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European Journal of Heart Failure 2001 3(5):535-543; doi:10.1016/S1388-9842(01)00160-X
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© 2001 European Society of Cardiology

A new model of congestive heart failure in the mouse due to chronic volume overload

Michaela Scheuermann-Freestonea,*, Nicholas Simon Freestoneb, Thomas Langenickela, Klaus Höhnela, Rainer Dietza and Roland Willenbrocka

a Franz-Volhard Clinic, Laboratory of Clinical and Experimental Heart Failure, Max Delbrück Center for Molecular Medicine Berlin, Germany
b The Rayne Institute, Cardiovascular Research, St. Thomas' Hospital London, UK

* Corresponding author. Present Address. Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK. Tel.: +44-1865-221875; fax: +44-1865-768844. E-mail address: mscheuer{at}bioch.ox.ac.uk (M. Scheuermann-Freestone)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Recently, deletion of specific genes by so called knock-out techniques has become important for investigating the pathogenesis of various diseases. This form of genetic engineering is widely performed in murine models. There are, however, only a limited number of mouse models available in cardiovascular pathology. The objective of this study, therefore, was to develop a new model of overt congestive heart failure associated with myocardial hypertrophy in the mouse.

Methods: Female C57/BL6 mice weighing 19–20 g were anesthetized with ether. After abdominal incision, the aorta was temporarily clamped proximal to the renal arteries. The aorta was then punctured with a needle (outer diameter 0.6 mm) and the needle was further advanced into the adjacent vena cava. After withdrawal of the needle, the aortic puncture site was sealed with cyanoacrylate glue. The clamp was removed, and the patency of the shunt was visually verified as swelling and mixing of venous and arterial blood in the vena cava. Sham-operated mice served as controls.

Results: Perioperative mortality of mice with aortocaval shunt was 42%. Four weeks after shunt induction, mice showed a significant cardiac hypertrophy with a relative heart weight of 7.5 ± 0.2 mg/100 g body weight (vs. 5.1 ± 0.7 mg/100 g in control mice, P < 0.001). While no changes in blood pressure and heart rate occurred, left ventricular enddiastolic pressure was significantly increased in mice with shunt, and left ventricular contractility was impaired from 6331 ± 412 to 4170 ± 296 mmHg/s (P < 0.05). Plasma concentrations of atrial natriuretic peptide (ANP) and its second messenger cGMP as humoral markers of heart failure as well as ventricular expression of ANP - and brain natriuretic peptide (BNP)-mRNA were significantly increased in mice with shunt compared to control mice.

Conclusions: The aortocaval shunt in the mouse constitutes a new model of overt congestive heart failure with impaired hemodynamic parameters and may be a useful tool to investigate the role of particular genes in the development of heart failure.

Key Words: Heart failure • Pathophysiology • Hemodynamics • Mouse • Natriuretic peptides

