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Meta-analyses showed that exercise training decreased mortality in patients after myocardial infarction, but no single adequately powered trial has shown this benefit. The purpose of this study was to evaluate the effect of cardiac rehabilitative exercise training on prognostic variables derived from the exercise tolerance test and whether these changes had an effect on predicted cardiovascular and all-cause mortality using externally validated risk scores. Two hundred ten consecutive patients who completed a 12-week cardiac rehabilitation program were analyzed. Peak MET level, heart rate recovery, chronotropic index, Duke prognostic score, and Cleveland Clinic Foundation risk score obtained at program entry and exit were compared. All prognostic variables and risk score-derived predicted 5-year mortality rates improved significantly after cardiac rehabilitation. Exercise capacity increased by 32% (6.6 +/- 2.7 to 8.7 +/- 2.9 METS; p0.0001), heart rate recovery increased by 20% (15 +/- 9 to 18 +/- 10 beats/min; p0.0001), and chronotropic index increased by 11% (56 +/- 22% to 62 +/- 22%; p0.0001). Duke prognostic score 5-year predicted cardiovascular mortality rate decreased by 33% (6 +/- 4% to 4 +/- 2%; p0.0001), and Cleveland Clinic Foundation risk score 5-year predicted total mortality rate decreased by 40% (5 +/- 7% to 3 +/- 5%; p0.0001). These improvements remained significant in high-risk subgroups. When controlled for age, gender, diabetes, MET level achieved, ejection fraction, and beta-blocker use, changes remained significant (p0.0001) for each outcome measure. In conclusion, exercise training in supervised cardiac rehabilitation programs significantly improved exercise capacity, measures of chronotropic dynamics, and prognostic risk scores. These differences translate into a decrease in predicted mortality.

Although peak oxygen consumption (VO(2)) during exercise is frequently used to help predict optimal timing for heart transplantation, its long-term prognostic value in women is not known. We followed 2,105 adult patients with heart failure (HF) and with impaired left ventricular (LV) systolic function for 5 years, including 525 women (25%) who underwent metabolic stress testing between January 1995 and December 2002. Multivariable proportional hazards modeling related VO(2) to survival with adjustments for30 confounders and with transplantation considered as a time-dependent covariate. During follow-up, 129 women (26%) died, as did 572 men (36%). There were 175 transplants, including 34 women. Women and men were similar in age (54 vs 55 years), but women were less likely to have coronary artery disease (28% vs 58%). Peak VO(2) was strongly predictive of time to death in women (adjusted hazard ratio [HR] for peak VO(2) decreasing from 15 to 14 ml/kg/min, 1.11, 95% confidence interval [CI] 1.05 to 1.18, p0.0001) and in men (adjusted HR 1.12, 95% CI 1.08 to 1.16, p0.0001). There was no gender interaction with peak VO(2) (p = 0.80), but for any given peak VO(2) women were at lower risk (adjusted HR for men compared with women 2.22, 95% CI 1.58 to 3.10, p0.0001). A significant interaction was found between gender and presence of coronary artery disease (p for interaction 0.02); in women, those with ischemic cardiomyopathy had a worse survival for any given peak VO(2). In conclusion, in this large cohort, peak VO(2) predicted survival in women and men whether or not coronary artery disease was present, but an interaction was noted between coronary artery, gender, and survival.

Chronotropic incompetence, or an inability to increase heart rate during exercise, independently predicts death in patients not taking beta blockers. Whether it predicts death in patients taking beta blockers is not known. Consecutive patients (n = 3,736; mean age 58 +/- 11 years; 68% men), who were taking either metoprolol tartrate or atenolol and were referred for symptom-limited exercise testing from 1990 to 2002 at a major academic medical center, formed the prospective study cohort. None had heart failure, pacemakers, atrial fibrillation, or any electrocardiographic abnormalities. Patients were followed for a median of 4.5 years for all-cause mortality. Chronotropic response was defined as the percentage of heart rate reserve used. A value ofor =62%, which was noted in 813 patients (22%), was considered abnormal, meaning that chronotropic incompetence was present. There were 173 deaths. After adjusting for age, gender, heart rate at rest, standard risk factors, other medications, Duke treadmill score, and heart rate recovery, chronotropic incompetence predicted death (adjusted hazard ratio 1.94, 95% confidence interval 1.43 to 2.64, p0.0001). The association of chronotropic incompetence with death was present, irrespective of which drug was taken or the number of half-lives that had elapsed since the last dose. In conclusion, in patients taking beta blockers, chronotropic incompetence is independently predictive of death.

