Réginald Nadeau

Epicardial and endocardial mapping of ventricular tachycardia in patients with myocardial infarction. Is the origin of the tachycardia always subendocardially localized

BackgroundLeft ventricular endocardial reentry is the conventional concept underlying surgery for ventricular tachycardia (VT). We assessed the incidences of patterns showing complete reentry circuits at either the subendocardial or subepicardial level and of patterns in which left ventricular endocardial mapping could only in part account for a reentrant mechanism. Methods and ResultsWe retrospectively analyzed epicardial and left ventricular endocardial isochronal maps of 47 VTs induced in 28 patients with chronic myocardial infarction (inferior, 14 patients; anteroseptal, 14 patients). Electrograms were recorded intraoperatively from 128 sites with epicardial sock and transatrial left ventricular endocardial balloon electrode arrays. Given the methodology used in this study, the mapping characteristics of the tachycardias suggested five types of activation patterns: 1) complete (90% or more ofVT cycle length) subendocardial reentry circuits in seven VTs (15%) and seven patients (25%), 2) complete subepicardial reentry circuits in fourVTs (9%o) and four patients (14%), 3) incompletely mapped circuits with a left ventricular endocardial breakthrough preceding the epicardial breakthrough in 25 VTs (53%) and 21 patients (75%), 4) incompletely mapped circuits with a left ventricular epicardial breakthrough preceding the endocardial breakthrough in three VTs (6%) and three patients (11%), and 5) a right ventricular epicardial breakthrough preceding the left ventricular endocardial breakthrough in eight VTs (17%) and seven patients (25%). After surgery, one type 3 VT and three type 5 VTs were reinducible. Thus, left ventricular endocardial reentry substrates (types 1 and 3) accounted for 68% of VTs, but substrates involving subepicardial (types 2 and 4) and deep septal layers (type 5) accounted for 32% of VTs. ConclusionsIn a substantial number of VTs, a substrate localization that is at variance with the conventional concept can be detected by simultaneous epicardial and endocardial mapping and may require modification of the surgical approach conventionally aimed at endocardial layers.

Regulation of norepinephrine release from cardiac sympathetic fibers in the dog by presynaptic alpha- and beta-receptors.

The effect of phenoxybenzamine (PBA), desmethylimipramine (DMI), clonidine (CLND), sotalol (STL), and isoproterenol (ISPR) on the release of endogenous norepinephrine (NE) from the heart on right cardioaccelerator nerve stimulation was studied in anesthetized dogs. Under control conditions, the catecholamine levels in coronary sinus blood increased linearly with increasing frequencies of stimulation up to 10 Hz and did not increase further at 30 Hz. The release of NE was markedly enhanced after PBA (1 mg/kg, iv) and DMI (1 mg/kg, iv). The enhanced release of NE after DMI, but not after PBA, was associated with a prolonged response in heart rate. In contrast, NE release was reduced after CLND (15 microgram/kg, iv) at stimulation frequencies of 1 and 2 Hz and this was associated with reduced responses in heart rate and left ventricular dtp/dt. STL (5 mg/kg, iv) reduced significantly the release of NE at stimulation frequencies of 1-5 Hz, whereas ISPR enhanced NE outflow at frequencies of 1-4 Hz. These results support the existence of both negative and positive feedback mechanisms on the release of norepinephrine by cardiac sympathetic fibers mediated through presynaptic alpha- and beta-adrenoreceptors, respectively. The functional significance of these mechanisms is also suggested by the correlation found between changes in NE release and variations in cardiac responses under the various drug treatements.

