Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.

Genetic factors contribute to the risk of sudden death from cardiac arrhythmias. Here, positional cloning methods establish KVLQT1 as the chromosome 11-linked LQT1 gene responsible for the most common inherited cardiac arrhythmia. KVLQT1 is strongly expressed in the heart and encodes a protein with structural features of a voltage-gated potassium channel. KVLQT1 mutations are present in affected members of 16 arrhythmia families, including one intragenic deletion and ten different missense mutations. These data define KVLQT1 as a novel cardiac potassium channel gene and show that mutations in this gene cause susceptibility to ventricular tachyarrhythmias and sudden death.

Locus heterogeneity of autosomal dominant long QT syndrome.

Autosomal dominant long QT syndrome (LQT) is an inherited disorder that causes syncope and sudden death from cardiac arrhythmias. In genetic linkage studies of seven unrelated families we mapped a gene for LQT to the short arm of chromosome 11 (11p15.5), near the Harvey ras-1 gene (H ras-1). To determine if the same locus was responsible for LQT in additional families, we performed linkage studies with DNA markers from this region (H ras-1 and MUC2). Pairwise linkage analyses resulted in logarithm of odds scores of -2.64 and -5.54 for kindreds 1977 and 1756, respectively. To exclude the possibility that rare recombination events might account for these results, we performed multipoint linkage analyses using additional markers from chromosome 11p15.5 (tyrosine hydroxylase and D11S860). Multipoint analyses excluded approximately 25.5 centiMorgans of chromosome 11p15.5 in K1756 and approximately 13 centiMorgans in K1977. These data demonstrate that the LQT gene in these kindreds is not linked to H ras-1 and suggest that mutations in at least two genes can cause LQT. While the identification of locus heterogeneity of LQT will complicate genetic diagnosis, characterization of additional LQT loci will enhance our understanding of this disorder.

Mutation-specific pharmacology of the long QT syndrome.

The congenital long QT syndrome is a rare disease in which inherited mutations of genes coding for ion channel subunits, or channel interacting proteins, delay repolarization of the human ventricle and predispose mutation carriers to the risk of serious or fatal arrhythmias. Though a rare disorder, the long QT syndrome has provided invaluable insight from studies that have bridged clinical and pre-clinical (basic science) medicine. In this brief review, we summarize some of the key clinical and genetic characteristics of this disease and highlight novel findings about ion channel structure, function, and the causal relationship between channel dysfunction and human disease, that have come from investigations of this disorder.

Mechanism of spermidine cytotoxicity at 37 degrees C and 43 degrees C in Chinese hamster ovary cells.

Spermidine (SPD) cytotoxicity is mediated largely through SPD oxidation by serum amine oxidases at both 37 degrees C and 43 degrees C. Alkaline sucrose gradient data suggest random induction of DNA strand breaks. A dose response with time at 37 degrees C or 43 degrees C (constant SPD) or with SPD concentration (constant time at 43 degrees C) was observed in terms of both DNA strand breaks and cell survival. The generation of peroxide was demonstrated in the absence of cells by the addition of SPD to medium containing 10% fetal bovine serum. Toxicity of SPD was reduced in saline, with catalase-thiourea and aminoguanidine, and enhanced by prior depletion of glutathione. Thermotolerance induced 16 h previously did not protect against SPD toxicity, suggesting that the reactive species from spermidine oxidation and heat damage do not produce related subcellular lesions.

Protection against thermal cell death in Chinese hamster ovary cells by glucose, galactose, or mannose.

