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We introduce random survival forests, a random forests method for the analysis of right-censored survival data. New survival splitting rules for growing survival trees are introduced, as is a new missing data algorithm for imputing missing data. A conservation-of-events principle for survival forests is introduced and used to define ensemble mortality, a simple interpretable measure of mortality that can be used as a predicted outcome. Several illustrative examples are given, including a case study of the prognostic implications of body mass for individuals with coronary artery disease. Computations for all examples were implemented using the freely available R-software package, randomSurvivalForest., Published in at http://dx.doi.org/10.1214/08-AOAS169 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)

“Let me tell you how I like to \_\_\_|\\_\_\_|\\_\_\_|\\_\__|.” Cardiovascular medicine trainees hear their faculty utter this phrase often. Let me tell you how I decide when, how, or whether to prescribe statins, or to order some type of noninvasive test, or to send a patient to the

Chronic kidney disease (CKD) increases cardiovascular risk and mortality. However, traditional cardiovascular risk factors do not adequately account for the substantial increase in mortality observed in CKD. The aim of this study was to examine the relative contributions of novel cardiovascular risk factors to the risk between CKD and mortality. The study population included 4,680 consecutive new patients from a tertiary care preventive cardiology program from 1996 to 2005. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) method. Baseline levels of traditional (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, hypertension, triglycerides, total cholesterol, and fasting glucose) and emerging (apolipoproteins A-I and B, lipoprotein[a], fibrinogen, homocysteine, and high-sensitivity C-reactive protein) risk factors were examined. All-cause mortality was obtained from the Social Security Death Index. There were 278 deaths over a median follow-up period of 22 months. CKD (estimated glomerular filtration rateor=60 ml/min/1.73 m(2)) was strongly associated with mortality after adjusting for traditional cardiovascular risk factors (hazard ratio 2.31, 95% confidence interval 1.77 to 3.11, p0.001) and with the addition of propensity score (hazard ratio 2.33, 95% confidence interval 1.75 to 3.10, p0.001). Of all the traditional and emerging risk factors monitored, only the addition of homocysteine and fibrinogen significantly attenuated the association between CKD and mortality (adjusted hazard ratio 1.73, 95% confidence interval 1.23 to 2.34, p0.001), explaining 38% of the attributable mortality risk from CKD. A significant interaction (p=0.004) between homocysteine and estimated glomerular filtration rate was observed whereby the annual mortality rate in subjects with CKD with homocysteine10 micromol/L (the bottom tertile) was similar to those with normal renal function (1% per year), whereas homocysteine levelsor=12.5 micromol/L (the top tertile) were associated with a sevenfold greater mortality risk. In conclusion, homocysteine and fibrinogen levels explain nearly 40% of the attributable mortality risk from CKD.

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.

Little is known about the association between exercise capacity and nonfatal cardiac events in patients referred for exercise treadmill testing (ETT). Our objective was to determine the prognostic importance of exercise capacity for nonfatal cardiac events in a clinical population.A cohort study was performed of 9191 patients referred for ETT. Median follow-up was 2.7 years. Exercise capacity was quantified as the proportion of age- and sex-predicted metabolic equivalents achieved and categorized as less than 85%, 85% to 100%, and greater than 100%. Individual primary outcomes were myocardial infarction, unstable angina, and coronary revascularization. All-cause mortality was a secondary outcome.Patients with lower exercise capacity were more likely to be female (55.38% vs 42.62%); to have comorbidities such as diabetes (23.16% vs 9.61%) and hypertension (59.43% vs 44.05%); and to have abnormal ETT findings such as chest pain on the treadmill (12.09% vs 7.63%), abnormal heart rate recovery (82.74% vs 64.13%), and abnormal chronotropic index (32.89% vs 12.20%). In multivariable analysis, including other ETT variables, lower exercise capacity (85% of predicted) was associated with increased risk of myocardial infarction (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.55-3.60), unstable angina (HR, 2.39; 95% CI, 1.78-3.21), coronary revascularization (HR, 1.75; 95% CI, 1.46- 2.08), and all-cause mortality (HR, 2.90; 95% CI, 1.88-4.47) compared with exercise capacity greater than 100% of predicted.Adjusting for patient characteristics and other ETT variables, reduced exercise capacity was associated with both nonfatal cardiovascular events and mortality in patients referred for ETT.

