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Heart contraction is coordinated by conduction of electrical excitation through specialized tissues of the cardiac conduction system. By retroviral single-cell tagging and lineage analyses in the embryonic chicken heart, we have recently demonstrated that a subset of cardiac muscle cells terminally differentiates as cells of the peripheral conduction system (Purkinje fibers) and that this occurs invariably in perivascular regions of developing coronary arteries. Cis regulatory elements that function in transcriptional regulation of cells in the conducting system have been distinguished from those in contractile cardiac muscle cells; eg, 5' regulatory sequences of the desmin gene act as enhancer elements in skeletal muscle and in the conduction system but not in cardiac muscle. We hypothesize that Purkinje fiber differentiation involves a switch of the gene expression program from that characteristic of cardiac muscle to one typical of skeletal muscle. To test this hypothesis, we examined the expression of myosin binding protein-H (MyBP-H) in Purkinje fibers of chicken hearts. This unique myosin binding protein is present in skeletal but not cardiac myocytes. A site-directed polyclonal antibody (AB105) was generated against MyBP-H. Immunohistological analysis of the myocardium mapped the AB105 antigen predominantly to A bands of myofibrils within Purkinje fibers. Western blot analysis of whole extracts from the ventricular wall of adult chicken hearts revealed that the AB105 epitope was restricted to a single protein of approximately 86 kD, the same size as MyBP-H in skeletal muscle. Biochemical properties of the Purkinje fiber 86-kD protein and RNase protection analyses of its mRNA indicate that Purkinje fiber 86-kD protein is indistinguishable from skeletal muscle MyBP-H. The results provide evidence that skeletal muscle MyBP-H is expressed in a subset of cardiac muscle cells that differentiate into Purkinje fibers of the heart.

Six cardiac patients had His bundle electrograms obtained prior to ventricular pacing. Hours to days after constant pacing, repeat His bundle electrograms were obtained. The H-Q interval increased after pacing in 5 of the 6 patients. The average H-Q interval of 55.8 msec increased to the post pacing value of 67.5 msec (p smaller 0.02). Thus ventricular pacing can produce a conduction delay in the His Purkinje system.

The effects of isoetharine on the His bundle electrogram were studied in 10 patients with heart disease. Recordings were made at varied heart rates using atrial pacing. Isoetharine significantly reduced the AH interval with atrial pacing, but it had no effect on the HV interval. Second degree heart block occurred at higher pacing rates after isoetharine treatment as compared to the control state. The heart rate and blood pressure showed no significant change after isoetharine. The functional and effective refractory period were measured with the use of the extra-stimulus technique. The functional refractory period of the AV node, as well as the effective refractory period of the atrium, significantly decreased after isoetharine. Thus, isoetharine can improve conduction through the atrioventricular node. The drug does have a cardiac effect as measured by its action on the human conduction system.

His bundle electrograms were performed in ten patients with organic heart disease. Recordings were made at various rates using right atrial pacing. Two grams of methylprednisolone were infused intravenously over a 20-minute period. The PI-A, A-H, H-Q, and H-S intervals were obtained before and up to 1 hour after the infusion of the steroid. The maximum effect was seen at 1 hour. All patients showed a significant prolongation in the A-H interval with negligible effects on other intervals. At the atrial pacing rate of 120 beats/minute, the average A-H interval increased from control of 119 milliseconds to 159 milliseconds after steroids (P smaller than 0.01). Second-degree heart block occurred at lower pacing rates after steroids in six patients as compared with the control state. The postsuppressive sinoatrial node recovery time was increased in seven cases after steroid infusion. Pharmacologic doses of steroids can impair conduction through the atrioventricular node.

A His bundle electrogram was obtained in a 65 year old male with syncopal episodes. A split bundle of His deflection was recorded. After the intravenous administration of phentolamine, a marked shortening of the H-H' interval was observed. This signifies an improvement in conduction at the bundle of His level.

