Plasma renin activity in the emergency department and its independent association with acute myocardial infarction

AJH

2000;13:855– 863

ORIGINAL CONTRIBUTIONS

Plasma Renin Activity in the Emergency Department and Its Independent Association With Acute Myocardial Infarction Jon D. Blumenfeld, Jean E. Sealey, Michael H. Alderman, Hillel Cohen, Richard Lappin, Daniel F. Catanzaro, and John H. Laragh

Elevated plasma renin activity (PRA) is associated with increased risk of future myocardial infarction (MI) in ambulatory hypertensive patients. The present study evaluated the relationship of PRA to the diagnosis of acute MI in patients presenting to an emergency department with suspected acute MI. PRA was measured upon entry to the emergency department, before any acute treatment, as part of the standard evaluation of 349 consecutive patients who were hospitalized for suspected MI. Diagnosis of acute MI was confirmed in 73 patients, and ruled out in 276. They did not differ in age (65.9 ⴞ 2 v 66.1 ⴞ 1 years), systolic (143 ⴞ 4 v 140 ⴞ 2 mm Hg), or diastolic (81 ⴞ 2 v 81 ⴞ 1 mm Hg) pressures. Median PRA was 2.7-fold higher in acute MI (0.89 v 0.33 ng/L/s; P < .001). In a multivariate analysis controlling for other cardiac risk factors and prior drug therapy, PRA as a continuous variable was the predominant

independent factor associated with acute MI (P < .0001), followed by white race (P ⴝ .002) and history of hypertension (P ⴝ .047). The height of the PRA level upon entry to the emergency department was directly and independently associated with the diagnosis of acute MI. These new findings extend earlier reports because they encompass acute MI patients, include both hypertensive and normotensive patients, and control for potentially confounding variables. Based on these observations, a randomized clinical trial is warranted to determine whether measurement of PRA in acute MI could refine the process by which treatments are applied. Am J Hypertens 2000;13:855– 863 © 2000 American Journal of Hypertension, Ltd. KEY WORDS:

Renin, myocardial infarction, angiotensin, cardiac risk factor.

e previously reported an association between medium and high plasma renin activity (PRA) values and an increased risk of myocardial infarction (MI) in ambulatory hypertensive patients.1,2 This as-

W

sociation, together with other clinical and experimental evidence, supports a role for excess renin-angiotensin system (RAAS) activity in the pathogenesis of acute MI.3–10 This participation of the renin system in the patho-

Received December 3, 1999. Accepted February 2, 2000. From The Cardiovascular Center, Division of Hypertension, and The Emergency Department, New York Presbyterian Hospital-Cornell Campus and Weill Medical College, New York, New York, and The Departments of Medicine and Epidemiology, Albert Einstein College of Medicine, Bronx, New York. This study was supported by The National Institutes of Health

(HL 56400), The May and Samuel Rudin Foundation, and The Michael Wolk Heart Foundation. Address correspondence and reprint requests to Jon D. Blumenfeld, MD, The Rogosin Institute, Centers for Medical Research and Health Care, Affiliated with New York-Presbyterian Hospital and Weill Medical College of Cornell University, 505 East 70th Street, New York, NY 10021.

© 2000 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.

0895-7061/00/$20.00 PII S0895-7061(00)00277-6

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genesis of acute MI and in other cardiovascular disease is further supported by the therapeutic benefits of specific pharmacologic antagonists of the RAAS.10 In animal models, blockade of the RAAS prevents angiotensin (Ang) II-mediated coronary vasoconstriction, reduces the incidence of pathologic cardiovascular changes, and prolongs survival.5,11,12 In clinical trials of acute MI involving more than 100,000 patients, treatment with angiotensin-converting enzyme (ACE) inhibitors substantially reduced morbidity and mortality.13 Similarly, in heart failure, treatment with ACE inhibitors decreased the risk of recurrent MI and death.14 –17 Furthermore, the Type 1 Ang II receptor (AT1) blocker, losartan, prolonged survival in heart failure patients at least as effectively as an ACE inhibitor.18 Addition of the aldosterone receptor blocker, spironolactone, to treatment with an ACE inhibitor and loop diuretic in heart failure patients further reduced the mortality rate and hospitalization rate by approximately 30%.19 Elevated PRA levels were previously reported in patients during acute MI.20 –25 However, conclusions regarding interactions between PRA and acute MI were limited either because potentially confounding variables were not adequately controlled, because renin assay methods may not have been done under optimal conditions, or because the study had other goals.14,20,21,23–26 Thus, the hypothesis that excess RAAS activity is important in the pathogenesis of MI has not been sufficiently explored. The purpose of the present study was to determine whether there truly is an association between the entry PRA level and the occurrence of acute MI. To accomplish this goal, we measured PRA levels in 349 patients with suspected acute MI upon entry to the emergency department, before drug treatment. We found that the entry PRA level was significantly higher in both normotensive and hypertensive patients who proved to have an acute MI than in patients in whom a diagnosis of acute MI was ruled out. Furthermore, after controlling for other cardiovascular risk factors and other relevant variables that may have confounded earlier studies, we identified a robust association between PRA and acute MI. These new findings support and extend the existing evidence in hypertensive patients that the PRA level is an independent factor associated with acute MI and, thus, suggests a pathophysiologic role for renin in acute MI. MATERIALS AND METHODS Study Population Subjects were recruited from the Emergency Department (ED) of The New York Presbyterian Hospital. They were eligible if they were to be hospitalized for evaluation and treatment of suspected acute MI. The protocol was approved by the Committee on

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Human Rights in Research at the Weill Medical College of Cornell University. After informed consent was obtained, a blood sample for PRA was collected in the ED before any medication was administered or other intervention implemented. Patients were excluded if they had previously participated in this study or if medication was administered in the ED before a blood sample for renin was obtained. Fewer than 10% of patients were excluded for these reasons. No eligible patient withheld consent. Patients with acute MI undergo, as part of the standard of care, measurement of left ventricular function within 5 days of hospitalization. Left ventricular ejection fraction was estimated either by transthoracic echocardiography,27 radionuclide cineangiography,28 or contrast ventriculography. Hormone Assays Blood was collected into K3EDTA Vacutainers, processed at room temperature within 24 h, and frozen at ⫺40°C. The PRA assay was performed within 1 week. We measured PRA using an enzyme kinetic assay in which Ang I was generated from endogenous angiotensinogen during a 3-h incubation at 37°C. Results are expressed as ng Ang I/L/s. Samples with low PRA values were reassayed using an 18-h incubation to gain sensitivity and to avoid the inaccuracy of blank subtraction.26 Diagnoses Diagnosis of acute MI required two or more of the following criteria: (i) elevated creatine kinase MB (CK-MB) fraction, (ii) electrocardiographic changes indicative of acute injury or ischemia, and (iii) history of chest pain or other symptoms of myocardial ischemia. Each patient’s physician determined their diagnosis and was unaware of the PRA level. The investigators did not assign the diagnosis and were not involved in the care of study patients. Data Analysis Demographic characteristics, laboratory values, blood pressure, and other known risk factors were assessed according to the primary diagnosis status of MI or non-MI. The odds ratio (OR) and 95% confidence intervals (CI) were calculated for low and high values for renin, using established cut points.1 Median values for PRA were compared with the Mann-Whitney test. For analyses with PRA as a continuous variable, a log (base10) transformation of PRA was used to achieve a more normal distribution. We analyzed PRA as a continuous variable, controlling for recognized cardiovascular risk factors and other relevant variables. Multivariate analysis was done with logistic regression models. Covariates that were entered in the first step of the logistic models were male gender, white race, systolic and diastolic pressure, body mass index, blood urea nitrogen (BUN), serum potassium, serum glucose, maximum

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TABLE 1. DEMOGRAPHIC CHARACTERISTICS OF MYOCARDIAL INFARCTION (MI) AND NON-MI GROUPS MI (n ⴝ 73)

Non-MI (n ⴝ 276)

