Endocardial stimulation of efferent parasympathetic nerves to the atrioventricular node in humans: optimal stimulation sites and the effects of digoxin.

UNLABELLED: The purposes of this study were to identify optimal sites of stimulation of efferent parasympathetic nerve fibers to the human atrioventricular node via an endocardial catheter and to investigate the interaction between digoxin and vagal activation at the end organ. METHODS: The ventricular rate was measured during atrial fibrillation, prior to and during parasympathetic nerve stimulation, in 8 patients taking digoxin and in 10 controls. High frequency electrical stimuli were delivered via an hexapolar or quadripolar electrode catheter, placed at the posteroseptal right atrium near the atrioventricular node (n=18 patients) or in the coronary sinus (n=12 of 18 patients). In 4 patients, stimulation was repeated after intravenous administration of 1 to 2 mg of atropine. RESULTS: Nerve stimulation prolonged the R-R interval in all patients. Stimulation close to the posteroseptal right atrium led to maximal atrioventricular nodal slowing. The mean R-R intervals at baseline and during parasympathetic nerve stimulation (60 mA) from the posteroseptal right atrium and the proximal coronary sinus were 581+/-79 ms, 2440+/-466, and 900+/-228 ms respectively (p=0.0001). The response to nerve stimulation was greater in patients taking digoxin than in patients not taking the drug (p=0.02). Junctional rhythm occurred during nerve stimulation in 8/8 patients taking digoxin and 0/10 not taking the drug (p=0.0001). The response to stimulation was eliminated after atropine (p=0.01). CONCLUSIONS: Parasympathetic nerves to the atrioventricular node were stimulated from the proximal coronary sinus as well as the posteroseptal right atrium. Stimulation at the posteroseptal right atrium resulted in the greatest response, and digoxin enhanced this response. The augmented response suggests that an interaction may exist between parasympathetic stimulation and digoxin at the end organ.

Risk of stroke in patients with atrial flutter.

Using a Medicare-based retrospective cohort study, the stroke risk in patients with atrial flutter (RR = 1.41) was determined to be greater than that in a control group (RR = 1.00) but less than that in an atrial fibrillation group (RR = 1.64). Furthermore, patients with atrial flutter who subsequently had an episode of atrial fibrillation had a higher risk of stroke (RR = 1.56) than patients with atrial flutter who never had a subsequent episode of atrial fibrillation (RR = 1.11).

Importance of atrial flutter isthmus in postoperative intra-atrial reentrant tachycardia.

BACKGROUND: In survivors of congenital heart surgery, intra-atrial reentrant tachycardia (IART) often develops. Previous reports have emphasized the atriotomy scar as the central barrier around which a reentrant circuit may rotate but have not systematically evaluated the atrial flutter isthmus in such patients. We sought to determine the role of the atrial flutter isthmus in supporting IART in a group of postoperative patients with congenital heart disease. METHODS AND RESULTS: Nineteen postoperative patients with IART underwent electrophysiological studies with entrainment mapping of the atrial flutter isthmus for determining postpacing intervals. Radiofrequency ablation was performed at the identified isthmus in an effort to create a complete line of block. Twenty-one IARTs were identified in 19 patients, with a mean tachycardia cycle length of 293+/-73 ms. The atrial flutter isthmus was part of the circuit in 15 of 21 (71. 4%). In the remaining 6 of 21, the ablation target zone was at sites near atrial incisions or suture lines. Ablation was successful in 19 of 21 (90.4%) IARTs and in 14 of 15 (93.3%) cases at the atrial flutter isthmus. CONCLUSIONS: In most of our postoperative patients, the atrial flutter isthmus was part of the reentrant circuit. The fact that the atrial flutter isthmus is vulnerable to ablation suggests that whenever IART occurs late after repair of a congenital heart defect, the atrial flutter isthmus should be evaluated. These data support the theory that some form of conduction block between the vena cava is essential for the establishment of a stable substrate for the atrial flutter reentrant circuit.

Influence of heart rate and sympathetic stimulation on arrhythmogenic T wave alternans.

