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1 Supplementary Online Content McEvoy JW, Chen Y, Ndumele CE, et al. Six-year change in high-sensitivity cardiac troponin T and risk of subsequent coronary heart disease, heart failure, and death. JAMA Cardiol. Published online June 8, doi: /jamacardio etable 1. Study Population for the Primary Analysis Evaluating the Association of hs-ctnt Change Between ARIC Visit 2 and Visit 4 With subsequent CHD, HF, or Death Occurring After Visit 4 etable 2. Crude Incidence Rates (per 1000 Person-years) and Adjusted* Hazard Ratios (95% CIs) for Incident Coronary Heart Disease, Heart Failure Hospitalization, or Death According To Sex-Specific Categories of 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) (N=8838) etable 3. Adjusted* Hazard Ratios (95% CIs) for Incident Coronary Heart Disease, Heart Failure, or Death According to Categories of 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) With and Without Further Adjustment for Either Change in NT-proBNP or Visit 4 hs-ctnt etable 4. Crude Incidence Rates (per 1000 Person-years) and Adjusted* Hazard Ratios (95% CIs) for Incident Coronary Heart Disease, Heart Failure Hospitalization, or Death According to 25% Relative Change of 6-Year Change in hs-ctnt etable 5. Net Reclassification Improvement for Coronary Heart Disease, Heart Failure and Death With the Addition of the First and Second hs-ctnt Values to a Traditional Risk Factor Prediction Model etable 6. Adjusted* Hazard Ratios (95% CIs) for Heart Failure Subtypes (HFrEF and HFpEF) Adjudicated After 2005 According to Categories of 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt): Full Model With and Without Further Adjustment for 6-Year Change in NT-proBNP efigure 1. Cumulative Survival Free of Coronary Heart Disease, Heart Failure Hospitalization, or Death Stratified by Categories of Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) During 6 Years (Incident Detectable, Incident Elevated, or Percent Relative Change*) efigure 2. Restricted Cubic Splines for Adjusted* Hazard Ratios (95% CIs) of Incident Coronary Heart Disease (CHD), Heart Failure (HF) Hospitalization, or Death According to Absolute 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) (per Unit Increase in ng/l) efigure 3. Restricted Cubic Splines for Adjusted* Hazard Ratios (95% CIs) of (a) Incident Coronary Heart Disease (CHD) (B) Heart Failure (HF) Hospitalization, or (C) Death According to Absolute 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) (per Unit Increase in ng/l) and Stratified by Visit 2 Concentration Groups (<5 ng/l, 5-13 ng/l, and 14 ng/l) efigure 4. Restricted Cubic Splines for Adjusted* Hazard Ratios (95% CIs) of Incident HFrEF or HFpEF according to Absolute 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) (per Unit Increase in ng/l) This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Study Population for the Primary Analysis Evaluating the Association of hs-ctnt Change Between ARIC Visit 2 and Visit 4 With subsequent CHD, HF, or Death Occurring After Visit 4 Exclusion Process Exclusion Population Participates at visit Prevalent CHD and HF at or prior to visit Missing model covariates at visit Missing hs-ctnt data at either visit 2 or visit Missing follow-up information for events after visit Non black or white, race-center exclusion Study population 8838

3 etable 2. Crude Incidence Rates (per 1000 Person-years) and Adjusted* Hazard Ratios (95% CIs) for Incident Coronary Heart Disease, Heart Failure Hospitalization, or Death According To Sex-Specific Categories of 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) (N=8838) Outcomes Absolute hs-ctnt change according to Gender MEN Incident Elevated (Baseline <24ng/L, Follow-up 24ng/L) WOMEN Incident Elevated (Baseline <14ng/L, Follow-up 14ng/L) No (N=3500) Yes (N=83) No (N=5040) Yes (N=108) Heart Failure n=367 n=31 n=489 n=41 Incidence Rate 8.3 ( ) 40.1 ( ) 7.4 ( ) 39.3 ( ) Demographic Model* ( ) ( ) ( ) ( ) Coronary Heart Disease n=652 n=29 n=416 n=23 Incidence Rate 15.9( ) 39.4 ( ) 6.3 ( ) 20.8 ( ) Demographic Model* ( ) ( ) ( ) ( ) Death n=870 n=45 n=791 n=53 Incidence Rate 19.2( ) 52.4 ( ) 11.6 ( ) 43.9 ( ) Demographic Model* ( ) ( ) ( ) ( ) * Demographic Model- Adjusted for age, race-center; Full Model- Adjusted for age,, race-center, body mass index (kg/m3), C-reactive protein (mg/l), smoking (current; former; never), drinking (current; former; never), systolic blood pressure (mmhg), current use of blood pressure-lowering medication (yes or no), diagnosed diabetes (yes or no), LDL-cholesterol (mg/dl), HDL-cholesterol (mg/dl), triglycerides (mg/dl), and current use of cholesterollowering medication (yes or no), estimated GFR (ml/min/1.73m2), and left ventricular hypertrophy (yes or no, by Cornell criteria).

