Effects of propafenone associated with propofol on myocardial contractility, heart rate, coronary flow, and the incidence of arrhythmia in isolated hearts of rats

Abstracts

OBJECTIVE: To study the influence of propafenone associated with propofol on myocardial contractility (dP/dt and heart rate), coronary flow, and the incidence of arrhythmia in isolated rat hearts. METHODS: Forty albino rats were anesthetized with sulfuric ether, a modified Langendorff method was performed, and the rats were fed with Krebs-Henseleit (K-H) solution, (95% O2, 5% CO2, pH 7.4±0.1, perfusion pressure between 90 and 100cm of water, and temperature 37± 0.5ºC). Control records were obtained after a stabilization period and rats were distributed into the following 4 groups: I (control), II (100mcg propafenone), III (25mcg propofol), and IV (propafenone-propofol). RESULTS: A decrease (P<0.05) in the heart rate in groups II and IV was observed, with a greater decrease in group II. A decrease was noted in the dP/dt ratio (P< 0.05) in groups II and IV, during all periods. Group III experienced depression from the 1st to the 3rd minute. Coronary flow had a decrease (P<0.05) in all groups, compared with the control group, especially in group IV with a decrease from 14mL/min to 11mL/min. Arrhythmogenic effects of propafenone (pro-arrhythmia) were verified in 50% of group II. In the association with propofol (group IV), no significant difference occurred, and arrhythmias (pro-arrhythmic effect) were observed in 40% of the hearts. CONCLUSION: The association propafenone-propofol was not harmful to the use of propafenone solely, regarding the effects observed in myocardial contractility, coronary flow, and in the incidence of arrhythmias.

myocardial contractility; propafenone; propofol

OBJETIVO: Estudar a influência da propafenona associada ao propofol na contratilidade miocárdica (dP/dt e freqüência cardíaca), fluxo coronariano e incidência de arritmia em corações isolados de ratos. MÉTODOS: Estudados 40 corações de ratos albinos anestesiados com éter sulfúrico, adaptados a sistema de perfusão, tipo Langendorff modificado, nutridos com solução de Krebs-Henseleit (K-H), (95% de O2, 5% de CO2, pH de 7,4±0,1, pressão de perfusão entre 90 e 100cm de água e temperatura de 37±0,5º C), obtidos registros de controle após período de estabilização e distribuídos em quatro grupos: I (controle), II (propafenona, na dose de 100mcg), III (propofol, na dose de 25mcg) e IV (propafenona-propofol). RESULTADOS: Verificou-se diminuição (p<0,05) da freqüência cardíaca nos grupos II e IV, com maior queda no grupo II. Na relação dP/dt, houve queda (p< 0,05) nos grupos II e IV, em todos os períodos, sendo que o grupo III apresentou depressão do 1º ao 3º minuto. O fluxo coronariano apresentou diminuição (p<0,05) em todos os grupos, em relação ao controle, principalmente no grupo IV com queda de 14 para 11ml/min. O efeito arritmogênico da propafenona (pró-arritmia) foi constatado em 50% no grupo II. Na associação com propofol (grupo IV), não houve diferença significativa, sendo observadas arritmias (efeito pró-arrítmico) em 40% dos corações. CONCLUSÃO: A associação propafenona-propofol não foi mais nociva do que o uso da propafenona isoladamente, quanto aos efeitos na contratilidade miocárdica, no fluxo coronariano e na incidência de arritmia.

contratilidade miocárdica; propafenona; propofol

ORIGINAL ARTICLE

Effects of propafenone associated with propofol on myocardial contractility, heart rate, coronary flow, and the incidence of arrhythmia in isolated hearts of rats

Nilcéa Leal de Moraes Assis; Otoni Moreira Gomes; Silvério Leonardo Macedo Garcia; Guilherme Gustavo do Valle

Fundação Cardiovascular São Francisco de Assis - Serviço do Coração - Belo Horizonte, MG - Brazil

^{Correspondence}

ABSTRACT

OBJECTIVE: To study the influence of propafenone associated with propofol on myocardial contractility (dP/dt and heart rate), coronary flow, and the incidence of arrhythmia in isolated rat hearts.

