A. Gabriela Rosales

Prediction of risk for first age-related cardiovascular events in an elderly population: the incremental value of echocardiography ☆

OBJECTIVES We sought to determine if echocardiography enhances prediction of first age-related cardiovascular events. BACKGROUND Whether echocardiographic assessment improves risk stratification for first cardiovascular events is not well known. METHODS This retrospective cohort study included randomly selected residents of Olmsted County, Minnesota, age >/=65 years, who had >/=1 transthoracic echocardiograms at the Mayo Clinic between 1990 and 1998, in sinus rhythm, without valvular or congenital heart disease, and followed through medical records for first myocardial infarction (MI), coronary revascularization, atrial fibrillation (AF), congestive heart failure (CHF), transient ischemic attack (TIA), stroke, or cardiovascular death. Patients were excluded if they had any of these events before the baseline echocardiogram. RESULTS Of 1,160 patients (age 75 +/- 7 years; 746 women) followed for a mean of 3.8 +/- 2.7 years, 333 (29%) first events occurred (70 AF, 67 coronary revascularization procedures, 65 CHF, 48 MI, 38 stroke, 25 TIA, and 20 cardiovascular deaths). In a multivariate model, age (p < 0.001), male gender (p < 0.001), diabetes mellitus (p = 0.005), systemic hypertension (p < 0.001), left atrial volume/body surface area >/=32 ml/m(2) (p = 0.003), left ventricular (LV) mass/height >/=120 g/m (p = 0.014), LV systolic dysfunction (p < 0.001), and LV diastolic dysfunction (p = 0.029) were independent predictors. A risk-scoring algorithm was developed and validated for the prediction of first events. The five-year event-free survival was 90%, 74%, and 50% for low-, medium-, and high-risk groups, respectively. CONCLUSIONS Echocardiography enhanced prediction of first cardiovascular events in this referral-based elderly cohort. Its role in risk stratification for primary prevention of these events in the community warrants further investigations.

Left Atrial Volume in the Prediction of First Ischemic Stroke in an Elderly Cohort Without Atrial Fibrillation

OBJECTIVE To determine the clinical importance of left atrial (LA) volume in the prediction of first ischemic stroke. PATIENTS AND METHODS This retrospective cohort study included randomly selected residents of Olmsted County, Minnesota, aged 65 years or older, who had undergone transthoracic echocardiography at least once at the Mayo Clinic in Rochester, Minn, between January 1, 1990, and December 31, 1998, were in sinus rhythm, and had no history of stroke, transient ischemic attack, atrial fibrillation, or valvular heart disease. Patients were monitored through medical records for first ischemic stroke or death. RESULTS Of 1554 residents (59% women) aged 75+/-7 years, 92 (6%) had experienced at least 1 ischemic stroke over 4.3+/-2.7 years (incident stroke rate, 1.4 per 100 person-years). Left atrial volume of 32 mL/m2 or greater (hazard ratio [HR], 1.63; confidence interval [CI], 1.08-2.46) was independent of age (HR, 1.04; CI, 1.02-1.07), diabetes (HR, 1.91; CI, 1.07-3.41), myocardial infarction (HR, 1.64; CI, 1.01-2.64), and hyperlipidemia (HR, 1.55; CI, 1.01-2.37) for the prediction of first ischemic stroke. When quartiles of LA dimension were plotted against quartiles of indexed LA volume, a stepwise increase in risk with each quartile increment was evident only for indexed LA volume. Also, an LA volume of 32 mL/m2 or greater was associated with an increased mortality risk (HR, 1.30; CI, 1.09-1.56), independent of age, sex, and stroke status. CONCLUSIONS In our elderly cohort with no prior atrial fibrillation, LA volume was independently predictive of first ischemic stroke, incremental to age, diabetes, myocardial infarction, and hyperlipidemia. It was also an independent predictor of death.

