Molecular pharmacology of the sodium channel mutation D1790G linked to the long-QT syndrome.

BACKGROUND: Multiple mutations of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, are linked to 1 form of the congenital long-QT syndrome (LQT-3). D1790G (DG), an LQT-3 mutation of the C-terminal region of the Na(+) channel alpha-subunit, alters steady-state inactivation of expressed channels but does not promote sustained Na(+) channel activity. Recently, flecainide, but not lidocaine, has been found to correct the disease phenotype, delayed ventricular repolarization, in DG carriers. METHODS AND RESULTS: To understand the molecular basis of this difference, we studied both drugs using wild-type (WT) and mutant Na(+) channels expressed in HEK 293 cells. The DG mutation conferred a higher sensitivity to lidocaine (EC(50), WT=894 and DG=205 micromol/L) but not flecainide tonic block in a concentration range that is not clinically relevant. In contrast, in a concentration range that is therapeutically relevant, DG channels are blocked selectively by flecainide (EC(50), WT=11.0 and DG=1.7 micromol/L), but not lidocaine (EC(50), WT=318.0 and DG=176 micromol/L) during repetitive stimulation. CONCLUSIONS: These results (1) demonstrate that the DG mutation confers a unique pharmacological response on expressed channels; (2) suggest that flecainide use-dependent block of DG channels underlies its therapeutic effects in carriers of this gene mutation; and (3) suggest a role of the Na(+) channel alpha-subunit C-terminus in the flecainide/channel interaction.

Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na(+) channel alpha-subunit: A computational analysis.

BACKGROUND: D1790G, a mutation of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, is linked to 1 form of the congenital long-QT syndrome (LQT-3). In contrast to other LQT-3-linked SCN5A mutations, D1790G does not promote sustained Na(+) channel activity but instead alters the kinetics and voltage-dependence of the inactivated state. METHODS AND RESULTS: We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na(+) channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na(+) channel activity prolong APs in a steeply heart rate-dependent manner not directly due to changes in Na(+) entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents. CONCLUSIONS: We conclude that the D1790G mutation of the Na(+) channel alpha-subunit can prolong the cardiac ventricular AP despite the absence of mutation-induced sustained Na(+) channel current. This prolongation is calcium-dependent, is enhanced at slow heart rates, and at sufficiently slow heart rate triggers arrhythmogenic early afterdepolarizations.

Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome?

BACKGROUND: Mutations in the cardiac sodium channel gene (SCN5A) can cause one variant of the congenital long-QT syndrome. The effects of some of these mutations on the alpha-subunit channel properties can be blocked by type Ib antiarrhythmic drugs. Recently, we have described a new SCN5A mutation (D1790G) that affects the channel properties in a manner suggesting that sodium blockers of the Ib type will be ineffective in carriers of this mutation. Hence, the ECG effects of flecainide-acetate, a type Ic sodium blocker, were evaluated in carriers of this mutation. METHODS AND RESULTS: Eight asymptomatic mutation carriers and 5 control subjects were studied. Intravenous lidocaine was tested first in only 2 mutation carriers and had no significant effect on any ECG parameter. Flecainide significantly shortened all heart rate-corrected repolarization duration parameters only in carriers and not in control subjects: QT(c) shortened by 9.5% (from 517+/-45 to 468+/-36 ms, P=0.011), and the S-offset to T-onset interval shortened by 64.7% (from 187+/-88 to 66+/-50 ms, P=0.0092). Flecainide also normalized the marked baseline repolarization dispersion in most mutation carriers. These effects among carriers were maintained during long-term (9 to 17 months) outpatient flecainide therapy with no adverse effects. CONCLUSIONS: This report is the first to describe SCN5A mutation carriers who significantly responded to flecainide therapy yet did not respond to lidocaine. These results have important implications for long-QT allele-specific therapeutic strategies.

Clinical implications for affected parents and siblings of probands with long-QT syndrome.

