Abstract
Background
Lipoprotein(a) [Lp(a)] has been established as a significant prognostic marker in patients with chronic total occlusion (CTO) of the coronary artery. Left ventricular systolic dysfunction (LVSD) is a common and serious complication associated with CTO. This study aimed to explore the relationship between Lp(a) and LVSD in patients with CTO.
Methods and results
A total of 309 patients with CTO who underwent elective percutaneous coronary intervention were consecutively enrolled in the study. The patients were stratified by left ventricular ejection fraction (LVEF) into the LVSD group (LVEF < 50%, n = 80) and preserved systolic function group (LVEF ≥ 50%, n = 229). The mean age of the cohort was 61.5 ± 11.3 years, 83.8% were males, and the prevalence of LVSD was 25.9%. Compared with patients with preserved systolic function, those with LVSD tended to be older, had a higher prevalence of arrhythmia, a history of myocardial infarction, and multivessel CTO disease, and exhibited more severe calcified lesions, while having a lower prevalence of hypertension. They also exhibited higher levels of Lp(a), NT-proBNP, and neutrophils, but had a lower body mass index, lower albumin levels, and a reduced LVEF (all P < 0.05). Multivariate regression analysis revealed that Lp(a) was significantly associated with LVSD, with an odds ratio (OR) per 100 mg/L of 1.149 (95% CI: 1.042–1.267; P = 0.005) after adjusting for potential confounding factors. Furthermore, incorporating Lp(a) into a model based on traditional risk factors significantly improved its discriminatory ability for LVSD (AUC = 0.839, 95% CI: 0.786–0.891, P < 0.001). Subgroup analysis indicated that the association between Lp(a) and LVSD was more pronounced in patients with multivessel CTO disease (P for interaction = 0.034).
Conclusion
Elevated Lp(a) levels were significantly associated with LVSD in patients with CTO of the coronary artery.
Keywords: Lipoprotein(a), Left ventricular dysfunction, Chronic total occlusion
Introduction
Coronary chronic total occlusion (CTO) is defined as a coronary artery lesion with thrombolysis in myocardial infarction (TIMI) grade 0 flow for more than 3 months, representing one of the most challenging clinical scenarios in percutaneous coronary intervention (PCI) [1–3]. Among patients with coronary artery disease who undergo coronary angiography (CAG), 16% to 20% present with CTO lesions [4]. Although collateral circulation may develop in some CTO patients, prolonged myocardial ischemia often leads to left ventricular dysfunction, a key determinant of adverse cardiovascular outcomes such as heart failure and cardiovascular mortality [5, 6]. While revascularization strategies, including PCI and coronary artery bypass grafting (CABG), can restore coronary blood flow, a substantial proportion of CTO patients still develop left ventricular systolic dysfunction (LVSD), which highlights the need for better risk stratification and early intervention [7]. In addition to traditional cardiovascular risk factors, lipoprotein(a) [Lp(a)] has garnered increasing attention in recent years.
Lp(a) is a lipoprotein particle consisting of a low-density lipoprotein-like structure covalently linked to apolipoprotein(a). It has been identified as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and a significant predictor of adverse clinical outcomes in both general and high-risk cohorts [8–10]. Recent evidence suggests that elevated Lp(a) may accelerate coronary plaque instability, thrombosis, inflammation, and microvascular dysfunction, potentially worsening myocardial damage during ischemic conditions [11, 12]. However, its specific role in CTO-related cardiac systolic dysfunction remains poorly understood, as most previous studies have focused on its association with acute coronary syndromes rather than chronic ischemic cardiomyopathy. Given the prognostic significance of systolic function in CTO patients and the limited evidence regarding the impact of Lp(a), this study aimed to examine the relationship between Lp(a) and LVSD, as assessed by left ventricular ejection fraction (LVEF) in clinical practice. The evaluation may provide new insights into the association of Lp(a) with CTO-induced left ventricular systolic dysfunction and suggest Lp(a) as a potential therapeutic target for preserving cardiac function and improving risk stratification.
Methods
Study patients
This retrospective cohort study was conducted at the Department of Cardiology of First Affiliated Hospital of Xi’an Jiaotong University. A total of 309 patients with CTO who underwent elective PCI between February 2024 and February 2025 were enrolled. The inclusion criteria were: (i) age ≥ 18 years; (ii) angiographic evidence of CTO treated with elective PCI; (iii) availability of baseline fasting serum Lp(a) levels measured at admission without prior treatment with PCSK9 inhibitors; (iv) availability of LVEF assessed by echocardiography before CTO-PCI. The exclusion criteria were: (i) acute myocardial infarction or cardiogenic shock; (ii) valvular heart disease or cardiomyopathy; (iii) immune system diseases, severe liver or kidney diseases, malignant tumors; (iv) prior PCI or CABG within 6 months; and (v) missing data for Lp(a) or LVEF.
This retrospective study was approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients. Given the observational nature of this study, clinical trial registration was not required.
Clinical data collection
Clinical data, including demographics, anthropometric parameters, comorbidities, and medical and medication histories, were collected from electronic medical records during hospitalization. The diagnoses of type 2 diabetes mellitus, hypertension, and dyslipidemia were based on the related guidelines [13–15]. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², calculated using the CKD-EPI equation. Arrhythmia was defined as a documented history of atrial fibrillation, atrial flutter, or sustained ventricular tachycardia, confirmed by electrocardiography or Holter monitoring. Smoking was defined as having smoked a cigarette in the past 30 days and more than 100 cigarettes in a lifetime. Alcohol consumption was defined based on the self-reported average daily intake over 12 months.
Laboratory measurement
Fasting venous blood samples were collected from the antecubital vein within 24 h of admission after an overnight fast. Laboratory parameters included lipid profile, fasting plasma glucose, glycosylated hemoglobin (HbA1c), liver and renal function, hemoglobin, neutrophil count, platelet count, and N-terminal pro-B-typenatriuretic peptide (NT-proBNP). Plasma Lp(a) concentrations were measured using an immunoturbidimetric assay, the most commonly used Lp(a) testing method in clinical laboratories, with a reportable range of 1.0–300 mg/L and a lower limit of detection of 1.0 mg/L.
LVEF measurement
LVEF was measured using the two-dimensional Simpson’s method from apical four- and two-chamber views to ensure measurement consistency. All echocardiographic examinations were performed within 24 h after admission and prior to the CTO-PCI procedure by certified sonographers who were blinded to the clinical and laboratory data. LVSD was defined as LVEF < 50%, whereas preserved systolic function was defined as LVEF ≥ 50%.
Coronary angiography
CAG was performed in a catheterization laboratory equipped with advanced imaging systems. The severity of coronary artery disease was evaluated according to the American College of Cardiology/American Heart Association lesion classification system [16]. Coronary CTO was defined as angiographic evidence of total occlusion with a TIMI flow grade of 0 and an estimated duration of at least 3 months. The indication for CTO-PCI was based on the presence of documented myocardial ischemia confirmed by at least one of the following: (i) symptoms of angina (Canadian Cardiovascular Society class ≥ II) refractory to optimal medical therapy; (ii) stress-induced wall motion abnormality or perfusion defect on stress echocardiography or myocardial perfusion imaging; or (iii) angiographically significant stenosis (≥ 70% diameter reduction by visual assessment) or functionally significant stenosis (fractional flow reserve < 0.80) [17]. The revascularization strategy and selection of lesions to be revascularized were individualized and determined at the discretion of the cardiac surgeons and interventional cardiologists at the center. Successful CTO-PCI was defined as a final TIMI flow grade 3 with residual stenosis < 30% in the treated vessel [3].
Statistical analysis
The sample size was calculated using G*Power software (version 3.1). We assumed a two-sided α of 0.05, power (1-β) of 0.80, and an estimated odds ratio of 2 for elevated Lp(a) in relation to left ventricular dysfunction based on literature-derived estimates [18]. The minimum required total sample size was calculated to be 285 patients, thus, the 309 patients enrolled in our study provided adequate power to detect the hypothesized association.
For continuous variables, normally distributed data were presented as the mean ± standard deviation, whereas non-normally distributed continuous data were expressed as the median along with the 25th and 75th percentiles. Categorical variables were presented as frequencies and corresponding proportions. Independent samples t-tests were used to analyze normally distributed variables.The Mann-Whitney U test was applied for comparison non-normally distributed variables. Categorical variables were compared using either the chi-squared (χ²) test or Fisher’s exact test. Lp(a) tertiles were defined based on its distribution across the entire cohort: Tertile 1 (T1: Lp(a) ≤ 133 mg/L), Tertile 2 (T2: 133 ≤ Lp(a) ≤ 298 mg/L), Tertile 3 (T3: Lp(a) > 298 mg/L). To assess the association between Lp(a) and LVSD, we selected variables for multivariate logistic regression based on clinical relevance and univariate significance. Following the 10 events per variable (EPV) rule (n = 80 LVSD events), we prioritized established LVSD-related confounders in the primary model. Although BMI and arrhythmia demonstrated statistical significance in univariate analysis, and pre-admission medications for ventricular remodeling might affect baseline LVSD, they were excluded from the primary model to avoid overfitting due to the limited sample size. To address potential selection bias and confounding by indication, we performed sensitivity analyses by adding BMI or pre-admission medications into the model to confirm the robustness of our findings. Arrhythmia was also excluded from the final model because of its small sample size (n = 28, ~ 9%); including it would lead to model overfitting and produce unstable estimates with wide confidence intervals.The discriminatory ability of the relevant factors was evaluated using receiver operating characteristic (ROC) curve analysis, and the area under the curve (AUC) was calculated. To investigate the consistency of the association between Lp(a) levels and LVSD, subgroup analysis was performed according to the presence of hypertension, diabetes, previous MI, and multivessel CTO disease. A two-tailed P-value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS version 22.0 and R software (version 4.3.1).
Results
Clinical characteristics of study participants
The study workflow was illustrated in Fig. 1. A total of 309 patients with CTO were enrolled in the study. Baseline characteristics stratified by LVEF at admission are summarized in Table 1. The mean age of the overall cohort was 61.5 ± 11.3 years, with a predominant male representation (83.8%), and the prevalence of LVSD was 25.9%. Compared with patients with preserved systolic function, those with LVSD were generally older and had higher rates of arrhythmia, previous MI, and use of oral medications (ACEI/ARBs, β-blockers, SGLT2 inhibitors), but a lower prevalence of hypertension at admission. The patients in the LVSD group also had higher levels of Lp(a), NT-proBNP, and neutrophils, and lower BMI, albumin, and LVEF (all P < 0.05).
Fig. 1.
Study population flowchart
Table 1.
Clinical characteristics of CTO patients stratified by LVEF
| Variables | Total (n = 309) |
LVEF < 50% (n = 80) |
LVEF ≥ 50% (n = 229) |
P value |
|---|---|---|---|---|
| Age, years | 61.5 ± 11.3 | 63.4 ± 11.0 | 60.6 ± 11.2 | 0.023 |
| Male, n(%) | 259(83.8%) | 70(87.5%) | 189(82.5%) | 0.299 |
| Hypertension, n(%) | 196(63.4%) | 42(52.5%) | 154(67.2%) | 0.018 |
| Diabetes, n(%) | 113(36.6%) | 31(38.8%) | 82(35.8%) | 0.897 |
| Chronic kidney diseases, n(%) | 20(6.5%) | 8(10.0%) | 12(5.2%) | 0.136 |
| Arrhythmia, n(%) | 33(10.7%) | 14(17.5%) | 19(8.3%) | 0.022 |
| Previous PCI, n(%) | 152(49.2%) | 44(55.0%) | 108(47.2%) | 0.304 |
| Previous CABG, n(%) | 3(1%) | 0(0) | 3(1.3%) | 0.185 |
| Previous MI, n(%) | 117(37.9%) | 52(65.0%) | 65(28.4%) | <0.001 |
| Family history of CAD, n(%) | 51(16.5%) | 12(15.0%) | 39(17.0%) | 0.674 |
| Smoke, n(%) | 202(65.4%) | 58(72.5%) | 144(62.9%) | 0.120 |
| Alcohol consumption, n(%) | 69(22.3%) | 20(25.0%) | 49(21.4%) | 0.505 |
| Antiplatet agents, n(%) | 306(99%) | 79(98.8%) | 227(99.1%) | 0.767 |
| Statins, n(%) | 301(97.4%) | 78(97.5%) | 223(97.4%) | 0.954 |
| ACEI/ARB, n(%) | 88(28.5%) | 77(33.6%) | 11(13.8%) | 0.001 |
| β-blocker, n(%) | 234(75.7%) | 71(88.8%) | 163(71.2%) | 0.002 |
| SGLT2i, n(%) | 148(48.1%) | 65(82.3%) | 83(36.2%) | <0.001 |
| BMI, kg/m2 | 24.74(22.76,27.18) | 24.01(21.90,26.30) | 24.95(23.13,27.58) | 0.003 |
| NT-proBNP, pg/ml | 236(82.4,695) | 958(321,2172) | 137(64.5,364) | <0.001 |
| Hemoglobin, g/L | 144(131,153) | 140(129,153) | 144(130,153) | 0.499 |
| Platelet, 109/L | 204(164,244) | 198(165,238) | 204(162,247) | 0.763 |
| Neutrophils, 109/L | 4.07(3.42,5.26) | 4.48(3.41,6.02) | 3.99(3.42,5.10) | 0.026 |
| Lymphocyte, 109/L | 1.43(1.12,1.82) | 1.41(1.04,1.81) | 1.43(1.12,1.83) | 0.573 |
| CRP, mg/L | 1.23(0.49,3.74) | 1.68(0.54,6.89) | 1.16(0.48,2.81) | 0.228 |
| AST, U/L | 23(20,28) | 23(19,27) | 23(20,28) | 0.456 |
| ALT, U/L | 25(19,36) | 25(17,36) | 25(19,36) | 0.459 |
| ALP, U/L | 78(68,92) | 79(70,97) | 78(68,90) | 0.079 |
| γ-GT, U/L | 24(17,39) | 24(17,47) | 24(17,38) | 0.630 |
| Albumin, g/L | 42.71 ± 4.35 | 41.14 ± 4.59 | 43.20 ± 4.18 | 0.001 |
| Creatinine, µmol/L | 69(60,82) | 71(61,83) | 69(60,82) | 0.476 |
| eGFR, mL/min/1.73m2 | 94.82(83.04,104.81) | 93.20(79.58,103.75) | 95.58(85.37,104.86) | 0.202 |
| TC, mmol/L | 3.17(2.66,3.87) | 3.35(2.67,3.96) | 3.16(2.65,3.81) | 0.350 |
| TG, mmol/L | 1.25(0.98,1.71) | 1.26(0.92,1.83) | 1.25(0.98,1.67) | 0.720 |
| LDL-C, mmol/L | 1.69(1.25,2.15) | 1.85(1.28,2.36) | 1.65(1.23,2.15) | 0.257 |
| HDL-C, mmol/L | 0.87(0.75,1.03) | 0.87(0.74,1.05) | 0.86(0.75,1.02) | 0.843 |
| apoA, g/L | 1.02(0.92,1.14) | 1.01(0.90,1.15) | 1.03(0.92,1.14) | 0.312 |
| apoB, g/L | 0.59(0.47,0.73) | 0.60(0.49,0.77) | 0.58(0.47,0.72) | 0.278 |
| apoE, mg/L | 30.3(24.5,37.1) | 31(25.5,41.9) | 30.1(24.2,35.6) | 0.255 |
| Lp(a), mg/L | 202(100,383) | 254(136,303) | 182(93,299) | 0.009 |
| FPG, mmol/L | 6.12(5.22,8.11) | 6.31(5.40,8.99) | 6.06(5.13,7.81) | 0.064 |
| HbAlc, % | 6.2(5.8,6.9) | 6.3(5.8,7.6) | 6.1(5.7,6.7) | 0.045 |
| LVEF, % | 64(49,68) | 42(37,46) | 66(62,69) | <0.001 |
CTO chronic total occlusion, BMI body mass index, CAD coronary artery disease, MI myocardial infarction, PCI percutaneous coronary intervention, CABG coronary artery bypass grafting, CRP C-reactive protein, NT-proBNP N-terminal pro-B type natriuretic peptide, ALT alanine aminotransferase, AST aspartate aminotransferase, ALP alkaline phosphatase, γ-GT γ-glutamyl transferase, FPG fasting plasma glucose, HbA1c glycosylated hemoglobin A1c, TC total cholesterol, TG triglyceride, LDL-C low-density lipoprotein cholesterol, HDL-C high-density lipoprotein cholesterol, apoA apolipoprotein A, apoB apolipoprotein B, apoE apolipoprotein E, Lp(a) lipoprotein(a), eGFR estimated glomerular filtration rate, LVEF left ventricular ejection fraction, ACEI/ARB angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, SGLT2i sodium-glucose cotransporter 2 inhibitor
Angiographic and procedural details were outlined in Table S1. Because the study focused on baseline LVEF measured prior to the procedure, the procedural characteristics were presented only for descriptive purposes and were excluded from the multivariable models for baseline LVSD. Of the 309 included patients, CTO-PCI was technically successful in 274 patients, yielding an overall technical success rate of 88.6%. Patients with failed CTO-PCI (n = 35) were not excluded from the primary analyses. Patients with LVSD were more prone to having multivessel CTO disease, and CTO of the circumflex artery (all P < 0.05). As shown in Fig. 2, patients in the high Lp(a) tertile had a higher proportion of LVSD (P < 0.05). The correlation between plasma Lp(a) levels and the severity of cardiac dysfunction was shown in Table S3. Median Lp(a) levels were 190 mg/L (IQR: 94–340) in the normal LVEF group (LVEF ≥ 50%), 259 mg/L (IQR: 137–513) in the mild-to-moderate LVSD group (40% ≤ LVEF < 50%), and 249 mg/L (IQR: 136–405) in the severe LVSD group (LVEF < 40%), demonstrating a significant difference among the three groups (overall P < 0.05). Furthermore, a trend test showed a significant positive association between Lp(a) levels and the severity of LVSD (Cochran-Armitage trend test, P < 0.05 ).
Fig. 2.
Prevalence of left ventricular systolic dysfunction (LVSD) across Lp(a) tertiles
Risk factors for LVSD
Univariate logistic regression analysis was presented in Table S2. Variables that were statistically significant in the univariate analysis, along with clinically established risk factors, were incorporated into the multivariate regression model. The association between Lp(a), treated as a continuous variable (per 100 mg/L increase), and LVSD remained consistent across different models. In the crude model, the OR was 1.141(95% CI: 1.049–1.241) per 100 mg/L increase in Lp(a). After further adjustment for multiple confounding variables, Lp(a) remained significantly associated with LVSD (OR per 100 mg/L: 1.149; 95% CI: 1.042–1.267; P = 0.005), as detailed in Table 2. Furthermore, patients were stratified into tertiles based on their baseline Lp(a) concentration(T1–T3). Taking the lowest quartile (T1) as the reference group, multivariate analysis revealed that the highest tertile (T3) was significantly associated with an increased odds of LVSD (OR = 2.15, 95% CI: 1.01–4.46; P = 0.024). In contrast, the risk elevation for the middle tertile (T2) did not reach statistical significance (OR = 1.63, 95% CI: 0.75–3.54; P = 0.216). The multivariate analysis also demonstrated that age (OR = 1.033, 95% CI: 1.003–1.063; P = 0.029), previous MI (OR = 4.808, 95% CI: 2.609– 8.861; P < 0.001), NT-proBNP (OR = 1.000, 95% CI: 1.000–1.001; P = 0.035), and multivessel CTO disease (OR = 2.698, 95% CI: 1.421–5.122; P = 0.002) were related to LVSD in patients with CTO. To assess the robustness of association of Lp(a) and LVSD, sensitivity analyses were performed by adding BMI or pre-admission medications into the multivariate regression model. The results showed that the association remained unchanged in the sensitivity analyses (Tables S4 and S5).
Table 2.
Multivariate logistic regression analysis of lipoprotein(a) and LVSD
| Variables | Model 1 | Model 2 | Model 3 | |||
|---|---|---|---|---|---|---|
| OR (95%CI) | P | OR (95%CI) | P | OR (95%CI) | P | |
| Lipoprotein(a),100 mg/L | 1.141(1.049–1.241) | 0.002 | 1.159(1.063–1.263) | 0.003 | 1.149(1.042–1.267) | 0.005 |
| T1 | 1.00(Reference) | 1.00(Reference) | 1.00(Reference) | |||
| T2 | 1.64(0.84–3.20) | 0.151 | 1.55(0.78–3.06) | 0.207 | 1.63(0.75–3.54) | 0.216 |
| T3 | 2.40(1.25–4.61) | 0.008 | 2.40(1.24–4.65) | 0.009 | 2.15(1.01–4.46) | 0.024 |
Model 1: Crude
Model 2: with adjustment for age, gender
Model 3: with adjustment for hypertension, previous MI, multivessel CTO, NT-proBNP, and HbAlc in addition to Model 2
OR odds ratio, CI confidence interval, MI myocardial infarction, NT-proBNP N-terminal pro-B type natriuretic peptide, HbA1c glycosylated hemoglobin A1c, LVSD left ventricular systolic dysfunction
Discriminative value of Lp(a) for LVSD
In the multivariate logistic regression analysis, age, previous MI, NT-proBNP, and multivessel CTO disease were associated with LVSD. The AUC for Lp(a) alone was 0.606 (95% CI: 0.534–0.678, P < 0.01). The model incorporated the four traditional risk factors (age, previous MI, NT-proBNP, and multivessel CTO disease) yielded an AUC of 0.777 (95% CI: 0.713–0.841) for discriminating LVSD. Notably, when Lp(a) was added into this four-factor model, the model’s discriminative performance improved significantly, driving the AUC upward to 0.839 (95% CI: 0.786–0.891, P < 0.001), as shown in Fig. 3; Table 3. The DeLong test confirmed that this improvement in AUC was statistically significant (P < 0.001). Furthermore, the addition of Lp(a) yielded a substantial clinical net reclassification improvement (NRI) of 0.622 (95% CI: 0.374–0.872; P < 0.001) and an integrated discrimination improvement (IDI) of 0.116 (95% CI: 0.069–0.162; P < 0.001).
Fig. 3.
ROC curves for identifying LVSD in patients with CTO. The traditional risk factors model included NT-proBNP, age, previous MI, and multivessel CTO disease
Table 3.
AUCs in ROC analysis of Lp(a) for identifying LVSD
| Variables | AUC | 95%CI | P value | Specificty | Sensitivity |
|---|---|---|---|---|---|
| Lp(a) | 0.606 | 0.534–0.678 | 0.005 | 0.491 | 0.692 |
| Traditional risk factors | 0.777 | 0.713–0.841 | <0.001 | 0.787 | 0.745 |
| Traditional risk factors + Lp(a) | 0.839 | 0.786–0.891 | <0.001 | 0.801 | 0.750 |
AUC area under the curve, ROC receiver operating characteristic, CI confidence interval, Lp(a) Lipoprotein(a), LVSD left ventricular systolic dysfunction
Subgroup analysis
Post hoc subgroup analyses were performed based on relevant clinical variables, including hypertension, diabetes, previous MI, and multivessel CTO disease. The statistical model used in these subgroup analyses was adjusted for all covariates included in Model 3, excluding the specific variables used for stratification in each subgroup. As shown in the forest plot in Fig. 4, the results demonstrated that Lp(a) levels (per 100 mg/L) were consistently associated with LVSD across these different subgroups, and this association was particularly pronounced in patients with multivessel CTO disease (P for interaction = 0.034).
Fig. 4.
Forest plot for subgroup analysis of the associations between lipoprotein(a) and LVSD in patients with CTO
Discussion
In this study, we found that Lp(a) levels were significantly elevated in CTO patients with LVSD when compared with those with preserved systolic function. Moreover, Lp(a) remained a risk indicator for LVSD even after adjustment for potential confounding factors. The integration of Lp(a) into a traditional risk model significantly enhanced its discriminative performance for LVSD.
Although elevated low-density lipoprotein cholesterol is a well-established driver of atherosclerosis, accumulating evidence supports a causal role of Lp(a) in ASCVD [19–21]. Despite the highly skewed distribution of serum Lp(a) levels within the population [22], its measurement is increasingly vital in clinical practice. Elevated Lp(a) levels have been independently linked to a higher prevalence of vulnerable plaques, greater coronary atheroma volume, and higher Gensini scores in patients with CTO or diffusely narrowed vessels [23–26]. A pooled analysis of five multi-ethnic prospective cohorts in the U.S. reported a 50% higher risk of atherosclerotic events associated with higher Lp(a) levels, which nearly doubled in diabetic patients [27]. A few small-scale studies have suggested inverse results hinting at a potential inverse relationship [28–30]. Nevertheless, the relationship between Lp(a) and cardiac function remains controversial. Heart failure represents a common and serious complication during CTO development [31]. Lp(a) can compete with plasminogen for fibrin-binding sites and promote thrombosis, precipitating slow-flow or no-reflow phenomena, and aggravating coronary microvascular dysfunction [32–34]. Several studies have linked elevated Lp(a) levels to impaired cardiac function in patients with CAD, including worse regional wall motion and reduced LVEF [35, 36]. Although an early retrospective study noted significantly lower Lp(a) levels in healthy controls than in heart transplant recipients or patients with congestive heart failure across both ischaemic and non-ischaemic etiologies, that investigation was inherently constrained by its small sample size and a lack of multivariable adjustment [37, 38]. A recent large-scale study found elevated Lp(a) and its corresponding LPA risk genotypes are associated with an increased risk of incident heart failure in the general population [39].
In our study, we examined the association of Lp(a) with LVSD in CTO patients. One notable finding is a lower prevalence of hypertension in the LVSD group, which appears inconsistent with the traditional view that hypertension is a risk factor for CTO. This can be explained by two factors. First, the predominant etiology of LVSD in our cohort was ischemic heart disease (CTO-related), rather than hypertensive heart disease. Second, long-term use of antihypertensive/remodeling agents (e.g., ACEIs/ARBs, β-blockers) may slow disease progression in hypertensive patients, leading to their under-representation in severe LVSD (selection bias). Nonetheless, residual confounding (e.g., hypertension duration, blood pressure control) cannot be excluded, and our findings require validation in larger prospective studies. This second factor also introduces potential confounding by indication, because pre-admission use of these medications is indicated for hypertension or prior myocardial infarction with left ventricular dysfunction, which are associated with LVSD, and these drugs improve ventricular remodeling, thereby modifying baseline LVSD. Our sensitivity analysis adjusted for pre-admission medication use and confirmed the robustness of our findings.
Having considered these factors, we identified Lp(a) as a factor associated with LVSD in patients with CTO, particularly in those with multivessel CTO. Although the absolute effect size of Lp(a) per mg/L is small, the odds ratio per 100 mg/L increment provides a clinically interpretable effect size, and the wide confidence intervals for the tertile analysis suggest imprecision. Therefore, the clinical significance of Lp(a) as a risk predictor should be interpreted conservatively. One possible explanation for the stronger association in multivessel CTO is that the pro-inflammatory and pro-thrombotic effects of Lp(a) are amplified under conditions of a greater ischemic burden and reduced coronary flow reserve. Alternatively, this finding could reflect residual confounding driven by a more extensive atherosclerosis. However, this post-hoc subgroup analysis is exploratory and requires external validation. Notably, while the integration of Lp(a) into the traditional risk model significantly expanded its discriminative capacity (with the AUC rising from 0.777 to 0.839), it remains susceptible to overfitting bias and should be considered hypothesis-generating rather than clinically applicable. Residual confounders such as ischemic burden, infarct size, myocardial viability, collateral circulation grade, and completeness of revascularization were not available and should be prioritized and validated in future studies. Regarding our choice of echocardiographic metrics, the Myocardial Performance Index (Tei Index) integrates systolic and diastolic function and offers superior discriminative ability [40]. However, given our focus on ventricular remodeling and clinical translatability, LVEF remains a practical measure despite its limitations (e.g., cardiac sphericity distorts EF and volumes). Multiple pathophysiological factors contribute to adverse ventricular remodeling, including large infarct size, excessive inflammatory responses, persistent microvascular dysfunction, extracellular matrix alterations, eccentric hypertrophy, and oxidative stress [41, 42]. Overall, direct evidence linking Lp(a) to LVSD in patients with CTO remains lacking, and the proposed associations require external validation in larger, multi-center cohorts. Several limitations should be acknowledged. First, this was a single-center cross-sectional study with a modest sample size, which precludes causal inferences. There was potential subjectivity in variable selection for the multivariate model, although sensitivity analyses confirmed the robustness. Multi-center, prospective studies with larger cohorts are warranted to verify this association. Second, LVEF was measured prior to PCI (within 24 h of admission) to reflect baseline left ventricular function but not assess whether coronary revascularization modifies the relationship between Lp(a) and left ventricular functional recovery. Serial echocardiography (e.g., at 3–6 months post-PCI) is needed. Third, Lp(a) was quantified in mg/L using an immunoturbidimetric assay (affected by apo(a) isoform size heterogeneity) rather than using the recommended isoform-independent concentration expressed in nmol/L. LPA genotyping was not performed to differentiate concentration from isoform sizes. The generalizability of our findings to other racial/ethnic populations may be limited. Consequently, our results should be interpreted with caution, and the use of isoform-calibrated assays in nanomoles per liter is recommended in future prospective studies.
Conclusion
Elevated Lp(a) levels were significantly associated with LVSD in patients with CTO, and adding Lp(a) to the conventional risk model significantly improved the discriminative performance for LVSD in this single-center study. However, these findings require external validation in larger, multi-center prospective studies before routine Lp(a) measurement can be recommended for clinical risk stratification.
Acknowledgements
We would like to express our sincere gratitude to all individuals who contributed to this study, especially Pengjie Gao for his valuable assistance with the statistical analysis.
Authors’ contributions
Suining Xu and Weihua Zhang conceptualized the idea of this study. Yan Zhuo handled data collection and analysis, and Lele Jing helped with the analysis through constructive discussions.
Funding
This study was supported by the Shaanxi Provincial Natural Science Basic Research Program (Grant No. 2024JC-YBQN-0817), and Science and Technology Program of Jiaxing (Grant No. 2022AD30058).
Data availability
The relevant data support the finding can be reasonably requested from the corresponding author.
Declarations
Ethics approval and consent to participate
The study protocol was conducted according to the principles in the Declaration of Helsinki.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Suining Xu and Yan Zhuo contributed equally to this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The relevant data support the finding can be reasonably requested from the corresponding author.