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Am J Physiol Heart Circ Physiol 294: H867-H874, 2008. First published November 30, 2007; doi:10.1152/ajpheart.00573.2007
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Temporal changes in cardiac force- and flow-generation capacity, loading conditions, and mechanical efficiency in streptozotocin-induced diabetic rats

Dong-Feng Yeih,1,2 Lian-Yu Lin,2 Hung-I Yeh,3 Yu-Jun Lai,3 Fu-Tien Chiang,2 Chuen-Den Tseng,2 Shu-Hsun Chu,1 and Yung-Zu Tseng2,4

1Department of Cardiology, Far Eastern Memorial Hospital, Pan-Chiao, Taipei; 3Departments of Internal Medicine and Medical Research, Mackay Memorial Hospital; Mackay Medicine, Nursing and Management College, Taipei Medical University, Taipei; 2Department of Internal Medicine, National Taiwan University Hospital, Taipei; and 4Department of Cardiology, Show Chwan Memorial Hospital, Chang-Hua, Taiwan

Submitted 17 May 2007 ; accepted in final form 24 November 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
 APPENDIX B
 GRANTS
 REFERENCES
 
Diabetes mellitus may result in impaired cardiac contractility, but the underlying mechanisms remain unclear. We aimed to investigate the temporal alterations in cardiac force- and flow-generation capacity and loading conditions as well as mechanical efficiency in the evolution of systolic dysfunction in streptozotocin (STZ)-induced diabetic rats. Adult male Wistar rats were randomized into control and STZ-induced diabetic groups. Invasive hemodynamic studies were done at 8, 16, and 22 wk post-STZ injection. Maximal systolic elastance (Emax) and maximum theoretical flow (Qmax) were assessed by curve-fitting techniques, and ventriculoarterial coupling and mechanical efficiency were assessed by a single-beat estimation technique. In contrast to early occurring and persistently depressed Emax, Qmax progressively increased with time but was decreased at 22 wk post-STZ injection, which temporally correlated with the changes in cardiac output. The favorable loading conditions enhanced stroke volume and Qmax, whereas ventriculoarterial uncoupling attenuated the cardiac mechanical efficiency in diabetic animals. The changes in Emax and Qmax are discordant during the progression of contractile dysfunction in the diabetic heart. In conclusion, our study showed that depressed Qmax and cardiac mechanical efficiency, occurring preceding overt systolic heart failure, are two major determinants of deteriorating cardiac performance in diabetic rats.

diabetes; contractile function; hemodynamics; mechanical efficiency; ventriculoarterial coupling

HEART FAILURE is one of the leading causes of morbidity and mortality in the diabetic population (49). Both insulin-dependent and non-insulin-dependent diabetes mellitus may result in depressed myocardial contractility in the absence of coronary artery disease and hypertension (19, 34, 35). Streptozotocin (STZ)-induced diabetic animals have been widely used to study the natural course and molecular mechanisms of diabetic cardiac dysfunction (25, 35). In most studies performed to date using diabetic animals, isolated heart preparations have provided valuable data regarding ventricular performance and cardiac metabolism under defined loading conditions (13, 16, 39, 46), without the effects of neural regulation and ventriculoarterial interaction. However, the diabetic hearts are sensitive to trauma and ischemia associated with the procedures of isolation and perfusion (48). In addition, the diabetic hearts are associated with altered myocardial substrate metabolism (1). However, identical perfusates are applied to hearts from both control and diabetic animals in most studies (16, 39, 46), which might lead to altered cardiac contractility and efficiency of energy transfer in diabetic hearts. Therefore, precise in vivo measurements are necessary to characterize the cardiac contractility and performance in diabetic animals.

It was once thought that instantaneous ventricular pressure was uniquely dependent on instantaneous ventricular volume in terms of time-varying elastance theory (40). However, accumulated evidence has shown that flow is also an independent determinant of left ventricular (LV) pressure (4, 36, 47). The ejecting flow decreases LV pressure, and the inverse linear relationship between LV pressure and flow has been conceptualized as an expression of the internal resistance of the LV. Two independent parameters generated in the elastance-resistance LV pump model to characterize systolic functions of the LV are the maximal systolic elastance (Emax) and the theoretical maximal flow (Qmax). Both Emax and Qmax quantify two separate facets of cardiac pumping function: capacity of force generation and capacity of flow generation. Emax, conceptually equivalent to tension generated by the muscle, is sensitive to changes in contractile state and is independent of loading conditions and heart rate (17). Qmax, which is conceptually equivalent to the maximal unloaded velocity of shortening in the muscle, is the amount of outflow generated by LV at zero pressure (47).

