Abstract
Background
The association between percutaneous coronary intervention (PCI) outcomes for moderate-to-severe coronary artery calcification (MSCAC) lesions and long-term clinical outcomes in individuals with varying levels of insulin resistance is not well-defined. This study aims to examine the relationship between MSCAC-PCI outcomes and long-term poor clinical outcomes in individuals with varying insulin resistance statuses.
Methods
This prospective cohort research comprised 4,087 patients who received MSCAC-PCI at Fuwai Hospital from January 2017 to December 2018. Patients were classified according to MSCAC-PCI outcomes: failure (device uncrossable or no change in lesion stenosis severity), suboptimal revascularization (meeting neither the criteria for optimal revascularization nor procedural failure), and optimal revascularization (post-PCI TIMI grade = 3 and residual stenosis < 30%). The insulin resistance status was assessed utilizing the triglyceride-glucose (TyG) index, and patients were classified based on baseline TyG tertiles (tertile 1 [T1]: <8.66; T2: 8.66–9.14; T3: ≥9.14). The primary outcome was the composite of cardiovascular (CV) death and target-vessel myocardial infarction (TVMI).
Results
During the median follow-up period of 3 years, 154 (3.77%) patients with primary outcomes were recorded. There were 267 instances of MSCAC-PCI failure, 274 instances of suboptimal revascularization, and 3546 instances of optimal revascularization. Patients who underwent optimal revascularization exhibited markedly reduced risks of CV death/TVMI (adjusted hazard ratio [aHR], 0.53; 95% confidence interval [CI], 0.32–0.87) in comparison to those experiencing MSCAC-PCI failure. No significant difference was observed between patients who got suboptimal revascularization and those with MSCAC-PCI failure. Subgroup analysis indicated that patients in the TyG T3 subgroup have a diminished risk of CV death/TVMI (aHR, 0.45; 95% CI, 0.21–0.97) following optimal revascularization, mostly attributable to a decreased risk of CV death (aHR, 0.29; 95% CI, 0.10–0.78) after optimal revascularization. No substantial variations were observed in PCI outcomes between the TyG T1 and T2 subgroups of patients.
Conclusions
Our findings suggest that optimal revascularization during PCI is associated with improved long-term clinical outcomes in patients with MSCAC, particularly in those with a high level of insulin resistance.
Graphical abstract
Supplementary Information
The online version contains supplementary material available at 10.1186/s12933-026-03196-y.
Keywords: Coronary artery calcification, Percutaneous coronary intervention, Insulin resistance, Triglyceride-glucose index
Research insights
What is currently known about this topic?
Moderate‑to‑severe coronary artery calcification (MSCAC) remains a challenge for percutaneous coronary intervention (PCI), and optimal revascularization is associated with better outcomes.
Insulin resistance (assessed by the triglyceride‑glucose [TyG] index) promotes atherosclerosis and vascular calcification.
What is the key research question?
Does the relationship between MSCAC‑PCI outcomes and long‑term prognosis differ across varying levels of insulin resistance?
What is new?
Optimal revascularization significantly reduced cardiovascular death/target‑vessel MI compared to PCI failure, whereas suboptimal revascularization did not.
The prognostic benefit of optimal revascularization was statistically significant only in patients with high insulin resistance (TyG T3).
How might this study influence clinical practice?
Achieving optimal revascularization is particularly important in high‑insulin‑resistance patients with MSCAC.
Metabolic phenotyping using the TyG index may help identify individuals who derive the greatest long‑term benefit from aggressive PCI strategies, guiding tailored revascularization and post‑procedural metabolic management.
Introduction
Calcified coronary artery lesions occur in a large proportion of patients undergoing percutaneous coronary intervention (PCI), and their prevalence is expected to rise further with population aging and increasing rates of diabetes and renal failure [1, 2]. Even with high-performance drug-eluting stents (DES), moderate-to-severe coronary artery calcification (MSCAC) lesions remain a procedural and therapeutic challenge, as substantial calcification increases the risk of DES under‑expansion, a proven predictor of stent failure, and may reduce effective dilatation before stent implantation [3]. Optimal lesion preparation is therefore essential for effective stent placement and expansion, and various interventional tools are available for this purpose, including debulking, ablation, and balloon‑based methods such as non‑compliant balloons, ultra‑high‑pressure balloons, cutting or scoring balloons, and intravascular lithotripsy [3, 4]. However, previous data suggest that while calcified lesion modification techniques may improve acute PCI outcomes, their effect on long‑term cardiovascular (CV) clinical outcomes remains unclear, highlighting the need for further evaluation of the association between acute procedural results and prognosis in this population.
Emerging evidence underscores insulin resistance as a pivotal pathophysiological driver of both accelerated atherosclerosis and vascular calcification [5–11]. Insulin resistance promotes endothelial dysfunction, chronic inflammation, and dysmetabolism, fostering a milieu conducive to the development of calcified plaques [12, 13]. The triglyceride-glucose (TyG) index, a readily calculable surrogate marker derived from fasting triglycerides and glucose, has gained substantial validation in CV metabolic research as a robust and accessible indicator of insulin resistance [8, 9, 14–18]. Its strong correlation with gold-standard measures and proven prognostic value across diverse cardiometabolic conditions make it a particularly relevant tool for risk stratification in complex coronary artery disease populations like those with MSCAC.
Despite the mechanistic links between insulin resistance and coronary artery calcification, the interplay between insulin resistance status, the efficacy of revascularization completeness, and long-term outcomes in MSCAC patients undergoing PCI remains inadequately explored. Current revascularization strategies for MSCAC are primarily guided by anatomical complexity, often neglecting the profound influence of underlying metabolic dysregulation [19, 20]. It is unknown whether the established benefits of optimal revascularization are uniformly applicable across varying degrees of insulin resistance, or whether specific insulin resistance phenotypes derive differential benefit from aggressive revascularization approaches and require tailored post-procedural management.