Correlation between the Response of the Heart to Sympathetic Stimulation and the Release of Endogenous Catecholamines into the Coronary Sinus of the Dog

The relationship between the increase in catecholamine levels of the coronary sinus b1lood and the amplitude of various cardiac responses to adrenergic nerve stimulation was studied in anesthetized dogs. Plasma catecholamine levels in both coronary sinus and aortic blood were measured by a modification of the radiometric enzymatic assay for tissue catecholamines and were found to be 0.622 ± 0.104 (SE) ng/ml and 0.933 ± 0.116 ng/ml, respectively, under basal conditions. The catecholamine levels in coronary sinus blood increased linearly during right cardioaccelerator nerve stimulation up to a frequency of 10 Hz. At this frequency, maximum values were observed in both coronary sinus blood catecholamine levels and cardiac responses. The correlation between the response in heart rate, mean coronary blood flow, and dP/dt of left ventricular pressure and the increase in endogenous catecholamine levels of coronary sinus blood was significant, but the relationship was nonlinear. The present experimental design may prove to be a reliable means of studying the role of the sympathetic nervous system in the regulation of cardiovascular function in vivo.

Effect of intravenous and oral calcium antagonists (diltiazem and verapamil) on sustenance of atrial fibrillation

Both verapamil and diltiazem are used to control ventricular response during atrial fibrillation (AF). Their effect on the maintenance of AF is not known. The effects of the intravenous and oral administration of verapamil and diltiazem were investigated in 35 patients, 18 with (group I) and 17 without (group II) documented paroxysmal AF. Programmed electrical stimulation, either extra-stimuli or burst atrial pacing, was used to induce AF. In group I, the mean values of the duration of AF before and after the intravenous and oral administration of the calcium antagonists were 31 +/- 12, 112 +/- 49 and 69 +/- 25 minutes, respectively. For group II, the values were 5 +/- 3.4, 39 +/- 13 and 14 +/- 7 minutes, respectively. The differences were statistically highly significant (p less than 0.001), after both oral and intravenous administration compared with the baseline value in both groups. The data suggest that both intravenously and orally administered calcium antagonists enhance sustenance of electrically induced AF, especially in patients with spontaneous arrhythmia. Thus, in patients with paroxysmal AF, verapamil or diltiazem should be administered cautiously, because these drugs may prolong the duration of arrhythmia. Further studies are warranted to investigate the role of calcium antagonists in spontaneously occurring paroxysmal AF.

Markedly different effects on ventricular remodelling result in a decrease in inducibility of ventricular arrhythmias

OBJECTIVES The purpose of this study was to determine whether the type and extent of ventricular remodeling after infarction influence inducibility of ventricular arrhythmias after infarction. BACKGROUND Although serious ventricular arrhythmias after infarction are related to ventricular dysfunction, the relation between inducibility of ventricular arrhythmias and ventricular remodeling remains incompletely understood. METHODS Rats that survived ligation of the left anterior descending coronary artery (n = 218) were randomized to receive placebo (saline solution) or captopril or propranolol therapy and were followed up for 5 weeks. Hemodynamic and neurohumoral blood measurements were obtained, and therapy was stopped. Two days later, susceptibility to ventricular arrhythmias was assessed by programmed electrical stimulation, and hearts were prepared for pathologic studies. RESULTS Placebo-treated rats with a large myocardial infarction had ventricular dysfunction, marked neurohumoral activation, ventricular enlargement (endocardial circumference 16 +/- 3 [mean +/- SD] to 20 +/- 4 mm, p < 0.05) and increased cardiac fibrosis (volume density of collagen 2.3 +/- 0.8% to 5.6 +/- 2.4%, p < 0.05). In many rats this resulted in easily inducible ventricular arrhythmias (inducibility quotient 4.9 +/- 2.2). Captopril attenuated the development of ventricular dysfunction, neurohumoral activation, ventricular hypertrophy and dilation (endocardial circumference 18 +/- 3 mm) and cardiac fibrosis (3.1 +/- 0.8%, p < 0.05). These modifications were accompanied by decreased inducibility of ventricular arrhythmias (inducibility quotient 1.1 +/- 2.0, p < 0.05). Propranolol did not prevent ventricular dysfunction, had variable effects on neurohumoral activation and led to increased ventricular dilation (endocardial circumference 25 +/- 4 mm, p < 0.05) and cardiac fibrosis (7.7 +/- 1.2%, p < 0.05). Nevertheless, these morphologic changes led to decreased inducibility of ventricular arrhythmias (inducibility quotient 2.2 +/- 2.5%, p < 0.05). CONCLUSIONS This study indicates that the inducibility of ventricular arrhythmias can be reduced as a result of markedly different effects on ventricular remodeling, indicating that the relation between ventricular remodeling, arrhythmias and survival is more complex than previously thought.