The addition of D-glucose, D-galactose, or D-mannose to culture medium increased survival of heated Chinese hamster ovary cells in a concentration- and time-dependent manner. Heat protection by sugars was not immediate but required prior incubation in the sugar medium before hyperthermia. The degree of heat protection conferred by each sugar and its time dependence differed characteristically: galactose protection appeared rapidly (within 1 hr) and was proportional to the galactose concentration in the medium up to 0.3 M. Glucose and mannose were less effective heat protectors at 0.3 M concentrations when compared with galactose, but cell survival after 40 min, 45 degrees, at concentrations below 0.1 M was similar in the three hyperosmotic sugar media. Heat protection by 0.3 M glucose under hyperosmotic conditions (600 mOSM) became apparent only after a preincubation period of at least 5 hr, 37 degrees. Under isoosmotic conditions (300 mOSM, 10% medium-10 mM morpholinopropanesulfonic acid-250 mM glucose), heat protection by glucose appeared more rapidly (3 hr), but the time dependence of heat protection was not eliminated. Under the same isoosmotic conditions in galactose medium, the survival of heated cells was not measurable. The 45 degrees survival curve in hyperosmotic galactose medium (6 hr, 37 degrees prior to heating, 0.3 M) was characterized by a DO of 10 min (controls, 3 min) and a quasithreshold dose of 17 min (controls, 17.5 min). When galactose-loaded cells were returned to fresh medium, heat protection decayed rapidly; cell survival measured 1 or 6 hr later showed a small degree of residual heat protection. A 5-hr incubation period at 37 degrees in galactose-supplemented medium resulted in a major intracellular accumulation of free galactose with smaller accumulations of glucose, sorbitol, and dulcitol. A similar incubation in glucose medium showed only minor intracellular elevations of polyols or sugars. A flow-cytometric analysis of the age distribution showed that incubation in the sugar-supplemented media slightly reduced the fractional cell population in G1 with concomitant gains in both the S- and G2-phase populations. Thus, heat protection by galactose or glucose is probably neither the result of a redistribution of cells in the cycle, nor does it always require the intracellular accumulation of free sugars and polyols. The greater degree of heat protection by galactose and its rapid manifestation under hyperosmotic conditions may be related to the intracellular accumulation of free galactose and/or its metabolites.

Cytotoxicity of hyperthermia combined with bleomycin or cis-platinum in cultured RIF cells: modification by thermotolerance and by polyhydroxy compounds.

The effect of thermotolerance and of polyhydroxy compounds on the cytotoxicity of bleomycin and cis-platinum was studied in cultured RIF tumor cells. Cell survival in response to drug-heat treatments was compared in cells not previously exposed to hyperthermia and in preheated cells that had developed thermotolerance. Since cellular accumulation of polyhydroxy compounds is a potential mechanistic basis of thermotolerance, we also compared cell survival of thermotolerant cells and chemically heat-protected cells. The cytotoxicity of bleomycin and cis-platinum in control cells treated with drug plus heat (43 degrees C, 1 h) was increased synergistically over the cytotoxicity of drug and heat alone. In thermotolerant cells, the synergistic interaction was largely reversed with the bleomycin-heat combination but retained with cis-platinum at 43 degrees C. In the absence of heat, bleomycin and cis-platinum showed similar cytotoxicity in control and thermotolerant cells. The addition of heat protectors (erythritol or galactose) modified the drug-heat cytotoxicity similar to thermotolerance. The synergistic interaction of bleomycin-43 degrees C, but not cis-platinum-43 degrees C, was reversed by the polyhydroxy compounds.

Characterization of a cisplatin-resistant subline of murine RIF-1 cells and reversal of drug resistance by hyperthermia.

The development of tumor cell drug resistance is a major obstacle which often leads to failure of cancer chemotherapy. Therefore, reversing the cell drug resistance would have important implications in cancer treatment. We have developed a cisplatin-resistant mouse tumor cell line from the radiation induced fibrosarcoma (RIF-1) parental line; this line is named RIF/ptr1 versus the parental line RIF/pts1. It is shown that the formation of cisplatin-DNA interstrand cross-links is the same for both cell lines although the intracellular cisplatin concentrations of resistant line is significantly lower. The cytosolic activities of glutathione reductase, glutathione peroxidase, and DT-diaphorase were the same in two cell lines. However, the concentration of glutathione was significantly higher in the resistant line. The resistant line was shown to be more sensitive to the cytotoxicity of heat (43 degrees C) but the combination of heat and drug had the same tumoricidal effect for both cell lines. The addition of verapamil also had a similar effect on both cell lines. We conclude that the major difference between these two lines was the glutathione-related detoxification of platinum. Regardless of drug resistance, the combination of drug and heat can effectively kill both cell lines. Elevated glutathione in RIF/ptr1 cells may be associated both with enhanced heat sensitivity and drug resistance such that combined treatments with drug and heat were equally effective in killing cells of either line.

Effect of step-down heating on the cytotoxicity of adriamycin, bleomycin, and cis-diamminedichloroplatinum.

