Charles K. Morris

Prediction of Cardiovascular Death in Men Undergoing Noninvasive Evaluation for Coronary Artery Disease

Clinical evaluation, exercise testing, and coronary angiography are used routinely by physicians to decide whether interventions are needed in patients with coronary artery disease [1, 2]. Various conflicting clinical prediction rules have been proposed [3]. In a first report, we described our method of outcome assessment in patients who had undergone exercise testing and coronary angiography within a 3-month period and compared our prediction rules with those from other samples [4]. Our two main findings were that the results of coronary angiography and exercise-induced ST depression were not independently associated with cardiovascular death or infarct-free survival. The purpose of this investigation was to predict cardiovascular death using variables available from a standard noninvasive work-up of patients with known or suspected coronary artery disease. The use of this larger cohort, uninfluenced by selection for cardiac catheterization, allowed assessment of work-up bias. Methods Patients Patients were selected from a consecutive series of 3609 persons who underwent routine clinical exercise testing between 1984 and 1990; 30% of this group had coronary angiography within 3 months of testing and were excluded from the analysis. Also excluded were women (who constituted less than 2% of the sample), patients with significant valvular disease, and those who had previous coronary artery bypass surgery. Most of the remaining 2456 (84%) patients had been referred for testing because of chest pain or for the evaluation of exercise capacity. Clinical Definitions Myocardial infarction was defined by the presence of two or more of the following factors: 1) serial electrocardiographic changes; 2) typical chest pain; and 3) myocardial enzyme increase. Congestive heart failure was defined by typical symptoms and signs, plus echocardiographic or radiographic confirmation of cardiomegaly and pulmonary edema. Before treadmill testing, angina pectoris was classified as typical if the patient described substernal pressure, tightness, or pain that was brought on by exertion or emotions, lasted several minutes, and was relieved by nitroglycerin or rest. Angina was considered atypical in the absence of one or more of these features if the pain was thought to be cardiac in origin. Exercise Testing The exercise test was done using a standard progressive treadmill protocol [5]. Except for patients undergoing testing before discharge after myocardial infarction, each test was sign or symptom limited using standard recommended criteria for termination [2]; fatigue or chest pain was the reason for termination in most patients. In addition to the maximal systolic blood pressure achieved, the blood pressure response during exercise was coded as a score reflecting exercise-associated changes in systolic blood pressure (0 points = increase > 40 mm Hg; 1 point = 31 to 40 mm Hg; 2 points = 21 to 30 mm Hg; 3 points = 11 to 20 mm Hg; 4 points = 0 to 11 mm Hg; and 5 points = decrease below standing systolic blood pressure taken before testing) [6]. The treadmill was stopped abruptly at the completion of exercise, and the patient was placed in the supine position within 1 minute [7]. Exercise capacity was estimated in multiples of resting oxygen consumption (METs) and was also analyzed as a percentage of normal for age according to an equation derived from a normal subset of our referral group [8]. Electrocardiographic Measurements Left ventricular hypertrophy was coded according to Romhilt and Estes criteria [9]. Patients lacking left ventricular hypertrophy with more than 0.5 mm ST depression in any lead were coded as having resting ST depression. The exercise electrocardiogram was interpreted as previously described [7]. Measurement of Outcome Variable Since 1984, the Department of Veterans Affairs Health Care System has developed a series of programs to support Veterans Affairs Medical Center clinical functions as part of the Decentralized Hospital Computer Project (DHCP). Death certificates are routinely completed by Veterans Affairs Medical Center physicians for inpatient and outpatient deaths. Information on care received elsewhere is routinely requested for clinical purposes, and all patients were scheduled for routine appointments at 6-month intervals after testing. Data on hospitalizations and deaths are entered, and retrieval programs are available to obtain dates and information regarding the most recent clinical visit and prescription received as well as those regarding hospitalization or death. To avoid bias, the coding of death certificates and other outcome variables was blinded to the predictor (exposure) variables. Although not designed for research purposes, this administrative and clinical database helped us obtain complete follow-up information. Data Analysis All data were entered into R:Base (Microrim, Redmond, Washington) and were analyzed using R:Base, Statgraphics (Statistical Graphics Corporation, Rockville, Maryland), True