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Biomedical subjects

D E Grobbee

Publications and source records attributed to D E Grobbee.

At least 271 records · Page 15Linked to original sources
PubMed1998

Number of perifoveal vessels in aging, hypertension, and atherosclerosis: the Rotterdam Study.

PURPOSE: To assess the associations among age, gender, hypertension, atherosclerosis, combined hypertension and atherosclerosis, and the number of perifoveal retinal arterioles and venules in the general elderly population. METHODS: A cross-sectional study was performed among subjects ranging in age from 55 to 74 years who participated in the population-based Rotterdam Study. Perifoveal vessels were counted in a masked way by two observers within 1500 microm from the foveola on fundus transparencies of 34 cases with hypertension, 55 with lower extremity arterial disease (LEAD), 27 with hypertension and LEAD, and 194 control subjects without either condition. Multiple linear regression analysis was used to study the associations. RESULTS: The mean number of perifoveal vessels was 12.0 (SD 2.0). The number of perifoveal vessels decreased with age in all groups, with an average of 0.4 per 5 years (95% confidence interval [CI], 0.2, 0.6, P=0.001). In women, the number of perifoveal vessels was on average 0.8 (95% CI, 0.3, 1.2, P=0.002) lower than in men. Patients with hypertension had a significantly lower number of vessels compared with control subjects: mean reduction 1.0 (95% CI, 0.2, 1.7), independent of age and sex. Patients with LEAD had 1.0 (95% CI, 0.4, 1.6) fewer perifoveal vessels, whereas the number in those with hypertension and LEAD was 1.8 (95% (CI, 1.0, 2.6) lower. Additional adjustment for established cardiovascular risk factors did not materially alter the findings. CONCLUSIONS: Increasing age, female gender, systemic hypertension, and LEAD were associated with a lower number of perifoveal arterioles and venules in the elderly.

Aged↗
PubMed1998

EUROPA substudies, confirmation of pathophysiological concepts. European trial on reduction of cardiac events with perindopril in stable coronary artery disease.

In patients with coronary disease, ACE inhibitors may improve endothelial function in the coronary arteries as well as peripheral arteries, and may have anti-proliferative effects which might result in retardation of progression of coronary artery disease. In order to verify these pathophysiological concepts, a series of substudies will be conducted as part of the EUROPA programme. Angiographic and intravascular ultrasound examination of coronary arteries will be performed in approximately 400 patients before and after 3 years' treatment with either perindopril or placebo, in order to assess progression and possible regression of coronary lesions. B-mode ultrasonography of the brachial artery will be used as a model for changes in the coronary arteries, to assess endothelial function in response to ischaemia (reactive hyperaemia) and to vasoconstriction (cold pressor test). Three hundred patients will be investigated before and at different intervals after initiation of study treatment. In addition genetic characterization will be performed of patients participating in EUROPA in order to assess whether specific genotypes do respond more or less favourably to perindopril. In addition, the effect of perindopril will be investigated in patients with diabetes type II, since ACE inhibition in such patients may improve microvascular function and renal function. Integration of these substudies, as well as detailed analysis of other specific subgroups in EUROPA, will help us understand the effects of treatment with perindopril in patients with stable coronary artery disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

An epidemic of heart failure? Recent evidence from Europe.

Recent evidence from studies based in the general population, general practice and hospital strongly suggest that an epidemic of heart failure is emerging in Europe. Notably, a further increase in the prevalence of the syndrome in the elderly is expected in the next decades. Importantly, current population-based studies suggest that the majority of men and women with left ventricular systolic dysfunction is asymptomatic. This finding, together with the beneficial effect of angiotensin-converting enzyme inhibition in these patients reported in randomized trials, will further fuel discussions regarding the potential of echocardiographic screening of large populations or high-risk patients. Moreover, the potential additive value of echocardiographic or neurohumoral assessments in general practice remains to be established. More clinical epidemiological studies are needed to facilitate optimization of diagnosing various stages of heart failure, as well as asymptomatic ventricular dysfunction.

Cardiac Output, Low↗
PubMed1997

Prolonged QT interval: a tricky diagnosis?