Depression of cardiac contractility has been observed in STZ diabetic rats as early as 4–8 wk post-STZ injection (10), and overt contractile dysfunction is generally developed 1 yr after the onset of diabetes (51). However, the temporal changes in cardiac mechanics and the underlying mechanisms in the evolution of systolic dysfunction remain unclear in STZ-induced diabetic rats. In this study, we therefore investigated the temporal alternations in cardiac Emax and Qmax, loading conditions, and mechanical efficiency (ME) in STZ-induced diabetic rats by using the elastance-resistance LV model.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 APPENDIX A
 APPENDIX B
 GRANTS
 REFERENCES
 
Animal preparations. This study was conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH Publications No. 85-23, revised 1996), and all procedures were approved by the Animal Care and Use Committee of the Far Eastern Memorial Hospital. Eight-week-old male Wistar rats (250–300 g), housed at 22°C with a 12:12-h light-dark cycle and free access to rodent chow and tap water, were anesthetized with ketamine (40 mg/kg) and injected with STZ (60 mg/kg) or vehicle (0.9% saline) via the penile vein. Later (48 h), whole blood obtained from the tail vein was used for glucose monitoring by a glucometer (Accu-Chek; Roche Diagnostics, Indianapolis, IN). STZ-treated rats with whole blood glucose levels <15 mmol/l or body weights exceeding 380 gram were excluded from the study.

Assessment of LV performance. Rats were examined using invasive hemodynamic studies at 8, 16, and 22 wk post-STZ injection. Rats were anesthetized with ketamine (60 mg/kg ip) and intubated for mechanical ventilation with a tidal volume of 15 ml/kg at a rate of 70–80 breaths/min. The chest was opened, a small incision was made in the LV apex, and a 2-Fr Millar catheter (Millar Instruments, Houston, TX) was introduced in the LV. A perivascular ultrasonic flowmeter (model T402; Transonic Systems, Ithaca, NY) was attached to the ascending aorta via the right second intercostal space to measure the pulsatile aortic flow. The electrocardiogram (ECG) of lead II was recorded with an amplifier (ML136 Animal BioAmp; ADInstruments, Sydney, Australia). After hemodynamics were stabilized, LV pressure, aortic flow, and ECG signals were digitized simultaneously at 1,000 Hz by using a data acquisition system (PowerLab/4SP; ADInstruments) and displayed on computer using Chart 5 software for Windows (ADInstruments). Four consecutive beats were obtained and averaged in the time domain. The resulting LV pressure and ascending aortic flow were subjected to further analysis as previously described (8). Briefly, we obtained the estimated instantaneous isovolumic contraction pressure [Piso(t)] from the measured LV pressure of an ejecting beat by fitting the isovolumic portions of the measured LV pressure curve with a sinusoidal function proposed by Sunagawa and coworkers (43) (see APPENDIX A for details). The estimated peak isovolumic pressure (Pisomax) is defined as the maximal value of Piso(t). Figure 1 displays the time course of LV pressures of both measured ejecting contraction and Piso(t). Second, the derived Piso(t) was then applied to the elastance-resistance model to find the optimal values of Qmax and effective end-diastolic volume (Veed) that minimized the difference between the measured and model-derived LV pressures at the time interval between the onset of ventricular ejection and the time of Pisomax (4, 8) (see APPENDIX B for details). The goodness of fit of model-derived LV pressure is determined by both Pearson's correlation coefficient method and standard error of the estimate (SEE). We looked for the coefficient of determination (r2) to be close to one and for SEE to be on the order of 5% or less when expressed relative to the observed mean LV pressure. The Emax can be calculated by the formula Emax = Pisomax/Veed. Considering the effect of cardiac size on determination of systolic elastance and maximal flow, Emax, was normalized by multiplying the LV weight (34a), whereas Qmax was normalized by dividing by the LV weight (36) for comparisons between control and diabetic rats.


