European Journal of Heart Failure

European Journal of Heart Failure 2006 8(8):777-783; doi:10.1016/j.ejheart.2006.03.001

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© 2006 European Society of Cardiology

Type II diabetic mice exhibit contractile dysfunction but maintain cardiac output by favourable loading conditions

An Van den Bergh, Willem Flameng and Paul Herijgers^*

Laboratory of Experimental Cardiac Surgery K.U. Leuven, Provisorium I, Minderbroedersstraat 17, 3000 Leuven, Belgium

^* Corresponding author. Tel.: +32 16 337298; fax: +32 16 337855. E-mail address: paul.herijgers{at}med.kuleuven.be

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusion Acknowledgments References

 
Background: Cardiomyopathy in type II diabetes is incompletely understood. The leptin receptor-deficient (db/db) mouse is a well-accepted model of type II diabetes. To date, left ventricular contractility has not been studied in animal models of type II diabetes with in vivo load-independent parameters.

Aim: To determine cardiac function in db/db mice in vivo.

Methods: Cardiac function in 12- and 24-week-old db/db and wild-type mice was assessed using a microtip-pressure-conductance catheter.

Results: Left ventricular contractile dysfunction, measured by load-independent parameters (preload recruitable stroke work, end-systolic elastance, dP/dt-V_ed), is present in diabetic mice from age 24 weeks onwards. Despite this contractile dysfunction, the conventional parameters cardiac output, ejection fraction and dP/dt_max were maintained, which was due to an increased preload and decreased afterload. Ventriculo-arterial coupling was increased and mechanical efficiency significantly reduced in db/db mice.

Conclusion: Our results demonstrate that, despite impaired cardiac contractility and mechanical efficiency, cardiac output is maintained in db/db mice by favourable loading conditions and that in vivo load-independent measurements are necessary to fully characterize cardiac performance in animal models of pathophysiological states.

Key Words: Contractility • Diabetes • Obesity

Received September 20, 2005; Revised November 29, 2005; Accepted March 8, 2006

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusion Acknowledgments References

 
Epidemiological and clinical evidence shows that type II diabetes mellitus is associated with cardiomyopathy, independent of other risk factors that are often associated with diabetes, such as coronary heart disease and hypertension [1]. Several small animal models of type II diabetes, which differ in the onset and severity of the diabetic status, are available [2]. The characterization of the cardiac phenotype in these experimental models is necessary in order to unravel the mechanisms of this diabetic cardiomyopathy and devise potential therapeutic measures. In most of the studies performed to date in these models, isolated heart preparations have been employed [3-6]. These in vitro studies provide the opportunity to quantify isolated ventricular chamber performance without the effects of neural control, ventricular vascular coupling and with defined loading conditions.

Undoubtedly, many valuable data can be obtained about cardiac performance and metabolism by use of ex vivo measurements in a Langendorff setup. However, some caveats must be attached when interpreting these data. Besides the possibility that diabetic hearts may be more sensitive to the trauma associated with isolation and perfusion, difficulties may arise when trying to mimic the in vivo situation, since the perfusate of the control group should have low glucose, low fatty acids (FA) and normal insulin levels, while the perfusate of the diabetic group should have high glucose, high FA and high insulin levels. However, in most studies, identical perfusates are used in both groups [3-5]. Moreover, diabetes is associated with a switch in myocardial substrate utilization [7], which might contribute to altered contractile function and efficiency [8-10]. As a consequence, the comparison of cardiac contractility between wild-type and diabetic mice using the same perfusate might not reflect the situation in vivo. Therefore, precise in vivo measurements are needed to characterize cardiac performance and contractility in diabetic hearts.

The leptin receptor-deficient db/db mouse is a well-established model of type II diabetes. In an isolated working heart setup (11 mM glucose, 0.7 mM FA, no insulin), hearts of these mice develop reduced cardiac mechanical performance, with an increase in left ventricular (LV) end-diastolic pressure, decreased LV developed pressure, and reductions in both cardiac output and cardiac power [4]. In vivo echocardiographic measurements in the same mice showed a decrease in fractional shortening (FS), velocity of circumferential fiber shortening (V_cf) and E/A ratio [11]. However, these measurements are highly influenced by loading conditions and heart rate.