Epistat (Epistat Services, Richardson, Texas), Confidence Interval Analysis (American College of Physicians, Philadelphia, Pennsylvania), and EGRET (SERC, Seattle, Washington) on a standard 80386-SX-based personal computer (Vectra RS/20C, Hewlett Packard, Palo Alto, California). Survival time in person-days was measured from the time of the exercise test and was censored at the time of noncardiac death, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty. Survival Analysis Analysis was done to predict cardiovascular deaths and infarct-free survival (that is, cardiovascular death and nonfatal myocardial infarction). Kaplan-Meier survival curves were evaluated stratifying one or more variables to explore the data for interactions. The Cox proportional-hazard model was then applied to clinical and resting electrocardiographic variables, hemodynamic variables from treadmill testing, and electrocardiographic changes and angina during the treadmill test. Each variable grouping was also analyzed independently and by combining the strongest or most logical variables. Analysis was also done on the total group, including those who underwent catheterization (588 patients) because they were seen before the decision to catheterize. Results Follow-up Computed clinical information was available for all 2546 patients, and follow-up was initiated in February 1991. Of these, 85% were confirmed to be alive by a clinic visit or prescription filled at a minimum of 1 year after their treadmill date, and 187 (7.5%) had died after a mean follow-up period of 45 17 months. Contact either by telephone or letter led to follow-up and verification of vital status in 99%. After review of autopsy, death certificate, or hospital charts, 119 of the deaths (63%) were classified as cardiovascular. Forty-four patients had nonfatal myocardial infarctions, 34 developed congestive heart failure, 46 underwent coronary bypass surgery, and 18 received one or more angioplasties. The average annual cardiac mortality rate was 1.5%. Clinical Characteristics Table 1 shows the clinical characteristics of the study cohort grouped by end point. The mean age (SD) was 59 10 years. One fifth of the patients had typical angina pectoris, and one fifth had a history of previous myocardial infarction or electrocardiograms with diagnostic Q waves. Medications were not changed or withheld before exercise testing; 22% were taking -blockers, and 8% were taking digoxin. Statistically significant differences between the no cardiovascular event and cardiovascular death groups were observed for age, congestive heart failure, myocardial infarction, digoxin use, and most resting electrocardiographic abnormalities (P < 0.01). Table 1. Clinical Features of the Total Study Population and Number and Percentage with a Given End Point Hemodynamic and Electrocardiographic Responses Group averages for pre-exercise standing heart rate, systolic blood pressure, and double product were 76 beats per minute, 130 mm Hg, and 9800 (heart rate times systolic blood pressure), respectively. Table 2 shows the hemodynamic and electrocardiographic responses during the exercise test. No significant differences were found among end point groups for perceived exertion and occurrence of premature ventricular contractions. Table 2. Hemodynamic and Exercise Electrocardiographic Features of the Total Study Population* Cox Proportional Hazards Model The univariate scores and P values for the variables are listed in Appendix Table. No significant interactions were discovered, and thus none are included. Similar results were obtained both when infarct-free survival was considered as an end point (variable order, coefficients, and level of significance) and when the entire cohort was analyzed. The score test statistic listed is the relative weight or importance assigned the variables in the Cox model. Using stepwise selection, the Cox model was allowed to build on each variable group (clinical variables alone entered first with subsequent addition of other variables) to arrive at the final model that chose history of congestive heart failure or digoxin use, the change in systolic blood pressure score, exercise capacity (METs), and exercise-induced ST depression. A score was then formed using the coefficients from the Cox model with only these four variables entered as follows: 5 x (congestive heart failure or digoxin use [yes = 1; no = 0]) + exercise-induced ST depression in millimeters + change in systolic blood pressure score METs. Three groups were formed using a scoring system in which 2 indicated low risk, 2 to 2 indicated moderate risk, and greater than 2 indicated high risk. The hazard ratios, confidence intervals (CIs), and P values for these groups are shown in Table 3, and the Kaplan-Meier survival curves are shown in Figure 1. This score enabled identification of a low-risk group (77% of the cohort) with an annual cardiovascular mortality rate of less th

Prediction of cardiovascular death by means of clinical and exercise test variables in patients selected for cardiac catheterization

The objective of this report is the development of a population-specific prediction rule based on clinical and exercise test data that would estimate the risk of cardiovascular death in patients selected for cardiac catheterization. Prospective data and follow-up information were obtained from patients who underwent cardiac catheterization soon after clinical assessment and exercise testing. Males (n = 588) referred for evaluation of coronary heart disease from 1984 to 1990 were selected after exclusion of patients with significant valvular heart disease and patients with prior cardiac surgery. Half had a prior myocardial infarction and half complained of typical angina pectoris. All patients performed a treadmill test and were selected for clinical reasons to undergo coronary angiography within 3 months. Over a mean follow-up period of 2.5 years (+/- 1.4 years), there were 39 cardiovascular deaths and 45 nonfatal myocardial infarctions. The Cox proportional hazards model demonstrated the following characteristics to be statistically significant independent predictors of time until cardiovascular death: history of congestive heart failure (hazards ratio of 4), ST depression on the resting ECG (hazards ratio of 3), and a drop in systolic blood pressure below the resting value during exercise (hazards ratio of 5). Exercise-induced ST depression was not associated with either death or nonfatal myocardial infarction. A simple score based on one item of clinical information (history of congestive heart failure), a resting ECG finding (ST depression), and an exercise test response (exertional hypotension) stratified our patients for 4 years after testing from 75% with a low risk (annual cardiac mortality rate of 1%), 17% with a moderate risk (annual mortality rate of 7%), and 1% with a high risk (annual cardiac mortality rate of 12%, with a hazards ratio of 20 and 95% confidence interval from 6 to 70X). It was concluded that the variables available from the usual noninvasive workup of patients with known or suspected coronary artery disease enable prediction of risk of cardiovascular death. Three quarters of those usually undergoing cardiac catheterization can be identified by simple noninvasive variables as being at such low risk that invasive intervention is unlikely to improve prognosis.

Prediction of atherosclerotic cardiovascular death in men using a prognostic score

Treadmill and clinical data were gathered prospectively on consecutive patients who underwent exercise testing for evaluation for coronary artery disease in a 1,200 bed Veterans Affairs Medical Center. From 3,609 men referred for exercise testing from 1984 to 1990, 3,134 patients remained after excluding those with significant valvular heart disease and those with prior coronary artery bypass surgery. Of these, 588 were selected for clinical reasons to undergo cardiac catheterization within 3 months of evaluation leaving 2,546 who were not selected. Over 3 years, there were 158 cardiovascular deaths, 99 nonfatal myocardial infarcts and 183 patients who underwent coronary artery bypass surgery. In the total population, the Cox proportional-hazards model demonstrated the following characteristics to be statistically significant independent predictors of time until cardiovascular death: a history of congestive heart failure and/or taking digoxin, exercise-induced ST depression, the change in systolic blood pressure during exercise, and exercise capacity in METs. Using the Cox model coefficients to weight the variables, a simple score (the Veterans Affairs Prognostic Score) was constructed based on these items. Average annual cardiovascular mortality was plotted against the score enabling its estimation for any given patient. In the subgroup selected for cardiac catheterization (n = 588), the mean score was greater, consistent with a poorer prognosis, compared with the total population; 53% (n = 312) had a score < -2 associated with an annual mortality < 2%. Thus, in over half of the patients selected for catheterization, the catheterization was unnecessary if performed to lessen their chance of cardiovascular death, since no intervention could improve their prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic determinants of exercise capacity in chronic atrial fibrillation