Therefore, this prospective cohort study consecutively enrolled patients undergoing PCI for at least one MSCAC lesion and stratified them by TyG index-defined insulin resistance status. We aimed to quantitatively evaluate the association between achieved revascularization completeness (optimal vs. suboptimal vs. failed revascularization) and long-term clinical outcomes within distinct insulin resistance strata.
Methods
Study design and population
This prospective cohort study consecutively recruited patients who received PCI for at least one MSCAC lesion at Fuwai Hospital, National Centre for Cardiovascular Diseases, from January 2017 to December 2018. The MSCAC diagnosis was determined using coronary angiographic results, evaluated by a minimum of two cardiologists. MSCACs were defined utilizing the standard assessment methodologies outlined by Mintz et al. [21]. Severe calcifications were characterized as radiopaque regions noted before contrast infusion, exhibiting little heart activity. Moderate calcifications were characterized as radiopaque areas identified during the cardiac cycle before contrast administration, extending partially into the target lesion. Additional lesions were classified as none or mild calcifications. Based on the PCI procedure outcomes, patients were classified into three categories: optimal revascularization, suboptimal revascularization, and failure. Optimal revascularization was characterized by the effective reperfusion of the target vessel, achieving TIMI flow grade 3, accompanied by residual stenosis of less than 30%. Procedural failure was defined as the inability of the device to pass the calcified lesion or no change in lesion stenosis severity before and after the procedure, and assessment by the interventional cardiologist as ineffective PCI treatment. Suboptimal revascularization is defined as meeting neither the criteria for optimal revascularization nor procedural failure, indicating that the interventional therapy achieved partial but incomplete revascularization [22, 23]. Patients with numerous MSCAC lesions with at least one instance of failed revascularization were categorized into the failure group [23]. Patients with multiple MSCAC lesions who attained reperfusion of all treated lesions but exhibited unsatisfactory revascularization (defined as a PCI result that does not meet the criteria for optimal revascularization and does not meet the criteria for procedural failure, i.e., suboptimal revascularization) in at least one lesion were classified into the suboptimal revascularization group [23]. In this study, all of the original treating interventional cardiologists had over 10 years of experience in MSCAC-PCI procedures.
This study initially evaluated 30,029 patients who underwent PCI. We excluded individuals with incomplete clinical data, none or mild coronary calcification, severe renal failure (estimated glomerular filtration rate [eGFR] < 30 mL/min) and those receiving renal replacement therapy, severe heart failure (left ventricular ejection fraction [LVEF] < 30%), or lost to follow-up. Based on the PCI outcomes, 267, 274, and 3,546 patients were categorized into the failure, suboptimal, and optimal groups, respectively (Fig. 1).
Fig. 1.
Study flowchart. eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction; MSCAC = moderate-to-severe coronary artery calcification; PCI = percutaneous coronary intervention; TyG = triglyceride-glucose.
This study was approved by the Fuwai Hospital Ethical Committee (Approval No. 2016 − 847). All participants provided written informed consent prior to enrollment. This study strictly adhered to the ethical principles outlined in the Declaration of Helsinki, and the reporting of results complied with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
Baseline information and biochemical analysis
Throughout hospitalization, all interventions and medical treatments were executed in accordance with established clinical criteria and the cardiologist’s clinical discretion. Patients were administered daily aspirin (100 mg) and clopidogrel (75 mg) for a minimum of 6 days, or ticagrelor (90 mg twice daily), or received loading doses of aspirin (300 mg) and clopidogrel (600 mg) or ticagrelor (180 mg) before to PCI. The extensive PCI strategy was formulated by seasoned interventional cardiologists. The intervention team exercised discretion in selecting coronary guidewires, devices, and supplementary diagnostic modalities, including intravascular ultrasonography (IVUS) and optical coherence tomography (OCT). Upon discharge, patients maintained indefinite aspirin therapy (100 mg/day), while clopidogrel (75 mg/day) or ticagrelor (180 mg/day) was administered for a minimum duration of 6 months.
Prior to coronary angiography, blood samples were obtained from the cubital vein of each participant after an overnight fast. All laboratory studies were conducted by the clinical chemistry department utilizing defined methodologies. Triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), and creatinine levels were quantified using enzymatic assays on an automated biochemical analyzer (Hitachi 7150, Tokyo, Japan). Glycated hemoglobin A1c (HbA1c) was evaluated utilizing a Tosoh Automated Glycohemoglobin Analyzer (HLC-723G8, Tokyo, Japan). Angiographic and procedural data were extracted from catheterization laboratory records and evaluated by three seasoned interventional cardiologists. Demographic data, cardiovascular risk factors, clinical attributes, laboratory and imaging results, coronary angiographic findings, procedural specifics, and discharge medication protocols were prospectively gathered using standardized questionnaires by independent research personnel.
The TyG index was calculated according to the following formula: Ln [fasting TG (mg/dL) × FBG (mg/dL)/2] [24], and patients would be categorized according to baseline TyG tertiles (tertile 1 [T1]: <8.66; T2: 8.66–9.14 and T3: ≥9.14). Individuals with a history of diabetes, receiving glucose-lowering treatment, or demonstrating an FBG ≥ 7.0 mmol/L, HbA1c ≥ 6.5%, or 2-hour plasma glucose ≥ 11.1 mmol/L during an oral glucose tolerance test were categorized as having diabetes [25]. Hypertension was defined by a systolic blood pressure of ≥ 140 mmHg, a diastolic blood pressure of ≥ 90 mmHg, or the administration of antihypertensive medication [26]. Dyslipidemia was defined by TG above 150 mg/dL, TC equal to or greater than 200 mg/dL, LDL-C equal to or exceeding 130 mg/dL, HDL-C below 40 mg/dL, or the use of cholesterol-lowering medications [27]. LVEF values were assessed at enrollment and computed utilizing the biplane-modified Simpson method [28].
