Abstract
The long-term prognostic significance of a coronary artery calcium (CAC) score of 0 is poorly defined in younger adults. We evaluated this among participants aged 45–55 years from the Multi-Ethnic Study of Atherosclerosis, and whether additional biomarkers can identify subgroups at increased absolute risk. We included 1,407 participants (61% women) without diabetes or severe hypercholesterolemia, with estimated 10-year risk <20% and CAC=0. We evaluated all and hard cardiovascular disease (CVD) events, overall and among individuals with each of: high-sensitivity C-reactive protein ≥2 mg/L, homocysteine ≥10 μmol/L, high-sensitivity cardiac troponin T ≥95th percentile, lipoprotein (a) >50 mg/dL, triglycerides ≥175 mg/dL, apolipoprotein B ≥130 mg/dL, albuminuria, thoracic aortic calcium, aortic valve calcium (AVC), mitral annular calcium, ankle-brachial index <0.9, any carotid plaque, and maximum internal carotid artery intima-media thickness (ICA-IMT) ≥1.5mm. Median follow-up was 16 years and overall CVD event rates were low (4% at 15 years). For most exposures evaluated, rates of all CVD events were <6 per 1,000 person-years, except for ICA-IMT ≥1.5mm (6.43) and AVC (13.8). The number needed to screen (NNS) to detect ICA-IMT ≥1.5mm was 8, and 84 for AVC. Among participants with borderline/intermediate risk or premature family history, hard CVD event rates were <7 per 1,000 for most exposures, except for ICA-IMT ≥1.5mm (8.25), albuminuria (8.30), and AVC (13.47). Non-smokers and those with ICA-IMT <1.5mm had very low rates. In conclusion, our results demonstrate a favorable long-term prognosis of CAC=0 among adults aged ≤55, particularly among non-smokers. ICA-IMT testing could be considered for further risk assessment in adults ≤55 years with CAC=0 and uncertain management.
Keywords: biomarkers, cardiovascular disease, coronary artery calcium, prevention, young
The coronary artery calcium (CAC) score is a guideline-endorsed test for further risk assessment in the primary prevention of atherosclerotic cardiovascular disease (ASCVD) (1–4). A CAC score of zero is strongly associated with low 10-year event rates in the general population free of clinical ASCVD (5,6), and identifies subgroups with the lowest event rates within populations at increased average risk (7–9). Based on this, a selective use of statins and a restrictive use of most expensive pharmacotherapies has been proposed for value-driven ASCVD prevention among individuals with CAC=0 who have prevalent risk factors or borderline/intermediate estimated risk (1–4,10,11). Nevertheless, the long-term prognostic implications of CAC=0 and its utility as a negative risk marker have been recently put into question in young-to-middle-aged adults (12). Absolute event rates in young-to-middle-aged adults with CAC=0 are low after up to 12.5 years of follow-up, and much lower than those observed if CAC>0 (13–16). However, longer timeframes may be more informative in young populations given the potential lifetime benefits of early preventive interventions. We aimed to evaluate the long-term prognosis of CAC=0 among participants aged ≤55 years from the Multi-Ethnic Study of Atherosclerosis (MESA), and whether additional biomarkers can help identify subgroups at increased absolute risk who could potentially benefit from an early, more aggressive risk reduction despite having CAC=0.
Methods
We used data from MESA, an NIH-funded, community-based, prospective cohort study of individuals without a history of CVD aged 45–84 years at baseline (17). A total of 6,814 participants of 4 racial/ethnic groups were enrolled between 2000 and 2002 from 6 sites in the US. The study protocol was approved by the Institutional Review Boards of each of the 6 sites, and all participants provided written informed consent before enrollment. Further details on the MESA study methods have been reported elsewhere and are also available online (17).
MESA participants underwent baseline non-contrast-enhanced cardiac computed tomography testing for CAC quantification, scored using Agatston’s method. For the present analysis, we included participants aged 45–55 with a CAC score of zero. Individuals with diabetes mellitus and those with severe hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] levels ≥190 mg/dL) were excluded, because in current American College of Cardiology/American Heart Association (ACC/AHA) and European guidelines both groups are recommended statins regardless of risk estimations or CAC burden (1,2). Participants with estimated 10-year ASCVD risk ≥20% using the Pooled Cohort Equations (PCE), statin users at baseline, and individuals with missing data on CVD events were also excluded (Figure 1).
Figure 1.
Flow of the participants included in the study.