Importance Electrocardiography is the most commonly used diagnostic test in cardiology. Properly interpreted, it contributes significantly to the diagnosis and management of patients with cardiac disorders. Importantly, it is essential to the diagnosis of cardiac arrhythmias and the acute

The exercise treadmill test is recommended for risk stratification among patients with intermediate to high pretest probability of coronary artery disease. Posttest risk stratification is based on the Duke treadmill score, which includes only functional capacity and measures of ischemia.To develop and externally validate a post-treadmill test, multivariable mortality prediction rule for adults with suspected coronary artery disease and normal electrocardiograms.Prospective cohort study conducted from September 1990 to May 2004.Exercise treadmill laboratories in a major medical center (derivation set) and a separate HMO (validation set).33,268 patients in the derivation set and 5821 in the validation set. All patients had normal electrocardiograms and were referred for evaluation of suspected coronary artery disease.The derivation set patients were followed for a median of 6.2 years. A nomogram-illustrated model was derived on the basis of variables easily obtained in the stress laboratory, including age; sex; history of smoking, hypertension, diabetes, or typical angina; and exercise findings of functional capacity, ST-segment changes, symptoms, heart rate recovery, and frequent ventricular ectopy in recovery.The derivation data set included 1619 deaths. Although both the Duke treadmill score and our nomogram-illustrated model were significantly associated with death (P0.001), the nomogram was better at discrimination (concordance index for right-censored data, 0.83 vs. 0.73) and calibration. We reclassified many patients with intermediate- to high-risk Duke treadmill scores as low risk on the basis of the nomogram. The model also predicted 3-year mortality rates well in the validation set: Based on an optimal cut-point for a negative predictive value of 0.97, derivation and validation rates were, respectively, 1.7% and 2.5% below the cut-point and 25% and 29% above the cut-point.Blood test-based measures or left ventricular ejection fraction were not included. The nomogram can be applied only to patients with a normal electrocardiogram. Clinical utility remains to be tested.A simple nomogram based on easily obtained pretest and exercise test variables predicted all-cause mortality in adults with suspected coronary artery disease and normal electrocardiograms.

Background: Patients often have chest pain during exercise treadmill testing (ETT). However, the evidence supporting chest pain as an independent adverse prognostic factor during ETT has been inconsistent. The objective of this study was to determine the importance of chest pain during ETT in predicting future nonfatal cardiac hospitalizations. Methods: This was a prospective cohort study of all patients undergoing ETT between July 2001 and June 2004 in a large managed care organization. The primary outcome of interest was nonfatal cardiac hospitalizations including myocardial infarction and unstable angina. Multivariable Cox proportional hazards regression assessed the independent association between chest pain during ETT and subsequent nonfatal cardiac hospitalizations, adjusting patient, clinical and other treadmill variables. Results: Of the 8,459 patients undergoing ETT, 697 (8.2%) patients had chest pain during the test. Patients with chest pain during ETT had more nonfatal cardiac hospitalizations compared to patients without chest pain (11.9% vs. 2.6%; p < 0.0001). In multivariable Cox regression analysis, patients with chest pain during ETT remained at significantly increased risk of nonfatal cardiac hospitalizations (HR 3.44; 95% CI 2.60–4.56). The association between chest pain and adverse outcomes was consistent among prespecified subgroups including patients without ST-segment changes and with good functional capacity on ETT. Conclusions: Chest pain during ETT, even without ECG changes, predicts subsequent cardiac hospitalizations. Future studies should evaluate whether aggressive management of such patients can prevent subsequent hospitalizations. Copyright © 2007 Wiley Periodicals, Inc.

The Screening for Heart Attack Prevention and Education (SHAPE) Task Force has recommended a strategy of screening for coronary heart disease in which nearly all middle-aged and older adults would undergo an imaging test. However, this approach is not supported by evidence and is not endorsed by professional societies or the US Preventive Services Task Force. Physicians should follow established guidelines such as those of the third Adult Treatment Panel of the National Cholesterol Education Program.

Some recent clinical trials have concluded the following: • Patients who need noncardiac surgery and who are at risk of major cardiac events should not undergo revascularization with the aim of achieving a better perioperative outcome. They should have an office evaluation only and be prescribed a beta-blocker, if indicated. • Except for unusual, high-risk cases, patients at risk of stroke due to atherosclerotic carotid artery stenosis should undergo carotid endarterectomy rather than carotid stenting. Because the technology is still developing, however, carotid stenting may still be appropriate as part of a clinical trial. • Although drug-eluting coronary stents reduce the risk of restenosis in the short term, they pose a small but significant risk of in-stent thrombosis. Clopidogrel (Plavix) should be prescribed for at least a year following drug-eluting stent placement, and perhaps indefinitely. • Patients with known coronary heart disease have better outcomes if they receive aggressive statin therapy (eg, atorvastatin [Lipitor] 80 mg/day) to lower their serum levels of low-density lipoprotein cholesterol to less than 70 mg/dL.

