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Ann Thorac Surg 1995;60:292-299
© 1995 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

3,5,3'Triiodo-L-Thyronine Pretreatment With Cardioplegic Arrest and Chronic Left Ventricular Dysfunction

Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. The active form of thyroid hormone, T₃, may be an important determinant of left ventricular (LV) function after hypothermic cardioplegic arrest and rewarming, particularly in patients with preexisting LV dysfunction. Thus, the present project tested the hypothesis that T₃ pretreatment will improve myocyte contractile performance after hypothermic cardioplegic arrest and rewarming in the setting of chronic LV dysfunction.

Methods. Control LV porcine myocytes (n = 160) and cardiomyopathic LV (rapid pacing for 3 weeks at 240 beats/min) myocytes (n = 100) were treated with or without 80 pmol/L T₃. Myocytes then were maintained in normothermic conditions (2 hours at 37°C in media) or exposed to hypothermic cardioplegic arrest ([K⁺], 24 mmol/L; 2 hours at 4°C) with subsequent rewarming.

Results. After cardioplegic arrest and rewarming, T₃ pretreatment increased myocyte velocity of shortening by 41% in control myocytes and by 35% in cardiomyopathic myocytes when compared to untreated myocytes. Furthermore, T₃ pretreatment followed by ß-adrenergic receptor stimulation with isoproterenol (25 nmol/L) improved myocyte velocity of shortening by 24% in control myocytes and 90% in cardiomyopathic myocytes after hypothermic cardioplegic arrest and rewarming, as compared with untreated myocytes.

Conclusions. In summary, this study provides evidence to suggest that preemptive treatment with T₃ may improve LV pump function and ß-adrenergic responsiveness after hypothermic cardioplegic arrest and rewarming in patients with underlying LV dysfunction.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 299.

Hyperkalemic, hypothermic cardioplegic arrest remains the most commonly used method of myocardial protection during cardiac operations. However, reperfusion and rewarming after hypothermic cardioplegic arrest has been associated with transient left ventricular (LV) dysfunction [1, 2]. An ever-increasing number of patients with underlying chronic LV dysfunction are presenting for cardiac surgical procedures [3]. In many of these patients, this preexisting LV dysfunction may be exacerbated after hypothermic cardioplegic arrest and rewarming. It has been demonstrated that patients with chronic LV dysfunction have an associated decrease in the level of the active form of thyroid hormone, 3,5,3' triiodo-L-thyronine (T₃) [4]. Furthermore, hypothermic cardioplegic arrest and rewarming with cardiopulmonary bypass causes decreased levels of T₃ [5]. Taken together, these observations suggest that T₃ may play a contributory role in the transient LV dysfunction after hypothermic cardioplegic arrest and rewarming, particularly in patients with preexisting cardiac disease [4, 5]. Both clinical and experimental studies have demonstrated that increased circulating levels of T₃ improved LV pump function in normal myocardium as well as after acute ischemic injury to the myocardium [5–1010]. Recently, this laboratory has demonstrated that T₃ improves contractile function in normal isolated myocytes [11]. Accordingly, the goal of the present study was to determine whether pretreatment with T₃ had direct and beneficial effects on myocyte contractile function in the setting of chronic LV dysfunction after hypothermic cardioplegic arrest and rewarming.

In the setting of chronic LV dysfunction, as well as after cardioplegic arrest and rewarming, a significant reduction in ß-adrenergic responsiveness has been reported [12–15]. Previously, it has been demonstrated that both chronic and acute administration of T₃ have direct effects on ß-adrenergic receptor density and responsiveness [16–18]. Therefore, we suspect that pretreatment with T₃ may have direct effects on isolated myocyte ß-adrenergic responsiveness after hypothermic cardioplegic arrest and rewarming in the setting of chronic LV dysfunction. This may have clinical significance as ß-adrenergic receptor agonists are commonly required after hypothermic cardioplegic arrest and rewarming, particularly in patients with preexisting LV dysfunction. Accordingly, a second objective of the present study was to examine whether pretreatment with T₃ would have direct and beneficial effects on myocyte ß-adrenergic responsiveness in the setting of chronic LV dysfunction after hypothermic cardioplegic arrest and rewarming.

