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EDITORIAL COORDINATIONOtoni M. Gomes (Brazil),

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CONTENTSCONTENTS

Page 5

Short-Term Analysis of Heart Rate Variability in Diabetic Patients.

E.R. Migliaro, P. Contreras

Role of ATP Dependent Potassium Channels in the Protection Against Ischemia-Reperfusion Damage in Consius Sheep

E. C. Lascano, H. F. del Valle, J. A. Negroni, A.J. Crottogini

Page 9

ORIGINAL ARTICLES / ARTIGOS ORIGINAIS

EDITORIAL

Cardiovasc Sci Forum Jul. /Sep. 2008 Vol. 3 / Number 3

La Investigación Basica y Clínica en Cardiologia: Premios y Castigos

H.E. Cingolani

UPCOMING MEETINGSPage 28

(Spanish)

INSTRUCTION TO AUTHORSPage 26

(Spanish)

(Spanish)

NOTÍCIAS ESPECIAIS / SPECIAL NEWSPage 25

PROGRAMA DO SIMPOSIO DE CELEBRAÇÃO DOS 50 ANOS DE CIRURGIA NA SLOVENIAAGRADECIMENTOS DECARDIO-SBCCV E DEPEX-SBCCV


EDITORIALEDITORIAL

Aunque la mayor parte de los médicos aceptamos que la investigación Básica es la hecha con animales y la Clínica la realizada en pacientes, esta clasificación ha sido cuestionada. Para algu-nos especialistas en el tema, la especie utilizada para probar una hipótesis no define qué clase de investigación se realiza. Una clasificación mejor sería posiblemente dividir la investigación en Bá-sica y Aplicada. La investigación Básica está des-tinada a describir mecanismos aún no conocidos sin pretender aplicación o rédito alguno (los inves-tigadores saben que si el mecanismo es nuevo y la investigación bien hecha, tarde o temprano, ten-drá aplicación práctica). Esta investigación Básica puede hacerse en animales o seres humanos.

¿Y la investigación Clínica? Alfredo Lana-ri decía que si hacíamos experimentos en la rata diabética o hipertensa hacíamos investigación clí-nica, puesto que pretendíamos resolver problemas de aplicación Clínica.

Debemos reconocer, con las salvedades anteriores, que generalmente se denomina inves-tigación Clínica a la realizada en pacientes; puede ser ésta Básica o Aplicada, pero en la mayoría de los casos es Aplicada puesto que busca encontrar una aplicación a un mecanismo muchas veces an-teriormente descripto. Cuando se describe un me-canismo nuevo la investigación es Básica aunque haya sido realizada en pacientes.

Bernardo Houssay escribía: “... la investi-gación Básica persigue hallar verdades nuevas aún desconocidas, las cuales en general son inespera-das y tendrán consecuencias no siempre previsi-bles al principio...”.

Comroe y Drips analizaron retrospectiva-mente durante 1971-1977 qué hizo posible lo que ellos consideraron los mayores diez adelantos de la Ciencia Médica durante los últimos años. Ana-lizaron 6.000 publicaciones científicas. Estos diez adelantos fueron:

LA INVESTIGACIÓN BÁSICA Y CLÍNICA EN CARDIOLOGIA “Premios y Castigos”“The Basic and Clinical Investigation in Cardiology: Prize and Punishment”

H. E. CingolaniDirector del Centro de Investigaciones Cardiovasculares - CONICET - UNLP

1. Antibióticos.2. Prevención de la Poliomielitis.3. Cirugía Cardíaca.4. Transplantes.5. Tratamiento de la hipertensión arterial.

6. Resucitación Cardíaca.7. Tratamiento de las Arritmias.8. Quimioterapia.9. Unidades intensivas.10. Tratamiento del infarto de miocardio.

CARDIOVASCULAR SCIENCES FORUM�

Luego de este meticuloso estudio llega-ron estos autores a la conclusión que los estudios “clave” que posibilitaron estos diez adelantos pro-venían 62% de la investigación Básica y 38% de la investigación Aplicada (observemos que no se especifica la especie usada). Del 62% de investi-gación Básica, un 42% no pretendían solucionar ningún problema ni tenían relación alguna con el tema en cuestión que posibilitaron.

La investigación cardiológica (Básica y Clínica) en Latinoamérica está subdesarrollada. Así lo muestra el escaso número de publicaciones o presentaciones en ambientes científicos en los cuales existe una selección rigurosa. Hoy en día en que todo parece que hubiese que convertirlo en cifras y medirlo, también se han mensurado las pu-

blicaciones científicas. Hay dos parámetros usados comunmente para evaluar una publicación cientí-fica: 1) El “impacto”; este representa el porcentaje de los trabajos publicados por esta revista que son citados en los dos años posteriores a la publicaci-ón; 2) La “vida media” de los trabajos publicados. Es decir un índice de por cuánto tiempo son cita-dos estos trabajos luego de publicados. El primero es el más conocido y usado de ellos. Combinando los dos se obtiene el “doble producto”. Cuando examinamos algunas pocas publicaciones cientí-ficas con este parámetro observamos que apare-cen primero Circulation Research seguida luego de Circulation, Journal of the American College of Cardiology, Cardiovascular Research y Journal Molecular and Celular Cardiology.

Fig. 1: Se examina con este parámetro, “doble producto”, cinco publicaciones científicas cardiológicas durante 1996, 1997, 1998 y 1999. La primer barra (la más alta) correspondió a Circulation Research, seguida de Circulation durante los 4 años examinados.