METHODS: Forty albino rats were anesthetized with sulfuric ether, a modified Langendorff method was performed, and the rats were fed with Krebs-Henseleit (K-H) solution, (95% O₂, 5% CO₂, pH 7.4±0.1, perfusion pressure between 90 and 100cm of water, and temperature 37± 0.5^oC). Control records were obtained after a stabilization period and rats were distributed into the following 4 groups: I (control), II (100mcg propafenone), III (25mcg propofol), and IV (propafenone-propofol).

RESULTS: A decrease (P<0.05) in the heart rate in groups II and IV was observed, with a greater decrease in group II. A decrease was noted in the dP/dt ratio (P< 0.05) in groups II and IV, during all periods. Group III experienced depression from the 1st to the 3rd minute. Coronary flow had a decrease (P<0.05) in all groups, compared with the control group, especially in group IV with a decrease from 14mL/min to 11mL/min. Arrhythmogenic effects of propafenone (pro-arrhythmia) were verified in 50% of group II. In the association with propofol (group IV), no significant difference occurred, and arrhythmias (pro-arrhythmic effect) were observed in 40% of the hearts.

CONCLUSION: The association propafenone-propofol was not harmful to the use of propafenone solely, regarding the effects observed in myocardial contractility, coronary flow, and in the incidence of arrhythmias.

Key words: myocardial contractility, propafenone, propofol

Cardiac rhythm disturbances are a frequent finding in patients with heart diseases, and are responsible for the development of increasing clinical and experimental research. To recognize and treat arrhythmias correctly is of utmost importance because they are risk factors for sudden cardiac death. Since the study by Wenckeback ¹, at the beginning of the 20th century, about the efficiency of antiarrhythmic therapy, several studies have been conducted demonstrating that the control of rhythm disturbances is essential in the prevention of sudden cardiac death and in the reduction of mortality because of acute myocardial infarction ^2-5.

Maintenance of arrhythmia control usually demands additional care, and chronic treatment is still a challenge, especially in light of evidence of the arrhythmogenic effects of most known medications ^6-9. The clinical decision to treat patients with cardiac arrhythmias involves careful analysis and knowledge of the elected antiarrhythmic medication.

Among the most commonly used antiarrhythmic medications in our country for the treatment of ventricular and supraventricular arrhythmias, propafenone stands out, classified as an IC drug according to Vaughan Willians ^10,11. 2-3 hydrochloride (hydroxy-2 propylamine) 3 propoxy phenyl (propafenone) was synthesized in 1970 and has been widely used in the suppression of supraventricular and ventricular arrhythmias. The medication contributes to the reduction of the permeability of the cellular membrane to sodium and to a lesser extent to calcium, disrupting the action potential of myocardial fibers ^12,13. It also has an antiadrenergic effect to block nonselective beta-adrenergic receptors. These mechanisms suggest negative inotropic and chronotropic effects especially if the dose exceeds that predicted.

Because of specific studies ^14-17 that demonstrated the antiarrhythmic efficiency of propafenone, it has been used in patients with heart diseases that can be surgically treated.

Regarding anesthesia in cardiovascular surgery, the severity of heart diseases leads to concern about the level of myocardial depression caused by most anesthetic medications.

Propofol (2,6-diisopropyphenol) is an intravenous anesthetic agent for use in the induction and maintenance of an anesthetized state with rapid action and elimination and is widely used in cardiovascular surgeries. Intravenous injection of a therapeutic dose produces hypnosis rapidly with minimal excitation. Propofol binds to plasma proteins above 95% with elimination through hepatic metabolism, forming inactive compounds that are eliminated in the urine¹⁸. Studies of propofol ^19-20 have demonstrated decreases in systolic and diastolic blood pressure and in the cardiac index, in addition to the decrease in peripheral vascular resistance without a significant alteration in heart rate. The negative inotropic effect has been presented both in clinical studies and in experimental models in animals ^21-24.

A special concern is that patients with heart diseases who use propafenone may undergo cardiac surgery and receive propofol, because both medications are myocardial depressors with the possibility of an enhancing effect concerning myocardial contractility. As studies in the literature about the possible enhancing effect of interaction of these medications were not found, the present experimental investigation was conducted aiming at studying the heart's performance, assessing the variables÷myocardial contractility, heart rate, coronary flow, and incidence of arrhythmias.

