confounding effect of increased heart mass caused by sex- and obesity-related changes in body mass. Since body mass is the most important nonpathological determinant of heart mass, it is often difficult to assess disease-related changes in heart mass in the presence of such alterations. It is well recognized that adult male rats continue to gain weight during aging, whereas adult females maintain a relatively constant body mass.23 For this reason, we have used female rats exclusively in our ventricular remodeling studies over the years.
Previous pathological examination of hearts from SHHF rats indicated the presence of increased myocardial fibrosis (replacement and interstitial) at 6 to 10 months of age.10 These changes were more prevalent in the inner one third of the left ventricle. Although preliminary ultrastructural studies of tissue from the LV free wall indicated the presence of some degenerative changes in rats with failure, myocardial pathology has not been extensively examined in this animal model. In general, however, the pathological profile appears to resemble closely that of patients with similar disease.1 24 Whole-tissue pathology was not possible with the rats involved in the present study because myocardial perfusion with collagenase to obtain isolated myocytes precludes assessment of tissue pathology. It should be noted, however, that areas of myocardial fibrosis were obvious in hearts from both rat groups on gross examination at the time of terminal experiments. Such lesions were much more extensive in hearts from the failure group.
Additional data, such as regional heart weight and myocyte volume percent, from other hearts would be necessary for calculation of changes in myocyte number. From 12 to 24 months, heart mass increased to a greater extent than myocyte volume, suggesting the presence of extensive myocardial fibrosis, myocyte hyperplasia, or both. Myocardial fibrosis is likely the underlying basis for this discrepancy because an increase in fibrosis from 12 to 24 months was obvious grossly, and our calculations indicate that it would take only a 10% reduction in myocyte volume percent to account for the discrepancy. Since there is no convincing evidence in the literature demonstrating that cardiac myocytes from adult mammals are able to proliferate, there is little reason to suspect that such a change occurred. Ongoing experiments in our laboratory should clarify this issue and other aspects of this model in the near future as more extensive temporal characterization continues. Related to the issue of further characterization of this model, it is important to note that LV myocyte length in 12-month-old nonfailing SHHF rats was longer than typically observed in normal adult female rats. Consequently, it is possible that the maladaptive remodeling of LV cardiac myocyte shape may begin earlier.
Application of the cell sizing methods used here has provided a clear understanding of the adaptive growth response of cardiac myocytes under various pathological and physiological loading conditions.25 Briefly, pressure overload (increased afterload) leads to enhanced wall thickness (concentric hypertrophy), which is reflected at the cellular level as an increase in myocyte cross-sectional area (diameter). Conversely, volume overload (increased preload) leads to a proportional increase in chamber diameter and wall thickness (eccentric hypertrophy) because of a proportional increase in myocyte length and diameter. Myocyte length-width ratio is a useful parameter because it is the cellular analogue of chamber diameter–wall thickness ratio. The precise mechanism by which changes in myocyte shape are regulated is poorly understood. It is likely that mechanical signals transmitted via myocyte cytoskeletal components and intermyocyte collagen struts are involved, but no direct evidence has been provided thus far.26 27 It appears that myocyte length-width ratio is tightly regulated in mammalian hearts within a narrow range.25 Cumulative data from animals with altered loading conditions suggest that myocyte length-width ratio is maintained during developing and compensated states of cardiac hypertrophy.25 28
Progression to LV failure in the SHHF rats used in the current study was associated with significant hypertrophy at the myocyte level. LV myocyte hypertrophy was exclusively due to an increase in cell length as cross-sectional area was unchanged. The cell-lengthening process was likely due to series addition of new sarcomeres because sarcomere length was not changed. It should be pointed out that we have never observed a change in isolated myocyte sarcomere length (resting unloaded) in any of the numerous pathological models used in our laboratory. The mechanism by which series sarcomeres are added to contracting myocytes is not known.
Although no direct measurements were made, left ventricles from rats with failure were obviously dilated. Ventricular dilation and increased chamber diameter–wall thickness ratio have been demonstrated previously in this animal model grossly and echocardiographically.10 12 29 Another recent echocardiographic study demonstrated that, compared with spontaneously hypertensive rats, 10- to 12-month-old SHHF rats with sustained hypertension developed ventricular dilation and an increased chamber diameter–wall thickness ratio well before the onset of clinical signs of heart failure.15 Thus, wall stress is elevated earlier in SHHF rats and may contribute to their predisposition to failure.