We determined the temporal stability of T wave alternans (TWA) during constant rate stimulation and the dependence of alternans on heart rate (HR) and beta-adrenergic stimulation. Although it is established that exercise can provoke microvolt-level TWA in patients at risk for reentrant ventricular arrhythmias, the mechanisms underlying TWA in humans are not well understood. Specifically, the temporal stability of alternans at any given HR and the influence of HR vs. sympathetic activation on alternans remain unclear. TWA was measured during prolonged fixed-rate atrial pacing at multiple cycle lengths (CLs) in 10 subjects referred for electrophysiological testing and in 14 additional subjects in whom atrial pacing was performed at identical pacing CLs with and without isoproterenol. During constant CL stimulation, TWA amplitude oscillated significantly over time (typically by 10 microV) in a quasiperiodic fashion with periodicity of approximately 2-3 min. Alternans amplitude was strongly dependent on HR but not on adrenergic stimulation. There was a patient-specific threshold HR over which alternans appeared. At higher HR, alternans amplitude increased and oscillations were less prominent. Adrenergic stimulation was required to produce TWA that was not already elicited by moderate elevation of HR in only 2 of 14 (14%) patients. In conclusion, TWA 1) fluctuates spontaneously over 2-3 min and 2) increases monotonically with increased HR (without a major adrenergic contribution in most patients). These data suggest that increased HR rather than sympathetic activation is responsible for arrhythmogenic microvolt-level TWA measured during exercise.

An approach to salvage a "frozen" pacing lead.

We report our experience with the use of an orthopedic drill to remove "frozen" pacemaker leads from the connector block during pacemaker generator replacements. Three cases are reported in which the leads were salvaged successfully using this technique.

Characterization of sinoatrial parasympathetic innervation in humans.

INTRODUCTION: The response to sinoatrial parasympathetic nerve stimulation (shortened atrial refractoriness) was used to determine the atrial distribution of these nerve fibers in humans. We hypothesized that, in humans, parasympathetic nerves that innervate the sinoatrial node also innervate the right atrium and that the greatest density of innervation is near the sinoatrial nodal fat pad. METHODS AND RESULTS: Temporary epicardial wire electrodes were sutured in pairs in the sinoatrial nodal fat pad, high right atrium, and right ventricle by direct visualization during coronary artery bypass surgery in nine patients. Appropriate electrode placement was confirmed by electrically stimulating the fat pad in the operating room to prolong sinus cycle length by 50%. Experiments were performed in the electrophysiology laboratory 1 to 5 days after surgery. Programmed atrial stimulation was performed via an endocardial electrode catheter advanced to the right atrium. The catheter tip electrode was moved in 1-cm concentric zones around the epicardial wires by fluoroscopic guidance. Atrial refractoriness was determined in the presence and absence of sinoatrial parasympathetic nerve stimulation at each catheter site. In 8 of 9 patients, parasympathetic nerve stimulation reproducibly prolonged sinus cycle length by 50%. There was no effect on AV nodal conduction (no prolongation of PR interval) and no change in AV nodal refractoriness. Atrial effective refractory periods reproducibly shortened in response to parasympathetic nerve stimulation in 1-cm zones up to 3 cm surrounding the fat pad, by a mean (+/- SEM) of 26.6+/-4.3 msec (zone 1), 11.4+/-1.8 msec (zone 2), and 10.0+/-2.5 msec (zone 3), respectively (P = 0.0001). At distances > 3 cm from the fat pad, the effective refractory period did not shorten. CONCLUSION: Stimulation of parasympathetic nerves that innervate the sinoatrial node shortened atrial refractoriness in humans.

Mechanisms and medical management of patients with atrial flutter.