Abbreviations: ASCVD = atherosclerotic cardiovascular disease; CAC = coronary artery calcium; LDL-C = low-density lipoprotein cholesterol; N = number
In addition to CAC scoring, as part of MESA Visit 1 participants underwent a comprehensive examination including questionnaires, measurement of blood biomarkers, and various tests aimed at detecting subclinical CVD and other markers of cardiovascular risk. The exposures of interest for the present analysis included: 1) traditional risk factors: hypertension (defined as a systolic blood pressure ≥130 mmHg and/or diastolic ≥80 mmHg, or treatment with blood pressure-lowering medications), high LDL-C levels (160 to <190 mg/dL) (1,2), low levels of high-density lipoprotein cholesterol (HDL-C; defined as <40 mg/dL in men or <50 mg/dL women (1,2)), dyslipidemia (high LDL-C, low HDL-C, or both), current cigarette smoking, and obesity (body mass index ≥30 kg/m2); 2) family history: having a family history of coronary heart disease (CHD; any), and a family history of premature CHD (first-degree male family member ≤55 years of age or a female family member <65); 3) blood and urine biomarkers: high-sensitivity C-reactive protein (hsCRP) levels ≥2 mg/L, homocysteine ≥10 μmol/L, 5th generation assay high-sensitivity cardiac troponin T ≥95th percentile (≥15.93 pg/mL), lipoprotein (a) >50 mg/dL, triglycerides ≥175 mg/dL, apolipoprotein B ≥130 mg/dL, and albuminuria; and 4) imaging and vascular biomarkers: thoracic aortic calcium (i.e., score >0), aortic valve calcium (AVC; >0), mitral annular calcification (>0), any extra-coronary calcification (ECC) (yes/no), ankle-brachial index (ABI) <0.9, any carotid plaque (stenosis >0%) in carotid ultrasound imaging, and a maximum internal carotid artery intima-media thickness (ICA-IMT) ≥1.5mm. Details on the methods used for each of these measurements have been reported (17–20).
As of February 2021, MESA participants had been followed by trained study personnel for incident CVD events for up to 17.5 years. Details on the event ascertainment methods in MESA have been described elsewhere (17). For the current analysis, the outcomes of interest were all CVD events (primary endpoint, inclusive of fatal/non-fatal myocardial infarction, fatal/non-fatal stroke, resuscitated cardiac arrest, other CVD death, definite angina, and probable angina followed by revascularization) and hard CVD events (secondary endpoint, inclusive of fatal/non-fatal myocardial infarction, fatal/non-fatal stroke, resuscitated cardiac arrest, and other CVD death). Events were adjudicated by the MESA mortality and morbidity review committee.
The baseline characteristics of the study participants were described overall and by incidence of CVD events during follow-up. We calculated the baseline frequency (%) of each of the exposures of interest in the study population. The number needed to screen (NNS) to detect an individual with each of the exposures of interest was computed as 1/frequency. Crude event rates per 1,000 person-years (with 95% confidence intervals [CIs]) were computed for all CVD events and hard CVD events, respectively, using all follow-up data available. These were calculated both overall and among individuals with and without each of the exposures of interest. Unadjusted Kaplan-Meier cumulative incidence functions were also used to ascertain the incidence (expressed as %) of the study endpoints censored at 10 and 15 years of follow-up, respectively. Incidence at 10 years is typically used in relevant guidelines to define risk thresholds for preventive interventions (1), and assessing incidence also at 15 years provides further information beyond the event rates per 1,000 person-years, which assume linearity in the incidence of CVD events during follow-up. For exposures with event rates (point estimate) ≥5 per 1,000 person-years, we used Cox regression models to evaluate the association between the presence of each exposure (compared to its absence) and all CVD events during follow-up, adjusting for age, sex, and race/ethnicity. This analysis was not conducted for exposures with event rates were <5 as the multivariable analyses were expected to be underpowered. In subgroup analyses, we described the frequency of the study exposures and incidence rates of CVD events specifically among individuals with either estimated borderline/intermediate (i.e., 5–20%) 10-year ASCVD risk using the PCE (1), or a family history of premature CHD. These are the groups in which CAC scoring has been most consistently recommended for further risk assessment (1–4). All analyses were performed using Stata version 16.
Results
The analysis included 1,407 MESA participants aged 45–55 years, with CAC=0 and free of diabetes mellitus and severe hypercholesterolemia at baseline. Per inclusion/exclusion criteria all participants had an estimated 10-year ASCVD risk <20% and were statin-naïve at enrollment (Figure 1). Mean age was 50 years and 61% were women (Table 1). The median estimated 10-year ASCVD risk using the PCE was 2.1%. The most frequent exposures were hsCRP ≥2.0 mg/L, dyslipidemia, which was mostly driven by low HDL-C, and a family history of CHD (Figure 2). In contrast, the least frequent were AVC, mitral calcification, and abnormal ABI.
