Winston E. Gaum

Crosstalk signaling between mitochondrial Ca2+ and ROS.

Mitochondria are central to energy metabolism as the source of much of the cells ATP, as well as being a hub for cellular Ca2+ signaling. Mitochondrial Ca2+ is a positive effector of ATP synthesis, yet Ca2+ overload can lead to mitochondrial dysfunction and cell death. Moreover, Ca2+ uptake by mitochondria is involved in shaping cellular Ca2+ dynamics by regulating the concentrations of Ca2+ within microdomains between mitochondria and sarco/endoplasmic reticulum and plasma membrane Ca2+ transporters. Reactive oxygen species (ROS) generated as a consequence of ATP production in the mitochondria are important for cellular signaling, yet contribute to oxidative stress and cellular damage. ROS regulate the activity of redox sensitive enzymes and ion channels within the cell, including Ca2+ channels. For both Ca2+ and ROS, a delicate balance exists between the beneficial and detrimental effects on mitochondria. In this review we bring together current data on mitochondrial Ca2+ uptake, ROS generation, and redox modulation of Ca2+ transport proteins. We present a model for crosstalk between Ca2+ and ROS signaling pathways within mitochondrial microdomains.

Alterations in canine myocardial excitability during ischemia.

SUMMARY Changes in the ventricular diastolic excitability threshold following occlusion of the left anterior descending coronary artery (LAD) were studied in open-chest anesthetized dogs by using a new automatic threshold-following pacemaker (ATFP). The ATFP measures the diastolic excitability threshold by successively decreasing the duration of regularly occurring pacing stimuli until the ventricle fails to respond. Under control conditions, the threshold stimulus duration was 60 ± 4 (mean ± SEM) &mgr;sec. In the first 1–3 minutes following occlusion of the LAD, the diastolic excitability threshold in the ischemic zone (IZ) decreased to 51 ± 5 &mgr;sec and then rapidly increased to 600 &mgr;sec at 5 minutes. The initial decrease in excitability threshold at IZ could be abolished by elevating the serum K+ concentration prior to the LAD occlusion. These changes in excitability threshold at IZ could be prevented by infusing nonoxygenated solutions into the LAD at a site distal to the occlusion. As the excitability threshold increased in IZ during ischemia, the earliest time at which IZ could be reactivated by a stimulus with a voltage equal to twice the preligation diastolic voltage threshold was increased. In nine of 16 dogs, after 5 minutes of LAD ligation, the IZ to normal zone (NZ) activation time (when stimulating at IZ) exceeded the NZ to IZ activation time (when stimulating at NZ) by an average of 9 msec. We also found that in four dogs the NZ to IZ activation time exceeded the IZ to NZ activation time by an average of 10 msec. We conclude from these findings that a gradient of increasing excitability threshold exists as one moves from normally perfused toward more ischemic tissue, passing through a heterogeneous border zone that manifests some areas which have a decreased excitability threshold and other areas which have an increased excitability threshold, and that these changes in excitability importantly influence the determination of refractory period durations and conduction times.

Ventricular arrhythmias in postoperative tetralogy of Fallot.

Ventricular arrhythmias in patients after total surgical repair of tetralogy of Fallot have been associated with late sudden death. In this large multicenter retrospective study of 359 patients with postoperative tetralogy of Fallot, spontaneous ventricular premature complexes (VPCs) on 24-hour ambulatory electrocardiographic monitoring and laboratory-induced ventricular tachycardia (VT) by electrophysiologic stimulation were analyzed. The mean age at surgical repair was 5 years and the mean follow-up duration after repair was 7 years. Spontaneous VPCs on ambulatory monitoring were found in 48% and induced VT on electrophysiologic stimulation was found in 17% of patients. Both spontaneous VPCs and induced VT were significantly related to delayed age at repair, longer follow-up interval, symptoms of syncope or presyncope and right ventricular systolic hypertension (greater than 60 mm Hg) (p less than 0.05), but not to right ventricular diastolic pressure greater than 8 mm Hg. The VPCs on ambulatory monitoring were more complex with increasing age at repair and follow-up duration. Induction of VT on electrophysiologic stimulation correlated with spontaneous VPCs including VT on 24-hour ambulatory electrocardiographic monitoring. The electrophysiologic stimulation protocol varied and the induction of VT increased with a more aggressive stimulation protocol. While induced sustained monomorphic VT was related to all forms of spontaneous VPCs, induced nonsustained polymorphic VT was related to more complex forms of VPCs on ambulatory monitoring. VT was not induced in asymptomatic patients who had normal 24-hour ambulatory electrocardiographic monitoring and normal right ventricular systolic pressure. (ABSTRACT TRUNCATED AT 250 WORDS)

Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs

The effects of various drugs on delayed activation of the ischemic myocardium and the incidence of ventricular arrhythmias were studied in 34 open-chest anesthetized dogs. The left anterior descending coronary artery was occluded for 6 minutes before and 42 minutes after administration of aprindine (2.85 mg/kg body weight), quinidine (8 mg/kg) and verapamil (0.2 mg/kg) and during infusion of isoproterenol (0.2 microng/min). The time intervals from the onset of the QRS complex to the major deflection of the bipolar electrograms recorded within the normal and ischemic zones were measured at cycle lengths of 500, 400 and 300 msec and were correlated with the development of ventricular arrhythmias. At a cycle length of 500 msec, aprindine increased by 19.5 msec the delay in activation time produced by coronary ligation alone (P less than 0.05), whereas verapamil reduced by 10 msec the extent of ischemia-induced conduction delay (P less than 0.05). The delay in activation time in the ischemic zone was not significantly altered by quinidine or isoproterenol. The incidence of ventricular arrhythmias was increased by aprindine (from 1 in 11 to 8 in 11 dogs), decresed by verapamil (from 3 in 7 to 0 in 7 dogs) and was not changes by quinidine or isoproterenol. Thus, delayed activation of the ischemic myocardium appears to play an important role in the genesis of early arrhythmias due to myocardial ischemia, and drugs that significantly depress conduction in the ischemic myocardium may predispose to the development of ventricular arrhythmia whereas those that improve conduction may be protective. Contrary to their effects on slow channel-dependent conduction, verapamil improved and isoproterenol worsened conduction during ischaemia.

Comparative electrophysiologic and coronary hemodynamic effects of diltiazem, nisoldipine and verapamil on myocardial tissue*

The effects of diltiazem, nisoldipine (a nifedipine derivative) and verapamil on electrical and mechanical activity were studied in isolated canine Purkinje fibers and in isolated human atrial appendage. The actions of these three drugs on atrioventricular (A-V) conduction and coronary resistance were studied in open chest dogs in which autonomic effects were minimized by alpha and beta receptor blockade, bilateral vagotomy and atrial pacing after crushing of the sinus node. In isolated canine Purkinje fibers superfused with 5.4 m M of potassium in Tyrodes solution, normal action potentials and tension development were observed. Administration of diltiazem, nisoldipine and verapamil produced complete excitation/contraction uncoupling. The 50 percent effective concentrations for each drug in relation to tension development were calculated to be: diltiazem, 3 × 10 −7 M ; nisoldipine, 1.4 × 10 −8 M ; and verapamil, 4.2 × 10 −8 M . The ease with which the effects of the drugs could be washed out differed among the three agents. The percent of control tension achieved during washout was 40 percent for diltiazem, 75 percent for nisoldipine and 90 percent for verapamil. The reductions in tension development were accompanied by reductions in plateau amplitude and action potential duration at 50 percent of repolarization. Action potential duration at 90 percent of repolarization was significantly decreased by diltiazem, unchanged by nisoldipine and significantly increased by verapamil. In potassium-depolarized, isoproterenol-restored canine Purkinje fibers that demonstrated slow channel-dependent electrical activity, diltiazem, nisoldipine and verapamil all blocked action potential and subsequent tension development. These effects of diltiazem were completely reversed after 30 minutes of washout, but the effects of nisoldipine and verapamil were more difficult to reverse. In human atrial tissue, these three agents also abolished spontaneous slow channel-dependent action potentials. All three drugs produced excitation-contraction uncoupling and blocked slow channel-dependent electrical activity in canine and human cardiac tissue presumably by blocking the slow inward current. The different effects of each drug on action potential configuration suggest that each drug may also significantly affect other membrane currents. In intact open chest dogs, each drug lengthened atrial-His conduction times without affecting intraatrial or intraventricular conduction times. Coronary resistance was also decreased by each drug. High concentrations of each drug produced second degree A-V block and severe hypotension. As with the studies in isolated tissues the decreasing order of potency was nisoldipine, verapamil and diltiazem.

Aprindine for treatment of supraventricular tachycardias. With particular application to Wolff-Parkinson-White syndrome.

