Journal of the American College of Cardiology Vol. 38, No. 5, by the American College of Cardiology ISSN /01/$20.

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1 Journal of the American College of Cardiology Vol. 38, No. 5, by the American College of Cardiology ISSN /01/$20.00 Published by Elsevier Science Inc. PII S (01) Myocardial Infarction High Level of Physical Activity Preserves the Cardioprotective Effect of Preinfarction Angina in Elderly Patients Pasquale Abete, MD, PHD,* Nicola Ferrara, MD, Francesco Cacciatore, MD, PHD,* Elio Sagnelli, MD,* Maria Manzi, MD,* Vincenzo Carnovale, MD,* Claudio Calabrese, MD,* Domenico de Santis, MD,* Gianluca Testa, MD,* Giancarlo Longobardi, MD, Claudio Napoli, MD, PHD, FACA, Franco Rengo, MD* Naples, Benevento and Larino/Termoli, Italy; and San Diego, California OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS The study investigated the effects of physical activity on preinfarction angina, a clinical equivalent of ischemic preconditioning (PC), in adult and elderly patients with acute myocardial infarction (AMI). Preinfarction angina seems to confer protection against in-hospital mortality in adult but not in elderly patients. However, it has been experimentally demonstrated that exercise training restores the protective effect of PC in the aging heart. We retrospectively verified whether physical activity preserved the protective effect of preinfarction angina against in-hospital mortality in 557 elderly patients with AMI. Physical activity was quantified according to the Physical Activity Scale for the Elderly (PASE). In-hospital mortality was 22.2% in elderly patients with preinfarction angina and 27.2% in those without (p 0.20). When the PASE score was stratified in quartiles (0 to 40, 41 to 56, 57 to 90, 90), a high score was strongly associated with reduced in-hospital mortality (30.8%, 32.2%, 17.2% and 15.3%, respectively, p for trend). Interestingly, a high level of physical activity reduced in-hospital mortality in elderly patients with preinfarction angina (35.7%, 35.4%, 12.3% and 4.23%, respectively, p for trend) but not in those without (23.0%, 27.2%, 26.0% and 35.0%, respectively, p 0.35 for trend). Accordingly, the protective role of preinfarction angina on in-hospital mortality was present only in elderly patients showing a high level of physical activity (adjusted odds ratio, 0.09; 95% confidence interval, 0.01 to 0.57; p 0.05). Physical activity and not preinfarction angina protects against in-hospital mortality in elderly patients with myocardial infarction. Nevertheless, the protective effect of preinfarction angina is preserved in elderly patients with a high level of physical activity. (J Am Coll Cardiol 2001; 38: ) 2001 by the American College of Cardiology Coronary heart disease (CHD) is associated with increased mortality in the aging population (1 5). Despite various hypotheses (6 9), the mechanisms underlying this intriguing phenomenon remain unclear. The most powerful en- See page 1366 dogenous protective mechanisms against myocardial ischemia are brief, repeated episodes of myocardial ischemia, the so-called ischemic preconditioning (PC) that is a harbinger From the *Cattedra di Geriatria and Cattedra di Medicina Interna, Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università degli Studi di Napoli Federico II, Naples, Italy; Cattedra di Geriatria, Dipartimento delle Malattie del Metabolismo e dell Invecchiamento, Seconda Università di Napoli, Naples, Italy; Centro Medico di Telese Terme, Fondazione Salvatore Maugeri, IRCCS, Benevento, Italy; U.O. Riabilitazione, A.S.L. 4 Basso Molise, Fondazione Salvatore Maugeri, Larino/Termoli, Italy; and Department of Medicine-0682, University of California, San Diego, California. This study was supported by Ministero della Ricerca e dell Università (MURST) grant 60%/99. Presented in abstract form at the American Heart Association 73rd Scientific Sessions, New Orleans, Louisiana, November 12 15, Manuscript received December 12, 2000; revised manuscript received April 19, 2001, accepted July 19, for the more prolonged ischemic episode (10,11). Patients with preinfarction angina, a clinical equivalent of PC, have a