Table 1.
Baseline characteristics of the study participants.
| Cardiovascular Disease Events |
||||
|---|---|---|---|---|
| Variable | All (n=1,407) | No (n=1,359) | Yes (n=58) | P value |
|
| ||||
| Age (years) | 49.8 (3.2) | 49.8 (3.2) | 50.3 (3.3) | 0.31 |
| Women | 852 (61%) | 824 (61%) | 28 (48%) | 0.05 |
| Race/ethnicity | 0.62 | |||
| Non-Hispanic White | 504 (36%) | 486 (36%) | 18 (31%) | |
| Non-Hispanic Black | 396 (28%) | 376 (28%) | 20 (35%) | |
| Hispanic | 343 (24%) | 328 (24%) | 15 (26%) | |
| Chinese | 164 (12%) | 159 (12%) | 5 (9%) | |
| Body mass index (kg/m2) | 28.2 (5.8) | 28.2 (5.9) | 28.6 (5.1) | 0.58 |
| Smoker | 0.009 | |||
| Current | 241 (17%) | 223 (17%) | 18 (31%) | |
| Former | 389 (28%) | 372 (28%) | 17 (29%) | |
| Never | 773 (55%) | 750 (56%) | 23 (40%) | |
| Systolic blood pressure (mm Hg) | 115 (17) | 115 (17) | 121 (18) | 0.02 |
| Diastolic blood pressure (mm Hg) | 71 (10) | 71 (10) | 74 (10) | 0.01 |
| Medication for hypertension | 230 (16%) | 217 (16%) | 13 (22%) | 0.2 |
| Total cholesterol (mg/dL) | 192 (34) | 192 (34) | 190 (38) | 0.74 |
| Low-density lipoprotein cholesterol (mg/dL) | 116 (29) | 116 (28) | 117 (32) | 0.74 |
| High-density lipoprotein cholesterol (mg/dL) | 51 (14) | 52 (15) | 47 (12) | 0.008 |
| Triglycerides (mg/dL) | 100 (71, 149) | 100 (71, 148) | 108 (72, 182) | 0.32 |
| Fasting blood glucose (mg/dL) | 86 (10) | 86 (10) | 87 (11) | 0.54 |
| Estimated 10-year risk* (%) | 2.1 (1.0, 4.1) | 2.0 (1.0, 4.1) | 3.9 (1.5, 6.5) | <0.001 |
| Estimated 10-year risk* | <0.001 | |||
| Low (<5%) | 1,145 (82%) | 1,108 (83%) | 37 (64%) | |
| Borderline (5–<7.5%) | 134 (10%) | 126 (9%) | 8 (14%) | |
| Intermediate (≥7.5%) | 117 (8%) | 104 (8%) | 13 (22%) | |
Ten-year risk of an atherosclerotic cardiovascular disease event, estimated using the Pooled Cohort Equations.
Results are presented as n (%), mean (standard deviation), or median (interquartile range).
Column percentages may not add 100% due to rounding.
Figure 2.
Prevalence of the study exposures and number needed to screen.
Abbreviations: ABI, ankle-brachial index; ApoB, apolipoprotein B; CHD, coronary heart disease; ECC, extra-coronary calcium; HDL-C, high-density lipoprotein cholesterol; hsCRP, high sensitivity C-reactive protein; ICA-IMT, internal carotid artery intima-media thickness; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); NNS, number needed to screen; TG, triglycerides
Median follow-up was 16.2 years and the longest follow-up accrued was 17.5 years. A total of 58 CVD events (4%) occurred, including 46 (79%) hard CVD events. Participants who had CVD events during follow-up were more frequently male and current smokers, had higher average blood pressure and lower HDL-C levels, and their median 10-year estimated risk was almost twice that of those without events (3.9% vs 2.0%, p<0.001; Table 1).
Overall, the crude incidence rate of all CVD events was 2.78 per 1,000 person-years and 2.20 for hard CVD events (Table 2). Event rates were higher in men compared to women, in those aged 50–55 years, and among subgroups with a stronger indication for clinical CAC scoring, particularly among individuals with intermediate estimated risk (rate of hard CVD events 6.08 per 1,000 person-years). For most exposures of interest, the point estimates for all CVD event rates were <5 per 1,000 person-years (Table 3). Exceptions to this were any ECC (5.27 per 1,000 person-years), current smoking, albuminuria, ICA-IMT ≥1.5mm, and AVC, although the absolute number of events for the latter was only 3. Event rates for current smoking were the highest among all traditional risk factors assessed. Rates of events for ABI <0.9 and mitral annulus calcium could not be computed as for both the number of events was 0. Event rates were even lower for hard CVD events, with point estimates <5 per 1,000 person-years for most risk factors and markers evaluated (exceptions: albuminuria, ICA-IMT ≥1.5mm, and AVC). The upper bound of the 95% CIs was <7.5 for most exposures as well (Table 3).