Symptoms that suggest myocardial ischemia raise two questions: does the patient have severe, hemodynamically obstructive coronary artery disease, and is he or she at risk for premature death or an early, major nonfatal cardiac event? Noninvasive cardiac testing may help with the first question in patients with an intermediate risk of coronary artery disease, and with the second question in patients with either an intermediate or a high risk of disease. Although the diagnostic value of noninvasive tests may be overestimated owing to referral bias, these tests are powerful when used for prognostic purposes. In patients with a normal resting electrocardiogram and no prior revascularization, a regular exercise stress test without imaging should suffice. However, no randomized trials have been done to determine if this strategy leads to better outcomes than with empiric therapy.

Background— Health-related quality-of-life instruments have become important measures of early health outcomes after cardiac surgery. The relationship between quality of life after recovery from surgery and subsequent long-term survival has not previously been explored. Our objective was to determine whether the Duke Activity Status Index (DASI) was predictive of subsequent time-related survival after recovery from cardiac surgery. Methods and Results— We examined survival status among 6305 patients who underwent isolated coronary artery bypass grafting with or without valve procedures or isolated valve procedure between May 1995 and June 1998 who had a preoperative baseline and follow-up DASI. The postoperative DASI was administered nominally at 6 and 12 months. Baseline and perioperative variables and postoperative morbid events were prospectively collected concurrently with patient care. The end point was all-cause mortality. The Social Security Death Index was queried for survival status. Cox proportional-hazards analysis was used to study the associations between DASI, a number of traditional risk factors, and survival. Median follow-up was 8.6 years. The “dose-response” relationship between baseline and follow-up DASI and risk of long-term death was established. Follow-up DASI was associated with risk-adjusted long-term survival hazard ratio of 0.98 per unit increase (confidence limits, 0.97 to 0.98; P P =0.0005). Conclusions— Poor health-related quality of life after recovery from cardiac surgery identifies patients who are at risk for reduced long-term survival.

Following the first convincing trials in humans on the benefits of cholesterol lowering for preventionof atheroscleroticrelated events, in 1985, then-Director of the National Heart, Lung, and Blood Institute Robert Levyasserted that the cholesterol“question”wasno longer whether to treat high cholesterol levels, but rather when, inwhom,andhow.1For 30years, it hasbeenwell known that lowering blood cholesterol concentrations by a variety of drugs and other approaches reduces cardiovascular disease (CVD) risk.2Withmore trials in patient groupswith lower risk, including thosewith relatively low levels of low-density lipoprotein cholesterol (LDL-C),3 it has become clear that atherosclerotic cardiovascular disease (ASCVD) canbeprevented by loweringLDL-C levels, especiallywith statindrugs,2,3 in broad segments of the general population. However, the critical questions—when, in whom, and how to lower cholesterol— still remain. This Editorial, with new evidence from 2 reports in this issueof JAMA, addresses 2 of thesequestions: inwhom and how to treat cholesterol levels in 2015. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines2 recommended consideration of statin treatment for 4 clinical scenarios: (1) patients with clinical ASCVD including those with myocardial infarction, angina, or previous coronary revascularization; (2) patients without clinical ASCVD but with an LDL-C level higher than 190 mg/dL and without secondary cause; (3) patients aged 40 through 75 years without clinical ASCVD but with diabetes mellitus and LDL-C levels from 70 through 189mg/dL; and (4) patients aged 40 through 75 years without clinical ASCVD and diabetes, but with an LDL-C level of 70 through 189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. For the first 3 clinical scenarios there was almost universal acceptance with general agreement that the new recommendations were based on strong and consistent data.4 However, nearly immediately after release of the guidelines therewas considerable scrutiny and controversy regarding the fourth clinical scenario: primary prevention in adults without diabetes butwith an estimated 10-yearASCVD risk of 7.5% or higher. One group reported a set of analyses suggesting that the new ACC/AHA Pooled Cohort Equation overestimated risk in various populations,5 whereas others reported that, in properly selected cohorts, the new equation performedmore accurately thanpreviouslyused risk equations.6 Uncertainties about the accuracy of the risk calculator raised concerns about the wisdom of the newly lowered treatment threshold.Would the new guidelines lead tomassive and unjustified overtreatment ofmillions of people? Thequestionof in whom to use statins lingered. Basedonevidence frommultipleclinical trials, statindrugs havebeenshownto lowerCVDrisk forprimarypreventioneven among relatively low-risk people and even among thosewith relatively low LDL-C concentrations.3 Although a 10-year ASCVD risk threshold of 7.5%orhighermight initially seem to be a low threshold, many, indeed most, CVD events occur among the low-riskmembers of thepopulation.7Rose first described theseemingparadox8 that relatively fewASCVDevents occur in high-risk individuals simply because there are so few high-risk people in the population. The vast majority ofASCVDeventsoccuramong lower-riskpersonsbecause they comprise the greatest portion of the population.9 To prevent manymoreASCVDevents, it is reasonable to considerwhether statin drugs should be used in lower-risk individuals, and whether risk assessment by the new Pooled Cohort Equation leads to a reasonable level of treatment of at-risk people and a rational use of medical resources, even if potentially billions of people worldwide would be recommended for statin drugs.10 In this issue of JAMA, 2 reports suggest that the new risk threshold is likely to be reasonable and cost-effective; it may not even go far enough. If true, even a risk calculator that overestimates risk might be reasonable to use in the clinical setting. In the first report, using FraminghamOffspring Study data, Pursnani et al11 sought to determine whether the 2013 ACC/AHA guidelines improved identification of individuals who developed incident ASCVD, had evidence of coronary artery calcium, or had both compared with the National Cholesterol Education Program’s 2004 Updated Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines. As expected, among 2435 statin-naive people, the new Pooled Cohort Equation led to many more people being eligible for statin therapy (39% for ACC/AHA guidelines vs 14% for ATP III guidelines). However, the newly statin-eligible people were at markedly increased risk for experiencing clinical events, for having elevated levels of coronary calcium, or for having both. These findings offer assurance that the 2013 Pooled Cohort Equation can efficiently and appropriately identify those destined to develop a major ASCVD event in the near future. However, identifying those at risk with reasonable accuracy is only part of the decision-making process. An imporRelated articles pages 134 and 142 Opinion

From the Editorialists: We thank Drs. Soriano and Morera for supporting the National Heart, Lung, and Blood Institute’s (NHLBI’s) recent Strategic Visioning effort to collectively identify the greatest unmet needs in heart, lung, blood, and sleep research (1). They are correct in noting the central role tobacco plays in many diseases that fall within the mission of the NHLBI. We are also grateful to Dr. Jiminez-Ruiz and colleagues from the European Respiratory Society's Tobacco Control Committee for their thoughtful letter and key literature highlighting the importance of strategies for the effective prevention and treatment of tobacco use to foster and preserve human health. The points made in these letters illustrate the kind of feedback we hope to receive from the research community on this and other topics as we move to shape future research priorities. The NHLBI will certainly consider mission-specific compelling questions and critical challenges identified through this process relating to tobacco and its adverse effects on heart, lung, blood, and sleep health. The NHLBI’s new Strategic Visioning forum (http://nhlbistrategicvisioning.ideascale.com/) provides the broad stakeholder community an opportunity to engage in real-time conversations around topics for the NHLBI to address over the next decade, including tobacco and many other important issues. We encourage our communities to actively participate in this novel process to shape our future research directions. We believe that joint efforts by the NHLBI and the research, patient, and provider communities will bring optimal and sustained cardiopulmonary health within reach, with the potential to improve the lives of millions of individuals.

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.

Ultrasonography can screen for abdominal aortic aneurysms (AAAs) safely, cheaply, and accurately. Once detected, an AAA can be monitored and repaired before it is likely to rupture. The US Preventive Services Task Force recently recommended a one-time screening for AAAs by ultrasonography for men age 65 to 75 years who have ever smoked. We should consider expanding the recommendations to include others at risk.

The purpose of this study was to develop 30-day and 1-year risk stratification models for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients that incorporate quantitative ST-segment depression and novel biomarkers.Several novel biomarkers have changed the risk profile of ACS; thus, the reassessment of traditional indicators such as ST-segment depression in this new context is warranted.Multivariable logistic regression was used to identify significant predictors of 30-day death and death/myocardial infarction (MI) and 1-year mortality in 7,800 NSTE-ACS patients enrolled in the GUSTO-IV (Global Utilization of Strategies to Open Occluded Arteries-IV ACS) trial between 1998 and 2000.Among all other predictors, the degree of ST-segment depression had the highest prognostic value for 30-day death, 30-day death/MI, and 1-year death. Troponin T (TnT), creatinine clearance, N-terminal pro-brain natriuretic peptide (NT-proBNP), heart rate, and age were also highly influential on adverse outcomes. Unlike TnT and NT-proBNP, C-reactive protein was only predictive of long-term death. In contrast to mortality, the contribution of TnT to predicting 30-day death/MI increased, whereas NT-proBNP's role was attenuated. The discriminatory power was excellent (c-index [adjusted for over-optimism]: 0.82 [30-day death]; 0.72 [30-day death/MI]; 0.81 [1-year]).In this large contemporary study of NSTE-ACS patients, novel insights into risk stratification were observed-in particular, the utility of quantitative ST-segment depression and multiple biomarkers. Collection of these indicators in future NSTE-ACS populations is recommended to evaluate generalizability and clinical application of these findings.

