Biomedical subjects
Publications and source records attributed to N El-Sherif.
We report 2 cases of exudative left pleural effusion following radiofrequency catheter ablation of cardiac arrhythmias complicated by cardiac perforation. We suggest that radiofrequency ablation may be a previously unsuspected cause of postcardiac injury syndrome.
Following myocardial Infarction (MI) the heart undergoes a process of remodeling characterized by considerable hypertrophy of the non-infarcted myocardium. We have recently characterized the molecular basis of key electrophysiologic alterations that may provide insight into the arrhythmogenecity of post-MI remodeled hypertrophied myocardium. To further characterize other key alterations in the pattern of cardiac gene expression in a time-dependent manner, we have measured mRNA and immunoreactive protein levels of selective cardiac genes in the remodeled hypertrophied left-ventricular (LV) myocardium of rats, 3 and 21 days after left-coronary ligation and compared the results with sham-operated rats. RNase protection assay was performed to assess the expression of c-fos, atrial natriuretic factor (ANF), brain natriuretic factor (BNF), alpha2/3 isoform of Na-K ATPase, cardiac alpha/beta isoform of myosin heavy chain (MHC). Compared to the sham group, the expression of c-fos was increased 10-fold (P<0.02) in the MI group on day 3, but unlike other overload hypertrophy models, the expression remained elevated by three-fold on day 21. Similar to other overload models, the ANF and BNF expression increased significantly. No alterations were observed in the expression of cardiac alpha-actin. There was reexpression of the fetal isogene form of MHC and Na-K ATPase after MI. The beta-MHC mRNA levels, the fetal isoform of MHC, returned to basal levels after 21 days. After an initial five-fold decrease the adult isoform of alphaNa-K ATPase, alpha2 Na-K ATPase mRNA, returned to control levels and similar changes were seen in the corresponding protein levels. These findings indicate that during LV remodeling and hypertrophy following MI, there is an upregulation of early response genes and fetal isogene expression. The pattern of activation, however, is distinct from that observed in other overload models, indicating the possible involvement of alternate signal transduction pathways.
Although a strong clinical association exists between congenital heart block (CHB) and an immune response to SSA/Ro and SSB/La proteins, a causative role of these antibodies in the pathogenesis is just emerging. In a preliminary report, we have demonstrated that IgG fractions isolated from the sera of mothers whose children have CHB are arrhythmogenic in the human fetal heart. To more precisely define the arrhythmogenic effect of anti-SSA/Ro-SSB/La antibodies, we used the readily available rat heart model to record: 1) ECGs from Langendorff beating hearts; 2) action potentials from atrioventricular (AV) nodal preparations; 3) L-type Ca currents, I(Ca) at the whole-cell and single channel levels; and 4) other currents such as the transient outward K+ current, I(to), the inward rectifier K+ current, I(K1), and the Na+ current, I(Na). Perfusion of hearts with purified IgG (800 microg/mL), isolated from the serum of a mother with SSA/Ro and SSB/La antibodies whose child had CHB, resulted in bradycardia associated with 2:1 AV block. Simultaneous action potentials were recorded from dissected atrial and AV nodal areas of the rat heart. Superfusion of these preparations with the same mother's IgG fraction resulted in 2:1 AV block followed by complete inhibition of AV nodal action potential. Because AV nodal electrogenesis is largely dependent on I(Ca), the effect of these antibodies on I(Ca) was subsequently determined. Superfusion of myocytes with whole serum or purified IgG (80 microg/mL) from the same mother consistently inhibited whole cell I(Ca), ensemble average Ba2+ currents (I(Ba)) and open state probability, p(o), without affecting the channel conductance. IgG had no significant effect on I(to), I(K1), or I(Na). Whole sera and IgG fractions from a healthy mother with no detectable anti-SSA/Ro or SSB/La antibodies did not inhibit I(Ca) or I(Ba). These results demonstrate that IgG containing anti-SSA/Ro and -SSB/La antibodies induces complete AV block in beating hearts and in multicellular preparations, thus implicating a preferential interaction of these autoantibodies with Ca channels and/or associated regulatory proteins. This is consistent with the observed inhibition of Ca channels that may be a critical factor contributing to the pathogenesis of CHB.
BACKGROUND: The long-QT syndrome (LQTS) is an electrophysiological (EP) entity characterized by prolongation of cardiac repolarization and the occurrence of polymorphic ventricular tachyarrhythmias (VTs), sometimes with a twisting QRS morphology, better known as torsade de pointes (TdP). In the present study, detailed analysis of ventricular tridimensional activation patterns during nonsustained TdP VT was performed to provide an EP mechanism of the periodic transition in QRS axis. METHODS AND RESULTS: The studies were conducted with the anthopleurin-A canine model of LQTS. Tridimensional isochronal maps of ventricular activation were constructed from 256 bipolar electrograms obtained from the use of 64 plunge needle electrodes. In 26 episodes of nonsustained TdP VT, detailed activation maps could be accurately constructed during QRS-axis transitions in surface ECGs. The initial beat of all VTs consistently arose as a subendocardial focal activity, whereas subsequent beats were due to reentrant excitation in the form of rotating scrolls. The VT ended when reentrant excitation was terminated. In 22 of 26 episodes, the transition in QRS axis coincided with the transient bifurcation of a predominantly single rotating scroll into two simultaneous scrolls involving both the right ventricle and left ventricle separately. The common mechanism for initiation or termination of bifurcation was the development of functional conduction block between the anterior or posterior right ventricle free wall and the ventricular septum. In 4 of 26 episodes, a fast polymorphic VT, with an apparent shift in QRS axis, was due to a predominantly single localized circuit that varied its location and orientation from beat to beat, with the majority of ventricular myocardium being activated in a centrifugal pattern. CONCLUSIONS: The study provides for the first time an EP mechanism for the characteristic periodic transition of the QRS axis during TdP VT in the LQTS.
This investigation was performed to evaluate the feasibility of detecting repolarization alternans with the heart rate elevated with a bicycle exercise protocol. Sensitive spectral signal-processing techniques are able to detect beat-to-beat alternation of the amplitude of the T wave, which is not visible on standard electrocardiogram. Previous animal and human investigations using atrial or ventricular pacing have demonstrated that T-wave alternans is a marker of vulnerability to ventricular arrhythmias. Using a spectral analysis technique incorporating noise reduction signal-processing software, we evaluated electrical alternans at rest and with the heart rate elevated during a bicycle exercise protocol. In this study we defined optimal criteria for electrical alternans to separate patients from those without inducible arrhythmias. Alternans and signal-averaged electrocardiographic results were compared with the results of vulnerability to ventricular arrhythmias as defined by induction of sustained ventricular tachycardia or fibrillation at electrophysiologic evaluation. In 27 patients alternans recorded at rest and with exercise had a sensitivity of 89%, specificity of 75%, and overall clinical accuracy of 80% (p <0.003). In this patient population the signal-averaged electrocardiogram was not a significant predictor of arrhythmia vulnerability. This is the first study to report that repolarization alternans can be detected with heart rate elevated with a bicycle exercise protocol. Alternans measured using this technique is an accurate predictor of arrhythmia inducibility.