Table 2.
Crude incidence rates per 1,000 person-years of cardiovascular disease events overall and by key subgroups, participants aged 45–55 years with a coronary artery calcium score of 0.
| All cardiovascular disease events |
Hard cardiovascular disease events |
||||
|---|---|---|---|---|---|
| Study groups | Number | Number of events | Event rates per 1,000 person-years | Number of events | Event rates per 1,000 person-years |
|
| |||||
| Overall study population | 1,407 | 58 | 2.78 (2.15, 3.59) | 46 | 2.20 (1.65, 2.93) |
| Sex | |||||
| Men | 555 | 30 | 3.65 (2.55, 5.23) | 22 | 2.66 (1.75, 4.05) |
| Women | 852 | 28 | 2.21 (1.53, 3.20) | 24 | 1.89 (1.27, 2.82) |
| Age (years) | |||||
| 45 to <50 | 651 | 23 | 2.37 (1.58, 3.57) | 17 | 1.75 (1.09, 2.81) |
| 50 to ≤55 | 756 | 35 | 3.13 (2.25, 4.36) | 29 | 2.59 (1.80, 3.72) |
| Subgroups with guideline indication for clinical coronary artery calcium scoring | |||||
| Borderline/intermediate risk* or family history of premature coronary heart disease | 444 | 31 | 4.80 (3.38, 6.83) | 25 | 3.85 (2.60, 5.70) |
| Borderline/intermediate risk* | 251 | 21 | 5.89 (3.84, 9.03) | 16 | 4.44 (2.72, 7.24) |
| Intermediate risk* | 117 | 13 | 8.03 (4.66, 13.82) | 10 | 6.08 (3.27, 11.31) |
Estimated using the Pooled Cohort Equations.
Data presented as incidence rates per 1,000 person-years and 95% confidence intervals, computed over 17.5 years of follow-up data (median follow-up 16.2 years).
Table 3.
Crude incidence rates per 1,000 person-years of cardiovascular disease events by presence of each of the study exposures.
| All cardiovascular disease events | Hard cardiovascular disease events | |
|---|---|---|
|
| ||
| Traditional risk factors | ||
| Hypertension | 3.04 (1.86, 4.96) | 2.27 (1.29, 4.00) |
| High low-density lipoprotein cholesterol | 3.88 (1.61, 9.31) | 3.10 (1.16, 8.26) |
| Low high-density lipoprotein cholesterol | 3.74 (2.58, 5.41) | 2.92 (1.92, 4.44) |
| Dyslipidemia | 3.60 (2.52, 5.15) | 2.87 (1.92, 4.28) |
| Current smoker | 5.32 (3.35, 8.45) | 4.10 (2.43, 6.93) |
| Obesity | 3.32 (2.16, 5.09) | 2.51 (1.54, 4.10) |
| Family history | ||
| Family history of coronary heart disease | 4.17 (2.90, 6.00) | 3.15 (2.07, 4.78) |
| Premature family history | 4.96 (3.13, 7.88) | 3.83 (2.27, 6.46) |
| Blood/Urine biomarkers | ||
| High sensitivity C-reactive protein ≥2 mg/L | 2.88 (1.96, 4.24) | 2.21 (1.43, 3.43) |
| Homocysteine ≥10 μmol/L | 3.10 (1.72, 5.61) | 2.82 (1.52, 5.24) |
| Lipoprotein (a) > 50mg/dL | 2.78 (1.50, 5.17) | 1.38 (0.57, 3.31) |
| Triglycerides ≥ 175 mg/dL | 4.19 (2.52, 6.94) | 2.77 (1.49, 5.14) |
| Apolipoprotein B ≥ 130 mg/dL | 4.64 (2.64, 8.17) | 3.45 (1.80, 6.64) |
| High sensitivity troponin T ≥95th percentile | 3.00 (0.97, 9.31) | 1.98 (0.49, 7.90) |
| Albuminuria | 5.33 (2.00, 14.21) | 5.31 (1.99, 14.15) |
| Imaging/Vascular biomarkers | ||
| Mitral annulus calcium | —* | —* |
| Aortic valve calcium | 13.81 (4.45, 42.81) | 9.20 (2.30, 36.8) |
| Thoracic aortic calcium | 3.56 (0.89, 14.23) | 3.56 (0.89, 14.23) |
| Any extra-coronary calcium | 5.27 (2.19, 12.65) | 4.21 (1.58, 11.23) |
| Ankle-brachial index <0.9 | —* | —* |
| Carotid plaque | 3.50 (1.98, 6.15) | 2.90 (1.56, 5.39) |
| Internal carotid artery intima-media thickness ≥1.5 mm | 6.43 (3.99, 10.34) | 5.67 (3.42, 9.40) |
There were no events among the few participants with these characteristics.