Figure 1
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  		Fig. 1. Estimation of isovolumic pressure of the left ventricle from an ejecting beat in rats. The solid curve indicates the measured left ventricular pressure and the dashed line indicates the estimated isovolumic contraction pressure curve. LVP, left ventricular pressure.

 
Effects of elevated afterload on measurement of Qmax. To study changes in Qmax in response to elevated afterload in each rat, we abruptly constricted the ascending aorta using a 3.0 silk suture to increase the LV systolic pressure by 10 mmHg immediately after manual constriction. Meanwhile, LV pressure, aortic flow, and ECG signals were recorded simultaneously. To avoid the Anrep effect (31) on determination of Emax and Qmax, only the first two consecutive beats after aortic constriction were subjected to analysis using the elastance-resistance model, as described above.

Estimation of end-systolic elastance, effective arterial elastance, and ventriculoarterial coupling. We used a single beat estimation technique to evaluate end-systolic elastance (Es) of the LV, as previously described (20, 43, 45). Briefly, we drew a tangential line from Pisomax to the right corner of the pressure-stroke volume (SV) loop, yielding a point referred to as the end-systolic equilibrium point (Fig. 2). The pressure at the equilibrium point was defined as the end-systolic pressure (Pes), and the slope of this line represented Es. The effective arterial elastance (Ea), the ratio of Pes to SV, was used to characterize the afterload of the LV (20, 41). The concept of ventriculoarterial coupling derived from the pressure-SV relationship was then applied to analyze the cardiac ME and hydraulic energy transfer from the LV to the aorta. The optimal afterload (Qload), defined as that which extracts the maximal external work from a heart with a given preload and contractility, was used to determine the efficiency of energy transmission from the LV to the aorta and is written as follows (22):

Formula 1(1)


Figure 2
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  		Fig. 2. Relationship between LVP and stroke volume. The absolute value of the slope of the solid line connecting estimated peak isovolumic pressure (Pisomax) to the end-systolic equilibrium point represents end-systolic elastance (Es) while the slope of the dotted line connecting the end-diastolic point to the end-systolic equilibrium point represents effective arterial elastance (Ea).

 
The cardiac ME is defined as the ratio of stroke work (SW) to the pressure-volume area (PVA) of the LV, and was determined as follows (18):

Formula 2(2)

Expression of endothelial nitric oxide synthase. To investigate the molecular mechanism of the temporal changes in afterload, the protein expression of aortic endothelial nitric oxide synthase (eNOS) was analyzed in diabetic rats 8 and 22 wk post STZ injection and in the control rats, respectively. Segments of endothelium-intact thoracic aorta were washed with cold PBS and were chilled in lysis buffer containing 50 mM Tris·HCl, 0.1 mM EDTA, 0.1 mM EGTA, 0.1% SDS, 0.1% Nonidet P-40, and 0.5% deoxycholate. Phenylmethylsulfonyl fluoride (1 mM), aprotonin (10 µg/ml), leupeptin (10 µg/ml), and pepstatin (10 µg/ml) were added as the protease inhibitors (all purchased from Sigma Chemicals). Tissues were then homogenized in lysis buffer, followed by centrifugation at 10,000 g for 15 min at 4°C. The supernatants were collected, and total protein concentration was determined by bicinchoninic acid protein assay reagent (Pierce). Protein (20 µg) was loaded on an 8% SDS-PAGE. The resolved proteins were then transferred to a nitrocellulose membrane. Blots were blocked in 5% skimmed milk in PBS for 1 h and then incubated with anti-eNOS (1:1,000; Transduction Laboratories) overnight at 4°C. The membranes were then stripped and reprobed with anti-β-actin antibody (1:20,000; Sigma Chemicals) for calibration of protein loading. After washing, horseradish-peroxidase-linked secondary antibody was added (1:5,000; Chemicon). Chemiluminescence detection was performed with a Western blotting enhanced chemiluminescence system (Millipore) and exposed to X-ray films. The autoradiographs were analyzed by densitometry software (Fuji film).