Aims The optimal revascularization strategy in patients with symptomatic multivessel coronary artery disease (CAD) and previous coronary artery bypass grafting (CABG) remains unknown. Methods and results We evaluated all patients with previous CABG undergoing isolated, non-emergency multivessel revascularization between 1 January 1995 and 31 December 2000. The analysis concentrated on the independent predictors of the revascularization method, as well as on long-term mortality and its predictors, after calculating a propensity score for the method of revascularization. There were 2191 patients (1487 with reoperation and 704 with percutaneous coronary intervention, PCI) in the study. The most important factors in choosing reoperation were presence of more diseased or occluded grafts, previous infarction, lower ejection fraction (EF), longer interval from first CABG, and more total occlusions of native arteries, as well as absence of a patent mammary graft. The distribution of the propensity score was skewed towards the two extremes. At 5 years, the unadjusted cumulative survival was 79.5% for CABG and 75.3% for PCI, P ¼ 0.008. After adjustment for the propensity score for PCI vs. CABG, PCI was associated with a hazard ratio of 1.47 (0.94–2.28), P ¼ 0.09. The most powerful predictors of mortality were higher age and lower EF. Conclusion The choice of the revascularization method in patients with previous CABG is dictated mostly by anatomical considerations and less by clinical characteristics. In contrast, clinical characteristics predominantly affect long-term outcome, whereas the method of revascularization has a limited effect. A randomized clinical trial addressing this important segment of the population with ischaemic heart disease is warranted.

BACKGROUND: Recent studies have demonstrated that exercise capacity is an independent predictor of mortality in women. Normative values of exercise capacity for age in women have not been well established. Our objectives were to construct a nomogram to permit determination of predicted exercise capacity for age in women and to assess the predictive value of the nomogram with respect to survival. METHODS: A total of 5721 asymptomatic women underwent a symptom-limited, maximal stress test. Exercise capacity was measured in metabolic equivalents (MET). Linear regression was used to estimate the mean MET achieved for age. A nomogram was established to allow the percentage of predicted exercise capacity to be estimated on the basis of age and the exercise capacity achieved. The nomogram was then used to determine the percentage of predicted exercise capacity for both the original cohort and a referral population of 4471 women with cardiovascular symptoms who underwent a symptom-limited stress test. Survival data were obtained for both cohorts, and Cox survival analysis was used to estimate the rates of death from any cause and from cardiac causes in each group. RESULTS: The linear regression equation for predicted exercise capacity (in MET) on the basis of age in the cohort of asymptomatic women was as follows: predicted MET = 14.7 - (0.13 x age). The risk of death among asymptomatic women whose exercise capacity was less than 85 percent of the predicted value for age was twice that among women whose exercise capacity was at least 85 percent of the age-predicted value (P

Background— Peak oxygen uptake (peak V̇ o 2 ) is a strong predictor of mortality and is commonly used in the evaluation of patients for cardiac transplantation. β-Blockers reduce mortality in patients with heart failure, without influencing peak V̇ o 2 , raising the possibility that peak V̇ o 2 is no longer suitable as an indicator of prognosis in these patients. Methods and Results— We analyzed prospectively gathered data on 2105 patients referred for cardiopulmonary testing for all-cause mortality and for occurrence of death or transplantation. Patients receiving β-blockers were younger, more likely to have coronary disease, and had a greater mean ejection fraction but had a similar peak V̇ o 2 . There were 555 deaths (26%) and 194 (9%) transplants during a median follow-up of 3.5 years. Peak V̇ o 2 was a predictor of mortality irrespective of β-blocker use; a decrease of 1 mL · kg −1 · min −1 resulted in an adjusted hazard ratio (HR) of 1.13 (95% CI 1.09 to 1.17, P P o 2 values became very low (≈10 mL · kg −1 · min −1 ), at which level survival rates were equally poor. Conclusion— Peak V̇ o 2 is a determinant of survival in patients in heart failure even in the setting of β-blockade. Because of improved survival in patients treated with β-blockers, the cut point value of 14 mg · kg −1 · min −1 for referral for cardiac transplantation in these patients requires reevaluation, and a lower cut point may be more appropriate.

This article updates the 1994 American Heart Association scientific statement on cardiac rehabilitation. It provides a review of recommended components for an effective cardiac rehabilitation/secondary prevention program, alternative ways to deliver these services, recommended future research directions, and the rationale for each component of the rehabilitation/secondary prevention program, with emphasis on the exercise training component.