The aim of this study was to investigate the in vivo cardiac phenotype of the db/db mouse at an early (12 weeks) and more advanced stage (24 weeks) of type II diabetes. To our knowledge, this is the first study to determine in vivo cardiac performance in a load-dependent and -independent way in mouse models of type II diabetes.

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusion Acknowledgments References

 
2.1. Experimental animals
In vivo cardiac function was assessed in C57BL/6J (WT) (n=24) and db/db (n=16) mice at 12 or 24 weeks of age, reflecting an early and a more advanced stage of diabetes. Db/db mice on a C57BL/6J background develop hyperphagia, obesity and insulin resistance, but their diabetic phenotype is less severe compared to the db/db mouse on a KsJ background [12]. We therefore studied somewhat older mice (12 and 24 weeks of age) compared with previous studies performed to date in db/db mice on KsJ background [3,4,11]. Body weight and plasma glucose levels of 12- and 24-week-old db/db and age-matched WT mice are shown in Table 1. The groups were sex-matched. Mice were purchased from Jackson Laboratory (Bar Harbor, Maine, USA). The investigation 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 1985).

View this table: [in this window] [in a new window]   Table 1 Comparison of haemodynamic variables for 12- and 24-week-old WT and db/db mice

 
2.2. In vivo haemodynamic measurements
Mice were anesthetized with a mixture of urethane (1200 mg/kg) and alpha-chloralose (50 mg/kg), injected intraperitoneally [13]. A tracheotomy was performed and the mice were mechanically ventilated (Minivent 845; Hugo Sachs/Harvard Apparatus, March-Hugstetten, Germany). Body temperature was maintained with a heating pad and monitored with a rectal probe. A pre-calibrated four-electrode pressure sensor catheter (1.4-Fr, SPR-839; Millar Instruments, Houston, TX) was inserted in the right carotid artery and advanced into the left ventricle to measure instantaneous intraventricular pressure and volume. After stabilization, steady-state measurements were recorded. Subsequently, left ventricular preload was decreased by occlusion of the inferior vena cava via a small laparotomy, to derive load-independent parameters of contractility. The parallel conductance attributed to the tissues surrounding the left ventricular cavity was estimated by injection of a 10 µl bolus of 30% saline into the jugular vein. During data acquisition (Powerlab/4SP ADInstruments, Castle Hill, Australia), the ventilation was momentarily turned off to avoid respiratory fluctuation of cardiac signals. Blood conductance was determined at the end of each experiment using four cylindrical chambers with known volume, loaded with fresh heparinized blood from each individual.

Analysis was performed with PVAN 2.9 software (Millar Instruments, Houston, TX). All data are the average of at least five measurements during the experiment, each measurement representing at least 10 successive loops. Steady-state measurements were used to obtain values for heart rate (HR), end-systolic volume (V_es), end-diastolic volume (V_ed), end-systolic pressure (P_es), end-diastolic pressure (P_ed), maximum pressure (P_max), minimum pressure (P_min), stroke volume (SV), ejection fraction (EF), cardiac output (CO), cardiac index (CI), stroke work (SW), arterial elastance (E_a), peak instantaneous rate of left ventricular pressure increase and decline (dP/dt_max, dP/dt_min) and the time constant of isovolumic left ventricular pressure decline (tau). Regression analysis of loops obtained during caval vein compression revealed values for end-systolic elastance (E_es) (Fig. 1A), preload recruitable stroke work (PRSW) (Fig. 1B), the slope of the dP/dt_max-V_ed relationship (slope dP/dt_max-V_ed) (Fig. 1C), the exponential fit of the end-diastolic pressure-volume relationship (EDPVR-exp), the ventriculo-arterial coupling ratio (E_a/E_es), the pressure-volume area (PVA) (defined as the sum of the area enclosed by the p-V loop (SW) and the triangular area delimited by the ESPVR, the EDPVR and the descending limb of the p-V loop (potential energy, PE)) and the cardiac mechanical efficiency (SW/PVA).

