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Sumario Vol. 42 - Nº 1 Enero - Marzo 2013

Early preconditioning against reperfusion arrhythmias in a conscious sheep model. Role of ATP-dependent potassium channels.

Elena C. Lascano†, Edmundo I. Cabrera Fischer*,
Jorge A. Negroni†.

†Departamento de Biología, Universidad Favaloro,
*AIDUF, CONICET, Buenos Aires, Argentina.
Solís 453.
CP 1075 Buenos Aires, Argentina
E mail

Recibido 04-SET-2012 - ACEPTADO despues de revisión 12-Octubre-2012.

The authors declare not having a conflict of interest.


Print version Imprimir sólo la columna central

 

 

SUMMARY

Early preconditioning (EP) against reperfusion arrhythmias is not clear in conscious animals.
Objective: To analyze the EP protection against reperfusion arrhythmias in a conscious sheep model undergoing reversible ischemia and the role of ATP-dependent potassium channels (KATP) as effectors of the protective mechanism.
Material and Methods: Adult sheep, prepared with an intraventricular pressure transducer, pacemaker wires in the right atrium to record the electrocardiogram, a pneumatic occluder in the distal third of the anterior descending coronary artery and piezoelectric microcrystals in the ischemic zone to measure wall thickness were used. One week after surgery, EP consisting of 6 periods of ischemia-reperfusion was performed 45 min before a12 min ischemia followed by 30 min reperfusion. Lambeth’s arrhythmia severity index (ASI) was compared with controls without EP. The role of KATP channels was analyzed with glibenclamide, non-selective inhibitor of KATP channels, HMR1098 and 5-HD, specific inhibitors of sarcolemmal and mitochondrial KATP channels, respectively, before the prolonged ischemia.
Results: EP reduced arrhythmias incidence (p<0.01). Glibenclamide and HMR1098 totally abolished EP protection, increasing ASI, and 5-HD had a lower inhibitory effect. Mechanical behavior matched the electrocardiographic response.
Conclusions: The prominent sarcolemmal KATP channel participation as effectors of EP protection against arrhythmias suggests that clinically-used drugs which might close them should be used cautiously.

Key words: Early preconditioning. Arrhythmias. KATP channels.
Rev Fed Arg Cardiol. 2013; 42(1): 20-28

 

 

 

INTRODUCTION
Preconditioning is a phenomenon of natural protection triggered by brief periods of ischemia-reperfusion that turns myocytes more resistant faced with more prolonged posterior ischemia, decreasing the size of infarction [1-2], mechanical dysfunction or stunning [3-5], and the severity of the arrhythmias of ischemia and reperfusion [6-8].

Preconditioning presents a biphasic behavior, with two phases or windows of protection that are called classical preconditioning, early preconditioning (EP), or first window of preconditioning, the effect of which prolongs up to a maximal of 2-3 h after the brief periods of ischemia-reperfusion, and late preconditioning or second window of preconditioning, which starts manifesting 12 h after the periods of ischemia-reperfusion, and reaches a peak of protection approximately in 24 h and may last up to 72 h.

In a parallel way to the numerous experimental works that show the protection by preconditioning, there are clinical findings where this strong cardioprotective phenomenon manifests, among which we find the increase in survival [9-11] and function [12] in patients who have suffered an infarction with angina pain prior to the reduction of ST segment elevation in successive occlusions during angioplasty [13], and the decrease in troponin I levels after the ischemic preconditioning protocols during cardiovascular surgery [14]. These self-defense expressions of the heart facing ischemic events in patients correspond to the description of early preconditioning since they occur within a brief lapse between triggering and the realization of protection. Therefore, the induction of preconditioning in clinical practice would allow patients affected by stress angina to increase their capacity of practicing more activities or exercise, facilitating the prolonged balloon inflation during angioplasty or being used to preserve the heart during surgery and heart transplant. These advantages have led to the realization of numerous works of basic investigation to unravel which are the mechanisms that trigger preconditioning and the protection ways with the aim of developing interventions or drugs that would resemble it. However, it was not possible to respond irrefutably to this need, since most of the studies have been made on myocytes, isolated hearts or in openchests in animals, with insufficient confirmations existing of the findings on the protection and the mechanisms that produce them being able to be reproduced in large conscious mammals as an experimental model closer to the clinical condition.