To evaluate the response of patients with chronic atrial fibrillation (AF) to exercise, 79 male patients (mean age 64 +/- 1 years) with AF underwent resting two-dimensional and M-mode echocardiography and symptom-limited treadmill testing with ventilatory gas exchange analysis. Patients were classified by underlying disease into five subgroups: no underlying disease (LONE: n = 17), hypertension (HT: n = 11), ischemic heart disease (n = 13), cardiomyopathy or history of congestive heart failure (CHF: n = 26), and valvular disease (n = 12). A higher maximal heart rate than expected for age was observed (175 vs 157 beats/min), which was most notable in the LONE and HT subgroups. Maximal oxygen uptake (VO2 max) was lower than expected for age in all groups. Patients with CHF had a lower resting ejection fraction than all other patients (p < 0.001), a lower VO2 max, and a lower maximal heart rate than LONE and HT patients (p < 0.001). Stepwise regression analysis demonstrated that echocardiographic measurements at rest were poor predictors of VO2 max and VO2 at the ventilatory threshold. Among clinical, morphologic, and exercise variables, maximal systolic blood pressure accounted for the greatest variance in exercise capacity, but it explained only 35%. In patients with AF the higher than predicted maximal heart rates may be a compensatory mechanism for maintaining exercise capacity after the loss of normal atrial function. However, even in the absence of underlying disease, it does not appear to compensate fully for a compromised exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular Benefits of Improved Exercise Capacity

SummaryThe evidence suggesting that regular exercise can help to prevent coronary artery disease is overwhelming. While some studies have suggested that exercise will not provide health benefits, our inactive population needs to pay heed to the substantial data presented by the many international health organisations suggesting the opposite. The American Heart Association Medical/Scientific Statement on Exercise emphasised the large role regular aerobic physical activity plays in the prevention of cardiovascular disease. Several human studies have also demonstrated the positive effects of long term exercise on the human heart. For example, it has been shown that a consistent exercise programme can lessen the impact of atherosclerotic plaques through increasing coronary artery diameter. Echocardiography studies on a training group of competitive swimmers have shown that exercise training can induce rapid changes in left ventricular dimensions and mass, which can ultimately lead to an increased stroke volume and increased maximal oxygen consumption. Studies on sedentary individuals have also demonstrated an increase in maximal oxygen uptake with a regular endurance exercise programme. In addition to these health benefits, habitual dynamic exercise can also decrease the likelihood of a cardiac event. Others have demonstrated a 50% lower incidence of coronary events in those individuals maintaining rigorous activity 2 days a week. With the preponderance of evidence revealing the health benefits of habitual exercise, it is striking to learn that more than 50% of the US population exercises for less than 20 minutes, 3 days a week. The widespread nature of this sedentary lifestyle makes inactivity an attributable fraction of the total risk factors associated with cardiac disease. The amount of exercise needed to reduce the risk of coronary artery disease is a minimum aerobic workout of 30 minutes, 4 to 5 times a week, such as a vigorous walk. Comprehensive programmes promoting exercise training should be implemented at a level appropriate to an individual’s capacity and need.

Exercise capacity and prognosis in patients with chronic atrial fibrillation.

To evaluate the response of patients with chronic atrial fibrillation (AF) to exercise and to demonstrate if prognosis could be predicted, 200 male patients (64 +/- 1 years) with AF were identified retrospectively who underwent resting echocardiography and symptom-limited treadmill testing. They were classified by underlying disease into three subgroups: hypertension or no underlying disease (LONE; n = 102), ischemic heart disease (IHD; n = 45) and history of congestive heart failure or valvular disease (CHF-VD; n = 53). Maximal exercise capacities for LONE, IHD and CHF-VD were (mean +/- 1 SEM) 8.0 +/- 0.3, 6.4 +/- 0.4 and 6.0 +/- 0.3 metabolic equivalents, respectively (p < 0.01), and resting left ventricular ejection fractions were 61.7 +/- 1.6, 60.1 +/- 2.2 and 49.5 +/- 1.9%, respectively (p < 0.01). Stepwise multiple regression analysis demonstrated that, except for group classification (R2 = 0.13, p < 0.01), no clinical, exercise or morphologic variables could predict exercise capacity. After a mean 39.1-month follow-up (range 1-78), 17 of the 200 had died from cardiovascular causes. The rate of cardiac death using Kaplan-Meier survival analysis was significantly greater in CHF-VD patients (p < 0.01). However, Cox hazard function and Kaplan-Meier survival analysis demonstrated that neither echocardiographic measurements of cardiac size or function at rest, nor exercise or clinical variables were significant predictors of outcome. AF patients with a history of CHF and/or VD demonstrated a reduced exercise tolerance ad a worse prognosis than those without morphologic heart disease or those with IHD.(ABSTRACT TRUNCATED AT 250 WORDS)

Predictors of disease severity and survival in patients with coronary artery disease.