Abstract Ten patients with recurrent or continuous Supraventricular tachycardia difficult to control with conventional antiarrhythmic agents were treated with aprindine, a new antiarrhythmic drug. Nine patients had Wolff-Parkinson-White syndrome. An electrophysiologic study was performed before and during oral administration of aprindine. At the time of the first study, circus movement Supraventricular tachycardia was initiated in Patients 1 to 8. During administration of aprindine, circus movement Supraventricular tachycardia could no longer be initiated in Patients 1 to 4 but was initiated with difficulty in Patients 5 and 6 and with greater ease in Patients 7 and 8. In Patient 9, aprindine therapy slowed the ventricular response during atrial flutter from 1:1 conduction over the accessory pathway to 2:1 conduction over the normal pathway; in Patient 10, it slowed the ventricular rate during atrial fibrillation from 140–180 to 80–100 beats/min. Patients 1 to 6, 9 and 10 had an excellent clinical response, but treatment with aprindine was discontinued in Patients 7 and 8. Electrophysiologic evaluation revealed that aprindine produced complete block or increased refractoriness of the accessory pathway in an antegrade direction in all patients and in a retrograde direction in all but two (Patients 7 and 8) tested. Aprindine also slowed conduction in the accessory pathway and, when Supraventricular tachycardia could still be initiated, it occurred at a slower rate. Neurologic side effects occurred primarily during the initial administration and dose adjustment of aprindine.

Procainamide for Rate Control of Postsurgical Junctional Tachycardia

Abstract. This study was conducted to determine the efficacy of procainamide therapy for rapid rate control of postoperative junctional tachycardia (JT). Postoperative JT is one of the most difficult forms of tachycardia to manage. Reported success with a variety of treatments of JT in infants and children has been inconsistent and limited. Rate control using procainamide was achieved in 17 children having rapid JT (heart rate >200 beats/min) between 1986 and 1997. In the first 5 patients (protocol A), following a loading dose of 3 mg/kg over 20 minutes, a continuous procainamide infusion was initiated at a rate of 20 μg/kg/min. The infusion dose was increased in 10 μg/kg steps every 30 minutes to 40–120 μg/kg/min until the heart rate decreased below the target rate of 180 beats/min. In the other 12 patients (protocol B), after a higher loading dose of 10 mg/kg the infusion rate was increased every 10–15 minutes until the heart rate decreased below the target rate of 180 beats/min. Procainamide decreased JT rates in all patients but the response was significantly faster in protocol B. In the patients treated with protocol A, pretreatment JT rates ranged from 203 to 240 (213 ± 17) beats/min and decreased to 195 ± 10 beats/min at 2 hours (p= ns), 186 ± 8.8 at 4 hours (p < 0.02), and 179 ± 8 at 6 hour postinitiation of PA. In protocol B, pretreatment JT rates ranged from 201 to 240 (218 ± 17) beats/min and decreased to 183 ± 20 beats/min at 2 hours (p < 0.001) and 171 ± 12 at 4 hours after starting the procainamide therapy. The mean duration to decrease JT rates below the target rate of 180 beats/min was 3.2 ± 1.1 hours in protocol B compared to 6.4 ± 3.8 hours in protocol A (p < 0.02). Eight of 12 patients in protocol B achieved rate control below the target rate of 180 beats/min within 4 hours despite remaining on significant inotropic support. The procainamide infusion rates to maintain heart rates below 180 beats/min were 40–120 (68.4 ± 22.1) μg/kg/min. No proarrhythmia, bradycardia, or significant hypotension was observed. In this series procainamide provided safe, effective, and rapid rate control of JT occurring in the immediate postoperative period.

Exaggerated blood pressure response to exercise in children with increased low-density lipoprotein cholesterol.