Prolonged heart-rate adjusted QT intervals on the electrocardiogram (ECG) are associated with an increased risk for coronary heart disease and sudden death. However, the diagnosis of the prolonged QT interval is hampered by lack of standards. We studied variations in the prevalence of prolonged QT, based on different common definitions, in a large nonhospitalized population, and compared our results with other studies applying the same definitions. The study population consisted of 2,200 men and 3,366 women participants of the Rotterdam Study, > or =55 years old. The QT interval was computed by our Modular ECG Analysis System (MEANS). Three different formulas to adjust QT for heart rate were used: Bazett's formula (QTc), a linear regression equation (QTlr), and the QT index (QTI). Prolonged QT occurred frequently in both men and women, and its prevalence increased with age. Women had longer heart-rate adjusted QT intervals than men (mean QTc 433 ms vs 422 ms), and mean values for QTlr were lower than for QTc (mean QTlr 422 ms in women and 412 ms in men). Prevalence was highest for prolonged QTlr (31% in men and 26% in women) and lowest for prolonged QTI (6% in men and 9% in women). Comparison with other studies applying the same correction formulas showed large discrepancies in prevalence estimates of prolonged QTc and QTlr, and to a lesser degree of prolonged QTI, possibly due to differences in measurement techniques. Future research is needed to relate QT interval to prognosis, to obtain measurement technique specific reference values of heart-rate adjusted QT measurements, and to obtain age- and sex-specific threshold values for prolonged QT. Such data are needed to use the QT interval with confidence.

Aged↗
PubMed1997

[Antithrombotic treatment following acute ischemic heart disease: acetylsalicylic acid and (or) oral anticoagulants?; ASPECT-II, a new study].

In order to compare the efficacy and safety of three regimens of long-term antithrombotic treatment in patients with acute ischaemic syndromes, a prospective, randomized, open-label, multicentre study is being conducted in which 60-70 Dutch hospitals will participate. Eligible patients discharged following hospitalization for acute myocardial infarction or unstable angina pectoris are randomly assigned to receive either (a) adjusted full intensity oral anticoagulation (target range: 3.0-4.0 International Normalised Ratio (INR), (b) low dose aspirin or (c) combined therapy of low dose aspirin and adjusted low intensity oral anticoagulation (target range INR: 2.0-2.5). It is planned to enroll 8,700 patients within three years. During an estimated mean follow-up of 2.5 years the evolutions of total mortality, non-fatal myocardial infarction, non-fatal stroke and major bleeding complication will be assessed.

Anticoagulants↗
PubMed1997

Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study.

BACKGROUND: Noninvasive assessment of intima-media thickness (IMT) is widely used in observational studies and trials as an intermediate or proxy end point for cardiovascular disease. However, data showing that IMT predicts cardiovascular disease are limited. We studied whether common carotid IMT is related to future stroke and myocardial infarction. METHODS AND RESULTS: We used a nested case-control approach among 7983 subjects aged > or =55 years participating in the Rotterdam Study. At baseline (March 1990 through July 1993), ultrasound images of the common carotid artery were stored on videotape. Determination of incident myocardial infarction and stroke was predominantly based on hospital discharge records. Analysis (logistic regression) was based on 98 myocardial infarctions and 95 strokes that were registered before December 31, 1994. IMT was measured from videotape for all case subjects and a sample of 1373 subjects who remained free from myocardial infarction and stroke during follow-up. The mean duration of follow-up was 2.7 years. Results were adjusted for age and sex. Stroke risk increased gradually with increasing IMT. The odds ratio for stroke per standard deviation increase (0.163 mm) was 1.41 (95% CI, 1.25 to 1.82). For myocardial infarction, an odds ratio of 1.43 (95% CI, 1.16 to 1.78) was found. When subjects with a previous myocardial infarction or stroke were excluded, odds ratios were 1.57 (95% CI, 1.27 to 1.94) for stroke and 1.51 (95% CI, 1.18 to 1.92) for myocardial infarction. Additional adjustment for several cardiovascular risk factors attenuated these associations: 1.34 (95% CI, 1.08 to 1.67) and 1.25 (95% CI, 0.98 to 1.58), respectively. CONCLUSIONS: The present study, based on a short follow-up period, provides evidence that an increased common carotid IMT is associated with future cerebrovascular and cardiovascular events.