Chronic pacing-induced tachycardia in animals causes a dilated cardiomyopathy [12, 1921–10] that is similar to the clinical spectrum of congestive heart failure in patients [3, 13, 14, 22]. Specifically, this laboratory has demonstrated that chronic supraventricular tachycardia in pigs caused LV dilatation, dysfunction, and neurohormonal activation [19, 20]. More important, the development of supraventricular tachycardia-induced cardiomyopathy was associated with myocyte contractile dysfunction and reduced ß-adrenergic responsiveness [12, 20]. Accordingly, the present study used this model of pacing-induced dilated cardiomyopathy to determine whether pretreatment with T₃ will improve myocyte contractile function and ß-adrenergic responsiveness after hypothermic cardioplegic arrest and rewarming.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Experimental Model
Twelve weight-matched pigs (Yorkshire strain, 28 kg) were randomly assigned to one of two groups: group 1, pigs subjected to supraventricular pacing tachycardia at 240 beats/min for 3 weeks (n = 6); group 2, sham-operated controls (n = 6). The pacing protocol was performed as described previously [19, 20]. Briefly, a stimulating electrode was sutured onto the left atrium and pacemakers were implanted and modified for programming heart rates up to 400 beats/min (Spectrax; Medtronic, Inc, Minneapolis, MN). Seven to 10 days after recovery from the surgical procedure, atrial pacing at 240 beats/min was initiated. Electrocardiograms were obtained frequently during the pacing protocol to ensure the presence of 1:1 conduction. The sham-operated controls were cared for in an identical fashion with the exception of the pacing protocol. All animals were treated and cared for in accordance with the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985)Au: have move ref 23 here.

On the day of study, the animals were sedated with 10 mg of midazolam (Versed; Hoffman-La Roche, Inc, Nutley, NJ), and placed in a custom-designed sling that allowed the animal to rest comfortably. A baseline electrocardiogram was established, and the pacemaker was deactivated (pacing group only). Two-dimensional and M-mode echocardiographic studies (2.25 MHz transducer; ATL Ultramark VI, Bothell, WA) were used to image the LV from a right parasternal approach. Echocardiographic measurements were performed as described previously [19, 20, 23]. Next, the animals were anesthetized with isoflurane (0.5%/1.5 L/min), and ventilated through a nonrecirculating anesthesia circuit. A sternotomy was then performed, and the heart was quickly extirpated and placed in an oxygenated Krebs solution. The LV and septum were quickly weighed. The region of the LV free wall comprising the left circumflex coronary artery was dissected free, the artery cannulated, and the tissue prepared for myocyte isolation.

Myocyte Isolation
Using methods described previously by this laboratory [24, 25], oxygenated modified Krebs solution containing aerobic substrates and collagenase (0.5 mg/mL, type II; 146 U/mg, Au: manufacturer, Worthington, PA) was perfused and recirculated through the cannulated circumflex artery for 20 minutes. The tissue was then minced into 2-mm sections and added to an oxygenated trituration solution containing 400 µmol/L CaCl₂ and collagenase (0.5 mg/mL). The tissue and trituration solution were transferred to a centrifuge tube and gently agitated. At 15-minute intervals, the supernatant was removed and filtered, and the cells were allowed to settle. The myocyte pellet (7000 viable myocytes/mL) was then resuspended in standard culture media (Media 199; Nutrient Mixture F-12, 2 mmol/L Ca²⁺; GIBCO Laboratories, Grand Island, NY). After baseline measurements of contractile performance, resuspended myocytes were randomly divided according to the treatment protocol described in the experimental design section.