The effects of phentolamine, 0-3 mg/min given intravenously for 15 minutes, on His bundle electrograms were studied in 11 patients with heart disease. Recordings were made at varied heart rates, using atrial pacing. Phentolamine significantly reduced the AH interval in every patient but it had no effect on the HV interval. Functional and effective refractory periods were measured with the use of the atrial extrastimulus technique. The effective refractory period of the atrium and atrioventricular node as well as the functional refractory period of the atrioventricular node all significantly decreased after phentolamine infusion. This improvement in conduction is probably mediated by a release of catecholamines.

Fifty-one patients required the implantation of a Cordis Omnis-Stanicor permanent pacemaker. His bundle electrograms studies, which included right atrial pacing and sinoatrial (SA) node postsuppression recovery times, were performed prior to the implantations. Pacing and sensing thresholds were obtained in all patients. Syncope or episodes of dizziness were the presenting symptoms in virtually every patient. Twenty-eight of the 51 patients had the sick sinus syndrome. Only nine patients were in complete heart block, and an additional nine were in second-degree heart block. The His bundle electrogram technique was not particularly helpful in selecting the potential pacemaker candidate. The symptomatic patient with second- or third-degree heart block requires a pacemaker. In the sick sinus syndrome, the His bundle electrogram was a disappointing tool in detecting abnormalities. In chronic bundle branch block, the His bundle electrogram appears to play a major role. A prolonged H-V interval in a symptomatic patient, in whom a specific noncardiac cause cannot be identified, signifies that a pacemaker is required.

Tachycardias may be associated with the pre-excitation syndrome, a short PR interval or a prolonged QT interval. This report describes seven patients whose electrocardiograms (ECGs) did not reveal any of the above-named conditions. All of the patients presented with syncopal episodes, and the history of palpitations was elicited in five of the patients. His bundle electrogram studies in all of the patients showed an essentially unchanged AH interval with atrial pacing rates up to 180 beats/min. This can only be explained by a total bypass of the AV node. Two of the patients were also paced from the ventricle, and an unchanged pacing stimulus to A wave interval was observed. This signifies in these patients a functioning bypass pathway in the retrograde direction as well. Thus it would appear that pre-excitation cannot by eliminated as a diagnostic possibility even if the ECG is normal.

There is little information on the effects of methyldopa on the human conduction system. His bundle ECGs were obtained in 11 patients before and after the intravenous infusion of 100 mg of methyldopa. Antegrade refractory periods were obtained with the extrastimulus method. The significant results were as follows: the sinus rate was 71 +/- 4 beats per minute before, and 65 +/- 3 beats per minute after methyldopa (P less than 0.01). The mean A-H interval at a paced rate of 120 beats per minute was 113 +/- 14 msec before, and 135 +/- 18 msec after, methyldopa (P less than 0.05). The mean atrioventricular nodal functional refractory period was 430 +/- 23 msec before and 452 +/- 24 msec after methyldopa administration (P less than 0.001). The mean effective refractory period was 385 +/- 29 msec before, and 388 +/- 27 msec after methyldopa (P less than 0.01). The sinus node recovery time in the control state was 989 +/- 55 msec and 1102 +/- 66 msec after methyldopa infusion (P less than 0.05). Thus, methyldopa can impair conduction through the atrioventricular node and depress the sinus node.

A His bundle electrogram was obtained in a 70 year old male with syncopal episodes. A split bundle of His deflection was recorded. After the intravenous administration of phentolamine, a marked shortening of the H-H' interval was observed. This signifies an improvement in conduction at the bundle of His level.

His Bundle recordings in a 75-year-old male with complete heart block exhibited split His Bundle potentials with three components thus demonstrating multiple conduction delays within the bundle of His.

Severe bradycardia has been reported with the use of cimetidine. This observation has been explained by histamines' known action in increasing the contraction rate of the spontaneously beating right atrium, strips of ventricular muscle, and whole heart of guinea pigs. Histamine can also produce cardiac arrhythmias in animals. There is evidence for H2 receptors in the heart. Black and his associates have shown that the characteristic effect of histamine on isolated guinea pig atrium could be selectively blocked by anti-H2 drugs. Thus cimetidine probably can produce a sinus bradycardia by blocking the H2-receptor site in the heart. Recently Engel and Luck reported that 300 mgs of intravenously administered cimetidine did not affect heart rate, sinus node recovery time, or sinoatrial conduction time. These workers concluded that there is insufficient evidence to demonstrate that cimetidine caused appreciable sinus node dysfunction in man. In view of the disparity in these reports, we investigated the effects of 300 mgs of intravenously administered cimetidine on the human conduction system.