Plasma catecholamines in acute myocardial infarction

Plasma catecholamine levels were determined in 26 cases of uncomplicated myocardial infarction within 24 hours of onset of acute chest pain. Blood samples were collected at time of entry and at 4-hour intervals during the 48 hours following admission. Average values of plasma catecholamines within 1 hour of onset of pain were 0.87 ng./ml +/- 0.21 and remained elevated during the first 24 hours period. A gradual fall in catecholamine values was observed during the second 24-hour period. Catecholamines were higher in patients with sinus tachycardia and lower in patients with sinus bradycardia, and were higher in patients with anterior or anterolateral infarction. Catecholamine values were significantly higher when determined while patients presented ventricular ectopic beats or ventricular tachycardia. Sinus tachycardia, ventricular arrhythmias, and elevated plasma catecholamine values may be considered indicators of pain, anxiety, and/or left ventricular dysfunction without necessarily being causally related between themselves.

Protective effects of bradykinin on the ischaemic heart: implication of the B1 receptor

1 We studied the role of bradykinin (BK) and its active metabolite Des‐Arg9‐BK on noradrenaline release in association with the incidence of ventricular arrhythmias at reperfusion of the ischaemic myocardium. 2 Experiments were performed in Langendorff perfused isolated hearts of rats subjected to 30 min no flow followed by 5 min reperfusion. The electrocardiogram was monitored continuously and noradrenaline was measured in the effluent as well as in the myocardial tissue. 3 In untreated hearts, cumulative noradrenaline overflow following global ischaemia reached 226 ± 35 pmol g−1 of heart (n = 8, P < 0.05) during the 5 min of reperfusion along with ventricular tachycardia and/or fibrillation. A decrease in myocardial noradrenaline (–31%) was also observed. 4 Bradykinin perfused at concentrations between 0.01 and 1 μm, 10 min before flow was stopped and at reperfusion, inhibited noradrenaline overflow in a concentration‐dependent manner. At a concentration of 1 μm, bradykinin completely abolished noradrenaline overflow. For the same concentration of bradykinin, myocardial noradrenaline contents were significantly higher (n = 5–8, P < 0.05). Ventricular fibrillation but not ventricular tachycardia was also prevented. 5 Des‐Arg9‐BK (0.1 μm) in the same experimental conditions had similar effects. While Hoe 140, a selective antagonist at B2 receptors, did not abolish the effects of bradykinin, Lys [Leu8] Des‐Arg9‐BK, an antagonist at B1 receptors, abolished the effects of both Des‐Arg9‐BK and bradykinin. 6 These results suggest that the cardioprotective action of bradykinin in the preparation may be mediated partially by an inhibitory effect on noradrenaline liberation which could be mediated by the activation of B1 receptors.