Although it is well established that cigarette smoking causes excess mortality, the extent of the increased risk has been challenged because self-selection biases and confounding factors may not have been adequately accounted for in prior studies. We therefore performed a propensity analysis on a population-based cohort. A logistic regression model was used to generate a propensity score for current smoking in 6,099 adults (mean age 46 years, 54% men, 36% current smokers) participating in the National Heart Lung and Blood Institute’s (NHLBI) Lipid Research Clinic Prevalence Study. During 12 years of follow-up, 513 subjects (8%) died. After adjusting for age, current smoking was strongly associated with death (compared with never and former smokers, relative risk [RR] 2.69, 95% confidence interval [CI] 1.98 to 0.64, p

Platelet glycoprotein IIb/IIIa inhibitors have been extensively studied in the treatment of patients with ischemic heart disease. Data regarding the use of these agents in the absence of concomitant intravenous heparin have been conflicting. We sought to determine, using propensity analysis, whether the benefit of eptifibatide, a IIb/IIIa inhibitor, in the treatment of acute coronary syndromes is affected by the concurrent administration of heparin. By trial design, patients were randomized to either eptifibatide or placebo, whereas use of intravenous heparin was left to the discretion of treating physicians. The effect of eptifibatide on the 30-day composite end point of death or myocardial infarction was studied in patients who received heparin and those who did not. Propensity analysis methods were used to control for confounding and presumed selection biases. Among 5,576 patients who were receiving heparin when the bolus dose of the study drug was administered, eptifibatide was associated with a reduced composite end point rate (13%) compared with that of placebo (14.5% vs 16.6%, p = 0.03). In contrast, among 1,441 patients who were not receiving heparin, there was no difference in 30-day event rates with eptifibatide compared with placebo (13.7% vs 13.1%, p > 0.7). After a propensity score for use of heparin was developed, however, use of heparin did not affect the reduced risk associated with eptifibatide (adjusted relative risk [RR] for heparin-eptifibatide interaction term 0.90, 95% confidence interval [CI] 0.61 to 1.32, p > 0.5), but the propensity for heparin use was a strong predictor of events (adjusted RR 1.76, 95% CI 1.42 to 2.17, p < 0.001). The use of eptifibatide independently predicted a lower risk of events (adjusted RR 0.31, 95% CI 0.10 to 0.93, p = 0.04). Thus, the apparent positive impact of heparin on the benefits of eptifibatide therapy was largely due to confounding and bias.

Effective allocation of medical resources in stable chest pain patients requires the accurate diagnosis of coronary artery disease and the stratification of future cardiac risk. We studied the relative predictive value for cardiac death of 3 commonly applied noninvasive strategies, clinical assessment, stress electrocardiography, and myocardial perfusion tomography, in a large, multicenter population of stable angina patients. The multicenter observational series comprised 7 community and academic medical centers and 8,411 stable chest pain patients. All patients underwent pretest clinical screening followed by stress (exercise 84% or pharmacologic 16%) electrocardiography and myocardial perfusion tomography. Risk-adjusted multivariable Cox proportional hazards models were developed to predict cardiac death. Kaplan-Meier rates of time to cardiac catheterization were also computed. Cardiac mortality was 3% during the 2.5 +/- 1.5 years of follow-up. The number of infarcted vascular territories and pretest clinical risk factors were strong predictors of cardiac mortality, whereas the number of ischemic vascular territories gained increasing importance when determining post-test resource use requirements (i.e., the decision to perform cardiac catheterization). Exertional ST-segment depression in a population with a high frequency of electrocardiographic abnormalities at rest was not a significant differentiator of cardiac death risk. Stable chest pain patients are accurately identified as being at high risk for near-term cardiac events by both physicians' screening clinical evaluation and by the results of stress myocardial perfusion imaging. Disease management strategies for stable chest pain patients aimed at risk reduction should incorporate knowledge of relevant end points in treatment and guideline development.

Left ventricular (LV) cavity obliteration during dobutamine echocardiography (DE) indicates a vigorous inotropic response to stress. Such a response may suggest the absence of coronary artery disease (CAD), but a small LV cavity may also preclude recognition of wall motion abnormalities. We sought to determine the frequency, correlates, accuracy, and prognostic value of the LV cavity obliteration response in 336 consecutive patients who underwent coronary angiography within 1 year of DE. Cavity obliteration was defined by contact of the opposite walls in the apical views during DE, and ischemia by detection of a new or worsening wall motion abnormality. Sensitivity was based on comparison with coronary anatomy in 220 patients without prior revascularization. The prognostic implications of cavity obliteration were examined by follow-up of 324 patients (96%) over 23 +/- 9 months for death, myocardial infarction, and late revascularization. Cavity obliteration was present in 86 of the 336 DE studies (26%). Baseline and stress hemodynamics were not predictive of cavity obliteration, which was associated with LV hypertrophy and female gender (p

Exercise treadmill testing is frequently performed to screen for coronary artery disease (CAD) in asymptomatic individuals; however, its clinical value is unclear. We examined a consecutive cohort of asymptomatic adults undergoing exercise treadmill testing at the Cleveland Clinic Foundation between September 1990 and December 1993. End points included (1) identification of subjects with severe CAD and (2) performance of any second diagnostic study within 90 days of the index exercise treadmill test. Screening exercise treadmill testing was performed in 4,334 adults (median age 51, 89% men); only 34% hador = 1 cardiac risk factor and 15% exhibited an abnormal response to exercise. A second test after treadmill testing was performed in 215 patients (in 110, coronary angiography; in 105, stress thallium scintigraphy, followed by coronary angiography in 16). The strongest predictor of referral for a second test was an ischemic ST-segment response (adjusted odds ratio [OR] 34, 95% confidence intervals [Cl] 24 to 47, p0.0001). The only clinical variable independently associated with referral for a second test was female gender (adjusted OR 0.35, 95% CI 0.21 to 0.60, p0.0001). Of the 126 patients who underwent coronary angiography, severe CAD was identified in only 19 individuals (10.44% of the original cohort, 95% CI 0.26% to 0.62%); coronary artery bypass grafting was performed in 14 of these patients. The estimated cost of exercise treadmill testing to identify 1 case of severe CAD for which surgical revascularization may provide a survival benefit was $39,623. The estimated cost per year of life saved was at least $55,274. Thus, as used in actual practice in 1 center, screening exercise treadmill testing has a low yield and is costly. This is perhaps in part because of the low-risk population that was selected and the failure to incorporate pretest variables, increasing probability of disease into post-test clinical decision making.

To investigate time-related trends in the use of preoperative invasive hemodynamics in patients with pure valvular stenosis, the preoperative evaluations and preoperative echocardiograms of consecutive patients who underwent aortic or mitral valve surgery from 1986 to 1994 at the Cleveland Clinic Foundation were reviewed. The study group consisted of 1,985 patients, 1,476 with aortic stenosis and 509 with mitral stenosis. Preoperative cardiac catheterization was performed in 1,456 patients with aortic stenosis (99%) and 488 with mitral stenosis (96%). Measurement of invasive hemodynamics (including transvalvular gradients and estimated valve areas) during catheterization decreased over time both in patients with aortic (from 64% in 1986 to 30% in 1994, test for trend p

This study evaluated the prediction of cardiac events (cardiac death, myocardial infarction, unstable angina, or late myocardial revascularization) in patients with submaximum responses to dobutamine stress, defined by attainment of

