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Elevated plasma homocysteine level is associated with poor ST-segment resolution in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention at high altitude

Liu, Bei1; Yang, Shujuan1; Yang, Lixia1; Zhang, Bin2; Guo, Ruiwei1,∗

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doi: 10.1097/CP9.0000000000000016
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Primary percutaneous coronary intervention (PPCI) is the standard treatment in patients with ST-segment elevation myocardial infarction (STEMI)[1]. ST-segment resolution after PPCI is a readily available index that reflects the degree of reperfusion. A number of studies have demonstrated strong association between impaired ST-segment resolution and poor outcome[2–4]. The rate of major adverse cardiac events (MACEs) in patients with acute myocardial infarction (AMI) is markedly higher in patients with impaired ST-segment resolution[5]. Indeed, the factors that influence impaired ST-segment resolution are unclear.

Homocysteine (HCY) is an intermediate in the metabolism of methionine and cysteine[6]. Serum HCY level varies depending on age, dietary habit, and genetic background[7]. A previous study suggested higher HCY level in the people who live in high altitudes[8].

Elevated HCY has been associated with increased risk of cardiovascular diseases, including stroke and coronary artery disease[9–11]. Elevated HCY is associated with mortality as well as serious non-fatal outcomes in patients with unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI)[12], and increased intracoronary thrombus burden in patients with acute coronary syndrome[13–14]. Previous observational studies in patients with STEMI suggested an association between elevated HCY level with impaired STR after fibrinolytic therapy[13,15]. We conducted a retrospective analysis to examine the potential relationship between elevated serum HCY and poor ST-segment resolution (STR) after PPCI.


Study population

We retrospectively screened a total of 322 patients who underwent PPCI for AMI at the People's Liberation Army 920 Hospital (altitude = 2,000 m), People's Hospital of Baoshan (altitude = 1,800 m), and People's Hospital of Lijiang (altitude = 2,200 m) from September 2021 to March 2022. The patients who died during PPCI (n = 14) were excluded. The final analysis included 308 patients. All patients received standard anticoagulant therapy (300 mg aspirin plus 600 mg clopidogrel or 180 mg ticagrelor) before PPCI. Activated clotting time was maintained at >300 s using heparin during PPCI. The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2013. The study protocol was approved by the Medical Ethics Committee of 920th Hospital of the People's Liberation Army Joint Logistics Support Force (No. 2019HB034; December 2019). Because it was a retrospective study, the ethics committee waived informed consent.

Assessment and variable definition

Culprit vessel blood flow was evaluated using thrombolysis in myocardial infarction (TIMI) grade. Serum HCY concentration was measured using blood sampled collected t 10 min prior to PCI with high performance liquid chromatography (HPLC). The specifications of HPLC were identical among the tree hospitals. Elevated HCY was defined as 15 μmol/L or higher. Complete ST-segment resolution was defined as ≥ 70% resolution based on 60-min ECG, as assessed by blinded cardiologists[16].

Statistical analysis

Continuous variables are presented as the mean ± standard deviation and were compared using the t-test in cases of two independent groups with parametric data. Continuous variables with skewed distributions are shown as median (IQR) and compared using Kruskal-Wallis rank-test (KW rank-test). Categorical variables are presented as frequencies with percentages, and comparisons were made using the Pearson's chi-squared test. Categorical variables are compared using fisher's exact test when expected frequency is less than 10. A multivariable logistic regression model was used to determine the plasma HCY levels on STR after PPCI. Univariate analysis was performed on each variable, and those with a P value less than 0.1 were included in the final regression equation. The following variables were entered into the model: age; sex; hypertension; diabetes; hypercholesterolemia; smoking history; previous angina pectoris; drugs given before AMI onset; P-to-B time; serological markers; multivessel disease; and details of PPCI treatment. A two-tailed probability (P < 0.05) was considered statistically significant. All analyses were performed using SPSS, version 19.0 software (IBM-SPSS, Inc., Chicago, IL, USA).


