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Can Timing of Exposure Predispose Older Adults to Disease? Douglas W. Dockery Effects of Air Pollution on Health of Older Adults June 14-15, 2005 Mickey Leland National Urban Air Toxics Research Center Loss of Function with Age Brain Weight (92%) Nerve Conduction Velocity (90%) Basal Metabolism (84%) Cardiac Output (70%) Kidney Filtration Rate (69%) Maximum Breathing Capacity (43%) Leap, Scientific American; 1973 Death (Harvesting) And so from hour to hour We ripe and ripe, And from hour to hour We rot and rot. Shakespeare As You like It PreNatal Genetic Childhood Experience Early Childhood Experience Rapid Decline Just as a twig is bent the tree inclines. Alexander Pope Moral Essays Chronic Obstructive Lung Disease • Cumulative loss of function (FEV1) from environmental insults during adulthood • Maximum attained function determined by growth (development) during childhood – Cumulative effects of environmental insults on growth retardation – Early childhood effects during lung development • Pre-natal or genetic factors define track (growth curve) Six Cities Mortality Study • 8111 adults followed up from 1974 to 1989 • Mortality risk ratios – Adjustment • • • • • Age, Sex Cigarette Smoking Occupational Exposure, Education Body Mass Index Chronic Disease • Compared to city-specific average PM2.5 (1979-86) Six Cities Cohort Mortality Mortality Risk Ratio 1.4 1.3 Steubenville Kingston 1.2 St. Louis 1.1 Topeka Watertown 1.0 Portage 0.9 0.8 0.7 0 5 10 15 20 PM2.5 (mg/m3) 25 30 35 Six Cities Mortality Follow-up • 1974 to 1989 follow-up • 1990 to 1998 follow-up – Annual returned postcards and National Death Index – 1,364 deaths in 104,243 person years – PM2.5 measurements 1979-1986 – National Death Index search – 1,368 deaths in 54,735 person years – PM2.5 estimated from PM10 1990-1998 Six Cities Cohort Follow-up Mortality Risk Ratio 1.4 1.3 Steubenville Kingston St. Louis 1.2 1.1 Topeka Portage 1.0 0.9 0.8 Watertown 0.7 0 5 10 15 20 PM2.5 (mg/m3) 25 30 35 Dublin Coal Ban • Sept 1, 1990:marketing, sale, and distribution of bituminous coals banned within city of Dublin. • Effect was an immediate and permanent reduction in average particulate concentrations. • Average black smoke concentrations declined by 35.6 mg/m3 (70%) after the ban on coal sales. Dublin Coal Ban • Total (non-trauma) death rates decreased by 5·7% (p<0·0001) • Cardiovascular deaths by 10·3% (p<0·0001) • Respiratory deaths by 15·5% (p<0·0001) • Effects seen within the same season Clancy et al, Lancet, 2002 Dublin County Borough 40 35 Black Smoke 600 Deaths 30 400 25 200 20 0 15 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 January 1982 Deaths Black Smoke (ug/m3) 800 Dublin 1980-1990 17 Deaths per Day 16 15 14 13 12 11 Mean of 20 consecutive points 10 9 0 100 200 300 3 Day Mean Black Smoke (ug/m3) 400 Reversible Decline Chronic Obstructive Lung Disease • Cumulative loss of function (FEV1) from environmental insults during adulthood • Maximum attained function determined by growth (development) during childhood – Cumulative effects of environmental insults on growth retardation – Early childhood effects during lung development • Pre-natal or genetic factors define track (growth curve) • Death more likely from acute events – Pneumonia – Acute cardiac event Coronary Heart Disease • Atherosclerosis – Plaque builds up in arteries over time – Can signficantly reduce blood flow • Carotid intima-media thickness (CIMT) – Ultrasound measure of atherosclerosis in carotid artery – Correlates well with coronary artery atherosclerosis – Associated with age and sex – Associated with long-term exposures to smoking and passive smoking Men Women IMT by age in patients with heterozygous familial hypercholesterolaemia (FH) and low-risk controls. Each dot represents the average IMT of 10 carotid and femoral IMTs of a subject. Kastelein et al,Atherosclerosis Suppl 4; 2003: 31-6 Ambient Air Pollution and Atherosclerosis in Los Angeles Kuenzli et al, EHP 2005 •798 participants in 2 clinical trials •Carotid intima-media thickness (CIMT) subclinical atherosclerosis. •Geocoded resident to assign annual mean PM2.5. •10 mg/m3 increase in mean PM2.5 associated with 5.9% (p=0.018) increase in CIMT •Stronger associations in Women and Older subjects Linkage of Atheroschlerotic Plaques and Acute Myocardial Infarction Determinants of MI Onset Study Peters et al, Circulation 2001 • 833 patients with confirmed myocardial infarction interviewed in the greater Boston area between 1995 and 1996. • Hourly PM2.5 data available during this period (24h-average: 12.1 µg/m3; max: 47.4 µg/m3). PM2.5 and Onset of Myocardial Infarction 1.8 24 Hr PM2.5 OR for MI Onset 1.6 1.4 1.2 1.0 0.8 1.6-6.4 6.5-8.6 8.7-11.5 11.6-16.2 PM2.5 (mg/m3) 16.3-52.2 Coronary Heart Disease • Cumulative build-up of plague in coronary arteries during adulthood – CIMT associatd with long term environmental exposures (active and passive smoking, air pollution) – Developing evidence that plague buildup begins in childhood • Pre-natal or genetic factors may define track (growth curve) • Death more likely from acute events – Plaque rupture, myocardial infarction, ischemic stroke Implantable Cardioverter Defibrillators (ICD) Devices • Implanted under skin with electrodes and leads attached to heart • Monitor cardiac rhythm abnormalities • On detecting potentially fatal arrhythmia, triggers cardioverter shock • Records date and time of all detected arrhythmias and therapies Air Pollution and Incidence of Cardiac Arrhythmias Dockery et al, EHP June 2005 • 203 patients with Implanted Cardioverter Defibrillators (ICDs) • Lived within I-495 in eastern Massachusetts • Followed 1995-2002, average 3.2 years • Abstracted ICD detected ventricular arrhythmias • Confirmed by cardiac electrophysiologist • Daily air pollution measurements – PM2.5, Black Carbon, SO4 – CO, O3, NO2 and SO2 • Weather – Temperature and humidity • Regression of cardiac arrhythmias against air pollution Air Pollution and Incidence of Cardiac Arrhythmias Dockery et al, EHP June 2005 • ICD detected ventricular arrhythmias (VA) in 203 patients in Boston • Increased risk of VA with 2-day mean PM2.5, Black Carbon, CO and NO2 for patients with a recent, previous arrhythmia • Air pollution is acute trigger of potentially lifethratening VA among patients with electrically unstable cardiac substrate Prior VA No Prior VA Environmental Effects on the Elderly • Compromised Substrate – Cumulative loss of function in adults – Compromise begins during childhood – Prenatal (genes) define growth curve (track) • Acute Trigger – Environmental exposures can also trigger acute response – With compromised substrate (inadequate reserve), pushed over edge Timing of Air Pollution Exposures • Acute exposures (hours to days) can trigger adverse events, particularly in the presence of compromised substrate • Medium term exposures (weeks to months) also can trigger adverse events • Long-term exposures (years to decades) can contribute to compormised substrate or loss of physiologic reserve • Early life exposures (perinatal and childhood) can define track for development of chronic condidtions