Methods

Forty adult albino Wistar rats housed in the vivarium at the Medical School of Barbacena – UNIPAC, were studied without regard to sex, with weights ranging from 210 to 350g (mean, 280g). All animals were treated according to the "Ethical Principles in Animal Research" adopted by the Brazilian College of Animal Experimentation (COBEA) ²⁵, and by the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health - USA ²⁶.

After anesthesia with inhalation of sulfuric ether, the animals underwent a wide thoracotomy. The anterior thoracic wall was reflected, and the heart and the great vessels were exposed. After that, 500 UI of sodium heparin were administered in the posterior vena cava to prevent thrombosis. The animal's aorta was isolated and repaired with a 2.0 cotton thread, and cannulated with a 20G-caliber plastic catheter, making sure that the integrity of the aortic valve was maintained during introduction of the catheter. The catheter was then fixed to the aorta with another 2.0 cotton thread. Next, the left ventricle was drained with the introduction of a fenestrated 18G-caliber plastic cannula through the left atrium and was taken out through the cardiac apex, avoiding greater coronary vessel lesions. The heart was released by cutting the vena cava, pulmonary artery, and the aorta above the cannulation region and was immediately connected to the coronary perfusion system.

The method used was the modified Langendorff ^27,28, using Krebs-Henseleit solution for perfusion (composition: NaCl 126mM/l, NaHCo₃ 25mM/l, KH₂PO₄ 1.2mM/l, KCl 4.8mM/l, MgSO₄ 1.2mM/l, CaCl₂ 2.5mM/l, and glucosin 11.5mM/l), gassed with a mixture containing 95% O₂ and 5% CO₂, obtaining 7.4±0.1 pH and 37±0.5^oC temperature with the use of a heating unit for thermal permutation (COMEX Ind. Com. Ltda, Belo Horizonte, MG). The solution was filtered with a CardioPro monofilament filter (American BioTech Corporation, New York, NY, USA) with holes of 3 micra, placed right after the deposit of the Krebs-Henseleit (K-H) solution. Perfusion pressure was kept constant, between 90 and 100cm H₂O.

After heart perfusion for 15 minutes, for the purpose of recovering and stabilizing cardiac activity, an empty plastic balloon was introduced into the left ventricle through a hole in the left atrium. The mitral valve was preserved, and the balloon was connected to a monitor (model DH 073, BESE-Bioengenharia, Belo Horizonte, MG) with the help of a metal cannula. Systolic and diastolic pressure, heart rate, and an electrocardiogram were recorded (printer Epson LX-810). Diastolic pressure was adjusted to 5+2 mmHg, through movements of introduction and withdrawal of redistilled water in the latex balloon in all periods of group I; in groups II, III, and IV, the diastolic pressure was not adjusted except in t₁ period (fig. 1). Coronary flow was determined by the assessment of the drained volume of the right and left cavities in 1 minute, collected in a graduated glass bottle. The incidence of arrhythmia was assessed by observing cardiac rhythm, recorded on the electrocardiogram in D₂ derivation by 2 electrodes placed on the heart.

The 40 hearts were distributed into 4 groups and prepared according to the method described. The groups were perfused with a Krebs-Henseleit solution at 37^oC temperature for 30 minutes, and the parameters were recorded in the control (t₀), after the 1st (t₁), 3rd (t₂), 5th (t₃), 10th (t₄), and 15th (t₅) minute. The groups can be characterized as follows: group I- control: 10 hearts without medication; group II - propafenone: 10 hearts differing from the control group due to the administration of 100mcg of propafenone diluted in 0.1 mL of the K-H solution via a proper lateral route above the bulb of the cannula inserted into the aorta; 10 hearts differing from the control group because of the administration of 25mcg of propofol diluted in 0.1 mL of the K-H solution via a proper lateral route above the bulb of the cannula inserted into the aorta; group IV - propafenone: 10 hearts differing from the previous groups by the administration of 0.1 mL of the K-H solution containing 100mcg of propafenone in an appropriate lateral vein above the cannular bulb inserted in the aorta followed by 0.1 mL of the solution containing 25 mcg of propofol by the same route.