Aged↗
PubMed1997

Physical activity and cardiovascular disease risk profile in women.

In a population of 4,576 Dutch women aged 49-70 years who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) in 1993-1995, the relation between physical activity and the presence of cardiovascular disease risk indicators was assessed cross-sectionally. Physical activity was determined from a self-administered questionnaire, while blood pressure, heart rate, body mass index, waist/hip ratio, and waist circumference were measured at the study center. Mean risk indicator levels were calculated for different activity categories. Blood pressure was most clearly associated with time spent in sports (mean systolic blood pressure, adjusted for age, level of education, and smoking, 128.9 mmHg in the highest sports tertile, and 132.1 mmHg in the lowest sports tertile; mean diastolic blood pressure, 77.8 mmHg and 79.0 mmHg, respectively). Body mass index, waist/hip ratio, and waist circumference showed an inverse relation with cycling, gardening, do-it-yourself-activities, and sports. In this population, leisure-time activity was inversely related to cardiovascular disease risk indicators, but work activity and housework were not. The authors conclude that if investigators wish to measure physical activity in women over age 50 years with the aim to identify high- and low-risk groups for cardiovascular disease, they should consider not only housework activity, but also leisure-time activities such as cycling, sports, and do-it-yourself activities.

Aged↗
PubMed1997

Tissue plasminogen activator and risk of myocardial infarction. The Rotterdam Study.

BACKGROUND: Impaired fibrinolytic capacity, as assessed by euglobulin clot lysis time or plasma concentration of fibrinolytic parameters, has been associated with an increased risk of myocardial infarction (MI). We studied the association of a polymorphism in the gene for TPA and of plasma concentrations of TPA (antigen and activity) with the prevalence of MI. METHODS AND RESULTS: A case-control study was performed. Subjects with a history of MI (n = 121) and controls (n = 250) were drawn from the Rotterdam Study, a population-based cohort study of 7983 subjects > or = 55 years old. We determined TPA antigen and activity in plasma and genotyped all subjects for the Alu repeat insertion/deletion polymorphism in intron h in the TPA gene. Homozygosity for the insertion was associated with twice as many cases of MI as was homozygosity for the deletion (odds ratio, 2.24; 95% CI, 1.11-4.50). TPA antigen was positively associated with the risk of MI; compared with that in the lowest quartile, the relative risks (odds ratio) in the second, third, and upper quartiles were 1.7 (CI, 0.9-3.3), 2.3 (1.2-4.4), and 2.0 (1.0-3.8), respectively. When adjusted for body mass index, HDL and total cholesterol, systolic and diastolic blood pressures, and current smoking, the risk associated with TPA antigen concentration was attenuated. Increased concentrations of TPA activity tended to be associated with an increased risk of MI. CONCLUSIONS: This study provides evidence for an independent association of the insertion allele of the insertion/deletion polymorphism in the TPA gene with nonfatal MI. Increased TPA antigen is associated with an increased risk of MI; however, this association was not independent of cardiovascular disease risk factors.

Aged↗
PubMed1997

Families and natural history of lipids in childhood: an 18-year follow-up study.

The natural history of total cholesterol and lipoprotein cholesterol in offspring was studied in relation to total cholesterol levels in their parents in the Epidemiological Prevention Study of Zoetermeer (EPOZ). All residents of 5 or more years who were living in two districts in the Dutch town of Zoetermeer were invited to participate in a study on indicators for chronic diseases between 1975 and 1978. In a random sample of 483 youngsters who were 5-19 years old, yearly measurements of cardiovascular risk factors were performed during a follow-up period of 18 years (average follow-up, 13.8 years). Total and subfraction cholesterol levels in offspring during follow-up were studied by tertiles of age-adjusted total cholesterol in their parents. Total and low density lipoprotein (LDL) cholesterol levels measured from childhood into young adulthood differed significantly between offspring whose fathers were in the highest total cholesterol tertile compared with those whose fathers were in the lowest tertile, amounting to 0.4 mmol/liter for total cholesterol and 0.5 mmol/liter for LDL cholesterol. Offspring differences by maternal tertiles amounted to 0.5 mmol/liter for total cholesterol and 0.6 mmol/liter for LDL cholesterol. Offspring (n = 53) with both parents in the upper cholesterol tertile had almost 1 mmol/liter higher cholesterol levels compared with offspring (n = 51) with both parents in the lowest tertile, whereas offspring (n = 48) with both parents in the middle tertile had intermediate levels. Differences remained after adjustment for sex, Quetelet index, systolic and diastolic blood pressure, and use of alcohol, cigarettes, and oral contraceptives. Offspring group differences in total and LDL cholesterol were already present in childhood and persisted into young adulthood. There was no clear relation between offspring change in cholesterol levels and parental total cholesterol levels. For high density lipoprotein cholesterol and its subfractions, no relations with parental total cholesterol levels were found. Based on the evidence of a strong positive relation between total cholesterol levels in parents and offspring levels of total and LDL cholesterol measured from childhood into young adulthood, the authors conclude that total and LDL cholesterol levels in offspring may already be characterized from young age and beyond through cholesterol levels in their parents.