Considerable controversy exists regarding whether women are less likely than men to be referred to coronary angiography after an abnormal noninvasive test. This prospective cohort study analyzed consecutive subjects (2,351 men and 1,318 women) with no prior history of invasive cardiac procedures who were referred for treadmill thallium testing at the Cleveland Clinic Foundation. The primary end point was performance of coronary angiography within 90 days of treadmill thallium testing. A secondary end point was all-cause mortality during 1.8 years of follow-up. Women were less likely than men to undergo coronary angiography (6% vs 14%, odds ratio [OR] 0.42, 95% confidence interval [CI] 0.33 to 0.54, p 0.9). Women were less likely to have severe coronary disease on angiography (15% vs 30%, p = 0.006). During 1.8 years of follow-up there were 26 deaths (2%) among women and 84 deaths (4%) among men. After adjusting for age, thallium abnormalities, and clinical characteristics in Cox regression analyses, women had a lower mortality rate than men (relative risk 0.58, 95% CI 0.36 to 0.94, p = 0.03). Thus, gender-related differences in referral for coronary angiography after treadmill thallium testing can be explained by a higher rate of abnormal tests in men. No evidence of a post-test gender bias was detected, but a pretest bias affecting referral to nuclear testing cannot be excluded. Furthermore, women have a lower prevalence of severe coronary disease and a lower adjusted mortality rate. (Am J Cardiol 1996;78:278–283)

Inappropriate chronotropic response to exercise has been observed to correlate with poor prognosis in patients with coronary disease, but the mechanism for this association is not well defined. We attempted to examine the association between chronotropic response to exercise and angiographic severity of coronary disease in patients with suspected or stable coronary artery disease. The chronotropic response, expressed as peak heart rate, chronotropic index (ratio of heart rate reserve and metabolic reserve utilized), or percent maximal heart rate achieved, was correlated with angiographic findings obtained within 180 days of the test. Significant coronary disease was defined as > or = 1 stenosis of > or = 50% in a major epicardial artery or its main branches; severe coronary disease was defined as > or = 50% stenosis in all 3 epicardial arteries, or in the left main coronary trunk, or 2-vessel disease with > or = 70% proximal left anterior descending artery stenosis. We observed that peak heart rate and percent maximal heart rate achieved were independent negative predictors of both significant and severe coronary disease by logistic regression. The chronotropic index predicted severe coronary disease only. All 3 parameters of chronotropic response exhibited a significant gradient of abnormality across the spectrum of coronary disease (p < 0.01 for all), expressed by the number of vessels involved and correlated with left anterior descending artery involvement (p < 0.05 for all). We conclude that chronotropic response to exercise predicts the presence and angiographic severity of coronary disease. This association is likely related to the proportion of left ventricular myocardium rendered ischemic during stress.

Left ventricular (LV) mass is determined to a large extent by body size. This has created controversy regarding the optimal method of defining normal values in the clinical setting. Previous groups have advocated indexing LV mass for body surface area, lean body mass, or height, which is an obesity-Independent measure of body size. This study describes a new approach that involves dividing LV mass by height raised to a noninteger power. In a sample of 387 men and 714 women who were between 20 and 45 years of age and who were free of cardiovascular disease, the height exponent was determined by logarithmic regression models to be 2.12 in men and 1.91 in women; in a pooled analysis, the height exponent was 1.97. This approach reduced male versus female differences in the mean and 95th percentile values for LV mass; mean value differences were reduced from 520% among raw values to 29% among adjusted values. Compared with height or body surface area indexation, it was found to slightly increase the correlation between LV mass and systolic blood pressure. In contrast, body surface area indexation reduced the association between LV mass and obesity. The current method of indexation is independent of obesity, reduces LV mass variability associated with body size and gender, and may therefore be a useful method for defining normal and abnormal values of LV mass in the clinical setting. The findings of this study also suggest that Indexation of LV mass for body surface area is inappropriate.