Statistical analysis. There were eight animals in each experimental group. Data for each group are expressed as means ± SE. The statistical significance of differences between mean values was assessed by the unpaired t-test or two-way ANOVA. A value of P < 0.05 was considered significant. Two-way ANOVA was used to test for significant differences in the effect of 1) diabetes; 2) age; and 3) the interaction of diabetes x age. The Bonferroni post hoc test was applied to assess significant differences in the effect of diabetes at 8, 16, and 22 wk post-STZ injection. Pearson correlation coefficient analysis was used to determine the relationship between two variables.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 APPENDIX A
 APPENDIX B
 GRANTS
 REFERENCES
 
Body and heart weights, blood glucose, and baseline hemodynamics. Fewer than 5% of STZ-treated rats were excluded from the experiment by the criteria mentioned above. Table 1 shows that, during the study, the body weight, heart weight, and heart rate were significantly lower in the diabetic animals than their age-matched controls (all P < 0.05); normalized LV weight (= wet LV weight/body weight) and blood glucose were significantly higher. SV and cardiac output (CO) values gradually increased with age in control rats, whereas diabetic animals had an initial rise at 16 wk post-STZ injection followed by a significant fall at 22 wk postinjection (P < 0.05, Table 1). Compared with age-matched controls, diabetic animals had significantly higher SV and CO at 8 and 16 wk post-STZ injection (P < 0.05 for all comparisons), but these parameters significantly decreased at 22 wk post-STZ injection. There were no significant differences in LV Pes and mean aortic pressure between control and diabetic rats.


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  		Table 1. Body and heart weight, blood glucose, and baseline hemodynamics

 
Effects of diabetes on LV systolic dynamics. Emax correlated well with Es derived from single-beat estimation of the end-systolic pressure-volume relationships (P < 0.001, r = 0.986, Fig. 3). Emax was dramatically depressed as early as 8 wk post-STZ injection and remained consistently lower than values for age-matched controls at 16 and 22 wk (P < 0.05 for comparisons at all time points, Fig. 4A). Analysis showed that the normalized Emax was also significantly lower in the diabetic groups than in their age-matched controls, and, according to two-way ANOVA, this effect of diabetes was significant and independent of age (all P < 0.05, Fig. 4B).


Figure 3
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  		Fig. 3. Correlation between maximal systolic elastance and Es. See text for details. Emax, maximal systolic elastance; DM, diabetic rats; C, control rats; W, wk; r, correlation coefficient.

 

Figure 4
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  		Fig. 4. Comparisons of left ventricular (LV) systolic dynamics using the elastance-resistance model. See text for details. The black bars indicate control rats, and the gray bars indicate diabetic rats. Data are means ± SE of 6 rats/group. P < 0.05 vs. age-matched controls (*) and vs. diabetic rats 16 wk post-STZ injection (**). C, age-matched control rats; Emaxn, normalized maximal systolic elastance (=Emax x LV weight); Veed, effective end-diastolic volume; Qmax, theoretical maximal flow; Qmaxn, normalized theoretical maximal flow (= Qmax/LV weight); NS, nonsignificant.

 
Veed was increased by 66%, 73%, and 70% in diabetic rats compared with their age-matched controls at 8, 16, and 22 wk post-STZ injection, respectively (all P < 0.01, Fig. 4C). However, Pisomax remained unchanged in both diabetic and control rats of all ages (Fig. 4D). These results, that is, the unaltered Pisomax and increased Veed as well as depressed Emax, suggested that ventricular remodeling occurred early after the onset of diabetes.

On the other hand, Qmax was higher in diabetic rats at both 8 and 16 wk post-STZ injection compared with their age-matched controls (all P < 0.05, Fig. 4E). The normalized Qmax (Qmaxn) showed a trend similar to that of Qmax, suggesting an enhanced capacity of flow generation and a fall in the resistive property of cardiac mechanics in diabetic rats. By contrast, values of both Qmax and Qmaxn in rats at 22 wk post-STZ injection were significantly attenuated compared with 8 and 16 wk and had declined to levels in age-matched control groups (P < 0.05 for both, Fig. 4, E and F). Also noted, the temporal changes in Qmax and Qmaxn correlated with changes in SV and CO. Two-way ANOVA of the data revealed a significant effect of diabetes that was independent of age for both Qmax and Qmaxn. Two-way ANOVA also disclosed an effect of age on both parameters.