Intervention and angiographic analysis
Coronary angiography was conducted and evaluated by a minimum of two cardiologists. Target vessels and lesions for intervention were determined based on the angiographic findings. The PCI operation for MSCAC lesions was performed by a team of over three trained physicians. The choice of guide catheter, stent type, and utilization of intravascular imaging were determined at the operators’ discretion. Lesion-specific angiographic data and the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score were evaluated by an independent core laboratory (Interventional Cardiovascular Imaging Core Laboratory, National Center for Cardiovascular Diseases, Beijing, China). Thereafter, the angiographic data were re-evaluated by a minimum of two cardiologists.
Follow‑up and endpoints
Participants were monitored at six-month intervals until December 31, 2021, following discharge. Endpoint data were obtained via medical records, clinical visits, and/or telephone interviews conducted by qualified investigators who were blind to the clinical data.
The primary outcome was the composite of CV death and target-vessel related myocardial infarction (TVMI) [23]. The secondary objectives encompassed all-cause mortality, myocardial infarction, each component of the primary outcome, any coronary revascularization, target vessel revascularization (TVR), and target lesion revascularization (TLR), which were utilized in the survival analysis. Death was classified as cardiac until a conclusive non-cardiovascular cause was established. Myocardial infarction (MI) was defined by increased cardiac troponin levels, concomitant characteristic chest pain, specific serial electrocardiogram changes, identification of an intracoronary thrombus through angiography or autopsy, or imaging that demonstrates recent loss of viable myocardium or a newly recognized regional wall-motion abnormality [29]. TVMI was characterized as the MI linked to the vascular addressed for MSCAC. TLR was characterized as any repeat PCI or coronary bypass graft surgery (CABG) necessitated by stenosis or occlusion occurring within the stent or within the 5 mm margins next to the stent. TVR was characterized as any revascularization occurring within the major coronary vessels, either proximal or distal to a target lesion, by repeat PCI or CABG. All instances were rigorously verified and evaluated by two independent cardiologists.
Statistical analysis
Continuous data were represented as mean ± standard deviation when normally distributed, otherwise as median (interquartile range). Categorical variables were presented as frequencies (percentages). Group differences were assessed using one-way ANOVA, the Kruskal-Wallis H test, Pearson’s chi-square test, or Fisher’s exact test, if appropriate. The cumulative incidence of clinical events was assessed using Kaplan-Meier curves, with differences investigated by the log-rank test. A multi-variable Cox regression model was used to assess the relationship between PCI results and the long-term risk of clinical outcomes, represented by hazard ratios (HRs) and 95% confidence intervals (CIs). The multivariable model was adjusted for age, male sex, BMI, ACS, family history of coronary artery disease (CAD), previous MI, previous revascularization, diabetes, hypertension, previous stroke, PAD, LVEF, serum creatinine, TC, HDL-C, LDL-C, hsCRP, SYNTAX score, CTO lesion, IVUS use, rotational atherectomy use, cutting balloon use, scoring balloon use, aspirin use, statins use, angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) use, and β blockers use. We additionally assessed the correlation between optimal revascularization of MSCAC-PCI and the risk of clinical outcomes stratified by different insulin resistance statuses. Subsequently, we analyzed the associations between sex and clinical outcomes, using variables such as age (≤ median or > median), sex, ACS (yes or no), LDL-C levels (≤ median or > median), and the presence of CTO lesions. We calculated P for interactions across all subgroup analyses. To address the potential confounding effect of CTO lesions on the association between PCI outcomes and long‑term prognosis, we performed a sensitivity analysis excluding patients with CTO lesions in which the guidewire failed to cross. A two-tailed P value of less than 0.05 was deemed statistically significant. All statistical analyses were conducted using R version 4.5.0 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline clinical characteristics and medical therapy at discharge
The baseline clinical features and comparisons across patients with varying procedure results are illustrated in Table 1. The average age was 62.01 ± 10.14 years, 979 (23.95%) patients were female, 2563 (62.71%) patients were diagnosed with ACS, 2705 (66.19%) patients suffered from hypertension, 1972 (48.25%) participants were diagnosed with diabetes, and 1169 (28.60%) of patients were current smokers.
Table 1.
Baseline clinical characteristics and medical therapy at discharge of the study population according to MSCAC-PCI outcomes
| Characteristics a | All (n = 4087) |
Failure revascularization (n = 267) |
Suboptimal revascularization (n = 274) |
Optimal revascularization (n = 3546) |
P value |
|---|---|---|---|---|---|
| Demographics | |||||
| Age, years | 62.01 ± 10.14 | 60.96 ± 10.73 | 64.19 ± 9.98 | 61.91 ± 10.08 | < 0.001 |