The variations of heart rate in bpm, of the velocity of circumferential cardiac fiber shortening (dP/dt in mmHg.s^-1), of coronary flow (mL/min), and the incidence of arrhythmias were studied. For statistical analysis, we used the Student t test for paired data (significance level: P<0.05) and single-factor analysis of variance with the same significance level.

Results

Heart rate decreased (P<0.05) in groups II and IV (1st to 15th min), and in group III, only in the 3rd and 10th minutes; however, no statistically significant difference existed in group I. In group II, a decrease was recorded from 100% (control) to 71% (1st min), 68% (3rd min), 71% (5th min), 83% (10th min), and 78% (15th min); in group IV decreases occurred from 100% to 77% (1st min), 69% (3rd min), 70% (5th min), 76% (10th min), and 80% (15th min), on average. In the comparison between groups, groups II and IV demonstrated significant variation compared with the control group; however, they did not have significant variation when compared with each other. Heart rate had a significant variation (P<0.05) only in the first minute in the comparison between groups II and III (fig. 2 and tab. I). The dP/dt decreased in group II (from the 1st to the 15th min), in group III (1st and 3rd min), and in group IV (from the 1st to the 15th min). In percentage values, in groupII, a decrease was recorded from 100% (control) to 62% (1st min), 75% (3rd min), 80% (5th min), 78% (10th min), and 76% (15th min). In group III, a percentage decrease occurred from 100% (initial) to 77% (1st min), and 86% (3rd min). In group IV, a percentage decrease occurred from 100% (initial) to 54% (1st min), 62% (3rd min), 68% (5th min), 73% (10th min), and 76% (15th min). All these decreases demonstrated in mean percentile values were statistically significant. In the comparison between groups, the dP/dt ratio was smaller (P<0.05) in group II when compared with that in the control group in all periods. Group III had a significant decrease (P<0.05) only in the first minute regarding the control group. Group IV had a significant decrease (P<0.05) from the first to the fifth minute compared with the control group. In the comparison between groups II and III, the dP/dT ratio did not have a significant decrease. Variations occurred between groups II and IV, and II and IV were not significant (fig. 3 and tab. II).

Coronary flow decreased in groups II and IV (1st to 15th min), and in group III (3rd, 5th, 10th, and 15th min). In terms of percentages, in group II a decreases from 100% (control), to 88% (1st min), 86% (3rd min), 80% (5th min), 75% (10th min), and 72% (15th min) was recorded. In group III, a percentage decrease from 100% (control), to 99% (1st min), 92% (3rd min), 89% (5th min), 84% (10th min), and 77% (15th min) was recorded. In group III, a percentage decrease from 100% (control), to 91% (1st min), 88% (3rd min), 85% (5th min), 79% (10th min), and 74% (15th min) was recorded.

All these decreases where statistically significant, demonstrated in mean percentage values (P<0.05). In the comparison between groups, coronary flow did not decrease in groups II and IV as compared with that in the control group. A significant decrease occurred (P<0.05) in the 10th and 15th minutes of group III, as compared with the control group. No significant difference occurred (P<0.05) between groups II and IV, between groups II and IV, and when group II was compared with group III (fig. 4 and tab. III).

During the study, arrhythmias were not present in groups I (control) and III (propofol). In group II (propafenone), arrhythmias were observed in 5 of the 10 hearts, and in the propofol-propafenone association (group IV) an increase in the arrhythmias were observed in 4 of the 10 hearts studied.

Discussion

Despite the great advances in clinical and experimental electrophysiology in the last 20 years, sudden cardiac death is still a complex physiopathologic event. Patients with coronary disease as well as those with congestive heart failure are an important risk group for sudden death ^29-31.

Around 75% of sudden deaths are due to episodes of ventricular tachycardia or ventricular fibrillation ^32-35. Patients with congestive heart failure experience severe ventricular arrhythmias and sudden death in up to 50% of cases³⁶. Aiming at preventing these severe complications, antiarrhythmic therapeutics are indicated. However, the proper treatment of a cardiac arrhythmia is a challenge in clinical practice due to the adverse effects of antiarrhythmic medications, which may even worsen the congestive heart failure due to the negative effect of myocardial contractility.

With these data, several studies have searched for the ideal antiarrhythmic medication to prevent and treat these arrhythmias. However, despite the studies conducted, some of the available antiarrhythmic drugs, have pro-arrhythmic effects, and may cause myocardial depression and increased mortality ^37,38.

The Cardiac Arrhythmia Suppression Trial (CASH) ³⁹, a randomized multicenter study, demonstrated that patients treated with IC antiarrhythmic medications have a greater risk of sudden death compared with the placebo group. Other studies ^40,41 demonstrated similar results with the use of IC medications, which led to the use of these antiarrhythmics only in potentially lethal cases, avoiding their chronic use.

The difficulties in approaching clinical treatment of a patient are frequently due to concomitant diseases, which requires the administration of several medications at the same time. The interaction of these medications may generate unexpected consequences in the initial approach to the patient. Several possibilities of interaction exist, and, therefore, they are an extensive research field, extremely important in clinical practice. The study of the interaction of these medications in clinical trials is difficult, and the use of experimental animal models is essential. In addition to that, the effects of an in vivo medication may be difficult to assess, due to the metabolic interferences of the autonomous nervous system and due to the changes in the heart rate, preload, and afterload.

Among the most commonly used medications in clinical practice, propafenone stands out because of its efficacy in suppressing ventricular and supraventricular arrhythmias. The use of this medication is not rare during surgeries where anesthesia is used, and therefore the possibility of an interactive effect is present.

Propofol is a medication that has been used frequently in cardiovascular surgeries with the possibility of interaction with propafenone. However, studies on the add-on effect of the propafenone-propofol association were not found. Taking into account that the 2 medications have a suppressor myocardial effect, a study is necessary.

Salerno et al ⁴² reported a decrease in left ventricular function in patients receiving propafenone. Baker et al ⁴³ reported similar results. Meneghin ⁴⁴ observed that even in healthy hearts, propafenone has a reversible negative inotropic effect. A similar fact was reported by Santana ⁴⁵, Faraj⁴⁶, and Nakamura et al ⁴⁷, all of whom studied isolated rat hearts.

In the present investigation, propafenone produced significant myocardial depression. However, associated with propofol it did not have an additive effect.

Rouby et al ⁴⁸, studying the effects of propofol in patients with artificial hearts, concluded that cardiovascular depression of propofol is associated with the venous and arterial vasodilation effect rather than with myocardial depression. However, in the present study the significant depressive myocardial effect of propofol was confirmed.

Heart rate significantly decreased in all assessed periods in the propafenone and propofol groups, contrary to the findings of Riou et al ²³ who did not demonstrate significant negative chronotropic effects in the myocardium of rats.

Coronary flow analysis did not demonstrate a significant decrease in groups II and IV in all times assessed, regarding the control groups apart from the 10th and 15th minutes of group II.

The pro-arrhythmic effect of propafenone was reported by Podrid ³⁷ and Zipes ³⁸. In our investigation, 50% of the hearts studied in group II experienced arrhythmias. However, with the use of propofol, in isolation, arrhythmias were not observed, and an increase in the incidence of arrhythmias associated with the use of propofol and propafenone did not occur.

Based on the results obtained, we conclude that propafenone has negative inotropic and chronotropic effects, with arrhythmogenic effects and decreases in coronary flow. Propafenone-propofol association neither exaggerated the negative inotropic effect of propafenone in isolation nor increased its arrhythmogenic effect.

