High-intensity interval training improves peak oxygen uptake and muscular exercise capacity in heart transplant recipients.

Heart transplant (HTx) recipients usually have reduced exercise capacity with reported VO(2peak) levels of 50-70% predicted value. Our hypothesis was that high-intensity interval training (HIIT) is an applicable and safe form of exercise in HTx recipients and that it would markedly improve VO(2peak.) Secondarily, we wanted to evaluate central and peripheral mechanisms behind a potential VO(2peak) increase. Forty-eight clinically stable HTx recipients >18 years old and 1-8 years after HTx underwent maximal exercise testing on a treadmill and were randomized to either exercise group (a 1-year HIIT-program) or control group (usual care). The mean ± SD age was 51 ± 16 years, 71% were male and time from HTx was 4.1 ± 2.2 years. The mean VO(2peak) difference between groups at follow-up was 3.6 [2.0, 5.2] mL/kg/min (p < 0.001). The exercise group had 89.0 ± 17.5% of predicted VO(2peak) versus 82.5 ± 20.0 in the control group (p < 0.001). There were no changes in cardiac function measured by echocardiography. We have demonstrated that a long-term, partly supervised and community-based HIIT-program is an applicable, effective and safe way to improve VO(2peak) , muscular exercise capacity and general health in HTx recipients. The results indicate that HIIT should be more frequently used among stable HTx recipients in the future.

A study of the labetalol-induced changes in conductivity and refractoriness of the dog heart in situ.

The effect of labetalol, an alpha- and beta- adrenergic receptor blocking agent, on the electrophysiology of the dog heart in situ was studied. Pentobarbital anaesthesia which is known to increase the sympathetic tone was used. Labetalolol in doses of 0.5 to 4.0 mg.kg-1 injected intravenously caused a slight decrease in median heart rate and a slight reduction in the median conduction velocity in the atrioventricular (A-V) node in six dogs. A significant increase in the functional refractory period of the A-V node occurred at doses of 1.0 to 4.0 mg.kg-1. The functional and the effective refractory periods of the right atrium and ventricle were increased by labetalol at all doses tested. The plasma concentrations of labetalol were in the range 0.05 ot 0.8 microgram.cm-3 in five out of six dogs at the three lowest doses tested which is far below the values which could be expected to cause a membrane-stabilising effect. The alpha and beta adrenoreceptor blocking effects of labetalol on cardiac electrophysiology in vivo are discussed.

N-acetylprocainamide induced changes in refractoriness and monophasic action potentials of the dog heart in situ.

The major metabolite of procainamide (PA) is N-acetylprocainamide (NAPA). The effect of this drug on the electrophysiology of the right ventricle was studied in the dog heart in situ by means of programmed electrical stimulation and monophasic action potential (MAP) recordings. A decrease in the beat interval caused a progressive decrease in refractoriness and MAP duration. Intravenous injection of NAPA 50 mg.kg-1 body weight increased refractoriness to a greater extent than MAP duration at shorter, while the opposite was observed at longer beat intervals. These observations are compatible with delayed recovery of excitability. On the basis of these findings, it is concluded that NAPA belongs to antiarrhythmic drugs of type I according to Vaughan Williams' classification, and NAPA may be an alternative drug for treatment of cardiac arrhythmias.

Acebutolol-induced changes in refractoriness and monophastic action potential of the right ventricle of the dog heart in situ.

The effect of acebutolol, a beta-adrenergic receptor blocking agent, on the electrophysiology of the right ventricle was studied in the dog heart in situ. Pentobarbital anaesthesia which is known to increase the sympathetic tone was used. Monophasic action potential recordings were obtained by the suction electode technique and refractoriness was measured by means of programmed electrical stimulation. A stepwise increase in the frequency of stimulation from 170 to 200, 230, and 260 per min caused a progressive decrease in the refractoriness as well as the duration of the monophasic action potential. Intravenous injection of acebutolol 2.0 mg.kg-1 increased the times for 50 and 90% repolarisation of the monophasic action potential. This increase is probably due to beta-adrenergic receptor blockade in the presence of alpha-adrenergic receptor stimulation. The effective and functional refractory periods, however, were increased to an even greater extent than the monophasic action potential duration. It is suggested that this is the result of a blockade of a catecholamine-induced increase in the velocity of the depolarisation.