Adolescent↗
PubMed1997

Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study.

BACKGROUND: Vascular disorders have been implicated in dementia, but whether atherosclerosis is related to the most frequent type of dementia, Alzheimer's disease, is not known. The apolipoprotein-E genotype has been associated with Alzheimer's disease, and we postulate that it plays a part, together with atherosclerosis, in the aetiology of Alzheimer's disease. We investigated the frequency of dementia and its subtypes in relation to atherosclerosis and apolipoprotein E. METHODS: We did a population-based study of 284 patients with dementia, 207 of whom had Alzheimer's disease, and 1698 individuals who were not demented. Indicators of atherosclerosis included vessel wall thickness and plaques of the carotid arteries, assessed by ultrasonography, and the ratio of ankle-to-brachial systolic blood pressure as a measure of generalised atherosclerosis. Based on these indicators participants were scored from 0 (no atherosclerosis) to 3 (severe atherosclerosis) for degree of atherosclerosis. Apolipoprotein-E polymorphisms were assessed in 246 patients and in 928 controls. FINDINGS: All indicators of atherosclerosis were associated with dementia (odds ratios ranging from 1.3 to 1.9) and its major subtypes Alzheimer's disease (odds ratios 1.3-1.8) and vascular dementia (odds ratios 1.9-3.2). The frequencies of all dementia. Alzheimer's disease, and vascular dementia increased with the degree of atherosclerosis. The odds ratio for Alzheimer's disease in those with severe atherosclerosis compared with those without atherosclerosis was 3.0 (95% CI 1.5-6.0; p = 0.001). In participants with the apolipoprotein-E epsilon 4 genotype and an atherosclerosis score of 2 or 3 the odds ratio for all dementia was 4.5 (2.0-10.1; p < 0.001), for Alzheimer's disease was 3.9 (1.6-9.6; p = 0.002), and for vascular dementia was 19.8 (4.1-95.0; p < 0.001). INTERPRETATION: These findings suggest that dementia and its two major subtypes Alzheimer's disease and vascular dementia are associated with atherosclerosis and that there is an interaction between apolipoprotein E and atherosclerosis in the aetiology of Alzheimer's disease.

Aged↗
PubMed1997

Usefulness of echocardiography in detecting left ventricular dysfunction in population-based studies (The Rotterdam Study).

In a population-based study, the routine 12-lead electrocardiogram was found to have a high negative predictive value for detecting left ventricular (LV) systolic dysfunction. Withholding echocardiography in persons without major electrocardiographic abnormalities, however, would result in a considerable underestimation of LV systolic dysfunction (sensitivity only 54%); thus, echocardiography remains an essential tool for detecting LV systolic dysfunction in population-based studies.

Echocardiography, Doppler↗
PubMed1997

Diabetes mellitus, impaired glucose tolerance, and hyperinsulinemia in an elderly population. The Rotterdam Study.