There is considerable interest in selecting the proper drug to preserve the ischemic myocardium, or twilight zone, in a patient with a recent myocardial infarction. Vasodilator therapy with an infusion of nitroprusside or phentolamine has been shown to improve left ventricular function by reducing both preload and afterload. Sublingual nitroglycerin as well as an infusion of nitroglycerin can also alleviate left ventricular failure in patients with an acute myocardial infarction. Similarly, chronic congestive heart failure patients, irrespective of the etiology, improve hemodynamically after an infusion of phentolamine, nitroprusside or hydralazine. Oral nitrates, phentolamine, and hydralazine have also been demonstrated to produce improvement in chronic heart failure patients. Recently data has become available on the effects of phentolamine, nitroglycerin and nitroprusside on cardiac conduction in man. However there is no information on the electrophysiological properties of hydralazine in man. The present study involving 12 human subjects was undertaken to determine what effect intravenously administered hydralazine has on the human conduction system.

His bundle electrograms were performed in eight patients with organic heart disease. Recordings were made at various rates utilizing right atrial pacing. A solution of 100 cc of iced cold 5% glucose and water was infused through a cardiac catheter placed at the level of the tricuspid valve. The P-A, A-H, H-Q and H-S intervals were determined before and immediately after the cold water infusion. A significant prolongation of the A-H interval occurred with negligible effects on the P-A, H-Q and H-S intervals. At the atrial pacing rate of 100/min the average A-H interval increased from the control value of 116 to 125 msec after the infusion (P less than 0.02); at the pacing rate of 140/min, the A-H interval increased from 147 to 158 msec (P less than 0.01). This represents an impairment in conduction through the atrioventricular node.

His bundle electrograms were recorded in 12 patients before and after the intravenous administration of 5 mEq of potassium. Antegrade and retrograde refractory periods were determined with the extrastimulus technique. The AH interval was 84 +/- 7 msec before and 89 +/- 7 msec after potassium (P < 0.05). The AH interval at an atrial pacing rate of 140/minute was 129 +/- 13 msec before and 143 +/- 16 msec after potassium (P < 0.02). The effective refractory period of the atrium was 264 +/- 9 msec before and 280 +/- 9 msec after potassium (P < 0.001). Thus small amounts of potassium delay conduction at the atrial and AV nodal level.

Furosemide has been extensively used in the treatment of heart failure and its effect on cardiovascular dynamics are well established. Clinical relief of the symptoms of pulmonary congestion frequently precedes any demonstrable diuretic effect, suggesting that extra renal factors may also be involved. More recent studies on the extra-renal action of furosemide showed an increase of venous capacitance as an early hemodynamic effect of the drug. In spite of furosemides wide use in the treatment of heart failure and hypertension, there is no information on the electrophysiologic properties of the drug in man. The present study involving 8 human subjects was undertaken to determine what effect intravenously administered furosemide has on the human conduction system.

Anorexia nervosa is a disorder characterized by excessive dieting, a morbid fear of becoming obese, a distorted body image and amenorrhea in women. The condition is seen chiefly in girls and young women but also occurs in men. Death in anorexia nervosa may be sudden, and the mortality rate is the highest of any psychiatric disease. Despite investigations of its endocrine and psychiatric manifestations, little has been written about cardiac conduction in this entity. We report a patient with anorexia nervosa who presented with syncope due to a sinus bradycardia. His bundle electrograms were performed during the course of her hospitalization, and revealed that the abnormalities were reversible with food intake.

The effects of nitroprusside on His bundle electrograms, when given intravenously for 10 minutes, were studied in 14 patients with heart disease. Recordings were made at varied heart rates using atrial and ventricular pacing. Nitroprusside significantly reduced the AH interval, but it had no effect on the HV interval. Functional and effective refractory periods were measured by the extrastimulus technique. The functional refractory period of the AV node as well as the effective refractory period of the ventriculoatrial conduction system significantly decreased after nitroprusside infusion. This improvement in conduction can probably be explained by the systemic hypotension produced by nitroprusside, which reflexly will increase sympathetic drive to the heart and decrease vagal tone.