Received October 3, 2000; Revised February 20, 2001; Accepted April 26, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Recently, the development of new genetic techniques and the application of novel molecular tools to particular models of various diseases has promised important insights into the understanding of underlying pathological mechanisms. Such molecular tools of targeting genes can involve either overexpression of specific genes in an organ of interest [1,2] or deletion of gene products through knock-out techniques [3,4]. The latter method, the ablation of a chosen gene, is only feasible in few organisms, where isolation of embryonic stem cells is possible. As the mouse has been described to fulfill these technical pre-suppositions, murine models are gaining more and more attention [5]. Consequently, the interest of many research groups in animal models, particularly in cardiac physiology has slowly been shifted from rat and dog models to the mouse model. To date, many genetic mouse models of various forms of diseases have been developed such as genetic models of hypertension [6–9], cardiomyopathy due to overexpression [10–12] or deletion of specific genes [13] and models of cardiac hypertrophy [14–16]. These models, however, have all been generated via genetic manipulation. On the other hand, only a few models of cardiovascular diseases induced independently of genetic alterations are known. So far, few publications of mouse models of heart failure due to ischemic heart disease [17] or due to chronic pressure overload [18–20] are known. Up to now, no reliable model of heart failure comparable to a common form of human heart failure, the dilated cardiomyopathy without myocardial scar and without pressure overload, is published. The aim of our study, therefore, was to develop and establish a new model of overt congestive heart failure in the mouse resembling the dilated cardiomyopathy with association of the development of myocardial hypertrophy together with impaired hemodynamic function. This model may then provide a useful tool to further study the role of particular genes in the development of heart failure through application in specific genetically altered strains of mice.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animals
Female C57/BL6 mice weighing 19–20 g from Charles River breeding farms, Germany, were used, as in previous experiments, male mice from the same strain showed little resistance to the general surgical procedure and demonstrated mortality rates above 80% after shunt induction. Mice were fed normal mouse chow and were allowed free access to tap water. Animals were housed in an approved facility with a 12-h light/dark cycle. Surgery was performed in the afternoon between 14.00 and 18.00 h. Hemodynamic measurements and blood withdrawals were performed in the mornings between 06.00 and 12.00 h. The study conforms with The Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.2. Induction of aortocaval shunt
For induction of heart failure due to chronic volume overload, the technique of induction of an aortocaval shunt formerly described in the rat [21] was modified and applied under the microscope. In brief, after anesthesia with ether, animals underwent an abdominal midline incision, the intestines were carefully put aside and the vena cava and the abdominal aorta were dissected free of surrounding tissue well above the renal arteries. After temporarily clamping the aorta proximal to the renal arteries, a disposable needle (outer diameter 0.6 mm, Braun Beckinson, Germany) was used to puncture the aorta distal to the renal arteries, and the needle was then advanced into the adjacent vena cava to connect both vessels. The needle was withdrawn, and the aortic puncture site sealed with a drop of cyanoacrylate glue (Krazy glue, Border, Willowdale, Canada). The clamp was carefully removed, and the patency of the aortocaval shunt was visually verified by swelling and mixing of venous and arterial blood in the vena cava. The intestines were put back into the abdominal cavity, and the abdominal wall, as well as the skin, were closed with single sterile sutures. The skin and the wound were disinfected, and the mice were allowed to recover from surgery. Sham-operated mice which served as control mice underwent the same procedure with exception of the puncture of the aorta and the vena cava. All further experiments were carried out 30 days after the surgical procedure in animals with aortocaval shunt and in animals from the control group. The investigator carrying out these experiments was blinded to the nature of the original surgical procedure.

2.3. Hemodynamic measurements
Thirty days after shunt induction, mice were anesthetized intraperitoneally with nembutal (sodium pentobarbital 1.9 µg/kg, Sanofi Ceva, Germany). For measurement of arterial blood pressure and heart rate and for withdrawal of arterial blood, a polyethylene (PE) 25 catheter filled with saline with an elongated and thinner end was used and inserted into the right carotid artery. Another similarly treated PE 25 catheter was inserted into the right jugular vein for measurements of central venous pressure. For measurement of left ventricular enddiastolic pressures and left ventricular contractility, the arterial catheter was carefully advanced through the carotid artery into the left ventricle, and its position was verified via typical pressure curves. All catheters were connected to a Statham P23XL transducer, which was connected to a Gould amplifier.