| Female sex | 979 (23.95) | 48 (17.98) | 67 (24.45) | 864 (24.37) | 0.061 |
| Body mass index, kg/m2 | 25.75 ± 3.25 | 25.88 ± 3.30 | 25.77 ± 3.14 | 25.74 ± 3.26 | 0.808 |
| LVEF, % | 61.39 ± 6.80 | 58.71 ± 8.57 | 59.51 ± 7.00 | 61.74 ± 6.56 | < 0.001 |
| Medical history | |||||
| Hypertension | 2705 (66.19) | 171 (64.04) | 186 (67.88) | 2348 (66.22) | 0.637 |
| Diabetes | 1972 (48.25) | 128 (47.94) | 148 (54.01) | 1696 (47.83) | 0.142 |
| Dyslipidemia | 3146 (76.98) | 218 (81.65) | 210 (76.64) | 2718 (76.65) | 0.172 |
| Current smoker | 1169 (28.60) | 102 (38.20) | 81 (29.56) | 986 (27.81) | 0.006 |
| Previous MI | 1079 (26.40) | 103 (38.58) | 94 (34.31) | 882 (24.87) | < 0.001 |
| Previous PCI | 1083 (26.50) | 72 (26.97) | 93 (33.94) | 918 (25.89) | 0.014 |
| Previous CABG | 140 (3.43) | 12 (4.49) | 18 (6.57) | 110 (3.10) | 0.006 |
| Peripheral artery disease | 279 (6.83) | 20 (7.49) | 32 (11.68) | 227 (6.40) | 0.003 |
| Previous stroke | 581 (14.22) | 38 (14.23) | 48 (17.52) | 495 (13.96) | 0.267 |
| Family history of CAD | 479 (11.72) | 28 (10.49) | 38 (13.87) | 413 (11.65) | 0.442 |
| Clinical indication for PCI | |||||
| Chronic coronary syndrome | 1524 (37.29) | 114 (42.70) | 104 (37.96) | 1306 (36.83) | 0.156 |
| Acute coronary syndrome | 2563 (62.71) | 153 (57.30) | 170 (62.04) | 2240 (63.17) | 0.156 |
| Unstable angina | 1904 (46.59) | 106 (39.70) | 112 (40.88) | 1686 (47.55) | 0.007 |
| NSTEMI | 282 (6.90) | 20 (7.49) | 28 (10.22) | 234 (6.60) | 0.069 |
| STEMI | 377 (9.22) | 27 (10.11) | 30 (10.95) | 320 (9.02) | 0.498 |
| Laboratory tests | |||||
| Serum creatinine, µmol/L | 83.64 ± 18.95 | 86.66 ± 19.22 | 83.82 ± 20.27 | 83.40 ± 18.80 | 0.025 |
| Fasting blood glucose, mmol/L | 6.82 ± 2.76 | 6.39 ± 1.89 | 7.34 ± 3.74 | 6.81 ± 2.72 | < 0.001 |
| HbA1c, % | 6.57 ± 1.28 | 6.46 ± 1.11 | 6.77 ± 1.49 | 6.56 ± 1.27 | 0.012 |
| TC, mmol/L | 4.02 ± 1.03 | 3.97 ± 0.92 | 3.87 ± 0.98 | 4.03 ± 1.04 | 0.024 |
| TG, mmol/L | 1.73 ± 1.17 | 1.73 ± 0.91 | 1.54 ± 0.79 | 1.75 ± 1.20 | 0.022 |
| LDL-C, mmol/L | 2.40 ± 0.88 | 2.43 ± 0.83 | 2.28 ± 0.84 | 2.41 ± 0.88 | 0.057 |
| HDL-C, mmol/L | 1.12 ± 0.30 | 1.05 ± 0.28 | 1.13 ± 0.33 | 1.12 ± 0.30 | 0.001 |
| hsCRP, mg/L | 1.50 (0.69–3.32) | 1.48 (0.72–3.42) | 1.60 (0.85–3.60) | 1.49 (0.68–3.28) | 0.336 |
| Medications at discharge | |||||
| Aspirin | 4069 (99.56) | 264 (98.88) | 273 (99.64) | 3532 (99.61) | 0.182 |
| P2Y12 inhibitor | |||||
| Clopidogrel | 3314 (81.09) | 227 (85.02) | 218 (79.56) | 2869 (80.91) | 0.204 |
| Ticagrelor | 773 (18.91) | 40 (14.98) | 56 (20.44) | 677 (19.09) | 0.204 |
| Statin | 4049 (99.07) | 266 (99.63) | 272 (99.27) | 3511 (99.01) | 0.813 |
| β blockers | 3671 (89.82) | 249 (93.26) | 256 (93.43) | 3166 (89.28) | 0.014 |
| ACEI/ARB | 1046 (25.59) | 72 (26.97) | 79 (28.83) | 895 (25.24) | 0.367 |
a Values are expressed as mean ± standard deviation, median (interquartile range) or count (percentage). CEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CABG = coronary artery bypass graft; CAD = coronary artery disease; HbA1c = glycosylated hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MSCAC = moderate-to-severe coronary artery calcification; NSTEMI = non-ST elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST elevation myocardial infarction; TC = total cholesterol; TG = triglyceride.
There were 267 instances of MSCAC-PCI failure, 274 instances of suboptimal revascularization, and 3546 instances of optimal revascularization. In comparison to patients with optimal revascularization, those experiencing MSCAC-PCI failure tended to be current smokers (PCI failure: 38.20%; suboptimal revascularization: 29.56%; optimal revascularization: 27.81%) and present with previous MI (PCI failure: 38.58%; suboptimal revascularization: 34.31%; optimal revascularization: 24.87%). Patients with MSCAC-PCI failure have higher serum creatinine (PCI failure: 86.66 ± 19.22 µmol/L; suboptimal revascularization: 83.82 ± 20.27 µmol/L; optimal revascularization: 83.40 ± 18.80 µmol/L), and lower LVEF (PCI failure: 58.71 ± 8.57%; suboptimal revascularization: 59.51 ± 7.00%; optimal revascularization: 61.74 ± 6.56%) and HDL-C (PCI failure: 1.05 ± 0.28 mmol/L; suboptimal revascularization: 1.13 ± 0.33 mmol/L; optimal revascularization: 1.12 ± 0.30 mmol/L).
Baseline angiographic and procedural characteristics
Concerning the characteristics of lesions, patients with MSCAC-PCI failure exhibited a higher likelihood of right coronary artery involved (PCI failure: 66.67%; suboptimal revascularization: 38.69%; optimal revascularization: 42.95%), severe calcification (PCI failure: 35.21%; suboptimal revascularization: 37.96%; optimal revascularization: 19.49%), CTO lesion (PCI failure: 83.15%; suboptimal revascularization: 23.36%; optimal revascularization: 12.38%), thrombotic lesion (PCI failure: 8.99%; suboptimal revascularization: 8.76%; optimal revascularization: 5.16%), type B2 or C lesion (PCI failure: 97.00%; suboptimal revascularization: 91.97%; optimal revascularization: 87.25%), higher SYNTAX score (PCI failure: 22.35 ± 9.17; suboptimal revascularization: 18.42 ± 10.13; optimal revascularization: 15.73 ± 9.33), and longer lesion length [PCI failure: 48.00 mm (IQR, 30.00–78.00); suboptimal revascularization: 40.00 mm (IQR, 26.00-57.75); optimal revascularization: 39.00 (IQR, 24.00–60.00)] than those with suboptimal revascularization and optimal revascularization (Table 2).
Table 2.