Si tomamos la primera de estas publicacio-nes, Circulation Research, vemos que se recibie-ron para ser considerados para su publicación, des-de 1-7-99 al 30-6-00, 1114 manuscritos; sólo 11 de ellos fueron de Latinoamérica. Brasil, Argentina, México y Chile fueron los países que enviaron manuscritos. La figura 2 muestra la distribución geográfica de los manuscritos recibidos por esta publicación en el lapso anteriormente menciona-

do. Sería necesario aclarar que estos no fueron los manuscritos publicados sino los que fueron envia-dos para ser considerados. Sólo un 20%, apróxi-madamente, de los manuscritos recibidos son pu-blicados. Observemos que sólo un 1% provenían de Latinoamérica. Cálculos similares podrían ha-cerse posiblemente en relación a otras prestigiosas revistas científicas o a la presentación de trabajos anuales a la American Heart Association.

Fig. 2: Distribución geográfica de los 1114 manuscritos recibidos para ser considerados para su publicación en Circulation Research desde 1-7-99 al 30-6-00. Se observa que sólo el 1% de ellos provenía de Latinoamérica. Note que éstos son los manuscritos recibidos para ser considerados para su publicación; sólo 20% de ellos fueron publicados

Las causas de este subdesarrollo en la in-vestigación cardiológica hay que buscarla posible-mente en la falta de “premios y castigos”. Por otro lado, el porcentaje del PBI que Latinoamérica de-dica a la investigación está muy por debajo del de los países desarrollados del resto del mundo.

Dado que la función principal de la cardio-

logía no sea posiblemente la de publicargeográfica de los manuscritos recibidos por esta publicación en el lapso anteriormente menciona trabajos sino la de curar enfermos cardiológicos, uno podría plantearse el interrogante si las otras dos “patas” del trípode Asistencia – Docencia – Investigación ayudan o son contraproducentes para la Asistencia.


Esto se ha mensurado y se llegó a establecer que en aquellas instituciones académicas en las cuales se hace investigación y docencia, a los pacientes les va mejor (Do “America´s best hospitals” perform better for acute myocardial infarction? Jersey Chen, et al. New England Journal of Medicine 340:286-292, 1999; Effects of admission to a teaching hos-

pital on the cost and quality of care for medicare beneficiaries. Donald H Taylos, et al. New England Journal of Medicine 340:293-2999, 1999.)

La Prestigiosa Universidad Norteamerica-na Jonhs Hopkins posee un logotipo que trata de resumir estos tres principios en los cuales descan-sa la Educación Médica.

Fig. 2: Distribución geográfica de los 1114 manuscritos recibidos para ser considerados para su publicación en Circulation Research desde 1-7-99 al 30-6-00. Se observa que sólo el 1% de ellos provenía de Latinoamérica. Note que éstos son los manuscritos recibidos para ser considerados para su publicación; sólo 20% de ellos fueron publicados

Volviendo a los “premios y castigos”, esto aunque discutible para quiernes piensan en que la Investigación Científica es una actividad creadora que no puede estar sujeta a “premios y castigos”, me ha hecho reflexionar en cuál sería la produc-ción científica sa la Educación Médica en países

desarrollados si no hubiera exigencias sobre ésta para subsistir académicamente. Por lo tanto, una política agresiva, invirtiendo fondos y aplicando “premios y castigos” ayudaría a impulsar la Inves-tigación Cardiológica Latinoamericana.


ORIGINAL ARTICLESORIGINAL ARTICLES

SHORT-TERM ANALYSIS OF HEART RATE VARIABILITY IN DIABETIC PATIENTS

E. R. Migliaro, P. Contreras.Departamento de Fisiologia. Facultad de Medicina. Montevideo, URUGUAY.

1. Summary The aim of this work was to assess the

value of a short-term routine to measure the Heart Rate Variability (HRV) and its parasympathetic and sympathetic components. We studied a group that was supposed to have low values of HRV owing to their long-lasting type I diabetes (n=15). None of these patients had symptoms of autonomic neuropathy. This group was compared with 13 healthy volunteers with similar gender and age profile. An ECG was obtained from an electrocardiograph and fed into a computer by means of an analog to digital converter. R waves were detected and visual inspection allowed the elimination of the non-sinusal beats. The normal R-R intervals (N-N) were measured and stored. Using the N-N lists we calculated two time-domain indexes: the standard deviation of intervals (SDNN) and the square root of the mean of the squared differences between adjacent intervals (rMSSD). Spectral analysis was done to study HRV in the frequency domain. The spectrum obtained was divided in different components: the high frequency band (HF) from 0.15 to 0.4 Hz and the low frequency band (LF) from 0.04 to 0.15 Hz. The HF component is considered dependent on the

parasympathetic activity and the LF component reflects both parasympathetic and sympathetic drive. The total power of the spectrum and the LF/HF ratio were also calculated. The results show a clear diminution of HRV in the diabetic patients in comparison with the control group. Such a reduction seems to reflect a parallel decrease of the sympathetic and parasympathetic flows.

Key Words: Heart rate variability, diabetic neuropathy, autonomic nervous system.