2.4. Determinations of plasma concentrations of ANP and cGMP
Blood samples for determination of ANP (400 µl) and its second messenger cGMP (150 µl) were withdrawn from the arterial catheter just before killing the animals after the hemodynamic measurements. The blood was withdrawn into NaEDTA-preloaded (final concentration 7 mmol/l) and pre-chilled tubes. Degradation of ANP and cGMP was prevented with addition of phenylmethylsulfonyl fluoride (final concentration 10 µmol/l), pepstatin (3 µmol/l) and isobutylmethylxanthine (1 mmol/l). Immediately after withdrawal, the blood was centrifuged at 4°C and with 2000xg for 10 min, the plasma was separated and kept at –80°C until further extraction. ANP plasma samples were extracted with C18 Sep-Pak columns, which had been activated with acetonitrile and ammonium acetate (0.2%, pH 4.0) according to a previously described protocol [22]. ANP was measured by radioimmunoassay performed with antibodies kindly donated by Dr Thibault and Dr Gutkowska, Montreal, Canada. The cGMP plasma samples were extracted with alumina (AG 7) and Dowex (AG 50W-X8) columns before assessment by radioimmunoassay. Antibodies were generously donated by Prof. Hamet, Montreal, Canada.

2.5. Determination of left ventricular ANP- and BNP-mRNA expression
After killing the mice, the hearts and lungs were rapidly dissected, washed in ice-cold diethylpyrocarbonate treated water (DEPC-water) and weighed under sterile conditions. Immediately after weighing of the whole heart, both atria were cut off, weighed and frozen in liquid nitrogen. The right ventricle was then cut off along the interventricular septum using the inflow tract from the dissected right atrium, and the septum was separated from the left ventricle. Chambers and septum were immediately weighed and frozen in liquid nitrogen. Before weighing and freezing the lungs, all surrounding soft tissue and the trachea was cut off. The organs were then kept at –80°C until RNA extraction. Total RNA was isolated from the left ventricles according to the method described by Chomczynski and Sacchi [23]. In brief, tissues were homogenized, and RNA from the aqueous phase was precipitated and centrifuged. The concentration of isolated RNA was determined spectrophotometrically at a wavelength of 260 nm. Mouse ANP, BNP and glycerolaldehyde-3-phosphate dehydrogenase (GAPDH)-cDNA probes for hybridization were generated from mouse RNA by reverse transcriptase polymerase chain reaction (RT-PCR Kit, Stratagene, La Jolla, USA) using specific ANP, BNP and GAPDH primer pairs. Primer pairs for ANP, BNP and GAPDH were as follows: ANP; 5'-CTTAATATGCAGAGTGGGAGAGGCA-3', BNP; 5'-ATCTCCTGAAGGTGCTGTCCCAGAT-3' and GAPDH; 5'-GTGGAGATTGTTGCCATCAACG-3'. The PCR products were purified by phenol–chloroform extraction and labelled with DIG (DIG DNA Labeling and Detection Kit, Boehringer Mannheim, Germany). Probes for all three peptides were verified by Northern Blot analysis. For measurement of specific ANP- and BNP-mRNA, 30 µg of total RNA were transferred to a nylon membrane (Hybond N+ nucleic acid transfer membrane, Amersham, Braunschweig, Germany) and hybridized at 42°C for 20 h. After washing the membrane with 2x SSC for 40 min and 0.1x SSC for 40 min, the detection of the DIG-labeled probe was performed by chemoluminescence. The membrane was exposed to an X-ray film and the optical density was quantified with NIH-image software (National Institute of Health, Bethesda, USA). All data were normalized to GAPDH-mRNA expression.

2.6. Data analysis
The differences between the groups were evaluated with the corrected unpaired Student's t-test. The significance level was set at P<0.05. All data are expressed as mean±standard error of the mean (S.E.M.).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Survival of mice and patency of shunt
In total, 78 mice underwent surgery, out of which 59 mice were randomized to induction of an aortocaval shunt and 19 were sham-operated. While no sham-operated animal died neither within the first days post-operatively nor within the following 30 days before performance of hemodynamic measurements, 25 mice with aortocaval shunt died within the first 72 h after shunt induction (Fig. 1). Post-mortem studies on these mice revealed severe pulmonary edema with markedly enlarged hearts as well as ascites, suggesting that these animals died of severe heart failure. Thereafter, no further deaths occurred. Consequently, the perioperative mortality of mice with aortocaval shunt was calculated to be 42%. Thirty days after shunt induction, only 4 mice showed a closure of the induced aortocaval shunt. The probability of a patent shunt therefore, was 93.2%.