Effect of afterload on Qmax in control and diabetic rats. Figure 5 demonstrates the relationship between Qmax and afterload of the LV. By logarithmic transformation and Pearson correlation coefficient analysis of data for all animals, we found that Qmax was inversely proportional to Ea (P < 0.001, r = 0.642, Fig. 5A). After abrupt aortic constriction to increase the afterload, the subsequent changes in Qmaxn and Ea in control and diabetic rats again followed an inverse linear relationship after logarithmic transformation of both variables (P < 0.001, r = 0.88, Fig. 5B). These results suggested that afterload might play an essential role in modulating Qmax in both control and diabetic animals. Considering the effects of afterload on flow-generation capacity, Qmax and Qmaxn were normalized by multiplying by Ea to compare diabetic and control animals. With this adjustment, the afterload-normalized Qmax (Qmaxad) and Qmaxn (Qmaxnad) in control animals still increased with age, although not statistically significant (Fig. 5, C and D); this change was similar to that observed for Qmax and Qmaxn (Fig. 4, B and C). By contrast, the Qmaxad in diabetic rats at 8, 16, and 22 wk post-STZ injection were significantly lower compared with age-matched controls (all P < 0.05, Fig. 5C). Similarly, the Qmaxnad was significantly lower in diabetic animals at 22 wk (P < 0.05 vs. age-matched controls, Fig. 5D). According to two-way ANOVA, the effect of diabetes on Qmaxad or Qmaxnad was significant and had a significant interaction with age. The magnitude of decrease in Qmaxnad varied with age in diabetic rats in the following order: 8 wk (13%) <16 wk (24%) <22 wk (40%). On the contrast, Qmaxnad varied with age in the opposite direction in sham control rats.


Figure 5
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  		Fig. 5. Relationship between the Qmax and the effective Ea. See text for details. A shows that Qmax is inversely proportional to Ea by logarithmic transformation and Pearson correlation analysis. B displays the serial changes in Qmaxn and Ea of the baseline and the first two consecutive beats after abrupt aortic constriction in control and diabetic rats (n = 4 in each group). C and D show that Qmax and Qmaxn are attenuated significantly after being normalized to Ea in the diabetic group compared with the corresponding age-matched controls. Data are means ± SE of 6 rats/group. *P < 0.05 vs. age-matched controls. Qmaxad, afterload-adjusted Qmax; Qmaxnad, afterload-adjusted Qmaxn.

 
Cardiac loading conditions, ventriculoarterial coupling, and ME in control and diabetic rats. In addition to intrinsic myocardial contractility, cardiac performance is also dependent on preload [i.e., Veed and LV end diastolic pressure (LVEDP)] and afterload (i.e., Ea) of the LV. At early stages, LVEDP was comparable in both diabetic and control rats. However, LVEDP became significantly higher in diabetic rats from 16 wk postinjection (P < 0.05, Fig. 6A). Similarly, Veed increased with time and was higher in diabetic rats at all stages than in their age-matched controls (all P < 0.05, Fig. 4C). By contrast, Ea was depressed as early as 8 wk post-STZ injection and remained significantly lower in all the diabetic groups than values for the corresponding age-matched controls (P < 0.05, Fig. 6B). These results suggested that favorable loading conditions, with increased preload and lower afterload, occurred over time in diabetic animals. Two-way ANOVA revealed a significant effect of diabetes that was independent of age for Veed, LVEDP, and Ea.


Figure 6
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  		Fig. 6. Cardiac loading conditions, mechanical efficiency, and the efficiency of hydraulic energy transfer from the LV to the aorta in control and diabetic rats. See text for details. Data are means ± SE of 6 rats/group. *P < 0.05 and **P < 0.01 vs. age-matched controls. LVEDP, left ventricular end-diastolic pressure; SW/PVA, cardiac mechanical efficiency; Qload, the optimal afterload, which is used to determine the efficiency of hydraulic energy transfer from the LV to the aorta.