Contractile Function Measurement
Myocyte contractile function was examined under basal normothermic conditions, after hypothermic cardioplegic arrest and rewarming, and after ß-adrenergic receptor stimulation using video-assisted microscopy techniques described previously [24, 25]. Myocytes were imaged on an inverted microscope (Axiovert IM35; Zeiss Inc, Oberkochen, Germany) in a 2.5-mL tissue chamber with a thermoregulator to maintain the media temperature at 37°C. Myocytes were stimulated at 1 Hz and contractions were imaged using a charge-coupled device (GPCD60; Panasonic, Secaucus, NJ). Myocyte motion signals were input through an edge detector system (Crescent Electronics, Sandy, UT), converted into a voltage signal, digitized, and input to a computer (80286;ZBV2526; Zenith Data Systems, St. Joseph, MI) for subsequent analysis [24, 25]. Stimulated myocytes were allowed a 5-minute stabilization period after which contraction data for each myocyte were recorded from a minimum of 20 consecutive contractions. Parameters computed from the digitized contraction profiles included percentage shortening (%), peak velocity of shortening (µm/s), peak velocity of lengthening (µm/s), total contraction duration (ms), and time to peak contraction (ms). Contractile measurements were obtained only on those myocytes that maintained a long axis orientation perpendicular to the microscope objective throughout the contraction profile.

Experimental Design: Effects of T₃; Normothermia and Hypothermic Cardioplegic Arrest
Isolated myocytes from normal pigs and pigs with tachycardia-induced dilated cardiomyopathy were studied under identical conditions: maintenance at normothermia for 2 hours followed by either 2 hours of normothermia or 2 hours of hypothermic cardioplegic arrest followed by subsequent rewarming. Media and cardioplegia were initially bubbled with 95% oxygen. Before initiation of the protocols, and after 2 hours at the completion of each protocol, media and cardioplegia pH and oxygen tension were measured (1312 Blood Gas Manager; Instrumentation Laboratory, Lexington, MA). Myocyte contractile function was examined under these conditions with and without pretreatment with 80 pmol/L T₃ (3,5,3' triiodo-L-thyronine, T₃; Sigma, St. Louis, MO). The isolated myocyte suspensions were randomized to ensure uniform basal function characteristics. The experimental design and randomization scheme are shown in Figure 1. The concentration of T₃ (80 pmol/L) was chosen based on previous dose–response studies [11].

View larger version (15K): [in this window] [in a new window]   Fig 1. . Experimental design used to examine the effects of T3 pretreatment on myocyte contractile function after hypothermic cardioplegic arrest and rewarming. Myocytes were incubated in media with or without 80 pmol/L T3 for 2 hours. Next, myocytes were subjected to 2 hours of hypothermic cardioplegic arrest or were maintained at normothermia, followed by resuspension in media and rewarming to 37°C. Contractile function was examined at the time points designated with an X. The composition of the media and cardioplegia solutions are described in Methods section. (CON = control; DCM = 3 weeks of supraventricular pacing at 240 beats/min; T3 = 3,5,3' triiodo-L-thyronine.)

To determine whether administration of T₃ or exposure to hypothermic cardioplegic arrest and rewarming had an effect on myocyte ß-adrenergic responsiveness in the setting of pacing-induced dilated cardiomyopathy, myocytes from each treatment protocol were exposed to the ß-adrenergic agonist, isoproterenol (25 nmol/L). This concentration of isoproterenol (25 nmol/L) was previously determined by dose–response studies as the effective dose for maximum response (ED₁₀₀) for this isolated myocyte preparation [24].

Data Analysis
The LV function was compared between the control and chronic tachycardia groups using a Student's t test. Indices of myocyte contractile function for the treatment groups shown in Figure 1 were compared using two-way analysis of variance. If the analysis of variance detected significant differences with respect to treatment, mean separation was performed using Bonferroni bounds [26]. In a similar manner, for the ß-adrenergic response studies, myocyte contractile function at baseline and after ß-adrenergic stimulation was directly compared using analysis of variance. All statistical procedures were performed using the BMDP statistical software package (BMDP Statistical Software Inc, Los Angeles, CA). Results are presented as mean ± standard error of the mean. A p value of less than 0.05 was considered to be statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Left Ventricular Function With Pacing-Induced Cardiomyopathy
All of the pigs subjected to 3 weeks of pacing-induced supraventricular tachycardia survived the pacing protocol and were found to have symptoms of dyspnea and tachypnea at terminal study. An LV echocardiographic study was performed on each pig at terminal study with results summarized in Table 1. Chronic pacing-induced supraventricular tachycardia caused LV dilatation and dysfunction consistent with results previously reported by this laboratory [12, 19–21]. At autopsy, all of the pigs that underwent chronic pacing-induced supraventricular tachycardia were found to have bilateral pleural effusions and ascites. Thus, chronic pacing-induced supraventricular tachycardia caused clinical and functional manifestations of a dilated cardiomyopathy (DCM).