Figure 1
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  		Fig. 1 Post-operative mortality in sham-operated mice and mice with aortocaval shunt.

 
3.2. Development of myocardial hypertrophy
Thirty days after shunt induction, mice showed a significant increase in the absolute as well as in the relative heart weight as depicted in Fig. 2. While body weight was not different compared to sham-operated control mice (24.1±0.3 g in mice with shunt vs. 23.5±0.4 g in control mice), the relative heart weight increased from 5.1±0.7 to 7.5±0.2 mg/g body weight, P<0.001). This development of myocardial hypertrophy was mirrored by a significantly enhanced weight in all four heart chambers (Table 1). Furthermore, pulmonary congestion was suggested in mice with aortocaval shunt due to an increased lung weight of 200.4±3.8 vs. 185.5±4.1 mg in control mice (P<0.05, Table 1).


Figure 2
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  		Fig. 2 Absolute and relative heart weight in mice with aortocaval shunt and control mice. ***P<0.001 vs. control.

 


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  		Table 1 Hemodynamic parameters and organ weights 30 days after shunt induction

 
3.3. Hemodynamic parameters
Even though saline filled catheters with only a limited sensitivity due to lower frequency response compared to Millar tip catheters were used, the pressure curves were reliable and the differences in the parameters measured were pronounced enough to reveal significant changes. For illustration of exemplary pressure curves, Fig. 3 and Fig. 4 show traces from a mouse with aortocaval shunt and from a control mouse, respectively. Mice with aortocaval shunt showed no differences in either blood pressure or heart rate compared to sham-operated control mice as depicted in Table 1. Central venous pressure, however, was significantly elevated from 0.8±0.5 to 2.3±0.4 mmHg (P<0.05) in mice with shunt due to the chronic volume overload caused by shunting of the arterial blood. The intraventricular pressures and left ventricular contractility were measured, and left ventricular enddiastolic pressure was markedly increased from 6.0±1.0 to 13.1±1.5 mmHg in mice with shunt compared to control mice (P<0.05, Fig. 5a). In parallel, left ventricular contractility was significantly decreased from 6331±412 to 4170±296 mmHg/s (P<0.05, Fig. 5b).


Figure 3
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  		Fig. 3 Exemplary pressure curves of a mouse with aortocaval shunt from aorta, left ventricle (a) at 50 mm/s and at 200 mm/s (b) as well as from the superior vena cava (c).

 


Figure 4
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  		Fig. 4 Pressure curves from aorta, left ventricle (a) at 50 mm/s as well as at 200 mm/s (b) and from the superior vena cava (c) of a control mouse.

 


Figure 5
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  		Fig. 5 Left ventricular enddiastolic pressure (a) and left ventricular contractility (b) in mice with aortocaval shunt and control mice. *P<0.01 vs. control.

 
3.4. ANP and cGMP plasma concentrations
For hormonal characterization of the aortocaval shunt, we determined plasma concentrations of ANP and its second messenger cGMP which are well known humoral markers of heart failure. As shown in Fig. 6a, there was a significant increase in ANP plasma concentrations 30 days after shunt induction from 44.9±3.2 in control mice to 72.8±3.6 pmol/l (P<0.001). Similarly, plasma concentrations of the second messenger cGMP were increased from 19.8±7.2 to 41.1±13.0 pmol/l (P<0.05, Fig. 6b).


Figure 6
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  		Fig. 6 Plasma levels ANP (a) and cGMP (b) in mice with shunt compared to control mice. *P<0.05; ***P<0.001 vs. control.

