Clinical Section: Research Article

Gerontology 2023;69:571–580 Received: August 2, 2022

Accepted: December 27, 2022
DOI: 10.1159/000528951 Published online: January 5, 2023

Lactate Dehydrogenase Predicts

Hemorrhagic Transformation in Patients
with Acute Ischemic Stroke

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Lingli Chen a Minjie Xu b Qiqi Huang c Caiyun Wen d Wenwei Ren a
aDepartment
of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; bSchool of
Mental Health, Wenzhou Medical University, Wenzhou, China; cDepartment of Cardiac Care Unit, The First Affiliated
Hospital of Wenzhou Medical University, Wenzhou, China; dDepartment of Radiology, The First Affiliated Hospital of
Wenzhou Medical University, Wenzhou, China

Keywords infarction subgroup (281.0 [230.0–340.0] U/L versus 258.0

Lactate dehydrogenase · Hemorrhagic transformation ·
Acute ischemic stroke · Risk · Association
Abstract
Introduction: Hemorrhagic transformation (HT) is a severe
but frequent complication of acute ischemic stroke (AIS).
This study aimed to evaluate the relationship between se-
rum lactate dehydrogenase (LDH) levels and HT. Methods:
We retrospectively included 542 AIS patients with HT and
1,091 age- and gender-matched patients without HT. De-
mographic and clinical data were obtained from medical
records, and blood samples were obtained within 24 h after
admission. The characteristics of the groups were compared.
With the receiver operating characteristic (ROC) curve anal-
ysis, we assessed the discriminating capacity of LDH levels
in predicting HT in patients with AIS. The logistic regression
model was used to determine the connection between LDH
and HT. Results: The HT group had considerably higher LDH
levels than the non-HT group (263.0 [216.0–323.3] U/L versus
178.0 [162.0–195.0] U/L, p < 0.001). We also observed that
the levels of LDH in the parenchymal hemorrhage sub-
group were significantly higher than those in the hemorrhagic
[209.0–311.0] U/L, p < 0.001). The area under the ROC curve
of LDH was 0.890 (95% confidence level [CI] 0.874–0.905,
p < 0.001). Besides, logistic regression revealed that high
LDH levels (LDH >215 U/L) showed a higher risk of HT (odds
ratio = 10.958, 95% CI 7.964–15.078, p < 0.001). Conclusion:
High LDH levels were linked with an increased risk of HT in
AIS patients. Practical measures should be considered in pa-
tients with increased LDH levels (LDH >215 U/L).
© 2023 S. Karger AG, Basel
Introduction
Hemorrhagic transformation (HT) is a common com-
plication of cerebral infarction, often leading to the dete-
rioration of clinical symptoms and increased death and
disability rates [1–4]. Exploring the risk factors for HT
may assist physicians in providing appropriate therapy
for patients with high HT risk after acute ischemic stroke
(AIS).
Lingli Chen, Minjie Xu, and Qiqi Huang have contributed equally to
this work.

Karger@karger.com © 2023 S. Karger AG, Basel Correspondence to:

www.karger.com/ger Caiyun Wen, wencaiyunwenzhou @ qq.com
Wenwei Ren, renwenwei @ wmu.edu.cn
 Downloaded from http://karger.com/ger/article-pdf/69/5/571/3949659/000528951.pdf by Univ. of California Davis user on 01 April 2024
Fig. 1. The flow of participants. AIS, acute
ischemic stroke; HT, hemorrhagic trans-
formation.

Fig. 2. CT scan illustrations of HI and PH, as

defined by the European Cooperative Acute
Stroke Study II criteria. HI, hemorrhagic in-
farction; PH, parenchymal hemorrhage.

Lactate dehydrogenase (LDH), an end product of
glycolysis, is a hydrogen transfer enzyme in many cells
and organs, including the heart, lung, liver, and central
nervous system [5–8]. The irregular extracellular occur-
rence of LDH, which can be detectable in serum to discov-
er cell or organ injury, has been noted as a warning sign
in a wide range of clinical situations, including myocardial
ischemia, myocarditis, hepatitis, liver cirrhosis, tumors,
pneumonia, and sepsis [9–13]. For the central nervous
system, patients with hypoxic-ischemic encephalopathy,
cerebral hemorrhage, posterior reversible encephalopathy
syndrome, and subarachnoid hemorrhage with delayed
cerebral ischemia had higher LDH levels than control
groups [10, 14, 15]. Previous studies have demonstrated

572 Gerontology 2023;69:571–580 Chen/Xu/Huang/Wen/Ren

DOI: 10.1159/000528951
that high LDH levels could predict elevated all-cause
mortality and poor functional outcomes in patients with
AIS [16]. Besides, a retrospective observational study
revealed a link between higher serum LDH levels and
all-cause mortality, including stroke, in patients with
metabolic syndrome [17]. Although LDH has long been
considered a predictor of various adverse health out-
comes and the LDH/pyruvate dehydrogenase activity
ratio increased following ischemia in rat brain slices,
the role of LDH in predicting HT in patients with AIS
is not well explored [18]. Cell death is usually accom-
panied by cytoplasmic destruction, which releases
LDH into the peripheral circulation [19]. HT patients

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often have more severe pathological destruction than Fig. 3. a The levels of LDH in HT and non-HT groups. b The lev-
els of LDH in the HI and PH subtypes. LDH, lactate dehydroge-
non-HT patients, with more cell necrosis and theoreti- nase; HT, hemorrhagic transformation; HI, hemorrhagic infarc-
cally higher peripheral LDH release than non-HT pa- tion; PH, parenchymal hemorrhage. **p < 0.01, ***p < 0.001.
tients [20, 21]. A recent study reported that elevated
serum LDH levels could predict unfavorable outcomes
following recombinant tissue plasminogen activator
thrombolysis in patients with AIS [22]. Therefore, we
speculate whether HT patients have higher serum LDH
levels than non-HT patients.
Based on these findings, this study aimed to determine
if LDH had a role in developing HT in patients with AIS.
We hypothesized that a high LDH was related to an in-
creased risk of HT in AIS patients.

Methods

Participants
We retrospectively analyzed consecutive patients with AIS be-
tween December 2012 and December 2021 from the First Affiliated
Hospital of Wenzhou Medical University. The following criteria
were used to determine inclusion: (1) age 18 years or older; (2) di-
agnosed with AIS and verified using MRI or CT; (3) onset of stroke
within 7 days; and (4) had undergone the follow-up CT or MRI
scans. Patients with incomplete data were excluded (Fig. 1).

Data Collection
The electronic medical record system was used to gather base-
line characteristics. General demographic factors included age,
gender, body mass index (BMI), smoking, and drinking history.
Hypertension, diabetes, and atrial fibrillation (AF) were all identi-
fied as comorbidities. The National Institutes of Health Stroke
Scale (NIHSS) score, systolic blood pressure, diastolic blood pres-
sure, the trial of ORG 10172 in acute stroke treatment (TOAST),
and infarct location were all collected clinically. Blood parameters,
including platelet count, creatinine, LDH, low-density lipoprotein
(LDL), prothrombin time (PT), the international normalized ratio
(INR), and the prothrombin time ratio (PTR), were measured in
the hospital biochemistry department after an overnight fast (at
least 8 h) within 24 h after admission. Therapy was divided into
conventional therapy and thrombolysis or thrombectomy therapy.
Fig. 4. The ROC curve of LDH predicts the risk of HT in individu-
als with AIS. ROC, receiver operating characteristic; LDH, lactate
dehydrogenase; HT, hemorrhagic transformation; AIS, acute is-
chemic stroke.
NIHSS score was used to assess the severity of the stroke. All
individuals were categorized into large artery atherosclerosis,
cardioembolism, small vessel occlusion, and other subtypes (in-
cluding stroke of other determined etiology and stroke of undeter-
mined etiology) using the TOAST criteria [23]. Infarct locations
were categorized as follows based on brain radiological examination:
lobar (frontal, insular, temporal, occipital, parietal), subcortical