Digoxin- and digitoxin-induced changes in monophasic action potential of the right ventricle of the dog heart.

The effects of digitoxin and digoxin on right ventricular monophasic action potentials were studied in intact dogs during an 8 hour observation period. Pentobarbital anaesthesia was used, and monophasic action potential recordings were obtained with the suction electrode technique. Intravenous injection of 2.0 mg digitoxin to six dogs, 2.0 mg digoxin to two dogs and 1.0 mg digoxin to five dogs caused a rapid increase in the time taken for 90% repolarisation with return to control values after 20 to 30 min. A late increase in 50 and 90% repolarisation times was observed 2 to 4 h after digitoxin, while digoxin had no such effect. The late action potential prolonging effect was inversely correlated to serum concentrations in the early elimination phase (2 to 8 h after the injection) since it reached a maximum towards the end of the observation period. Digitoxin and digoxin thus differed in their late effects on ventricular monophasic action potentials in intact dogs and may possess different antiarrhythmic activity.

Influence of beta-adrenergic and cholinergic blockade on the electrophysiological effects of melperone in the dog heart in situ.

Melperone (0.5 to 12.5 mg.kg-1) reduced mean aortic blood pressure in pentobarbital anaesthetised dogs to a greater extent after beta1-adrenergic receptor blockade with atenolol than after cholinergic blockade with atropine. Electrophysiological studies demonstrated that increased heart rate and decreased atrioventricular nodal refractoriness after lower doses of melperone (0.5 to 2.5 mg.kg-1), could be prevented by pretreatment with atenolol. The melperone-induced decrease in atrioventricular nodal conduction time was, however, not affected by pretreatment with atenolol or atropine. Intra-atrial and His-Purkinje conduction times and QRS width were not affected by atenolol or atropine plus melperone. Melperone caused a dose-dependent and very pronounced increase in ventricular and, even more, atrial refractoriness after atenolol. The ventricular and atrial refractoriness increased less after pretreatment with atropine. Some of the cardiac electrophysiological effects of melperone thus depend on the degree of beta-adrenergic stimulation. The overall cardiac electrophysiological effects of melperone results from a combination of direct and indirect actions of the drug.

Monophasic action potentials in patients with coronary artery disease: reproducibility and electrical restitution and conduction at different stimulation rates.

Monophasic action potentials were recorded in the outflow tract of the right ventricle in patients with coronary artery disease during ventricular pacing at different basic cycle lengths and programmed stimulation. During continuous pacing (basic cycle length 600 ms) the time for 90% repolarisation (MAP90) and the QTa interval decreased exponentially during the first 1.5-2 min of pacing to 90% of control values. The reproducibility of the monophasic action potential signals and the ventricular effective refractory period were assessed as good when studied after repetitive trains of 8 beats for more than 1.5 min. The reproducibility of conduction, however, was less good. Electrical restitution of MAP90 duration of the premature beats determined at three different basic cycle lengths was different from that in single muscle preparations. The curves showed two phases with unchanged MAP90 durations despite longer coupling intervals. The first phase was close to the ventricular effective refractory period, probably because subnormal conduction left the diastolic interval constant for the earliest premature beats. This indicates that subnormal conduction may influence the premature dispersion of repolarisation.

Electrophysiological effects of melperone in the dog heart in situ - a new antiarrhythmic drug.

In pentobarbital anaesthetised dogs, melperone (a neuroleptic butyrophenone) reduced mean aortic blood pressure and at lower doses (0.5 and 2.5 mg . kg-1) increased the heart rate. By means of His bundle electrography and programmed electrical stimulation, conduction velocity and refractoriness were measured at different frequencies of stimulation (170, 200, 230 and 260 beats.min-1). Melperone 0.5 and 2.5 mg.kg-1 decreased the atrioventricular nodal conduction time and refractoriness. Melperone (0.5 to 12.5 mg.kg-1) did not affect the intra-atrial or His-Purkinje conduction times or the QRS width. However, melperone increased the functional and effective refractory period of the right atrium and ventricle dose-dependently at all frequencies studied. This suggests that melperone may be a valuable drug in treating selected cardiac arrhythmias.