BACKGROUND: Whenever a proband is identified with long-QT syndrome (LQTS), his or her parents and siblings should be evaluated regarding the possibility of carrying the disorder. In the majority of cases, one of the proband's parents and one or more siblings are affected. The aim of this study was (1) to determine whether the clinical severity of LQTS in the proband is useful in identifying first-degree family members at high risk for cardiac events, and (2) to evaluate the clinical course of affected parents and siblings of LQTS probands. METHODS AND RESULTS: The clinical and ECG characteristics of 211 LQTS probands and 791 first-degree relatives (422 parents and 369 siblings) were studied to determine if the clinical profile of the proband is useful in determining the clinical severity of LQTS in affected parents and siblings. Affected female parents of an LQTS proband had a greater cumulative risk for a first cardiac event than affected male parents. The probability of a parent or sibling having a first cardiac event was not significantly influenced by the severity of the proband's clinical symptoms. Female sex and QT(c) duration were risk factors for cardiac events among affected parents, and QT(c) was the only risk factor for cardiac events in affected siblings. CONCLUSIONS: The severity profile of LQTS in a proband was not found to be useful in identifying the clinical severity of LQTS in affected first-degree relatives of the proband.

Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome.

BACKGROUND: beta-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of beta-blockers in this disorder have not been evaluated. METHODS AND RESULTS: The study population comprised 869 LQTS patients treated with beta-blockers. Effectiveness of beta-blockers was analyzed during matched periods before and after starting beta-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed beta-blockers. After initiation of beta-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97+/-1.42 to 0.31+/-0.86 events per year) and in affected family members (0. 26+/-0.84 to 0.15+/-0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before beta-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during beta-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed beta-blockers. Patients with a history of aborted cardiac arrest before starting beta-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed beta-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on beta-blockers. CONCLUSIONS: beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers, particularly in those who were symptomatic before starting this therapy.

Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes.

BACKGROUND: Congenital long-QT syndrome (LQTS) is caused by mutations of genes encoding the slow component of the delayed rectifier current (LQT1, LQT5), the rapid component of the delayed rectifier current (LQT2, LQT6), or the Na(+) current (LQT3), resulting in ST-T-wave abnormalities on the ECG. This study evaluated the spectrum of ST-T-wave patterns and repolarization parameters by genotype and determined whether genotype could be identified by ECG. METHODS AND RESULTS: ECGs of 284 gene carriers were studied to determine ST-T-wave patterns, and repolarization parameters were quantified. Genotypes were identified by individual ECG versus family-grouped ECG analysis in separate studies using ECGs of 146 gene carriers from 29 families and 233 members of 127 families undergoing molecular genotyping, respectively. Ten typical ST-T patterns (4 LQT1, 4 LQT2, and 2 LQT3) were present in 88% of LQT1 and LQT2 carriers and in 65% of LQT3 carriers. Repolarization parameters also differed by genotype. A combination of quantified repolarization parameters identified genotype with sensitivity/specificity of 85%/70% for LQT1, 83%/94% for LQT2, and 47%/63% for LQT3. Typical patterns in family-grouped ECGs best identified the genotype, being correct in 56 of 56 (21 LQT1, 33 LQT2, and 2 LQT3) families with mutation results. CONCLUSIONS: Typical ST-T-wave patterns are present in the majority of genotyped LQTS patients and can be used to identify LQT1, LQT2, and possibly LQT3 genotypes. Family-grouped ECG analysis improves genotype identification accuracy. This approach can simplify genetic screening by targeting the gene for initial study. The multiple ST-T patterns in each genotype raise questions regarding the pathophysiology and regulation of repolarization in LQTS.

Prognostic significance of nonfatal myocardial reinfarction. Multicenter Diltiazem Postinfarction Trial Research Group.

