Funded by US Department of Homeland Security FEMA #EMW-2006-FP-01744 Framingham Risk Score Is Poorly Associated With Subclinical Carotid Atherosclerosis: Results From Firefighter Heart Disease Prevention Project Funded by US Department of Homeland Security FEMA #EMW-2006-FP-01744

Background Firefighters are fit and generally believed to follow a vigorous life-style Cardiovascular disease and cardiovascular mortality has been reported to be highly prevalent in firefighters In the Toronto Fire Department study the mortality ratio for fire fighters aged 45-49 years was 1.73 (p<0.005) compared to non-firefighters CDC has reported that among volunteer firefighters sudden cardiac death and MVA during emergency response are the leading cause of death and among career firefighters, sudden cardiac death and asphyxiation are the leading causes of death Compared to non-emergency duties, fire suppression and alarm response carried significantly higher risks (OR =6.4 and 5.6 respectively) of CHD death Bates JT. J Occup Med. 1987 Feb;29(2):132-5 MMWR Morb Mortal Wkly Rep 2006;55:453-455 Kales SN. Environ Health 2003;2:14 Kales SN N Engl J Med. 2007;356(12):1207-15.

Background

Background More than one million firefighters in US About 100 firefighters die each year on-Duty (1 in 10,000 per year) 1977-2004, CVD has caused ~45% on-Duty Deaths % of On-Duty Deaths caused by CVD Firefighters 45% Police 22% Overall* 15% Construction 11.5%%

Background Etiology of this high CVD risk in firefighters is unclear Various biologically plausible explanations include smoke and chemical exposure, irregular physical exertion, the handling of heavy equipment, heat stress, shift work, a high prevalence of cardiovascular risk factors, and psychological stressors One study describing the prevalence of CHD risk factors among 200 firefighters has reported that the prevalence of obesity, elevated blood cholesterol, and elevated BP exceeded the Healthy People 2010 targets and were higher than the general population We investigated the relationship between noninvasive measures of atherosclerosis to phenotypic and genotypic markers of atheroslcerosis risk in asymptomatic professional firefighters in order to determine which factors were most closely linked to evidence of atherosclerosis and thus, increased risk for cardiovascular events Byczek L. AAOHN J. 2004;52:66-76

Methods 300 active duty firefighters over the age of 40 years were recruited from the Gwinnett County Fire Department which serves a population of approximately 800,000 individuals Series of questionnaires that address standard demographic, nutrition, exercise, lifestyle, and family history variables. Standard physiologic measurements were obtained including, resting 12-lead EKG, blood pressure, ankle-brachial index (ABI), height/weight, and waist-to-hip measurements Coronary Artery Calcium Scoring, carotid intima media thickness Blood samples were obtained following a 16 hour fast for Plasma lipid and lipoprotein cholesterol, Apolipoprotein B, Lp(a), CRP (hs-CRP), homocysteine and other serological markers

Methods Framingham risk scores (FRS) are used to estimate the 10-year coronary heart disease (CHD) risk in individuals Non-invasive assessment of subclinical atherosclerosis by means of carotid intima media thickness (cIMT) and coronary artery calcium score (CAC) could improve risk stratification in high risk groups like firefighters We examined the distribution of FRS scores of cIMT, CAC positive and negative individuals We hypothesize that FRS is a poor indicator of sub-clinical atherosclerosis in professional firefighters

Methods We studied 159 male firefighters (age, 47±5 yrs) without known coronary, peripheral, or cerebral vascular disease. Each participant underwent clinical and serologic risk factor screening, cIMT, and CAC. Abnormal cIMT was defined as >0.9 mm and CAC score > 0 was considered as evidence of early atherosclerosis

Distribution of various cardiovascular risk factors in cIMT+ and cIMT – firefighters p-value Age 53.21±5.59 45.91±4.58 1.01E-07 hsCRP 3.42±1.45 2.06±3.53 0.155 Total cholesterol 213.57±31.15 202.73±35.22 0.2689 HDL2b 20.21±3.96 21.60±4.69 0.2869 Lp(a) 64.85±56.04 58.13±67.37 0.7183 logLp(a) 3.73±1.09 3.41±1.18 0.346 HDL-C 46.78±12.82 48.54±13.95 0.652 LDL-C 148.00±32.15 132.95±13.55 0.09 TG 140.92±55.90 137.53±89.14 0.889 SBP average 133.47±14.36 123.22±10.40 0.00087 DBP average 82.71±8.21 77.75±7.90 0.026 Insulin 9.64±5.10 9.46±5.71 0.909 Glucose 89.43±5.10 86.32±9.22 0.245 BMI 29.48±5.86 29.19±3.93 0.807 WH 0.92±0.056 0.91±0.064 0.668

Distribution of cIMT+ and cIMT – firefighters based on Framingham risk scores

FRS threshold of 20% (corresponding to low-medium risk) has poor sensitivity for identifying people with abnormal CIMT FRS(>20%) FRS(0-20%) CIMT + - 2 30 145 false negative rate of 93% false positive rate of 0%. When using a 20% FRS threshold to predict subclinical carotid atherosclerosis, FRS offers 100% specificity with 7% sensitivity. Thus while this FRS threshold avoids misidentifying individuals without atherosclerosis as being high risk, this same threshold fails to identify individuals who do have atherosclerosis.