Preoperative Aspirin Therapy Is Associated With Improved Postoperative Outcomes in Patients Undergoing Coronary Artery Bypass Grafting

Background—Aspirin is beneficial in the setting of atherosclerotic cardiovascular disease. There are limited data evaluating preoperative aspirin administration preceding coronary artery bypass grafting and associated postoperative outcomes. Methods and Results—Using prospectively collected data from 1636 consecutive patients undergoing first-time isolated coronary artery bypass surgery at our institution from January 2000 through December 2002, we evaluated the association between aspirin usage within the 5 days preceding coronary bypass surgery and risk of adverse in-hospital postoperative events. A logistic regression model, which included propensity scores, was used to adjust for remaining differences between groups. Overall, there were 36 deaths (2.2%) and 48 adverse cerebrovascular events (2.9%) in the postoperative hospitalization period. Patients receiving preoperative aspirin (n=1316) had significantly lower postoperative in-hospital mortality compared with those not receiving preoperative aspirin [1.7% versus 4.4%; adjusted odds ratio (OR), 0.34; 95% CI, 0.15 to 0.75; P=0.007]. Rates of postoperative cerebrovascular events were similar between groups (2.7% versus 3.8%; adjusted OR, 0.67; 95% CI, 0.32 to 1.50; P=0.31). Preoperative aspirin therapy was not associated with an increased risk of reoperation for bleeding (3.5% versus 3.4%; P=0.96) or requirement for postoperative blood product transfusion (adjusted OR, 1.17; 95% CI, 0.88 to 1.54; P=0.28). Conclusions—Aspirin usage within the 5 days preceding coronary artery bypass surgery is associated with a lower risk of postoperative in-hospital mortality and appears to be safe without an associated increased risk of reoperation for bleeding or need for blood product transfusion.