Ventricular dilation and failure are associated with a decline in dP/dtmax and LV systolic pressure. These hemodynamic changes were noted in the rats used in the present study and confirm previous findings by McCune et al.12 It is not clear from the current data whether functional deterioration and myocyte lengthening occur in conjunction or if one event precedes the other. Documentation of sequential alterations of various structural, functional, and molecular parameters as the heart progresses to failure is needed to clarify the underlying etiology of this disease. It seems that inadequate transverse growth, rather than excessive myocyte lengthening, may be more critical because the wall stress normalizing effects of increased myocyte cross-sectional area and the associated wall thickening would likely retard further ventricular dilation. Data from other animal models of heart failure support the concept that myocyte elongation without concomitant transverse growth may be a hallmark of ventricular dilation and heart failure.8 30 Myocyte length-width ratio increases similarly in humans with heart failure from ischemic and dilated cardiomyopathy.6 7 Cumulatively, these data suggest that a final common pathway may be involved in this maladaptive change in cardiac myocyte shape.
The major goal of the current study was to examine myocyte remodeling during the progression to heart failure in an animal model of hypertension and heart failure. Control data were not included for several reasons: (1) It is not clear whether suitable controls exist for SHHF rats; (2) control animals 12 and 24 months of age are not readily available; and (3) the relevance of such data to the progression to failure in the SHHF rat is questionable.
It is unlikely that LV myocyte remodeling during the progression to failure is due to aging alone because it has been demonstrated that myocyte shape is not altered in 2-year-old Sprague-Dawley rats.23 We recognize that aging could be a contributing factor in this model. Nonetheless, this is a part of the natural history of this disease and does not distract from the relevance of our findings.
Human data pertinent to the rat data reported here have been collected in our laboratory in the past. Isolated myocytes were collected from three nonfailing unsuitable donors with hypertension and four patients with ischemic cardiomyopathy and a prior history of hypertension.13 Thus, these patients had cardiac disease that was comparable to that in the 12-month-old SHHF rats (hypertension/compensated hypertrophy) and the 24-month-old SHHF rats (hypertension/failure), respectively. Although sample size was small, it is interesting to note that myocyte size changes in these patients were virtually identical to those in the rats reported here. In both cases, LV myocyte cross-sectional area was very high because of pressure-overload hypertrophy and was unchanged in the progression to failure (369±40 µm2 in nonfailing versus 365±45 µm2 in failing hearts from humans). Failure resulted in a selective increase in myocyte length only (141±16 µm in nonfailing versus 206±15 µm in failing hearts from humans). The remarkable similarity of these data suggests that this animal model of heart failure may prove very useful in understanding the cellular mechanisms that lead to heart failure in humans with hypertension. It is also interesting to note that mean myocyte cross-sectional area was in the range of 350 to 400 µm2 for LV myocytes from SHHF rats and human hypertensive patients in failure and RV myocytes from SHHF rats with LV failure. With one exception, these are the largest values for myocyte cross-sectional area that we have ever observed. It is possible that this represents an upper limit for myocyte cross-sectional growth. The only time that we have observed a greater degree of myocyte cross-sectional growth was in 90-day-old rats with severe hypertension induced by aortic constriction at 5 days of age.31 This unusually enhanced growth response was likely related to the increased plasticity of young growing tissue.
Over the past few decades, numerous morphometric data related to myocyte changes in hypertrophy and failure have appeared in the literature. Unfortunately, most of those studies reported changes in myocyte diameter or cross-sectional area only and are of little use in understanding remodeling of cardiac myocyte shape. In addition to the incomplete nature of most available data on myocyte remodeling, errors associated with morphometric measurements are rarely considered. To our knowledge, these are the only comprehensive data on remodeling of cardiac myocyte shape in an animal model of hypertension progressing to heart failure.