In most risk stratification and intervention postinfarction trials, cardiac mortality is used as the major outcome end point either alone or in combination with nonfatal reinfarction. However, the independent risk carried by nonfatal reinfarction for subsequent cardiac death has not been quantified. The prognostic significance of nonfatal reinfarction was determined from the multicenter diltiazem trial data base of 1,234 patients treated with placebo followed up for 1 to 4 years after acute myocardial infarction. One hundred sixteen patients had at least one nonfatal reinfarction, 14 (12%) of whom subsequently experienced cardiac death. Of the remaining 1,118 patients without nonfatal reinfarction, 110 (9.8%) experienced cardiac death. Compared with event-free patients, patients with nonfatal reinfarction were more likely (p less than 0.05) to be women, to have had an infarction before their index event and to have had prior cardiac-related symptoms. Cox survivorship analyses, using pertinent baseline clinical variables along with nonfatal reinfarction as a time-dependent predictor variable, revealed that nonfatal reinfarction carried a significant and independent risk for subsequent cardiac mortality (hazard ratio 3.0, p = 0.002), which was greater than that carried by other significant predictor variables (New York Heart Association functional class, pulmonary congestion on chest radiograph, blood urea nitrogen level, predischarge Holter-recorded ventricular premature complexes and radionuclide ejection fraction). The cardiac mortality risk associated with nonfatal reinfarction was further increased in patients whose index event was their first infarction (hazard ratio 5.4, p = 0.0006). Thus, nonfatal reinfarction carries a strong, significant and independent risk for subsequent cardiac death in patients surviving an acute myocardial infarction.

Ischemic threshold during two exercise testing protocols and during ambulatory electrocardiographic monitoring.

OBJECTIVES: The aim of this study was to examine the dependence of the ischemic threshold during exercise testing on the exercise protocol employed and to determine the relation between the ischemic thresholds observed during exercise and during daily activity. BACKGROUND: The ischemic threshold (heart rate at 1-mm ST segment depression) during daily activity has been reported to be lower than that observed during exercise testing. Recent reports have hypothesized that this difference is probably dependent on the exercise protocol employed. METHODS: Twenty-two patients with known coronary artery disease, not receiving antianginal medications, were evaluated by repeated exercise testing according to the Bruce and the modified Davidson protocols and by 48-h ambulatory electrocardiographic monitoring. RESULTS: Although the heart rate at 1-mm ST segment depression was somewhat lower with the Davidson than with the Bruce protocol (112 +/- 14 vs. 115 +/- 14 beats/min), the rate-pressure product at 1-mm ST segment depression was similar during the two protocols (16,900 +/- 4,000 vs. 17,700 +/- 3,600). The mean heart rate (100 + 12 beats/min) at 1-mm ST segment depression during ambulatory ischemic episodes (n = 137) was significantly lower than that observed during both exercise protocols (p < 0.001 for both comparisons). CONCLUSIONS: Exercise-induced ischemia occurs at a relatively fixed threshold that is mainly dependent on myocardial oxygen demand and is independent of the exercise protocol employed. Ischemia on ambulatory monitoring, however, occurs at a much more variable threshold that is commonly lower than that observed during exercise and is therefore dependent on other factors in addition to increased demand.

The prognostic significance of first myocardial infarction type (Q wave versus non-Q wave) and Q wave location. The Multicenter Diltiazem Post-Infarction Research Group.

The prognostic significance of the type of first acute myocardial infarction (Q wave versus non-Q wave) and Q wave location (anterior versus inferoposterior) was determined from a multicenter data base involving 777 placebo-treated patients who were participants in the Multicenter Diltiazem Post-Infarction Trial. There were 224 patients (29%) with a non-Q wave infarction, 326 (42%) with an inferoposterior Q wave infarction and 227 (29%) with an anterior Q wave infarction. Mean left ventricular ejection fraction was significantly (p less than 0.001) lower in patients with an anterior Q wave infarction than in the other two groups (anterior Q wave 0.39; inferior Q wave 0.52; non-Q wave 0.53). Nevertheless, the total cardiac mortality rate during the follow-up period (average 25 months per patient) was only marginally higher (p = 0.42) in the anterior Q wave group (8.4%) than in the other two groups (inferoposterior Q wave 7.1%; non-Q wave 6.3%). The total first recurrent cardiac event was somewhat higher (p = 0.08) in the anterior Q wave group (18.1%) than in the other two groups (inferoposterior Q wave 11.7%; non-Q wave 15.6%). Survivorship analyses extending over 3 years revealed that electrocardiographic classification of the type of first infarction and Q wave location did not make significant independent contributions to the risk of postinfarction cardiac death or first recurrent cardiac event, either before or after adjustment for baseline clinical variables.

Limited usefulness of exercise testing and thallium scintigraphy in evaluation of ambulatory patients several months after recovery from an acute coronary event: implications for management of stable coronary heart disease. Multicenter Myocardial Ischemia Research Group.

OBJECTIVES: This study evaluated the value of noninvasive testing to predict cardiac events in patients with stable coronary disease after hospital admission (and risk stratification) for an acute coronary event. BACKGROUND: Exercise testing with thallium perfusion imaging identifies patients with obstructive coronary artery disease and has been used to stratify patients after myocardial infarction. Its usefulness for predicting cardiac events in patients with stable coronary disease after recovery from an acute coronary event was explored. METHODS: Nine hundred thirty-six patients were enrolled 1 to 6 months after hospital admission for a coronary event. Patients underwent exercise treadmill testing with planar thallium-201 scintigraphy and were followed up for an average of 23 months (range 6 to 43). End points were 1) unstable angina requiring hospital admission, nonfatal myocardial infarction or cardiac death; 2) nonfatal infarction or cardiac death; or 3) cardiac death alone. RESULTS: Twelve patients died of cardiac causes (1.2%); 32 had a nonfatal myocardial infarction (3.4%); and 79 patients (8.4%) developed unstable angina in the first year. Exercise testing improved proportional hazards models constructed from clinical variables for all three end points (p < 0.05). The perfusion scan further improved models for the end points (nonfatal infarction or cardiac death and cardiac death alone, p < 0.05). However, the exercise test with or without thallium added little to the overall prediction of primary events (area under the receiver operating curve increased from 0.649 to 0.663), and only 2% to 13% of patients with abnormal results either had a nonfatal infarction or died. CONCLUSIONS: Thallium-201 scintigraphy and exercise testing variables identify patients at risk for subsequent cardiac events. However, the poor predictive performance of these tests in this group of patients with stable coronary disease severely limits their usefulness. These results suggest a limited role for exercise and thallium testing in predicting cardiac events in patients with known coronary disease.

Holter recording during treadmill testing in assessing myocardial ischemic changes.

One hundred forty-four patients underwent a Bruce protocol treadmill exercise test during which an electrocardiogram (ECG) was recorded simultaneously with a 2-channel Holter recorder with bipolar V3- and V5-like leads and by a conventional 12-lead system. Sixty-eight patients had no ST depression on either the Holter or on the 12-lead ECG during the exercise test, whereas in 70 patients ischemic changes were recorded by both methods; thus, in 138 of the 144 patients (96%), the results of the 2 tests were concordant. The severity of ST depression, as judged by the heart rate at which ischemic changes were first noted and the maximal ST depression observed, were similar on both recording systems. The Holter system identified 6 of the 7 patients whose ischemic changes were confined to the inferior wall on the 12-lead ECG. The addition of the V3 lead as a second ischemic lead increased the ischemia detection by 10%. Ninety-five patients also underwent coronary arteriography. In these patients the sensitivity of the Holter system during exercise in detecting significant coronary artery disease was 81% and that of 12-lead ECG was 84%, the specificity was 85% and 85%, respectively, and the positive predictive value 91% and 91%, respectively. Thus, the 2-channel Holter recording system with bipolar V3- and V5-like leads was as accurate as the 12-lead system in detecting ischemic changes during exercise and proved that ambulatory monitoring system can reliably reproduce ST segment.

Occurrence, characteristics and prognostic significance of early postacute myocardial infarction angina pectoris.

