Serum Creatinine Concentration and Risk of Cardiovascular Disease
A Possible Marker for Increased Risk of Stroke
Background and Purpose Elevated serum creatinine has been associated with increased mortality in hypertensive persons, the elderly, and patients with myocardial infarction or stroke in whom cardiovascular disease is the major cause of death. We have examined the relationship between serum creatinine concentration and the risk of major ischemic heart disease and stroke events and all-cause mortality in a general population of middle-aged men.
Methods We present a prospective study of middle-aged men (aged 40 to 59 years) drawn from 24 British towns who have been followed up for an average of 14.75 years. Data on serum creatinine were available for 7690 men in whom there were 287 major stroke events, 967 major ischemic heart disease events, and 1259 deaths from all causes during follow-up.
Results The median serum creatinine concentration was 98 μmol/L (95% range, 76 to 129 μmol/L). Stroke risk was significantly increased at levels above 116 μmol/L (90th percentile) even after adjustment for a wide range of cardiovascular risk factors (relative risk [RR], 1.6; 95% CI, 1.1 to 2.1; ≥116 μmol/L versus the rest). Risk of a major ischemic heart disease event was significantly increased at or above 130 μmol/L (97.5 percentile), but this was attenuated after adjustment (RR, 1.2; 95% CI, 0.8 to 1.7; ≥130 μmol/L versus the rest). There was a weak but significant positive association between diastolic blood pressure and creatinine concentration. However, elevated creatinine concentration (≥116 μmol/L) was associated with a significant increase in stroke in both normotensive and hypertensive men. All-cause mortality and overall cardiovascular mortality were significantly increased only above the 97.5 percentile, and no significant association was seen with cancer or other noncardiovascular mortality.
Conclusions A high serum creatinine concentration within the normal range is a marker for increased risk of cerebrovascular disease in both normotensive and hypertensive subjects. These findings support the evidence indicating that subtle impairment of renal function is a factor for increased risk of stroke and suggest mechanisms in the pathogenesis of stroke that warrant further investigation.
A number of studies indicate that elevated serum creatinine may be an independent predictor of all-cause and of cardiovascular disease mortality.1 2 3 4 These studies have focused on specific groups, such as hypertensive individuals,1 the elderly,2 patients with recent stroke,3 and survivors of myocardial infarction,4 in all of whom cerebrovascular and coronary heart disease are the major causes of death. In the Hypertension Detection and Follow-up Program study, the 8-year mortality risk increased progressively with increasing concentration of creatinine from low levels. In multivariate analysis, there was a more than twofold increased risk of death (mainly from cardiovascular disease) in subjects with serum creatinine at or above the 97th percentile relative to those with creatinine below this level.1 It has been suggested that serum creatinine acts as a marker for generalized vascular disease. The role of hypertension in determining the serum creatinine level in individuals has been examined in all of these studies but with no firm conclusion as to the primacy of blood pressure in determining the fatal outcome. Furthermore, few studies have addressed specific cardiovascular disease end points in detail, and the prognostic importance of serum creatinine in the incidence of major cerebrovascular or coronary heart disease events in the general population is uncertain. We have therefore examined the relationship between serum creatinine and the subsequent risk of major IHD and stroke (fatal and nonfatal) and all-cause mortality in a prospective population-based study of middle-aged British men. We have focused in particular on the role played by blood pressure and other potential confounders and on possible interactions with blood pressure status.
Subjects and Methods
The British Regional Heart Study is a large prospective study of cardiovascular disease comprising 7735 men aged 40 to 59 years selected from the age-sex registers of one group general practice in each of 24 towns in England, Wales, and Scotland (78% response rate). The criteria for selecting the town, the general practice, and the subjects, as well as the methods of data collection, have been reported.5 The practices selected in each town had a social class distribution representative of men in that town, and the overall social class distribution of the cohort closely resembled that of middle-aged men in Great Britain. In 1978 through 1980, research nurses administered to each man a standard questionnaire that included questions on smoking habits, alcohol intake, physical activity, and medical history. Several physical measurements were made, including height and weight, and blood samples (nonfasting) were taken throughout the day between 8:30 am and 6:30 pm. Blood samples for biochemical and hematological measurements were drawn into five separate evacuated Vacutainer tubes using a Velcro tourniquet on the upper arm. Serum separation tubes were allowed to stand for 30 minutes and spun for 10 minutes. All biochemical samples were stored vertically at 4°C and dispatched overnight to the Wolfson Research Laboratories, Queen Elizabeth Hospital, Birmingham, UK, where estimations were completed by noon on the following day. Thirteen biochemical measurements including serum creatinine were made using an autoanalyzer (model SMA 12/60) and standard Technicon methods. Serum creatinine was not estimated in 45 men.