Severe mitral regurgitation developed in a patient after a lateral-impact motor vehicle accident. The papillary muscle head was disrupted without evidence of other myocardial injury. We hypothesize that a dramatic and sudden increase in intrathoracic pressure may have produced the injury. The patient experienced progressive heart failure and underwent successful mitral valve repair 9 days after the accident.

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.

ContextThe usefulness of exercise stress test results and global cardiovascular risk systems for predicting all-cause mortality in asymptomatic individuals seen in clinical settings is unclear.ObjectivesTo determine the validity for prediction of all-cause mortality of the Framingham Risk Score and of a recently described European global scoring system Systematic Coronary Risk Evaluation (SCORE) for cardiovascular mortality among asymptomatic individuals evaluated in a clinical setting and to determine the potential prognostic value of exercise stress testing once these baseline risks are known.Design, Setting, and ParticipantsProspective cohort study of 3554 asymptomatic adults between the ages of 50 and 75 years who underwent exercise stress testing as part of an executive health program between October 1990 and December 2002; participants were followed up for a mean of 8 years.Main Outcome MeasuresGlobal risk based on the Framingham Risk Score and the European SCORE. Prospectively recorded exercise stress test result abnormalities included impaired physical fitness, abnormal heart rate recovery, ventricular ectopy, and ST-segment abnormalities. The primary end point was all-cause mortality.ResultsThere were 114 deaths. The c-index, which corresponds to receiver operating characteristic curve values, and the Akaike Information Criteria found that the European SCORE was superior to the Framingham Risk Score in estimating global mortality risk. In a multivariable model, independent predictors of death were a higher SCORE (for 1% predicted increase in absolute risk, relative risk [RR], 1.07; 95% confidence interval [CI], 1.04-1.09; P

Background— Although most randomized clinical trials have suggested that long-term survival rates after percutaneous coronary intervention (PCI) or surgical multivessel coronary revascularization (CABG) are equivalent, some post hoc analyses in high-risk groups and adjustment for severity of coronary disease have suggested higher mortality after PCI. Methods and Results— We studied 6033 consecutive patients who underwent revascularization in the late 1990s. PCI was performed in 872 patients; 5161 underwent CABG. Half the patients had significant left ventricular dysfunction or diabetes. Propensity analysis to predict the probability of undergoing PCI according to 22 variables and their interactions was used. The C-statistic for this model was 0.90, indicating excellent discrimination between treatments. There were 931 deaths during 5 years of follow-up. The 1- and 5-year unadjusted mortality rates were 5% and 16% for PCI and 4% and 14% for CABG (unadjusted hazard ratio, 1.13; 95% CI, 1.0 to 1.4; P =0.07). PCI was associated with an increased risk of death (propensity-adjusted hazard ratio, 2.3; 95% CI, 1.9 to 2.9; P P ≤0.01 for all) were renal dysfunction, age, diabetes mellitus, chronic lung disease, peripheral vascular disease, left main trunk stenosis, and extent of coronary disease (Duke angiographic score). Conclusions— In patients with multivessel coronary artery disease and many high-risk characteristics, CABG was associated with better survival than PCI after adjustment for risk profile.

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.

Donor cause of death has been suggested to have a significant impact on cardiac transplant morbidity and mortality. Our objective was to evaluate the impact of donor spontaneous intracranial bleeding on clinical outcome after heart transplantation. A group of 160 recipients underwent cardiac transplantation from donors with spontaneous intracranial bleeding (ICB group). These were compared with 197 recipients who were transplanted from trauma donors (Trauma group). A higher 4-year mortality rate was noted in the ICB group (24% vs. 14%, p=0.015). ICB as a cause of donor death was an independent predictor of recipient mortality (adjusted hazard ratio 2.02, 95% CI 1.27-3.40, p

An extensive literature search that involves diverse populations has convincingly and consistently shown a very powerful and inverse association between functional capacity and risk of death (1–12). Although most studies have focused on men, more recent work has shown that a very similar pattern exists among women: those more physically active or who have a greater exercise capacity are substantially less likely to die or experience major cardiovascular events (13–16). This chapter reviews the evidence relating functional capacity in women to cardiovascular outcome and also discusses the ongoing sedentary lifestyle epidemic among women of all ages.

The decision to prescribe aspirin to prevent a coronary event is not straightforward, and requires physicians to balance the risk of a coronary event with the risk of adverse events from aspirin. Although evidence-based medicine shows the way, it does not answer all the questions, especially for patients at intermediate risk.