Results are presented as incidence rates per 1,000 person-years and 95% confidence intervals.
Consistent trends were observed in analyses of cumulative incidence of all CVD events at 10 and 15 years of follow-up, respectively (Figure 3). For all features for which 10-year incidence could be computed (17 out of 21), except for ICA-IMT ≥1.5mm and AVC, this was consistently lower than 5%, and even ≤3% for most features. Although absolute incident events remained low in most subgroups at 15 years of follow-up, there was a marked increase between years 10 and 15 of follow-up in several subgroups, particularly among current smokers, those with low HDL-C, and those with increased levels of other lipids.
Figure 3.
Cumulative incidence of cardiovascular disease events (all) at 10 and at 15 years of follow-up, respectively.
There were no events at 15 years of follow-up among the few participants with mitral annulus calcium, thoracic aortic calcium, or ABI <0.9.
Abbreviations: ABI, ankle-brachial index; ApoB, apolipoprotein B; CHD, coronary heart disease; ECC, extra-coronary calcium; HDL-C, high-density lipoprotein cholesterol; hsCRP, high sensitivity C-reactive protein; ICA-IMT, internal carotid artery intima-media thickness; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); NNS, number needed to screen; TG, triglycerides.
The strongest negative risk marker in this population with CAC=0 was absence of any family history of CHD (Table 4). Normal HDL-C levels and no current smoking ranked second and third strongest negative risk markers, respectively. In analyses of hard CVD events, ICA-IMT <1.5 mm and absence of dyslipidemia were the strongest negative risk markers followed by absence of any family history. No current smoking also had very low rates of hard CVD events.
Table 4.
Crude incidence rates per 1,000 person-years of cardiovascular disease events by absence of each of the study exposures.
| All cardiovascular disease | Hard cardiovascular disease | |
|---|---|---|
| Absence of: | ||
|
| ||
| Traditional risk factors | ||
| Hypertension | 2.69 (1.99, 3.64) | 2.17 (1.55, 3.04) |
| High low-density lipoprotein cholesterol | 2.71 (2.07, 3.56) | 2.13 (1.57, 2.90) |
| Low high-density lipoprotein cholesterol | 2.26 (1.58, 3.23) | 1.80 (1.21, 2.69) |
| Dyslipidemia | 2.26 (1.56, 3.27) | 1.77 (1.17, 2.69) |
| Current smoker | 2.29 (1.68, 3.12) | 1.83 (1.29, 2.58) |
| Obesity | 2.54 (1.84, 3.51) | 2.06 (1.44, 2.94) |
| Family history | ||
| Family history of coronary heart disease | 2.17 (1.50, 3.14) | 1.78 (1.18, 2.67) |
| Premature family history | 2.46 (1.76, 3.42) | 1.96 (1.35, 2.84) |
| Blood/Urine biomarkers | ||
| High sensitivity C-reactive protein ≥2 mg/L | 2.65 (1.86, 3.77) | 2.13 (1.44, 3.15) |
| Homocysteine ≥10 μmol/L | 2.73 (2.05, 3.63) | 2.08 (1.50, 2.89) |
| Lipoprotein (a) > 50mg/dL | 2.81 (2.12, 3.73) | 2.40 (1.77, 3.26) |
| Triglycerides ≥ 175 mg/dL | 2.50 (1.86, 3.37) | 2.09 (1.51, 2.90) |
| Apolipoprotein B ≥ 130 mg/dL | 2.72 (1.97, 3.75) | 2.05 (1.41, 2.97) |
| High sensitivity troponin T ≥95th percentile | 2.78 (2.14, 3.62) | 2.22 (1.66, 2.98) |
| Albuminuria | 2.70 (2.07, 3.53) | 2.10 (1.55, 2.84) |
| Imaging/Vascular biomarkers | ||
| Mitral annulus calcium | 2.81 (2.17, 3.63) | 2.22 (1.66, 2.96) |
| Aortic valve calcium | 2.66 (2.04, 3.47) | 2.12 (1.58, 2.85) |
| Thoracic aortic calcium | 2.76 (2.12, 3.58) | 2.16 (1.61, 2.90) |
| Any extra-coronary calcium | 2.66 (2.03, 3.48) | 2.10 (1.55, 2.84) |
| Ankle-brachial index <0.9 | 2.80 (2.17, 3.62) | 2.22 (1.66, 2.96) |
| Carotid plaque | 2.67 (2.00, 3.57) | 2.09 (1.50, 2.89) |
| Internal carotid artery intima-media thickness ≥1.5 mm | 2.35 (1.73, 3.19) | 1.77 (1.24, 2.52) |
Results are presented as incidence rates per 1,000 person-years and 95% confidence intervals.