The Natural History of Lone Atrial Flutter

Context While the adverse consequences of atrial fibrillation have received much attention, we know little about the outcomes of people with lone atrial flutter. Contribution Among 59 patients with lone atrial flutter cared for at the Mayo Clinic between 1965 and 1995, 33 developed atrial fibrillation and 19 sustained a cerebrovascular event over an average follow-up of 10 years. The rate of thromboembolic events observed in this sample of patients with lone atrial flutter was at least as high as that observed in patients with atrial fibrillation. Cautions This observational study cannot tell us whether treatment for atrial flutter and anticoagulation would improve outcomes for people with lone atrial flutter. The Editors The objective of this study was to determine the long-term rate of thromboembolism and the risk for subsequent development of atrial fibrillation in patients who initially presented with lone atrial flutter. Methods Between 1965 and 1995, 567 patients from Olmsted County, Minnesota, were seen with atrial flutter. We excluded patients with any of the following conditions at the time of initial presentation: coronary artery disease, hyperthyroidism, valvular heart disease, congestive heart failure, cardiomyopathy, congenital heart disease, obstructive pulmonary disease, uncontrolled hypertension, or antecedent atrial fibrillation. We included patients with a history of controlled hypertension. We also excluded patients who were missing electrocardiographic documentation of atrial flutter, who had life-shortening disease, or whose atrial flutter occurred only as a consequence of an acute illness. Two physicians reviewed electrocardiograms to confirm the diagnosis. Atrial flutter was defined as a regular monomorphic rhythm with atrial rate greater than 240 beats/min and less than 350 beats/min. The Mayo Institutional Review Board, Rochester, Minnesota, approved the study. Control Groups The first control group was a previously defined sample in Rochester, Minnesota, in which age- and sex-specific ischemic cerebrovascular event rates were determined for the period of 1965 to 1994 (referred to as the incident cohort). The second control group consisted of Olmsted County patients who had no history of hypertension and received a diagnosis of lone atrial fibrillation from 1950 to 1980 (1, 2). Statistical Analysis Continuous variables were summarized as means 1 SD, and categorical variables were summarized as percentages. Survival without atrial fibrillation or stroke or transient ischemic attack was estimated by using the KaplanMeier method, and comparisons between patient groups were based on the log-rank test. The standardized stroke or transient ischemic attack rates were defined as the ratio of observed strokes or transient ischemic attacks in the patient cohorts divided by the expected number of strokes or transient ischemic attacks when applying the age- and sex-specific rates obtained from the incident cohort. The estimated rate of survival without stroke is expressed as the ratio of observed rates to the age- and sex-adjusted expected rates. Cox proportional hazards techniques were used to identify variables associated with rates of survival without atrial fibrillation and survival without stroke or transient ischemic attack. Because of the small numbers of events, the multivariate models consisted of only 3 variables: age; sex; and 1 of the following: body mass index, ejection fraction, duration of first atrial flutter episode (dichotomized as <24 hours or 24 hours), diabetes, history of cerebrovascular event, history of hypertension, and symptoms. All tests were 2-tailed, and a P value of 0.05 was the level of significance. Follow-up continued until January 2001 or death. A neurologist adjudicated all cerebrovascular events. Role of the Funding Source This study was funded through a grant from Mayo Foundation, which had no role in the collection, analysis, or interpretation of the data or in the decision to publish the manuscript. Results Fifty-nine patients developed lone atrial flutter during the 30-year period (Table); 75% developed recurrent episodes or chronic flutter. The average age at diagnosis was 70 years (range, 40 to 97 years). No patient with atrial flutter had clinically evident heart disease at the time of initial diagnosis. However, 20 patients had controlled hypertension, 11 had diabetes mellitus, 3 had had a transient ischemic attack (2 years, 6 years, and 10 years before diagnosis of atrial flutter, respectively), and 1 had had an ischemic stroke (9 years before diagnosis of atrial flutter). The clinical characteristics of the patients with controlled hypertension and atrial flutter did not statistically significantly differ from those of the nonhypertensive patients with atrial flutter. Table. Characteristics of Patients with Lone Atrial Flutter Medical therapy was started in 88% of patients: digitalis (61%), -blockers (17%), calcium-channel blockers (31%), and antiarrhythmic drugs (24%). Four patients underwent atrial flutter ablation. At the time of diagnosis, 31 patients received antithrombotic or antiplatelet therapy (25 patients received aspirin, and 6 patients received warfarin) to prevent embolic events. The other patients did not receive any antithrombotic or antiplatelet therapy. At latest follow-up, 41 patients were being treated with antithrombotic or antiplatelet agents (28 patients received aspirin, and 13 patients received warfarin) to prevent embolic events. Subsequent Development of Atrial Fibrillation Atrial fibrillation developed in 33 patients (paroxysmal in 25 patients and chronic in 8 patients). The average (SD) time from atrial flutter diagnosis to atrial fibrillation was 5 6 years (range, 0 to 25 years) (Figure). Unadjusted associations for the risk for atrial fibrillation were female sex (hazard ratio, 2.0 [95% CI, 0.95 to 4.2]; P = 0.07), diabetes (hazard ratio, 2.6 [CI, 1.1 to 6.0]; P = 0.028), hypertension (hazard ratio, 2.9 [CI, 1.4 to 6.1]; P = 0.005), recurrent atrial flutter (hazard ratio, 2.6 [CI, 0.91 to 7.6]; P = 0.074), and older age at the time of diagnosis of atrial flutter (hazard ratio, 1.05 [CI, 1.01 to 1.08]; P = 0.007). Significant age- and sex-adjusted predictors for developing atrial fibrillation were diabetes (hazard ratio, 2.7 [CI, 1.1 to 6.4]; P = 0.029), hypertension (hazard ratio, 2.4 [CI, 1.2 to 5.1]; P = 0.02), and recurrent atrial flutter (hazard ratio, 3.1 [CI, 1.03 to 9.1]; P = 0.044). Figure. KaplanMeier curves depict the time without conversion to atrial fibrillation from the initial lone atrial flutter diagnosis. Cerebrovascular Events Nineteen patients, with a mean (SD) age of 80 10 years, experienced at least 1 cerebrovascular ischemic event during follow-up. The mean (SD) time from atrial flutter diagnosis to cerebrovascular event was 4.3 3.9 years. Of the 19 patients, 6 developed atrial fibrillation after the atrial flutter diagnosis but before the event. Of the 4 patients with a history of stroke or transient ischemic attack before the atrial flutter diagnosis, only 1 patient had a cerebrovascular event during follow-up. Among patients with atrial flutter, 77% were free of ischemic stroke or transient ischemic attack, whichever occurred first, at 5 years and 65% were free of one of these events at 10 years. Among the incident cohort, 94% at 5 years and 89% at 10 years were free of one of these events (standardized stroke or transient ischemic attack rate, 3.3 [CI, 2.1 to 5.2]; P < 0.001). Patients with controlled hypertension and atrial flutter had an estimated 5- and 10-year survival rate without cerebrovascular events of 70% and 52%, respectively, as compared with 80% and 75% for nonhypertensive patients, respectively (log-rank P = 0.099), with an age- and sex-adjusted hazard ratio of 2.3 (CI, 0.87 to 6.0; P = 0.094). However, both the patients with controlled hypertension and atrial flutter and nonhypertensive patients with atrial flutter had statistically significant higher rates of stroke or transient ischemic attack than the incident cohort (standardized stroke or transient ischemic attack rate, 5.2 [CI, 2.7 to 9.9; P < 0.001] and 2.5 [CI, 1.3 to 4.6; P = 0.002], respectively). Comparison with Patients with Lone Atrial Fibrillation Data from the 59 patients with atrial flutter were compared with those from 145 patients with atrial fibrillation. The atrial flutter group had a larger percentage of women (44% vs. 28%; P = 0.04), was older on average (70 12 years of age vs. 55 17 years of age; P < 0.001), and had less follow-up time on average (10 6 years vs. 13 8 years; P = 0.002) than the atrial fibrillation group. Also, the atrial fibrillation group excluded patients with a history of hypertension before their diagnosis. After adjustment for age and sex, patients with atrial flutter had a higher incidence of ischemic stroke or transient ischemic attack than patients with atrial fibrillation (hazard ratio, 2.6 [CI, 1.2 to 5.3]; P = 0.011). Moreover, when nonhypertensive patients with atrial flutter were compared with patients with atrial fibrillation, the rate of stroke or transient ischemic attack did not differ (hazard ratio, 1.9 [CI, 0.85 to 4.4]; P = 0.119). Discussion In our study, 32% of patients with atrial flutter had a cerebrovascular event at 10-year follow-up. Compared with the age- and sex-adjusted expected thromboembolic rates, patients with atrial flutter experienced a statistically higher risk. Also, the rate of thromboembolism was higher in the patients with atrial flutter than in patients with atrial fibrillation. This observation, in part, is probably due to inclusion of patients with controlled hypertension in the atrial flutter group. However, when nonhypertensive patients with atrial flutter were compared with the incident cohort, there was a higher incidence of thromboembolic events in patients with atrial flutter. This suggests that atrial flutter, even without hypertension, carries