Prediction of Hemorrhagic Gerontology 2023;69:571–580 573

Transformation DOI: 10.1159/000528951
 Table 1. Comparison of clinical features between HT and non-HT groups

Variables Non-HT (n = 1,091) HT (n = 542) Statistic p value

Age, years (median, IQR) 72.0 (62.0–78.0) 72.0 (62.0–78.3) −0.018 0.986
Gender, n (%)
Male 743 (68.1) 371 (68.5) 0.020 0.887
Female 348 (31.9) 171 (31.5)
BMI, kg/m2 (median, IQR) 23.5 (22.2–24.8) 23.8 (22.8–24.8) −2.749 0.006
Smoking, n (%) 442 (40.5) 223 (41.1) 0.060 0.807
Drinking, n (%) 373 (34.2) 190 (35.1) 0.120 0.729
Hypertension, n (%) 755 (69.2) 342 (63.1) 6.117 0.013
Diabetes, n (%) 331 (30.3) 157 (29.0) 0.325 0.568
Atrial fibrillation, n (%) 107 (9.8) 231 (42.6) 237.520 <0.001
NIHSS (median, IQR) 2.0 (1.0–4.0) 3.0 (1.0–8.0) −9.154 <0.001

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SBP, mm Hg (median, IQR) 153.0 (138.0–169.3) 155.0 (138.0–168.0) −0.337 0.736
DBP, mm Hg (median, IQR) 84.0 (76.0–92.0) 86.0 (75.0–93.0) −0.985 0.325
TOAST, n (%)
Large artery atherosclerosis 543 (49.8) 169 (31.2) 246.547 <0.001
Cardioembolism 102 (9.3) 221 (40.8)
Small vessel occlusion 75 (6.9) 2 (0.4)
Other subtypes 371 (34.0) 150 (27.7)
Therapy, n (%)
Conventional therapy 1,090 (99.9) 499 (92.1) 84.933 <0.001
Thrombolysis or thrombectomy 1 (0.1) 43 (7.9)
Infarct location, n (%)
Lobar 149 (13.7) 113 (20.8) 530.666 <0.001
Subcortical 543 (49.8) 37 (6.8)
Brainstem 178 (16.3) 5 (0.9)
Cerebellum 20 (1.8) 35 (6.5)
Mixed type 201 (18.4) 352 (64.9)
HT, n (%)
Non-HT 1,091 (100) 0 (0) 1,633.000 <0.001
HI 0 (0) 351 (64.8)
PH 0 (0) 191 (35.2)
Platelet count, 109/L (median, IQR) 209.0 (174.0–249.0) 196.0 (162.0–234.4) −4.124 <0.001
Creatinine, μmol/L (median, IQR) 72.0 (61.0–86.0) 74.0 (62.0–88.0) −1.100 0.271
LDH, U/L (median, IQR) 178.0 (162.0–195.0) 263.0 (216.0–323.3) −25.687 <0.001
LDH >215 U/L, n (%) 124 (11.4) 408 (75.3) 673.384 <0.001
LDL, mmol/L (median, IQR) 2.55 (2.04–3.11) 2.64 (2.17–3.22) −2.505 0.012
PT, s (median, IQR) 13.6 (13.1–14.2) 13.9 (13.3–14.5) −5.393 <0.001
INR (median, IQR) 1.05 (1.01–1.11) 1.07 (1.02–1.14) −4.490 <0.001
PTR (median, IQR) 0.98 (0.93–1.03) 0.97 (0.92–1.02) −2.614 0.009

IQR, interquartile range; HT, hemorrhagic transformation; HI, hemorrhagic infarction; PH, parenchymal
hemorrhage; BMI, body mass index; NIHSS, Institutes of Health Stroke Scale; SBP, systolic blood pressure; DBP,
diastolic blood pressure; TOAST, the trial of ORG 10172 in acute stroke treatment; LDH, lactate dehydrogenase; LDL,
low-density lipoprotein; PT, prothrombin time; INR, international normalized ratio; PTR, prothrombin time ratio.