The age-, sex-, and race/ethnicity-adjusted hazard ratios of all CVD events were 1.90 (95% CI 0.74, 4.86) for any ECC, 2.33 (95% CI 1.33, 4.11) for current smoking, 1.95 (95% CI 0.70, 5.44) for albuminuria, 2.78 (95% CI 1.58, 4.90) for ICA-IMT ≥1.5mm, and 4.52 (95% CI 1.37, 14.87) for AVC.
In analyses restricted to individuals at either borderline/intermediate estimated 10-year ASCVD risk or with family history of premature CHD (N=444), the point estimates of all CVD event rates were <7.5 per 1,000 person-years for all exposures evaluated, except for albuminuria, ICA-IMT ≥1.5mm, current smoker, and AVC (Table 5). In this subgroup, albuminuria was present in 4% of participants, 20% had ICA-IMT ≥1.5mm, 30% were current smokers, and 3% had AVC (Figure 4). In analyses of negative risk markers, no tobacco use ranked first for both all CVD events and hard CVD events, followed by ICA-IMT <1.5mm (Table 6).
Table 5.
Crude incidence rates per 1,000 person-years of cardiovascular disease events among individuals at borderline/intermediate estimated risk and/or family history of premature coronary heart disease, by presence of each of the study exposures.
| Variable | All cardiovascular disease events | Hard cardiovascular disease events |
|---|---|---|
|
| ||
| Hypertension | 4.62 (2.62, 8.13) | 3.81 (2.05, 7.08) |
| High low-density lipoprotein cholesterol | 5.49 (1.77, 17.03) | 5.49 (1.77, 17.03) |
| Low high-density lipoprotein cholesterol | 5.48 (3.36, 8.95) | 4.43 (2.57, 7.63) |
| Dyslipidemia | 5.34 (3.32, 8.59) | 4.37 (2.59, 7.39) |
| Current smoker | 9.23 (5.74, 14.85) | 6.95 (4.04, 11.97) |
| Obesity | 4.38 (2.42, 7.90) | 3.55 (1.85, 6.82) |
| Family history of coronary heart disease | 5.28 (3.37, 8.27) | 4.15 (2.50, 6.88) |
| Premature family history | 4.96 (3.13, 7.88) | 3.83 (2.27, 6.46) |
| High sensitivity C-reactive protein ≥2 mg/L | 4.46 (2.69, 7.39) | 3.53 (2.01, 6.23) |
| Homocysteine ≥10 μmol/L | 3.31 (1.38, 7.95) | 3.31 (1.38, 7.95) |
| Lipoprotein (a) > 50mg/dL | 3.61 (1.50, 8.67) | 2.15 (0.69, 6.66) |
| Triglycerides ≥ 175 mg/dL | 6.20 (3.34, 11.53) | 3.66 (1.64, 8.15) |
| Apolipoprotein B ≥ 130 mg/dL | 7.29 (3.65, 14.58) | 5.36 (2.41, 11.94) |
| High sensitivity troponin T ≥95th percentile | 5.70 (1.84, 17.66) | 3.70 (0.93, 14.81) |
| Albuminuria | 8.30 (2.07, 33.17) | 8.30 (2.07, 33.17) |
| Mitral annulus calcium | —* | —* |
| Aortic valve calcium | 20.21 (6.52, 62.66) | 13.47 (3.37, 53.87) |
| Thoracic aortic calcium | —* | —* |
| Any extra-coronary calcium | 7.27 (2.35, 22.52) | 4.85 (1.21, 19.39) |
| Ankle-brachial index <0.9 | —* | —* |
| Carotid plaque | 6.12 (3.18, 11.76) | 4.71 (2.25, 9.89) |
| Internal carotid artery intima-media thickness ≥1.5 mm | 9.08 (5.03, 16.34) | 8.25 (4.44, 15.33) |
There were no events among the few participants with these characteristics.