To estimate the prevalence of glucose intolerance in the elderly, oral glucose tolerance tests were performed as part of the Rotterdam Study, a population-based study in subjects aged 55 years and over. The study population consisted of 2,668 men and 3,950 women. Diabetes mellitus was defined as the use of antidiabetes medication, or a random or post-load serum glucose level of > or = 11.1 mmol/liter. Impaired glucose tolerance was defined as a post-load serum glucose between 7.8 and 11.1 mmol/liter. In men, the frequency of diabetes mellitus ranged from 5.9% in ages < 60 years to 19.8% in ages > 85 years, and in women from 3.8% in ages < 60 years to 18.9% in ages > 85 years; more than half of the subjects with diabetes were newly diagnosed. The prevalence of impaired glucose tolerance ranged from 8.8% and 11.0% in men and women aged < 60 years to 24.3% and 34.7% in men and women aged > 85 years. The prevalence of diabetes mellitus in the total Rotterdam Study population of 7,439 elderly men and women was estimated to be 11.3% (95% confidence interval (CI) 10.5-12.0). Waist/hip ratio, systolic blood pressure, hypertension, and number of cigarettes smoked increased with a worsening of the glucose tolerance from normal, hyperinsulinemia, impaired glucose tolerance to diabetes in both men and women (p < 0.01, adjusted for age). Body mass index was higher in subjects with glucose intolerance, but the frequency of obesity showed a relative decrease with worsening of glucose tolerance. These results show that glucose intolerance, especially impaired glucose tolerance and undetected diabetes mellitus, is common in the elderly. Moreover, not only subjects with diabetes mellitus but also subjects with hyperinsulinemia and impaired glucose tolerance have an increase of cardiovascular risk factors.

Age Distribution↗
PubMed1997

Dietary antioxidants and Parkinson disease. The Rotterdam Study.

OBJECTIVE: To investigate whether high dietary intake of antioxidants decreases the risk of Parkinson disease (PD). SETTING: The community-based Rotterdam Study, the Netherlands. DESIGN: The cross-sectional study formed part of a large community-based study in which all participants were individually screened for parkinsonism and were administered a semiquantitative food frequency questionnaire. The study population consisted of 5342 independently living individuals without dementia between 55 and 95 years of age, including 31 participants with PD (Hoehn-Yahr stages 1-3). RESULTS: The odds ratio for PD was 0.5 (95% confidence interval [CI], 0.2-0.9) per 10-mg daily dietary vitamin E intake, 0.6 (95% CI, 0.3-1.3) per 1-mg beta carotene intake, 0.9 (95% CI, 0.4-1.9) per 100-mg vitamin C intake, and 0.9 (95% CI, 0.7-1.2) per 10-mg flavonoids intake, all adjusted for age, sex, smoking habits, and energy intake. The association with vitamin E intake was dose dependent (P for trend = .03). To assess whether the association was different in participants with more advanced disease, we excluded those with PD who had a Hoehn-Yahr stage of 2.5 or 3. This did not fundamentally alter the results. CONCLUSION: Our data suggest that a high intake of dietary vitamin E may protect against the occurrence of PD.

Aged↗
PubMed1997

Characteristics and determinants of sumatriptan-associated chest pain.

BACKGROUND: Serious cardiac adverse reactions, including myocardial infarction, have been attributed to the antimigraine drug sumatriptan succinate. Chest pain is considered to be a relatively common adverse reaction to sumatriptan. DESIGN: Postmarketing study. PATIENTS AND METHODS: The study was a part of a national cohort study on adverse reactions to sumatriptan, which was performed with the assistance of drug-dispensing general practitioners in the Netherlands. After data were collected on observed adverse reactions, the patients received a second questionnaire, with specific questions regarding the adverse event, and questions regarding medical history, other health complaints, and smoking habits. Furthermore, they had a physical examination and a blood cholesterol measurement. RESULTS: A total of 137 patients with chest pain associated with intake of sumatriptan were identified and compared with 229 consumers of sumatriptan without this adverse reaction. After multivariate analysis, young age, hypertension, general complaints of abdominal pain, and a family history of myocardial infarction were associated with an increased risk of chest pain attributed to sumatriptan. Hypertension in particular was a risk factor for sumatriptan-induced chest pain in men (relative risk, 8.0; 95% confidence interval, 1.8-40) compared with hypertension as a risk factor in women (relative risk, 1.63; 95% confidence interval, 0.9-3.1). CONCLUSIONS: Young age, hypertension, general complaints of abdominal pain, and a family history of myocardial infarction are associated with an increased risk of chest pain attributed to sumatriptan. Sex is an effective modifier of risk factors of sumatriptan-induced chest pain. In particular, hypertension is a strong risk factor in men.

Adult↗
PubMed1997

Longitudinal changes in ultrasound parameters of the calcaneus.

We examined with a median follow-up of 1.4 years (range 1.0-2.0 years) the rates of change per year in ultrasound parameters of the calcaneus. Speed of sound (SOS), Broadband ultrasound attenuation (BUA) and Stiffness were measured twice in 543 subjects (224 men) participating in the Rotterdam Study. SOS fell by -2.5 m/s per year in both sexes (95% CI -4.0 to -1.1 m/s per year in men and -3.6 to -1.4 m/s per year in women). Stiffness decreased by -0.62 (-1.33 to 0.09) per year in men and -0.66 (-1.24 to -0.08) per year in women. In men the rate of change in SOS and Stiffness tended to increase with age. BUA did not change significantly during follow-up in either sex. The prospectively assessed rates of loss differed considerably from those observed cross-sectionally, especially for SOS in men (cross-sectional -0.7 m/s per year, longitudinal -2.5 m/s per year). There was substantial variation between individuals both in changes per year in SOS and in changes per year in BUA. With a median follow-up time of 1.4 years, approximately 27% of the variation in the rate of change for SOS could be explained by measurement error while for BUA this was approximately 9% and for Stiffness 11%. Only a small percentage of subjects had changes larger than could be accounted for by measurement error (SOS: men 26.8%, women 21.6%; BUA: men 28.5%, women: 38.8%; Stiffness: men 32.6%, women 35.1%). The latter may limit the use of ultrasound measurements as a follow-up tool in individuals rather than in populations.

Age Factors↗
PubMed1997

Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance.

Glucocorticoid resistance due to mutations in the gene for the glucocorticoid receptor has been suggested to be more common than is thought at present, owing to the relative mildness of its symptoms and the difficulty of its diagnosis. To investigate the prevalence of mutations in the glucocorticoid receptor gene responsible for relative insensitivity to glucocorticoids, we carried out polymerase chain reaction/single-strand conformation analysis of the glucocorticoid receptor gene in a group of 20, otherwise healthy, persons with a reduced response in a dexamethasone suppression test and in 20 controls. We did not find mutations or polymorphisms associated with a reduced sensitivity to glucocorticoids. However, we identified five novel polymorphisms in the gene for the human glucocorticoid receptor, which may be useful in analyzing whether loss of (part of) the glucocorticoid receptor gene plays a role in glucocorticoid-resistant malignancies. Although relative resistance to glucocorticoids seems to be rather frequent in otherwise healthy persons, it is not usually associated with mutations or polymorphisms in the glucocorticoid receptor gene.

Aged↗
PubMed1997

Distribution of central corneal thickness and its association with intraocular pressure: The Rotterdam Study.

PURPOSE: To perform a cross-sectional study on the distribution of central corneal thickness and its association with intraocular pressure in an elderly population. METHODS: We measured central corneal thickness and intraocular pressure in 395 subjects (352 control subjects, 13 patients with ocular hypertension, and 30 patients with primary open-angle glaucoma) aged 55 years or more. RESULTS: Mean central corneal thickness in the 352 control subjects was 537.4 microm (95% confidence interval [CI], 533.8 to 540.9 microm; range, 427 to 620 microm), with a maximal difference between eyes of 42 microm. There were no differences between sexes and no significant association with age. Linear regression analysis showed an increase of 0.19 mm Hg in intraocular pressure with each 10-microm increase in central corneal thickness (95% CI, 0.09 to 0.28 mm Hg). This association was similar in both eyes and in both sexes. The 13 patients with ocular hypertension had corneas a mean of 16.0 microm thicker (95% CI, -2.6 to +34.6 microm) compared with control subjects (P = .093); the 30 patients with primary open-angle glaucoma had corneas a mean of 21.5 microm thinner (95% CI, 8.8 to 34.1 microm) compared with control subjects (P = .001). CONCLUSION: Mean central corneal thickness was similar to that found in clinical studies, was slightly higher in patients with ocular hypertension, and was significantly lower in patients with primary open-angle glaucoma. Intraocular pressure was positively related with central corneal thickness. Central corneal thickness may influence the division between normal and increased intraocular pressure at a simple cutoff point of 21 mm Hg.

Aged↗