P

65.9 ⫾ 2

66.1 ⫾ 0.9

.91

69.9 30.1

57.6 42.4

.06

83.6 4.1 4.1 4.1 4.1

62.7 11.9 16.3 6.2 2.9

.001 .05 .007 .50 .60

Age (years) Gender (%) Male Female Race (%) White Black Hispanic Asian Other

TABLE 3. BLOOD PRESSURE AND BODY MASS INDEX (BMI)

Systolic (mm Hg) Diastolic (mm Hg) Heart rate (beats/min) BMI (kg/m2) ⫾ SEM

MI (n ⴝ 73)

Non-MI (n ⴝ 276)

P

143 ⫾ 4 81 ⫾ 2 88 ⫾ 3 26.4 ⫾ 0.8

149 ⫾ 2 81 ⫾ 1 83 ⫾ 1 27.2 ⫾ 0.5

.14 .87 .08 .55

Abbreviation as in Table 1.

CK, any cardiovascular medication use (ie, ACE inhibitors, ␤-adrenergic blockers, diuretics, ␣1-adrenergic blockers, calcium channel blockers), and history of prior MI, MI in a family member at age ⱕ 60 years, hyperlipidemia, hypertension (blood pressure ⱖ 140/ 90 mm Hg, or current antihypertensive treatment), diabetes, cigarette use, heart failure, or either coronary artery bypass graft or coronary angioplasty. Time of entry into the ED was categorized into 2-, 4-, and 6-h blocks. Statistical analyses were performed with SPSS (version 7.0) software run on a Windows 95 platform. RESULTS Demographics Table 1 shows the demographic characteristics of the 349 consecutive patients participating in this study. In accordance with previous studies, there was a greater prevalence of white patients in the MI group than the non-MI group. However, there were similar frequencies in other cardiovascular risk factors (Tables 1, 2) including age, male gender, and history of hypertension, diabetes mellitus, previous MI, cigarette use, hypercholesterolemia, or a family

TABLE 2. PREVALENCE (IN %) OF CARDIAC RISK FACTORS History of Cardiac Risk Factors

MI (n ⴝ 73)

Non-MI (n ⴝ 276)

P

Cigarette use Previous MI Hypertension Family history of MI Heart failure Diabetes Hypercholesterolemia

58.5 26.2 63.0 12.3 35.4 31.5 27.7

47.1 29.4 50.9 21.2 27.5 26.1 26.7

.10 .60 .09 .11 .21 .36 .87

Abbreviation as in Table 1.

857

history of MI. A history of heart failure occurred with comparable frequency in the MI and non-MI groups. Primary diagnoses in the non-MI group included angina (36%), atrial arrhythmia (7%), heart failure (15%), and noncardiac diseases (21%). The final diagnosis was uncertain in 21% of the non-MI group. Hemodynamic and Biochemical Characteristics Mean blood pressure, heart rate, body mass index, and median left ventricular ejection fraction were comparable in the two groups (Table 3). Blood glucose and blood urea nitrogen levels were slightly higher in the MI group. However, there were no differences in serum total cholesterol, creatinine, sodium, or potassium levels (Table 4). Plasma Renin Activity The median PRA level was 2.7-fold higher in the MI group (P ⬍ .0001; Fig. 1, Table 4). Moreover, PRA levels were designated as high in 51% with MI, but in only 24% of those without MI (OR 3.3; 95% CI: 1.9 to 5.6; P ⬍ .0001). Conversely, PRA levels were low in only 12% of the MI group compared with 27% of the non-MI group (OR 0.38; 95% CI: 0.18 to 0.80; P ⬍ .01). We measured PRA in another control group of 92

TABLE 4. LABORATORY VALUES IN MI AND NON-MI GROUPS

PRA (ng/L/s) PRA (log10) (ng/L/s) Glucose (mmol/L) Serum Na⫹ (mmol/L) Serum K⫹ (mmol/L) BUN (mmol/L) Serum creatinine (␮mol/L) Total cholesterol (mmol/L) ⫾ SEM

MI (n ⴝ 73)

Non-MI (n ⴝ 276)