Role of Endothelial NO Synthase Phosphorylation in Cerebrovascular Protective Effect of Recombinant Erythropoietin During Subarachnoid Hemorrhage– Induced Cerebral Vasospasm

Background and Purpose— In the present study, the effect of subarachnoid hemorrhage (SAH) on the phosphorylation of endothelial NO synthase (eNOS) and the ability of recombinant erythropoietin (Epo) to augment this vasodilator mechanism in the spastic arteries were studied. Methods— Recombinant adenoviral vectors (109 plaque-forming units per animal) encoding genes for human Epo (AdEpo), and &bgr;-galactosidase were injected immediately after injection of autologous arterial blood into the cisterna magna (day 0) of rabbits. Cerebral angiography was performed on day 0 and day 2, and basilar arteries were harvested for Western blots, measurement of cGMP levels, and analysis of vasomotor functions. Results— Injection of autologous arterial blood into cisterna magna resulted in significant vasospasm of the basilar arteries. Despite the narrowing of arterial diameter and reduced expression of eNOS, expressions of phosphorylated protein kinase B (Akt) and phosphorylated eNOS were significantly increased in spastic arteries. Gene transfer of AdEpo reversed the vasospasm. AdEpo-transduced basilar arteries demonstrated significant augmentation of the endothelium-dependent relaxations to acetylcholine, whereas the relaxations to an NO donor, 2-(N,N-diethylamino)diazenolate-2-oxide sodium salt, were not affected. Transduction with AdEpo further increased the expression of phosphorylated Akt and eNOS and elevated basal levels of cGMP in the spastic arteries. Conclusions— Phosphorylation of eNOS appears to be an adaptive mechanism activated during development of vasospasm. The vascular protective effect of Epo against cerebral vasospasm induced by SAH may be mediated in part by phosphorylation of Akt/eNOS.