Classification methods for smoking status, alcohol consumption, social class (longest held occupation), and physical activity have been reported.5 6 7 The men were classified according to their current smoking status into six groups: those who had never smoked cigarettes, ex-cigarette smokers, and four groups of current smokers (1 to 19, 20, 21 to 39, and ≥40 cigarettes per day). Those who had only ever smoked a pipe and/or cigars were grouped as never smoked. Ex-cigarette smokers who currently smoked a pipe or cigars were grouped as ex-smokers. The men were classified into five groups based on weekly alcohol intake: none, occasional, light, moderate, and heavy.6 Heavy drinking is defined as drinking more than 6 units (1 UK unit=8 to 10 g alcohol) daily or on most days in the week. A physical activity score was derived for each man on the basis of frequency and type of activity, and the men were grouped into six broad categories on the basis of their total score.7 Obesity was defined as BMI ≥28 kg/m2, the top fifth of the distribution.
The London School of Hygiene sphygmomanometer (a random zero device) was used to measure blood pressure twice in succession with the subject seated and with the arm supported on a cushion. The mean of the two readings was used in the analysis, and all blood pressure readings were adjusted for observer variation within each town.8 The men were also asked whether they were receiving regular antihypertensive treatment. Men with adjusted SBP ≥160 mm Hg or adjusted DBP ≥90 mm Hg or subjects taking regular antihypertensive treatment were regarded as hypertensive.
Preexisting IHD, Stroke, and Diabetes
The men were asked whether a doctor had ever told them that they had angina or myocardial infarction (heart attack, coronary thrombosis), stroke, and a number of other disorders. The WHO (Rose) chest pain questionnaire9 was administered to all men at the initial examination, and a three-orthogonal lead ECG was recorded at rest.
Evidence of a previous stroke was determined by the subject’s recall of such a diagnosis being made by a doctor. There were 52 such men in the study.
Ischemic Heart Disease
The men were separated into three groups according to the evidence of IHD at screening: (1) no evidence of IHD on WHO chest pain questionnaire or ECG and no recall of a doctor diagnosis of IHD (n=5757); (2) men with evidence suggesting IHD short of a definite myocardial infarction, including those with ECG evidence of possible or definite myocardial ischemia or possible myocardial infarction (asymptomatic), those with angina or a possible myocardial infarction on WHO (Rose) chest pain questionnaire, or with recall of a doctor diagnosis of angina (symptomatic) (n=1508); and (3) men with a previous definite myocardial infarction on ECG or who recalled a doctor diagnosis of a myocardial infarction (“heart attack”) (n=425).
The classification of men with preexisting IHD consists of groups 2 and 3 combined.
Diabetes mellitus prevalence was based on recall of a doctor diagnosis of the condition (n=121).
Left Ventricular Hypertrophy
The diagnosis of LVH was based on R wave amplitude, ST-T abnormalities, and abnormal QRS vector orientation. A scoring system was used,10 with 6 points representing definite hypertrophy and 4 to 5 points representing possible or probable hypertrophy. Definite LVH equates with Minnesota code 3-1, and possible or probable equates with code 3-3. Men with LVH included both definite and possible (4 to 6 points).
All men were followed up for all-cause mortality and for cardiovascular morbidity.11 All cardiovascular events occurring in the period through December 1993 are included in the study, for an average follow-up of 14.75 years (range, 13.5 to 16.0 years), and follow-up has been achieved for 99% of the cohort. Information on death was collected through the established “tagging” procedures provided by the National Health Service registers in Southport (England and Wales) and Edinburgh (Scotland). Nonfatal stroke events were those that produced a neurological deficit that was present for more than 24 hours. Evidence regarding such episodes was obtained by reports from general practitioners, by semiannual reviews of the patients’ notes through to the end of the study period, and from personal questionnaires to surviving subjects at the 5th year and 12th year after initial examination. Fatal stroke episodes were those coded on the death certificate as ICD 430 to 438. All death certificates in which it appeared that coding to stroke was not appropriate, or in which stroke was not the attributed code when it might have been, were explored by correspondence with the certifying doctor and the hospital concerned. No information on the type of stroke was available.