We have previously shown that alpha1-adrenergic activation inhibited beta-adrenergic-stimulated L-type Ca2+ current (I(Ca)). To determine the role of protein kinase C (PKC) in this regulation, the inositol trisphosphate pathway was bypassed by direct activation of PKC with 4beta-phorbol 12-myristate 13-acetate (PMA). To minimize Ca2+-induced Ca2+ inactivation, Ba2+ current (I(Ba)) was recorded through Ca2+ channels in adult rat ventricular myocytes. We found that PMA (0.1 micromol/L) consistently inhibited basal I(Ba) by 40.5+/-7.4% and isoproterenol (ISO, 0.1 micromol/L)-stimulated I(Ba) by 48.9+/-7.8%. These inhibitory effects were not observed with the inactive phorbol ester analogue alpha-phorbol 12,13-didecanoate (0.1 micromol/L). To identify the PKC isozymes that mediate these PMA effects, we intracellularly applied peptide inhibitors of a subclass of PKC isozymes, the C2-containing cPKCs. These peptides (betaC2-2 and betaC2-4) specifically inhibit the translocation and function of C2-containing isozymes (alpha-PKC, betaI-PKC, and betaII-PKC), but not the C2-less isozymes (delta-PKC and epsilon-PKC). We first used the pseudosubstrate peptide (0.1 micromol/L in the pipette), which inhibits the catalytic activity of all the PKC isozymes, and found that PMA-induced inhibition of ISO-stimulated I(Ba) was reduced to 16.8+/-7.4% but was not affected by the scrambled pseudosubstrate peptide. The effects of PMA on basal and ISO-stimulated I(Ba) were then determined in the presence of C2-derived peptides or control peptides. When the pipette contained 0.1 micromol/L of betaC2-2 or betaC2-4, PMA-induced inhibition of basal I(Ba) was 26.1+/-4.5% and 23.6+/-2.2%, respectively. Similarly, ISO-stimulated I(Ba) was inhibited by 29.9+/-6.6% and 29.3+/-7.8% in the presence of betaC2-2 and betaC2-4, respectively. In contrast, there was no significant change in the effect of PMA in the presence of control peptides, scrambled betaC2-4, or pentalysine. Finally, PMA-induced inhibition of basal and ISO-stimulated I(Ba) was almost completely abolished in cells dialyzed with both betaC2-2 and betaC2-4. Together, these data suggest a role for C2-containing isozymes in mediating PMA-induced inhibition of L-type Ca2+ channel activity.
BACKGROUND: The electrophysiological mechanisms of spontaneous termination of sustained monomorphic ventricular tachycardia (SMVT), in the postinfarction heart, generally considered secondary to a reentrant mechanism, have not been fully investigated. METHODS AND RESULTS: Epicardial activation maps of spontaneous termination of 20 different episodes of SMVT (lasting 30 seconds to 10 minutes) from 8 dogs, 4 to 5 days after one-stage ligation of the left anterior descending coronary artery, were analyzed with the use of 254 bipolar electrode recordings with high density (2.5 to 2.8 mm between bipolar electrodes) in the ischemic zone. All ventricular tachycardias (VTs) were due to circus movement reentry with a characteristic figure-8 configuration. Termination always occurred when the two circulating wave fronts blocked in the central common pathway (CCP). Two basic mechanisms of spontaneous termination were observed: (1) In 15 episodes, acceleration of conduction occurred in parts of the reentrant circuit and was associated with slowing of conduction and finally conduction block in the CCP. Acceleration of conduction occurred in the last few cycles of VT both at the outer border of the arcs of functional conduction block in the "normal" myocardial zone and at the pivot points to the entrance to the CCP. When acceleration of conduction was compensated on a beat-to-beat basis by an equal degree of slowing in the CCP, there was no discernible change in the cycle length of the VT in the ECG. In some episodes, the termination of the original reentrant circuit was followed by the development of a different, slower reentrant pathway that lasted for one or a few cycles prior to termination. (2) In 5 VT episodes, the activation wave front in the CCP abruptly broke across a stable arc of functional conduction block, resulting in premature activation of the CCP and conduction block. CONCLUSIONS: Distinct electrophysiological changes always preceded spontaneous termination of stable SMVT. The electrophysiological basis for acceleration of conduction in parts of the reentrant circuit during the last few beats prior to termination and of the abrupt reactivation across a stable arc of block remains to be determined.
BACKGROUND: To study the transient outward current (I(to)) investigators often use sodium-free external solution to minimize the possible contamination of I(to) by sodium current. Removal of extracellular sodium creates reversal of sodium gradient and thus possibly contributing to I(to) mainly at positive potentials. METHODS AND RESULTS: To address this issue, whole-cell I(to) was recorded in sodium-free choline chloride and cobalt solutions, from rat ventricular myocytes known to exhibit a prominent I(to). Depolarizing pulse to 40 mV from -100 mV holding potential every 10 seconds elicited a fast activating and time-dependent inactivating components. The activation of I(to) was fast and complete within 10 ms at 40 mV, and the decay was rapid over the first 100 ms of the pulse and slower thereafter. External superfusion of the cell with 50 µM tetrodotoxin reversibly reduced I(to) amplitude by 25% from 1.47 +/- 0.2 to 1.1 +/- 0.3 nA (P <.04, n = 9). When sea anemone toxin (ATXII), known to selectively enhanced I(Na) by causing a delay in the inactivation gate, is applied to the cell, I(to) amplitude increased in a time- and dose-dependent manner (EC(50) =.86.4 nM). ATXII (100 nM) dramatically increased I(to) amplitude at all voltages between -20 and 60 mV (from 1.51 +/- 0.4 to 3.35 +/- 0.8 nA at 40 mV, P <.003, n = 12). Superfusion of cells with 5 mM 4-AP resulted in 82% reduction in I(to) amplitude at 40 mV (from 1.95 +/- 0.5 to 0.37 +/- 0.2 nA, P <.02, n = 8). Addition of ATXII to 4-AP containing solution increased peak I(to) by 965% (from 0.37+/-0.2 to 3.95 +/- 0.9, n = 8, P <.0003). However, in 11 other cells, addition of tetrodotoxin (50 µM) to the ATXII-containing solution blocked ATXII-induced outward current (from 3.51 +/- 0.64 nA to 1.60 +/- 0.17 nA, P <.05). The conductance (G(Ito)) was calculated by dividing peak I(to) by (Vm-E(K)), with an E(K) of -75 mV. G(Ito) was increased at all voltages (greater than -40 mV). Normalized G(Ito) was fitted by Boltzmann equation and ATXII did not significantly modify V(0.5) and k (from -20.5 +/- 3.9 to -17.0 +/- 3.5 mV for V(0.5), and 12.2 +/- 2.6 to 13.4 +/- 2.1 mV for k, n = 4). Also, atropine (1 µM) did not have any significant effect on I(to) (from 1.92 +/- 0.15 nA to 1.85 +/- 0.25 nA, n = 5). CONCLUSIONS: The results showed that, in sodium-free external solution I(to) is tetrodotoxin but not atropine sensitive. ATXII-induced I(to) increase is 4-aminopyridine insensitive but tetrodotoxin sensitive. These data suggest that outward Na current due to reversal of Na gradient in the absence of external Na contributes to I(to). Caution must be taken when studying kinetics and pharmacology of I(to) in external sodium-free solutions.
Nonsustained ventricular tachycardia is not uncommon both in the presence and absence of organic heart disease and in the latter situation, is usually not associated with an increased risk. However, in patients with ischemic heart disease, especially in the post-infarction period, nonsustained ventricular tachycardia is associated with an increased risk of sudden, and possibly non-sudden, cardiac death. Several non-invasive and invasive tests have been utilized, individually or in combination, to risk stratify those patients. Left ventricular ejection fraction, the signal averaged electrocardiogram, and especially programmed ventricular stimulation have been commonly utilized to identify those patients at high risk for malignant tachyarrhythmias and to evaluate the potential benefit from antiarrhythmic treatment. At present, however, there is no consensus as to the best strategy to identify and treat high risk patients. Several ongoing multicenter clinical trials may eventually provide such guidelines. In the meantime, an algorithm for the management of those patients is suggested.