References

Received 11/19/02

Accepted 5/5/03

• 1. Wenckebach KF. Cinchona derivatives in the treatment of heart disorders. JAMA 1923; 81:472-4.
• 2. Ianhez L E, Brito FS. Fibrilação ventricular na fase aguda do enfarte do miocárdio recuperada no domicílio com unidade coronariana móvel. Arq Bras Cardiol 1972; 25:369-73.
• 3. Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation 1971; 44:130-42.
• 4. Funck-Brentano C, Kroemer HK, Lee JT, Roden DM. Propafenone. N Engl J Med 1990; 322: 518-25.
• 5. Brito FS, Pereira MHB, Castro I, Maia GI. O propafenon na disritmia ventricular da cardiopatia isquêmica: Estudo quantitativo pelo sistema Holter. Arq Bras Cardiol 1979; 33:303-10.
• 6. Podrid PJ, Lampert S, Graboys TB, Blatt CM, Lown B. Aggravation of arrhythmia by antiarrhythmic drugs - Incidence and predictors. Am J Cardiol 1987; 59: 38E-44E.
• 7. Faucon G, Aupetit JF, Gerents-Chassagne I, Lou Foua-moundanga J, Larbre JP, Timour Q. Arrhythmogenic risk of antiarrhythmic drugs: study with class IC drug during myocardial ischemia. Bull Acad Natle Méd 1991; 175: 217-25.
• 8. Roden DM. Drug therapy: risks and benefits of antiarrhythmic therapy. N Engl J Med 1994; 331:785-91.
• 9. Moroe K, Annoura M, Matsuo K, Yamanouchi Y, Kumagai K, Arakawa K. Proarrhythmic effects of class IC drugs. Clin Therapeutics 1993; 15: 559-66.
• 10. Vaughan Willians EM. Classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 1984; 24: 129-47.
• 11. Vaughan Willians EM. Classifying antiarrhythmic actions: by facts or speculation. J Clin Pharmacol 1992; 32: 964-77.
• 12. Santanna JR, Mattos E, Belardinelli L, Lucchese FA. Estudo experimental da ação cardiovascular do propafenon. Arq Bras Cardiol 1979; 33: 153-9
• 13. Ledda F, Mantelli L, Manzini S, Amerini S, Mugelli A. Electrophysiological and antiarrhythmic properties of propafenon in isolated cardiac preparations. J Cardiovasc Pharmacol 1981; 3: 1162-73.
• 14. Coumel P, Leclercq JF, Assayag P. European experience with the antiarrhythmic efficacy of propafenone for supraventricular and ventricular arrhythmias. Am J Cardiol 1984; 54:60-6.
• 15. Connoly SJ, Kates RE, Lebsack CS, Echt DS, Mason JW, Winkle RA. Clinical efficacy and electrophysiology of oral propafenone for ventricular tachycardia. Am J Cardiol 1983; 52 : 1208-13.
• 16. Connoly SJ, Kates RE, Lebsack CS, Harrison DC, Winkle RA. Clinical pharmacology of propafenone. Circulation 1983; 68: 589-96.
• 17. Figueira RH. Estudo de um novo antiarrítmico-propafenona em arritmias ventriculares na unidade coronariana. Arq Bras Cardiol 1979; 33:233-9.
• 18. Coetzee A, Fourie P, Coetzee J, et al. Effect of various propofol plasma concentrations on regional myocardial contractility and left ventricular afterload. Anesth Analg 1989; 69:473-83.
• 19. Brussel T, Theissen JL, Vigfusson G, Lunke PP, Van Aken H, Lawin P. Hemodynamic and cardiodynamic effects of propofol and etomidate: negative inotropic properties of propofol. Anesth Analg 1989; 69: 35-40.
• 20. Dupuy P, Pery N, Boisson A, Sirodot M, Langeron O, Payen D. Myocardial depression induced by propofol is not of ischemia originin. Ann Fr Anesth Reanim 1989; 8:14.
• 21. Pagel PS, Warltier DC. Negative inotropic effects of propofol as evaluated by the regional preload recruitable stroke work Relationship in chronically instrumented dogs. Anesth Analg 1993; 78:100-8.
• 22. Shyr M, Yang C, Kuo TBJ, Pan WHT, Tan PPC, Chan SHH. Power spectral analysis of the electroencephalographic and hemodynamic correlates of propofol anesthesia in the rat: intravenous bolus administration. Neuroscience Letters 1993; 153: 161-4.
• 23. Riou B, Besse S, Lecarpentier Y, Viars P. In vitro effects of propofol on rat myocardium. Anaesth Analg 1992; 76:609-16.
• 24. Puttick RM, Terrar DA. Effects of propofol and enflurane on action potentials, membrane currents and contraction of guinea-pig isolated ventricular myocytes. Br J Pharmacol 1992; 107: 559-65.