A nonfatal myocardial infarction was diagnosed according to WHO criteria, which included any report of myocardial infarction accompanied by at least two of the following: a history of severe chest pain, ECG evidence of myocardial infarction, and cardiac enzyme changes associated with myocardial infarction. Fatal events were defined as death from IHD (ICD, 9th revision, codes 410 to 414) as the underlying code.
The Cox proportional hazards model was used to assess the independent contributions of serum creatinine to the risk of stroke and coronary heart disease and to obtain the RRs adjusted for age and the other risk factors.12 Age, DBP, and BMI were fitted as continuous variables. Smoking (six levels), physical activity (six levels), diabetes (yes/no), preexisting stroke (yes/no), use of antihypertensive treatment (yes/no), and preexisting IHD on questionnaire/ECG (three levels) were fitted as categorical variables. Direct standardization was used to obtain age-adjusted rates per 1000 person-years using the study population as the standard.
Data on serum creatinine were available for 7690 men. The median was 98 μmol/L (95% range, 76 to 129 μmol/L). Only 27 men had levels above 150 μmol/L (1.7 mg), a level generally regarded as hypercreatinemia.
Serum Creatinine and Risk of Stroke Events
During the mean follow-up period of 14.8 years in the 7690 men with data on serum creatinine, there were 287 major stroke cases (73 fatal and 214 nonfatal). The men were initially divided into approximate equal fifths of the ranked distribution of serum creatinine concentration of <88 (n=1583), 88 to 94 (n=1446), 95 to 100 (n=1627), 101 to 108 (n=1512), and ≥109 μmol/L (n=1522). Because of the particular interest in those with high serum creatinine1 and to separate those above the normal range, we have further separated those in the top fifth into three groups at percentile points representing approximately 80%, 90%, and 97.5% of the total distribution (109 to 115 μmol/L, n=720; 116 to 129 μmol/L, n=622; and ≥130 μmol/L, n=180). Thus, seven groups are used in Fig 1⇓ to show the age-adjusted stroke rate per 1000 person-years. In men with levels <116 μmol/L (1st through 9th decile), there was little difference in age-adjusted stroke rates (range, 2.2 to 2.9 cases per 1000 person-years). Stroke risk was significantly increased at levels of 116 to 129 μmol/L (3.7 per 1000 person-years) and rose sharply to 7.5 per 1000 person-years in the top 2.5% of the population. The age-adjusted RRs and 95% CIs in men with levels 116-129 and ≥130 μmol/L compared with all those with levels <116 μmol/L were 1.5 (1.1 to 2.1) and 3.0 (1.9 to 4.7), respectively. In subsequent analyses, we have focused on the risk of stroke in all men with levels ≥116 μmol/L (upper decile of the serum creatinine distribution) relative to the rest of the distribution.
Serum Creatinine and Risk of Major IHD Events
During the follow-up period, there were 967 cases of major IHD events. Fig 2⇓ shows the age-adjusted rate per 1000 person-years for the seven groups. Risk of major IHD events increased slightly at the 90th percentile (≥116 μmol/L) and was only significantly increased in the top 2.5% of the men (≥130 μmol/L). The age-adjusted RRs and 95% CIs in men with levels 116-129 and ≥130 μmol/L relative to those with levels <116 μmol/L were 1.1 (0.9 to 1.3) and 1.5 (1.1 to 2.1), respectively.
Serum Creatinine and Cardiovascular Risk Factors
Table 1⇓ shows the levels of established risk factors for cardiovascular disease in men in the top decile and in the rest of the men. Men with elevated creatinine were significantly older and heavier, were more likely to have hypertension (SBP ≥160, DBP ≥90 mm Hg, or taking antihypertensive treatment), had higher prevalence of preexisting IHD (in particular, definite myocardial infarction), and had a higher prevalence of previous stroke. They had somewhat higher prevalence of LVH and diabetes, slightly higher mean blood glucose levels, and lower levels of physical activity, but these differences were not significant. They showed significantly lower rates of current smoking but higher rates of ex-smoking status. No association was seen with heavy drinking or social class.