ObjectivesThe study was done to determine the prognostic importance of frequent ventricular ectopy in recovery after exercise among patients with systolic heart failure (HF).BackgroundAlthough ventricular ectopy during recovery after exercise predicts death in patients without HF, its prognostic importance in patients with significant ventricular dysfunction is unknown.MethodsSystematic electrocardiographic data during rest, exercise, and recovery were gathered on 2,123 consecutive patients with left ventricular systolic ejection fraction ≤35% who were referred for symptom-limited metabolic treadmill exercise testing. Severe ventricular ectopy was defined as the presence of ventricular triplets, sustained or nonsustained ventricular tachycardia, ventricular flutter, polymorphic ventricular tachycardia, or ventricular fibrillation. The primary end point was all-cause mortality, with censoring for interval cardiac transplantation.ResultsOf 2,123 patients, 140 (7%) had severe ventricular ectopy during recovery. There were 530 deaths (median follow-up among survivors 2.9 years). Severe ventricular ectopy during recovery was associated with an increased risk of death (three-year death rates 37% vs. 22%, hazard ratio [HR] 1.76; 95% confidence interval [CI] 1.32 to 2.34, p < 0.0001). After adjustment for ventricular ectopy at rest and during exercise, peak oxygen uptake, and other potential confounders, severe ventricular ectopy during recovery remained predictive of death (adjusted HR 1.48; 95% CI 1.10 to 1.97; p = 0.0089), whereas ventricular ectopy during exercise was not predictive of death in this cohort.ConclusionsSevere ventricular ectopy during recovery after exercise is predictive of increased mortality in patients with severe HF and can be used as a prognostic indicator of adverse outcomes in HF cohorts.

Elevated inflammatory markers are associated with worse outcome after percutaneous coronary artery interventions (PCI). An elevation in the white blood cell (WBC) count is a nonspecific response to inflammation. We hypothesized that an elevated WBC count would be a predictor of death in patients undergoing PCI.A total of 4450 patients undergoing percutaneous coronary artery intervention were divided into quintiles, based on their preprocedural WBC count (mean WBC count: quintile 1, 5.08 x 10(3)/muL; quintile 2, 6.58 x 10(3)/muL; quintile 3, 7.70 x 10(3)/muL; quintile 4, 9.14 x 10(3)/muL; and quintile 5, 13.4 x 10(3)/muL). Vital status was assessed through the use of the Social Security Death Index.There were a total of 504 deaths over a follow-up period of 48 months. The best survival was seen in quintile 2, with an increase in long-term mortality rates seen with both a higher or a lower WBC count (P.001). This J-shaped curve was preserved after multivariate adjustment, with the adjusted hazard ratio of mortality relative to quintile 2 being 1.95 (95% CI, 1.40 to 2.73) in quintile 1, 1.66 (95% CI, 1.18 to 2.33) in quintile 3, 2.31 (95% CI, 1.67 to 3.17) in quintile 4, and 2.42 (95% CI, 1.76 to 3.34) in quintile 5.A low or an elevated preprocedural WBC count in patients undergoing PCI is associated with an increased risk of long-term death. Our result provides further evidence to support the important role of inflammation in coronary artery disease.

OBJECTIVES We sought to determine the association of etiology of constrictive pericarditis (CP), pericardial calcification (CA), and other clinical variables with long-term survival after pericardiectomy. BACKGROUND Constrictive pericarditis is the result of a spectrum of primary cardiac and noncardiac conditions. Few data exist on the cause-specific survival after pericardiectomy. The impact of CA on survival is unclear. METHODS A total of 163 patients who underwent pericardiectomy for CP over a 24-year period at a single surgical center were studied. Constrictive pericarditis was confirmed by the surgical report. Vital status was obtained from the Social Security Death Index. RESULTS Etiology of CP was idiopathic in 75 patients (46%), prior cardiac surgery in 60 patients (37%), radiation treatment in 15 patients (9%), and miscellaneous in 13 patients (8%). Median follow-up among survivors was 6.9 years (range 0.8 to 24.5 years), during which time there were 61 deaths. Perioperative mortality was 6%. Idiopathic CP had the best prognosis (7-year Kaplan-Meier survival: 88%, 95% confidence interval [CI] 76% to 94%) followed by postsurgical (66%, 95% CI 52% to 78%) and postradiation CP (27%, 95% CI 9% to 58%). In bootstrap-validated proportional hazards analyses, predictors of poor overall survival were prior radiation, worse renal function, higher pulmonary artery systolic pressure (PAP), abnormal left ventricular (LV) systolic function, lower serum sodium level, and older age. Pericardial calcification had no impact on survival. CONCLUSIONS Long-term survival after pericardiectomy for CP is related to underlying etiology, LV systolic function, renal function, serum sodium, and PAP. The relatively good survival with idiopathic CP emphasizes the safety of pericardiectomy in this subgroup.