2. Introduction The duration of normal heart beat intervals

display subtle variations which lead to changes in heart rate known as Heart Rate Variability (HRV). The main determinants of HRV in healthy people are the respiratory changes, resting heart rate and age (1). All of them are related with the autonomic nervous system (ANS) activity. The former is the well-known respiratory sinus arrhythmia, the normal variation of heart rhythm coupled with respiration which is more evident in young people (2). Resting heart rate expresses the sympatho-vagal balance, when it is shifted towards increments of resting heart rate, HRV diminishes. Influence

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of age could be related with autonomic aging (HRV diminishes as age increases) (3). Besides such physiological changes, many pathological states also affect HRV. Among them,the most wildly studied are: coronary disease (4)(5), heart failure (6),(7), anxiety or phobias (8), and diabetes mellitus (9),(10),(11). Diabetes delays neural conduction as a consequence of either vascular alteration (microangiopathy of the vasa nervorum) or of metabolic or autoimmune changes in the myelin sheath (12). Sensitive-motor dysfunctions (somatic neuropathy) are found in the spinal nerves of diabetic patients, while in the ANS this illness causes alterations related to the denervation of the viscera (autonomic neuropathy).

The cardiovascular autonomic neuropathy may play a main role in causing arrhythmias and sudden death (13),(14). The interest of studying the cardiovascular modifications in the autonomic neuropathy of diabetic patients is based on their early appearance. Compared with other tests used to diagnose autonomic neuropathy, HRV is preferred by its simplicity, which explains why its analysis has represented an important tool in the study of this pathology (15).

Methods for HRV analysis. The introduction of microcomputers

allowed the improvement of the recording method and the measurement of HRV. In brief, HRV can be measured in short-term recordings (few minutes) or in long lasting ones (24 h Holter monitorization). In each case, a list of successive R-R intervals is obtained. Noise and non-sinusal beats are removed and the resulting normal intervals (N-N) can be processed in many ways, (statistical methods, non-linear analysis, frequency domain studies). Here we chose two of them:

Time-domain analysis.The numeric expression of the dispersion

of data is the standard deviation of the N-N intervals (SDNN) or the indexes that derive from it (16). Another useful time-domain index is the square root of the mean of the squared differences between adjacent intervals (rMSSD) that evaluates more accurately the beat to beat changes (17),(5).

Frequency-domain analysis.The succession of intervals over time

(tachogram) can be analyzed as a new complex signal, then its power spectral density can be estimated.. In this work we computed the values between 0.0033 and 0.50 Hz (referred as total power). The analysis of HRV in the frequency domain introduces a main aspect that refers to the possibility of separating influences of both branches of the ANS. Most researchers agree that the high frequency band power (HF, 0.15 to 0.40 Hz) is related to the modulation of the parasympathetic branch (18),(11). The low frequency band power (LF, from 0.04 to 0.15 Hz) represents both autonomic branches and other non-autonomic influences (11). The basis of the components of frequencies below 0.04 Hz (“ultra low frequency” and “very low frequency” bands) still remain unclear (19). In addition, our short-term study do not assess properly those frequencies.

The aim of the present work was the evaluation of a short-term study as a diagnostic tool for HRV in a group of patients that is supposed to have low values of HRV owing to their long-lasting type I diabetes.

3. Material and methods. We studied 15 diabetic patients (7 men and

8 women) aged between 44 and 66 years (mean

JUL. / SEP. 2008 - VOL. 3 - NUMBER 3 ��

[± SD] 53.8 ± 7.4). All of them were insulin-dependent and had had diabetes mellitus for a long time (mean [± SD] diabetes duration 38.33 ± 8.5 years). They were allowed to receive their usual medication (digitalis, calcium antagonists, converting enzyme inhibitors).

The control group was composed by 13 healthy volunteers (5 men and 8 women) aged between 45 and 70 years (mean [± SD] 55.8 ± 7.8 years). The volunteers were non-smokers and were not receiving any medication. We excluded for the study people who had arrhythmia in the clinical examination or in the ECG or Holter recording.

HRV was assessed measuring the intervals between heart beats recorded in a conventional ECG. The procedure for recording was the following: Subjects were asked not to perform heavy exercise or take coffee or alcohol 24 h prior to the study. Electrodes for the ECG recording were placed on the chest, two of them were used to obtain a bipolar derivation. We connected the ECG with the computer by means of an analog to

digital (A/D) converter. Such connection allowed the acquisition of the entire ECG. The sampling frequency was 500 Hz. In order to achieve a good relaxation the subject lied for 20 min in supine position in a quiet room. After that, we began the recording period which lasted for 10 min. All the studies were done between 4:00 and 6:00 PM.

In an off-line analysis, a special program detected each R wave. A visual inspection routine allowed the validation of the detected R waves, correcting those related with premature beats and movements (false positives). After that, we obtained a train of N-N (normal to normal) intervals. Another program measured the N-N intervals in ms. With the lists obtained, a software calculated the indexes for time domain HRV analysis: SDNN and rMSSD. For the frequency domain analysis, graphs of the total spectrum were plotted (Figure 1); then, we computed the spectral density and calculated: total power, LF power, HF power and LF/HF ratio 1 .

The statistical comparisons were done with a non-parametric test (Mann-Whitney). Values of p<0.05 were considered significant.

Fig 1 - Spectral analysis of two subjects matched by age and sex. The control has higher values of spectral density than the diabetic patient in all frequencies.

1 - The original software for acquisition, visual inspe-ction, N-N measurements and calculus of HRV indexes were developed by El. Eng. R. Canetti and El..Eng. M. Hackas from the Instituto de Ingeniería Eléctrica. Facultad de Ingeniería Montevideo, Uruguay.