Blood Pressure and Serum Creatinine
Men receiving antihypertensive treatment (n=375) showed significantly higher mean levels of serum creatinine than men not being treated (106.7 versus 97.5 μmol/L). The relationship between SBP and DBP and creatinine was examined separately in men with and without antihypertensive treatment (Table 2⇓). In men not being treated, a significant positive association was seen with DBP and with SBP (P<.0001), which was attenuated on adjustment for age and BMI, although the relationship with DBP remained significant (P=.004). In men with treatment, no significant association was seen between DBP or SBP and creatinine, although men with DBP ≥110 mm Hg had somewhat higher mean creatinine than those with blood pressure levels <110 mm Hg.
Adjustment for Confounders
We have examined the relationship between serum creatinine and major stroke events, adjusting in succession for potential risk factors for stroke that have been shown to be associated with creatinine. Age adjustment alone produced an RR of stroke in the 10th decile (≥116 μmol/L) relative to the 1st through 9th deciles combined RR of 1.8 (95% CI, 1.3 to 2.4). Additional adjustment for BMI, smoking, DBP, preexisting IHD, and use of antihypertensive drugs, as well as diabetes and physical activity, reduced the risk slightly (RR, 1.6; 95% CI, 1.1 to 2.1), and further adjustment for LVH made no difference. Exclusion of the small number of men with previous stroke (n=52) did not alter the findings.
Ischemic Heart Disease
The significantly increased age-adjusted risk seen for IHD in the top 2.5% (≥130 μmol) was attenuated after adjustment for the potential confounders and was no longer statistically significant (RR, 1.2; 95% CI, 0.8 to 1.7).
Age, Preexisting IHD, and Risk of Stroke
The relationship between elevated creatinine (top decile) and risk of stroke was seen within all age groups (<50, 50 to 54, and 55 to 59 years), although it was more marked in the older age groups. The fully adjusted RRs (95% CI) (top decile versus the rest) were 1.3 (0.6 to 2.7), 1.9 (1.1 to 3.3), and 1.6 (1.0 to 2.5) for the three age groups, respectively. The increased risk of stroke in the upper decile of the creatinine distribution was more marked in men with preexisting IHD. The fully adjusted RRs (95% CI) were 1.2 (0.7 to 2.0) and 2.0 (1.3 to 2.9) in men with (n=1933, 110 cases) and without (n=5757, 177 cases) preexisting IHD, respectively, but a test for interaction was not significant (P=.2).
Creatinine, Hypertension, and Risk of Stroke
Because of the strong association between hypertension and stroke and the association seen between blood pressure and serum creatinine, and to assess the specific effects of elevated creatinine in hypertensive persons, we have examined the relationship between creatinine and stroke separately in normotensive and hypertensive subjects (DBP ≥90 mm Hg or SBP ≥160 mm Hg or antihypertensive treatment). Elevated creatinine (≥116 μmol/L) was present in 8.6% of normotensives and in 13.8% of hypertensives (test for difference, P<.001). In both normotensive and hypertensive subjects, elevated creatinine was associated with a significant increase in risk of stroke even after adjustment for the potential confounders, including DBP and LVH. In normotensive subjects, the RR was 1.7 (95% CI, 1.0 to 2.9; P=.04); in hypertensives, those with creatinine levels ≥116 μmol/L showed an RR of 1.5 (95% CI, 1.1 to 2.5; P=.03) compared with hypertensives with levels <116 μmol/L.
Table 3⇓ shows the combined effect of hypertension and elevated creatinine on risk of stroke with use of normotensive subjects with creatinine levels <116 μmol/L as the reference group after full adjustment. In hypertensive men with creatinine levels <116 μmol/L, risk of stroke was increased 2.6-fold, and this increased to over fourfold in men with elevated creatinine. Exclusion of men taking antihypertensive treatment did not make a major difference to the increased risk seen in hypertensive subjects with elevated creatinine (Table 3⇓).