To determine the incidence, clinical characteristics and prognostic significance of early spontaneous angina after acute myocardial infarction (AMI), the database involving the 867 participants of the Multicenter Post-AMI Program, who were followed for 1 to 4 years after AMI, was analyzed. Two hundred eighty-six patients (33%) had in-hospital postinfarction angina. During a mean follow-up of 31 months, patients with postinfarction angina were more frequently (p less than 0.001) hospitalized for cardiac causes and underwent coronary artery bypass graft surgery; however, their cardiac mortality rates at 1 year (8.4%) and at 4 years (14.3%) were not significantly different from those among patients without postinfarction angina (7.1 and 12.9%, respectively). The only anginal characteristic found to be associated with increased subsequent cardiac mortality (17.9% at 1 year, 39.2% at total follow-up) was high frequency angina (greater than or equal to 1 daily episodes). High frequency angina occurred in a small subset of 28 patients (3.2% of the study population, 9.8% of patients with postinfarction angina). Clinical variables representing higher grades of mechanical dysfunction and electrical instability after infarction were significantly more common among patients with high frequency angina than among those with low frequency angina. Cox survivorship analysis revealed that high frequency angina made a significant contribution to the risk of post-AMI cardiac death (hazard ratio 2.5, p = 0.01), which was independent of the effect of predischarge reduced radionuclide ejection fraction and Holter-recorded frequent or repetitive ventricular premature complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial ischemia during daily activities and stress.

Twenty-four-hour, 2-channel Holter monitoring during daily activities was performed in 210 patients; during the same day a Bruce protocol treadmill test was also performed and the electrocardiogram was recorded using the same Holter system. Significant ST-segment depression was observed during daily activities in 97 patients, while similar changes were recorded during the treadmill test in 122 patients. Thus, 77% of patients with ST depression during the provocation of the treadmill test had ischemic episodes during their everyday life. On the other hand, 3 patients with proven significant coronary artery disease had spontaneous ischemic episodes during daily activities, but had a negative stress test. The ischemic changes during daily activity developed at a lower heart rate than during stress testing (94 beats/min vs 109 beats/min, respectively, p less than 0.05). A total of 351 ischemic episodes were recorded during daily activities, 241 (69%) of these were asymptomatic. In 46 patients all episodes were asymptomatic, in 15 all were symptomatic, while in 36 both symptomatic and silent episodes were detected. The mean duration of the symptomatic episodes was 13.7 minutes and that of the asymptomatic ones was 14.9 minutes (difference not significant). The degree of ST depression in these 2 groups was also similar. Because of more advanced symptomatology in 143 patients, coronary arteriography was performed; 43 had normal and 100 had pathologic coronary arteries. In this selected group, the sensitivity of Holter monitoring during daily activity was 87% and during stress 97%; the specificity during daily activity was 95% and during stress 88%.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of right atrial pacing soon after myocardial infarction with treadmill testing 6 months later.

Seventy-four patients recovering from acute myocardial infarction underwent right atrial pacing before hospital discharge, and treadmill exercise testing 6 months later. The early right atrial pacing test was positive in 32 patients (43 percent) and the late treadmill test was positive in 32 patients (42 percent). The results of the two tests were concordant in 77 percent of the patients, 23 with an ischemic response and 34 with a normal response on both tests. In nine patients a positive right atrial pacing test was followed by a negative treadmill test, and in eight patients a negative pacing test was followed by a positive treadmill test. A positive right atrial pacing test at hospital discharge had an 81.0 percent predictive accuracy for a positive late treadmill test; chest pain, congestive heart failure or increased cardiothoracic ratio at discharge had a predictive value of only 52.9, 42.8 and 42.8 percent, respectively. Both the early right atrial pacing test and the late treadmill test were positive in a significantly higher proportion of patients with inferior or subendocardial infarction than of patients with anterior myocardial infarction. During early right atrial pacing the mean maximal heart rate achieved was higher than that during late treadmill testing (148 versus 133 beats/min) and the mean systolic blood pressure was lower (137 versus 162 mm Hg), but the pressure-rate product was similar on the two tests (20,282 versus 21,455 mm Hg/min). This finding may explain the similar frequency of ischemic responses to the two tests. These results indicate that the response to right atrial pacing soon after myocardial infarction is a good predictor for the presence or absence of an ischemic response to treadmill testing 6 months later. Thus, early right atrial pacing at the time of hospital discharge may be used to determine the pace of rehabilitation and short-term prognosis.