Angiographic and procedural characteristics of the study population according to PCI outcomes
| Characteristics a | All (n = 4087) |
Failure revascularization (n = 267) |
Suboptimal revascularization (n = 274) |
Optimal revascularization (n = 3546) |
P value |
|---|---|---|---|---|---|
| Angiographic characteristics | |||||
| Multivessel coronary artery disease | 3246 (79.42) | 223 (83.52) | 222 (81.02) | 2801 (78.99) | 0.167 |
| Lesion location | |||||
| LMCA | 262 (6.41) | 7 (2.62) | 25 (9.12) | 230 (6.49) | 0.008 |
| LAD | 2307 (56.45) | 110 (41.20) | 149 (54.38) | 2048 (57.76) | < 0.001 |
| LCX | 983 (24.05) | 61 (22.85) | 82 (29.93) | 840 (23.69) | 0.059 |
| RCA | 1807 (44.21) | 178 (66.67) | 106 (38.69) | 1523 (42.95) | < 0.001 |
| Bypass graft | 21 (0.51) | 3 (1.12) | 4 (1.46) | 14 (0.39) | 0.024 |
| Target lesion morphology | |||||
| Severe calcification | 889 (21.75) | 94 (35.21) | 104 (37.96) | 691 (19.49) | < 0.001 |
| Bifurcation | 690 (16.88) | 29 (10.86) | 53 (19.34) | 608 (17.15) | 0.016 |
| CTO | 725 (17.74) | 222 (83.15) | 64 (23.36) | 439 (12.38) | < 0.001 |
| In-stent restenosis | 351 (8.59) | 25 (9.36) | 26 (9.49) | 300 (8.46) | 0.755 |
| Thrombotic lesion | 231 (5.65) | 24 (8.99) | 24 (8.76) | 183 (5.16) | 0.002 |
| Total lesion length (mm) | 40.00 (24.00–60.00) | 48.00 (30.00–78.00) | 40.00 (26.00-57.75) | 39.00 (24.00–60.00) | < 0.001 |
| Type B2 or C lesion | 3605 (88.21) | 259 (97.00) | 252 (91.97) | 3094 (87.25) | < 0.001 |
| SYNTAX score | 16.34 ± 9.53 | 22.35 ± 9.17 | 18.42 ± 10.13 | 15.73 ± 9.33 | < 0.001 |
| Procedural characteristics | |||||
| Arterial access site | 0.001 | ||||
| Radial | 3750 (91.75) | 220 (82.40) | 242 (88.32) | 3288 (92.72) | |
| Femoral | 337 (8.25) | 47 (17.60) | 32 (11.68) | 258 (7.28) | |
| Number of lesions treated | 1.28 ± 0.52 | 1.28 ± 0.53 | 1.40 ± 0.61 | 1.28 ± 0.52 | 0.001 |
| IVUS | 560 (13.70) | 34 (12.73) | 36 (13.14) | 490 (13.82) | 0.850 |
| Rotational atherectomy | 120 (2.94) | 0 (0.00) | 6 (2.19) | 114 (3.21) | 0.008 |
| Cutting balloon | 242 (5.92) | 3 (1.12) | 14 (5.11) | 225 (6.35) | 0.002 |
| Scoring balloon | 263 (6.44) | 5 (1.87) | 20 (7.30) | 238 (6.71) | 0.007 |
| IABP (prior or during PCI) | 54 (1.32) | 6 (2.25) | 12 (4.38) | 36 (1.02) | < 0.001 |
a Values are expressed as mean ± standard deviation, median (interquartile range) or count (percentage). CAD = coronary artery disease; CTO = chronic total occlusion; IABP = intra-aortic balloon pump; LAD = left anterior descending; LCX = left circumflex; LM = left main coronary artery; PCI = percutaneous coronary intervention; RCA = right coronary artery; SYNTAX = SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery
For the characteristics of PCI treatment, patients with MSCAC-PCI tended to have more femoral arterial access sites (PCI failure: 17.60%; suboptimal revascularization: 11.68%; optimal revascularization: 7.28%), and less use of rotational atherectomy (PCI failure: 0%; suboptimal revascularization: 2.19%; optimal revascularization: 3.21%), cutting balloon (PCI failure: 1.12%; suboptimal revascularization: 5.11%; optimal revascularization: 6.35%), and scoring balloon (PCI failure: 1.87%; suboptimal revascularization: 7.30%; optimal revascularization: 6.71%) (Table 2).
Optimal revascularization of MSCAC-PCI and the long-term prognosis
During the follow-up with a median time of 3 years, 154 (3.77%) cases of primary outcomes, including 69 (1.69%) cases of CV death and 99 (2.42%) TVMI, were recorded. The association of the procedural outcomes with clinical outcomes is shown in Table 3. Compared with patients with MSCAC-PCI failure, those with optimal revascularization showed a significantly lower risk of CV death/TVMI (adjusted HR, 0.53; 95% CI, 0.32–0.87). The survival analysis also showed that optimal revascularization was significantly associated with a lower risk of all-cause death (adjusted HR, 0.48; 95% CI, 0.29–0.80) and CV death (adjusted HR, 0.29; 95% CI, 0.15–0.54). No significance could be seen between suboptimal revascularization and MSCAC-PCI failure in all clinical outcomes (Table 3 and Table S1). KM plots presented consistent results (P for log-rand < 0.001) (Fig. 2).
Table 3.