Type I atrial flutter is due to reentrant excitation, principally in the right atrium. The standard ECG remains the cornerstone for its clinical diagnosis. Acute treatment should be directed at control of the ventricular response rate and, if possible, restoration of sinus rhythm. Radiofrequency catheter ablation therapy provides the best hope of cure, although atrial fibrillation may subsequently occur after an ostensibly successful ablative procedure. Alternatively, antiarrhythmic drug therapy to suppress recurrent atrial flutter episodes may be useful, recognizing that occasional recurrences are common despite therapy. Radiofrequency ablation of the His bundle ablation with placement of an appropriate pacemaker system may be useful in selected patients.

Favorable results of implantable cardioverter-defibrillator implantation in patients older than 70 years.

BACKGROUND: The clinical results of implantable cardioverter-defibrillator (ICD) implantation in the elderly have received limited documentation. As the longevity of the U.S. population has increased, so has the need for ICD implantation in the elderly. We evaluated the efficacy and outcome of ICD implantation in elderly patients (>70 years) compared with younger patients. METHODS: The case records of all consecutive patients who underwent ICD implantation at our institution between 1986 and 1994 were reviewed. Of a total of 238 patients, 78 patients were 70 years of age or older and 160 patients were younger than 70 years of age. RESULTS: The mean age of the younger group was 58 years and that of the elderly group was 74 years. There were no statistical differences in the presence of coronary artery disease, left ventricular systolic function, the inducibility of arrhythmias, or the history of sudden cardiac death. The hospital morbidity rate was similar in both groups (6.9% in the younger group and 7.7% in the elderly group; p = not significant). The operative mortality rate was 1.9% for the younger group and 1.3% for the elderly group (p = not significant). At a mean follow-up of 33 +/- 26 months, Kaplan-Meier survival curves demonstrated similar survival rates, with 93%, 82%, and 65% of the patients alive at 1, 3, and 6 years, respectively. CONCLUSIONS: Implantable cardioverter-defibrillator implantation was equally effective in the treatment of patients older than 70 years as in younger patients. No differences in theoretic survival or morbidity were observed.

Late results with concomitant coronary artery bypass grafting and ICD implantation.

BACKGROUND: To determine the influence of left ventricular function on the long-term survival of patients with coronary artery disease and lethal ventricular arrhythmias, who undergo concomitant coronary artery bypass grafting (CABG) and implantable cardiovertor defibrillator (ICD) implantation, we studied survival in 54 consecutive patients who underwent CABG and ICD implantation. METHODS: Group I consisted of 35 patients with left ventricular ejection fraction (LVEF) < or = 35% (mean 25.3 +/- 5.6) and Group II consisted of 19 patients with LVEF > 35% (mean 47.5 +/- 6.6). The two groups were similar with regards to age, gender, clinical presentation, induced arrhythmias, and the number of grafts placed at the time of surgery. RESULTS: Two in-hospital deaths (3.7%) occurred, both in Group I. During follow-up (42.5 +/- 21.8 months), there were 10 deaths in Group I (1 noncardiac, 1 sudden, and 8 heart failure), and 1 death in Group II (heart failure) (p < 0.04). CONCLUSIONS: Concomitant CABG and ICD implantation can be performed with an acceptable in-hospital mortality, even in patients with poor left ventricular function. Although freedom from sudden cardiac death remains excellent, overall long-term survival is limited by refractory heart failure, especially in those patients with left ventricular dysfunction at the time of surgery.

A highly immunogenic putative Mycobacterium kansasii lipoprotein.

The resurgence of tuberculosis, the emergence of multiple drug resistant tuberculosis, and the increasing prevalence of mycobacterial disease in AIDS patients have increased the importance of defining new mycobacterial antigens that can be utilized in the development of improved diagnostic reagents and more effective vaccines. In this report, a highly immunogenic Mycobacterium kansasii protein (MK35) and the gene encoding this antigen were characterized. MK35 gene probes reacted with genomic DNA from M. avium, M. bovis BCG, M. intracellulare and M. tuberculosis but not with DNA isolated from nine other mycobacterial species. Nucleotide sequence analysis showed that the MK35 gene encodes a 26 kDa protein which contains a consensus bacterial lipoprotein processing sequence. In addition, detergent-phase separation studies strongly suggested that MK35 is a lipoprotein. Skin test assays demonstrated that MK35 elicited a strong response in guinea pigs sensitized with M. kansasii but did not react in M. tuberculosis-sensitized guinea pigs. These results further suggest that mycobacterial lipoproteins are immunogenic antigens that should be considered in the development of new mycobacterial vaccines and diagnostic reagents.