There is no information on the effects of coffee on the human conduction system. His bundle electrograms were obtained in 12 patients before and 20 minutes after the ingestion of coffee containing 150 mg caffeine. Antegrade and retrograde refractory periods were obtained with the extrastimulus method. The effective and functional refractory period of the atrioventricular node decreased after coffee ingestion. This improvement in conduction is probably mediated by a release of catecholamines.

Ethacrynic acid is a potent oral diuretic and saluretic agent. It has been used extensively in the treatment of heart failure and its effects on cardiovascular dynamics are well established. The clinical relief of the symptoms of pulmonary congestion frequently precedes any demonstrable diuretic effect suggesting that extra renal factors may also be involved. In spite of ethacrynic acid's wide use in the treatment of heart failure and hypertension, there is no information on the electrophysiologic properties of the drug in man. The present study involving 10 human subjects was undertaken to determine what effect intravenously administered ethacrynic acid has on the human conduction system.

The effects of Isuprel administered by means of a mistometer were studied in 8 patients with heart disease. Recordings were made at varied heart rates using atrial pacing. In addition, the functional and effective refractory periods were measured with the use of the extra stimulus technique. Four inhalations of the mistometer were administered to each patient (0.5 mg). The AH interval was 100 +/- 13 msec before and 93 +/- 23 msec 5 minutes after the Isuprel administration (p less than 0.05). Isuprel significantly reduced the AH interval with atrial pacing. The AH interval at an atrial pacing rate of 100/minute was 148 +/- 70 msec before and 131 +/- 51 msec after Isuprel (p less than 0.05). Isuprel had no significant effect on the HV interval. The effective and functional refractory period of the atrioventricular node was not significantly changed after Isuprel. The heart rate and blood pressure showed no significant change after Isuprel. No cardiac arrhythmias were seen. (The systemic absorption of the drug was probably minimal.) Isuprel administered by means of the mistometer can improve conduction through the atrioventricular node. Nevertheless, the potent bronchodilating effects of Isuprel and the absence of tachycardia and cardiac arrhythmias does attest to the safety of this agent.

Thirty-seven patients with acute myocardial infarction complicated by atrioventricular or bundle branch block, or a combination of both, has His bundle electrogram studies performed during their stay in the coronary care unit. The acute mortality of the 14 patients with a complicating bundle branch was 50%. Pump failure was the main cause of death. Three patients in this group had a prolonged H-V interval and one patient had a split blundle of His. The presence or absence of a prolonged H-V interval did not affect mortality in this group of patients. The acute mortality of the 16 patients with an inferior wall myocardial infarction was 6%. The H-V interval was normal in all but one of these patients. The atrioventricular block was caused by a proximal block in all cases. The acute mortality of the seven patients with an anterior wall myocardial infarction was 29%. The H-V interval was prolonged in two of seven patients. Pump failure was the acute cause of the deaths. The presence or absence of a prolonged H-V interval did not affect mortality in this group of patients.

His bundle electrograms were performed on 10 patients with organic heart disease. Six patients had had a recent myocardial infarction. Recordings were made at various rates utilizing right atrial pacing. Nitroglycerin, 1/150 gr, was administered to all 10 subjects, and the P-A, A-H, H-Q and H-S intervals were determined before, and immediately after the disappearance of the sublingually administered nitroglycerin. A significant decrease in the A-H interval occurred with negligible effects on the P-A, H-Q and H-S intervals. At the atrial pacing rate of 100/min, the average A-H interval fell from the control value of 152 msec to 129 msec after the administration of nitroglycerin (p less than 0.02); at the pacing rate of 130/min, the A-H interval decreased from 194 to 133 msec (p less 0.05). Second degree heart block occurred at higher pacing rates in six patients after nitroglycerin administration as compared to the control value. The average postsuppression sinoatrial recovery time control value of 1,083 msec decreased to 906 msec after nitroglycerin administration (p less than 0.01). These findings demonstrate that nitroglycerin can improve conduction through the A-V node.