BackgroundThe objective of this study was to determine whether coronary angiographic findings and survival could be predicted using standard clinical and exercise-test data. MethodsFive hundred and ninety-five men who had undergone both exercise treadmill testing and cardiac catheterization were followed for up to 5 years. Left main (LM) disease (≥50% stenosis) was present in 42 patients, whereas 30 patients had LM equivalent disease (≥70% stenosis of both the proximal left anterior descending and circumflex coronary arteries). Patients were divided into six exclusive groups using angiography: no coronary artery disease (n= 152), one-vessel disease (n = 186), two-vessel disease (n = 118), three-vessel disease (n = 67), LM or LM equivalent disease without significant (≥70%) right coronary artery involvement (n = 26), and LM or LM equivalent disease with right coronary artery involvement (n = 46). ResultsST-segment depression was more marked, whereas ejection fraction, maximal heart rate, maximal systolic blood pressure, and exercise capacity were lower in each group as disease severity worsened. Using Kaplan-Meier analysis, the subgroup with the poorest survival was found to be those with LM or LM equivalent disease with right coronary artery disease, and the next worse was the three-vessel disease group, in which survival was poorer than in all other subgroups (P < 0.01). Stepwise regression analysis revealed that the most powerful predictor for coronary artery disease severity was exercise-induced ST depression (P < 0.001), but it predicted survival poorly. History of congestive heart failure, low ejection fraction (50% or lower), and poor exercise capacity (5 metabolic equivalents or less) emerged as strong predictors of survival using stepwise Cox regression analysis (P < 0.001). ConclusionExercise-induced ST depression predicted the severity of angiographic disease but not survival, whereas the strongest predictors of survival were history of congestive heart failure, low ejection fraction, and poor exercise capacity.

Influence of right coronary artery stenosis on exercise test responses and survival in patients with left main or left main equivalent disease

Forty-two patients with angiographically documented left main coronary artery (LM) disease (luminal occlusion > or = 50%) and 30 patients with left main equivalent (LMEQ) disease (> or = 70% luminal occlusion of both the proximal left anterior descending artery and proximal left circumflex artery) were studied to determine the role of right coronary artery (RCA) involvement on exercise test responses and survival. Significant (> or = 70%) RCA stenosis was present in 30 (72%) of the 42 LM patients and 16 (53%) of the 30 LMEQ patients. No significant differences were observed between LM and LMEQ patients in any clinical or exercise variables or survival. Thus both groups were combined for analysis of the influence of RCA involvement (i.e., LM/LMEQ with RCA versus LM/LMEQ without RCA disease). Greater ischemic responses were observed in the LM/LMEQ group with significant stenosis of the RCA. The presence of RCA stenosis was associated with significantly greater horizontal or downsloping ST-segment depression during exercise (2.4 +/- 1.2 mm vs 1.3 +/- 1.4 mm; p < 0.001), and prolonged recovery time until normalization of the ST segment (3.2 +/- 1.4 min vs 2.0 +/- 1.9 min; p < 0.01). The LM/LMEQ without RCA disease group behaved like the subgroup with two-vessel disease, and responses of the LM/LMEQ group with RCA disease were similar to the group with three-vessel disease. The annual survival in LM/LMEQ with RCA disease was worse than that in LM/LMEQ without RCA disease (average annual mortality rates = 7.5% vs 1.0%, respectively; p = 0.05). Infarct-free survival in LM/LMEQ with RCA disease was also lower than that in LM/LMEQ without RCA disease. Thus although patients with LM and LMEQ were similar in terms of survival and exercise responses, the presence of RCA stenosis was associated with significantly greater ST-segment depression, a prolonged recovery time until normalization of the ST segment, a fivefold increase in the death rate, and higher morbidity from myocardial infarction over a 5-year period of follow-up. Involvement of the RCA should be considered when making decisions concerning medical-surgical management of patients with severe coronary artery disease.

Cardiovascular Screening for High Altitude Trekking

This article briefly reviews some of the important aspects of high altitude cardiovascular physiology related to the known and as yet unknown risks to the cardiac patient. Recommendations are made by the authors regarding the screening and risk stratification of cardiac patients preparing to venture on a high altitude trek.