A substantial number of low FRS individuals (defined as those with scores < 10%) and medium FRS individuals (defined as those who have scores between 10% and 20%) have clinically significant carotid intima-media thickness (> 0.9 mm)

Distribution of various cardiovascular risk factors in CAC+ and CAC – firefighters N=159 CAC + CAC - p-value Age 48.72±5.62 45.89±4.76 2.73E-03 hsCRP 2.29±1.88 2.15±3.77 0.821 Total cholesterol 209.43±40.71 201.94±32.97 0.254 HDL2b 21.19±4.57 21.56±4.67 0.667 Lp(a) 64.21±69.35 55.84±65.39 0.321 Log Lp(a) 3.68±1.11 3.37±1.19 0.158 HDL-C 49.78±16.77 47.95±12.84 0.483 LDL-C 139.89±39.02 132.57±29.22 0.221 TG 132.81±58.44 139.36±93.62 0.688 SBP average 128.64±13.56 122.76±9.96 0.00045 DBP average 81.21±8.92 77.27±7.53 0.0084 Insulin 10.24±6.02 9.24±5.71 0.348 Glucose 89.62±9.79 85.79±9.28 0.026 BMI 29.90±4.07 29.02±4.12 0.249 WHR 0.92±0.06 0.91±0.066 0.6

Distribution of CAC+ and CAC – firefighters based on Framingham risk scores (FRS)

FRS threshold of 20% (corresponding to low-medium risk) has poor sensitivity for abnormal CAC + - 2 35 122 false negative rate of 95% false positive rate of 0%. When using a 20% FRS threshold to predict CAC, FRS offers 100% specificity but only 5% sensitivity A substantial number of low FRS individuals (defined as those with scores < 10%) and medium FRS individuals (defined as those who have scores between 10% and 20%) have clinically significant coronary calcification There is no significant correlation between CAC and FRS (B = 0.00314 and p-value 0.675, age adjusted)

Conclusions In this active professional firefighter cohort, FRS underestimated the presence of premature, subclinical carotid and coronary atherosclerosis. In our observations, a large number of firefighters with low to moderate Framingham risk scores who are not currently treated to the maximal goals have already have evidence of early carotid atherosclerosis.

Age adjusted logistic Regression P value In Asymptomatic Firefighters the Burden of Subclinical Atherosclerosis as Measured by both Coronary Artery Calcification and Carotid Intimal Medial Thickening is associated with Metabolic Abnormalities and but Not with Standard Traditional Serological Risk Factors n=219 CAC+ CIMT+ (n=52) CAC- CIMT- (n=167) P value Age adjusted logistic Regression P value log Lp(a) 3.7 + 1.3 3.4 + 1.2 0.116 0.106 TC 193 + 45 202 + 38 0.175 0.567 LDL-C 124 + 40 132 + 34 0.138 0.499 TG 146 + 58 139 + 79 0.128 0.11 HDL-C 49 + 16 48 + 12 0.31 0.67 HDL 2b% 21 + 5 21 + 4 0.78 0.537 Apo B 93.64+/-25.32 98.58+/-24.98 0.23 0.73 BMI 31 + 5 30 + 4 0.135 0.018 WHR 0.93 + 0.06 0.91 + 0.06 0.03 0.046 SBP 131 + 13 122 + 10 0.000001 0.003 WC 7.1+/-2.45 5.92+/-1/24 7.41E-006 0.01 Insulin 11.65+7.05 10.44+6.39 0.24 0.26 Glucose 99.29+/-26.49 88.41+/-15.44 30.65+/-5.26 29.53+/-4.5 0.13 0.02

Metabolic syndrome +(n=59) Metabolic syndrome -(n=236) P value Metabolic Syndrome in Firefighters is Associated with Increased Thrombotic and Inflammatory Markers n=295 Metabolic syndrome +(n=59) Metabolic syndrome -(n=236) P value Age adjusted logisticregression P value CAC (AU) 124±342 39±174 0.007 0.022 cIMT (mm) 0.76±0.28 0.66±0.20 0.001 0.005 Total Chol 197±39 201±40 0.425 0.386 Lp(a) (mg/dl) 48±73 65±77 0.140 0.171 Fibrinogen (mg/dl) 351±67 330±58 0.019 0.028 PAI-1 (U/ml) 29±17 15±10 2.543E-14 7.58E-09 hs CRP (mg/l) 4.5±7.2 2.3±4.9 0.031 WBC (x10^9/l) 7.0±1.7 6.0±1.7 0.0002 Ferritin (mg/l) 157±128 123±94 0.026 0.042 Distribution of Various risk factors in Firefighters with and with out Metabolic Syndrome

Our investigation found that 35 Our investigation found that 35.6% of active duty professional firefighters have evidence of subclinical CHD based on noninvasive imaging and was linked to characteristics of the insulin resistance, or the metabolic syndrome.