4. ResultsAs we mentioned earlier both groups are

similar in age and gender distribution. The values of their mean (± SD) resting heart rate are: 73.9 ± 9.4 beats/min in the diabetic group and 69.7 ± 5.2 beats/min for the control group. Such figures are not statistically different.

Time-domain analysis.Mean values of SDNN and rMSSD in each

group, are shown in Figure 2. As we can see, values for the diabetic group are significantly lower than those for the controls.

Frequency-domain analysis.The average values of spectral density are

shown in Table 1. The diabetic patients show a significant reduction of the mean values of the total power as well as HF and LF bands. Nevertheless, values of LF/HF ratio are not statistically different.

Fig 2 - Time-domain indexes of HRVBar graphs show the comparison of SDNN (upper graph) and rMSSD (lower graph) between control group and diabetic patients. Figures inside the boxes correspond to the mean values ± S.D. The symbol (*) indicates p<0.05. See text for discussion.

TABLE 1 Diabetic Control

Mean SD Mean SD P

TPSD 558.67 637.24 1801.50 1263.40 0.0004

LF 138.44 187.70 501.48 410.53 0.0004

HF 86.11 124.92 263.68 311.88 0.007

LF/HF 2.695 1.838 2.849 2.056 N.S.

Table 1 - Frequency-domain indexes of HRVMean values (± S.D.) of: Total power spectrum density (TPSD), LF band, HF band LF/HF ratio. All values but the LF/HF ratio. are statistically significant See text for discussion.

JUL. / SEP. 2008 - VOL. 3 - NUMBER 3 �3

5. CommentsHRV is often studied by means of Holter

monitorization. This procedure has the advantage that circadian variations of HRV are recorded. On the other hand, its acquisition frequency is lower than the one we use (128 vs. 500 Hz). In addition, Holter studies are usually done using tape recorders and small variations in tape speed can induce abnormal HRV measurements.

On the contrary, short-term studies are performed in control conditions, i.e. all subjects are in the same environment without external influences. The acquisition is performed with a computer through an A/D converter, in this way tape speed changes are avoided and the acquisition frequency can be increased. Using this short-term procedure, our results agree with those of other authors which point out the affectation of the ANS in diabetes mellitus.

The concomitant reduction of LF and HF bands and therefore, the non-significant variation of the LF/HF ratio seems to show that the decrease of HRV in the diabetic group is based on a similar

affectation of the sympathetic and parasympathetic branches. Other authors have obtained evidence about an early affectation of both branches of the ANS in this pathology (20)(11). Meanwhile, there are reports that states an increase (21) or a decrease (22) in LF/HF ratio in diabetic compared with controls.

In the earliest studies of diabetic neuropathy, a rest taquicardia was described, which would imply an premature parasympathetic affectation (23). In our groups, the differences between the mean values of heart rate is not significant, which agrees with the parallel reduction of the HF and LF components.

6. ConclusionsOur short-term procedure is useful enough

to the diagnosis of the HRV impairment in diabetes. In the present study, the diabetic patients show a clear reduction of their HRV when compared with the control volunteers. Such a reduction seems to reflect a parallel affectation of the sympathetic and parasympathetic branches.

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06. Stein, P. K., Rich, M. W., Rottman, J. N., and Kleiger, R. E,. Stability of index of heart rate variability in patients with congestive heart failure. Am Heart J (1995) 129:975-981.

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08. Kawachi, I., Sparrow, D., Vokonas, P. S., and Weiss, S. T. Decreased heart rate variability in men with phobic anxiety (data from the Normative Aging Study). Am J Cardiol (1995) 75:882-885.

09. Malpas, S. C. and Maling, T. J. Heart rate variability and cardiac autonomic function in diabetes. Diabetes (1990) 39:1177-1181.

10. Thomaseth, K., Cobelli, C., Bellavere, F., Balzani, I., De Masi, G., Bax, G., and Carenza, P. Heart rate spectral analysis for assesing autonomic regulation in diabetic patients. J Auton Nerv Syst (1990) 30:S169-S172.

11. Malik, M. Heart Rate Variability. In: Zipes D., Jalife J. Eds. Cardiac Electrophysiology. Third. Edition. Philadelphia. W.B.Saunders Company. 1999. 753-762.

12. Cotran , R. S., Kumar, V., and Robbins, S. T. El páncreas. In: Robbins S.T. Ed. Patología estructural y funcional. Madrid. McGraw-Hill - Interamericana. 1990. 1033-1062.

13. Rathmann, W., Ziegler, D., Jahnke, M., Haastert, B., and Gries, F. A. .Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med (1993) 10:820-48.

14. Ong, J. J., Sarma, J. S., Venkataraman, K., Levin, S. R., and Singh, B. N.. Circadian rhythmicity of heart rate and QTc interval in diabetic autonomic neuropathy: implications for the mechanism of sudden death.. Am Heart J (1993) 125:744-752.

15. Howorka, K., Pumprla, J., and Schabmann, A. Optimal parameters of short-term heart rate spectrogram for routine evaluation of diabetic cardiovascular autonomic neuropathy. J Auton Nerv Syst. (30-4-1998) 69:164-172.16 Kleiger, R., Stein, P., Bossner, M., and Rottman, J. Time domain measurements of heart rate varibility. Cardiol Clin (1992) 10:487-498.

17. von Neumann, J., Kent, R. H., Bellinson, R. H., and Hart, B. I. The mean square succesive difference. Ann Math Stat (1941) 12:153-162.

18. Appel, M. L., Berger, R. D., Saul, J. P., Smith, J. M., and Cohen, R. J.,.Beat to beat variability in cardiovascular variables: Noise or music? J Am Coll Cardiol (1989) 14 nº 5:1139-1148.

19. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate Variability. Standards of measurement, physiological interpretation, and clinical use. Circulation (1996) 93:1043-1065.

20. Weise, F. and Heydenreich, F. A non-invasive approach to cardiac autonomic neuropathy in patients with diabetes mellitus. Clin Physiol (1990) 10:137-145.

21. Weston, PJ., James, MA., Panerai, RB., McNally, PG., Putter, JF., and Thurson, E. Evidence of defective cardiovascular regulation in insuline.dependant diabetic patients without clinical autonomic dysfunction. Diabetes Res Clin.Pract (1998) 43:141-148.

22. Singh, JP, Larson, M. G., O´Donnell, CJ, Wilson, PF, Tsuji, H., Lloyd-Jones, DM, and Levy, D. Association of hyperglicemia with reduce heart rate variability. (The Framinham heart study). Am J Cardiol. (2000) 86:309-312.

23. Lloyod-Mostyn, R. and Watkins, P. Defective inervation of heart in diabetic autonomic neuropathy. BMJ (1975) 3:15.


E. C. Lascano, H. F. del Valle, J. A. Negroni, A. J. CrottoginiDepartment of Physiology, Pharmacology and Biochemistry,

Favaloro University, Buenos Aires, Argentina.

ROLE OF ATP DEPENDENT POTASSIUM CHANNELS IN THE PROTECTION AGAINST

ISCHEMIA-REPERFUSION DAMAGE IN CONSIOUS SHEEP

1. AbstractThe participation of ATP-dependent

potassium (KATP) channels on postischemic functional recovery is not fully known. The purpose of this study was thus to analyze the role of KATP channels on myocardial recovery from stunning in a conscious sheep model. Adult sheep were instrumented with a pneumatic occluder around the distal third of the anterior coronary artery, a venous catheter for drug infusion, an intraventricular pressure microtransducer, and a pair of piezoelectric crystals in the zone to be rendered ischemic to measure wall thickness and calculate percent wall thickening fraction (%WTh): 100(systolic thickness-diastolic thickness)/diastolic thickness. The animals were divided in 3 groups, Control (CONT): consisted in 12 min ischemia followed by 2 reperfusion hours; Glibenclamide (GLIB): the same as in control except that glibenclamide (0.4 mg/kg), inhibitor of KATP channels was administered 30 min before the 12 min ischemia; Glibenclamide sham (GLIB SHAM): same as the glibenclamide group, except that no ischemia was performed. Ischemia and reperfusion recovery were expressed as percent of basal preischemic conditions taken as 100. Monophasic action potential duration

(APD) was measured in an additional group of open chest animals to evaluate the activity of KATP channels with and without glibenclamide during ischemia and reperfusion. Results showed that APD90 shortened to 50% during ischemia with respect to preischemia and that this response was inhibited by the employed dose of glibenclamide. Ischemia produced stunning during reperfusion in CONT, which was intensified in the GLIB group. However, glibenclamide had no effect on %WTh when no ischemia was performed, indicating that a vasoconstrictive action of this drug was negligble. These results suggest that opening of KATP channels during ischemia protects the heart during recovery from stunning, since their inhibition worsens it. The protection afforded by KATP channel opening could be ascribed to reduced calcium entry because impairment of cardiac recovery due to inhibition of KATP channels is probably due to calcium overload and not to a vasoconstrictive action of the drug.

2. IntroductionATP-dependent potassium (KATP)

channels, a subtype of potassium channels essentially regulated by intracellular ATP concentration, have been identified in many cell

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types, including skeletal muscle, brain, kidney, pancreatic b-cells, smooth muscle and heart. In ventricular myocytes, a high ATP concentration inhibits the KATP channel keeping it in its closed position, whereas a low ATP concentration opens it producing potassium efflux from the cell (1) with a concommitant reduction of action potential duration (2). Opening of cardiac KATP channels during ischemia have therefore been suggested to have a cardioprotective role, since the decrease in action potential duration would reduce calcium entry into the cell, avoiding calcium overload and preserving energy reserves which could be used during early reperfusion to improve myocardial function recovery (3). If KATP channels are cardioprotective structures, then KATP channel blockers might have deleterious cardiovascular actions. The latter seems to be true since glibenclamide, a second generation sulfonylurea that inhibits KATP channels eliminating action potential duration reduction during ischemia in dogs (3), rabbits (4) and pigs (5) has been found to abolish cardiac cell protection induced by ischemic preconditioning (6), KATP channel openers (7) and isoflurane anesthesia (8). Although KATP channels have demonstrated to protect against infarction and some malignant arrhythmias, it is not fully known their participation in cardiac protection against ventricular postischemic dysfunction (stunning), particularly following a completely reversible ischemia, and only one study has shown that the KATP channel opener, nicorandil, enhanced the recovery of regional contractile function during reperfusion following a 10 min occlusion in conscious dogs (9). The purpose of this work was thus to further study the role of KATP channels on myocardial recovery from stunning in a conscious sheep model.

3. Material and MethodsSurgical preparationThe present investigation conformed with

the Guide for the Care and Use of Laboratory Animals, published by the US National Institute of Health (NIH Publication No. 85-23, revised 1996).