Acute effects of lidocaine on repolarization and conduction in patients with coronary artery disease.

Right ventricular repolarization and refractoriness were studied during continuous infusion of lidocaine in patients with coronary artery disease. Compared with baseline the duration of monophasic action potential was shortened (p less than 0.01) at constant and premature stimulation. Early premature action potentials were less shortened (p less than 0.05). Therefore the difference between the longest and shortest action potential duration elicited 2 to 150 msec after refractoriness decreased during lidocaine infusion (p less than 0.01). The right ventricular effective refractory period was shortened similarly to the action potential duration. Lidocaine did not change the conduction of constant paced beats, whereas the more rapid conduction of the midrange premature beats was inhibited (p less than 0.01). The inhibition of premature conduction 50 to 150 msec from the right ventricular effective refractory period may be attributed to the effect of lidocaine on the rate-dependent recovery from inactivation. The effect on the restitution curve indicates that lidocaine may influence the dispersion of premature action potentials in human beings.

Plasma levels and cardiac electrophysiological effects of melperone in the dog.

The butyrophenone neuroleptic melperone has recently been shown to possess antiarrhythmic properties in man and animals. We studied the correlation between plasma concentration of melperone and the electrophysiological and blood pressure effects of the drug in 20 pentobarbital-anaesthetized dogs. Linear correlations were found between the log melperone plasma concentration and decreases in mean aortic blood pressure and heart rate, and increases in atrial and AV nodal refractoriness. The correlations were better after pretreatment with the beta 1-blocker atenolol. There was a linear correlation between log melperone plasma concentration and increases in ventricular refractoriness only after atenolol. No correlation was found between log melperone plasma concentration and decreases in AV nodal conduction time. Apart from the effect on AV nodal conduction time, the relationship between plasma concentration of melperone and the electrophysiological and blood pressure effects after beta 1-blockade fits well into an overall log concentration-effect relationship. The poorer correlation without beta 1-blockade was probably due to a combination of direct and indirect effects of the drug.

Temperature-controlled radiofrequency catheter ablation with a 10-mm tip electrode creates larger lesions without charring in the porcine heart.

BACKGROUND: Radiofrequency catheter ablation of atrial flutter, atrial fibrillation or ventricular tachycardia may be favoured by large lesions. We compared lesions created in unipolar mode using 10-mm/8 F electrodes with those of 4-mm/7 F catheters. METHODS: Ablations were first performed in porcine hearts in vitro (70 degrees C, 60 s, tangential catheter tip-tissue orientation). Anaesthetized pigs were thereafter ablated with 10- or 4-mm catheters in the right atrial free wall (RAFW), inferior vena cava-tricuspid valve (IVC-TV) isthmus and left ventricle (LV). RESULTS: In vitro, lesion length doubled and lesion volume tripled using the 10-mm catheter. Average power supply was 69 (SD12) (10-mm tip) versus 26 (SD7) W (4-mm tip). In vivo, lesion length increased by 50% and lesion volume fivefold. Charring at the lesion surface or sudden impedance rises were not observed in vivo. Histologically, coagulation necrosis and minor haemorrhages were found. One RAFW lesion (10-mm) showed a dissection approaching the epicardium. Fibrinous platelet clots or overt thromboses covered the endocardial surface in half of all lesions. Three 10-mm electrode isthmus lesions extended to the right descending posterior artery and one LV lesion to the left anterior descending artery, but there was no damage to the arterial walls. Following six ablations with the 10-mm electrode and two with the 4-mm tip, injury to the adjacent lung tissue of 0.5 to 6.0 mm depth was found (p = 0.22). CONCLUSION: RF ablation using 10-mm/8 F electrodes created significantly larger lesions. 10-mm electrodes appeared safe in the porcine IVC-TV isthmus and LV, but not in the RAFW.