Usefulness of severity of myocardial ischemia on exercise testing in predicting the severity of myocardial ischemia during daily activities.

To determine the relation between myocardial ischemic indexes on exercise testing and on ambulatory Holter recording, 60 patients with stable coronary artery disease who exhibited an ischemic response to both testing procedures were studied. All patients performed a Bruce protocol exercise test and underwent 24-hour Holter recording within 2 weeks without antianginal medications. Mean exercise duration was 7.4 +/- 2.8 minutes, mean heart rate at 1-mm ST depression was 118 +/- 20 beats/min and mean maximal ST depression during exercise was 2.2 +/- 1 mm. During Holter recording the average number of ischemic episodes was 4.7 +/- 2.6 per patient, mean duration of daily ischemia was 62 +/- 54 minutes, mean maximal ST depression was 3.2 +/- 1.3 mm and average heart rate at 1-mm ST depression was 93 +/- 17 beats/min. Overall, the correlations between ischemic indexes on both testing procedures were very weak (mean r2 = 0.054). The only exercise variable that had a significant correlation (p less than 0.05) with all Holter variables was heart rate at 1-mm ST depression, yet it correlated very weakly (0.064 less than or equal to r2 less than or equal to 0.125) with most Holter covariates and had a better correlation (r2 = 0.256) only with average heart rate at 1-mm ST depression during Holter. Thus, ischemic indexes on exercise testing cannot accurately predict ischemic indexes on ambulatory Holter recording in patients with stable coronary artery disease who exhibit ischemic changes on both tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Characteristics of silent and symptomatic myocardial ischemia during daily activities.

In 191 patients with proven coronary artery disease, 24-hour Holter monitoring detected 587 transient episodes of ST depression during daily activities. Of that total, 424 episodes were silent (72.3%) and 163 were symptomatic (27.7%). There were no statistically significant differences between silent and symptomatic episodes as to their mean duration (15.1 vs 14.3 minutes, respectively), heart rate at onset of ST depression (93 vs 96 beats/min, respectively), heart rate at the time of maximal ST depression (114 beats/min, both) and mean maximal ST depression (1.9 vs 2.0 mm, respectively). Of the 191 patients, 104 (55%) had only silent episodes, 33 (17%) only symptomatic episodes and 54 (28%) had both types ("mixed"). All patients, regardless of episode type, were of similar age, received comparable medical therapy, had a similar extent of angiographically documented coronary artery disease and similar episode characteristics. However, mixed-episode patients had significantly more ischemic episodes per day (4.8) than silent-episode (2.6) and symptomatic-episode (1.9) patients (p less than 0.001 for both) and a longer total period of daily ischemia (60 minutes), than the other 2 groups (36 and 28 minutes, respectively, p less than 0.001 for both). Of the 191 patients, 97 (51%) had had a previous myocardial infarction. The characteristics of their silent and symptomatic episodes were similar to the 94 (49%) patients without infarction, except for a longer duration of the silent episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Day-to-day variability of myocardial ischemic episodes in coronary artery disease.

Twenty patients with chronic stable angina pectoris, proved coronary artery disease, positive treadmill stress test response, and at least 2 episodes of ischemia per day underwent 72 hours of Holter monitoring during daily activities. During this period they had 389 ischemic episodes: 104 (27%) symptomatic and 285 (73%) silent. Marked variability was observed between patients in the number of ischemic episodes (range 2 to 15 per day, mean 6.5), duration of ischemia (range 6 to 419 minutes/day, mean 76.5), maximal ST depression (range 1 to 6 mm, mean 3.4) and heart rate at the beginning of ST depression (range 75 to 105 beat/min, mean 91). The day-to-day variability in individual patients between the different days in the number of ischemic episodes was 36%, in duration 51%, and in maximal degree of ST depression 31%. Only 9% variability was noted in heart rate at the beginning of ST depression. Similar day-to-day variability in individual patients was noted in the symptomatic and silent episodes. For clinical purposes of evaluation of ischemia during daily activities, 1 day of monitoring appears to be sufficient because within the first day, 78% of the maximal number of ischemic episodes, 64% of their duration, and 84% of the maximal degree of ST depression were detected. However, for evaluation of anti-ischemic drugs at least 2 monitoring days are required.