In the 375 men receiving antihypertensive treatment, in whom there were 42 stroke cases, the age-adjusted stroke rate was significantly higher than in hypertensive men not taking treatment and in normotensive men (7.6 per 1000 person-years versus 4.0 and 1.7 per 1000 person-years, respectively). Elevated creatinine (≥116 μmol/L) was present in 29% (n=109) of these 375 men and was associated with a higher rate of stroke compared with men receiving antihypertensive treatment with levels <116 μmol/L (age-adjusted rate 9.6 per 1000 person-years versus 6.7 per 1000 person-years; RR, 1.4; 95% CI, 0.8 to 2.6), although the difference was not statistically significant, possibly because of small numbers. Adjustment for potential confounders made little difference to the increased risk seen (RR, 1.5; 95% CI, 0.8 to 2.9).
Other Renal Function
Blood urea was significantly correlated with serum creatinine (r=.4), and we therefore examined the relationship between blood urea and risk of stroke. An association similar to but slightly weaker than that observed with creatinine was seen, with risk of stroke significantly increased in the top decile of the ranked distribution of blood urea even after adjustment for potential confounders (fully adjusted RR, 1.5; 95% CI, 1.1 to 2.1). However, the positive association seen between the top decile of serum creatinine and risk of stroke persisted after adjustment for blood urea (RR, 1.5; 95% CI, 1.1 to 2.0). The positive association with blood urea was slightly attenuated and of marginal significance (P=.06) after adjustment for serum creatinine (RR, 1.4; 95% CI, 1.0 to 1.9).
Serum Creatinine and All-Cause Mortality
The relationship between elevated serum creatinine and all-cause mortality were examined initially in the seven original creatinine groups shown in Figs 1⇑ and 2⇑. There was little difference in all-cause, cardiovascular, and noncardiovascular mortality in men in the five groups with levels <116 μmol/L (1st through 9th decile), and these men have been combined so that the three groups presented in Table 4⇓ represent the 1st through 9th deciles and the 90th and 97.5th percentiles of the ranked distribution. For all causes and for cardiovascular disease, age-adjusted mortality increased slightly at the 90th percentile and was significantly raised in the top 2.5% of the men (≥130 μmol/L) (Table 4⇓). No association was seen with cancer mortality. Other noncardiovascular mortality was highest in the top 2.5%, but the increase was not significant. The increased risks for total and cardiovascular mortality in the top 2.5% (≥130 μmol/L) remained significant even after adjustment for the potential confounders.
In this study of middle-aged men, elevated serum creatinine concentration (≥116 μmol/L) was associated with a significantly increased risk of all major stroke events after adjustment for a number of confounding factors, including SBP and antihypertensive treatment. The increased risk was seen in the top decile of the distribution in which the majority of values would be considered to be within the normal range. There was little association between serum creatinine and risk of major IHD events after adjustment. The risk of all-cause mortality was increased only in the upper 2.5% of the distribution (≥130 μmol/L). Deaths from cancer and other noncardiovascular mortality were not associated with the creatinine concentration.
Our findings are similar to those of the Hypertension Detection and Follow-up Program, in which a significantly increased risk of all-cause, cardiovascular, cerebrovascular, and noncardiovascular mortality was observed in the top 3% of the creatinine distribution; no association was seen with cancer mortality.1 The authors suggested that the “elevated creatinine represents the influence of generalized vascular disease in the kidney.” This was also suggested in a prospective study in New Zealand, which found serum creatinine to be a strong and independent predictor of survival after stroke in the elderly.3 However, in a Danish study of 223 elderly subjects without diabetes or recent stroke, serum creatinine was also an independent predictor of mortality, suggesting that serum creatinine predicts survival in elderly people irrespective of the presence or absence of stroke.2 In a study of survivors of myocardial infarction, serum creatinine was independently associated with all-cause and coronary heart disease mortality.4 No significant association was found between serum creatinine and the severity of coronary heart disease or peripheral vascular disease, suggesting that a higher creatinine level was not simply a manifestation of generalized atherosclerosis. Given the weak association between creatinine and risk of IHD in the present study, generalized vascular disease is unlikely to explain the association between elevated creatinine and stroke. Furthermore, in the present study the increased risk of stroke was of greater magnitude in men with no evidence of preexisting IHD at screening than in those with preexisting IHD.
The increased risk was seen even after adjustment for doctor diagnosis of diabetes at screening. It is unlikely that subclinical diabetes or glucose intolerance could account for the increased risk, since serum creatinine was only weakly related to blood glucose levels, and hyperglycemia without a doctor diagnosis of diabetes is not an independent risk factor for stroke in our study (S.G.W. and I.J.P., unpublished data, 1996).