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

Background:Although myocardial revascularization is often performed to alleviate dwumented myocardial ischemia, the impact of this practice on survival has not been demonstrated in randomized trials. Standard obsewatlonal analyses suffer from severe confounding and selection biases. Methods:We used propensity analysis to determine whether revascularization following stress echocardiography (STE) improved survival among 7957 patients in 3 different institutions. During the first 3 months after STE, 317 (4%) underwent revascularization. We generated a propensity score using logistic modeling involving 13 demographic, clinical, and echocardiographic variables. Results: Patients who underwent revascularization were older (64 vs. 61 years) and more likely to have ischemia (63% vs. 20%). We propensity matched these 317 patients with 317 patients who did not undergo revascularization with resulting similarities of age (64 vs 64 years) and equivalent rates of ischemia (63% vs 62%). During 5 years of follow- up, 75 patients (25%) who did not undergo revascularization died, whereas only 50 patients (16%) who did undergo revascularization died (propensity and covariate adjusted hazard ratio after 3 months 0.51, 95% Cl 0.31-0.83, P=O.O073). Absolute benefits were primarily noted in patients with ischemia in 12 vascular territories (Figure). Conclusion: Early myocardial revascularization is likely to lead to a survival benefit, especially among patients with inducible multivessel ischemia.

Exercise-induced ventricular ectopy predicts an increased risk of death in population-based cohorts. We sought to examine in a clinical cohort the prognostic importance of ventricular ectopy immediately after exercise, when reactivation of parasympathetic activity occurs. We hypothesized that ventricular ectopy after exercise (i.e., during the recovery phase) would predict an increased risk of death better than ventricular ectopy during exercise.We studied 29,244 patients (mean [+/-SD] age, 56+/-11 years; 70 percent men) who had been referred for symptom-limited exercise testing without a history of heart failure, valve disease, or arrhythmia. Frequent ventricular ectopy was defined by the presence of seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, ventricular couplets or triplets, ventricular tachycardia, ventricular flutter, torsade de pointes, or ventricular fibrillation.Frequent ventricular ectopy occurred only during exercise in 945 patients (3 percent), only during recovery in 589 (2 percent), and during both exercise and recovery in 491 (2 percent). There were 1862 deaths during a mean of 5.3 years of follow-up. Frequent ventricular ectopy during exercise predicted an increased risk of death (five-year death rate, 9 percent, vs. 5 percent among patients without frequent ventricular ectopy during exercise; hazard ratio, 1.8; 95 percent confidence interval, 1.5 to 2.1; P0.001), but frequent ventricular ectopy during recovery was a stronger predictor (11 percent vs. 5 percent; hazard ratio, 2.4; 95 percent confidence interval, 2.0 to 2.9; P0.001). After propensity matching for confounding variables, frequent ventricular ectopy during recovery predicted an increased risk of death (adjusted hazard ratio, 1.5; 95 percent confidence interval, 1.1 to 1.9; P=0.003), but frequent ventricular ectopy during exercise did not (adjusted hazard ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.53).Frequent ventricular ectopy during recovery after exercise is a better predictor of an increased risk of death than ventricular ectopy occurring only during exercise.

Event rates associated with a normal or low-risk myocardial perfusion SPECT imaging study have been shown by numerous investigators to be associated with1%/y of follow-up. Thus, the aim of this study was to evaluate the prognostic value of a normal (99m)Tc-tetrofosmin study in a geographically diverse registry of patients undergoing stress myocardial perfusion SPECT. A total of 4,728 consecutively tested patients who underwent stress (99m)Tc-tetrofosmin SPECT at 5 U.S. hospitals were included in this series.Patients were monitored for the occurrence of major cardiac events and hospitalizations. Uniform methods of data collection and standardized epidemiologic methods for follow-up were used at all centers. We used a risk-adjusted, Cox proportional hazards model to assess time to cardiac death.Of the 4,728 patients, one third underwent adenosine stress SPECT and two thirds underwent treadmill exercise. The observed annualized survival rate for those patients with a normal (99m)Tc-tetrofosmin study was 0.6%. Similarly, excellent survival rates were noted for the male and female subsets of this population as well as for patients who could exercise and for those undergoing pharmacologic stress testing. Compared with prior published outcomes studies on stress (201)Tl or (99m)Tc-sestamibi SPECT, the overall survival rates were similar and ranged from 99.3% to 99.7%.Results from this large multicenter registry provide further supportive evidence that the excellent prognosis associated with a normal SPECT scan is independent of the radiopharmaceutical used.