Primary clinical outcomes of the study population according to PCI outcome in the Cox regression analysis
| Endpoints | Event (%) | Univariable analysis | Multivariable analysis a | ||
|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | ||
| CV death/TVMI | |||||
| Failure revascularization | 20 (7.49) | Reference | - | Reference | - |
| Suboptimal revascularization | 16 (5.84) | 0.72 (0.36–1.43) | 0.360 | 0.64 (0.32–1.28) | 0.213 |
| Optimal revascularization | 118 (3.33) | 0.59 (0.36–0.96) | 0.033 | 0.53 (0.32–0.87) | 0.012 |
| All-cause death | |||||
| Failure revascularization | 19 (7.12) | Reference | - | Reference | - |
| Suboptimal revascularization | 21 (7.66) | 1.14 (0.61–2.13) | 0.665 | 1.01 (0.53–1.90) | 0.968 |
| Optimal revascularization | 107 (3.02) | 0.52 (0.31–0.85) | 0.010 | 0.48 (0.29–0.80) | 0.004 |
| CV death | |||||
| Failure revascularization | 14 (5.24) | Reference | - | Reference | - |
| Suboptimal revascularization | 8 (2.92) | 0.60 (0.25–1.45) | 0.263 | 0.50 (0.20–1.23) | 0.136 |
| Optimal revascularization | 47 (1.33) | 0.33 (0.18–0.61) | < 0.001 | 0.29 (0.15–0.54) | < 0.001 |
| TVMI | |||||
| Failure revascularization | 10 (3.75) | Reference | - | Reference | - |
| Suboptimal revascularization | 10 (3.65) | 0.83 (0.33–2.09) | 0.699 | 0.82 (0.32–2.09) | 0.685 |
| Optimal revascularization | 79 (2.23) | 0.79 (0.40–1.55) | 0.509 | 0.74 (0.37–1.46) | 0.390 |
CV= cardiovascular; HR = hazard ratio; CI = confidence interval; TVMI = target vessel-related myocardial infarction. a Models adjusted for age, male sex, BMI, ACS, family history of CAD, previous MI, previous PCI, previous CABG, diabetes, hypertension, previous stroke, PAD, LVEF, serum creatinine, TC, HDL-C, LDL-C, hsCRP, SYNTAX score, CTO lesion, IVUS use, rotational atherectomy use, cutting balloon use, scoring balloon use, aspirin use, statins use, ACEi/ARB use, and β blockers use.
Fig. 2.
Cumulative incidence of A CV death/TVMI, B All-cause death, C CV death, and D TVMI according to PCI outcomes in patients with MSCAC. CV = cardiovascular; TVMI = target vessel-related myocardial infarction
In the cohorts of patients with optimal or suboptimal revascularization, final TIMI flow 1–2 grade was associated with a significant higher risk of CV death/TVMI (adjusted HR, 2.01; 95%CI 1.02–3.93), all-cause death (adjusted HR, 3.15; 95%CI, 1.66–5.97), CV death (adjusted HR, 2.91; 95%CI, 1.02–8.27), and TVMI (adjusted HR, 2.26; 95%CI, 1.03–4.96) (Table S5). Meanwhile, residual stenosis ≥ 30% was only associated with a significant higher risk of all-cause death (adjusted HR, 1.94; 95%CI, 1.17–3.21) (Table S2).
Optimal revascularization and the long-term prognosis stratified by insulin resistance statuses
To evaluate the influence of insulin resistance statuses on the relationship between MSCAC-PCI results and adverse clinical events, patients were categorized into subgroups according to TyG teritles, whose baseline demographic and angiographic characteristics could be seen in Table S3 and Table S4. Compared to patients in the TyG T1 and TyG T2 groups, those in the TyG T3 group were more likely to be younger females and presented with ST elevation myocardial infarction (STEMI), diabetes, hypertension, a history of PCI, higher BMI, FBG, HbA1c, TC, TG, LDL-C, serum creatinine, and hsCRP. Regarding angiographic and procedural characteristics, patients in the TyG T3 group had an increased likelihood of complex lesions, including multivessel coronary artery disease, in-stent restenosis, thrombotic lesion, and longer lesion length than those in TyG T1 and T2 groups. The results of the stratified multivariate Cox regression analysis for MSCAC-PCI outcomes and clinical outcomes are displayed in (Table S5).
For the TyG T1 and T2 subgroup, patients with optimal revascularization had a comparable incidence of CV death/TVMI compared with those with MSCAC-PCI failure. No significant differences could be observed between suboptimal revascularization and MSCAC-PCI failure in the incidence of all clinical outcomes (all P values > 0.05). Similar trends could be seen in the occurrence of all-cause death, CV death, and TVMI (Table S5).
For the TyG T3 subgroup, patients with optimal revascularization had a significantly lower risk of CV death/TVMI (adjusted HR, 0.45; 95%CI, 0.21–0.97), which mainly (Fig. 3) came from the differences in the reduced risk of all-cause death (adjusted HR, 0.42; 95%CI, 0.18–0.93) and CV death (adjusted HR, 0.29; 95%CI, 0.10–0.78) compared with MSCAC-PCI failure. No significant differences could be observed between suboptimal revascularization and MSCAC-PCI failure in the incidence of all clinical outcomes (all P values > 0.05) (Table S5).
Fig. 3.
Multivariable Cox regression analyses of A CV death/TVMI, B All-cause death, C CV death, and D TVMI according to TyG index tertiles and PCI outcomes. CV= cardiovascular; HR = hazard ratio; CI = confidence interval; TVMI = target vessel-related myocardial infarction; TyG = triglyceride-glucose.
Subgroup analysis
Subgroup analyses revealed that age and ACS were significantly associated with the relationship between optimal revisualization and reduced risk of CV death/TVMI (P for interaction = 0.003 and 0.004, respectively) (Tables S9). It is worth noting that both optimal and suboptimal revascularization have a lower risk of CV death/TVMI than MSCAC-PCI failure patients with age ≥ 62 years (optimal vs. failure: adjusted HR, 0.33, 95%CI, 0.16–0.68; suboptimal vs. failure: adjusted HR, 0.33, 95%CI, 0.13–0.85), and those with ACS (optimal vs. failure: adjusted HR, 0.33, 95%CI, 0.17–0.67; suboptimal vs. failure: adjusted HR, 0.38, 95%CI, 0.15–0.67). The primary endpoint analysis showed that the association between optimal revisualization and reduced risk of CV death/TVMI remained stable across the sex, LDL-C (≤ 2.26 or > 2.26 mmol/L), and CTO (No or Yes) subgroups with similar levels of interaction (all P for interaction > 0.05).