 
3.5. Expression of ANP- and BNP-mRNA in the left ventricle
As the expression of the natriuretic peptides ANP and particularly BNP seem to be a sensitive marker for myocardial hypertrophy and cardiac failure, we measured mRNA expression of both ANP and BNP in the left ventricle of mice with aortocaval shunt and their sham-operated counterparts. When normalized to the expression of the housekeeping gene GAPDH, the expression of ANP-mRNA in mice with aortocaval shunt (Fig. 7a) was significantly upregulated from 1.1±0.3 to 2.8±1.1 arbitrary units (AU) compared to sham-operated mice (P<0.01). Fig. 7b shows a typical Northern Blot of mRNA from sham-operated mice and mice with aortocaval shunt, demonstrating clearly the more pronounced expression of ANP in mice with heart failure. Similar results were found when measuring the expression of BNP-mRNA. As depicted in Fig. 8a, the expression of BNP-mRNA in mice with aortocaval shunt was approximately five-fold increased from 0.3±0.1 in sham-operated mice to 1.6±0.4 AU (P<0.05). Accordingly, the representative Northern Blot in Fig. 8b shows a stronger signal due to the increased BNP-mRNA expression in the left ventricle in mice with heart failure compared to control mice.


Figure 7
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  		Fig. 7 Expression of left ventricular ANP-mRNA in mice with aortocaval shunt compared to control mice. **P<0.01 vs. control.

 


Figure 8
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  		Fig. 8 Expression of left ventricular BNP-mRNA in mice with aortocaval shunt compared to control mice. *P<0.05 vs. control.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The main purpose of this study was the establishment and characterization of a new model of overt heart failure in the mouse. With the induction of chronic volume overload by an aortocaval shunt we were able to induce congestive heart failure in the mouse, which resulted in the development of myocardial hypertrophy and impaired cardiac function together with increased expression of the natriuretic peptides in the left ventricle as markers of hypertrophy and cardiac failure. In such, this model is novel in the mouse, even though the basic surgical technique for creating an aortocaval shunt with consequent volume overload, inducing congestive heart failure, is established and published in the rat.

Until now, investigations into pathophysiological mechanisms were possible in animal models with pharmacological interventions or with genetic manipulation via overexpression [1,2] or deletion of specific genes of interest [3,4]. Particularly, the latter method of generation of knock-out animals by ablation of genes seems to offer promising insights into pathopysiology. The mouse is one of the species where the technique of gene ablation is well established. To date, there are few models of overt heart failure known in this species. These comprise mainly models with genetic disorders causing hypertension [6–8] or cardiomyopathy due to overexpression [10,11] or deletion [13] of particular candidate genes. Furthermore, some models have been developed to study the effect of experimental myocardial ischemia [17] or chronic pressure overload [18–20] on hemodynamics and structural changes of the myocardium. These models, however, assume skilful surgical techniques and temporary intubation and respiration of the animals used in these studies, while the outcome and degree of impairment of myocardial function is difficult to standardize. We have, therefore, developed and established a new model of heart failure in the mouse, which is easily reproducible, requires no open chest surgery and leads to the development of myocardial hypertrophy and overt heart failure due to chronic volume overload. The surgical technique we applied for induction of chronic volume overload was the aortocaval shunt. Previously, the induction of an aortocaval shunt was performed both with microsurgical methods [24,25] and with the needle technique by our group and by others [21,26,27] in the rat. As the needle technique, in particular, offers the advantage of generating a reproducible and predictable shunt magnitude along with a low mortality [21], we aimed to modify this technique in order to apply it to the mouse for inducing heart failure due to chronic volume overload.