The experiments were performed in Male Hampshire Down sheep aged 7 to 9 months (25 to 30 kg). The animals were deparazited with ivermectine, and vaccinated against tetanus, anthrax, gas gangrene and clostrydial enterotoxemia. During 10 days before surgery, the animals were adapted to the laboratory environment. After sedation with acepromazine maleate, 0.3 mg/kg, anesthesia was induced with thiopental sodium, 20 mg/kg. Following intubation and connection to mechanical ventilation (Neumovent 910, Córdoba, Argentina), anesthesia was maintained with 3% enflurane carried in oxygen and fentanyl citrate, 0.1 mg. A sterile thoracotomy was performed at the left fifth intercostal space. The heart was suspended in a pericardial cradle, and a solid-state pressure (P) microtransducer (Konigsberg P7, Pasadena, CA) was inserted in the left ventricular cavity through a stab wound in the apex. A tygon fluid-filled catheter was inserted in the mammary vein for drug infusion and another fluid-filled catheter was inserted in the left ventricle for later calibration of the pressure microtransducer. The left anterior descending coronary artery was dissected free from adjacent tissue just distal to the second diagonal branch, and a pneumatic cuff occluder was positioned around it. A pair of 5 MHz piezoelectric crystals was placed well within the zone to be rendered ischemic to measure left ventricular wall thickness. For appropriate placement of the crystals, the ischemic zone


was visually assessed by transitory inflation of the coronary cuff. All wires and catheters were tunnelled subcutaneously to emerge between the scapulae, and the thoracotomy was closed without pericardial closure. The venous and left ventricular catheters were flushed daily with heparinized (500 IU) saline. Cephalomycin, 1g i.v., was given immediately after surgery and continued during 3 days at a dose of 1 g/day i.m. At the end of the experiment the animals were sacrificed with an overdose of thiopental sodium followed by a bolus injection of potassium chloride. Correct positioning of the crystals was verified at necropsy.

Experimental protocolSeven to 10 days after surgery, the animals

were studied in the conscious, unsedated state, standing in a cage. The Konigsberg transducer and the ultrasonic crystals were connected to pressure and sonomicrometer modules of a System 6 Physiological Monitoring System (Triton Technology, San Diego, CA). The fluid filled catheter was connected to a pressure transducer (DT-XX, Viggo-Spectramed, Oxnard, CA) previously calibrated using a transducer calibration system (Xcaliber, Viggo-Spectramed, Oxnard, CA). The zero pressure point was set approximately at the level of the right atrium, and the signal generated by the Konigsberg transducer was adjusted to match that of the external transducer. The ultrasonic crystals were calibrated in mm using the sonomicrometer internal calibration. At the start of reperfusion a bolus of lidocaine (1-2 mg/kg) was administered upon arrhythmia occurrence.

Fig. 1 shows the experimental design. The experimental groups were :

1. CONT (Control) (N=8): The animals were subjected to 20 min of control recordings,

a 12 minute ischemic period and 2 hours of reperfusion.

2. GLIB (Glibenclamide) (N=7): The same procedure as in CONT was performed, except that glibenclamide (0.4 mg/kg, dissolved in 1ml ethanol, 1ml propylene glycol and 1 ml of 1.0 N NaOH) was administered in 15 ml saline during 10 min before the 20 min control recordings.

3. GLIB SHAM (Glibenclamide sham) (N=4): Same as GLIB except that no ischemia was performed.

The duration of ischemia (12 min) was determined on the basis of pilot experiments. We found that 12 minutes of ischemia produced a significant degree of myocardial stunning during reperfusion with no histological evidence of myocardial necrosis.

At each acquisition time, the signals of consecutive steady beats were digitized at 4 msec intervals over 15 sec using a personal computer equipped with an A/D converter (National Instruments Lab-PC, Austin, Texas) and software developed in our laboratory. Measurements were processed at 0, 5, 10, 15 and 20 min before ischemia; at 3, 7 and 12 min of ischemia, at every 5 min during the first reperfusion hour and at every 10 min during the second reperfusion hour.

Epicardial monophasic action potential:Monophasic action potential duration

(APD) was measured in an additional group (N=4) of open chest animals to evaluate the activity of KATP channels with and without glibenclamide during ischemia and reperfusion. A Ag/AgCl suction bipolar electrode (10) was placed on the epicardium of a zone to be rendered ischemic. Control recordings were taken during basal preischemic, steady state ischemia (12 min


occlusion) and at 5 min reperfusion. Following full recovery of the monophasic action potential, 0.4 mg/kg glibenclamide was infused through a venous catheter. Thirty 30 min after glibenclamide administration, basal preischemic, ischemia and reperfusion recordings were acquired in another ischemic zone at the same time points as in control. APD was determined at a repolarization of 90% (APD90) of maximal plateau amplitude (4).

Data analysisEnd diastole was defined to occur at the

onset of the rapid upstroke of the digitally obtained time derivative of left ventricular pressure (dP/dt), end systole as the time where dP/dt was 10% of the peak value of negative dP/dt and end ejection as the time of maximal WTh occurring within a period of 20 ms preceding the peak value of negative dP/dt (11).

Percent regional wall thickening fraction (%WTh) was calculated as:%WTh = 100 · (WThe-WThd)/WThd where WThe was end ejective wall thickness and WThd was end diastolic wall thickness.