(corona radiata, corpus callosum, thalamus, basal ganglia, internal
capsule), brainstem (medulla, midbrain, pons), cerebellum, and the
mixed type (comprises at least two of the types mentioned above).
Two neuroimaging physicians retrospectively evaluated MRI or
CT scans. The European cooperative acute stroke study classifica-
tion criteria were used to classify HT, and examples of HT subtypes
(hemorrhagic infarction [HI] and parenchymal hemorrhage [PH])
were given in Figure 2 [24]. When a dispute arose, the third neu-
roimaging physician made the decision.
Statistical Analyses
Continuous data were presented as mean ± standard devia-
tion or median and interquartile range, depending on the data
distribution. The normally distributed continuous variables
were compared with the Student’s t test and one-way analysis of
variance. For non-normally continuous variables, the Mann-
Whitney U test was applied to assess the differences between two
groups, while the Kruskal-Wallis test was for three or more
groups. Categorical variables were represented as frequencies or

574 Gerontology 2023;69:571–580 Chen/Xu/Huang/Wen/Ren

DOI: 10.1159/000528951
Table 2. Comparison of subtypes

Variables Non-HT (n = 1,091) HI (n = 351) PH (n = 191) Statistic p value

Age, years (median, IQR) 72.0 (62.0–78.0) 71.0 (61.0–78.0) 72.0 (64.0–79.0) 1.870 0.393
Gender, n (%)
Male 743 (68.1) 232 (66.1) 139 (72.8) 2.564 0.277
Female 348 (31.9) 119 (33.9) 52 (27.2)
BMI, kg/m2 (median, IQR) 23.5 (22.2–24.8) 23.8 (22.6–24.7) 24.0 (22.9–24.9) 9.197 0.010
Smoking, n (%) 442 (40.5) 138 (39.3) 85 (44.5) 1.438 0.487
Drinking, n (%) 373 (34.2) 121 (34.5) 69 (36.1) 0.270 0.874
Hypertension, n (%) 755 (69.2) 223 (63.5) 119 (62.3) 6.201 0.045
Diabetes, n (%) 331 (30.3) 119 (33.9) 38 (19.9) 11.909 0.003
AF, n (%) 107 (9.8) 140 (39.9) 91 (47.6) 242.055 <0.001
NIHSS (median, IQR) 2.0 (1.0–4.0) 3.0 (1.0–8.0) 6.0 (2.0–9.0) 93.430 <0.001

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SBP, mm Hg (median, IQR) 153.0 (138.0–169.3) 155.0 (139.0–168.0) 154.0 (134.0–167.0) 2.212 0.331
DBP, mm Hg (median, IQR) 84.0 (76.0–92.0) 87.0 (76.0–92.0) 83.0 (74.0–95.0) 1.440 0.487
TOAST, n (%)
Large artery atherosclerosis 543 (49.8) 117 (33.3) 52 (27.2) Fisher <0.001
Cardioembolism 102 (9.3) 125 (35.6) 96 (50.3)
Small vessel occlusion 75 (6.9) 2 (0.6) 0 (0)
Other subtypes 371 (34.0) 107 (30.5) 43 (22.5)
Therapy, n (%)
Conventional therapy 1,090 (99.9) 329 (93.7) 170 (89.0) 95.475 <0.001
Thrombolysis or thrombectomy 1 (0.1) 22 (6.3) 21 (11.0)
Infarct location, n (%)
Lobar 149 (13.7) 80 (22.8) 33 (17.3) 535.246 <0.001
Subcortical 543 (49.8) 27 (7.7) 10 (5.2)
Brainstem 178 (16.3) 3 (0.9) 2 (1.0)
Cerebellum 20 (1.8) 22 (6.3) 13 (6.8)
Mixed type 201 (18.4) 219 (62.4) 133 (69.6)
Platelet count 109/L (median, IQR) 209.0 (174.0–249.0) 201.0 (167.0–235.0) 188.0 (156.0–230.0) 20.348 <0.001
Creatinine, μmol/L (median, IQR) 72.0 (61.0–86.0) 71.0 (61.0–86.0) 76.0 (64.0–88.0) 5.355 0.069
LDH, U/L (median, IQR) 178.0 (162.0–195.0) 258.0 (209.0–311.0) 281.0 (230.0–340.0) 664.270 <0.001
LDH >215 U/L, n (%) 124 (11.4) 255 (72.6) 153 (80.1) 676.514 <0.001
LDL, mmol/L (median, IQR) 2.55 (2.04–3.11) 2.64 (2.14–3.21) 2.6 (2.20–3.25) 6.666 0.036
PT, s (median, IQR) 13.6 (13.1–14.2) 13.8 (13.2–14.4) 14.0 (13.4–14.6) 32.441 <0.001
INR (median, IQR) 1.05 (1.01–1.11) 1.07 (1.02–1.13) 1.08 (1.02–1.15) 22.870 <0.001
PTR (median, IQR) 0.98 (0.93–1.03) 0.96 (0.92–1.01) 0.98 (0.93–1.03) 15.207 <0.001