Arterial vascular responses are characteristically altered with hypercholesterolemia: conduit vessels manifest increased stiffness, and conduit and resistance vessels demonstrate impaired endothelium-dependent dilation and augmented vasoconstriction to neurohumoral stimulation. These changes should be reflected in an exaggerated blood pressure increase in response to exercise. To evaluate this hypothesis, we compared the blood pressure response to treadmill exercise in children with hypercholesterolemia and children with normal lipid levels. In a preliminary retrospective study, 15 hypercholesterolemic boys 10 to 18 years old underwent treadmill exercise testing, and their blood pressure results were compared with those of 32 normolipidemic children in the same age group who had undergone treadmill exercise electively in the same time period. In the second phase, 10 hypercholesterolemic boys and 10 normolipidemic age-matched boys were evaluated prospectively according to the same protocol. Treadmill exercise involved a modified Bruce protocol with heart rate and blood pressure measured before exercise, immediately after exercise, and throughout recovery. Office blood pressures were normal in all children, with no significant difference between groups. With treadmill exercise, all subjects achieved >95% of predicted maximum heart rate and endurance times, maximum oxygen consumption, and maximum respiratory ratio did not differ between groups. Results of the retrospective and prospective groups were similar and were therefore combined. Children with increased low-density lipoprotein (LDL) cholesterol had significantly higher systolic and diastolic blood pressures immediately before treadmill exercise (systolic 120 +/- 13 mm Hg vs 113 +/- 13 mm Hg, p < 0.03; diastolic 68 +/- 8 mm Hg vs 63 +/- 9 mm Hg, p < 0.01). After exercise, blood pressures were again significantly higher in the subjects with high LDL cholesterol (systolic 182 +/- 20 mm Hg vs 160 +/- 23 mm Hg, p < 0.0003; diastolic 77 +/- 12 mm Hg vs 72 +/- 9 mm Hg, p < 0.03). At the end of recovery, systolic blood pressures remained significantly higher in subjects with high LDL cholesterol (120 +/- 9 mm Hg vs 112 +/- 12 mm Hg, p < 0.005). In this study, children with severely increased LDL cholesterol had an exaggerated blood pressure response to exercise when compared with normolipidemic control subjects. The study findings suggest that control of arterial vascular tone may already be altered in children with hypercholesterolemia.

Loss of Sinus Rhythm After Total Cavopulmonary Connection

BACKGROUND Total cavopulmonary connection (TCPC) to repair functional single ventricle involves the sinus node area, in contrast to the Fontan procedure. We compared ECG findings after TCPC and Fontan to evaluate the impact of the cavopulmonary connection on sinus rhythm postoperatively. METHODS AND RESULTS The Fontan group consisted of 17 patients repaired at 7.8 +/- 3.1 years of age (mean +/- SD): 11 for tricuspid or pulmonary atresia (TA/PA) and 6 for single ventricle. The TCPC group consisted of 19 patients repaired at 5.1 +/- 3.2 years of age (mean +/- SD) (P < .001): 9 for TA/PA, 4 for single ventricle, and 6 for hypoplastic left heart syndrome. Mean follow-up after Fontan was 7.7 +/- 2.7 years versus 2.8 +/- 1.6 years for TCPC (P < .001). Preoperative ECGs on all TCPC patients showed sinus rhythm (SR), whereas 16 of 17 Fontan patients had SR and one had nonsinus atrial rhythm (NSAR) since birth. On the first postdischarge ECG, 12 of 19 TCPC patients (63%) were in SR, 4 were in junctional rhythm (JR), and 3 were in NSAR. In comparison, 15 of 17 Fontan patients (88%) were in SR with 1 of 17 in NSAR and 1 in supraventricular tachycardia (P < .05 with chi 2 test). By 2 years postoperatively, only 6 of 15 TCPC patients available for follow-up (40%) were in SR, with 7 of 15 in JR and 2 of 15 in NSAR. By contrast, 13 of 17 Fontan patients (76%) remained in SR, with 1 in NSAR and 3 in JR (P < .05 with chi 2 test). TCPC patients with loss of SR did not differ from other patients in the group in age at repair, preoperative diagnosis, or surgeon performing the procedure. CONCLUSIONS This significant incidence of loss of SR temporally related to surgery suggests that operative compromise of the sinus node area is common with TCPC.

Primary benign intramural ventricular tumors in children: pre- and postoperative electrocardiographic, echocardiographic, and angiocardiographic evaluation.

The clinical, ECG, echocardiographic, and angiographic data, as well as the operative findings and postoperative courses of three children with intramural ventricular tumors are presented. In all three children, the specific diagnosis of intramural tumor was unsuspected. The ECGs showed a superior axis in all patients. M-mode echocardiography missed the mass in one patient and was nonspecific in the other two; however, two-dimensional echo (2DE) was able to accurately delineate the tumors preoperatively in all three. Angiographic findings were nonspecific, only demonstrating the presence of space-occupying lesions. All three patients underwent surgery and the tumors were removed successfully. This investigation emphasizes the clinical picture that led to the diagnostic evaluations, and demonstrates the usefulness of 2DE in accurately diagnosing the intramural ventricular tumors. In addition, the sequential ECGs and 2DEs after removal of the tumors are delineated as well as showing the resolution of the tumor craters by 2DE examinations.