4 etable 3. Adjusted* Hazard Ratios (95% CIs) for Incident Coronary Heart Disease, Heart Failure, or Death According to Categories of 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) With and Without Further Adjustment for Either Change in NT-proBNP or Visit 4 hs-ctnt Outcomes Absolute hs-ctnt change among all participants Incident Detectable (Baseline <5ng/L, Follow-up 5ng/L) No (N=3888) Yes (N=2152) Incident Elevated (Baseline <14ng/L, Follow-up 14ng/L) No (N=8155) Relative change among persons with measurable hs-ctnt values >50% Decrease Change 50% >50% Increase Yes (N=443) (N=74) (N=2227) (N=1147) Heart Failure n=235 n=260 n=761 n=134 n=10 n=309 n=234 Additional adjustments Coronary Heart Disease Additional adjustments 1.96 ( ) 1.86 ( ) 2.78 ( ) 2.54 ( ) 0.49 ( ) 0.94 ( ) 1.60 ( ) 1.34 ( ) n=330 n=301 n=969 n=119 n=9 n=374 n= ( ) 1.37 ( ) 1.75 ( ) 1.68 ( ) 0.47 ( ) 0.79 ( ) 1.28 ( ) 1.14 ( ) Death n=508 n=486 n=1496 n=209 n=17 n=584 n=392 Additional adjustments 1.50 ( ) 1.46 ( ( ) 1.97 ( ) 0.57 ( ) 0.89 ( ( ) 1.23 ( ) 1.68) 1.46) * Full Model- Adjusted for age, sex, race-center, body mass index (kg/m3), C-reactive protein (mg/l), smoking (current; former; never), drinking (current; former; never), systolic blood pressure (mmhg), current use of blood pressure-lowering medication (yes or no), diagnosed diabetes (yes or no), LDL-cholesterol (mg/dl), HDL-cholesterol (mg/dl), triglycerides (mg/dl), and current use of cholesterol-lowering medication (yes or no), estimated GFR (ml/min/1.73m2), and left ventricular hypertrophy (yes or no, by Cornell criteria). Sample (N=3448) includes only those who have measurable hs-ctnt values ( 3 ng/l) at both visits. Relative change is calculated as a percent of baseline hs-ctnt. The full model for this relative change exposure is further adjusted for visit 2 hsctnt. Additional adjustment is for 1) continuous absolute change in NT-proBNP (in pg/ml) between visits 2 and 4 for the incident detectable and incident elevated models and 2) both adjusting for absolute change in NT-proBNP and for visit 4 hs-ctnt instead of visit 2 hs-ctnt for the relative change model.