PR interval in middle-aged men with overt and latent coronary heart disease compared to PR in angionegative and normal men of similar age.

PR was measured prospectively in 2014 apparently healthy men ranging in age from 40 to 59 years (P subjects), and retrospectively in 652 hospitalized men with a diagnosis of coronary heart disease (CHD) (R subjects). A cardiovascular survey examination suggested CHD in 115 of the 2014 P subjects, coronary angiography of 105 of these confirmed this suspicion in 69. The following observations concerning PR were made: (1) the shortest PR was found in angiopositive P subjects, intermediate PR in 1832 normal P subjects, and PR was longest in 36 angionegative subjects. (2) PR was shortest in angiopositive P subjects with triple-vessel disease, and longest in P subjects with single-vessel disease, (3) PR increased with age, and an inverse association was found between PR and resting heart rate in P-subjects. (4) In 98 of 1832 normal P subjects, all without signs or symptoms of heart disease, PR was greater than or equal to 0.22 s. (5) Prolonged PR was no more frequent among the 652 R subjects than among P subjects, despite significant CHD in 595, and a frequent use of drugs known to delay atrioventricular conduction. It is suggested that advanced stable clinical CHD only rarely gives rise to prolonged PR at rest, and that PR in subjects with latent CHD may have somewhat shorter PR than age counterparts without symptoms or signs of CHD. Conflicting data in the literature are probably related to differences in material and methods.

Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers.

Mutations in the KCNQ1, HERG, SCN5A, minK and MiRP1 genes cause long QT syndrome (LQTS), of which there are two forms: the Romano Ward syndrome and the Jervell and Lange-Nielsen syndrome. We have performed DNA sequencing of the LQTS-associated genes in 169 unrelated patients referred for genetic testing with respect to Romano Ward syndrome and in 13 unrelated patients referred for genetic testing with respect to Jervell and Lange-Nielsen syndrome. A total of 37 different mutations in the 5 genes, of which 20 were novel, were identified. Among patients with the most stringent clinical criteria of Romano Ward syndrome, a mutation was identified in 71%. Twelve of the 13 unrelated patients referred for genetic testing with respect to Jervell and Lange-Nielsen syndrome were provided with a molecular genetic diagnosis. Cascade genetic screening of 505 relatives of index patients with molecularly defined LQTS identified 251 mutation carriers. The observed penetrance was 41%. Although caution must be exerted, the prevalence of heterozygotes for mutations in the LQTS-associated genes in Norway could be in the range 1/100-1/300, based on the prevalence of patients with Jervell and Lange-Nielsen syndrome.

The modifying effect of autonomic blockade on digitoxin-induced changes in monophasic action potential and refractoriness of the right ventricle of the dog heart.

The aim of the present investigation was to study the modifying effect of autonomic blockade with atropine plus propranolol and atropine alone on the electrophysiologic response to digitoxin during an observation period of 8 hours. Twenty-five pentobarbital-anaesthetised Labrador dogs were used. Pacing and programmed electrical stimulation were used to determine heart rate independent changes in repolarisation times and the effective (V-ERP) and the functional (V-FRP) refractory periods. The dogs were divided into three groups and all dogs got digitoxin (2.0 mg) intravenously during 5 min. Fourteen dogs were given digitoxin without blockade, while 5 dogs were pretreated with propranolol 0.5 mg/kg plus atropine 0.05 mg/kg every hour for 8 hours and 6 dogs with atropine in the same dose and with the same interval. Digitoxin alone increased 50 and 90% repolarisation times 2-4 hours after injection of the drug. During autonomic blockade digitoxin induced a shortening of action potential duration, and thus digitoxin interacts with autonomic transmitters resulting in prolongation of action potential duration. The "direct" effects of digitoxin, the action potential shortening effect, the decrease in membrane responsiveness (i.e. V-ERP/50% repolarisation time) reached a maximum 2-3 hours after injection of the drug.

Vagus-induced changes in ventricular electrophysiology of the dog heart with and without beta-blockade.

