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Am J Physiol Heart Circ Physiol 290: H2344-H2350, 2006. First published December 30, 2005; doi:10.1152/ajpheart.00917.2005
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Intracoronary infusion of Gd3+ into ischemic region does not suppress phase Ib ventricular arrhythmias after coronary occlusion in swine

José A. Barrabés, David Garcia-Dorado, Luis Agulló, Antonio Rodríguez-Sinovas, Ferran Padilla, Lourdes Trobo, and Jordi Soler-Soler

Servicio de Cardiología, Hospital Universitari Vall d'Hebron, Barcelona, Spain

Submitted 25 August 2005 ; accepted in final form 27 December 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Increased mechanical tension in the ischemic region during acute coronary occlusion might favor the occurrence of phase Ib ventricular arrhythmias. We aimed to investigate whether intracoronary administration of Gd3+, a stretch-activated channel blocker, into the ischemic zone reduces the incidence of these arrhythmias. In thiopental-anesthetized, open-chest pigs, the left anterior descending coronary artery (LAD) was ligated for 45 or 48 min. Phosphate-free, HEPES-buffered saline bubbled with 100% N2 was infused into the ischemic region for 4 min, starting 5 min (series A; n = 16) or 20 min (series B; n = 16) after coronary occlusion, at a rate doubling the baseline blood flow. Animals were blindly allocated to receive 40 µM Gd3+ or only the buffer during the final 2 min of the infusion. There were no differences between groups with respect to hemodynamic variables, plasma K+ levels, or size of the ischemic region. In neither series was the number of phase Ib premature ventricular beats reduced by Gd3+ (46 ± 20 in untreated vs. 91 ± 37 in Gd3+-treated animals in series A and 19 ± 7 vs. 22 ± 13, respectively, in series B; both P = not significant). The occurrence of ventricular tachycardia or fibrillation was significantly associated with the magnitude of early ischemic expansion of the LAD region, as measured by ultrasonic crystals, but was also not prevented by Gd3+. These results argue against a major role of stretch-activated channels inside the area at risk in the genesis of phase Ib ischemic ventricular arrhythmias.

ischemia; stretch; mechanoelectrical coupling; ventricular dilation; sudden death

VENTRICULAR FIBRILLATION secondary to acute myocardial ischemia is one of the major causes of sudden cardiac death in humans, but the mechanisms of ischemic ventricular arrhythmias remain unclear (43). There is special uncertainty on the determinants of the Ib phase of arrhythmias, which takes place ~12 to 40 min after interruption of coronary flow (23) and accounts for most early lethal arrhythmias in animal studies (4, 5, 12, 13, 23, 36). Because phase Ib arrhythmias coincide with the rise in tissue resistivity and are facilitated by connexin deficiency, it has been suggested that cellular uncoupling favoring inhomogeneous conduction and reentry might be the underlying mechanism (12, 14, 15, 25, 28, 36), although nonreentrant mechanisms and neural influences have been proposed as well (1, 10, 23, 32, 34, 35).

On the other hand, it is well known that myocardial stretch induces electrophysiological changes and arrhythmias (2, 6, 7, 18, 20, 26, 38, 44, 45), and there are clinical and experimental data suggesting that stretch is arrhythmogenic in chronic infarctions (9, 17, 24). Because coronary occlusion causes within minutes the dilation of the ischemic region (3, 39), the possibility that mechanical changes underlie early ischemic ventricular arrhythmias is the focus of increased attention (4, 5, 13, 19, 31, 43).

Stretch-induced arrhythmias can be suppressed in vitro by gadolinium (Gd3+), a potent blocker of stretch-activated ion channels (6, 18, 24, 41, 44). This compound, however, has an avid binding to anions present in blood that limits its applicability to test stretch-activated channel function under physiological conditions (8). Therefore, in the present study, we tested whether direct, intracoronary administration of Gd3+ into the ischemic region after coronary occlusion reduces the incidence of phase Ib ventricular arrhythmias in anesthetized pigs.


   METHODS
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 METHODS
RESULTS
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Animal preparation. After approval by the institutional Research Commission and in accordance with "Guiding Principles in the Care and Use of Animals" of the American Physiological Society, 40 farm pigs of either sex (30–40 kg) received 10 mg/kg intramuscular azaperone, followed by an intravenous bolus (30 mg/kg) of thiopental sodium. Animals were intubated and connected to a mechanical ventilator (model MA-1B; Bennett, Santa Monica, CA) supplying room air, and anesthesia was maintained with a continuous infusion of thiopental. One femoral artery and vein were catheterized, the right carotid artery was dissected, a midline sternotomy was performed, and the pericardium was opened. The left anterior descending coronary artery (LAD) was dissected free at its midpoint and surrounded by an elastic snare. A 2-mm width Doppler flow probe (Transonic Systems, Ithaca, NY) was placed adjacent to the snare. Two pairs of ultrasonic crystals 1 mm in diameter were inserted into the inner third of the left ventricular wall. The crystals of each pair were placed ~1 cm apart along a plane perpendicular to the long axis of the ventricle. One pair was implanted in the myocardium to be made ischemic, and the other pair was implanted in the lateral wall. A micromanometer-tipped catheter (Mikro-tip, Millar, Houston, TX) was advanced into the left ventricle through a small incision in its lateral wall.

Experimental protocol. After hemodynamic stability was ensured, an intravenous bolus of 150 U/kg heparin sodium was administered, and the left coronary artery was catheterized by means of a Judkins 7-Fr guiding catheter introduced through the carotid artery, as described previously (4, 33). A 2.5-Fr infusion catheter (Cordis, Miami, FL) was introduced into the guiding catheter and advanced into the distal LAD. The guiding catheter was pulled back to the aorta, and the infusion catheter was slowly withdrawn until its tip was positioned a few millimeters distal to the dissection site. The LAD was then occluded by tightening the snare.

Phosphate-free, HEPES-buffered saline (in mM: 137 NaCl, 5.4 KCl, 1.0 CaCl2, 0.5 MgCl2, and 5.0 HEPES; 37°C) bubbled with 100% N2 was infused into the ischemic region for 4 min, starting either 5 min (series A) or 20 min (series B) after coronary occlusion. The infusion, the pH of which was adjusted to 7.4 in series A and to 6.4 in series B, was delivered by means of a digital peristaltic pump (505-Du, Watson-Marlow, Falmouth, UK) at a rate doubling the baseline blood flow, to ensure a uniform distribution of the solution in the area at risk. Animals were blindly allocated to receive 40 µM Gd3+, a concentration that has been shown to effectively block stretch-activated channels and suppress stretch-induced arrhythmias (6, 18, 24), or only the buffer during the final 2 min of the infusion (Fig. 1). After the end of the infusion, the intracoronary catheter was left in place to prevent any volume of blood from entering the ischemic region.


Figure 1
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  		Fig. 1. Study design; n, number of animals.

 
Eight animals were excluded due to left main artery thrombosis, displacement or kinking of the infusion catheter, refractory ventricular fibrillation immediately after coronary occlusion, or air embolism. Thus 32 animals were finally included, 16 (8 receiving and 8 not receiving Gd3+) in each series.

Study monitoring. Serial arterial blood gases were obtained to adjust the ventilatory parameters. Serum potassium levels were measured at the beginning of the experiment. Aortic blood pressure was continuously monitored with a crystal quartz transducer (Coulburn Instruments, Lehigh Valley, PA). The ultrasonic segment length signals were analyzed by means of an ultrasonic dimension system (System 6/200, Triton Technology, San Diego, CA) and monitored with an oscilloscope (model HM 205-3, Hameg, Frankfurt, Germany). These signals, along with lead II of the electrocardiogram, aortic pressure, and left ventricular pressure and its first derivative (dP/dt), were digitized in a ML795 PowerLab System (AD Instruments, Mountain View, CA) and continuously recorded at a sampling rate of 200 kHz on a thermic pad recorder (MT-9500, Astro-Med, West Warwick, RI). When ventricular fibrillation occurred, it was converted to sinus rhythm by internal countershocks of 10–20 J.

Segment length measurements and ventricular arrhythmias. As described previously (3–5, 33), segment length measurements and identification of ventricular arrhythmias were performed manually on the digital records at the maximal spatial resolution allowed by the program (8 s/screen) by an investigator blinded to treatment allocation. End diastole was defined as the beginning point of the rapid upslope of the dP/dt tracing, and end systole was defined as the point of minimum dP/dt (Fig. 2). End-diastolic and end-systolic segment lengths (EDL, ESL) and maximal segment length were measured before coronary occlusion and 5, 15, 30, and 45 min after occlusion. Systolic shortening was calculated as follows: systolic shortening (%) = (EDL – ESL) x 100/EDL. EDL was expressed as a percentage of values before coronary occlusion. Systolic bulging was defined as the ratio of maximal segment length during systole and EDL of the same beat times 100%. The number of premature ventricular complexes was counted, and the occurrence of ventricular tachycardia (3 or more consecutive ventricular beats) or fibrillation was analyzed in both series. In the cases of ventricular tachyarrhythmia, only the initiating beat was counted as a premature beat. Phase Ib arrhythmias were defined as those occurring between 10 min of coronary occlusion and the end of the experiment. In series B, particular attention was paid to ventricular arrhythmias occurring after completion of the infusion.


Figure 2
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  		Fig. 2. Example of ECG and hemodynamic and segment length variables in a Gd3+-treated animal from series A. CO, coronary occlusion; ED, end diastole; ES, end systole; LVP, left ventricular pressure; dP/dt, first derivative of LVP; AP, arterial pressure.

 
Postmortem studies. Forty-five minutes (in series A) or 48 min (in series B) after coronary occlusion, 5 ml of 10% fluorescein were injected into the left atrium, and the heart was excised and cut into 5- to 7-mm slices perpendicular to its long axis. The reason for extending the duration of the ischemic period in series B was to increase somewhat the chance of detecting ventricular arrhythmias, given that the observation period after the intervention was shorter in this series. The slices were weighed, illuminated from the basal side with ultraviolet light to outline the area at risk, and photographed, along with a reference scale, with a digital camera. The area at risk was measured semiautomatically in the digitized images using commercially available software (Microimage 3.0, Olympus Optical, Hamburg, Germany), and the mass of the ischemic region was calculated from these measurements and the weight of the slices.

Myocardial samples were obtained from the ischemic and nonischemic zones in the second and third slices (1.5 ± 0.3 g of sampling in each zone per animal) for analysis of water content in animals from series A. As described previously (33), these samples were introduced in crystal tubes that had been weighed in a high-precision scale (Precisa 180A, Pacisa, Barcelona, Spain), and the tubes containing the samples were weighed immediately before and after desiccation during 24 h at 100°C (Selecta 200, P. Selecta, Abrera, Spain). Myocardial water content was calculated as the difference between fresh and dry weight divided by dry weight and expressed as milliliters of water per 100 g of dry tissue.

Statistical analysis. According to the frequency and variability of phase Ib premature ventricular beats in a recent study using the same model in our laboratory (5), the sample size in each series was powered to detect, with {alpha}- and beta-probabilities of 0.05 and 0.3, respectively, a 75% reduction in the number of these premature beats. Statistical analysis was performed using SPSS software. Data are expressed as means ± SE. Paired Student's t-tests or analysis of variance for repeated measures (testing the interaction effect with the treatment received when needed) was used to assess changes in physiological parameters within the same animal. Comparisons between groups were performed by {chi}2-tests and by Student's t-tests. The association between early ventricular dilation and the number of premature ventricular beats was analyzed by means of simple regression analysis. P values <0.05 were considered significant.


   RESULTS
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Hemodynamic data. Hemodynamic data are summarized in Table 1. Immediately before coronary occlusion, the hemodynamic parameters were within the normal range and were similar among the groups in both series. In series A, heart rate and mean aortic pressure experienced minor changes during the experiment. In series B, heart rate increased significantly (P = 0.001) throughout the occlusion period, and mean aortic pressure decreased transiently after coronary occlusion (P < 0.001 with respect to the baseline value) and tended to recover thereafter. Left ventricular end-diastolic pressure increased in both series after coronary occlusion (both P < 0.001), without differences between groups. Before coronary occlusion, blood flow at the mid-LAD averaged 11 ± 1 ml/min in series A and 19 ± 2 ml/min in series B, without differences between groups.


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  		Table 1. Hemodynamic data

 
Segment length changes. Segment length measurements are summarized in Table 2. Before coronary occlusion, systolic shortening was similar in animals allocated to Gd3+ and in those receiving only the buffer in both series. In the nonischemic region, EDL experienced a minor, though significant (P = 0.01), increase throughout the experiment in series A and did not change in series B, and systolic shortening remained stable during the experiment in both series. In the LAD region, coronary occlusion induced in both series a rapid and pronounced increase in EDL (both P < 0.001 by repeated-measures analysis of variance) that tended to be higher in animals allocated to Gd3+ and abolished systolic shortening (both, P < 0.001). The magnitude of systolic bulging during the occlusion period remained stable in both series. Segment length parameters were not modified by the intracoronary infusion per se nor by the treatment administered. The maximum bulging was always measured within the first quarter of the systolic period, and its timing was not modified by Gd3+ [at the end of the infusion, the maximum bulging occurred at 15 ± 1 and 16 ± 1% of the total systolic period in untreated and Gd3+-treated animals, respectively; P = not significant (NS)].


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  		Table 2. Segment length measurements

 
Serum potassium, size of ischemic region, and myocardial water content. Baseline serum potassium concentration was 3.1 ± 0.1 meq/l in untreated animals and 3.1 ± 0.2 meq/l in those allocated to Gd3+ in series A (P = NS). In series B, serum potassium averaged 3.2 ± 0.2 and 3.3 ± 0.1 meq/l, respectively (P = NS).

In series A, the ischemic region weighed 15.5 ± 1.7 g (11.7 ± 1.1% of ventricular mass) in untreated animals and 17.2 ± 1.0 g (13.2 ± 0.7%) in those receiving intracoronary Gd3+ (both, P = NS). In series B, these figures were 22.0 ± 2.0 g (15.2 ± 1.0%) and 24.2 ± 1.4 g (17.3 ± 1.1%), respectively (both P = NS).

In animals from series A, myocardial water content in the nonischemic zone at the end of the experiment was 379 ± 8 ml/100 g of dry tissue, without between-group differences. In the ischemic region, myocardial water content was 427 ± 20 ml/100 g of dry tissue (P = 0.01 with respect to the value in the nonischemic zone) and was also similar in animals infused with vehicle and in those receiving intracoronary Gd3+ (428 ± 28 and 426 ± 30 ml/100 g of dry tissue, respectively; P = NS).

Ventricular arrhythmias. The distribution of premature ventricular beats during coronary occlusion is depicted in Fig. 3. In series A, the mean number of premature beats during the first 10 min of coronary occlusion was 4 ± 2, without between-group differences. The total number of premature ventricular beats between 10 and 45 min of coronary occlusion (Ib phase) averaged 46 ± 20 in animals infused with vehicle and 91 ± 37 in those receiving intracoronary Gd3+ (P = NS). In series B, the number of premature ventricular beats averaged 7 ± 2 and 23 ± 7 during phases Ia and Ib, respectively, without differences between groups. In this series, the number of phase Ib premature beats occurring between the completion of intracoronary infusion and the end of the experiment was 19 ± 7 in untreated animals and 22 ± 13 in those receiving Gd3+ (P = NS).


Figure 3
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  		Fig. 3. Distribution of premature ventricular beats during coronary occlusion in the two treatment groups in both series. n, Number of animals.

 
Figure 4 illustrates the occurrence of ventricular tachyarrhythmias. Of the 22 episodes of ventricular tachycardia identified, one degenerated into ventricular fibrillation and the rest were nonsustained (10 of them triplets). Nine animals (25%) had ventricular fibrillation, always in the phase Ib (29 ± 3 min after coronary occlusion). In series A, the incidence of ventricular fibrillation was 0% in untreated animals and 37.5% in Gd3+-treated animals (P = NS). In series B, ventricular fibrillation occurred after completion of the infusion in 12.5% and 37.5% of the animals, respectively (P = NS). If episodes of ventricular tachycardia or fibrillation occurring after treatment administration were considered altogether, the overall incidence would be 12.5% in untreated animals and 75.0% in the Gd3+ group in series A (P = 0.044) and 12.5% and 37.5%, respectively, in series B (P = NS).


Figure 4
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  		Fig. 4. Distribution of episodes of ventricular tachycardia (rhombi) or fibrillation (circles) in both series. Each line represents a separate animal. Arrows indicate the end of intracoronary infusion.

 
Overall, neither the size of the ischemic region as a percentage of ventricular mass nor baseline serum potassium levels or the increase in EDL was correlated with the number of phase Ib premature ventricular beats. When compared with the remaining animals, those presenting ventricular tachycardia or fibrillation during the Ib phase of arrhythmias had a similar area at risk (15.1 ± 0.9 vs. 13.8 ± 0.8% of ventricular mass, respectively; P = NS) and baseline serum potassium (3.2 ± 0.1 vs. 3.2 ± 0.1 meq/l, respectively; P = NS), but they showed a greater dilation of the ischemic region (15 min after coronary occlusion, EDL was 121.3 ± 2.6 vs. 112.6 ± 1.5% of the baseline value, respectively; P = 0.005). The increase in EDL and the size of the ischemic region were not significantly associated (r = 0.31; P = NS).


   DISCUSSION
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 ABSTRACT
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In the present study, intracoronary administration of the stretch-activated ion channel blocker Gd3+ into the area at risk did not reduce the number of premature ventricular beats nor protect against ventricular tachycardia or fibrillation during the Ib phase of ventricular arrhythmias after coronary occlusion in swine. These results argue against a major involvement of stretch-activated channels located inside the ischemic zone in the genesis of these arrhythmias.

Mechanoelectrical feedback and ischemic ventricular arrhythmias. Mechanoelectrical feedback might contribute to ventricular arrhythmias in patients with chronic myocardial infarction. In support of this, although not as proof of causality, left ventricular dilation is one of the strongest predictors of electrical instability and sudden death in infarct survivors (17). In addition, studies in isolated hearts or ventricular muscle preparations have shown that healed infarctions have an increased sensitivity to stretch-induced electrophysiological changes and arrhythmias (9, 24), which can be suppressed with Gd3+ (24).

Information on the possible influence of stretch on ventricular arrhythmias during acute ischemia is scarce. Horner et al. (19) described that increasing the loading conditions may affect the action potential duration after coronary occlusion. We have previously reported that the expansion of the ischemic region that immediately follows coronary occlusion is a strong and independent predictor of the subsequent occurrence of phase Ib ventricular fibrillation in anesthetized pigs (4, 5). In isolated pig hearts, Coronel et al. (13) have reported that increasing left ventricular wall stress augments the incidence of ventricular arrhythmias early after coronary occlusion and that these arrhythmias frequently occur after a potentiated beat induced by a pause. Reciprocally, regional ischemia has been shown to facilitate stretch-induced arrhythmias in isolated rabbit hearts (31).

Involvement of stretch-activated channels. Recently, in our laboratory, intravenous administration of Gd3+ started prior to coronary occlusion at doses that had apparently been successful in blocking stretch-activated channels in vivo (30, 37) did not reduce significantly the number of premature ventricular beats or the incidence of ischemic ventricular fibrillation in swine (5). However, because of the unpredictable availability of Gd3+ after intravenous injection (8), a significant involvement of stretch-activated channels could not be excluded. The results of the present study, in which this compound was administered directly into the ischemic region in the absence of blood or phosphate in the infusion solution, provide further evidence against a major role of stretch-activated ion channels inside the ischemic region in the genesis of type Ib ventricular arrhythmias.

It has been described in canines that most ischemic ventricular tachyarrhythmias originate from the ischemic area (1). However, in species lacking native collateral circulation, as is the case in swine, the role of this electrically depressed region in arrhythmogenesis is probably less important. In this respect, it has been shown in isolated pig hearts subjected to regional ischemia that both early (21) and phase Ib (13) focal arrhythmias originate preferentially at the ischemic border. The border zone also modulates the spatial distribution of wave breaks during ventricular fibrillation in the same model, regional ischemia increasing wave break incidence at this zone while decreasing it inside the ischemic region (42). Because in the present study the outer side of the ischemic border was not infused, our results do not allow exclusion of a contribution of stretch-activated channels located in this zone, which represents a significant limitation. However, because the inner side of the border—a nonnegligible origin of focal activity in this animal model (13)—was infused, the fact that treated animals did not show any trend toward fewer phase Ib arrhythmias suggests that the contribution of stretch-activated channels to these arrhythmias may not be critical.

In agreement with our previous observations (4, 5), the increase in EDL in the ischemic region was not associated with the number of type Ib premature ventricular beats. In contrast, the increase in EDL was significantly higher in animals that had ventricular tachycardia or fibrillation during this phase, which extends our previous observations of an association between regional ischemic expansion and ventricular fibrillation (4, 5) to the whole spectrum of phase Ib ventricular tachyarrhythmias. Taken together, these results, along with the lack of effect of Gd3+ in reducing the number of premature ventricular beats, suggest that regional ischemic dilation might facilitate the occurrence of ventricular tachyarrhythmias by making the substrate more favorable for these arrhythmias to occur rather than by acting on the triggers. Previous studies (14) have shown that the Ib phase of spontaneous arrhythmias coincides with an enhanced inducibility of ventricular fibrillation during acute ischemia.

Alternative mechanisms. There are alternative mechanisms that could account for the association between regional ischemic expansion and phase Ib ventricular tachyarrhythmias. First, there is an activation of autonomic reflexes by the excitation of mechanoreceptors in the acutely ischemic region (29, 40). Previous studies have shown that an increased sympathetic activity or a reduced vagal traffic may critically determine the vulnerability to ventricular fibrillation during acute (10) or chronic (11, 16) coronary occlusion. The potential importance of autonomic influences is further supported by the finding by Coronel et al. (13) that ventricular arrhythmias after coronary occlusion in swine are more frequent in vivo than in isolated hearts, in which spontaneous ventricular fibrillation rarely occurred even after the loading conditions were increased. Second, increasing mechanical load causes beta-adrenergic receptor activation (27) and potentiates the electrophysiological effects of sympathetic stimulation on the myocardium (20). Finally, stretch induces changes in the cytoplasmic calcium concentration—partly through stretch-activated channels but also by increasing the affinity of the contractile proteins (26, 38)—that may be arrhythmogenic.

Methodological considerations and limitations. The trend toward more ventricular arrhythmias observed in animals receiving Gd3+ raises the question as to whether this compound might have been arrhythmogenic in this model. However, besides not reaching statistical significance, the trend toward more premature beats in treated animals was observed only in series A. In addition, the size of the area at risk and the magnitude of ischemic expansion, both of which are associated with phase Ib ventricular tachyarrhythmias (4, 5, 22), tended to be larger in animals allocated to Gd3+. These differences, clearly not attributable to the intervention itself—the trend toward larger expansion was already present before intracoronary infusion—may explain the apparently increased susceptibility to these arrhythmias in treated animals observed in our study. On the other hand, it seems unlikely that the infusion of a protein-free solution had influenced the results, because the edema in the ischemic region was not severe (3, 33) and also because the incidence of arrhythmias was within the expected range according to previous studies in the same model without intracoronary infusion (4, 5, 12, 13, 36).

Besides the incomplete infusion of the border zone mentioned above, several limitations must be acknowledged in relation to this study. First, only one concentration of Gd3+ was used and the drug was infused for only 2 min. Although multiple concentrations and infusion times would have been ideal, a 40 µM concentration was selected because it had previously produced a potent blockade of stretch-activated channels (6, 18, 24). We chose this short period of treatment to avoid having the results influenced by changes in the experimental preparation that would have been introduced by a prolonged infusion. Because the LAD was always maintained occluded to prevent Gd3+ from leaking out of the area at risk and this compound was equally ineffective if administered shortly after coronary occlusion or later on in the ischemic period, it seems unlikely that the negative results are explained by a rapid loss of effect of Gd3+. Second, the study was not powered to detect a modest antiarrhythmic effect of Gd3+. However, the trends toward more premature ventricular beats and more ventricular tachyarrhythmias in treated animals strongly argue against a significant protective effect. Finally, there are stretch-activated channels insensitive to Gd3+ (8). The identification of new blockers of stretch-activated channels with more favorable bioavailability (7) could help overcome some of these limitations.

In conclusion, the results of the present study argue against a major role of stretch-activated ion channels located inside the area at risk in the genesis of type Ib ventricular arrhythmias after coronary occlusion. While the role of stretch-activated channels from the border zone deserves further investigation, the results indirectly support that alternative mechanisms might contribute to the increased susceptibility to phase Ib malignant ventricular tachyarrhythmias associated with early regional expansion observed in this as well as in previous studies (4, 5).


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This study was partially supported by a grant from the Fondo de Investigación Sanitaria (FIS 05/1745) and Red Temática de Enfermedades Cardiovasculares (RECAVA).


   FOOTNOTES
 

Address for reprint requests and other correspondence: David Garcia-Dorado, Servicio de Cardiología, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119–129, E-08035 Barcelona, Spain (e-mail: dgdorado{at}vhebron.net)

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.


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