Myocyte Contractile Function With T₃: Normothermia and Hypothermic Cardioplegic Arrest and Rewarming
After 2 hours of incubation in either normothermic culture medium or after hypothermic cardioplegic arrest, the oxygen tension of the incubation medium ranged from 165 to 270 mm Hg and the pH was 7.3 to 7.5. At each timepoint outlined in the protocol (Fig 1), contractile function in DCM myocytes remained significantly lower than in control myocytes. In both control and DCM myocytes incubated with 80 pmol/L T₃ for 2 hours at 37°C, contractile function was significantly higher than in untreated myocytes (Table 2). Thus, consistent with a previous recent report from this laboratory, under normothermic conditions, T₃ improved contractile function in control myocytes [11]. More important, results from the present study demonstrated that pretreatment with T₃ improved myocyte contractile function under normothermic conditions in the setting of dilated cardiomyopathy.

View larger version (32K): [in this window] [in a new window]   Fig 2. . Absolute change in myocyte velocity of shortening after ß-adrenergic receptor stimulation with isoproterenol. Pretreatment with T3 improved myocyte contractile performance after hypothermic cardioplegic arrest and rewarming in control and DCM myocytes. More important, T3 preserved ß-adrenergic responsiveness after hypothermic cardioplegic arrest and rewarming in DCM myocytes. (CON = control; DCM = 3 weeks of supraventricular pacing at 240 beats/min; HCAR = hypothermic cardioplegic arrest and rewarming; normothermia = media at 37°C; *p < 0.05 versus no T3; #p < 0.05 versus normothermia.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Previous studies have demonstrated the beneficial effects of treatment with T₃ in the setting of LV dysfunction as well as after systemic hypothermia with extracorporeal circulation [5, 6]. For example, in a clinical study, Novitzky and colleagues [5] examined the effects of administration of T₃ at the termination of cardiopulmonary bypass in patients with preexisting LV dysfunction and reported a reduced inotropic requirement. Morkin and co-workers [7] reported that chronic administration of thyroxine for 3 days in an experimental model of chronic LV dysfunction in rats produced by coronary artery ligation resulted in improved LV-developed pressure. Finally, a recent report from this laboratory demonstrated that acute administration of T₃ improved myocyte contractile function with tachycardia-induced dilated cardiomyopathy [27]. These results provide evidence that T₃ exerts direct and beneficial effects on myocyte contractile function in the setting of LV dysfunction. The present study builds on these previous reports by demonstrating that pretreatment with T₃ improved myocyte contractile function in cardiomyopathic myocytes after hypothermic cardioplegic arrest and rewarming.

ß-Adrenergic receptor agonists are commonly administered in the settings of LV dysfunction and after cardiopulmonary bypass to augment LV pump performance. However, chronic LV dysfunction, as well as cardiopulmonary bypass with hypothermic cardioplegic arrest and rewarming have been associated with alterations in the ß-adrenergic receptor system, which decrease the response to conventional ß-adrenergic agonist therapy in patients [12–15]. For example, Bristow [13] demonstrated that down-regulation and uncoupling of the ß-adrenergic receptor system caused a decrease in ß-adrenergic responsiveness in patients with chronic LV dysfunction [13]. Schwinn and colleagues [15] reported a decrease in ß-adrenergic receptor density in dogs after cardiopulmonary bypass. Furthermore, at the cellular level, it has been reported that tachycardia-induced dilated cardiomyopathy caused a decrease in ß-adrenergic receptor density and responsiveness [12]. Thus, the present study used this model of dilated cardiomyopathy to examine the direct effects of pretreatment with T₃ on ß-adrenergic responsiveness after hypothermic cardioplegic arrest and rewarming. Results from the present study demonstrated that pretreatment with T₃ improved ß-adrenergic responsiveness after hypothermic cardioplegic arrest and rewarming in control and cardiomyopathic myocytes. More important, this study uniquely demonstrated that pretreatment with T₃ in cardiomyopathic myocytes preserved ß-adrenergic responsiveness after hypothermic cardioplegic arrest and rewarming. This finding has particular clinical relevance in that preemptive treatment with T₃ may be a useful therapeutic adjunct by preserving responsiveness to conventional ß-adrenergic agonist therapy in the setting of chronic LV dysfunction and after cardioplegic arrest.