0.89 0.14 ⫾ 0.02 9.2 ⫾ 0.4 138 ⫾ 0.5 4.0 ⫾ 0.1 9.3 ⫾ 0.7

0.33 ⬍.0001* 0.03 ⫾ 0.01 ⬍.0001 7.9 ⫾ 0.3 .05 138 ⫾ 0.2 .08 4.2 ⫾ 0.1 .86 7.7 ⫾ 0.4 .05

P

114.9 ⫾ 8.8

106.1 ⫾ 8.8

.43

5.5 ⫾ 0.2

5.2 ⫾ 0.1

.07

PRA ⫽ plasma renin activity; BUN ⫽ blood urea nitrogen; other abbreviation as in Table 1. * Mann-Whitney test comparison of median PRA values. To convert PRA to ng/mL/h, multiply values by 3.6.

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FIG. 1. Cumulative frequency of plasma renin activity (PRA) levels for all patients in the MI and non-MI groups. Higher PRA values were more prevalent in the MI group (right curve) than in the non-MI group. The median PRA level (50th percentile) was significantly higher in the MI group (P ⬍ .0001).

consecutive patients evaluated in the emergency department for chest pain that was not considered to be of cardiac origin and did not require hospitalization. Their median PRA of 0.33 ng/L/s was below that of the MI group (P ⬍ .0001), but was comparable to the non-MI group (P ⫽ NS). By multivariate analysis, PRA was found to be strongly associated with acute MI, followed by white race and history of hypertension (Fig. 2). The hazard ratio for MI of quintile 5 of PRA was 4.5 (95% CI: 2.29 to 8.82; P ⬍ .0001), with quintiles 1 through 3 as a reference (Fig. 3). In the MI group, there was no association between the PRA level at the time of entry to the ED and the peak CK-MB level (r ⫽ 0.02, P ⫽ NS). Furthermore, there was no correlation between the PRA level and the left ventricular ejection fraction for either group (MI group r ⫽ ⫺0.067, P ⫽ NS; non-MI group, r ⫽ 0.025, P ⫽ NS) or for both groups combined (r ⫽ 0.02, P ⫽ NS). Other factors that were not associated with acute MI included age, blood pressure, BUN, serum glucose, total cholesterol, or history of diabetes, hypercholesterolemia, or time of entry to the ED. When the MI group was compared with a subset of the non-MI group whose diagnosis was for another cardiovascular condition (ie, angina, heart failure), PRA remained strongly associated with MI (OR 2.8;

95% CI 1.6 to 4.9), as did white race (OR 2.9; 95% CI 1.2 to 6.8). Most patients in this study (60.2%) were taking medication at the time of presentation to the ED (Table 5). Long-acting dihydropyridine calcium channel blocker use was more prevalent in the MI group (34% v 17%; OR ⫽ 2.5; 95% CI 1.3 to 4.7; P ⬍ .01). However, in a multivariate analysis, the relationship between the PRA level and MI was not influenced by treatment with calcium blockers or with other drug classes. DISCUSSION The principal findings in this study are that the median PRA value was 2.7-fold higher in ED patients experiencing an acute MI than in those in whom the diagnosis of acute MI was ruled out, and that the association of acute MI with an elevated entry PRA level was more powerful than with traditional cardiac risk factors tested in the present study, including gender and history of either hypertension, hypercholesterolemia, or diabetes. These new findings confirm and extend observations from prior studies that were limited to ambulatory hypertensive patients,1,2 or that did not control for confounding factors (eg, cardiac risk factors, concurrent medications, and heart failure).20 –25 Altogether, these results support the hypoth-

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FIG. 2. Association of acute MI with renin and other factors. The PRA level was related to the incidence of acute MI. This association of MI with PRA was more robust than for other cardiovascular risk factors.

esis that overactivity of the renin-angiotensin system can contribute to the pathogenesis of acute MI in both hypertensive and normotensive patients. Other evidence indicates that excess Ang II participates directly in the pathogenesis of cardiovascular

disease, including acute MI, either via direct coronary artery vasoconstriction or possibly in concert with other vasoconstrictors. First, in animal models, systemic infusion of Ang II causes coronary vasoconstriction, myocyte necrosis, and coronary vascular dam-

FIG. 3. Distribution of PRA (ng/L/s) by quintiles in the MI and non-MI groups. The incidence of acute MI was greater for the 5th quintile for renin than for the bottom 3 quintiles combined. % MI/Total ⫽ percentage of patients in each quintile with acute MI relative to the total number in each quintile.