better outcome than those without angina (12 16). Experimental (17,18) and clinical (19,20) studies show that aging reduces the efficiency of PC. Several studies have indicated that physical activity reduces CHD-related mortality in elderly patients (21 23). In addition, it has been experimentally demonstrated that exercise training restores PC in the aging heart (24). Consequently, the goal of our study was to verify retrospectively whether physical activity preserves clinically the cardioprotective effect afforded by preinfarction angina on several in-hospital end points, including mortality and cardiogenic shock, in elderly patients with acute myocardial infarction (AMI). METHODS Study design. Between January 1995 and December 1998, a total of 557 patients age 65 years with AMI were admitted to our coronary care unit (CCU) regardless of their

2 1358 Abete et al. JACC Vol. 38, No. 5, 2001 Physical Activity and Preinfarction Angina in the Elderly November 1, 2001: Abbreviations and Acronyms AMI acute myocardial infarction CCU coronary care unit CHD coronary heart disease CI confidence interval CK creatine kinase CK-MB creatine kinase-myoglobin fraction ECG electrocardiographic OR odds ratio PASE Physical Activity Scale for the Elderly PC ischemic preconditioning PTCA percutaneous transluminal coronary angioplasty functional status. Patients were included in this retrospective study if they had at least two of the following criteria: 1) typical chest pain; 2) electrocardiographic (ECG) changes with evolution of Q waves (transmural infarction); and 3) elevation of creatine kinase (CK) levels. Nontransmural infarction was diagnosed by typical changes in the S-T segment and T-wave accompanied by increased CK levels. The medical records of these patients were individually reviewed according to criteria that have been described previously (19). Thrombolytic therapy was given to all patients except those presenting with complicating illness, absence of chest pain on admission or nonspecific ECG abnormalities considering age 65 years not a contraindication. Patients with advanced or terminal illness, cerebrovascular disease and such neuropsychiatric disorders as dementia and delirium were not included in the study. In particular, 11 patients (1.9%) with terminal illness, 13 patients (2.3%) with cerebrovascular disease and 23 patients (4.1%) with dementia were excluded according to the DSM-IV (American Psychiatric Association). The final number of patients included in the study was 510. Assessment of physical activity. Physical activity was evaluated with the Physical Activity Scale for the Elderly (PASE) (25). The total PASE score was computed by multiplying the amount of time spent in each activity (h/day) or participation (yes/no) in an activity by the Table 1. PASE Activities, Performances and Weight Scores Activity Performance Item Weight Walking and bicycling Hour/day 20 Light SRA Hour/day 21 Moderate SRA Hour/day 23 Heavy SRA Hour/day 23 Muscle strength/endurance Hour/day 30 Paid/unpaid work Yes/no 21 Light housework Yes/no 25 Heavy housework Yes/no 25 Home repairs Yes/no 30 Lawn work Yes/no 36 Gardening Yes/no 20 Caring for others Yes/no 35 PASE Physical Activity Scale for the Elderly; SRA sport and recreational activities. Table 2. Baseline Characteristics of Elderly Patients With or Without Preinfarction Angina Characteristics Angina (n 323) No Angina (n 187) p Value Age, mean SD Male, n (%) 203 (62.8) 137 (73.3) 0.05 Family history, n (%) 136 (42.1) 65 (34.7) 0.10 PASE, mean SD Low educational level, n (%) 49 (15.2) 35 (18.7) 0.29 Chronic angina, n (%) 107 (33.1) 51 (27.3) 0.16 Previous AMI, n (%) 52 (16.1) 34 (18.2) 0.54 Smoking, n (%) 235 (72.7) 161 (86.0) 0.06 Hypertension, n (%) 169 (52.3) 91 (48.7) 0.42 CHF, n (%) 24 (7.43) 18 (9.63) 0.38 Diabetes, n (%) 114 (35.3) 72 (38.5) 0.46 Cholesterol, mean SD Nitrates, n (%) 164 (50.8) 23 (12.3) Beta-blockers, n (%) 17 (5.26) 3 (1.60) 0.05 Calcium blockers, n (%) 77 (23.8) 35 (18.7) 0.17 Aspirin, n (%) 142 (44.0) 5 (2.67) Rales 1/3 lung fields, n (%) 57 (18.4) 27 (14.7) 0.29 AMI acute myocardial infarction; CHF congestive heart failure; PASE Physical Activity Scale for the Elderly. empirically derived item weights and summing over all activities (Table 1). The item weights are based on comparison with physical activity derived by regressing a component score developed from a three-day motion sensor count, three-day physical activity diary, and global activity assessment (25). The total PASE score obtained was stratified in quartiles (0 to 40, 41 to 56, 57 to 90 and 90) for statistical analysis. Analysis of preinfarction angina. A staff physician collected a detailed clinical history for all patients. Patients who had not experienced chest pain, chest discomfort or left arm and jaw pain 24 h before the episode leading to admission were defined as having no preinfarction angina. Patients showing angina, persisting for no more than 30 min within 24 h prior to the AMI, were defined as having preinfarction angina. Patients with a history of angina at any time before the AMI were defined as having chronic angina. In-hospital outcomes. In-hospital end points in the CCU were death, cardiogenic shock (marked and persistent hypotension with systolic arterial pressure 80 mm Hg and a reduction of cardiac index to 1.8 l/mm 2 ), extension, persistent chest pain, creatine kinase-myoglobin fraction (CK-MB) peak, ventricular fibrillation and tachycardia and high-grade atrioventricular block. Statistical analysis. The statistical power of detecting a clinically significant difference in elderly patients with AMI was 95%, under a type 1 error of 0.05 and an odds ratio (OR) as large as 3.00 (corresponding to a mortality rate of 20% in patients without physical activity before AMI). The power declined progressively to 85%, 75% and 60% with an OR of 2.50, 2.00 and 1.75, respectively. In the comparison between patients with and without preinfarction angina, categorical data and continuous variables were analyzed by chi-square test and the Student t test, respectively. In the comparison among patients stratified in quartiles of physical

3 JACC Vol. 38, No. 5, 2001 November 1, 2001: Abete et al. Physical Activity and Preinfarction Angina in the Elderly 1359 Table 3. Baseline Characteristics of Elderly Patients (n 510) With AMI According to the Quartiles of Physical Activity (PASE) activity (0 to 40, 41 to 56, 57 to 90 and 90), categorical data were analyzed by chi-square tests (modified for linear trend) and continuous variables by analysis of variance. Logistic regression analysis was used to assess the role of preinfarction angina on death, cardiogenic shock and the combined end points independently from physical activity, chronic angina, thrombolytic therapy, primary percutaneous transluminal coronary angioplasty (PTCA), antianginal treatment and several demographic variables (age, gender, previous AMI, congestive heart failure, hypertension, diabetes, family history, smoking and cholesterolemia). The role of preinfarction angina on death, cardiogenic shock and the combined end points was also assessed in elderly patients stratified in quartiles of physical activity (0 to 40, 41 to 56, 57 to 90 and 90). The p values are reported for two-sided testing and are considered significant if less than RESULTS Characteristics 0 40 (n 136) (n 124) Baseline characteristics of elderly patients with AMI according to the presence or absence of preinfarction angina and to the quartiles of physical activity. Elderly patients with and without preinfarction angina differed from each other in gender and cholesterol levels (Table 2). In addition, elderly patients with angina were slightly older, took more nitrates, beta-blockers and aspirin, with somewhat more incidence of family history, chronic angina and hypertension than those without preinfarction angina (Table 2). Age, male gender, low educational level and clinical symptoms of heart failure progressively decreased with the increase in physical activity in elderly patients with AMI (Table 3). In-hospital outcomes of elderly patients according to the presence or absence of preinfarction angina and to the quartiles of physical activity. In-hospital outcomes did not differ between elderly patients with and without preinfarction angina. In particular, death (p 0.20), cardiogenic PASE (n 139) >90 (n 111) p Value for Trend Age, mean SD Male, n (%) 107 (78.7) 74 (59.7) 91 (65.5) 68 (61.3) 0.01 Family history, n (%) 44 (32.3) 52 (41.9) 57 (41.0) 48 (43.2) 0.09 Low educational level, n (%) 34 (25.0) 20 (16.1) 12 (8.63) 18 (16.2) 0.01 Previous angina 84 (61.7) 79 (63.7) 89 (64.0) 71 (63.9) 0.70 Chronic angina, n (%) 44 (32.3) 32 (25.8) 42 (30.2) 40 (36.0) 0.47 Previous AMI, n (%) 26 (19.1) 21 (16.9) 28 (20.1) 11 (9.91) 0.13 Smoking, n (%) 115 (84.5) 80 (64.5) 124 (89.2) 77 (69.3) 0.57 Hypertension, n (%) 69 (50.7) 66 (53.2) 74 (53.2) 51 (45.9) 0.53 CHF, n (%) 12 (8.82) 13 (10.5) 11 (7.91) 6 (5.41) 0.27 Diabetes, n (%) 53 (39.0) 44 (35.5) 55 (39.6) 34 (30.7) 0.31 Cholesterol, mean SD Nitrates, n (%) 53 (39.0) 48 (38.7) 52 (37.4) 34 (30.6) 0.19 Beta-blockers, n (%) 6 (4.41) 4 (3.23) 6 (4.32) 4 (3.60) 0.86 Calcium blockers, n (%) 32 (23.5) 25 (20.2) 37 (26.6) 18 (16.2) 0.41 Aspirin, n (%) 38 (27.9) 30 (24.2) 45 (32.4) 34 (30.6) 0.36 Rales 1/3 lung fields, n (%) 29 (22.1) 25 (21.5) 12 (8.76) 18 (16.7) 0.05 AMI acute myocardial infarction; CHF congestive heart failure; PASE Physical Activity Scale for the Elderly. shock (p 0.64) and the combined end points (p 0.08) were similar in elderly patients with and without preinfarction angina (Table 4, Fig. 1). As shown in Table 5 and Figure 1, when elderly patients with AMI were stratified in quartiles of physical activity, in-hospital death progressively decreased (from 30.8% to 15.3%, p for trend) as PASE scores increased; similarly, cardiogenic shock decreased from 39.0% to 10.8% (p for trend) and the combined end points from 44.8% to 18.0% (p for trend). Non Q-wave AMI significantly increased, whereas the CK-MB peak, ventricular tachycardia and fibrillation and atrioventricular block significantly decreased with increasing physical activity (Table 5). When elderly patients with preinfarction angina were stratified in quartiles of physical activity, in-hospital death progressively decreased Table 4. In-Hospital Outcomes of Elderly Patients With and Without Preinfarction Angina Outcomes, n (%) Angina (n 323) No Angina (n 187) p Value Death 72 (22.2) 51 (27.2) 0.20 Cardiogenic shock 82 (25.4) 51 (27.2) 0.64 Death cardiogenic shock 100 (30.9) 72 (38.5) 0.08 Thrombolytic therapy 97 (30.0) 48 (25.6) 0.29 Time to lytic therapy 4 h 80 (24.7) 34 (18.1) h 17 (5.2) 14 (7.4) 0.44 Primary PTCA 19 (5.8) 14 (7.5) 0.47 In-hospital reinfarction 24 (7.43) 16 (8.56) 0.64 Recurrent ischemic pain 52 (16.1) 28 (15.0) 0.73 Non Q-wave AMI 50 (15.4) 36 (19.2) 0.18 CK-MB peak (IU/l) Ventricular fibrillation 26 (8.00) 24 (12.8) 0.11 Ventricular tachycardia 89 (27.5) 44 (23.5) 0.31 Atrioventricular block 40 (12.3) 28 (14.9) 0.40 AMI acute myocardial infarction; CK-MB creatine kinase-myoglobin fraction; PTCA percutaneous transluminal coronary angioplasty.

4 1360 Abete et al. JACC Vol. 38, No. 5, 2001 Physical Activity and Preinfarction Angina in the Elderly November 1, 2001: Figure 1. Death, cardiogenic shock and the combined end points in elderly patients with and without preinfarction angina (left) and according to the quartiles of physical activity (PASE) (right). (from 35.7% to 4.2%, p for trend) as PASE scores increased. Moreover, cardiogenic shock also decreased from 45.2% to 2.8% (p for trend) and the combined end points from 50% to 7% (p for trend) in elderly patients with preinfarction angina and a high PASE score (Table 6, Fig. 2). In this subset of elderly patients, non Q-wave AMI significantly increased, whereas CK-MB peak, ventricular tachycardia and fibrillation and atrioventricular block significantly decreased as physical activity scores increased (Table 6). In contrast, in elderly patients without preinfarction angina, a high PASE score did not seem to influence the occurrence of in-hospital death, cardiogenic shock and the combined end points (Fig. 2), or the other outcomes considered (Table 6). Logistic regression models for death, cardiogenic shock and the combined end points (in-hospital death and cardiogenic shock) in elderly patients with AMI. We evaluated the role of preinfarction angina using logistic regression analysis with death, cardiogenic shock and the combined end points (in-hospital death and cardiogenic shock) as dependent variables. When the analysis was performed for all patients, age was predictive, with all dependent variables considered (OR: 1.04, 1.06 and 1.04, respectively; 95% confidence intervals [CI] , and , respectively). In contrast, physical