IQR, interquartile range; HT, hemorrhagic transformation; HI, hemorrhagic infarction; PH, parenchymal hemorrhage; BMI, body mass
index; NIHSS, Institutes of Health Stroke Scale; SBP, systolic blood pressure; DBP, diastolic blood pressure; TOAST, the trial of ORG 10172 in
acute stroke treatment; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; PT, prothrombin time; INR, international normalized
ratio; PTR, prothrombin time ratio.

percentages, and their significance was determined using the χ2
test or Fisher’s exact test. The receiver operating characteristic
(ROC) curve was used to assess the discrimination ability of
LDH level in predicting HT in total patients, patients receiving
conventional therapy, and patients undergoing thrombolysis or
thrombectomy therapy. Multivariate logistic regression analysis
was used to determine the impact of LDH levels contributing to
HT, with the confounders being controlled. The multivariate lo-
gistic regression analysis adjusted confounders with the p < 0.05
in Table 1, including BMI, AF, NIHSS score, TOAST criteria,
infarct location, platelet count, LDL, PT, and INR. Additionally,
age, gender, and hypertension (all p > 0.05) were included in the
regression analysis due to their clinical importance in HT [2, 25,
26]. SPSS version 21.0 and R (version 4.0.3) were used for all
statistical analyses.
Results
Comparisons between HT and Non-HT Patients
As shown in Figure 1, 4,389 patients were screened.
Nine hundred sixty patients were eliminated, and 3,429
patients were initially enrolled in this research. We used

Prediction of Hemorrhagic Gerontology 2023;69:571–580 575

Transformation DOI: 10.1159/000528951
Table 3. Multivariate logistic model of the
clinical determinants of HT Variable OR (95% CI) p value

BMI 1.030 (0.967–1.097) 0.354

Hypertension 0.824 (0.594–1.145) 0.249
AF 1.656 (0.829–3.309) 0.153
NIHSS 1.069 (1.021–1.119) 0.004
TOAST
Large artery atherosclerosis 0.987 (0.683–1.427) 0.944
Cardioembolism 1.109 (0.529–2.324) 0.784
Small vessel occlusion 0.530 (0.119–2.371) 0.406
Other subtypes Reference
Infarct location
Lobar 0.640 (0.434–0.944) 0.024
Subcortical 0.087 (0.056–0.135) <0.001
Brainstem 0.051 (0.019–0.132) <0.001

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Cerebellum 1.806 (0.873–3.736) 0.111
Mixed type Reference
Therapy
Conventional therapy 0.027 (0.003–0.223) 0.001
Thrombolysis or thrombectomy Reference
Platelet count 0.999 (0.996–1.001) 0.302
LDL 1.212 (1.007–1.459) 0.042
PT 2.056 (0.806–5.244) 0.131
INR 0.001 (0.000–7.205) 0.126
PTR 0.739 (0.463–1.178) 0.203
LDH
LDH >215 10.958 (7.964–15.078) <0.001
LDH ≤215 Reference