Using female mice at a relatively early age, we developed a modified technique of an infrarenal shunt induction applying a needle with an outer diameter of 0.6 mm. The surgery was performed under ether anesthesia and neither mice with aortocaval shunt nor mice with sham-operation died during anesthesia. While no control mouse died within the 30 days of duration of the study, the mortality of animals with aortocaval shunt within the first 3 days after surgery was 42%. Post-mortem examinations on some mice revealed an extremely enlarged heart together with pleural and peritoneal effusions. These findings suggest a rapidly evolving form of heart failure resulting in cardiovascular death. As no telemetric studies of these mice were performed, arrhythmogenic causes of death cannot be ruled out. Mice that had survived the first 3 days after shunt induction showed no further increased mortality and hemodynamic and hormonal studies could be performed 30 days later. The patency of the shunt, directly after shunt induction, as well as 30 days after surgery, was visually verified under the microscope and 30 days after shunt induction, 93% of mice showed a marked swelling of the vena cava together with a mixing of arterial and venous blood indicating a patent aortocaval shunt. This underlines that the technique represents a valid method of inducing chronic shunting of arterial blood. Only animals with a patent shunt were included in the hemodynamic and hormonal studies.

In mice with aortocaval shunt, all typical features of overt heart failure were obvious. The relative and absolute heart weight, as well as the weight of all four single heart chambers was significantly increased in animals due to chronic volume overload suggesting cardiac hypertrophy. Furthermore, lung weight was markedly increased, revealing pulmonary congestion. Systolic, diastolic and mean blood pressure only showed a slight tendency to decrease. The central venous pressure, however, was significantly elevated due to the chronic volume overload. Interestingly, heart rate in mice with aortocaval shunt was not different compared to sham-operated mice. As the hemodynamic measurements were not done in conscious mice, these findings may be due to the barbiturate anesthesia that was used in the animals. As further characteristic features of heart failure, the left ventricular enddiastolic pressure of mice with aortocaval shunt was significantly increased and myocardial contractility was impaired. ANP plasma levels, which have been described as an index of left ventricular enddiastolic pressure [28] as well as the levels of its second messenger cGMP were increased, demonstrating activation of the natriuretic peptide system as a characteristic feature of heart failure [29–32]. Furthermore, not only was the peptide level of ANP elevated, but ANP-mRNA expression in the left ventricle of mice with aortocaval shunt was significantly enhanced, being in accordance with recently published data showing increased ANP expression in the myocardium of failing hearts [33,34]. Recently, another member of the natriuretic peptide family, the brain natriuretic peptide BNP, was proposed to be a more sensitive and specific marker than ANP for manifest heart failure by us and other groups [35–38]. Therefore, we also measured the level of expression of BNP-mRNA in the left ventricle and found this to be similarly increased to ANP-mRNA expression in mice with aortocaval shunt. These findings suggest that BNP may be differentially regulated in heart failure compared to ANP [39].

In summary, we have established a new mouse model displaying signs of overt heart failure and myocardial hypertrophy, which can be used to study the development and pathophysiology of heart failure. In contrast to other models of heart failure such as myocardial infarction or aortic banding going along with intrathoracic surgery, this model avoids thoracotomy, which renders the surgical procedure less painful and less risky and therefore, offers a relatively simple and rapid way of inducing heart failure. Used in various models of genetically altered mouse strains such as overexpressing or knock-out mice, this model may provide a useful tool to further study the role of a particular gene in the development and outcome of heart failure.