860

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TABLE 5. PREVALENCE (IN %) OF PRIOR DRUG TREATMENT IN MYOCARDIAL INFARCTION (MI) AND NON-MI GROUPS Drug

MI

Non-MI

P

Dihydropyridine Calcium channel blocker ACE inhibitor ␤-blocker Diuretic ␣-blocker Other

33.9

17.3

.007

32.1 25.0 19.6 7.1 24.1

23.5 37.1 24.4 5.6 29.3

.18 .09 .45 .67 .44

age3,4 that can be prevented by pretreatment with an AT1 receptor blocker.5 Second, patients with essential hypertension characterized by high and medium renin levels are at significantly greater risk for future MI than those with a low renin level.1,2 These findings support our earlier hypothesis, derived from patients with malignant hypertension, that high PRA levels are vasculotoxic to heart, kidney, and cerebral arterioles over the longer term in patients with so-called “benign” essential hypertension.29 Third, treatment of acute MI and of heart failure with drugs that interrupt the RAAS (eg, ACE inhibitors, AT1 receptor blockers, and ␤-adrenergic receptor blockers) promptly and persistently decreases the risk of recurrent MI and death.13,18,30,31 Several factors relevant to this study might affect PRA levels. Increased PRA often occurs in heart failure24,32,33 and, as expected, a greater proportion of our acute MI patients with heart failure had high PRA levels (43% v 26%, P ⬍ .01). Nonetheless, the prevalence of heart failure in the present study was similar in the MI and non-MI groups. The PRA level is also affected by commonly used drugs. Diuretics increase PRA and Ang II production. ACE inhibitors increase PRA, but they block its effect by preventing conversion of Ang I to Ang II.34 By contrast, ␤-blockers consistently suppress renin secretion, thereby lowering PRA and Ang II levels.35,36 In this study, blood samples for PRA were obtained before any new treatment was initiated, but drugs used concurrently could have affected PRA. Although the prevalence of longacting dihydropyridine calcium channel antagonists was higher in the acute MI group, these agents do not substantially increase the PRA level.37 The prevalences of all other drug classes were similar in the MI and non-MI groups. Therefore, neither the type of drug being taken at entry nor the presence of heart failure could account for the observed association of PRA with acute MI. Furthermore, although the BUN and blood glucose levels were slightly higher in the MI group, it is seems unlikely that these modest dif-

ferences could account for the significant and robust relationship between PRA and MI. Prior studies seem to indicate that PRA and Ang II levels are elevated in acute MI at the time of hospital entry, although an independent association between these factors and the diagnosis of acute MI was not reported previously.20,21,23–25 This relationship may not have been identified because of confounding factors, including concurrent cardiovascular drug use that was not controlled for by multivariate analysis, absence of a control group of acutely ill non-MI patients, insufficient sample size, assay conditions that were either unspecified24 or may have been less than optimal, or because that was not the primary goal of the study. By controlling for these factors, the present study identified a powerful independent association between PRA and acute MI that was not described previously. Physical and mental stress, including the diurnal changes in stress hormone levels, may trigger acute MI.38 However, in the present study, the time of entry to the ED was not associated with either the diagnosis of acute MI or the entry PRA level. Although psychologic stress was not evaluated in this study, it is unlikely to have contributed significantly to the higher renin level in the MI group because both the MI and non-MI patients were acutely ill and were subjected to the same ED protocols until the blood sample for renin was obtained. This study does not reveal whether the elevated renin level in patients entering with acute MI is an accelerating or initiating factor or whether it is part of a generalized, acute neurohormonal response either to the myocardial injury or to the events that preceded it. It is established that there is sympathetic activation during myocardial infarction20,24,25 and it is known that renin release can be stimulated by activation of renal ␤1-adrenergic receptors.39 However, plasma catecholamine levels do not change together with plasma renin-angiotensin levels during acute MI,24,25 nor are they consistently related to the renin level observed in ambulatory hypertensive patients,40 indicating that other factors can affect renin release. This may also reflect the well-known, serious limitations of plasma catecholamine measurements as markers of sympathetic nervous system activity.41– 43 Moreover, there is equally convincing evidence showing that Ang II can augment the effects of the sympathetic nervous system in several ways: by increasing sympathetic discharge from the brain, by increasing epinephrine and norepinephrine release from the adrenal medulla, by facilitating norepinephrine release and inhibiting its reuptake at presynaptic sites, and by causing an enhanced response to norepinephrine at postsynaptic sites.44 The reinforcing effects of these two systems on the coronary circulation have been elucidated. In pa-