View larger version (9K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 (A) Representative example of pressure-volume relationships during temporary preload reduction in a WT () mouse and a db/db () mouse (24 weeks of age). Ees and slopeEDPVR are the slopes of the end-systolic, respectively, end-diastolic pressure-volume relationship. (B) SW-Ved relationship in a representative WT () and db/db () mouse at 24 weeks of age. The slope of this relationship is a parameter for contractility and is lower in the db/db mouse compared with the WT mouse. (C) dP/dtmax-Ved relationship in a representative WT () and db/db () mouse at 24 weeks of age. The slope of this relationship is a parameter for contractility and is lower in the db/db mouse compared with the WT mouse.

 
2.2.1. Statistical analysis
Data are expressed as mean±S.D. Differences between groups were compared by Student's t-test (Statistica 6.0, Statsoft, Tulsa, OK). A value of p<0.05 was considered significant.

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusion Acknowledgments References

 
The results of the comparison of the haemodynamic variables in WT versus db/db mice at 12 and 24 weeks are presented in Table 1.

3.1. Comparison of WT and db/db mice at 12 weeks of age
Heart rates were equal in the two groups. End-diastolic volume was comparable in both groups (Fig. 2A), while end-systolic volume was smaller in db/db mice (8.8±3.3 µl) versus WT mice (13.0±3.6 µl). Measurements of LV pressures revealed no differences between WT and db/db mice. The conventional, but load-dependent parameters of contractility, ejection fraction and dP/dt_max, were significantly higher in db/db mice (respectively 69.3±7.4% and 9539±1371 mm Hg/s) versus WT mice (52.7±7.4% and 6723±1474 mm Hg/s). Arterial elastance, a parameter for afterload, was significantly lower in db/db mice (4.6±0.5 mm Hg/µl) versus WT mice (7.0±1.5 mm Hg/µl) (Fig. 2B). The load-independent parameter of contractility end-systolic elastance (E_es) was lower in db/db than in WT (5.2±1.7 mm Hg/µl in db/db versus 8.2±2.3 mm Hg/µl in WT). PRSW (Fig. 2D) and dP/dt-V_ed were not different for diabetic db/db mice at 12 weeks. Parameters for diastolic function (dP/dt_min, tau, EDPVR-exp) did not reveal any difference between the two groups. Cardiac output was significantly higher in db/db mice (9166±1645 µl/min) versus WT (6615±1198 µl/min) (Fig. 2C), while cardiac index was significantly lower in db/db mice (207±32 µl/min/g) versus WT (275±55 µl/min/g). Ventriculo-arterial coupling, as described by E_a/E_es, and cardiac mechanical efficiency, as calculated by SW/PVA (Fig. 2E), were comparable in both groups.

View larger version (15K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 (A) End-diastolic volume (Ved), (B) arterial elastance (Ea), (C) cardiac output (CO), (D) preload recruitable stroke work (PRSW) and (E) SW versus PVA relationship (SW/PVA) in function of age, for WT () and db/db () mice. Data are represented as mean±S.E.M.

 
3.2. Comparison of WT and db/db mice at 24 weeks of age
No statistical differences in HR between db/db and WT mice at 24 weeks were observed. End-diastolic volume was significantly higher in db/db mice (34.8±6.6 µl) versus WT (27.7±8.2 µl) (Fig. 2A); end-systolic volume was comparable. End-systolic pressure was significantly lower in db/db mice (67.9±5.4 mm Hg) versus WT (83.9±11.7 mm Hg), whereas end-diastolic pressure was significantly higher in db/db mice (5.1±1.2 mm Hg) versus WT (1.5±1.3 mm Hg). Arterial elastance was still significantly lower in db/db mice, when compared with WT (2.8±0.7 mm Hg/µl in db/db versus 6.1±1.6 mm Hg/µl in WT) (Fig. 2B). In contrast to the results at 12 weeks of age, dP/dt_max in db/db was comparable to WT at 24 weeks EF was still slightly higher compared to WT. All load-independent contractility parameters were worse in db/db mice than in WT mice at 24 weeks (E_es, 2.5±0.8 mm Hg/µl in db/db versus 9.1±2.8 mm Hg/µl in WT; PRSW, 58.6±15.1 mm Hg in db/db versus 80.3±11.6 mm Hg in WT; dP/dt_max-V_ed, 216±82 mm Hg µl/s in db/db versus 436±129 mm Hg µl/s in WT) (Fig. 1A,B,C). A significant reduction was evident in relaxation in db/db mice at 24 weeks of age (dP/dt_min, –5821±1256 mm Hg/s in db/db versus –7485±1485 mm Hg/s in WT; tau, 6.4±1.2 ms in db/db versus 5.4±0.7 ms in WT). Ventricular stiffness, described by the exponential fit of the end-diastolic pressure-volume relationship (EDPVR-exp), was unchanged in db/db mice. Cardiac output was still significantly higher in db/db mice (13,008±4120 µl/min) versus WT (8187±2837 µl/min) (Fig. 2C), and cardiac index was still significantly lower in db/db mice (217±80 µl/min/g) versus WT (302±61 µl/min/g). Ventriculo-arterial coupling was higher in db/db mice (1.19±0.28) compared with WT (0.72±0.23). Mechanical efficiency was significantly reduced in db/db mice (0.54±0.06 in db/db versus 0.63±0.06 in WT) (Fig. 2E).