   Acknowledgements
 
The authors thank A. Schiche, J. Mothes and R. Günzel for excellent technical assistance. We are grateful to P. Hamet, Montreal, Canada, for donation of antibodies for the cGMP measurements and to J. Gutkowska and G. Thibault, Montreal, Canada, for providing antibodies against ANP. This project is supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) to R. Willenbrock (Wi 814/7-1).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Mullins L.J., Mullins J.J. Transgenesis in the rat and larger mammals. J Clin Invest (1996) 97:1557–1560.[Web of Science][Medline]
  2. Shuldiner A.R. Molecular medicine. Transgenic animals. N Engl J Med (1996) 334:653–655.[Free Full Text]
  3. Koss K.L., Kranias E.G. Phospholamban: a prominent regulator of myocardial contractility. Circ Res (1996) 79:1059–1063.[Free Full Text]
  4. Sharp M.G.F., Mullins J.J. Loss of gene function methodology. J Hypertens (1993) 11:339–343.[CrossRef][Web of Science][Medline]
  5. Packer M. Is tumor necrosis factor an important neurohormonal mechanism in chronic heart failure? Circulation (1995) 92:1379–1382.[Free Full Text]
  6. Merrill D.C., Thomson M.W., Carney C.L., Granwehr B.P., Schlager G., Robillard J.E. Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. J Clin Invest (1996) 97:1047–1055.[Web of Science][Medline]
  7. Hamet P., Malo D., Tremblay J. Increased transcription of a major stress gene in spontaneously hypertensive mice. Hypertension (1990) 15:904–908.[Abstract/Free Full Text]
  8. John S.W.M., Krege J.H., Oliver P.M., et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science (1995) 267:679–681.[Abstract/Free Full Text]
  9. Oliver P.M., Fox J.E., Kim R., et al. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci USA (1997) 94:14730–14735.[Abstract/Free Full Text]
  10. Mende U., Kagen A., Cohen A., Aramburu J., Schoen F.J., Neer E.J. Transient cardiac expression of constitutively active G{alpha}q leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. Proc Natl Acad Sci USA (1998) 95:13893–13898.[Abstract/Free Full Text]
  11. Kubota T., McTiernan C.F., Frye C.S., et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-{alpha}. Circ Res (1997) 81:627–635.[Abstract/Free Full Text]
  12. Chu G., Dorn I.I.G.W., Luo W., et al. Monomeric phospholamban overexpression in transgenic mouse hearts. Circ Res (1997) 81:485–492.[Abstract/Free Full Text]
  13. Arber S., Hunter J.J., Ross J., et al. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell (1997) 88:393–403.[CrossRef][Web of Science][Medline]
  14. Hasenfuss G. Animal models of human cardiovascular disease, heart failure and hypertrophy. Cardiovasc Res (1998) 39:60–76.[Abstract/Free Full Text]
  15. Kudej R.K., Iwase M., Uechi M., et al. Effects of chronic β-adrenergic receptor stimulation in mice. J Mol Cell Cardiol (1997) 29:2735–2746.[CrossRef][Web of Science][Medline]
  16. Vikstrom K.L., Bohlmeyer T., Factor S.M., Leinwand L.A. Hypertrophy, pathology, and molecular markers of cardiac pathogenesis. Circ Res (1998) 82:773–778.[Abstract/Free Full Text]
  17. Patten R.D., Aronovitz M.J., Deras-Mejla L., et al. Ventricular remodeling in a mouse model of myocardial infarction. Am J Physiol (1998) 274:H1812–H1820.[Web of Science][Medline]
  18. Sakata Y.J., Hoit B.D., Liggett S.B., Walsh R.A.D.G.W. Decompensation of pressure-overload hypertrophy in G{alpha}q -overexpressing mice. Circulation (1998) 97:1488–1495.[Abstract/Free Full Text]
  19. Rockman H.A., Wachhorst S.P., Mao L., Ross J. ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice. Am J Physiol (1994) 266:H2468–H2475.[Web of Science][Medline]
  20. Rockman H.A., Ross R.S., Harris A.N., et al. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc Natl Acad Sci USA (1991) 88:8277–8281.[Abstract/Free Full Text]