 
The energy transmission from the LV to the aorta, determined by Qload, was unchanged in diabetic rats until 22 wk postinjection when Qload became significantly higher compared with controls (P < 0.05, Fig. 6C). By contrast, cardiac ME in the diabetic animals was comparable to age-matched controls at 8 and 16 wk but became significantly lower at 22 wk post-STZ injection (P < 0.05, Fig. 6D). Two-way ANOVA revealed an effect of diabetes that was independent of age for both cardiac ME and Qload.

Aortic expression of eNOS protein. The aortic expression of eNOS protein was significantly enhanced in the diabetic rats at 8 and 22 wk post-STZ injection compared with their age-matched control rats (P < 0.01, Fig. 7, A and B). However, the magnitude of increase varied with age in the following order: 8 wk (8.3-fold) >22 wk (3.9-fold). Two-way ANOVA of the data revealed a significant effect of age, with the impact of the diabetes being significant and dependent on age.


Figure 7
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  		Fig. 7. Analysis of endothelial nitric oxide synthase (eNOS) protein expressed in the aortas. A: representative Western blots show the expression of eNOS in different groups of animals. Blot on bottom shows the expression of the constitutive protein β-actin. B: bar chart of the densitometric values in arbitrary units. Data are means ± SE of 4 rats/group. Statistics are as follows: 2-way ANOVA followed by Bonferroni post hoc test. P < 0.01 vs. age-matched controls (*) and vs. diabetic rats 8 wk post-STZ injection (**).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
APPENDIX A
 APPENDIX B
 GRANTS
 REFERENCES
 
The most striking finding in the present study is that diabetes has disparate effects on force-generation capacity (Emax) and flow-generation capacity (Qmax) of the LV. We showed that Emax had good agreement with Es and was depressed by 8 wk post-STZ injection. In addition, the present study indicates that the depressed Emax is accompanied by unchanged Pisomax and markedly increased Veed and SV. Because Veed approximates LVEDV, an index reflecting both cardiac size and preload, the results of the present study suggest that ventricular remodeling, characterized by progressive chamber dilatation and contractile dysfunction, might play a pivotal role in deteriorating myocardial contractility at early stages of diabetes. On the other hand, the flow-generation capacity of the LV chamber is progressively enhanced at early stages of diabetes. Similar to the velocity-force relationship in isolated cardiac muscle, the enhanced Qmax can offset the depressed Emax, and the cardiac performance is preserved. However, Qmax and Qmaxn become significantly attenuated and are temporally correlated with the declines in SV and CO in the diabetic rats 22 wk post-STZ injection. We had performed echocardiographic measurements, and the data indicated that the fractional shortening was mildly but significantly decreased in the group of 22 wk post-STZ injection compared with the age-matched control rats (41.5 ± 0.97% vs. 36.5 ± 1.31%, n = 8, P < 0.01). This result is similar to previous studies (33, 51) and could explain why the temporal changes in Emax are not evident and Qmax and Qmaxn are only mildly reduced in diabetic rats 22 wk post-STZ injection. However, the trends toward a decrease in Emax and Qmax are apparent. If the observation period was extended, we expect that the systolic function might become worse, and the changes in Emax and Qmax might be more evident. It is hard to explain the dynamic changes in cardiac performance in diabetic rats by using the systolic elastance alone. However, after integration of flow-generation capacity in the conventional elastance model, we have successfully demonstrated that Qmax can serve as a velocity-dependent dimension of cardiac contractile function. The dynamic changes in Emax and Qmax help us unravel the mechanical mechanisms in the evolution of contractile dysfunction in STZ-induced diabetic rats. Further studies are needed to evaluate the relative contribution of contractile apparatus, extracellular components, and LV geometry to both Emax and Qmax.