Sensitivity analysis
To evaluate whether the inclusion of CTO lesions with failed guidewire crossing influenced our findings, we performed a sensitivity analysis excluding these patients (n = 170). In this subset, optimal revascularization remained significantly associated with a lower risk of CV death/TVMI (adjusted HR, 0.47; 95% CI, 0.23–0.95) than failed revascularization, and there was no significant difference observed between suboptimal revascularization and MSCAC-PCI failure in the incidence of all clinical outcomes (all P values > 0.05). Similar trends could be seen in the occurrence of all-cause death, CV death, and TVMI (Table S6).
Discussion
In this study, we first investigated the association between optimal revascularization for MSCAC and long-term outcomes in patients with different TyG-driven insulin resistance statuses. Our major findings included: [1] Compared to MSCAC-PCI failure, only optimal revascularization improved the prognosis of patients with MSCAC; [2] The primary baseline differences associated with adverse PCI outcomes were current smoking, prior history of MI, poorer cardiac and renal function, and more complex coronary artery disease. Patients with these characteristics warrant thorough assessment of revascularization indications and consideration of more aggressive revascularization strategies; [3] TIMI flow grade 1–2 emerged as a major adverse prognostic factor and should be a key procedural evaluation metric in this study population; [4] The prognostic benefit of optimal revascularization was primarily observed in the group with high level of insulin resistance (TyG T3 group); [5] Subgroup analysis primarily indicated that the association between optimal revascularization and improved clinical outcomes was significant in elderly patients and those with ACS. Furthermore, within these subgroups, achieving even suboptimal revascularization was associated with improved clinical outcomes.
Our study demonstrates that for patients with MSCAC, only optimal revascularization significantly improves long-term prognosis compared to PCI failure. This underscores the critical clinical implication that revascularization indications in this challenging population require meticulous assessment, with a concerted effort to achieve complete revascularization whenever feasible. We identified key baseline characteristics associated with adverse PCI outcomes, including current smoking, prior MI, poorer cardiac and renal function, and more complex coronary artery disease. Mechanistically, these high-risk features likely contribute to adverse outcomes through multiple pathways: [1] smoking exacerbates endothelial dysfunction and inflammation with increased plaque vulnerability [30, 31]; [2] prior MI might reflect a more advanced, unstable atherosclerotic substrate; [3] impaired ventricular function reduces hemodynamic reserve [32]; [4] renal dysfunction promotes vascular calcification and alters platelet reactivity [33]; and [5] complex CV disease signifies a greater burden of calcified, fibrotic plaque inherently resistant to conventional PCI techniques [34, 35]. Pre-procedural identification of the above high-risk featured patients, based on the clinical and angiographic profile we identified, may facilitate earlier planning and adoption of these advanced techniques, potentially increasing the likelihood of successful lesion preparation and complete revascularization.
Intravascular imaging (IVUS and OCT) is pivotal in this decision-making process, providing essential criteria for determining the need for modification and, crucially, defining the depth, distribution, and extent of calcification [36, 37]. It is important to acknowledge, however, that these imaging techniques were not performed in the present study; PCI guidance was solely angiographic. In real-world practice, the application of IVUS or OCT in the treatment of MSCAC lesions has been limited due to several practical challenges, including the need for additional specialized equipment and operator expertise, higher procedural costs, and the difficulty of advancing thicker imaging catheters through severely narrowed and calcified lesions, which may increase the risk of ischemia during the procedure [38]. Given these constraints, along with the relatively high diagnostic specificity of angiography for detecting MSCAC lesions [39], we believe that studies based on angiography-detected MSCAC, such as the present investigation, remain clinically valuable. Our findings should therefore be interpreted with an understanding of this methodological context, and future studies incorporating IVUS or OCT guidance are warranted to further validate and extend our results.
The imperative for optimal revascularization in MSCAC is mechanistically linked to overcoming the significant technical hurdles these lesions pose [19]. Heavily calcified plaques impede device delivery, increase the risk of stent underexpansion, and are independently associated with worse clinical outcomes compared to non-calcified lesions [40]. Achieving optimal results, including adequate lesion preparation and stent expansion, typically necessitates dedicated plaque modification to disrupt the calcific sheet or nodule. Contemporary management of MSCAC-PCI leverages several plaque modification techniques, each with distinct mechanisms and indications. Rotational atherectomy, long a mainstay, and excimer laser coronary atherectomy (ELCA) are established tools. The recent advent of intravascular lithotripsy (IVL), which delivers sonic energy capable of penetrating deeper calcium layers, has substantially altered practice patterns, becoming the most frequently used modification technique [41, 42]. While the goal of all techniques, effective calcified plaque modification, is shared, their application requires a nuanced approach dictated by lesion morphology. Rotational atherectomy excels against superficial calcium but is less effective for deep or thick calcific plates; conversely, IVL’s energy propagation makes it better suited for these deeper deposits. Intravascular imaging-guided assessment of calcium depth and distribution may significantly enhance the selection of the ideal plaque modification tool and potentially avoid suboptimal initial device choices, which recent reports indicate necessitated a second device in 10–14% of cases [3]. However, the precise impact of this approach on outcomes warrants further investigation.