Concordant activity of transgene expression cassettes inserted into E1, E3 and E4 cloning sites in the adenovirus genome

Expression cassettes can be inserted at several positions into recombinant adenoviral genomes but the implications of this choice for transgene expression level have not been determined. Knowledge of the relative expression levels of transgenes inserted at different sites in the adenoviral genome is of particular significance for transgene expression monitoring approaches that rely on the concordant expression of a marker transgene inserted elsewhere in the viral genome.

An Echocardiographic Left Ventricular Wall Area Index for Functional Detection of Myocardial Injury in Hemodynamically Unloaded Hearts

Functional assessment of the left ventricle is affected by loading conditions. Detection of rejection‐mediated myocardial injury in a heterotopic heart transplant model is a challenge for the echocardiographer because the heart is in an unloaded state. We examined the relationship of a novel left ventricular (LV) wall area index (LVWAI) and serum cardiac troponin T (cTnT) levels. The LVWAI, based on prior methods of determining LV mass, was defined as the difference between epicardial and endocardial areas divided by the epicardial area. The biphasic morphometric response of LVWAI reflected changes in the cTnT levels and allowed echocardiographic detection of myocardial injury in hemodynamically unloaded hearts.

1166-210 Silent atrial fibrillation: An important contributor to total burden of atrial fibrillation in Olmsted, County, MN (1980–1989)

Background: The short-term reliability of patient reported symptoms as a marker of atrial tachyarrhythmia or atrial fibrillation (AT/AF) recurrence has been studied. However, the long-term correlation of symptoms with continuous monitoring of AT/AF episodes during pacing is unknown. Methods: This prospective multicenter trial assessed the development of AT/AF in paced patients by examining the correlation of patient-reported symptoms with device-detected AT/AF event data in patients with bradyarrhythmias and > 1 episode of AT/AF in the prior year. Full disclosure device datalogs with electrogram (EGM) validation of AT/AF events were obtained from a pacemaker (AT500, Medtronic) that records the daily frequency, atrial and ventricular cycle length, EGM, and duration of AT/AF episodes. Patients logged symptomatic events into the device memory via an external manual activator. Following a one-month lead-in period, patients were followed for an additional 12 months and were contacted weekly to ensure compliance with activator usage. Episodes were classified as symptomatic AT/AF, asymptomatic AT/AF, or symptomatic “non-AT/AF” depending on concordance between patient-indicated symptoms and device-detected AT/AF. Results: 48 patients (28 M, 76±10 yr) were implanted and followed for 12±2 months. Arrhythmia-related symptoms were noted in 8% of all device-detected AT/AF episodes (sensitivity).Only 19% of all patient symptoms were associated with device documented AT/AF events (positive predictive value). A paired analysis in a subset of patients (n=15) with both symptomatic and asymptomatic stored episodes indicated no difference (p=NS) with respect to median ventricular rate (94 vs 94 bpm), atrial cycle length (230 vs 235 ms), or episode duration (103 vs 75 s). Conclusion: Over a long-term follow-up, the vast majority of AT/AF episodes are asymptomatic and patient symptoms are seldom associated with AT/AF episodes. Hence, patient symptoms are an unreliable index of recurrent AF in clinical studies of AF therapies and in management of anticoagulation therapy. Continuous monitoring via implantable device datalogs provides objective early and reliable detection of AF during followup.