The cytotoxicity of a number of anticancer drugs can be potentiated by mild hyperthermia. Since the cytotoxicity of low-hyperthermic temperatures in the range of 39-43 degrees can be potentiated by using a step-down heating (SDH) sequence (short times at greater than or equal to 45 degrees followed by longer times at lower temperatures), we investigated the combined effects of SDH (specifically 45 degrees, 10 min, followed by time at 41.5 degrees) and three chemotherapeutic drugs known to be more toxic at elevated temperatures. In agreement with previous observations with Chinese hamster cells, we found that cultured RIF tumor cells showed an increased rate of cell killing at 41.5 degrees when the low-temperature heat treatment was preceded by an acute heat shock of 10 min, 45 degrees. Similarly, RIF cells showed enhanced cytotoxicity of Adriamycin, bleomycin, and cisplatin at 41.5 degrees over that at 37 degrees, as reported previously for hamster cells. When SDH and drug exposures were combined, the rate of cell killing was greater than that observed with the drugs at a constant 41.5 degrees. SDH alone reduced the Do on the 41.5 degrees survival curve from approximately 500 min to 100 min after 10 min at 45 degrees. Adriamycin cytotoxicity (0.3 microgram/ml) at 41.5 degrees was characterized by a Do of approximately 160 min for treatment times of 1 to 4 hr; with SDH, this was reduced to 52 min. Similarly, bleomycin (5 micrograms/ml) and cisplatin (0.5 microgram/ml) showed a decrease in Do by factors of 1.4 (68 to 48 min) and 2 (25.2 to 13.5 min), respectively, with the SDH sequence when compared with drug toxicity at 41.5 degrees alone. However, the sensitization to cisplatin was the same when 10 min at 45 degrees was followed by drug exposure at 37 degrees, or at 41.5 degrees. The results indicate that Adriamycin and bleomycin, but not cisplatin, cytotoxicity was increased by SDH over that achievable with 41.5 degrees alone. Possible clinical implications are discussed briefly.

Immunochemical quantitation of DNA adducts derived from the human bladder carcinogen 4-aminobiphenyl.

To assess target-tissue exposure to the human urinary bladder carcinogen 4-aminobiphenyl (ABP), we have developed a sensitive immunochemical method for measuring the major arylamine-DNA adduct formed, N-(guan-8-yl)-ABP (Gua-C8-ABP). High-affinity polyclonal antisera from rabbits immunized with N-(guanosin-8-yl)-ABP coupled to keyhole limpet hemocyanin were characterized and shown to have high specificity for antigenic determinants on the purine and biphenyl rings of Gua-C8-ABP and minimal cross-reactivity with ABP, deoxyguanosine, or hydrolyzed DNA. Assay standards containing ABP-modified DNA were prepared by reacting [3H]N-hydroxy-ABP with calf thymus DNA. DNA samples were hydrolyzed with trifluoroacetic acid and dried under vacuum, and the residues were dissolved in dimethyl sulfoxide under argon. Using a streptavidin-biotin amplified enzyme-linked immunosorbent assay, DNA hydrolysates competed at 25 micrograms DNA/microtiter well for a limiting amount of anti-keyhole limpet hemocyanin-(Gua-C8-ABP) in the presence of excess solid-phase bovine serum albumin-(Gua-C8-ABP) coating antigen. The limit of sensitivity for this assay using 25 micrograms DNA was 2 adducts/10(8) nucleotides. Gua-C8-ABP adducts in liver and bladder epithelial DNAs were readily quantified after p.o. administration of 5 mg/kg ABP to dogs. This methodology is capable of detecting adducts at levels of biological significance and should be applicable to human target-tissue dosimetry.

Anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients. Thrombogenic Factors, and Recurrent Coronary Events Investigators.