Results are presented as incidence rates per 1,000 person-years and 95% confidence intervals.
Figure 4.
Prevalence of the study exposures in participants with borderline/intermediate estimated atherosclerotic cardiovascular disease risk and/or family history of premature coronary heart disease, and number needed to screen.
Abbreviations: ABI = ankle-brachial index; ApoB = apolipoprotein B; CHD = coronary heart disease; ECC = extra-coronary calcium; HDL-C = high-density lipoprotein cholesterol; hsCRP = high sensitivity C-reactive protein; ICA IMT internal = carotid artery intima-media thickness; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); NNS = number needed to screen; TG = triglycerides
Table 6.
Crude incidence rates per 1,000 person-years of all and hard cardiovascular disease events at 16.2 years of median follow-up among individuals at borderline/intermediate risk and/or a family history of premature coronary heart disease, by absence of each of the exposures.
| All cardiovascular disease events | Hard cardiovascular disease events | |
|---|---|---|
| Absence of: | ||
|
| ||
| Hypertension | 4.93 (3.14, 7.73) | 3.88 (2.34, 6.43) |
| High low-density lipoprotein cholesterol | 4.70 (3.22, 6.85) | 3.63 (2.37, 5.56) |
| Low high-density lipoprotein cholesterol | 4.24 (2.56, 7.04) | 3.37 (1.91, 5.94) |
| Dyslipidemia | 4.28 (2.54, 7.23) | 3.34 (1.85, 6.03) |
| Current smoker | 3.04 (1.80, 5.12) | 2.60 (1.47, 4.57) |
| Obesity | 5.07 (3.27, 7.86) | 4.04 (2.48, 6.60) |
| Family history of coronary heart disease | 4.75 (2.70, 8.37) | 3.92 (2.11, 7.29) |
| Premature family history | 4.82 (2.67, 8.71) | 3.93 (2.04, 7.55) |
| High sensitivity C-reactive protein ≥2 mg/L | 4.91 (2.96, 8.14) | 3.91 (2.22, 6.88) |
| Homocysteine ≥10 μmol/L | 5.26 (3.58, 7.72) | 4.01 (2.59, 6.22) |
| Lipoprotein (a) > 50mg/dL | 5.16 (3.51, 7.58) | 4.34 (2.86, 6.60) |
| Triglycerides ≥ 175 mg/dL | 4.34 (2.83, 6.65) | 3.91 (2.50, 6.13) |
| Apolipoprotein B ≥ 130 mg/dL | 4.52 (2.88, 7.09) | 3.55 (2.14, 5.90) |
| High sensitivity troponin T ≥95th percentile | 4.72 (3.26, 6.84) | 3.86 (2.57, 5.81) |
| Albuminuria | 4.72 (3.28, 6.79) | 3.72 (2.47, 5.59) |
| Mitral annulus calcium | 4.84 (3.40, 6.88) | 3.88 (2.62, 5.74) |
| Aortic valve calcium | 4.44 (3.07, 6.43) | 3.62 (2.41, 5.45) |
| Thoracic aortic calcium | 4.98 (3.50, 7.08) | 3.99 (2.70, 5.91) |
| Any extra-coronary calcium | 4.63 (3.20, 6.71) | 3.78 (2.51, 5.69) |
| Ankle-brachial index <0.9 | 4.82 (3.39, 6.86) | 3.87 (2.61, 5.72) |
| Carotid plaque | 4.48 (2.95, 6.81) | 3.65 (2.30, 5.79) |
| Internal carotid artery intima-media thickness ≥1.5 mm | 3.99 (2.57, 6.18) | 2.97 (1.79, 4.93) |
Results are presented as incidence rates per 1,000 person-years and 95% confidence intervals.
Discussion
Uncertainty has been expressed as to whether in young-to-middle-aged adults, CAC=0 is sufficiently reassuring in the long term to safely refrain from preventive statin therapy, particularly in the presence of cardiovascular risk factors and/or borderline/intermediate estimated risk (12). Our results show that individuals aged 45–55 years from the general primary prevention population who have CAC=0 and not a major indication for statins (severe hypercholesterolemia, diabetes, estimated risk ≥20%) have low long-term CVD event rates.