• ²⁵
  Colégio Brasileiro de Experimentação Animal (COBEA) - Princípios Éticos na Experimentação Animal. COBEA, SP, 1991.
• ²⁶
  National Institutes of Health. Guide for Care Use of Laboratory Animal Washington: US Government Printing office, 1985.
• 27. Langendorff O. Untersuchungen am Uberlebenden Sauge thierherzen. Arch Ger Physiol 1985, 61:291.
• 28. Krebs HA, Henseleit K. Untersuchungen ober die Han stoffbildung im tierkorper. Hope Seylers Z Physiol Chem 1932, 210:33.
• 29. Roberts WC, Jones AA. Quantitation of coronary arterial narrowing at necropsy in sudden coronary death: analysis of 31 patients and comparison with 25 control subjects. Am J Cardiol 1979; 44: 39-45.
• 30. Luna BA, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989; 117:151-9.
• 31. Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R. Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994; 344:493-8.
• 32. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA 1993;270:1589-95.
• 33. Shaffer WA, Cobb LA. Recurrent ventricular fibrillation and modes of death in survivors of out-of-hospital ventricular fibrillation. N Engl J Med 1975; 293: 259-62.
• 34. Kempf FC, Josephson ME. Cardiac arrest recorded on ambulatory electrocardiograms. Am J Cardiol 1984; 53: 1577-82.
• 35. Fozzard HA. Electromechanical dissociation and its possible role in sudden cardiac death. Am J Cardiol 1985; 5: 31-4.
• 36. Grandman A, Deedwania P, Cody R, et al. Predictors of total mortality and sudden death in mild to moderate heart failure. J Am Coll Cardiol. 1989, 14; 564-70.
• 37. Podrid PJ. Aggravation of arrhythmia: a complication of antiarrhythmic drug therapy. Eur Heart J 1989; 10: 66-72.
• 38. Zipes DP. Proarrhythmic effects of antiarrhythmic drugs. Am J Cardiol 1987; 59: 26-30.
• 39. Siebels J, Cappato R, Rüppel R, Schneider MAE, Kuck KH, and the CASH investigators. Preliminary results of the cardiac arrest study Hamburg (CASH). Am J Cardiol 1993;72: 109-14.
• 40. De Paola AAV, Horowitz LN, Morganroth J, et al. Influence of left ventricular dysfunction on flecainide therapy. J Am Coll Cardiol 1987; 9: 163-8.
• 41. Morganroth J, James EG. Quinidine related mortality in short to medium term treatment of ventricular arrhythmias. Circulation 1991; 84: 1977-83.
• 42. Salerno DM, Granrud G, Sharkey P, Asinger R, Hodges M. A controlled trial of propafenone for treatment of frequent and repetitive ventricular premature complexes. Am J Cardiol 1984; 53:77-83.
• 43. Baker BJ, Dinh H, Kroskey D, Soyza NDB, Murphy ML, Franciosa JA. Effect of propafenone on left ventricular ejection fraction. Am J Cardiol 1984; 54: 20-2.
• 44. Meneghin MM. Efeitos da associação propafenona e diazepam na contratilidade miocárdica, freqüência cardíaca, fluxo coronariano e incidência de arritmia em corações isolados de ratos. Arq Bras Cardiol 1999;71:195-6.
• 45. Santana TMGQ. Efeitos da associação propafenona midazolan na contratilidade miocárdica, freqüência cardíaca, fluxo coronariano e incidência de arritmia em corações isolados de ratos. Arq Bras Cardiol 1999;71:200-1.
• 46. Faraj M. Efeitos da associação propafenona-fentanil na contratilidade miocárdica, freqüência cardíaca e fluxo coronariano em corações isolados de ratos. Arq Bras Cardiol 1999;71:191- 2.
• 47. Nakamura T, Kashimoto S, Oguchi T, Kumazawa T. Effects of propafenone on function and metabolism in the ischemic working rat heart. Heart Vessels 1992; 7:169-74.
• 48. Rouby JJ, Andreev A, Léger P, Arthaud M, Landault C, Vicaut E, Maistre G, Eurin J, Gandjbakch I, Viars P. Peripheral vascular effects of thiopental and propofol in humans with artificial hearts. Anesthesiology 1991, 75: 32-42.

Publication Dates

• Publication in this collection
  16 Feb 2004
• Date of issue
  Jan 2004

History

• Accepted
  05 May 2003
• Received
  19 Nov 2001