Echocardiographic predictors of clinical outcome were examined in subjects from the Framingham Heart Study with overt coronary artery disease. The study population consisted of 185 men and 147 women with coronary artery disease who underwent M-mode echocardiography and were followed for a mean of 3.90 years. At baseline, 37 men (18.4%) and 16 women (10.9%) had reduced fractional shortening, 43 men (23.2%) and 28 women (19%) had left ventricular (LV) dilatation, and 76 men (41%) and 76 women (51.7%) had LV hypertrophy. During the follow-up period new cardiovascular disease events (coronary disease, stroke, transient ischemic attack, claudication, heart failure and deaths from cardiovascular disease) occurred in 60 men (32%) and 58 women (39%). With use of age-adjusted proportional hazards analyses, LV mass/height in men (relative risk [RR] = 1.25 50 g/m increment, 95% confidence interval [CI] 1.01 to 1.55) and LV end-diastolic diameter in women (RR = 1.36 5 mm increment, 95% CI 1.05 to 1.76) were predictors of new cardiovascular disease events. Cardiovascular risk was also associated with LV end-systolic diameter in both sexes (in men RR = 1.28 1 SD increment, 95% CI 1.02 to 1.63; in women RR = 1.40 1 standard deviation increment, 95% CI 1.09 to 1.82). Reduced fractional shortening alone (RR = 1.91, 95% CI 1.11 to 3.31) and in combination with LV dilatation (RR = 2.13, 95% CI 1.13 to 4.02) was associated with the incidence of new cardiovascular disease outcomes in men. In women, cardiovascular risk was increased with LV hypertrophy (RR = 2.30, 95% CI 1.29 to 4.12), high LV wall thickness (RR = 3.36, 95% CI = 1.18 to 9.55), high LV end-systolic diameter (RR = 2.59, 95% CI 1.45 to 4.62) and a combination of low fractional shortening and LV dilatation (RR = 3.25, 95% CI 1.28 to 8.25). Thus, M-mode echocardiography has prognostic value in identifying subjects with coronary artery disease who are at increased risk for new morbid or fatal events.

Animal experimental data have shown that lipid-lowering agents reduce myocardial infarct size. This association has not been well studied in humans. We compared infarct size in 10,548 patients in the GUSTO IIb and PURSUIT trials who were (n = 1,028) or were not (n = 9,520) on lipid-lowering therapy before an enrolling myocardial infarction (MI). Patients using lipid-lowering agents before their index MI had smaller infarcts than those who were not using these agents (median peak creatine kinase [CK]-MB 4.2 vs 5.2 times the upper limit of normal [ULN]; p0.0001). Similarly, in an unadjusted model, patients on previous lipid-lowering therapy were less likely to have a peak CK-MB3 times the ULN (620 of 1,028 [60.3%] vs 6,486 of 9,520 patients [68.1%]; p0.001; relative risk 0.88, 95% confidence interval 0.84 to 0.93, p0.0001). In a covariate- and propensity-adjusted multivariable model, the association between pretreatment with lipid-lowering agents and smaller infarct size persisted (relative risk for CK-MB3 times the ULN 0.94, 95% confidence interval 0.88 to 0.99, p = 0.04). In conclusion, patients on lipid-lowering agents before an MI had significantly smaller infarcts. These findings suggest that lipid-lowering therapy may exert additional salutary effects in the setting of acute coronary syndromes.

During metabolic stress testing, 9 of 20 patients with left ventricular assist devices exhibited a lag in peak device rate by < or = 85% of peak native heart rate (group I), with peak device rates of 118 +/- 9 beats/min compared with group II, in which peak device rate nearly equaled peak native rates. Peak systolic blood pressure was significantly greater in group II than group I, but there was no significant difference in peak oxygen consumption, anaerobic threshold, or peak flows.

The prognostic values of tissue Doppler imaging and color M-mode diastolic indexes were studied in 225 patients who had symptomatic systolic heart failure in the ADEPT study. The primary end point of death, transplantation, or hospitalization due to heart failure occurred in 65 patients and was independently predicted by shorter deceleration time, lower ratio of pulmonary vein systolic to diastolic velocity, and increasing levels of the ratios of early transmitral velocity to early annular velocity or velocity of propagation. For the ratio of early transmitral velocity to early annular velocity, this prediction was additive to deceleration time. Newer diastolic indexes provide an independent prediction of clinical outcomes.