5 JACC Vol. 38, No. 5, 2001 November 1, 2001: Abete et al. Physical Activity and Preinfarction Angina in the Elderly 1361 Table 5. In Hospital Outcomes of Elderly Patients (n 510) According to the Quartiles of Physical Activity Outcomes, n (%) 0 40 (n 136) (n 124) PASE (n 139) >90 (n 111) p Value for Trend Death 42 (30.8) 40 (32.2) 24 (17.2) 17 (15.3) Cardiogenic shock 53 (39.0) 42 (33.9) 26 (18.7) 12 (10.8) Death cardiogenic shock 61 (44.8) 54 (43.5) 37 (26.6) 20 (18.0) Thrombolytic therapy 40 (29.4) 27 (21.7) 45 (32.3) 33 (29.7) 0.53 Time to lytic therapy 4 h 34 (25.3) 23 (18.7) 41 (29.4) 29 (26.4) h 6 (4.4) 4 (3.2) 4 (2.8) 4 (3.6) 0.65 Primary angioplasty 6 (4.4) 10 (8.0) 9 (6.4) 8 (7.2) 0.47 In-hospital reinfarction 12 (8.82) 10 (8.06) 5 (3.60) 13 (11.7) 0.84 Recurrent ischemic pain 15 (11.0) 26 (21.0) 23 (16.5) 16 (14.4) 0.60 Non Q-wave AMI 18 (13.2) 16 (12.9) 29 (20.8) 23 (20.7) 0.05 CK-MB peak (IU/l) Ventricular fibrillation 22 (16.1) 11 (8.87) 11 (7.9) 7 (6.3) Ventricular tachycardia 44 (32.3) 34 (27.4) 37 (26.6) 18 (16.2) Atrioventricular block 27 (19.8) 17 (13.7) 14 (10.1) 10 (9.01) AMI acute myocardial infarction; CK-MB creatine kinase-myoglobin fraction; PASE Physical Activity Scale for the Elderly. activity protected against all the dependent variables considered (OR: 0.987, and 0.984, respectively; 95% CI , and , respectively). Preinfarction angina did not exert a protective effect when analyzed in all patients irrespective of physical activity; however, when we examined preinfarction angina according to quartiles of physical activity, we found it had a protective effect in the subset of patients with the highest PASE scores (Table 7). DISCUSSION This study confirms that in elderly patients, differently from adult patients, preinfarction angina does not exert a protective effect against in-hospital outcomes such as mortality, cardiogenic shock and the combined end points. However, stratifying in quartiles of physical activity, a high level of physical activity seemed to preserve the protective role of preinfarction angina against these in-hospital outcomes. The occurrence of mortality, cardiogenic shock and the combined end points progressively decreased as PASE scores increased in elderly patients with preinfarction angina but not in those without preinfarction angina. Similarly, CK-MB peak, number of Q wave AMIs, ventricular fibrillation and tachycardia and atrioventricular block were significantly less in this subgroup of patients. Adjusted regression analysis demonstrated the protective role of preinfarction angina irrespective of the use of thrombolytic therapy and antianginal drugs and demographic variables such as AMI only in elderly patients with a high level of physical activity. CHD and aging. More than 80% of all AMI-related deaths occur in patients 65 years old (1 5). Advanced age is a multivariate predictor of hospital mortality after AMI (7,8). In fact, in-hospital mortality was three times higher in older than in younger patients (8). Why mortality is higher in older patients with AMI remains unclear. Age-related changes such as increased myocardial mass (26), reduced diastolic relaxation (27), and impairment of angiogenesis (28) might render the AMI more susceptible to severe complications in elderly patients. In addition, comorbidity, which is very common in elderly patients, may predispose to complications and increased mortality after AMI (6 9). However, Tofler et al. (6) have demonstrated that even adverse baseline characteristics do not justify the increased in-hospital mortality observed in the elderly. Elderly patients are frequently treated with less aggressive therapy, including thrombolytic therapy (3,4,29). Nevertheless, Maggioni et al. (8) have demonstrated that age remains a powerful independent predictive factor of in-hospital mortality in patients with AMI who received thrombolytic therapy. PC and aging. Our working hypothesis is that the higher mortality due