OR, odds ratio; CI, confidence level; HT, hemorrhagic transformation; BMI, body mass
index; NIHSS, Institutes of Health Stroke Scale; TOAST, the trial of ORG 10172 in acute stroke
treatment; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; PT, prothrombin
time; INR, international normalized ratio; PTR, prothrombin time ratio.

the propensity score matching approach at a ratio of 1:2
to match 1,091 age- and gender-matched AIS patients
without HT to 542 consecutive patients with HT.
Differences in the demographic, clinical, and laboratory
features between HT and non-HT patients are shown in
Table 1. LDH levels were significantly higher in the HT
group than in the non-HT group (263.0 [216.0–323.3] U/L
versus 178.0 [162.0–195.0] U/L, p < 0.001), as shown in
Table 1 and Figure 3a. Patients with a higher BMI, a history
of AF, no history of hypertension, higher NIHSS scores, a
higher percentage of cardioembolism, treatment with
thrombolysis or thrombectomy therapy, a lower platelet
count, a higher LDL, more prolonged PT, a higher INR, and
a lower PTR were more likely to develop HT (all p < 0.05).
In addition, there were differences in infarct location be-
tween the HT and non-HT groups (p < 0.001). However,
these groups had no statistical differences regarding age,
gender, smoking, drinking, diabetes, systolic blood pressure,
diastolic blood pressure, and creatinine level (all p > 0.05).
Comparative Analysis of Subtypes
The subgroup analysis of patients with HT is shown
in Table 2. There were 351 patients with HI (351/542,
64.76%) and 191 patients with PH (191/542, 35.24%). A
significant difference (p < 0.001) was found in LDH lev-
els among the non-HT, HI, and PH groups with the
Kruskal-Wallis test (Table 2), and the LDH level was sig-
nificantly higher in the PH group than in the HI group
after the Bonferroni modification (281.0 [230.0–340.0]
U/L versus 258.0 [209.0–311.0] U/L, p < 0.001) (Fig. 3b).
In addition, there were also differences in BMI, hyper-
tension, AF, NIHSS score, TOAST criteria, therapy, in-
farct location, platelet count, LDL, PT, INR, and PTR
(all p < 0.05).
Associations between LDH and HT
As seen in Figure 4, the area under the ROC curve
(AUC) of LDH in predicting the occurrence of HT in to-
tal AIS patients was 0.890 (95% CI: 0.874–0.905, p <