5 etable 4. Crude Incidence Rates (per 1000 Person-years) and Adjusted* Hazard Ratios (95% CIs) for Incident Coronary Heart Disease, Heart Failure Hospitalization, or Death According to 25% Relative Change of 6-Year Change in hs-ctnt Outcomes Relative change among persons with measurable hs-ctnt values >25% Decrease Change 25% >25% Increase (N=414) (N=1377) (N=1657) Heart Failure n=50 n=185 n=318 Incidence Rate Demographic Model* 0.88 ( ) 1.53 ( ) 0.83 ( ) 1.54 ( ) Coronary Heart Disease n=69 n=226 n=327 Incidence Rate Demographic Model* 1.07 ( ) 1.24 ( ) 1.04 ( ) 1.21 ( ) Death n=96 n=357 n=540 Incidence Rate Demographic Model* 0.93 ( ) 1.29 ( ) 0.86 ( ) 1.29 ( ) * Demographic Model- Adjusted for age, sex, race-center; Full Model- Adjusted for age, sex, race-center, body mass index (kg/m3), C-reactive protein (mg/l), smoking (current; former; never), drinking (current; former; never), systolic blood pressure (mmhg), current use of blood pressure-lowering medication (yes or no), diagnosed diabetes (yes or no), LDL-cholesterol (mg/dl), HDL-cholesterol (mg/dl), triglycerides (mg/dl), and current use of cholesterol-lowering medication (yes or no), estimated GFR (ml/min/1.73m2), left ventricular hypertrophy (yes or no, by Cornell criteria) and visit 2 hs-ctnt. Relative change sample (N=3448) only includes those who have measurable hs-ctnt values ( 3 ng/l) at both visits. Relative change is calculated as a percent of baseline hs-ctnt.

6 etable 5. Net Reclassification Improvement for Coronary Heart Disease, Heart Failure and Death With the Addition of the First and Second hs-ctnt Values to a Traditional Risk Factor Prediction Model Continuous NRI Coronary heart disease Heart failure All-cause mortality Model Overall NRI p value Overall NRI p value Overall NRI p value Model 1 (vs. base model*) -2% % % Model 2 (vs. model 1) +7% % % *Base model is adjusted for age, sex, race-center, smoking (current; former; never), systolic blood pressure (mmhg), current use of blood pressure-lowering medication (yes or no), diagnosed diabetes (yes or no), LDLcholesterol (mg/dl), HDL-cholesterol (mg/dl) *Model 1 is base model + v4 hs-ctnt. *Model 2 is base model + v4 hs-ctnt +v2 hs-ctnt.

7 etable 6. Adjusted* Hazard Ratios (95% CIs) for Heart Failure Subtypes (HFrEF and HFpEF) Adjudicated After 2005 According to Categories of 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt): Full Model With and Without Further Adjustment for 6-Year Change in NT-proBNP Heart Failure Subtypes Absolute hs-ctnt change among all participants Incident Detectable (Baseline <5ng/L, Follow-up 5ng/L) No (n=3599) Yes (n=1867) Incident Elevated (Baseline <14ng/L, Follow-up 14ng/L) No (n=7306) Relative change among persons with measurable hs-ctnt values >50% Decrease Change 50% >50% Increase Yes (n=286) (n=71) (n=2038) (n=996) HFrEF n=88 n=72 n=256 n=30 n=5 n=121 n=77 Additional adjustment for 6-year change in NT-proBNP 1.54 ( ) 1.43 ( ) 2.43 ( ) 2.31 ( ) 0.85 ( ) 0.87 ( ) 1.26 ( ) 1.24 ( ) HFpEF n=69 n=67 n=199 n=17 n=3 n=76 n=46 Additional adjustment for 6-year change in NT-proBNP 1.72 ( ) 1.68 ( ) 1.80 ( ) 1.70 ( ) 1.06 ( ) 1.10 ( ) 1.16 ( ) 1.09 ( ) * Demographic Model- Adjusted for age, sex, race-center; Full Model- Adjusted for age, sex, race-center, body mass index (kg/m3), C-reactive protein (mg/l), smoking (current; former; never), drinking (current; former; never), systolic blood pressure (mmhg), current use of blood pressure-lowering medication (yes or no), diagnosed diabetes (yes or no), LDL-cholesterol (mg/dl), HDL-cholesterol (mg/dl), triglycerides (mg/dl), and current use of cholesterol-lowering medication (yes or no), estimated GFR (ml/min/1.73m2), and left ventricular hypertrophy (yes or no, by Cornell criteria). Sample (N=3448) only includes those who have measurable hs-ctnt values ( 3 ng/l) at both visits. Relative change is calculated as a percent of baseline hs-ctnt. The full model for this exposure is further adjusted for visit 2 hs-ctnt.