Baseline characteristics

The final analysis included 308 patients: 153 had elevated HCY and the remaining 155 had normal HCY. The elevated HCY group had higher percentage of men (92.81% vs. 80.00%; P = 0.001) and smokers (63.87% vs. 79.08%; P = 0.003) (Table 1). The two groups did not differ significantly in other characteristics, including diabetes, hypertension, hyperlipidemia, family history, previous angina pectoris, baseline drug treatment (aspirin, clopidogrel, ticagrelor, statins, β-blockers, and angiotensin converting enzyme inhibitors), Pain to balloon time (P-to-B time), time form first medical contact to needle (FMC-to-N time), and mortality.

Table 1 - Clinical baseline characteristics
Normal HCY group (n = 155) High HCY group (n = 153) P value
Age (years) 59.50 ± 11.61 57.80 ± 12.90 0.211
Male 124 (80.00%) 142 (92.81%) 0.001
Risk factor
 Diabetes 30 (19.36%) 29 (18.95%) 0.929
 Hypertension 90 (58.07%) 80 (52.29%) 0.308
 Hyperlipidemia 15 (9.68%) 9 (5.88%) 0.214
 Smoking 99 (63.87%) 121 (79.09%) 0.003
 Family history 9 (5.81%) 4 (2.61%) 0.164
 Previous angina pectoris 42 (27.10%) 47 (30.72%) 0.483
Medications before PPCI
 Aspirin 153 (98.71%) 150 (98.40%) 0.988
 Clopidogrel 125 (80.65%) 127 (83.01%) 0.591
 Ticagrelo 28 (18.07%) 22 (14.38%) 0.381
 Statins 12 (7.74%) 6 (3.92%) 0.153
 β-block 8 (5.16%) 2 (1.31%) 0.113
 ACEI 9 (5.81%) 6 (3.92%) 0.442
Time intervals
 FMC to N time (h) 5.06 ± 3.36 5.05 ± 4.45 0.995
 P-to-B time (min) 38.01 ± 16.97 42.73 ± 52.86 0.293
P<0.05. Data are expressed as n (%) or mean±SD as appropriate. Continuous variables were compared using the unpaired Student's t-test. Categorical variables were compared using the Pearson's Chi-squared test.ACEI: angiotensin-converting enzyme inhibitor; FMC to N time: time from first medical contact to needle; HCY: homocysteine; PPCI: primary percutaneous coronary intervention; P-to-B time: pain to balloon time.

Laboratory testing, lesion characteristics and PPCI procedure

In comparison to the normal HCY group, patients in the elevated HCY group had higher plasma creatinine concentration (83.71 ± 27.44μmmol/L vs. 74.50 ± 21.34 μmol/L; P < 0.001; Table 2). All other serological markers did not differ significantly between the two groups. The two groups also did not differ significantly in lesion characteristics, use of balloon and stents, and final TIMI flow (Table 3).

Table 2 - Laboratory examination before primary percutaneous coronary intervention
Normal HCY group (n = 155) High HCY group (n = 153) P value
Creatinine (μmol/L) 74.50 ± 21.34 83.71 ± 27.44 <0.001
Uric Acid (μmol/L) 398.53 ± 100.87 412.552 ± 113.54 0.253
Peak CK (U/L) 2999.10 ± 2547.59 3023.26 ± 2061.21 0.927
GLU (mmol/L) 8.90 ± 3.93 8.405 ± 3.29 0.230
TG (mmol/L) 1.42 ± 1.69 1.71 ± 2.51 0.239
TCH (mmol/L) 4.90 ± 1.04 7.86 ± 35.59 0.302
LDL (mmol/L) 3.13 ± 0.99 3.32 ± 2.19 0.325
HDL (mmol/L) 1.08 ± 0.37 1.07 ± 0.32 0.892
P < 0.05. Continuous variables are expressed as mean±SD and were compared using the unpaired Student's t-test.CK: creatine kinase; GLU: glucose; HCY: homocysteine; HDL: high density lipoprotein; LDL: low density lipoprotein; PPCI: primary percutaneous coronary intervention; TCH: cholesterol; TG: triglyceride.