to AMI might be explained at least in part by the age-related reduction of an endogenous protective mechanism such as PC (10). This phenomenon is characterized by reduced electromechanical dysfunction after a prolonged ischemic period when preceded by brief and repeated episodes of myocardial ischemia triggered by several mediators including adenosine and norepinephrine (11). The clinical equivalents of PC are preinfarction angina, warm-up phenomenon, and ischemic episodes during PTCA (11). In particular, preinfarction angina has been shown to reduce left ventricular impairment (12), infarct size (14) and the risk of right ventricular infarction (16), and to improve short-term prognosis (13) and in-hospital outcome (15) after AMI. However, these findings were observed only in adult patients with AMI. Age-related reduction of PC was first demonstrated in an experimental model and was attributed to an age-related reduction of norepinephrine release in response to myocardial ischemia and/or

6 1362 Abete et al. JACC Vol. 38, No. 5, 2001 Physical Activity and Preinfarction Angina in the Elderly November 1, 2001: Table 6. In-Hospital Outcomes of Elderly Patients With and Without Preinfarction Angina (n 323) According to the Quartiles of Physical Activity Angina (n 323) No Angina (n 187) PASE PASE p Value for Trend >90 (n 40) (n 50) (n 45) 0 40 (n 52) p Value for Trend >90 (n 71) (n 89) (n 79) 0 40 (n 84) Outcomes, n (%) Death 30 (35.7) 28 (35.4) 11 (12.3) 3 (4.23) (23.0) 12 (26.6) 13 (26.0) 14 (35.0) 0.35 Cardiogenic shock 38 (45.2) 30 (38.0) 12 (13.5) 2 (2.82) (28.8) 12 (26.6) 14 (28.0) 10 (25.0) 0.73 Death cardiogenic shock 42 (50.0) 37 (46.8) 16 (18.0) 5 (7.0) (36.5) 17 (37.7) 21 (42.0) 15 (37.5) 0.79 Thrombolytic therapy 21 (25.0) 21 (26.6) 28 (31.5) 27 (38.0) (36.5) 6 (13.3) 17 (34.0) 6 (15.0) 0.12 Primary PTCA 2 (2.3) 6 (7.5) 5 (5.6) 6 (8.4) (7.7) 4 (8.8) 4 (8.0) 2 (5.0) 0.64 In-hospital reinfarction 6 (7.14) 6 (7.59) 3 (3.37) 9 (12.7) (11.5) 4 (8.8) 2 (4.00) 4 (10.0) 0.53 Recurrent ischemic pain 9 (10.7) 16 (20.2) 13 (14.6) 14 (19.7) (11.5) 10 (22.2) 10 (20.0) 2 (5.00) 0.49 Non Q-wave AMI 7 (8.3) 11 (13.9) 18 (20.2) 14 (19.7) (21.1) 5 (11.1) 11 (22.0) 9 (22.5) 0.96 CK-MB peak (IU/l) Ventricular fibrillation 12 (14.2) 6 (7.59) 4 (4.49) 4 (5.63) (19.0) 5 (11.1) 7 (14.0) 3 (7.5) 0.15 Ventricular tachycardia 30 (35.7) 27 (34.1) 20 (22.4) 12 (16.9) (26.9) 7 (15.5) 17 (34.0) 6 (15.0) 0.60 Atrioventricular block 18 (21.4) 13 (16.4) 6 (6.7) 3 (4.2) (17.3) 4 (8.8) 8 (16.0) 7 (17.5) 0.80 PTCA percutaneous coronary angioplasty; other abbreviations as in Table 5. to age-related impairment of the sarcoplasmic reticulum (17,18), and then in clinical studies (19,20,30,31). Protective effect of preinfarction angina both against in-hospital outcomes (19) and in five-year survival rate was lost in elderly patients (20), indicating that the higher mortality observed in elderly patients might be justified in part by the age-related reduction of PC. Here, this mechanism seems to be preserved in elderly AMI patients who have high physical activity scores. Physical activity, aging and CHD. Several epidemiological studies indicate that physical activity offers partial protection against primary or secondary events of CHD and associated mortality among middle-aged and older men (32). This is true in older men in whom disability is particularly frequent (33). In the Goteborg study, the most active men, after 20 years of follow-up, had a relative risk of death from CHD of 0.72 (95% CI: ) (21). In the British Heart Study, light, moderate and vigorous activity reduced mortality and heart attacks in older men by 0.61 (95% CI: ), 0.50 (95% CI: ), and 0.65 (95% CI: ), respectively (22). In the Honolulu Heart Program, the risk of CHD was reduced in physically capable elderly men with the distance walked (23). It is uncertain how physical activity could reduce mortality due to CHD in elderly people. Various factors have been implicated in this beneficial effect: a lipid-lowering effect (34), increased insulin sensitivity (35), reduced arterial pressure (36), increased coronary vasodilatory capacity (37) and coronary perfusion (38), correction of endothelial dysfunction (39), and the antiarrhythmic effect due to the reduction of heart rate and sympathetic activity (40). Similarly, experimental (41 43) and clinical (44 47) studies have demonstrated that physical activity can correct most of the cardiovascular alterations induced by aging. Indeed, exercise training preserves PC in the aging rat heart by safeguarding norepinephrine release in response to myocardial ischemia (24). Study limitations. In general, data from retrospective studies should be viewed with caution. Prospective studies are needed to verify the absence of the protective effect of preinfarction angina in the elderly. Moreover, despite the inclusion criteria of our CCU, only 32% of the elderly patients underwent reperfusion therapy. In the experimental setting, a sustained, complete reperfusion is necessary after prolonged occlusion in order to obtain the reduction of infarct size (11). Thus, studies that contain one-third or even fewer patients receiving reperfusion therapy should be regarded with caution. However, when additional analysis in the reperfused group (145 thrombolytic therapy and 33 primary PTCA) was performed, no significant differences between elderly patients with preinfarction angina in comparison to those without preinfarction angina were found. In fact, the percentages of in-hospital mortality, cardiogenic shock and the combined end points in elderly patients with and without preinfarction angina were 24.1% versus 22.5%

7 JACC Vol. 38, No. 5, 2001 November 1, 2001: Abete et al. Physical Activity and Preinfarction Angina in the Elderly 1363 Figure 2. Death, cardiogenic shock and the combined end points in elderly patients with (ANGINA, right) and without preinfarction angina (NO ANGINA, left) according to the quartiles of physical activity (PASE). (p 0.855, NS), 30.1% versus 38.7% (p 0.316) and 30.3% versus 27.4% (p 0.586), respectively. Similarly, CK-MB peak was IU/l in elderly patients with and in elderly patients without preinfarction angina (p 0.399). Nevertheless, physical activity continues to exert its protective role also in this subgroup of patients (data not shown). The effect of physical activity on the cardioprotection afforded by preinfarction angina should be due to a difference in the incidence of chronic angina, and thus to a well-developed collateral circulation (14,15). However, the incidence of chronic angina is greater both in elderly patients with the highest physical activity either with or without preinfarction angina (42.2% vs. 35.0%; p 0.75). Hence, the beneficial effect of preinfarction angina in elderly patients with the highest physical activity is independent from chronic angina. Conclusions. We confirm that the protective effect of preinfarction angina against in-hospital outcomes is reduced in elderly patients according to a growing bulk of evidence (48,49). Furthermore, we demonstrate that this beneficial effect is preserved in elderly patients who are characterized by a high level of physical activity. Thus, preservation of PC could explain, at least in part, the mechanism whereby physical activity exerts cardioprotective effects against AMI in elderly patients.

8 1364 Abete et al. JACC Vol. 38, No. 5, 2001 Physical Activity and Preinfarction Angina in the Elderly November 1, 2001: Table 7. Effect of Preinfarction Angina in Elderly Patients According to the Quartiles of Physical Activity on In-Hospital Death, Cardiogenic Shock and Combined End Points of In-Hospital Death and Cardiogenic Shock Death Cardiogenic Shock Death Cardiogenic Shock OR (95% CI) p Value OR (95% CI) p Value OR (95% CI) p Value All patients* ( ) ( ) ( ) 0.11 PASE ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.01 *The model was simultaneously adjusted for age, physical activity, chronic angina, gender, previous myocardial infarction, thrombolytic therapy, primary angioplasty, hypertension, diabetes, family history, smoking, nitrate, beta-blockers, calcium-antagonist, aspirin, cholesterolemia. The model was simultaneously adjusted for the same variables except for physical activity. PASE Physical Activity Scale for the Elderly; OR odds ratio; CI confidence interval. 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