Signal processing and parameter calcu-lation were performed at each time of data ac-quisiton. End systolic pressure (Pes), end dias-

tolic pressure (Pd), heart rate (HR) and %WTh were calculated from each recorded beat and the average of processed beats (15 to 30 beats) was the sample value assigned to the corres-ponding acquisition time. To reduce random dispersion, the sample values were averaged as the time integral (trapezoidal rule) of the sam-ples divided by the same time interval. Results were thus calculated as the average of basal conditions (before ischemia), ischemia, and of each 30 min during reperfusion. Ischemia and reperfusion recovery were expressed as percent of basal conditions taken as 100. The obtained values were assigned to 0, 30, 60, 90 and 120 min of reperfusion, respectively.

Statistical AnalysisResults were expressed as mean ± SE. He-

modynamic variables and APD were tested using a one way ANOVA. If F was significant, post hoc analysis were performed using Scheffé test for multiple comparisons. A t test was used to analyse differences of the GLIB SHAM group with respect to 100 and an unpaired t test to assess differences of percent recovery of %WTh between CONT and GLIB groups. Differences were considered to be significant when p< 0.05.

Fig. 1 - The experimental groups were control (CONT) subjected to 12 min ischemia followed by 2 hours reperfusion; glibenclamide (GLIB) similar to CONT with glibenclamide 20 min before ischemia and a sham group with glibenclamide but without ischemia (GLIB SHAM). In this last group samples were acquired at the same times as in CONT or GLIB.


Table 1 - Basal hemodynamic and regional values

Hemodynamic and regional values calculated in each animal as the average of basal (preischemic samples). CONT: control; GLIB: glibenclamide; Pes: end-systolic pressure; Pd: end-diastolic pressure; HR: Heart rate; %WTh: percent thickening fraction. Data are mean±SE.

4. ResultsOf the 29 operated sheep, 4 died of ven-

tricular fibrillation at the start of reperfusion and 2 were discarded because of defective wall thickness signals. Results of 23 animals are thus presented.

Basal hemodynamic and regional values were similar both in CONT and GLIB (Table 1), indicating that the drug per se did not affect the global performance of the heart. Table 2 shows the temporal evolution of hemodynamic varia-bles in each experimental group. The variables remained stable throughout the experiment in CONT and GLIB, except for Pd which increa-sed during ischemia, returning to basal values by 30 min of the reperfusion period, confirming that the ischemic region was small enough not to affect ventricular pump function.

Fig. 2 and Table 3 show that in CONT, APD90 shortened to 50% during ischemia with

respect to preischemia. This response was inhi-bited by glibenclamide, indicating that the used dose was adequate to completely block KATP channels.

Ischemia caused postischemic stunning during the 2 hour reperfusion period in CONT. Stunning was exacerbated by glibenclamide tre-atment 30 min before ischemia (GLIB) during the whole recorded reperfusion period (Fig. 3). However, in normally perfused hearts (GLIB SHAM), glibenclamide administration did not have any effect on the % recovery of %WTh, as shown by the lack of difference with respect to 100% (t test). This indicates that opening of KATP channels during ischemia protects the heart during recovery from stunning, since their inhibition worsens it, and that glibencla-mide has no other effect on %WTH, as shown by this unaltered index when no ischemia was performed.


Table 2 - Percent changes of hemodynamic values during ischemia and reperfusion

Basal Ischemia Reperfusion

30 min 60 min 90 min 120 min

Pes

CONT 100 95±6 96±2 93±1 93±1

GLIB 100 105±3 100±3 100±3

Pd

CONT 100 159±29† 124±22 124±22 103±15 89±12 88±11

GLIB 100 152±16† 111±13 111±13 106±12 110±10 111±15

HR

CONT 100 109±3 103±3 103±3 103±3 103±3 103±3

GLIB 100 108±4 116±9 116±9 107±5 104±4 96±4

Fig. 2 - Basal, ischemic and reperfusion recordings of monophasic action potentials in open chest sheep during control and 30 min after glibenclamide (0.4 mg/kg) administration.

Time evolution of hemodynamic variables with respect to basal preischemic values taken as 100. Abbreviations as in Table 1. Data are mean±SE; †<0.01 with respect to basal, ANOVA (one way, followed by Scheffé for multiple comparisons).

JUL. / SEP. 2008 - VOL. 3 - NUMBER 3 2�

Preisch. Isch. (12 min) Reperf. (5 min)

Control 304±11 151±18† 312±8

Glibenclamide 326±4 329±3 330±8

Table 3 - Action potential duration during control and 30 minutes after glibenclamide injection.

Action potential duration (msec) at repolarization 90% (APD90) of maximal plateau am-plitude was measured in open chest sheep using a Ag/AgCl suction electrode placed in the ische-mic region (see text). Data are mean±SE; N=4; † p<0.01, Isch. (Ischemia) vs Preisch. (Preische-mia) and vs Reperf. (Reperfusion) (ANOVA, one way, followed by Scheffé for multiple compa-risons).

Fig. 3 - Mean time course of % thickening fraction (%WTh) expressed as percentage of basal conditions (mean of acquired values 20 min before ischemia), # p<0.01, unpaired t test between CONT and GLIB. Data are expressed as mean±SE. Abbreviations as in Fig. 1.


5. DiscussionThe present results show that a glibencla-

mide concentration of 0.4 mg/kg impairs myocar-dial functional recovery from stunning following a reversible ischemia in conscious sheep. This effect could be ascribed to contractile damage due to in-creased calcium entry as a consequence of APD lengthening (3).