BACKGROUND: The association of anticardiolipin (aCL) antibodies with coronary artery disease has been shown in several studies but remains controversial. We evaluated the association of aCL and anti-beta(2)-glycoprotein I (abeta(2)GPI) antibodies with the risk of recurrent cardiac events in postinfarction patients. METHODS AND RESULTS: The study population consisted of 1150 patients with acute myocardial infarction. Levels of IgG and IgM aCL and abeta(2)GPI antibodies were determined on sera collected before hospital discharge. There were 131 recurrent cardiac events (nonfatal myocardial infarctions or cardiac deaths) over a mean follow-up period of 24.6 months. Patients with elevated IgG aCL antibodies had a higher event rate than patients with low levels (P:=0.05). Multivariate Cox analysis after adjustment for relevant clinical covariates showed that elevated levels of IgG aCL (hazard ratio=1. 63; P:=0.01) and low levels of IgM aCL (hazard ratio of 1.76; P:=0. 02) antibodies contribute independent risks for recurrent cardiac events. Patients with elevated IgG aCL and low IgM aCL antibody levels had a 3-fold higher risk of recurrent cardiac events than patients with low IgG aCL and elevated IgM aCL antibody levels (P:<0. 001). There was no significant association of the abeta(2)GPI antibodies with recurrent cardiac events. CONCLUSIONS: In postinfarction patients, elevated IgG aCL and low IgM aCL antibodies are independent risk factors for recurrent cardiac events. Patients with both elevated IgG aCL and low IgM aCL antibodies have the highest risk. These findings shed additional light on the mechanistic role of aCL antibodies in coronary artery disease in patients without autoimmune diseases.

Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.

BACKGROUND: Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. METHODS AND RESULTS: We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals). CONCLUSIONS: KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.

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.

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.

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.

Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.

BACKGROUND: The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. METHODS AND RESULTS: We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. CONCLUSIONS: Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

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.

Marked reduction in long-term cardiac deaths with aspirin after a coronary event. Multicenter Myocardial Ischemia Research Group.

OBJECTIVES: We sought to assess the role of aspirin in a precisely defined cohort with coronary disease receiving current therapy. BACKGROUND: Prior results suggest that aspirin modestly decreases cardiac mortality in patients with coronary disease. However, these findings reflect heterogeneous study conditions and earlier management strategies. METHODS: We utilized findings from the Multicenter Study of Myocardial Ischemia, which enrolled 936 subjects 1 to 6 months after an acute myocardial infarction (n = 651 [70%]) or unstable angina (n = 285 [30%]). The follow-up period averaged 23 months, with treatment determined by referring physicians. RESULTS: At enrollment, 751 patients (80%) took aspirin regularly, usually 250 to 325 mg/day. Before enrollment, 291 patients (31%) had thrombolysis, and 352 (38%) had coronary angioplasty. During follow-up, cardiac death occurred in 22 patients, all-cause mortality in 31 and cardiac death or nonfatal myocardial infarction in 70. Each of these outcomes was significantly less frequent among aspirin users. Cardiac death rate was markedly reduced: 1.6% for aspirin users and 5.4% for nonusers (p = 0.005). These differences were not explained by imbalances in predictors of postinfarction risk or therapy other than aspirin (Cox hazard ratio 0.37, p = 0.023). They persisted at least 2 years after enrollment. The difference in mortality rate was particularly prominent after thrombolysis: 0.9% for aspirin users and 8.8% for nonusers (p = 0.004). CONCLUSIONS: Reduction in cardiac deaths among aspirin users is substantially greater than that reported previously. Although derived secondarily, our findings suggest that current practice leads to situations in which aspirin exerts a long-term, life-protecting action, particularly after thrombolysis.

T wave alternans in idiopathic long QT syndrome.

OBJECTIVES: The study evaluates the association between T wave alternans and the risk of cardiac events (syncope, aborted cardiac arrest or cardiac death) in a large population of patients with idiopathic long QT syndrome. BACKGROUND: T wave alternans is an infrequently recorded electrocardiographic (ECG) finding in patients with delayed repolarization, and its clinical significance is not clear. METHODS: A total of 4,656 ECG recordings in 2,442 patients enrolled in the International Long QT Syndrome Registry were reviewed for episodes of T wave alternans. To determine the risk associated with T wave alternans, independent of corrected QT interval (QTc) duration, patients with T wave alternans were matched for QTc value (every 0.025 s1/2) to patients with long QT syndrome without T wave alternans. RESULTS: T wave alternans was identified in 30 patients (25 of whom had a QTc interval > 0.50 s1/2). A strong association between QTc prolongation and T wave alternans was observed (odds ratio 1.23 per 0.01-s1/2 unit increase in QTc, p < 0.0001). Conditional logistic regression analyses with adjustment for age, gender, status and QTc value revealed that T wave alternans did not make a significant independent contribution to the risk of cardiac events. The risk of experiencing a major cardiac event was primarily related to length of QTc. CONCLUSIONS: T wave alternans, a marker of electrical instability and regional heterogeneity of repolarization, identifies a high risk subset of patients with prolonged repolarization. Patients with T wave alternans have an increased risk of cardiac events, but this risk is primarily related to the magnitude of repolarization delay (QTc prolongation). T wave alternans does not make an independent contribution to the risk of cardiac events after adjustment for QTc length.