RV myocyte size nearly doubled as a result of LV failure in SHHF rats. Unlike the situation in the left ventricle, however, myocyte length-width ratio was maintained in the right ventricle. Unfortunately, rats with heart failure were very fragile and did not tolerate an additional RV catheterization procedure. Consequently, RV function was not assessed in these rats. It is likely that RV function was beginning to deteriorate in 24-month-old SHHF rats because they showed some signs of right-sided failure (eg, ascites, hepatic congestion). Results from a previous study examining remodeling of RV and LV myocytes 1 month after a transmural LV infarction was created in rats are similar to data reported here.30 In the rat myocardial infarction model, LV function was depressed and myocyte length-width ratio was increased. In the right ventricle, however, systolic pressure and dP/dtmax were elevated and myocyte length-width ratio was normal despite severe cellular hypertrophy caused by LV failure. Unlike LV myocytes, RV myocytes appear to be responding appropriately to loading conditions (eg, increased myocyte length and cross-sectional area associated with chamber dilation and increased afterload). The underlying basis of this regional difference in cell shape regulation is presently unknown. Nonetheless, the regional myocyte shape difference is an exciting finding because examination of regional differences in gene expression in this model may provide important insight into the molecular mechanism of ventricular dilation in heart failure.
In summary, a dramatic increase in length-width ratio occurred in LV myocytes during the progression to failure in SHHF rats, a genetic model of hypertension and heart failure. This change appears to be maladaptive because it is associated with known alterations in ventricular architecture that contribute to elevated wall stress. The observed myocyte changes are remarkably similar to data collected from humans with comparable disease. RV myocytes develop substantial hypertrophy as a result of LV failure. Unlike the situation in the left ventricle, however, it appears that myocyte shape was properly regulated in the right ventricle. This model should prove useful in defining the molecular basis of heart failure in patients with similar disease.
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Acknowledgments |
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This work was supported by grants HL-48835 and HL-30696 from the National Institutes of Health. Salaries and research support were also provided in part by state and federal funds appropriated to the Ohio Agricultural Research and Development Center, Ohio State University. The authors are grateful to Dr Faqian Li and Suleman Said for technical assistance.
Received February 28, 1996; first decision April 19, 1996; accepted June 3, 1996.
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 R. Kacimi and A. M. Gerdes Alterations in G Protein and MAP Kinase Signaling Pathways During Cardiac Remodeling in Hypertension and Heart Failure Hypertension, April 1, 2003; 41(4): 968 - 977. [Abstract] [Full Text] [PDF]
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P. M. L. Janssen, L. B. Stull, M. K. Leppo, R. A. Altschuld, and E. Marban Selective contractile dysfunction of left, not right, ventricular myocardium in the SHHF rat Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H772 - H778. [Abstract] [Full Text] [PDF]
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X. P. Yi, A. M. Gerdes, and F. Li Myocyte Redistribution of GRK2 and GRK5 in Hypertensive, Heart-Failure-Prone Rats Hypertension, June 1, 2002; 39(6): 1058 - 1063. [Abstract] [Full Text] [PDF]
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 M.H. Yacoub A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery Eur. Heart J., April 1, 2001; 22(7): 534 - 540. [PDF]
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T. Tamura, S. Said, J. Harris, W. Lu, and A. M. Gerdes Reverse Remodeling of Cardiac Myocyte Hypertrophy in Hypertension and Failure by Targeting of the Renin-Angiotensin System Circulation, July 11, 2000; 102(2): 253 - 259. [Abstract] [Full Text] [PDF]
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M. R. Bergman, R. H. Kao, S. A. McCune, and B. J. Holycross Myocardial tumor necrosis factor-alpha secretion in hypertensive and heart failure-prone rats Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H543 - H550. [Abstract] [Full Text] [PDF]
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N. G. Perez, K. Hashimoto, S. McCune, R. A. Altschuld, and E. Marban Origin of Contractile Dysfunction in Heart Failure : Calcium Cycling Versus Myofilaments Circulation, March 2, 1999; 99(8): 1077 - 1083. [Abstract] [Full Text] [PDF]
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T. Tamura, S. Said, and A. M. Gerdes Gender-Related Differences in Myocyte Remodeling in Progression to Heart Failure Hypertension, February 1, 1999; 33(2): 676 - 680. [Abstract] [Full Text] [PDF]
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K. M. Anderson, A. D. Eckhart, R. N. Willette, and W. J. Koch The Myocardial ß-Adrenergic System in Spontaneously Hypertensive Heart Failure (SHHF) Rats Hypertension, January 1, 1999; 33(1): 402 - 407. [Abstract] [Full Text] [PDF]
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T. Onodera, T. Tamura, S. Said, S. A. McCune, and A. M. Gerdes Maladaptive Remodeling of Cardiac Myocyte Shape Begins Long Before Failure in Hypertension Hypertension, October 1, 1998; 32(4): 753 - 757. [Abstract] [Full Text] [PDF]
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