The experiments were performed in she-ep since they are very docile animals that can be studied in the conscious state, without sedation. The dose of glibenclamide (0.4 mg/kg) was wi-thin the range used in dog (12) and rabbit (0.3 mg/kg) (4), but lower than that reported for swi-ne (0.5mg/kg as bolus followed by 50 mg/min) (5). It effectively blocked sarcolemmal KATP channels, as shown by complete abrogation of APD shortening, similarly to reported results in swine (5) and rabbits (4). Because according to Bekheit et al (13), 0.4 mg/kg produces a plas-matic level of 2.7 mM, above the inhibitory effect on sarcolemmal (4) and mitochondrial KATP channels (14), the used dose ensured not only sarcolemmal blockade but also mitochon-drial KATP channel inhibition.

Results showed that function remained de-pressed even after full recovery of electrical activi-ty. Similar findings were reported in arterially per-fused guinea pig right ventricular wall (3). In those experiments, the decreased decline of APD90 with 10 mM glibenclamide during 20 min ischemia was accompanied by a fall in developed tension, which remained depressed after 60 min reflow, although electrical activity was restored.

Different reports have shown that there is a dose dependent effect of glibencamide on pos-tischemic mechanical recovery. At a dose of 0.3 mg/kg (within the range employed here) gliben-

clamide did not increase postischemic stunning in anesthetized dogs, whereas a higher dose (1mg/kg) resulted in reduced postischemic functional re-covery following reversible ischemia in the same model (12) and in a model of conscious dog with regional heart infarct (15). The possible mecha-nisms of the deleterious action of glibenclamide on functional recovery could be: a) inhibition of sarcolemmal and or mitochondrial KATP channels and b) a vasoconstrictive effect of the drug. Since calcium overload is one of the theories postulated to explain myocardial stunning (16), intracellular calcium accumulation produced by action poten-tial lengthening due to blockade of sarcolemmal KATP channels during ischemia, could explain depressed myocardial function during reperfusion. Recently, mitochondrial KATP channels have been postulated as the likely effectors of cardio-protection (17). Thus, glibenclamide, which also inhibits these channels could also blunt their as yet unknown mechanism of protection. Regarding the effect of glibenclamide on coronary flow, contra-dictory results have been reported. Billman et al (15) found that the glibenclamide induced decre-ase in the maximum derivative of left ventricular pressure (dP/dt max) was accompanied by redu-ced mean coronary blood flow in the non-infarc-ted region, whereas others found that there was no effect on coronary flow both with unchanged (7, 12) or increased postischemic stunning (12). The present study shows that in conscious sheep, a glibenclamide concentration within the range that in other species does not have a detrimen-tal action on postischemic mechanical recovery, has a deleterious effect evidenced by a mean 50% decrease of % WTh. Even though coronary blood flow was not measured, a vasoconstricti-ve action of glibenclamide would be negligible,

JUL. / SEP. 2008 - VOL. 3 - NUMBER 3 23

as evidenced by the unaltered % WTh in the GLIB SHAM group. Moreover, a linear relatioship be-tween %WTh and myocardial flow was establi-shed, where a percent decline in flow was accom-panied by a similar percent decrease in function (18). Therefore, a possible flow reduction could not explain the serious mechanical impairment ob-served in this study. It is then highly plausible that the reduction in regional functional recovery in glibenclamide treated animals could be attributed to increased stunning due to augmented calcium entry at the onset of reperfusion.

6. ConclusionsIn conclusion, the present study reinforces

the protective role of KATP channels in the setting

of ischemia and reperfusion. This protection could be ascribed to reduced calcium entry as a conse-quence of KATP opening, since worsening of car-diac recovery due to inhibition of KATP channels is probably due to calcium overload and not to a vasoconstrictive action of the drug.

7. AcknowledgementsWe wish to thank J. Martínez for micro-

crystal preparation and surgical assistance and F. Gauna for technical assistance during the experi-ments.

We are also grateful to Drs. M. I. Besansón, P. Iguaín and M. Tealdo for veterinarian support, and the personnel of the animal house, J. Ocampo, O. Sosa and J.C. Mansilla.

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14. Jaburek M, Yarov-Yarovoy V, Paucek P, Garlid KD. State-dependent inhibition of the mitochondrial KATP channel by glyburide

and 5-hydroxydecanoate. J Biol Chem 1998 273:1378-1382.

15. Billman GE, Englert HC, Schölkens B. HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive potassium channel. Part II: Effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs.

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17. Sato T, Sasaki N, Seharaseyon J, O’Rourke B, Marbán E. Selective pharmacological agents implicate mitochondrial but no sarcolemmal KATP channels in ischemic cardioprotection. Circulation 2000;101:2418-2423.

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SPECIAL NEWSSPECIAL NEWS

Petek, 10. oktober 2008 / Friday, 10 October 200810.00 -14.30 Simpozij v Kosovelovi dvorani / Kosovel Hall Symposium

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(if not the first). City: Publisher, Year: Number of pages (or that specific for reference).

10.1 3 - Chapter in a book: Author (s) name (s) of

the chapter. Title of the chapter. In: Author (s) name (s) of the book, eds. Title of the book. Edition (if not the first). City: Publisher, Year: first and last pages of the referred chapter.

10.1 4 - Thesis: Autor’s Name, Title (Thesis de-

gree), City, University, Year.

10.1 5 - Annals of Congress: Name of the author (s)

- Title of the paper published. In: Annals of the... name of the Congress. City: Promoter Society of Institution, Year: page.

11 - “Unpublished observations” and “personnal communications” should not be used as references. They are included in the text, within parenthesis marks, or, if extensive, appear as footnotes. Include among references: papers accepted but not yet published, designating the journal and adding “In press” (within parenthesis marks).


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