We tested the electrophysiologic effects of vagus stimulation in six dogs in the presence or absence of beta-adrenoreceptor blockade. Monophasic action potentials were obtained by the suction electrode technique and programmed electrical stimulation was used to determine heart rate-independent changes in 50 and 90% repolarization times and in the effective (V-ERP) and functional (V-FRP) refractory periods of the right ventricle. Vagus stimulation decreased heart rate both in the presence and in the absence of beta-adrenoceptor blockade. It also increased action potential duration and refractoriness during high sympathetic tone induced by pentobarbital anesthesia. The effect is probably due mainly to inhibition of beta 1-adrenoreceptors, since it was decreased by beta 1-adrenoceptor blockade with atenolol. We conclude that stimulation of the vagus has antiarrhythmic effects in ventricles under high sympathetic stimulation.

Effects of autonomic blockade on the inotropic and electrophysiologic response to digitoxin in the intact dog.

Inotropic and electrophysiologic effects in dogs of a single dose of digitoxin with and without autonomic blockade with propranolol plus atropine were observed for 8 hr. Left heart catheterization and His bundle registration were performed in 14 Labrador dogs anesthetized with pentobarbital. Pacing and programmed electrical stimulation were used to determine heart rate-independent changes in dP/dt, intra-atrial, AV nodal, His-Purkinje, and intraventricular conduction velocity. The effective and the functional refractory periods of the atrium, and the functional nodal refractory period (AV-FRP) were measured. Six dogs were given propranolol 0.5 mg/kg plus atropine 0.05 mg/kg every hour. After determination of inotropic and electrophysiologic parameters, digitoxin (2.0 mg) was given to 5 of the dogs, while 1 dog served as control. The other 8 dogs were given only digitoxin (2.0 mg). The dP/dt increased after digitoxin in both groups with maximum values after 2 hr. The autonomic nervous system had only minor influence on changes in contractility caused by digitoxin. The marked fall in heart rate and increase in A-H time (i.e., AV nodal conduction time) and AV-FRP after digitoxin were almost completely blocked by atropine and propranolol. Minor increases in A-H time and AV-FRP indicated a slight direct effect of digitoxin on the AV node.

The effect of prolonged pentobarbital anaesthesia on cardiac electrophysiology and inotropy of the dog heart in situ.

The effect of prolonged pentobarbital anaesthesia was tested on the dog heart in situ by means of His bundle electrography and programmed electrical stimulation, monophasic action potential recordings from the right ventricle and measurements of peak dp/dt obtained by Millar tip transducer in the left ventricle. Sixteen dogs were used. Immediately after catheterization during anaesthesia, a slight decreased heart rate, a reduction in the conduction velocity and an increase in the functional refractory period of the atrioventricular node occurred. From 15 to 30 min. after catheterization we observed no change in cardiac electrophysiology during the 8 hrs observation period. A slight decrease in contractility, however, appeared towards the end of the period. We conclude that dogs anaesthetized with pentobarbital could serve as a suitable model for testing drug effect on cardiac electrophysiology and contractility. The limitations of the model area are discussed.

The effect of nifedipine on the sinus and atrioventricular node of the dog heart after beta-adrenergic receptor blockade.

The effect of nifedipine (BAY 1040), a calcium-antagonistic inhibitor of the electromechanical coupling process was tested on atrioventricular conduction and refractoriness of the dog heart in situ by means of His-bundle electrography and programmed electrical stimulation. The animals were anaesthetized with sodium pentobarbital. As the basic effects of the compound can be altered by release of catecholamines from sympathetic nerves of heart and vessels, the dogs were pretreated with acebutolol, a beta-adrenergic receptor blocking agent, which decreased heart rate and prolonged atrioventricular conduction and refractoriness. Nifedipine 1,6 and particularly 30 microgram/kg body weight increased the heart rate and decreased atrioventricular conduction time during atrial pacing, whereas atrioventricular conduction time during sinus rhythm and atrioventricular refractoriness were only affected by nifedipine 30 microgram/kg. In this respect, nifedipine differs distinctly from another calcium antagonistic compound, verapamil.