Relation between myocardial infarct location and stroke.

OBJECTIVES: We sought to compare the likelihood of stroke in patients with anterior versus nonanterior myocardial infarction. BACKGROUND: The association between anterior infarction and left ventricular thrombus has led to the assumption that embolization from thrombi is an important cause of stroke in patients with anterior infarction. We hypothesized that if anterior infarction is a cause of left ventricular thrombi, the number of strokes should be disproportionately higher in patients with anterior than nonanterior infarction. METHODS: We performed a retrospective analysis of 2,466 patients randomized from day 3 to day 15 after infarction as part of a multicenter placebo-controlled study of diltiazem to prevent cardiac death or myocardial infarction. Any acute focal cerebral disorder resulting in localizing findings characterized as a stroke or transient ischemic attack was considered an event. RESULTS: Of 91 events during a follow-up period of 12 to 52 months, 23 (3.2%) occurred in 724 patients with an anterior and 68 (3.9%) in 1,742 patients with a nonanterior myocardial infarction (relative risk 0.81; 95% confidence interval 0.51 to 1.30). Power analysis revealed that the negativity of the study was not the result of inadequate sample size. Life table analysis showed no difference in cumulative event rate (p = 0.42) according to site of infarction. Cox regression analysis showed that of 10 clinical covariates, only systolic blood pressure was predictive of stroke (p < 0.001). The use of warfarin did not contribute to the model. Finally, the addition of site of infarction (anterior vs. nonanterior) did not contribute significantly to the Cox model. CONCLUSIONS: Although there is a significant incidence of stroke after acute myocardial infarction, there is no relation between the occurrence of stroke and site of infarction. These data do not support the presumed causal relation between anterior myocardial infarction, thrombus and stroke.

Clinical implications of silent versus symptomatic exercise-induced myocardial ischemia in patients with stable coronary disease.

OBJECTIVES: This study was undertaken to better understand the functional and prognostic significance of silent relative to symptomatic ischemia. BACKGROUND: Previous studies have reached conflicting conclusions as to whether painless ischemia identified during noninvasive cardiac testing is related to a lesser extent of myocardial ischemia or a different prognosis than ischemia accompanied by angina, or both. METHODS: Nine hundred thirty-six clinically stable patients 1 to 6 months after an acute coronary event, either myocardial infarction or unstable angina, underwent ambulatory monitoring, exercise treadmill testing and stress thallium-201 scintigraphy. They were then followed up prospectively for a mean of 23 months for recurrent cardiac events (cardiac death, nonfatal myocardial infarction or unstable angina). RESULTS: Compared with patients with symptomatic ischemia during testing (n = 125), those with silent ischemia (n = 378) demonstrated less severe and extensive reversible defects on stress thallium scintigraphy (p = 0.0008), less functional impairment during treadmill testing manifested by longer exercise duration (640 +/- 173 vs. 529 +/- 190 s, p = 0.002) and longer time to ST segment depression (530 +/- 215 vs. 419 +/- 205 s, p = 0.0001) and less frequent ST segment depression during ambulatory monitoring (9% vs. 19%, p = 0.005). Patients with symptomatic ischemia had a significantly (p = 0.004) increased number of subsequent recurrent cardiac events (28.8%) versus those with silent (18.0%) or no (17.3%) ischemia. Adverse outcomes were especially concentrated in the subgroup with symptomatic ischemia and poor exercise tolerance. The difference in cardiac event rates between patients with silent versus symptomatic ischemia persisted after adjustment for baseline clinical characteristics by Cox regression analysis. CONCLUSIONS: Patients with painless ischemia during exercise testing 1 to 6 months after recovery from a coronary event have less jeopardized ischemic myocardium and fewer recurrent cardiac events than patients with symptomatic ischemia.