576 Gerontology 2023;69:571–580 Chen/Xu/Huang/Wen/Ren

DOI: 10.1159/000528951
0.001). With a cut-off value of 215 U/L in total patients,
the prediction of HT was the best: 63.91% accuracy,
88.63% specificity, and 75.28% sensitivity in total pa-
tients. Patients were then classified into high-LDH
(LDH >215 U/L) and low-LDH (≤215 U/L) groups
based on the best ROC cut-off value. As seen in Table 3,
multivariable logistic regression analysis revealed that
those with a high LDH level (LDH >215 U/L) were more
prone to developing HT after adjusting the confounding
variables with p < 0.05 (BMI, hypertension, AF, NIHSS
score, TOAST criteria, therapy, infarct location, platelet
count, LDL, PT, INR, and PTR) (odds ratio [OR] =
10.958, 95% CI: 7.964–15.078, p < 0.001). Furthermore,
the findings remained significant when LDH was added
as a continuous variable in the multivariable logistic re-
gression model (p < 0.001).
Further analysis was conducted on the patients receiv-
ing conventional therapy or thrombolytic and thrombec-
tomy therapy. The results showed that the AUC of LDH
in patients with conventional therapy was 0.888 (95% CI:
0.872–0.904, p < 0.001), and the results of the multivariate
logistic regression analysis were consistent with that in
the total patients (OR = 17.268, 95% CI: 12.054–24.739, p
< 0.001). In patients with thrombolytic or thrombectomy
therapy, there were 43 patients (43/224, 19.20%) with HT
and 181 patients (181/224, 80.80%) without HT. Further
analysis showed that the AUC of LDH in patients with
thrombolysis or thrombectomy therapy was 0.714 (95%
CI: 0.650–0.773, p < 0.001). As seen in online Supple-
mentary Figure 1(for all online suppl. material, see www.
karger.com/doi/10.1159/000528951), the predictive value
of LDH in conventional treatment was much higher than
that in patients with thrombolysis or thrombectomy ther-
apy (AUC: 0.888 vs. 0.714, p < 0.001). While after adjust-
ing for confounding factors in the multivariate logistic
regression analysis, no significant correlation was found
between LDH and HT in patients receiving thrombolysis
or thrombectomy therapy (OR = 2.152, 95% CI: 0.806–
5.745, p = 0.126), which may be owing to the small sample
size of patients with HT (n = 43).
Discussion
To the best of our knowledge, this is one of the few
studies comprehensively evaluating the effects of LDH
levels on HT after AIS. In the current study, we found that
LDH was significantly linked with the occurrence of HT
in patients with AIS, and patients with LDH levels >215
U/L had a higher risk of HT.
Prediction of Hemorrhagic
Transformation
A recent study reported that elevated serum LDH lev-
els could predict unfavorable outcomes following recom-
binant tissue plasminogen activator thrombolysis in pa-
tients with AIS [22]. While no relationship between LDH
and symptomatic HT was found in that study, this dispar-
ity may be attributable to their limited sample size of pa-
tients with symptomatic intracranial hemorrhage (n =
28). This study preliminarily explored and compared the
predictive value of LDH for HT in patients with and
without thrombolytic or thrombectomy therapy. The re-
sults showed that the predictive value of conventional
treatment was much higher than that of thrombolysis or
thrombectomy therapy. However, the sample size of pa-
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tients receiving thrombolytic or thrombectomy therapy
was relatively limited (n = 43), which may limit the cred-
ibility of the results. In the future, we will expand the
sample size to further explore the predictive value of
LDH on HT in patients with thrombolytic or thrombec-
tomy therapy.
LDH, mainly found in the cytoplasm and mitochon-
dria of numerous organs, plays a vital role in different
diseases [8, 12, 27, 28]. LDH releases into the extracellular
space upon tissue injury, resulting in an elevated serum
LDH concentration. Since it reflected cardiomyocyte ne-
crosis, LDH was historically used to diagnose myocardial
infarction [12, 29]. Additionally, LDH is a generic sign of
acute or chronic tissue injury and is considered an in-
flammatory marker [30]. Infection with COVID-19,
chronic obstructive pulmonary disease, acute lung injury,
and pulmonary embolism have been reported to be asso-
ciated with elevated blood LDH levels [30–32]. Previous
research has shown that LDH was not only associated
with activating certain proto-oncogenes but also played a
critical role in the maintenance of tumor invasiveness,
metastatic potential, chemoresistance, and radioresis-
tance [6, 33–35]. Besides, LDH is involved in immuno-
suppression [34, 35]. LDH may be used as a prognostic
marker for immune surveillance, and the aberrant eleva-
tion of LDH was predictive of poor outcomes in cancer
patients [35].
The above research results suggested that serum LDH
has substantial predictive value in various disorders of
other systems. Previous studies revealed that LDH also
played a role in central nervous system diseases [9, 10,
16, 18]. According to a survey based on proteomics anal-
ysis, serum LDH was found to independently predict the