We compared a novel strategy of carotid stenting (CS) followed by open heart surgery (OHS) to the combined carotid endarterectomy (CEA) and the OHS approach in patients requiring coronary and carotid revascularization. Between 1997 and 2002, CS as a prelude to OHS was performed in 56 patients, and 111 patients underwent combined CEA+OHS. Adverse events included stroke, myocardial infarction (MI), death, and their combinations. At baseline, the CS+OHS group had more unstable/severe angina (52% vs 27%, p = 0.002), severe left ventricular dysfunction (20% vs 9%, p = 0.05), symptomatic carotid disease (46% vs 23%, p = 0.002), and the need for repeat OHS (32% vs 9%, p = 0.0002). Severe contralateral carotid disease was more prevalent in the CEA+OHS group (28% vs 11%, p = 0.01). At 30 days, CS+OHS patients had a significantly lower incidence of stroke or MI (5% vs 19%, p = 0.02). A propensity score was created for each patient to account for baseline differences. In a final logistic regression model that included the propensity score, CS+OHS was associated with a trend toward reduced stroke or MI (odds ratio 0.26, 95% confidence interval 0.06 to 1.09, p = 0.06) and reduced death, stroke, or MI (odds ratio 0.40, 95% confidence interval 0.12 to 1.27, p = 0.12). In conclusion, despite a higher baseline risk profile, patients who underwent CS+OHS had significantly fewer adverse events than those undergoing CEA+OHS. CS may be a safer carotid revascularization option for this challenging patient population.

Although it is well established that a blunted chronotropic response to exercise is associated with a higher risk of death, recent data suggest a similar association between mortality risk and blunted heart rate response to vasodilatory stress. We investigated the heart rate response to dipyridamole-induced stress as a predictor of death in the setting of normal myocardial perfusion and a normal electrocardiogram. We followed 1,087 patients for 8 years (range 5.7 to 11.8) who underwent dipyridamole vasodilator stress and had normal perfusion scans and electrocardiograms. None had heart failure, known left ventricular systolic dysfunction, pacemaker implantation, or valve disease. Heart rate response was assessed as the ratio of heart rate at peak stress to heart rate at rest. The primary end point was all-cause mortality. Quartile values for the peak-to-rest heart rate ratio were1.19, 1.19 to 1.30, 1.31 to 1.44, and1.44. There were 246 deaths. Death rates according to quartiles of heart rate ratio were 103 of 271 (38%), 64 of 272 (24%), 52 of 272 (19%), and 27 of 272 (10%). After adjusting for age, gender, heart rate at rest, blood pressure response, standard cardiovascular risk factors, and other confounders, a blunted heart rate response remained predictive of death (adjusted hazard ratio for lowest vs highest quartile 3.3, 95% confidence interval 2.1 to 5.1, p0.0001). When considered as a continuous variable, the logarithm of the heart rate ratio was the strongest predictor of death, aside from age. Thus, among patients who have normal myocardial perfusion and normal electrocardiograms, a blunted heart rate response to vasodilator stress is predictive of a marked increase in risk of death.

The combination of abciximab with thrombolytic therapy when treating acute ST-elevation myocardial infarction has been hypothesized to enhance microvascular perfusion. Resolution of ST-segment elevation after thrombolytic therapy is believed to be a marker of myocardial reperfusion and to predict mortality rate. Among 16,588 patients enrolled in the Fifth Global Use of Strategies to Open Occluded Arteries in Acute Myocardial Infarction trial, 1,764 consecutive patients from selected centers had their study electrocardiograms evaluated by a core laboratory for ST-segment deviation resolution 60 minutes after treatment. Patients were categorized into 4 groups: complete resolution (70%), partial resolution (70% to 30%), no resolution (30%), and worsening ST-segment deviation. Patients treated with reteplase or a combination of reteplase plus abciximab had similar rates of complete resolution (32% vs 34%), partial resolution (29% vs 27%), no resolution (15% vs 16%), and worsening ST-segment elevation (23 vs 23%; p = 0.59). The 30-day mortality rates in these 4 groups were 2.1%, 5.2%, 5.5%, and 8.1% (p0.001). Even after accounting for baseline variables, incomplete ST-segment resolution (70%) was associated with an increased risk of death within 30 days (adjusted hazard ratio 2.41, 95% confidence interval 1.25 to 4.63, p0.008). Thus, ST-segment resolution at 60 minutes was no different in patients treated with full-dose reteplase from those treated with a combination of abciximab and reteplase. Patients with70% ST-segment resolution within 60 minutes had markedly decreased mortality rates, irrespective of treatment.