Acute and Chronic Cardiovascular Effects of 6-Hydroxydopamine in Dogs

Acute and chronic cardiovascular effects of repeated injections of 6-hydroxydopamine were studied in unanesthetized dogs. The acute response to initial injections of small doses of 6-hydroxydopamine consisted of an intense sympathomimetic effect characterized by a marked increase in blood pressure and a reflex bradycardia. Three days after the administration of a total dose of 50 mg/kg of 6-hydroxydopamine, significant decreases in heart rate, blood pressure, and total peripheral resistance were observed, but cardiac output remained unchanged. The absence of a response to intravenously injected tyramine, to electrical stimulation of the right stellate ganglion, and to bilateral carotid occlusion was consistent with a state of complete peripheral sympathectomy. Along with the functional impairment of transmission at the sympathetic nerve endings, marked endogenous norepinephrine depletion was observed in the heart, carotid sinus, and spleen. In contrast, endogenous norepinephrine was increased in the stellate ganglion. The response to electrical stimulation of the distal end of the right vagus was not altered by treatment with 6-hydroxydopamine. In anesthetized dogs treated with 6-hydroxydopamine, clamping of the hilar vessels of the adrenal glands for 10 minutes caused hypotension, but the same procedure in normal dogs did not affect blood pressure, demonstrating the importance of the compensatory role of the adrenal medulla in sympathectomized animals. It is concluded that 6-hydroxydopamine can be used effectively to obtain a generalized chemical sympathectomy in unanesthetized dogs and provides a useful means for studying the role of the autonomic nervous system in the regulation of cardiovascular functions.

Direct evidence of caeruloplasmin antioxidant properties

The chain-breaking antioxidant potential of caeruloplasmin and bovine serum albumin (BSA) has been investigated in comparison with other well-established antioxidants. Their Oxygen Radical Absorbing Capacity (ORAC), was measured by using β-phycocyanin (β-PC) as a fluorescent indicator protein, 2,2′-azobis (2-amidinopropane) hydrochloride (AAPH) as a peroxyl radical generator and the water soluble vitamin E analogue, Trolox, as a reference standard. The relative peroxyl absorbing capacities/mole for Trolox, caeruloplasmin, heat-denatured caeruloplasmin (hCP), catalase, bovine serum albumin (BSA), superoxide dismutase (SOD), and deferoxamine were 1; 2.6; 3.3; 3.7; 1.2; 0.1; 0.2, respectively. Caeruloplasmin was far more effective as a peroxyl radical scavenger than SOD, deferoxamine and BSA, but slightly less effective than catalase. The peroxyl radical absorbing capacity of caeruloplasmin was enhanced by heat-denaturation of the protein. Electron paramagnetic resonance (EPR) spectroscopy using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin-trap, was applied in order to measure the scavenger abilities of caeruloplasmin on superoxide radical and hydroxyl radical production and the concentration required to inhibit by 50% oxygen free radical formation (IC50) was determined. The IC50 values of caeruloplasmin, hCP, and BSA for the superoxide radical were 12, 2, 260 μM and for the hydroxyl radical 15, 2, 200 μM. These results show that caeruloplasmin is an effective chain-breaking antioxidant for a variety of radicals, independently of its catalytic ferroxidase activity.

Effect of enalaprilat on bradykinin and des‐Arg9‐bradykinin release following reperfusion of the ischaemic rat heart

1 The release of bradykinin (BK) and its metabolite, des‐Arg9‐bradykinin (des‐Arg9‐BK), was studied following reperfusion of a globally ischaemic rat heart. 2 BK‐like immunoreactivity increased from 13±3 (preischaemic value) to 48±12 fmol min−1 g−1 (P<0.05, n = 14) 30 s after reperfusion. No difference in BK release was found between control hearts and hearts pretreated with the angiotensin converting enzyme (ACE or kininase II) inhibitor, enalaprilat (50 ng ml−1). 3 No significant change in des‐Arg9‐BK‐like immunoreactivity during reperfusion was observed in control hearts. In contrast, des‐Arg9 ‐ BK ‐ like immunoreactivity rose from 44 ± 15 to 177 ± 61 fmol min−1 g−1 (P<0.05, n = 7) 30 s after reperfusion in enalaprilat‐treated hearts. 4 In conclusion, BK is released upon reperfusion of the globally ischaemic rat heart. ACE inhibitors, through the inhibition of kininase II, increase the formation of the active metabolite, des‐Arg9‐BK.