The ST alternans was recorded during at least one ischemic attack with ST elevation in nine of 65 patients with variant angina. The magnitude and duration of ST elevation during ischemic attacks were significantly greater in patients with than in those without ST alternans. It always appeared during the occlusion phase and disappeared during the reperfusion phase of ischemic attacks. In patients with episodic ST alternans, the ischemic attacks showed a greater ST elevation and a longer duration in the presence of ST alternans than in its absence. The incidence of occlusion phase ventricular arrhythmias was greater in patients with than in those without ST alternans; the incidence of reperfusion phase ventricular arrhythmias was similar in the two groups. The ST alternans always preceded the onset of occlusion phase arrhythmias. Thus, in variant angina, ST alternans represents an index of the severity of ischemia and a precursor of ventricular arrhythmias.
As with all skilled techniques, there is a learning curve for percutaneous coronary angioplasty. This curve has been well described in the literature and it is generally quoted that an initial success rate of 70 to 75 percent in reaching and crossing lesions is to be expected during the first 20 cases. However, the introduction of the steerable or guidewire-directed dilation catheter has altered the learning curve. After an initial experience of six nonsteerable percutaneous transluminal coronary angioplasty procedures, 20 consecutive steerable percutaneous transluminal coronary angioplasty procedures were performed without a single failure to reach or cross a lesion. These 20 consecutive steerable coronary angioplasty procedures included eight single left anterior descending lesions, two double (lesions located in series) left anterior descending lesions, six single right coronary lesions, one double (lesions located in series) right coronary lesion, and three single circumflex lesions. It is concluded that the introduction of the steerable system for percutaneous transluminal coronary angioplasty has shifted the learning curve, and that skilled and experienced coronary angiographers beginning a coronary angioplasty program can expect an initial success rate in reaching and crossing obstructive coronary lesions far in excess of the figures quoted in the literature. This may have significant implication for the ultimate availability of percutaneous transluminal coronary angioplasty to patients with coronary artery disease.
Enhanced susceptibility to toxic arrhythmias by digitalis administration has been reported in clinical and experimental myocardial infarction. To investigate the mechanism responsible for this phenomenon, the effects of superfusion with normal Tyrode's solution and superfusion with Tyrode's solution containing 4 X 10(-8)M of ouabain in ischemic Purkinje fibers were compared. Ischemic Purkinje fibers of small endocardial preparations from 1 day old myocardial infarcts in 18 dogs were used for the study. During control conditions, these endocardial preparations demonstrated delayed afterdepolarizations and triggered activity. Superfusion with normal Tyrode's solution resulted in a gradual increase in maximal diastolic potential and action potential amplitude, a decrease in delayed afterdepolarizations amplitude and slowing and termination of triggered activity. Superfusion for 90 minutes with Tyrode's solution containing ouabain resulted in: 1) an increase in the magnitude of delayed afterdepolarizations in preparations demonstrating subthreshold delayed afterdepolarizations, 2) sustainment of triggered activity in preparations showing nonsustained triggered activity, and 3) shortening of cycle lengths of the triggered activity in preparations demonstrating sustained triggered activity before superfusion with ouabain. These effects occurred despite the gradual increase in maximal diastolic potential and action potential amplitude. Superfusion of normal Purkinje fibers with Tyrode's solution containing 4 X 10(-8)M of ouabain for 90 minutes did not result in delayed afterdepolarizations or triggered activity. Thus, ouabain at a concentration that has no toxic effect on normal Purkinje fibers may enhance arrhythmias in ischemic Purkinje fibers by increasing the magnitude of delayed afterdepolarizations and enhancing triggered activity.
One-stage surgery was successfully performed in a 44-year-old hypertensive man with uncontrolled angina, multiple coarctations of the thoracic and abdominal aorta, and a previous subtotal gastrectomy. There was a gradient of 120 mm Hg between the thoracic and abdominal aorta. A graft was placed retroperitoneally from the infrarenal aorta to the ascending aorta and was followed by a coronary artery bypass graft. Twenty-four months postoperatively, the patient was free of angina, and his hypertension was easily controlled.