Our study also reveals a critical interaction between metabolic dysregulation and revascularization efficacy in calcified coronary disease. The finding that the prognostic benefit of complete revascularization was predominantly confined to the high insulin resistance cohort (TyG T3 group) carries profound pathophysiological and clinical implications. This observation aligns with the established biological interplay between insulin resistance and coronary artery calcification [11, 43, 44]. Insulin resistance promotes endothelial dysfunction, vascular inflammation, and accelerated atherosclerosis, culminating in more extensive and metabolically active calcified plaques [45]. These plaques are inherently more resistant to conventional percutaneous techniques and prone to suboptimal stent deployment and adverse long-term outcomes [19, 22]. Therefore, achieving complete revascularization in this vulnerable subgroup may represent a pivotal intervention to disrupt the vicious cycle of insulin resistance-driven plaque progression and ischemia. Meanwhile, the persistent milieu of hyperinsulinemia, hyperglycemia, and associated metabolic toxicity creates an environment highly conducive to accelerated neoatherosclerosis within stents, endothelial dysfunction in non-target vessels, and progression of native disease in patients with high level of insulin resistance [46, 47]. Hence, we considered that intensified post-procedural glycemic management might be helpful for this specific subgroup [48]. Our previous study found controlled glycemia associated with improved CV outcomes in patients with diabetes and established coronary artery disease, especially in those with high TyG index levels [48]. This necessitates a paradigm shift from viewing revascularization as a standalone procedure to integrating it as a key component within a comprehensive, longitudinal metabolic management plan. Early and aggressive intervention, ideally initiated peri-procedurally, should aim for stringent glycemic targets (e.g., HbA1c < 7.0% or lower if safely achievable) utilizing agents with proven cardiovascular benefit, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) [49, 50]. Furthermore, protocols should incorporate structured lifestyle modification programs addressing diet, exercise, and weight management, as these synergistically enhance insulin sensitivity and stabilize plaque biology [51]. Close collaboration between interventional cardiologists, endocrinologists, and primary care providers is paramount to ensure seamless transition and sustained adherence to this intensified management strategy, thereby consolidating the initial gains achieved through successful revascularization and maximizing long-term event-free survival.
The subgroup analyses reveal pivotal nuances in revascularization efficacy for high-risk MSCAC cohorts. Specifically, the robust association between complete revascularization and enhanced clinical outcomes was most pronounced in elderly patients and those with ACS, highlighting their heightened vulnerability to residual ischemic burden. This finding is biologically plausible: elderly individuals often exhibit diminished physiological reserve, multivessel involvement, and increased frailty, rendering them less tolerant of incomplete revascularization [52]; concurrently, the prothrombotic and inflammatory milieu of ACS amplifies the risk posed by untreated non-culprit lesions [53]. Notably, even suboptimal revascularization conferred measurable prognostic benefits within these subgroups—a finding of profound clinical relevance. For frail elderly patients with prohibitive technical challenges, strategically addressing flow-limiting stenoses in dominant territories may yield significant gains despite falling short of angiographic completeness [54]. Similarly, in ACS beyond culprit-lesion intervention, mitigating ischemia in critical non-culprit vessels during the index hospitalization appears crucial, irrespective of achieving perfect TIMI flow grade resolution [34, 55].
Strengths and limitations
To the best of our knowledge, this study was the first and largest to highlight the significance of MSCAC-PCI outcomes in predicting clinical outcomes for patients with different insulin resistance statuses. However, some limitations should be considered. First, the study employed a prospective observational design rather than a randomized controlled trial, which may affect the generalizability of the findings. Second, there was insufficient data on serial LDL‑C levels, glycemic control, LVEF, medication use, risk factor management, and lifestyle changes over the follow-up period. Future studies should aim to incorporate related measurements to provide a more comprehensive understanding of those above dynamic changes effect on clinical outcomes. Third, even though potential confounders were included as covariates in our multivariable regression models, the influence of unmeasured confounding factors cannot be entirely ruled out. Fourth, the use of advanced plaque modification techniques, particularly rotational atherectomy, was infrequent in our study, reflecting real‑world clinical practice in China during the enrollment period [56, 57]. The absence of rotational atherectomy in the PCI failure group suggests a missed opportunity for bail‑out modification, which may have influenced procedural success rates. Fifth, our study period (2017‑2018) predates the widespread availability of certain advanced plaque modification techniques, such as orbital atherectomy, which has since been reported as a successful tool for calcified nodules [58]. Therefore, the applicability of our findings to contemporary practice incorporating these newer devices requires further validation. Sixth, the imbalanced group distribution limited statistical precision, and the similar point estimates between optimal and suboptimal revascularization suggest that non‑significant findings may be due to insufficient power. Nevertheless, these findings offer a theoretical foundation for future investigations with larger sample sizes and more balanced groups. Finally, our participants were exclusively Chinese, hence the findings of our study may not be applicable to other ethnic groups.
Conclusion
In conclusion, optimal revascularization is associated with improved long-term clinical outcomes in patients with MSCAC, particularly those with a high level of TyG index-defined insulin resistance, suggesting that MSCAC-PCI might offer prognostic benefits in this population.
Supplementary Information
Below is the link to the electronic supplementary material.
Abbreviations
- ACEi
Angiotensin-converting enzyme inhibitor
- ARB
Angiotensin II receptor blocker
- BMI
Body mass index
- CABG
Coronary artery bypass graft
- CAD
Coronary artery disease
- CTO
Chronic total occlusion
- DES
Drug eluting stent
- eGFR
Estimated glomerular filtration rate
- HbA1c
Glycosylated hemoglobin A1c
- HDL-C
High-density lipoprotein cholesterol
- hsCRP
High-sensitivity C-reactive protein
- IABP
Intra-aortic balloon pump
- LAD
Left anterior descending
- LCX
Left circumflex
- LDL-C
Low-density lipoprotein cholesterol
- LMCA
Left main coronary artery
- LVEF
Left ventricular ejection fraction
- MI
Myocardial infarction
- MSCAC
Moderate-to-severe coronary artery calcification
- NSTEMI
Non-ST elevation myocardial infarction
- PCI
Percutaneous coronary intervention
- RCA
Right coronary artery
- SYNTAX
SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery
- STEMI
ST elevation myocardial infarction
- TIMI
Thrombolysis in myocardial infarction
- TC
Total cholesterol
- TG
Triglyceride
- TyG
Triglyceride-glucose
Author contributions
ZL and YS contributed to the study design and interpretation of the results. SY, BL, and JH contributed to the collection, analysis, or interpretation of data. ZL and YS prepared the manuscript. KD critically revised the manuscript. All authors read and approved the final manuscript.
Funding
This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0548200).
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study was approved by the Fuwai Hospital Ethical Committee (Approval No. 2016 − 847). All participants provided written informed consent prior to enrollment. This study strictly adhered to the ethical principles outlined in the Declaration of Helsinki, and the reporting of results complied with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
Consent for publication
Not applicable.
Competing interests
3The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Zhangyu Lin and Yanjun Song contributed equally to this work.
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Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.