formation of early hematomas in individuals with spon-
taneous intracerebral hemorrhage [10]. Another study
revealed that increased LDH level was statistically asso-
ciated with hematoma expansion [9]. Data from the
Gerontology 2023;69:571–580 577
DOI: 10.1159/000528951
third China National Stroke Registry (CNSR-III), a na-
tionwide prospective registry with 9,796 patients who
submitted to 201 medical institutions in 22 provinces
and four municipalities with AIS or TIA, demonstrated
that an increased LDH level is independently related to
adverse outcomes, including all-cause death and high
modified Rankin Scale scores at 3 months and 1 year in
patients with AIS or TIA [16]. Furthermore, higher se-
rum LDH levels were found in electrocoagulation-in-
duced thrombotic focal ischemic rats receiving an intra-
venous infusion of tissue plasminogen activator 6 h after
ischemia. By modulating LDH and endogenous metabo-
lites, pinocembrin prevents HT after delayed tissue plas-
minogen activator therapy in thromboembolic stroke
rats [18].
As shown in online supplementary Figure 2, there
were various reasonable explanations for the relation-
ship between LDH and HT. First, structurally, research
showed that the breakdown of the blood-brain barrier is
the fundamental mechanism resulting in blood extrava-
sation [36, 37]. The release of LDH by cell disruption
may lead to the destruction of the blood-brain barrier
and the triggering of HT through inflammatory re-
sponse, vasodilation, and oxidative stress. For inflam-
matory response, LDH has been touted as a potential
biomarker for inflammatory loads. Its inhibitors have
anti-inflammatory properties and play a role in oxida-
tive stress cascade, associated with the destruction of the
blood-brain barrier, leading to HT [37–40]. For vasodi-
lation, LDH catalyzes the conversion of glucose to lac-
tate acid, which has been shown to cause vasodilation
via various pathways [41–43]. For oxidative stress, LDH
weakens the integrity of the basal layer and tight endo-
thelial connections through oxidative stress cascades
and may be the trigger of HT [25, 37, 44]. Secondly, after
the occurrence of HT, a series of cascade reactions fur-
ther promote cell necrosis and release more LDH [19,
21, 22]. The above reasons may be the cause of elevated
LDH in HT patients. However, in vitro and in vivo ex-
periments are needed to further clarify the relationship
between LDH and HT in the future.
This research had several limitations. First, this was
a retrospective investigation, and a causal link between
LDH and HT could not be established. Second, since
the patients were from a single institution in China, ad-
ditional confirmation of the findings in other areas is
required. Third, this study only measured the LDH lev-
el once at admission. As LDH levels may fluctuate over
time, it is preferable to test LDH more times during
hospitalization.
578 Gerontology 2023;69:571–580
DOI: 10.1159/000528951
Conclusion
LDH may be a biomarker of HT in individuals with
AIS. HT risk should be noted when AIS individuals show
a high level of LDH (LDH >215 U/L).
Acknowledgments
We express our gratitude to all the patients who participated in
our study. Key Laboratory of Intelligent Treatment and Life Sup-
port for Critical Diseases of Zhejiang Province, Wenzhou 325000,
Zhejiang, People’s Republic of China.
Downloaded from http://karger.com/ger/article-pdf/69/5/571/3949659/000528951.pdf by Univ. of California Davis user on 01 April 2024
Statement of Ethics
This retrospective review of patient data did not require written
informed consent from participants in accordance with local/na-
tional guidelines. The Medical Ethics Committee of the First Affili-
ated Hospital of Wenzhou Medical University authorized this re-
search with the registration number KY2021-R077. The study com-
plied with the guidelines for human studies and was conducted
ethically in accordance with the World Medical Association Decla-
ration of Helsinki.
Conflict of Interest Statement
The authors declare that the research was conducted without
any commercial or financial relationships construed as a potential
conflict of interest.
Funding Sources
The present study was supported by the Zhejiang Provincial
Natural Science Foundation of China (Grant No. LQ22H020003;
to LL.C.) and Wenzhou’s Science and Technology Bureau Project
(Grant No. Y2020934; to LL.C.).
Author Contributions
Wenwei Ren engaged in the conception and design of the re-
search. Lingli Chen, Minjie Xu, and Qiqi Huang gathered the clinical
data. Lingli Chen was in charge of data analysis and paper writing.
Caiyun Wen reviewed and modified the manuscript. All authors
contributed to the article and approved the submitted version.
Data Availability Statement
The raw data supporting the conclusions of this article will be
made available by the authors without undue reservation. Further
inquiries can be directed to the corresponding author.
Chen/Xu/Huang/Wen/Ren
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580 Gerontology 2023;69:571–580 Chen/Xu/Huang/Wen/Ren

DOI: 10.1159/000528951