A comparison of the T cell delayed-type hypersensitivity epitopes of the 19-kD antigens from Mycobacterium tuberculosis and Myco. intracellulare using overlapping synthetic peptides.

Mycobacterial disease remains a serious international public health concern. Improved methods to rapidly and specifically detect mycobacterial infections would greatly enhance clinical management of these diseases. To define species-specific T cell epitopes that may be useful for the immunodiagnosis of mycobacterial infections, polymerized synthetic peptides from the 19-kD Mycobacterium tuberculosis and Myco. intracellulare protein homologues were tested in guinea pig DTH assays. Five Myco. tuberculosis and eight Myco. intracellulare peptides evoked skin test responses. Although all of the active Myco. tuberculosis and seven of the Myco. intracellulare peptides elicited non-specific DTH reactions, the peptide IN13 induced a Myco. intracellulare-specific skin test reaction, and thus represents a specific Myco. intracellulare T cell DTH epitope. This result suggests that the development of monospecific peptide-based immunodiagnostic reagents may be feasible for future clinical use.

Observations of angina and myocardial infarction in constrictive pericarditis.

The common symptoms of constrictive pericarditis, i.e. dyspnea on exertion, shortness of breath and cough, relate to impairment of ventricular filling and to a progressive rise in systemic and pulmonary venous pressures. Myocardial ischemia, angina and myocardial infarction are rarely associated with this disease. We have encountered two patients with constrictive pericarditis, one presenting with angina and the other with acute anterior wall infarction. Possible etiologies of constrictive pericarditis in the first case include cardiac surgery, chronic renal failure and myocarditis; in the second case, Crohn's disease. The proposed mechanism of chest pain in the first patient was a reduced cardiac output resulting in underperfusion of the coronary arteries, although it is possible that the patient experienced angina due to the presence of severe coronary artery disease. In the second patient an anterior wall infarction and post-infarction angina were attributed to obliteration of the left anterior descending artery by constraint of a thickened pericardium. In both cases non-invasive imaging modalities were not of use in establishing the diagnosis of constrictive pericarditis. Clinical awareness and accurate hemodynamic measurements continue to play a key role in the diagnostic process.

Skin testing with recombinant Mycobacterium intracellulare antigens.

The immunoreactivity of four recombinant Mycobacterium intracellulare beta-galactosidase fusion proteins, which correspond to 22, 40, 43 and 85 kDa M. intracellulare antigens, was assessed. Lymphoproliferative assays demonstrated that Escherichia coli lysates containing each of the fusion proteins stimulated T cells in vitro. Purified preparations of three of these recombinant M. intracellulare antigens (22, 43 and 85 kDa) also induced delayed-type hypersensitivity (DTH) reactions in sensitized guinea pigs. However, the skin test responses evoked by each of these antigens was not species-specific. Given these results, the potential utility as skin test reagents of the purified antigens or peptides derived from these proteins is discussed.

Anomalous septal perforator artery: a source for supportive circulation in severe coronary artery disease--case reports.

Anomalous origin of a septal perforator artery is an infrequent angiographic finding. However, its recognition is important in patients with coronary artery disease in order to avoid misdiagnosis and consequent management mistake. In 2 patients, coronary arteriography demonstrated an anomalous septal perforator artery supplying significant blood flow to a myocardial region previously perfused by a severely obstructed major coronary vessel. It appears that an anomalous septal artery can serve as an important source for supportive circulation in severe coronary artery disease.

The Vineberg procedure revisited: angiographic evaluation and coronary artery bypass surgery in a patient 21 years following bilateral internal mammary artery implantation.