This was also true among individuals with borderline/intermediate estimated 10-year risk and/or a family history of premature CHD. These are the groups with the most consistent indication for CAC scoring across guidelines (1–4), and our results should provide further reassurance. Of note, a family history of premature CHD was more frequent than a borderline/intermediate risk and may represent a major driver of clinical CAC testing in younger adults. Importantly, the rate of hard CVD events, which is the outcome typically used to define treatment thresholds in primary prevention guidelines (1,2), was only 6 per 1,000 person-years in this group. Nonetheless, the 95% CI was wide, and larger studies are needed.
We also evaluated whether traditional risk factors and various biomarkers/tests could have value in helping to identify subgroups at significantly increased absolute risk among those with CAC=0 aged ≤55, who could potentially derive large absolute benefit from statins on a ~15-year time frame. For most exposures evaluated, their presence was still associated with low event rates—particularly in analyses restricted to hard events. Also, for most of the few biomarkers with CVD event rates >5 per 1,000 person-years (albuminuria, AVC, any ECC), their prevalence was low, resulting in NNS that ranged from 22–83. The prevalence increased in analyses restricted to individuals with borderline/intermediate estimated 10-year risk and/or a family history of premature CHD, however, event rates remained low for most exposures. These findings suggest that screening for biomarkers such as the ABI or markers of inflammation is likely to have little clinical value in younger adults with CAC=0.
On the other hand, screening for albuminuria is already recommended in patients with diabetes or hypertension, and our results do not suggest otherwise. Also, the strong association between AVC and incident CVD events could lead to the consideration of including AVC scoring as part of standard non-contrast cardiac computed tomographic scans for CAC quantification. Although the NNS was high even in analyses restricted to candidates with a stronger recommendation for CAC scoring, AVC is that it can be measured semi-automatically and with little additional cost. In the CAC Consortium, AVC provided additional prognostic value among participants with CAC<100 (21). Finally, ICA-IMT ≥1.5mm combined a relatively low NNS, the second highest CVD rates among all tests evaluated, and absence of this feature was a powerful negative risk marker. Therefore, measurement of ICA-IMT, which has been evaluated in multiple cohorts (20,22,23), could be considered for further reassurance in younger patients uncertain about their risk management despite CAC=0, particularly if male, age close to 55 years, and borderline/intermediate estimated 10-year risk.
It could be argued that in young populations, given the potential lifetime benefits of early preventive interventions, relative increases in event rates may be more relevant than absolute rates to inform early preventive interventions (12). Also, the marked increase in events observed in our study between years 10 and 15 could be used to make the case for initiating preventive statin therapy early in life even in the presence of CAC=0. However, it is important to note that current ACC/AHA and European guidelines recommend re-evaluating ASCVD risk every 5 years (1,2). This means that in younger adults with CAC=0, there will be additional opportunities to re-assess risk over time. Individuals with CAC=0 can also undergo repeat testing later in time should their risk management remain uncertain after updated clinical risk estimation. Such a strategy is currently endorsed in various guidelines (3,4), and the so-called warranty period of CAC=0 is now well defined, informing a tailored CAC re-screening (24). Implementation of these recommendations can help minimize additional baseline testing or a widespread use of pharmacological preventive therapies close to a treat-all approach.
In addition, other considerations need to be accounted for when deciding the resources that societies are willing to invest to further reduce CVD events in the general population. Rather than a focus on expanded, long-term use of chronic statin therapy in young adults (12) or on additional testing with progressively diminishing returns, an alternative approach could focus on health protection policies (25,26). These can shift the cardiovascular risk of the whole population downward, resulting in dramatic reductions in events (25), and are particularly well suited to tackle the prevention paradox (12,25). Our results suggest that restrictions to the use of tobacco products can be particularly impactful.
This study has some limitations. The number of events was low, even using all follow-up time available. This is, however, an inherent characteristic of studies of young contemporary cohorts with CAC=0. Also, MESA participants were recruited 2 decades ago. Since then, ASCVD event rates have decreased significantly in the US, albeit less so in younger individuals (27). Therefore, it is likely that the low rates observed would have been even lower in more contemporary cohorts. Finally, although follow-up was 17.5 years, even longer timeframes may be more meaningful in young populations. Future analyses using 20 and 30-year data in MESA will inform this notion, however, their relevance to contemporary populations may be limited.
In conclusion, our results confirm the favorable long-term prognosis of CAC=0 among adults aged ≤55. ICA-IMT testing could be considered for further risk assessment in those with uncertain management, and prevention of tobacco use can have a large impact curtailing premature ASCVD events.
ACKNOWLEDGEMENTS
The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.
Sources of Funding:
This research was supported by contracts HHSN268201500003I, N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute (NHLBI), and by grants UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, and UL1-TR-001881 from the National Center for Advancing Translational Sciences.
Footnotes
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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