Plasma brain natriuretic peptide (BNP) levels have been associated with left ventricular dysfunction and acute myocardial infarction. Although natriuretic peptide responses have been linked to exercise-induced myocardial ischemia, it is not known whether BNP levels predict dobutamine-induced myocardial ischemia. The aim of this study was to determine whether elevations in BNP levels immediately before or after dobutamine-induced stress are associated with echocardiographic myocardial ischemia. Plasma BNP was measured before and after stress during dobutamine-stress echocardiography in 317 patients (aged 68 ± 11 years; 46% women) who had creatinine

Chronotropic incompetence, or an attenuated heart rate response to exercise, has been shown to be associated with an adverse outcome. It is not known whether chronotropic incompetence predicts all-cause mortality independent of angiographic severity of coronary artery disease (CAD). Study subjects included consecutive patients who underwent first-time, symptom-limited exercise treadmill testing and coronary angiography within 90 days; no patient was taking beta blockers or had a history of heart failure, valve disease, or prior revascularization. Chronotropic response was measured in 2 ways: (1) failure to reach 85% of the age-predicted maximum heart rate, and (2) a low chronotropic index, a measure of exercise heart rate response that accounts for effects of age, physical fitness, and resting heart rate. Angiographic severity of CAD was assessed using the Duke Prognostic Weight Score, with a score > or = 42 considered to be indicative of severe CAD. Among 384 eligible patients, failure to reach 85% of the age-predicted maximum heart rate occurred in 61 (16%) and a low chronotropic index was noted in 133 (35%). Severe CAD was present in 63 (16%). During 6 years of follow-up there were 56 deaths. Mortality was predicted by failure to reach target heart rate (RR 1.85, 95% confidence interval [CI] 1.01 to 3.39, chi-square = 4, p = 0.05), by severe CAD (RR 2.21, 95% CI 1.24 to 3.95, chi-square = 8, p = 0.007), and, most strongly, by a low chronotropic index (RR 2.72, 95% CI 1.60 to 4.61, chi-square = 15, p = 0.0002). In a multivariable model, low chronotropic index remained predictive of death (adjusted RR 2.22, 95% CI 1.29 to 3.82, p = 0.004), whereas severe CAD no longer predicted death (adjusted RR 1.27, 95% CI 0.70 to 2.31, p > 0.4). Thus, chronotropic incompetence is a strong and independent predictor of death, even after accounting for the angiographic severity of CAD.

The clinical importance of an exaggerated systolic blood pressure (BP) response to exercise, or exercise hypertension, is unclear. We have previously reported that exercise hypertension is associated with less severe angiographic coronary artery disease. This study sought to examine the association between exercise hypertension and ischemic "burden," as assessed by thallium-201 single-photon emission computed tomography. The cohort was comprised of consecutive adults (2,216 men, 1,229 women) referred for symptom-limited exercise thallium testing to evaluate known or suspected coronary artery disease. The main variable measured was exercise hypertension, defined as a peak systolic BPor =210 mm Hg in men andor =190 mm Hg in women. Thallium perfusion defects were described as: (1) any perfusion abnormality, (2) reversible abnormalities, and (3) any abnormality inor =3 of 12 myocardial segments ("extensive abnormalities"). Exercise hypertension was present in 1,319 subjects (39%). Patients with exercise hypertension were less likely to have any thallium perfusion abnormality (16% vs 25%, odds ratio [OR] 0.58, 95% confidence intervals [CI] 0.49 to 0.69, p0.001), reversible thallium abnormalities (7% vs 12%, OR 0.71, 95% CI 0.57 to 0.90, p0.001), and extensive abnormalities (8% vs 14%, OR 0.53, 95% CI 0.42 to 0.67, p0.001). After adjusting for possible confounders, the same trend was seen. During 6 years of follow-up there were 283 deaths with no association between exercise hypertension and mortality risk. Thus, exercise hypertension is associated with a lower likelihood of myocardial perfusion abnormalities and is not associated with an increased mortality rate.