The effects of chronic administration of T₃ on LV function and metabolism have been well described previously [7, 10]. For example, Buccino and colleagues [28] induced a chronic hyperthyroid state in cats that was characterized by tachycardia, increased indices of oxygen consumption, and improved contractile performance in papillary muscle strips. Clinically, chronically elevated levels of T₃ cause a hyperdynamic state with increased cardiac output and heart rate, and decreased systemic vascular resistance [7, 10]. However, the effects of a single dose of T₃ on LV function and myocyte contractile performance are not as well understood. In experimental models of cardiopulmonary bypass, Novitzky and colleagues [6, 29] demonstrated an increase in survival, LV-developed pressure, and myocardial ATP content after a single dose of T₃ given at the termination of cardiopulmonary bypass. Administration of T₃ induces changes in LV loading conditions as well as alterations in neurohormonal systems that make interpretation of the effects of T₃ on LV contractile performance difficult [7, 10]. To address this issue, a previous study by this laboratory measured isolated LV myocyte contractile performance in the presence of T₃ [11]. This previous report demonstrated that T₃ directly improved myocyte contractile performance independent of loading conditions and extracellular influences. The present study built on these previous reports by demonstrating that pretreatment with T₃ had direct and beneficial effects on contractile function in myocytes from both normal and cardiomyopathic ventricles after exposure to hypothermic cardioplegic arrest and rewarming. Two important limitations to the present study must be recognized. First, the changes seen with T₃ in the present study using an isolated myocyte model may not reflect changes in whole heart or animal physiology with T₃. However, the model used in the present study was intended to evaluate the effects of T₃ on the myocyte devoid of the influences of nonmyocyte populations, neurohormonal changes, and alterations in loading conditions. Additional experiments with T₃ in whole heart and animal models are warranted with specific attention to differences in the effects of T₃ on nonmyocyte populations such as endothelial cells. Second, the fundamental mechanisms responsible for the acute effects of T₃ remain unknown. On the basis of the results from the present study in which pretreatment with T₃ had direct and beneficial effects on myocyte contractile performance after hypothermic cardioplegic arrest and rewarming, future studies elucidating the basic mechanisms for these effects are warranted. Nevertheless, the present study suggests that a single presurgical treatment with T₃ in patients with preexisting LV dysfunction may provide direct and beneficial effects on myocyte contractile function, and therefore, may improve LV pump performance after separation from cardiopulmonary bypass.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was funded by National Institutes of Health grant HL45024 to Dr Spinale. Doctor Spinale is an Established Investigator of the AHA. Doctor Walker received the Nina S. Braunwald Research Fellowship of The Thoracic Surgery Foundation for Research and Education and the Medical University of South Carolina Postdoctoral Research Fellowship Award.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Thirty-first Annual Meeting of The Society of Thoracic Surgeons, Palm Springs, CA, Jan 30–Feb 1, 1995.

Address reprint requests to Dr Spinale, Medical University of South Carolina, 171 Ashley Ave, CSB 418, Charleston, SC 29425.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jennifer D. Walker Fred A. Crawford, Jr Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Walker, J. D. Articles by Spinale, F. G. Search for Related Content PubMed PubMed Citation Articles by Walker, J. D. Articles by Spinale, F. G.