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusion Acknowledgments References

 
To our knowledge, this is the first study to determine in vivo cardiac performance in a load-dependent and -independent way in a mouse model with type II diabetes. A decrease in contractile function of the LV is demonstrated in type II diabetic mice with increasing age. However, despite the impaired contractility, cardiac output was increased, which can be attributed to the favourable loading conditions, with increased preload and low afterload. The mechanical efficiency (SW/PVA) however was significantly reduced. Of course, the influence of body weight on some haemodynamic variables should not be ignored. Correction of the variables can be made by dividing through body weight. However, in morbidly obese animals (like the db/db mouse), body weight is predominantly increased by an increase in abdominal fat. It is uncertain whether the large abdominal mass receives a comparable amount of blood flow as other vital organs. This might lead to an ‘overcorrection’ of the parameter when divided through body weight.

4.1. Systolic function
Systolic function, as determined by the conventional parameters EF and dP/dt_max, was higher in 12-week-old db/db mice when compared with WT. At 24 weeks, however, EF remained high, whereas dP/dt_max decreased slightly, to a level comparable with WT. Ventricular systolic function is dependent not only on intrinsic myocardial contractility, but also on heart rate and loading conditions. Even though HR was somewhat lower in the db/db mice at 24 weeks, it was still in the range where mouse hearts display minimal force-frequency dependence [14]. Preload, described by V_ed and P_ed was comparable in db/db and WT at 12 weeks of age, but at 24 weeks preload was markedly higher in db/db mice. E_a, as a parameter for afterload, was lower at both ages in db/db mice than in WT. Thus, the reported EF and dP/dt_max in 12- and 24-week-old db/db mice could be caused by the differences in ventricular loading conditions or by differences in intrinsic contractility. Load-independent parameters of contractility can be derived from the pressure-volume relationship. Our data show an age-dependent decrease in E_es, PRSW and dP/dt_max-V_ed in diabetic mice, which was not observed in the WT (Fig. 1A,B,C). The apparently improved systolic function in db/db mice at 12 weeks of age, as evaluated by EF and dP/dt_max, could therefore be explained by alterations in loading conditions and not by an increase in intrinsic contractility.

Barouch et al. reported echocardiographically in 24-week-old db/db mice on C57BL/6J background an unchanged fractional shortening (FS), which is a load-dependent measure of systolic function [15]. However, FS is not very sensitive for small differences and thus might have missed the differences we observed [16]. Wall thickness, LV mass and myocyte diameters were reported to be larger in the db/db mice compared to WT, indicating a hypertrophied myocardium [15]. This might be related to an increase in afterload or to direct cardiac factors. Since we have shown in this study that afterload was significantly lower in 24-week-old db/db mice, we presume that the observed features on cardiac morphology in these mice were attributable to direct hypertrophic effects of the absent leptin signalling, in accordance with the findings of Barouch in ob/ob mice [15]. A comparable FS, together with a decreased afterload, unchanged cavity dimensions and LV hypertrophy, indicate a worse intrinsic contractile function, which is consistent with our measurements. Thus, db/db mice on C57BL/6J background develop contractile dysfunction, but can nevertheless preserve the routinely used load-dependent parameters of contractility by alterations in loading conditions. It has to be kept in mind that the interaction of genotype and background might play an important role in the cardiac phenotype too. As previously mentioned, db/db mice on a KsJ background develop a more severe diabetic phenotype compared with db/db mice on a C57BL/6J background. The latter are more severely insulin resistant but less hyperglycaemic compared with the former mice [12]. Db/db mice on C57BL/6J background develop higher plasma FA levels compared with db/db mice on KsJ background [17]. These metabolic differences might have an impact on cardiovascular function and subsequently they might explain the differential evolution of cardiac performance in both strains of db/db mice [4,11,17].