The electrophysiologic effects of propafenone were studied by conventional microelectrode techniques in ischemic myocardial and Purkinje fibers from 1-day-old myocardial infarction in the dog. Propafenone reduced the amplitude and rate of rise of normal myocardial and Purkinje action potentials and had little effect on the resting potential. In the control state, both ischemic myocardial and Purkinje fibers had reduced resting potential, action potential amplitude and upstroke velocity. These fibers were more susceptible to the depressant effects of propafenone than normal fibers. Ischemic myocardial fibers were particularly sensitive to the actions of propafenone that resulted in marked depression of action potential characteristics, with little effect on resting potential. These changes resulted in cycle length-dependent conduction disorders in ischemic epicardial preparations. However, in ischemic endocardial preparations in which triggered activity could be initiated, propafenone reversibly suppressed the triggered activity. Termination of the triggered activity was preceded by slowing of the rate, which was attributed to a decrease in the rate of rise of the delayed afterdepolarizations. This activity terminated when the delayed afterdepolarization failed to attain threshold potential. This study suggests that propafenone has a membrane-anesthetic effect, with the abnormal fast channel in ischemic cells being more sensitive; propafenone depresses delayed afterdepolarizations in ischemic Purkinje fibers; and the actions of propafenone could result in an antiarrhythmic effect in vivo on both reentrant ventricular rhythms in ischemic myocardium and triggered rhythms in ischemic Purkinje fibers.
Triggered activity arising from a delayed afterdepolarization occurs in canine subendocardial Purkinje fibers 1 day after myocardial infarction (MI). Standard microelectrode techniques were used to study small preparations (20 to 48 mm2) in vitro. Nifedipine, 1 mg/liter, reversibly suppressed triggered activity by reducing maximum diastolic potential, action potential amplitude and the rate of depolarization of the delayed afterdepolarization. Complete quiescence or exit block resulted. The effects of nifedipine were antagonized by elevating extracellular calcium ion concentration. These results suggest that spontaneous ectopic rhythms 1 day after MI that are the result of triggered activity are dependent on transmembrane calcium ion movement, which nifedipine can directly antagonize.
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A case of catheter-induced proximal dissection of an angiographically normal left coronary artery is reported. Dissection was not associated with pressure damping and myocardial ischemia was delayed until 1 hour after dissection occurred. Prompt recognition of this entity is essential as emergency revascularization is the treatment of choice when significant amounts of myocardium are threatened.
We studied the effects of intravenous amiodarone administration (5 mg/kg) on reproducible repetitive ventricular responses and ventricular tachycardia (VT) induced by programmed electrical stimulation of the heart in 32 patients. Intravenous amiodarone prevented induction of bundle branch reentry in only 2 of 11 patients (18.2%) and did not change His-Purkinje conduction and refractoriness in the remaining 9 of 11 (81.8%) patients. In contrast to the small effect of intravenous amiodarone on bundle branch reentry, the drug completely abolished intraventricular reentry in three of nine (33.3%) patients and in the remaining six of nine (66.7%) patients decreased the number of intraventricular reentrant beats from up to five beats in control to one to two beats after the drug. The drug also prevented induction of VT (greater than or equal to 5 ventricular ectopic beats in a row) in three of five (60%) patients with nonsustained VT and in three of seven (42.9%) patients with sustained VT. In two of seven (28.6%) patients with sustained VT, only nonsustained tachycardia could be induced after drug administration. In another two of seven (28.6%) patients, sustained VT with slower rates was induced after the drug. In 11 of 12 (91.7%) patients with VT the coupling interval between the last stimulus and the first ventricular beat increased after drug administration. These effects of intravenous amiodarone occurred in the absence of effect on ventricular effective refractory period. These findings suggest that intravenous amiodarone might have greater effect on diseased ventricular tissue, the site of reentry in VT, than on healthy ventricular tissue.