Prior studies have shown that both peak shortening and maximal unloaded velocity of shortening (32, 50) are decreased in cardiomyocytes isolated from diabetic rats 4 to 8 wk post-STZ injection. However, our in vivo study indicates that Qmax is enhanced in diabetic rats 8 and 16 wk after the onset of diabetes. This discrepancy may arise from the influences of afterload. Our study demonstrated that Qmax is progressively depressed in response to elevated afterload by manual constriction of ascending aorta. The afterload-adjusted maximal flow-generation capacity (i.e., Qmaxad) became depressed as early as 8 wk in the diabetic animals, which is consistent with previous reports showing that maximal unloaded velocity of shortening is attenuated in isolated cardiomyocytes of diabetic rats (32, 50). Another interesting finding in the present study is that the afterload is significantly lower in diabetic rats than in control rats, which is consistent with previous studies (7, 14). The reduced afterload might play beneficial roles in enhancing flow-generation capacity of cardiac systolic mechanics and maintaining CO in the evolution of systolic dysfunction in diabetic animals. The underlying mechanism of this interesting phenomenon in diabetic rats remains not fully clear, but it has been shown to be associated with increased production of nitric oxide (9, 29). eNOS was reported to be activated in response to increased blood flow and shear force, as confirmed in the diabetic rats of the present study (23, 52). In addition, the nitric oxide synthesis and pathway have been shown to mediate the inhibitory serotoninergic response of the pressor effect elicited by sympathetic stimulation in diabetic rats (12). Recently, Kobayashi et al. (21) reported that, in the aortas of early diabetic rats, enhanced ACh-induced vascular relaxation and impaired norepinephrine-induced contraction are attributed to overproduction of eNOS and its product nitric oxide plus increased {alpha}2D-adrenoreceptor. Our results showed that the protein expression of aortic eNOS was enhanced in diabetic rats, and the magnitude of increase was significantly attenuated with time, which corresponded to a lowered Ea in the early stage of the disease and a later rise of Ea in diabetic rats 22 wk postinjection. Our present study suggests that the aortic eNOS might play a role in regulating afterload in diabetic rats. However, further studies are needed to investigate the causal effect of eNOS on Ea as well as Qmax in STZ diabetic rats.

Because SV is directly proportional to Veed and is inversely related to peripheral resistance (42), the favorable loading conditions are beneficial to maintain cardiac performance in diabetic animals, especially when systolic elastance is depressed. In addition, the total blood volume was reported to be significantly increased 12 wk after induction of diabetes (5, 26). These hemodynamic alternations mimic a state of high-output heart failure. Although untreated diabetic rats exhibited a dramatic diabetic state with high blood glucose level not comparable to a condition in humans, it is reasonable that these alternations are helpful in understanding the pathophysiology of congestive heart failure in diabetic humans (5).

We found that myocardial ME was depressed significantly preceding overt heart failure, but the aortic hydraulic energy transfer was enhanced in rats 22 wk after induction of diabetes. To our knowledge, this is the first in vivo study showing that the cardiac ME is attenuated earlier than the aortic hydraulic energy transfer from the LV to the aorta and might play an essential role in deteriorating cardiac systolic function in diabetic animals. The altered myocardial substrate metabolism (2, 44), together with accumulated lipid intermediates and increased oxygen consumption, has been shown to exert a detrimental effect on cardiac efficiency in diabetic rats (15, 27). We do not have direct measurement of myocardial oxygen consumption in this study because the in vivo assays of coronary oxygen content and coronary flow are not feasible in a small rat model. Further studies are needed to study the conversion efficiency of myocardial oxygen consumption to mechanical energy (PVA/MFormula 2o2) in larger animal models.

STZ-induced diabetic rats are characterized by not only decreased afterload but bradycardia. The impact of slow heart rate on LV function depends on the severity of bradycardia. Several studies have shown that bradycardia can improve myocardial energetics and is a major mechanism by which β-blockers are effective for restoration of contractile function in heart failure (11, 24, 30). However, severe bradycardia, such as seen in a complete heart block canine model with 60–70% lower than baseline heart rate, would deteriorate cardiac dysfunction because of volume overload of the LV and subsequent systolic dysfunction. A recent study has shown that reducing heart rate by 20% improves systolic function and increases SV, preserving CO in a rat heart failure model (28). In our present study, the magnitude of heart rate reduction in diabetic rats is ~25%; therefore, the effect of reduced heart rate on deteriorating systolic function might be neglected in diabetic rats.

In summary, we demonstrate that contractile dysfunction in STZ-induced diabetic rats is characterized by distinct changes in force-generation capacity and flow-generation capacity in terms of systolic mechanics of the LV. At early stages of diabetes, the enhanced Qmax and favorable loading conditions play complementary roles to early occurring and persistently depressed Emax, and cardiac performance is then well preserved. However, Qmax is attenuated at later stages, which is temporally correlated with the declines in SV and CO. The compensatory offset between Emax and Qmax would be lost, and depressed cardiac performance would then ensue. Like systolic elastance, Qmax can serve as a velocity-dependent dimension of cardiac contractile function and can predict the occurrence of overt systolic dysfunction. In addition, cardiac ME, rather than aortic hydraulic energy transfer, is diminished preceding overt systolic heart failure and may play a detrimental role in the evolution of contractile dysfunction in STZ-induced diabetic rats. By unraveling the temporal changes in Emax and Qmax, and loading conditions as well as cardiac ME, our present study provides a comprehensive understanding of the pathogenesis of contractile dysfunction in diabetic rat heart.


   APPENDIX A
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
APPENDIX B
 GRANTS
 REFERENCES
 
Estimation of isovolumic pressure of LV from an ejecting beat. To obtain the estimated instantaneous LV pressure [Piso(t)] from an ejecting beat, a nonlinear least-squares approximation technique proposed by Sunagawa et al. (43) was used:

Formula 3(3)
where Pmax is an estimated peak isovolumic developed pressure, {omega} is an angular frequency, c is a phase shift angle of the sinusoidal curve, and EDP is the left ventricular end-diastolic pressure. Piso(t) was obtained by fitting the measured LV pressure curve segments from the end-diastolic pressure point to the maximal rate of LV pressure rise (dP/dtmax) and from the pressure point of the minimal rate of LV pressure rise (dP/dtmin) to the same level as the end-diastolic pressure of the preceding beat (Fig. 1). The maximal value of Piso(t), defined as the estimated peak isovolumic pressure (Pisomax), is the sum of Pmax and EDP. The LV end-diastolic point was defined as the pressure at which dP/dt first exceeded 1.2 mmHg/ms.


   APPENDIX B
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
 APPENDIX B
GRANTS
 REFERENCES
 
Calculation of model parameters in the elastance-resistance model. According to the elastance-resistance model, the relationship between instantaneous LV pressure, aortic flow, and isovolumic pressure can be written as follows (3, 4, 37):

Formula 4(4)
where Pmod(t) is the model-derived LV pressure in the elastance-resistance model, and Vej(t) is the instantaneous ejected volume computed by calculating the running integral of aortic flow signal Q(t). Qmax is the theoretical maximal flow, and Veed is the effective end-diastolic volume, defined as the difference between left ventricular end-diastolic volume (LVEDV) and the zero-pressure volume axis intercept (V0). Pmod(t) can be derived from the measured LV pressure of an ejecting beat by making use of Eq. 3. A previous study demonstrated that the predicted LV pressure in Eq. 4 correlated well with the measured LV pressure at the time interval between the onset of ventricular ejection and the time of Pisomax (4). The optimal values of both Veed and Qmax were estimated using an iterative, least-squares minimization procedure (8, 38) to minimize the normalized root-mean-square value (ep). The ep can be written as follows:

Formula 5(5)
where P(i), Pmod(i), and Formula 5 are sampled values of observed pressure, model-derived pressure, and observed mean pressure of LV, respectively.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
 APPENDIX B
 GRANTS
REFERENCES
 
This study was supported in part by the Sin-Yuan Medical Research and Education Foundation, and by a research grant from the Far-Eastern Memorial Hospital (FEMH-94-D-036). H.-I. Yeh and Y.-J. Lai were supported by the Mackay Memorial Hospital (MMH-E-95003).


   ACKNOWLEDGMENTS
 
We thank Yu-Ying Kao for expert technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Y.-Z. Tseng, Dept. of Internal Medicine, National Taiwan Univ. Hospital, 7, Chung-Shan South Road, Taipei, 10016 Taiwan, Republic of China (e-mail: yztseng{at}ntu.edu.tw)

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.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
 APPENDIX B
 GRANTS
 REFERENCES
 

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