Reciprocal electrocardiographic changes in acute myocardial infarction.

If reciprocal electrocardiographic changes during acute myocardial infarction (AMI) are a result of ischemia of the wall opposite the AMI, a stress test is expected to induce similar changes in the corresponding electrocardiographic leads. Right atrial pacing was used as a myocardial stress method in 137 consecutive patients recovering from a transmural AMI, and the appearance of pacing-provoked ischemia before hospital discharge was correlated to the presence of absence of ST depression in the opposite wall during the initial 48 hours. Of the 137 patients, 83 (61%) had reciprocal changes; they were more common in inferior (87%) than in anterior (37%) AMI (p less than 0.01). Of 54 patients without reciprocal changes, only 5 (9%) had ST depression during predischarge pacing; however, of the 83 patients with reciprocal changes, 41 had pacing-induced ischemia (p less than 0.01) and 42 did not, indicating that in half of this group the reciprocal changes represent ischemia of the opposite wall. In the other half of the group, without ST depression during pacing, these changes may be a "mirror image" phenomenon. Follow-up showed that angina pectoris, positive treadmill test response 6 months later, or recurrent AMI all consequences of impaired myocardial blood supply, were significantly more frequent in patients with reciprocal changes. This group could be further separated according to the results of right atrial pacing, because angina pectoris or recurrent AMI were infrequent among those with reciprocal changes and negative pacing responses, but was frequent among those with reciprocal changes and positive pacing responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in myocardial ischemic threshold during daily activities.

This study assesses the variations in myocardial ischemic threshold (heart rate at the onset of ischemia) during daily activities in patients with ischemic episodes on Holter monitoring. Eighty patients with known coronary artery disease, positive treadmill stress test results and greater than or equal to 2 ischemic episodes during a 24-hour period of Holter monitoring were studied. The lowest and the highest ischemic thresholds were determined for each patient. The mean lowest ischemic threshold was 85 beats/min, and the mean highest ischemic threshold was 109 beats/min. The highest ischemic threshold was identical to ischemic threshold values noted during exercise. Of the 895 ischemic episodes, 654 (74%) were preceded by a moderate (greater than 10%) increase in heart rate. The variability of ischemic threshold (difference in percentage between the highest and lowest ischemic thresholds) increased with the number of ischemic episodes (range 2 to 60%). However, in different patients with a similar number of ischemic episodes, different variability was observed. These differences in ischemic thresholds are probably indirect indicators of the vasomotor activity of the coronary arteries in different patients.

Early right atrial pacing after myocardial infarction. I. Comparison with early treadmill testing.

Right atrial (RA) pacing and modified treadmill testing (TT) were performed in 111 patients recovering from acute myocardial infarction (MI) before hospital discharge to determine whether ischemic responses are more common with RA pacing than with TT and whether the prognosis could be better determined by the results of 1 test compared with the other. Patients with predischarge congestive heart failure, chest pain, physical disability or age older than 70 years were excluded. Ischemic responses were significantly more frequent during RA pacing than during TT (41% vs 34%, p = 0.02). The results of the 2 tests were concordant in 102 patients (92%): Both were positive in 37 and both negative in 65. In 8 patients, results of RA pacing were positive and results of TT were negative; only 1 patient had positive TT and negative RA pacing responses. The higher percentage of positive responses during RA pacing than during TT can be attributed to the significantly higher pressure-rate product achieved during pacing (18,773 vs 16,831 mm Hg/min, p less than 0.001). The ischemic threshold, defined as the pressure-rate product at which an ischemic change was first noted in a particular patient, was almost identical in both tests. During a mean follow-up period of 16 months, 10 patients had recurrent MI; 8 had positive predischarge RA pacing but only 5 had positive TT responses (p = 0.008). Six patients died; in 3 RA pacing responses were positive and in 2 TT responses were positive.(ABSTRACT TRUNCATED AT 250 WORDS)