8 efigure 1. Cumulative Survival Free of Coronary Heart Disease, Heart Failure Hospitalization, or Death Stratified by Categories of Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) During 6 Years (Incident Detectable, Incident Elevated, or Percent Relative Change*)

9

10 *Incident Detectable=Baseline <5ng/L, Follow-up 5ng/L; Incident Elevated=Baseline <14ng/L, Follow-up 14ng/L. Percent relative change sample (N=3448) only includes those who have measurable hs-ctnt values ( 3 ng/l) at both visits. Relative change is calculated as a percent of baseline hs-ctnt

11 efigure 2. Restricted Cubic Splines for Adjusted* Hazard Ratios (95% CIs) of Incident Coronary Heart Disease (CHD), Heart Failure (HF) Hospitalization, or Death According to Absolute 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) (per Unit Increase in ng/l) *Adjusted for age, sex, race-center, body mass index (kg/m3), C-reactive protein (mg/l), smoking (current; former; never), drinking (current; former; never), systolic blood pressure (mmhg), current use of blood pressure-lowering medication (yes or no), diagnosed diabetes (yes or no), LDL-cholesterol (mg/dl), HDL-cholesterol (mg/dl), triglycerides (mg/dl), and current use of cholesterol-lowering medication (yes or no), estimated GFR (ml/min/1.73m2), left ventricular hypertrophy (yes or no, by Cornell criteria), and visit 2 hs-ctnt (ng/l). Sample (N=3448) only includes those who have measurable hs-ctnt values ( 3 ng/l) at both visits. Background histogram displays the frequency distribution of hs-ctnt change in the sample. Splines are centered at the median of hs-ctnt change and are truncated at the 1 st and 99 th percentile.

12 efigure 3. Restricted Cubic Splines for Adjusted* Hazard Ratios (95% CIs) of (a) Incident Coronary Heart Disease (CHD) (B) Heart Failure (HF) Hospitalization, or (C) Death According to Absolute 6-Year Change in High- Sensitivity Cardiac Troponin T (hs-ctnt) (per Unit Increase in ng/l) and Stratified by Visit 2 Concentration Groups (<5 ng/l, 5-13 ng/l, and 14 ng/l) A- CHD

13 B- Heart Failure

14 C- Death (All-cause Mortality) *Adjusted for age, sex, race-center, body mass index (kg/m3), C-reactive protein (mg/l), smoking (current; former; never), drinking (current; former; never), systolic blood pressure (mmhg), current use of blood pressure-lowering medication (yes or no), diagnosed diabetes (yes or no), LDL-cholesterol (mg/dl), HDL-cholesterol (mg/dl), triglycerides (mg/dl), and current use of cholesterol-lowering medication (yes or no), estimated GFR (ml/min/1.73m2), and left ventricular hypertrophy (yes or no, by Cornell criteria). Sample (N=3448) only includes those who have measurable hs-ctnt values ( 3 ng/l) at both visits. Background histogram displays the frequency distribution of hs-ctnt change in the sample. Splines are centered at the median of hs-ctnt change and are truncated at the 1 st and 99 th percentile.

15 efigure 4. Restricted Cubic Splines for Adjusted* Hazard Ratios (95% CIs) of Incident HFrEF or HFpEF according to Absolute 6-Year Change in High-Sensitivity Cardiac Troponin T (hs-ctnt) (per Unit Increase in ng/l) - HFREF - HFPEF *Adjusted for age, sex, race-center, body mass index (kg/m3), C-reactive protein (mg/l), smoking (current; former; never), drinking (current; former; never), systolic blood pressure (mmhg), current use of blood pressure-lowering medication (yes or no), diagnosed diabetes (yes or no), LDL-cholesterol (mg/dl), HDL-cholesterol (mg/dl), triglycerides (mg/dl), and current use of cholesterol-lowering medication (yes or no), estimated GFR (ml/min/1.73m2), left ventricular hypertrophy (yes or no, by Cornell criteria), and visit 2 hs-ctnt (ng/l). Sample (N=3448) only includes those who have measurable hs-ctnt values ( 3 ng/l) at both visits. Background histogram displays the frequency distribution of hs-ctnt change in the sample. Splines are centered at the median of hs-ctnt change and are truncated at the 1 st and 99 th percentile.