Table 3 - Primary percutaneous coronary intervention management
Normal HCY group (n = 155) High HCY group (n = 153) P value
Multivessel disease 137 (88.39%) 141 (92.16%) 0.265
Culprit vessel
 Left main 1 (0.65%) 1 (0.65%) 1
 Left anterior descending 87 (56.13%) 74 (48.37%) 0.173
 Left circumflex 15 (9.68%) 13 (8.50%) 0.719
 Right coronary artery 52 (33.54%) 65 (42.48%) 0.106
Times of balloon dilatation 3.26 ± 1.41 3.05 ± 1.46 0.181
Length of stents (mm) 30.31 ± 14.49 31.05 ± 16.21 0.672
Diameter of stents (mm) 3.15 ± 0.63 3.15 ± 0.57 0.936
Use of GPI 74 (47.74%) 83 (54.25%) 0.253
Use of nicorandil 9 (5.81%) 17 (11.11%) 0.094
Use of Thrombectomy devices 4 (2.58%) 3 (1.96%) 0.715
IABP 21 (13.55%) 18 (11.77%) 0.638
Temporary pacemaker 28 (18.07%) 26 (16.99%) 0.805
Final TIMI flow
 TIMI 3 149 (96.13%) 139 (90.85%) 0.060
 TIMI 3- 6 (3.87%) 14 (9.15%) 0.060
EF in patients 45.63 ± 4.81 46.09 ± 4.90 0.404
Mortality 1 months after PPCI 2 (1.29%) 3 (1.96%) 0.732
Mortality 3 months after PPCI 3 (1.94%) 3 (1.96%) 0.972
Data are expressed as n (%) or mean±SD as appropriate. Continuous variables were compared using the unpaired Student's t-test. Categorical variables were compared using the Pearson's Chi-squared test. GPI: platelet glycoprotein IIb/IIIa receptor inhibitor; HCY: homocysteine; IABP: intra-aortic balloon pump; PPCI: primary percutaneous coronary intervention; TIMI: thrombolysis in myocardial infaction.

Association between plasma HCY and ST-segment resolution

Percentage of the patients with complete ST-segment resolution (≥70%) was significantly lower in the patients with elevated HCY (49.67% vs. 83.23%; P < 0.001; Table 4). As a result, we performed univariable regressions analysis to assess the effects of a high plasma HCY level before AMI on STR after PPCI. The HCY level before AMI predicted STR after PPCI univariably (OR = 1.83; 95% CI = 1.28–2.53; P < 0.001). In the multivariable regression analysis, poor STR (<70% resolution) was associated with longer P-to-B time (OR 0.832; 95%CI: 0.775–0.894; P < 0.001), lower uric acid (OR 1.003; 95%CI: 1.000–1.005; P = 0.035), and elevated HCY (OR 0.957 vs. normal HCY; 95%CI: 0.937–0.977; P < 0.001; Table 5).

Table 4 - The plasma HCY levels and the ST-segment resolution after primary percutaneous coronary intervention
No. HCY (μmol/L) STR after PPCI (>50%)
Normal HCY group 155 10.67±2.87 129 (83.23%)
High HCY group 153 26.32±15.06 76 (49.67%)
P value 0.001 <0.001
P<0.05. Data are expressed as n (%) or mean±SD as appropriate. Continuous variables were compared using the unpaired Student's t-test. Categorical variables were compared using the Pearson's Chi-squared test.HCY: homocysteine; STR: ST-segment resolution; PPCI: primary percutaneous coronary intervention.

Table 5 - Multivariate Logistic Regression Determinants of STR after primary percutaneous coronary intervention
B OR 95%CI P value
HCY −0.044 0.957 0.937 0.977 <0.001∗∗
P-to-B time −0.184 0.832 0.775 0.894 <0.001∗∗
Uric acid 0.003 1.003 1.000 1.005 0.035
P < 0.05; ∗∗P < 0.001. Variables entered for the multivariable logistic regression analyses are age, gender, hypertension, diabetes, hypercholesterolemia, smoking, previous angina pectoris, peak creatine kinase, drugs given before onset of AMI, P-to-B times, multivessel disease, length and diameter of stents, and serological markers before AMI.CI: confidence interval; HCY: homocysteine; P-to-B time: pain to balloon time.


Elevated plasma total HCY level has been reported to be an independent risk factor for poor prognosis in patients with AMI[17]. High plasma HCY level has also been reported in people who dwell in high altitude[18]. The present results demonstrated significantly lower rate of complete ST-segment resolution (≥70%) after PPCI in patients with STEMI in a high-altitude population. Regression analysis showed that in addition to longer P-to-B time and lower uric acid level, elevated plasma HCY level was also independently associated with poor ST-segment resolution.

ECG-based STR has been increasingly used to assess myocardial perfusion in STEMI patients undergoing PPCI and post-PPCI complete ST-segment resolution has been validated as a surrogate marker for improved outcomes[3–4]. The association between elevated plasma total HCY with poor STR as observed in the current study is generally consistent with the results of a study by Anderson et al. showing that plasma HCY predicts mortality independently of traditional risk factors in patients with angiography-defined CAD[17]. Stubbs et al. also reported that elevated total HCY level on admission is a strong predictor of late cardiac events in patients with acute coronary syndrome[9]. A meta-analysis that was based on a large number of prospective studies and corrected for regression dilution bias also showed a significant association between elevated serum HCY level and incident CVD[19]. However, the current study failed to show increased mortality in patients with elevated total HCY level despite of poor STR, possibly due to small sample size and relatively short follow-up period (only 3 months).

Ample evidence demonstrated that HCY accelerates the process of atherosclerosis. Ma et al. showed that HCY could influence the methylation status of phosphatase and tensin homologue on chromosome 10, which in turn promotes the proliferation of vascular smooth muscle cells (VSMCs) – the primary pathologic event in the development of atherosclerosis[20]. HCY inhibits endothelial progenitor cell proliferation via DNMT1-mediated hypomethylation of cyclin A[21]. HCY also aggravates vascular damage by oxidative stress, endothelial dysfunction, hypercoagulability, and endoplasmic reticulum stress[21–22]. Platelet activation may also participate in the HCY-induced vascular damage, since HCY-mediated oxidant stress has been shown to trigger platelet activation, and ultimately a tendency to develop thrombotic events[23]. There are also some evidence to support the involvement of the nitric oxide pathway and PKC activation in HCY-induced platelet aggregation[24]. The current study also showed an independent association between poor STR with lower uric acid level. Such an observation is in contrast to a previous study by Mandurino-Mirizzi et al. showing an association with elevated serum uric acid with higher inflammatory biomarkers and higher mortality in patients undergoing PPCI for STEMI[25]. Large prospective studies with long-term follow-up are needed to resolve this issue.

Study limitations

The current study has several limitations. First, the retrospective nature of the study renders it to biases caused by confounding factors. Second, the sample size is relatively small; subgroup analysis is thus not possible. Several variables that could affect STR were not documented, and thus not included in the analysis.


Elevated plasma HCY level was associated with poor ST-segment resolution in patients undergoing PPCI STEMI at high altitude.


This work was funded by internal support by Joint Logistics Support Force and 920th Hospital.

Author contributions

BL and SY did data collection. BL and SY contributed equally to this work. LY made the experimental guidance for the design. BZ made a statistical analysis. RG made an experimental design.

Conflict of interest statement

The authors declare that they have no conflict of interest with regard to the content of this manuscript.


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High altitude; Homocysteine; Percutaneous coronary intervention; ST-segment elevation myocardial infarction; ST-segment resolution

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