For this reason, the study of preconditioning in absence of necrosis, without the contamination of an increase in the improvement by decrease of the size of infarction, is important to analyze the protection against arrhythmias, a phenomenon insufficiently studied and that in the only work on conscious animals yielded negative results [15].

Although numerous molecules released during ischemia or pharmacological agents that trigger protection have been found, to this time it is not known with certainty which is the final effector. Between the effectors in charge of protecting by preconditioning, we find the ATP-dependent K channels (KATP), located in the sarcolemma and the mitochondria. The opening of sarcolemmal KATP, which produces shortening of action potential and consequently, less calcium overload, has been extensively studied in ischemia models in isolated hearts and open chests in animals. In spite of this, there are still doubts about its exclusive or relative participation, since other experiences point out that mitochondrial KATP would be responsible of the protection.

Consequently, the protection by EP was studied against arrhythmias in conscious sheep that underwent completely reversible ischemia to simulate experimental situations closer to the clinical condition. As to the mechanism of protection, since the role of sarcolemmal and mitochondrial KATP is still being discussed, and there is no data in conscious animals, the participation of KATP in the EP mechanism against reperfusion arrhythmias was analyzed.

 

MATERIAL AND METHODS
Young adult sheep were used, of the Hampshire Down race, which were used simultaneously for the study of mechanical recovery by preconditioning. In brief, for 10 days before the surgery, the animals adapted to the environment and staff of the vivarium of the Favaloro University, certified according to the standards of care and humanitarian use of lab animals by the ANMAT (1320/07) and the National Institute of Health (certification No: A5556-01) and treated according to the Guide for the Care and Use of Laboratory Animals, published by the US National Institute of Health (No. 85-23, reviewed in 1996).

The surgical procedure was already made previously in the lab [16-19]. The day of the surgery, it was sedated with acepromazine (0.3 mg/Kg) before anesthesia was induced with sodium thiopental (20 mg/Kg). After intubating and connecting to mechanical ventilation, the anesthesia was maintained with enflurane 2-3% vaporized with oxygen and fentanyl citrate (0.1 mg). A thoracotomy was carried out in the 5th left intercostal space, and the mammary vein was dissected, introducing in it a K31 catheter of Tygon for the infusion of drugs. The pericardiotomy was made and through an incision in the apex of the heart a microtransducer of pressure (Konigsberg P7, Pasadena, Cal, USA) was introduced, along with a catheter K31 of Tygon filled with saline solution for a subsequent calibration. The anterior descending artery was dissected distally to the second diagonal branch and the dissected portion was mechanically occluded to verify visually that the area that would undergo ischemia (area in risk) was no greater than 20% of theleft ventricular mass. A couple of piezoelectric crystals of 5 MHz were placed (one in the subendocardium and the other in the epicardium) in the center of the area in risk to measure the regional parietal thickness by the sonomicrometry technique. Later, a pneumatic occlusor was placed around the dissected arterial portion. Pacemaker leads were placed in the right atrium to register the electrocardiogram (ECG). Finally, all cables and catheters were tunneled, making them emerge between the shoulder blades and the thoracotomy was closed by planes. When the surgery ended and for 3 or more days, cephamycin 1 g/day IV intramuscular was injected. The post-surgical care of the animals was the responsibility of the veterinarian and technical staff of the vivarium. Before the experimental protocol and since the second post-surgical day, each animal underwent 5-7 daily sessions of adjustment to the environment where the experiences would be made, controlling the quality of the signals and that heart rate would decrease gradually with the adjustment toward normal values for a conscious animal (70-80 bpm). When the experimental protocol was completed, the animal was subsequently used in other experimental protocols after at least one week of separation between experiments, and at the end its useful life it was sacrificed with an overdose of sodium thiopental followed by an injection in bolus of potassium chloride. The signal of thickness allowed to verify the ischemia in the place of occlusion and the signal of pressure was used to separate the cardiac cycles and jointly with the ECG verify the existence of arrhythmias.

Seven to ten days after the surgery, the animals were studied within the cart in a conscious state, without sedation. In the sides, at the level of the heart, 2 electrodes connected to a defibrillator (Rhomicron, Argentina) were placed in the case of having to cardiovert the animal during the ischemia or early reperfusion. The Konigsberg microtransducer of pressure and the leads of the sonomicrometry crystals were connected to the respective modules of a System 6 equipment (Triton Technology, San Diego, Cal) and the leads of the pacemaker to a universal differential amplifier (Instituto de Ing. Biomédica, Fac. de Ingeniería, UBA). The fluid-filled catheter to calibrate the microtransducer of pressure was connected to a transducer pressure of the Statham type (DT-XX, Viggo-Spectramed, Oxnard Call), previously calibrated by a digital pressure calibrator (Xcaliber, Viggo-Spectramed, Oxnard Cal). The point of zero pressure was established approximately at the level of the right atrium, and the signal generated by the microtransducer Konisberg was adjusted in level and amplification until it corresponded to that of the external transducer. The electrical signal of thickness was calibrated in mm using the internal calibration of the sonomicrometer.

When episodes of arrhythmia occurred during ischemia or reperfusion, the experiment continued if there was spontaneous reversion to sinus rhythm. In the cases in which the arrhythmia evolved into ventricular tachycardia of more than 30 sec of duration, a bolus of lidocaine was administered (1-2 mg/kg), and when the tachycardia evolved into ventricular fibrillation and this did not revert spontaneously after 30 sec, an electric cardioverter shock was applied (200-300 Joules) with the defibrillator. In the case that two attempts of cardioversion were unsuccessful, the animal was sacrificed with on overdose of sodium thiopental.

Experimental protocol
The animals were divided into the following groups:

  1. Control (CONT); N=9; 12 min of ischemia were conducted, followed by 30 min of reperfusion.
  2. Early preconditioning (EP); N=9: six terms of 5 min of ischemia-5 min of reperfusion were conducted; 45 min before the 12 min of ischemia and 30 min of reperfusion.
  3. Early preconditioning + glibenclamide, unspecific KATP inhibitor of sarcolemmal and mitochondrial channels, before the prolonged ischemia (EPG), N=6: equal to EP, except that after the preconditioning periods, glibenclamide was infused (0.4 mg/kg), during 10 min, starting 30 min before the 12 min ischemia.
  4. Early preconditioning + sodium salt of (1-[5-[2-(5-chloro-o-anisidine) ethyl]-2-methoxyphenyl] sulfonyl-3-methyl-thiourea) (HMR 1098), specific sarcolemmal KATP inhibitor, before prolonged ischemia (EPHMR), N=6; equal to EP, except that HMR1098 was infused (12 mg/kg in distilled H2O) in 15 min bolus before the 12 min ischemia.
  5. Early preconditioning + sodium salt of 5-Hydroxydecanoic acid (EP5HD), specific inhibitor of mitochondrial KATP before the prolonged ishcemia (EP5HD); N=6: equal to EP with 5-HD (5 mg/kg) administered 10 min before the 12 min ischemia.

Acquisition and analysis of data
In each time of acquisition, the consecutive signals of stable beats were digitized for 15 sec, with a sampling interval of 4 ms, using a personal computer equipped with an analog-to-digital converter (National Instruments Lab-Pc; Austin, Texas, USA) and software developed in the lab. The parietal thickness measures considered in this work were those acquired every 5 min during the 20 min prior to ischemia (the average of these measures corresponds to the value of basal conditions), in the last minute of ischemia and every 10 min during the first half hour of reperfusion.

The effectiveness of the number and duration of the preconditioning periods to produce protection, as well as the duration of prolonged ischemia (12 min) were determined on the basis of prior experiments for a late preconditioning against stunning [18].

Likewise, in a previous paper, it was established by the measurement of the action potential duration (APD90) obtained by monophasic potentials in open chest in animals, that the doses of the drugs were the minimal ones producing the expected effect on sarcolemmal KATP [19].

Data analysis
End of diastole was defined at the beginning of the positive deflection of the derivative of the left ventricular pressure obtained digitally (dP/dt) and end of systole as the thickness measured in the time in which 10% of the dP/dtmin previous to the value of it is reached. The systolic wall thickening fraction (SWTF) was estimated in the following manner:

SWTF=(St-Dt)/Dt

where St is the ventricular regional thickness of end of systole, and Dt is ventricular regional thickness of end of diastole.


The processing of signals and the estimation of parameters were made for each time of data acquisition. The pressure of end of systole (Esp) and the dP/dtmax, heart rate (HR) and the SWTF were estimated in each recorded beat and the average of processes beats during the 15 sec of acquisition (15 to 30 beats) was the value ascribed to the sample for that time. The values of ischemia and reperfusion were expressed as percentage of basal value considered as 100%.

Analysis of arrhythmic episodes
The arrhythmias were detected from the electrogram and intraventricular pressure signals during ischemia and reperfusion and diagnosed according to the Lambeth conventions as premature ectopic beats (PEB), ventricular tachycardia salvos (VTS), ventricular tachycardia (VT) and ventricular fibrillation (VF) [20]. The severity of the arrhythmias was evaluated through an index of severity of arrhythmias (ASI) [21] to allow the statistical comparison in experiments with tachyarrhythmias. The values assigned to each type of arrhythmic episode were the following: sinus rhythm=0; premature ectopic beats (PEB)=1; ventricular tachycardia salvos (VTS)=2; ventricular tachycardias (VT)=3; reversible ventricular fibrillation (RVF)=4; and irreversible ventricular fibrillation (IVF)=5. The value of ASI of each animal corresponded to that of the most severe event.

Statistical Analysis
The results were expressed as average±SE. Student’s t-test was used to compare differences between 2 groups and ANOVA to compare differences between more than 2 groups. One-way ANOVA was used to analyze the effect of time over the hemodynamic variables. In both cases, if F was significant, a subsequent analysis was made applying Scheffé’s test for multiple comparisons. The differences were considered significant for p<0.05.

 

RESULTS
Table 1 shows that the Esp had no significant differences in regard to the basal value at the end of the ischemic period and during all the reperfusion in none of the groups studied. This shows that the differences in the recovery of the mechanical function and the generation of arrhythmias would be due to the effect of the control occlusion or preconditioning and not to the variations in the hemodynamic response to ischemia. In agreement with the results of Esp, dP/dtmax displayed values similar to the basal ones when the ischemia ended, which were maintained along the reperfusion in all groups. Since dP/dtmax is an index of contractility, these results suggest that the inotropic state of the left ventricular did not have alterations during ischemia or reperfusion. HR stability, with values similar to the basal ones, showed that the size of the area subjected to ischemia was small enough to not having to compensate with a higher rate, a decrease in the contractile capacity of the heart. Likewise, its regularity is indicative of the ischemia and reperfusion not altering the animal, which along with the uniformity of the Esp and and dP/dtmax show that the function of pumping of the heart was not affected by the size or the duration of ischemia.

TABLE 1.:Basal hemodynamic values, at the end of
ischemia and during the first 30 min of reperfusion.

 

Basal

12 min of ischemia

10 min of reperfusion

20 min of reperfusion

30 min of reperfusion

CONT

 

 

 

 

 

Esp

105.3±4.1

103.2±6.7

110.2±6.6

104.9±5.5

102.1±5.0

dP/dtmax

2597±136

2392±86

2409±124

2420±147

2461±145

HR

88.1±5.5

90.9±6

90.3±6.4

87.1±6.0

85.6±6.2

EP

 

 

 

 

 

Esp

103.0±4.5

96.6±2.7

105.3±2.2

103.9±3.4

103.7±4.2

dP/dtmax

2206±146

2063±131

2053±147

2076±136

2090±125

HR

68.7±3.0

69.8±3.3

66.9±3.4

67.5±3.0

67.7±2.6

EPG

 

 

 

 

 

Esp

99.9±3.2

106.1±3.4

105.4±4.2

99.1±4.3

99.2±3.6

dP/dtmax

2097±224

2069±248

2104±185

2080±205

2115±220

HR

80.5±7.2

84.8±9.0

86.8±7.7

85.5±8.1

83.8±7.7

EPHMR

 

 

 

 

 

Esp

99.42.7

99.9±4.9

100.8±5.3

99.0±4.7

93.9±4.4

dP/dtmax

2197±218

2124±178

2089±146

2084±121

2081±135

HR

69.0±4.0

67.4±4.0

68.0±3.9

67.7±5.3

62.7±3.3

EP5HD

 

 

 

 

 

Esp

93.5±1.3

93.6±2.2

96.5±1.9

94.7±1.6

95.9±2.2

dP/dtmax

2925±443

3021±404

2943±446

3016±412

3118±400

HR

105.9±4.8

109.4±4.0

104.1±5.1

103.5±7.5

105.3±9.2

Esp: End of systole pressure; dP/dtmax: Maximal derivative of ventricular pressure;
HR: Heart rate; CONT: Control; EP: Early preconditioning;
EPG: Early preconditioning with glibenclamide before ischemia;
EPHMR: Early preconditioning with HMR1098 before ischemia;
EP5HD: Early preconditioning with 5-hydroxydecanoate before ischemia. Average±SE.

In the CONT group, severe arrhythmias were generated when reperfusing the heart after 12 min of ischemia. Figure 1 shows the recordings of sinus rhythm in an animal during the basal period of normoperfusion and during ischemia, and of VT and VF during early reperfusion.

Figure 1. Sinus rhythm during normoperfusion and ischemia, and tachycardia and its evolution into ventricular fibrillation at the moment of reperfusion. The times during reperfusion are seconds after it starts.

 

Early preconditioning offered protection against arrhythmias shown by a significantly reduced ASI in regard to the CONT group (Figure 2A). In these conditions, 8% of the animals of the EP group presented only premature contractions at the time of reperfusion and the rest did not show alterations of the sinus rhythm at any time of the experience.

Figure 2. A:Index of severity of arrhythmias (ASI) in the Control (CONT) and early preconditioning (EP) groups. Average±SE, # P<0.01 vs CONT (Student’s t test). CONT (N=14), EP (N=9). B: Systolic thickening fraction (STF), expressed as % of basal value. Average±SE, # P<0-01 vs CONT.

 

The administration of glibenclamide had an adverse effect on the protection granted by EP against arrhythmias, not just abolishing the decrease in the value of ASI obtained in the EP group, but also increasing the triggering of arrhythmic episodes, although not significantly, in regard to CONT (Figure 3A).

Figure 3. A: Index of severity of arrhythmias (ASI) in Control (CONT), early preconditioning (EP) and EP with glibenclamide (EPG). Average±SE, *P<0.05 EP vs CONT and EPG (ANOVA followed by Scheffé). CONT (N=12), EP (N=9), EPG (N=8). B: STF as % of the basal value. Average±SE, # P<0.01 vs CONT.

 

HMR1098 had an enhancing effect on arrhythmias, similar to that obtained with glibenclamide, removing not just the protection of preconditioning, but increasing, although not significantly, the arrhythmic episodes above the CONT group (Figure 4A).

Figure 4. A: Arrhythmias severity index (ASI) in Control (CONT), early preconditioning (EP) and EP with HMR-1098 (EPHMR). Average±SE, P<0.05 EP vs CONT and EPHMR (ANOVA followed by Scheffé). CONT (N=9), EP (N=6); EPHMR (N=7). B: STF as % of the basal value. Average±SE,  # P<0.01 vs CONT.

5-HD had an intermediary response in the inhibition of arrhythmias, since it did not display significant differences in regard to the CONT or EP group. It did not have a promoting effect for them either, as it was observed with glibenclamide and HMR1098, since the EP5HD group showed a tendency to decrease the incidence of arrhythmic episodes in regard to the CONT group (Figure 5A).

 

Figure 5. A: Arrhythmias severity index (ASI) in Control (CONT), early preconditioning (EP) and EP with 5-HD (EP5HD). Average±SE, # P<0.01 vs CONT (ANOVA followed by Scheffé). CONT (N=10), EP (N=8), EP5HD (N=6). B: STF as % of basal value. Average±SE, * P<0.05 vs CONT; # and ** P<0.01 vs CONT; & P<0.01 vs EP5HD (ANOVA followed by Scheffé).

The electrical response of the heart was in all the groups in agreement with the mechanical response (Figure 6), with a greater recovery of thickness fraction being observed during the first 30 minutes of reperfusion in the EP group in comparison with CONT (Figure 2B), which was completely abolished in the GLI and HMR groups (Figures 3B and 4B) and partially in the 5-HD group (Figure 5B).

 

Figure 6. Relation between the average of systolic thickening fraction (STF) at 30 min of reperfusion, and the average of the arrhythmias severity index (ASI) for the CONT, EP, EPG, EPHMR and EP5HD groups. STF is expressed as % of recovery in regard to the basal value considered as 100%.