  21. Garcia R., Diebold S. Simple, rapid, and effective method of producing aortocaval shunts in the rat. Cardiovasc Res (1990) 24:430–432.[Abstract/Free Full Text]
  22. Gutkowska J., Bonan R., Roy D., et al. Atrial natriuretic factor in human plasma. Biochem Biophys Res Commun (1986) 139:287–295.[CrossRef][Web of Science][Medline]
  23. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem (1987) 162:156–159.[Web of Science][Medline]
  24. Liu Z., Hilbelink D.R., Crockett W.B., Gerdes A.M. Regional changes in hemodynamics and cardiac myocyte size in rats with aortocaval fistulas. 1. Developing and established hypertrophy. Circ Res (1991) 69:52–58.[Abstract/Free Full Text]
  25. Liu Z., Hilbelink D.R., Gerdes A.M. Regional changes in hemodynamics and cardiac myocyte size in rats with aortocaval fistulas. Circ Res (1991) 69:59–65.[Abstract/Free Full Text]
  26. Willenbrock R., Scheuermann M., Thibault G., et al. Angiotensin inhibition and atrial natriuretic peptide release after acute volume expansion in rats with aortocaval shunt. Cardiovasc Res (1999) 42:733–742.[Abstract/Free Full Text]
  27. Willenbrock R., Stauss H., Scheuermann M., Osterziel K.J., Unger T., Dietz R. Effect of chronic volume overload on baroreflex control of heart rate and sympathetic nerve activity. Am J Physiol (1997) 273:H2580–H2585.[Web of Science][Medline]
  28. Tsutamoto T., Bito K., Kinoshita M. Plasma atrial natriuretic polypeptides as an index of left ventricular end-diastolic pressure in patients with chronic left-sided heart failure. Am Heart J (1989) 117:599–606.[CrossRef][Web of Science][Medline]
  29. Wei C.M., Heublein D.M., Perrella M.A., et al. Natriuretic peptide system in human heart failure. Circulation (1993) 88:1004–1009.[Abstract/Free Full Text]
  30. Azizi C., Maistre G., Kalotka H., et al. Plasma levels and molecular forms of proatrial natriuretic peptides in healthy subjects and in patients with congestive heart failure. J Endocrinol (1996) 148:51–57.[Abstract/Free Full Text]
  31. Yamamoto K., Burnett J.C.J., Redfield M.M. Effect of endogenous natriuretic peptide system on ventricular and coronary function in failing heart. Am J Physiol (1997) 273:H2406–H2414.[Web of Science][Medline]
  32. Cowie M.R., Struthers A.D., Wood D.A., Coats A.J.S., Thompson S.G., Poole-Wilson P.A. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet (1997) 350:1347–1351.
  33. Saito Y., Nakao K., Arai H., et al. Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart. J Clin Invest (1989) 83:298–305.[Web of Science][Medline]
  34. Lattion A.L., Michel J.B., Arnauld E., Corvol P., Soubrier F. Myocardial recruitment during ANF mRNA increase with volume overload in the rat. Am J Physiol (1986) 251:H890–H896.[Web of Science][Medline]
  35. Grantham J.A., Borgeson D.D., Burnett J.C.J. BNP: pathophysiological and potential therapeutic roles in acute congestive heart failure. Am J Physiol (1997) 272:R1077–R1083.[Web of Science][Medline]
  36. Anderson E.A., Wallin B.G., Mark A.L. Dissociation of sympathetic nerve activity in arm and leg muscle during mental stress. Hypertension (1987) 9:III114–III119.[Medline]
  37. Magga J., Vuolteenaho O., Tokola H., Marttila M., Ruskoaho H. Involvement of transcriptional and posttranscriptional mechanisms in cardiac overload-induced increase of B-type natriuretic peptide gene expression. Circ Res (1997) 81:694–702.[Abstract/Free Full Text]
  38. Langenickel T., Pagel I., Höhnel K., Dietz R., Willenbrock R. Differential regulation of cardiac ANP and BNP mRNA in different stages of experimental heart failure. Am J Physiol (2000) 278:H1500–H1506.[Web of Science]
  39. Luchner A., Stevens T.L., Borgeson D.D., et al. Differential atrial and ventricular expression of myocardial BNP during evolution of heart failure. Am J Physiol (1998) 274:H1684–H1689.[Web of Science][Medline]

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