This study sought to determine the association of exercise-induced ventricular ectopic activity with thallium perfusion defects and severity of angiographic coronary artery disease (CAD). Two cohorts consisting of adults without heart failure or known severe ventricular ectopic activity at rest were studied. The first cohort consisted of adults (n = 2,743) who underwent maximum exercise thallium stress testing. The second cohort consisted of adults (n = 423) who underwent coronary angiography within 90 days of treadmill testing. Significant exercise-induced ventricular ectopic activity was defined as frequent ventricular premature complexes or nonsustained ventricular tachycardia. Severe CAD was defined as left main CAD (or = 50% stenosis), 3-vessel CAD (or = 70% stenosis), or 2-vessel CAD withor = 70% stenosis of the proximal left anterior descending artery. In the thallium cohort, exercise-induced ventricular ectopic activity was associated with a greater frequency of thallium defects (35.2% vs 18.7%, odds ratio [OR] 2.35, 95% confidence intervals [CI] 1.62 to 3.42, p0.001); after adjusting for possible confounders, this association persisted (for any defect adjusted OR 1.66, 95% CI 1.09 to 2.53, p = 0.02; for septal defect adjusted OR 2.77, 95% CI 1.51 to 5.07, p0.001). There was no association between exercise-induced ventricular ectopic activity and mortality during 2 years of follow-up. In the angiographic cohort, there was no association of exercise-induced ventricular ectopy with severe CAD (19% vs 20%, OR 0.93, 95% CI 0.41 to 2.09, p = NS). Exercise-induced ventricular ectopic activity was associated with a greater likelihood of thallium perfusion defects, but was not associated with angiographic severity of coronary disease or with short-term mortality.

Electrocardiographic left ventricular (LV) hypertrophy has long been known to be associated with an abnormal ST-segment response to exercise; this association has been considered to represent a false-positive finding. There is a paucity of data relating echocardiographic LV mass to exercise ST-segment responses and other exercise parameters. As part of a routine evaluation, 1,408 men and 1,618 women from the Framingham Heart Study who were free of clinical cardiac disease underwent echocardiography and exercise treadmill testing according to the Bruce protocol at the same clinic visit. Abnormal ST-segment responses were defined both by standard criteria and the delta ST/heart rate index. LV mass was calculated from M-mode echocardiography. Echocardiographic LV hypertrophy was associated with an abnormal delta ST/heart rate index (in men, odds ratio [OR] 1.78, 95% confidence interval [CI] 1.05 to 3.01, p = 0.03; in women, OR 2.13, 95% CI 1.31 to 3.44, p = 0.002) but not with an abnormal response according to standard criteria. Echocardiographic LV hypertrophy was also associated with a lower likelihood of achieving an age-predicted target heart rate (in men, OR 0.45, 95% CI 0.31 to 0.65, p < 0.001; in women, OR 0.53, 95% CI 0.37 to 0.76, p < 0.001) and with a lower exercise capacity. Despite these associations, echocardiographic LV hypertrophy was associated with a higher peak heart rate-systolic blood pressure double product. In conclusion, echocardiographic LV hypertrophy is associated with an abnormal ST-segment response, a lower likelihood of achieving target heart rate, decreased exercise capacity, and an increased double product, which is a reflection of myocardial oxygen demand.

To determine the prognostic significance of asymptomatic left ventricular (LV) dilatation and LV systolic dysfunction, 1,493 men who were free of symptomatic cardiovascular disease underwent M-mode echocardiography and were then followed for a mean of 4.15 years. At baseline examination, 170 men (11.4%) had an abnormally high end-diastolic LV internal dimension (> or = 56 mm) and 76 (5.1%) had an abnormally low fractional shortening (< or = 30%). During the follow-up period, 68 men experienced 92 cardiovascular disease events. After adjusting for age and traditional cardiovascular disease risk factors in proportional-hazards analyses, fractional shortening was a significant independent predictor of cardiovascular risk (relative risk [RR] = 1.42, 95% confidence interval [CI] 1.12 to 1.81, for decrease of fractional shortening by 4%). Increased risk was also associated with combinations of low fractional shortening and high end-diastolic internal dimension (RR = 3.77, 95% CI 1.59 to 8.93) and with low percent fractional shortening with LV hypertrophy (RR = 5.93, 95% CI 1.97 to 17.85). In conclusion, subclinical LV dilatation and LV systolic dysfunction, although uncommon in men free of overt cardiovascular disease, are associated with increased risk for new cardiovascular disease events.