4.2. Diastolic function
Measurements of diastolic function can be divided into those that reflect the process of active relaxation and those that reflect passive stiffness [18]. In vivo diastolic function has not been evaluated in db/db mice on C57BL/6J background to date. Active relaxation, as determined by dP/dt_min and tau, was impaired in db/db mice from the age of 24 weeks onwards, whereas passive stiffness, as determined by EDPVR-exp, did not reveal any dysfunction in the db/db mice, compared with WT. In db/db mice on KsJ background, in vivo diastolic function is also impaired, as evaluated echocardiographically [11]; however, it is still unclear whether this impairment is attributable to abnormal relaxation, increased stiffness or both. Interstitial deposits of collagen, however, were observed in db/db hearts on KsJ background [21], which could increase myocardial stiffness and reduce diastolic function, although this remains speculative until more precise measurements are performed.

4.3. LV mechanical efficiency
The most accepted definition of total mechanical work is Suga's concept of the PVA [22]. PVA represents the amount of energy generated by the left ventricle and is defined as the sum of external mechanical work (SW), and the potential energy necessary to overcome the viscoelastic properties of the myocardium itself. It is generally accepted that PVA is directly correlated with myocardial oxygen consumption [23]. Therefore, it can be used to evaluate the coupling of LV mechanical performance to energy use [24]. The cardiac mechanical efficiency can be defined by the SW-to-PVA ratio, representing the amount of energy that can be transformed into external work. Our results demonstrated a significantly lower LV mechanical efficiency in db/db mice from the age of 24 weeks onwards, compared with WT.

Another index to define cardiac efficiency is the ventriculo-arterial coupling ratio (E_a/E_es).Our results demonstrated an increase in E_a/E_es ratio in 24-week-old db/db mice, and thus a decrease in mechanical efficiency compared with WT [25] and this despite a decrease in E_a. E_es decreases to an even larger extent than E_a, resulting in an increase in E_a/E_es ratio.

Decreased cardiac efficiency may be attributable to inefficient oxygen-use for ATP-production (energy efficiency) or to inefficient transfer of energy from total mechanical energy of the ventricle into effective delivered external work (mechanical efficiency). We report an age-dependent decrease in cardiac mechanical efficiency in db/db mice from the age of 24 weeks onwards. To the best of our knowledge, in vivo mechanical efficiency was not yet reported in diabetic mouse models. The observed decreased mechanical efficiency might be related to a decreased energy efficiency, since ATP production from FA metabolization requires more oxygen, compared with glucose utilization [5], and since diabetic hearts are known to have an over reliance on FA to extract energy [7], although our results cannot directly confirm this. Recently, the influence of substrate supply on cardiac energy efficiency has been studied in ex vivo murine preparations [6,8]. A decreased cardiac energy efficiency in response to increased rates of cardiac fatty acid metabolism was observed. Interestingly, it was recently reported that obese women with insulin resistance exhibited decreased myocardial efficiency, which was linked to increased fatty acid uptake [26].

	5. Conclusion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusion Acknowledgments References

 
Phenotyping of ventricular function ex vivo could differ from in vivo assessments. Therefore, ventricular function should also be tested in vivo in order to characterize the exact cardiac phenotype. By use of pressure-volume analysis, cardiac performance can be accurately determined on a load-dependent and -independent way. Although cardiac contractility, active relaxation and cardiac efficiency were impaired in db/db mice from the age of 24 weeks onwards, cardiac output was preserved, which was attributable to the favourable loading conditions.

	Acknowledgments

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusion Acknowledgments References

 
An Van den Bergh received a pre-doctoral bursary of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-SB/23231). This research was supported by funds from a Research Programme of the Research Foundation-Flanders (FWO-Vlaanderen, G.0381.05 to Paul Herijgers) and the Onderzoeksfonds K.U. Leuven/Research Fund K.U. Leuven (OT05/55 to Paul Herijgers).

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