Blood Pressure and Creatinine
Hypertension is clearly an important potential confounder in the association between creatinine and risk of stroke. An association between blood pressure and serum creatinine has been observed both in hypertensive persons and the general population. In the Multiple Risk Factor Intervention Trial cohort of 5524 men with mild to moderate hypertension (baseline DBP ≥90 mm Hg), no relationship was seen between blood pressure at baseline and serum creatinine levels, but those with higher blood pressures showed the greatest increase in serum creatinine over a 6-year follow-up. Treatment resulting in reduction of DBP was associated with an improvement in renal function.13 The suggestion that current blood pressure may indicate the long-term likelihood of increasing levels of creatinine is supported by a study of 1399 middle-aged subjects from a community-based cohort.14 In this study, a graded and significant association was found between serum creatinine levels and blood pressures taken 12 to 15 years previously but not with current blood pressures. In a study of 897 subjects followed up for 9 years,15 subjects with essential hypertension had a significantly greater rate of decline in renal function compared with normotensive subjects. These observations suggest that blood pressure elevations below the usual levels at which definite hypertension is diagnosed may induce early renal damage.
In the present study, a weak but significant association was seen between DBP but not SBP and serum creatinine after adjustment for age and BMI. However, the relationship between serum creatinine and risk of stroke appeared to be independent of current blood pressure. Although blood pressure was measured on a single occasion, it is unlikely that the increased risk associated with elevated creatinine reflected higher average blood pressures, since blood pressure at screening examination is almost invariably higher than usual. In addition, the increased risk was seen in both normotensive and hypertensive subjects, and there was no evidence of an interaction between current blood pressure and serum creatinine.
Aside from confounding due to hypertension and vascular disease, an alternative explanation for the association between “high normal” creatinine and risk of stroke merits consideration. It is possible that in the upper decile of the creatinine distribution there are individuals who are susceptible to hypertension-associated renal impairment at relatively low blood pressure levels and that such individuals are also more susceptible to the cerebrovascular effects of raised blood pressure. This possibility is supported by the observation that at similar blood pressure levels, black Americans are at greater risk of both renal disease and stroke than white Americans.16
These findings have implications for further research and clinical practice. In particular, they add to the growing evidence that subtle impairment of renal function is a potent marker of increased risk of cardiovascular disease.17 18 Serum creatinine in particular would appear to be a sensitive indicator of the long-term effects of raised blood pressure, not only on the kidney but on end organs. In the present study, about 14% of the hypertensive subjects had serum creatinine levels ≥116 μmol/L, the level at which a significantly increased risk of stroke was observed. Clearly, a single serum creatinine measurement provides an insensitive marker of early renal impairment, and it is likely that repeated measurements and the use of additional indices of renal function, such as reciprocal creatinine slopes,13 urinary albumin excretion rate,17 and estimation of glomerular filtration rate, will be of value in identifying hypertensive persons at particularly high risk of cardiovascular disease.
In this study of middle-aged British men followed up for almost 15 years, a baseline serum creatinine level in the upper decile of the distribution (≥116 μmol/L) was associated with a significantly increased risk of major stroke events in both normotensive and hypertensive individuals. No independent association was seen with major IHD events. An elevated serum creatinine concentration may be a marker for subtle renal damage consequent to raised blood pressure and may constitute an additional risk factor for cerebrovascular disease. Alternatively, some individuals may have increased susceptibility to hypertension-associated renal impairment and to the cerebrovascular effects of raised blood pressure. Whatever the mechanism, subtle renal impairment of renal function appears to be a marker of increased risk of cerebrovascular disease in both normotensive and hypertensive subjects.
Selected Abbreviations and Acronyms
|BMI||=||body mass index|
|DBP||=||diastolic blood pressure|
|ICD||=||International Classification of Diseases|
|IHD||=||ischemic heart disease|
|LVH||=||left ventricular hypertrophy|
|SBP||=||systolic blood pressure|
|WHO||=||World Health Organization|
The British Regional Heart Study is a British Heart Foundation Research Group and receives support from The Stroke Association and the Department of Health. Dr Wannamethee is a British Heart Foundation Research Fellow.
- Received November 4, 1996.
- Revision received December 10, 1996.
- Accepted December 10, 1996.
- Copyright © 1997 by American Heart Association
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