A patient receiving bilateral internal mammary implantation (Vineberg's operation) in 1969 was symptom free for a period of 21 years. In 1990 he developed acute myocardial infarction followed by post-infarction angina. Cardiac catheterization revealed severe left main and three vessel disease and patency of both mammary implants which filled the left anterior descending and circumflex coronary arteries via collaterals. Coronary artery bypass surgery was indicated due to the native coronary artery disease and inability of the internal mammary grafts' blood flow to alleviate symptoms. The patient underwent direct coronary artery bypass grafting utilizing femoral vessels for cannulation and saphenous veins for grafting, while preserving the mammary implants. This unique case attests to the longevity of the internal mammary artery grafts. These grafts, even if directly implanted, can serve as a crucial source of blood to an otherwise severely underperfused myocardium. Strategy and technical aspects of surgical redo in patients who underwent Vineberg's operation are discussed.

Immunological characterization of recombinant antigens isolated from a Mycobacterium avium lambda gt11 expression library by using monoclonal antibody probes.

Nontuberculous mycobacteria, particularly Mycobacterium avium, have been isolated from a significant percentage of patients with AIDS. Early detection of M. avium infection is difficult, and treatment regimens are often ineffective. Much needs to be learned about antigens and factors responsible for immunity to and pathogenesis of the disease. Specific antigens and diagnostic procedures for infection need to be developed. To address some of these problems, we have generated 25 different monoclonal antibodies against a serovar 4 strain of M. avium isolated from a patient with AIDS. Protease sensitivity studies have demonstrated that each of these antibodies recognizes a protein-associated epitope. Immunoblot analyses suggest that seven of these monoclonal antibodies react specifically with M. avium and M. intracellular epitopes. Immunoreactive bacteriophages were identified from an M. avium lambda gt11 expression library with two of these monoclonal antibodies (3808 C3 and 3954 B12). Lambda lysogens, generated from the immunoreactive bacteriophages, overproduced beta-galactosidase fusion proteins which were reactive with the two monoclonal antibodies in immunoblot assays. The purified fusion proteins were shown to elicit skin test reactions in sensitized guinea pigs.

Calcium-induced sensitization of the central helix of calmodulin to proteolysis.

The rate of proteolysis of trypsin-sensitive bonds was used to examine the nature of the structural changes accompanying Ca2+ and Mg2+ binding to calmodulin. In the Ca(2+)-free form, the rates of proteolysis at Arg-106 and Arg-37 are rapid (greater than 300 and 28 nmol min-1 mL-1, respectively), the bonds at Arg-74, Lys-75, and Lys-77, in the central helix, are cleaved more slowly (10 nmol min-1 mL-1), and a lag in the cleavage at the remaining bonds (Lys-13, Lys-30, Arg-86, Arg-90, and Arg-126) suggests that they are not cleaved in the native protein. High concentrations of Ca2+, but not Mg2+, almost completely abolish proteolysis at Arg-106 and drastically reduce the rate of cleavage at Arg-37. Both Ca2+ and Mg2+ exert a moderate protective effect on the proteolysis of the central helix. These results suggest that the F-helix of domains III and, to a lesser extent, the F-helix of domain I are somewhat flexible in the Ca(2+)-free form and are stabilized by Ca2+. Whereas full occupancy of the four Ca(2+)-binding sites produces little change in the susceptibility of the central helix to proteolytic attack, binding of two Ca2+ produces a 10-fold enhancement of the rate of proteolysis in this part of the molecule. We propose that at intermediate Ca2+ levels the flexibility of the central helix of calmodulin is greatly increased, resulting in the transient formation of intermediates which have not been detected by spectroscopic techniques but are trapped by the irreversible action of trypsin.

Hyperadrenergic orthostatic intolerance as a result of postpartum blood loss.

This article describes a young women in whom orthostatic intolerance developed as a result of protracted postpartum vaginal bleeding. The cardiovascular abnormalities were unresponsive to usual treatment measures, and she required combination therapy directed at increasing plasma volume and decreasing sympathetic nervous system activity. After resolution of her symptoms, the patient required no long-term therapy. Chronic blood loss has not been reported as a cause of this syndrome.