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tients with relatively mild coronary artery stenosis (⬍ 50% stenosis), sympathetic activation does not increase coronary artery resistance unless it is accompanied by an intracoronary infusion of a subconstrictor of Ang II.45 This increment in resistance is attributed to enhanced arteriolar vasoconstriction. In patients with more severe coronary artery disease, adrenergic stimulation can increase coronary vascular resistance and this response is attenuated by ACE inhibition.46 Moreover, in patients with heart failure or with hypertension and chronic renal insufficiency, ACE inhibition reduces muscle sympathetic nerve activity (MSNA) and restores towards normal the baroreflex activation of (MSNA).47,48 Altogether, these results indicate that the RAAS and the sympathetic nervous system are mutually reinforcing, so that the effects of activation of the sympathetic nervous system are amplified by an increased circulating renin activity. In addition to its effect as a potent vasoconstrictor, Ang II has other direct cellular effects on the coronary vasculature and myocardium that appear to influence the atherosclerotic process.10 Specifically, Ang II stimulates vascular smooth muscle cell growth and migration, promotes oxidative stress by enhancing superoxide radical (O2⫺) formation, activates monocyte/ macrophage migration and release of adhesion and inflammatory molecules, and is prothrombotic via stimulation of plasminogen activator inhibitor.7–9,49 –51 These effects can be attenuated by ACE inhibition or by AT1 receptor blockade, further implicating a direct role for the RAAS in the pathogenesis of this process.6,8 Based upon the findings in the present study, and from prior studies that have demonstrated a role for excess RAAS activity in the pathogenesis of acute MI and as a predictor of outcome in heart failure,52–54 we propose that knowledge of the PRA level in acute MI patients might be used to further stratify the risks and benefits of ACE inhibitor treatment. Accordingly, a high PRA level might identify the patient with the greatest potential benefit from an ACE inhibitor, as well as the increased risk of side effects (ie, hypotension, acute renal failure) that occur commonly with these agents.13 Several cardiac risk factors were not associated with acute MI in this study. This almost certainly reflects the high prevalence of these risk factors in both the MI and non-MI populations studied. Furthermore, although a high PRA value was a powerful predictor of MI, it was not an invariable finding and, therefore, by itself can not replace conventional diagnostic tests. Thus, the occurrence of acute MI in some patients with low PRA levels supports the concept that there is heterogeneity in its risk profile. In summary, a strong independent association between the entry PRA level and acute MI was found

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among 349 consecutive patients entering an emergency department with suspected acute MI. This relationship was not influenced by coexisting heart failure, hypertension, or by prior drug treatments. Our findings support and extend existing evidence from ambulatory hypertensive and heart failure patients that the height of the PRA level is a powerful independent factor associated with acute MI. These findings suggest that, in acute MI, as in hypertension and heart failure, an elevated PRA level identifies the patient who is at high risk for cardiovascular complications and is most likely to benefit from drug treatments directed against the renin system (ie, ACE inhibitor, AT1 receptor antagonist, ␤-adrenergic receptor blocker). These conclusions establish the need for a randomized clinical trial to determine whether the measurement of plasma renin might refine the process by which drug treatment is used in patients with acute myocardial infarction. ACKNOWLEDGMENTS We are grateful to the nursing staff of the Emergency Department of The New York Hospital-Cornell Medical Center for their enthusiastic efforts during this study.

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