 

 

DISCUSSION
The present study shows that there is early ischemic preconditioning against arrhythmias and post-ischemic stunning in conscious animals and that KATP participate as effectors of the protective mechanism. Within KATP, a very manifest participation of sarcolemmal KATP was verified as effector of defense against arrhythmias, considering its opening, which reduces the action potential duration preventing Ca2+ overload, was completely abolished by glibenclamide and HMR1098, unspecific and specific inhibitors respectively, of these channels. On the other hand, mitochondrial KATP seem to be less important as effectors of the defense mechanism, since the specific antagonist to its opening (5-HD) caused a weaker inhibition of the preconditioning against arrhythmias. This variation in the degree of participation of sarcolemmal and mitochondrial KATP manifested in a similar way in the case of mechanical response to EP.

Different works [6-8] have verified the role of defense against the arrhythmias provided by EP. However, the only study that analyzed the protection against arrhythmias by EP induced by 10 events of 2 min of ischemia-2 min of reperfusion in conscious pigs, did not find variations in regard to controls when ectopic beats or ventricular tachycardia were considered after 40 min of ischemia [4]. Unlike this work, the present study established a defense against the incidence of arrhythmias of reperfusion in conscious animals before a reversible sustained ischemia, which allowed analyzing the protection without the added effects that may produce cell death.

The significance of sarcolemmal and mitochondrial KATP in the mechanism of early preconditioning is still being discussed. First, it was assumed that sarcolemmal KATP opening during ischemia, with the subsequent decrease in action potential duration, protected the myocardium by decreasing Ca2+ overload [22-23]. This mechanism, backed by the inhibition of the protection with glibenclamide [24-25] was later questioned due to the finding of the pharmacological preconditioning, with no reduction in action potential duration [26], shifting the attention to mitochondrial KATP as protective agents [27]. Thanks to the discovery of thioureas, HMR1833 and sodium salt HMR1098 [28] as selective inhibitors of sarcolemmal KATP, it was possible to verify later the participation of both types of channels in the mechanism of defense of preconditioning [29-31].

Nevertheless, in relation to the participation of sarcolemmal KATP in the protection against arrhythmias, several studies of ischemia without preconditioning in isolated rat hears [32], of protection by exercise before reversible ischemia in rabbits [33] or rats [34] or intermittent stimulation before a prolonged event of ischemia in embryonic hearts of chickens [35] have found that the closure of these channels protects instead of inhibiting the electrical alterations. These results are in contrast with those obtained in conscious sheep, where the inhibition of KATP with glibenclamide promoted the triggering of arrhythmias of reperfusion after 12-min ischemia [17]. On the other hand, Light et al [30], found that the inhibition of sarcolemmal KATP with HMR1098 produced a marked increase of intracellular Ca2+ in isolated myocytes after a period of hypoxia induced by drugs, and this increase could be linked to the triggering of arrhythmias [36-37].

The results obtained in this work could be attributed to the use of a different animal species, to the experimental protocol in conscious animals, or to the doses and/or lack of specificity of the drugs used to inhibit KATP. In the case of 5-HD, to verify if the lack of a greater blockade of arrhythmias was due to an insufficient dose, pilot tests were made at a dose of 10 mg/kg, with (unpublished) results similar to those obtained with 5 mg/kg, which is the dose used usually in other studies, which allows ruling out a limiting effect of the dose as an explanation for the lack of response of mitochondrial KATPfacing 5-HD. Likewise, there is evidence that indicates that 5-HD could also act on sarcolemmal KATP [38], indicating a relative specificity of this inhibitor. In the case of HMR1098, the dose of 12 mg/kg was the one achieving total inhibition of sarcolemmal KATP, although the dose of 3 mg/kg used in most of works is capable of inhibiting the protection by preconditioning against stunning [19].

 

CONCLUSIONS
The present study has contributed to prove the participation of sarcolemmal KATP as effectors of the protection against arrhythmias in a model of large conscious mammal, which suggests that the inhibiting drugs used clinically, as for example glibenclamide, should be used with caution.

 

Acknowledgements
The authors thank Dr. Goegelain of Aventis Pharma for his generous donation of HMR-1098. This work was made with the support of the subsidy Préstamo BID PICT-2008-0340.

 

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Publication: March 2013

 
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8vo. Congreso Virtual de Cardiología

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