Author + information
- Published online October 2, 2017.
- Adam J. Brown, MD, PhD,
- Anoop S.V. Shah, MD,
- Nick E.J. West, MD,
- Charis Costopoulos, MD,
- Mateusz Orzalkiewicz, MD,
- David E. Newby, MD,
- Martin R. Bennett, MD, PhD,
- Nicholas L. Mills, MD and
- Patrick A. Calvert, MD, PhD∗ ()
- ↵∗Department of Cardiology, Papworth Hospital NHS Trust, Papworth Evarard, Cambridgeshire, CB23 3RE, United Kingdom
Cardiac troponin I (cTnI) is a marker of myocardial injury, and improvements to assay sensitivity allow for precise quantification at extremely low concentrations. In stable coronary artery disease (CAD), high-sensitivity (hs)-cTnI concentrations are independently associated with subsequent cardiac death and myocardial infarction (MI). However, the underlying pathological mechanism remains unknown.
Patients (n = 99) who underwent percutaneous coronary intervention for stable CAD in the Virtual Histology in Vulnerable Atherosclerosis trial (1) were included in this study. Baseline 3-vessel intravascular ultrasound (IVUS) virtual histology was performed, which recorded plaque burden (PB). Plaque ruptures were cavity-containing plaques with overlying tissue fragments. Thin-cap fibroatheroma (TCFA) had a >10% confluent necrotic core in luminal contact for 3 consecutive frames, with ≤10% dense calcium (1). A hs-cTnI assay (ARCHITECTSTAT, Abbott Laboratories, Abbott Park, Illinois) quantified concentrations on serum samples taken before intervention (limit of detection: 1.2 ng/l; 99th percentile: 34 ng/l in men and 16 ng/l in women) (2). Patients were grouped based on hs-cTnI concentrations into low (≤3.0 ng/l), intermediate (3.1 to 5.9 ng/l), and high (≥6.0 ng/l) levels. Major adverse cardiac events (MACE) were determined at follow-up (mean: 1,104 ± 348 days, 1,247 ± 366 days, and 1,086 ± 405 days for the increasing group; p = 0.25) and were defined as a composite of death, MI, unstable angina, or unplanned revascularization. hs-cTnI was naturally log-transformed, with linear regression models that included variables that predicted serum hs-cTnI (age, sex, and renal function). Univariable and multivariable analyses for MACE were performed using Cox regression. All calculations were performed in SPSS version 21.0.0 (IBM, Armonk, New York), with p < 0.05 considered significant.
Serum hs-cTnI concentrations were above the limit of detection in 95 patients (96.0%) and >99th percentile in 2 men and 1 woman (3.0% of whole population). Patient age increased progressively through the hs-cTnI groups (p = 0.006), as did smoking (p = 0.01), and previous MI (p = 0.04). Ninety-eight percent of patients received statins, and therapy duration was similar among the groups (p = 0.44).
IVUS pullback length among the groups was similar (182.9 ± 39.4 mm vs. 201.1 ± 59.2 mm vs. 181.5 ± 57.4 mm; p = 0.35). A total of 657 plaques were analyzed (median 6.0; range 4.0 to 8.0 plaques per patient). Mean PB was 49.7 ± 7.2% versus 51.1 ± 7.0% versus 50.7 ± 7.5% (p = 0.12) for the group in which hs-cTnI increased. Ninety-eight plaques were classified as TCFA (14.9%), and 28 patients had ≥2 TCFAs. Although plaque numbers were similar across the groups (p = 0.90), there were more high-risk plaques per patient with increasing hs-cTnI, namely, PB ≥70% (p = 0.02) and TCFA (p = 0.048) (Figure 1). Plaque rupture was observed in 12 nontarget lesions, but the frequency of nontarget lesion rupture was similar across the groups (8.0% vs. 9.1% vs. 22.2%; p = 0.20 for intergroup comparison). Serum hs-cTnI concentrations were increased in patients with ≥2 high-risk plaques, including PB ≥70% (p = 0.03) and TCFA (p = 0.002). TCFA number remained the only variable independently associated with hs-cTnI concentration on multivariable linear regression (beta = 0.15; 95% confidence interval [CI]: 0.03 to 0.27; p = 0.014).
At follow-up, 18 patients had MACE, including 3 deaths, 5 MIs, 12 unplanned revascularizations, and 12 unstable angina presentations. hs-cTnI concentration was associated with MACE in univariable analysis (hazard ratio [HR] 1.43; 95% CI: 1.11 to 1.84; p = 0.006). This association persisted despite adjustment for age, sex, and the number of high-risk plaques per patient (HR: 1.48; 95% CI: 1.13 to 1.95; p = 0.004).
In the PROSPECT (Prospective Natural-History Study of Coronary Atherosclerosis) study, nonculprit lesions with PB ≥70%, minimal luminal area ≤4 mm2, and TCFA predicted MACE at 3.4 years with rates of 9.6%, 5.3%, and 4.9%, respectively (3). We found that stable CAD patients in the highest hs-cTnI group had more PB ≥70% and TCFA plaques, whereas those patients with ≥2 high-risk plaques had increased hs-cTnI concentrations. Furthermore, hs-cTnI was independently associated with TCFA frequency. Therefore, these results might imply that hs-cTnI has clinical potential for identifying the “vulnerable patient” in the absence of unstable symptoms, which would allow tailored preventative therapies for those at highest risk of future events.
Approximately 60% of ischemic coronary events are precipitated by plaque rupture followed by thrombosis, but not all ruptures result in clinical symptoms. Although we found a higher frequency of nontarget lesion ruptures on IVUS, there was no statistical difference among the groups. Future studies should consider using novel imaging methods that better detect rupture to assess whether elevated hs-cTnI concentrations in patients with stable CAD is associated with plaques undergoing repetitive cycles of subclinical rupture and repair.
In conclusion, increased hs-cTnI concentrations in patients with stable CAD are associated with high-risk plaques and independently with MACE. Although these data should be viewed as hypothesis-generating, hs-cTnI measurement has the potential to identify stable CAD patients who display an adverse pattern of coronary atherosclerosis and worse clinical outcomes.
The authors would like to thank the patients and staff at Papworth Hospital NHS Trust for their ongoing support and KRCI for Core Laboratory analysis of the radiofrequency backscatter IVUS data.
Please note: This study was funded by the British Heart Foundation (FS/13/33/30168), the Cambridge NIHR Biomedical Research Centre, BHF Cambridge Centre for Research Excellence, and the Academy of Medical Sciences. Dr. Newby is supported by the British Heart Foundation (CH/09/002) and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr. Shah has received speaker’s fees from Abbott Diagnostics. Dr. Mills has been a consultant to and has received research grants from Abbott Diagnostics. Dr. Calvert has received honoraria from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation