Introduction
Coronary heart disease (CHD) refers to coronary atherosclerotic heart disease, a chronic inflammatory disease caused by lesions in the inner walls of the coronary arteries, resulting in insufficient blood supply to the heart and causing a series of symptoms and lesions. The main symptoms include angina pectoris, acute myocardial infarction, and arrhythmia, etc. The treatment of CHD is comprehensive, among which, percutaneous coronary intervention (PCI) is a fast and effective treatment to dilate the narrowed arteries and improve the blood supply to the heart. From the earliest days of balloon angioplasty to coronary stent placement and the use of drug-eluting stents (DES), PCI can reduce CHD symptoms and prevent myocardial infarction and other complications.1
Although PCI procedures can reduce CHD symptoms by dilating the artery and placing a stent, the incidence of in-stent restenosis (ISR) and the resulting repeated revascularization is still high.2 The underlying mechanism for the development of ISR is mainly responsible for inflammation triggered by endothelial and vascular injury occurring 6 months after PCI, and the development of neointimal atherosclerosis within the stent by late endothelial hyperplasia.3 The rate of progression of stent atherosclerosis is slow, but organized thrombus may contribute to rapid growth of neointima.4 The average time from PCI to ISR is 12–24 months for DES, which is prone to early development of atherosclerosis and inevitably carries the risk of late stent thrombosis.5,6 As thrombosis can occur symptomatically or asymptomatically, in-stent plaque rupture may be the cause of associated thrombotic events and may be a substrate for ISR.7
Dual antiplatelet therapy (DAPT) with aspirin combined with a P2Y12 inhibitor is standard drug therapy after coronary stenting.8 Several studies have shown that routine postoperative use of DAPT does not completely prevent the occurrence of ISR. Some studies tried to decrease DAPT usage duration to reduce the rate of bleeding, it increased the rate of stent thrombosis;9 and the rate of bleeding events was significantly higher with post-PCI triple therapy. Therefore, even with conventional drug therapy after the procedure, ISR formation may not be completely prevented.10
Radix Salviae decoction (RSD), an herbal formula containing a variety of active ingredients,11 including Radix Salviae, sandalwood, and sand kernel, is known for its ability to activate blood circulation, remove blood stasis, and relieve pain.11 In basic research, the active ingredients of RSD have been shown to have a variety of different mechanisms of action,12 such as anticoagulation, anti-inflammatory, antioxidant,13 endothelial cell protection,14 reduction of mitochondrial depolarization, reduction of pro-apoptosis, and increase of anti-apoptotic proteins,15 thus reducing ischemia-reperfusion injury, vascular endothelial injury, and thrombosis. In clinical studies, several studies have shown that RSD can improve the symptoms of CHD, angina pectoris, and slow arrhythmias in heart disease.16 Through its pharmacological mechanism, it can reduce the risk of myocardial ischemia and myocardial infarction,17 and improve cardiac function and myocardial metabolism, etc.18 In addition, network pharmacology has been increasingly used to explore potential mechanisms of herbs including Radix Salviae.19–21 Our previous study used network pharmacology to find that a total of 33 bioactive compounds from Radix Salviae, including luteolin and Tanshinone IIA, were involved in PI3K-Akt and lipid-atherosclerosis pathways.21
Thus, it is of great significance to reduce the incidence of ISR and decrease repeated revascularization after PCI in the clinic, which is still too frequent with conventional DAPT treatment. Fortunately, both clinical and basic studies of RSD have shown that its components have potential therapeutic effects for CHD. Based on the above analysis of ISR formation mechanism and RSD mechanism of action, it is therefore hypothesized that RSD may be effective in preventing ISR formation. However, there was no solid clinical report investigating the efficacy and safety of RSD in preventing ISR occurrence. Thus, this pilot prospective clinical study was designed to investigate the effectiveness of the RSD herbal formula for preventing coronary stenosis and restenosis in the CHD patients after PCI, in order to provide pioneering clinical evidence for further large-scale multicenter studies.
Methods
Ethical approval and informed consent
This study was carried out in accordance with the recommendations of the 2019 Guidelines for Percutaneous Coronary Intervention in China (Chinese Society of Cardiology). The protocol was approved and registered at the Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (http://183.62.15.51:9081/GZGCP/index.jsp ), with the approval number BF2022-052. All subjects gave written informed consent in accordance with the Declaration of Helsinki. This study is registered at https://www.chictr.org.cn/index.html . The registration identification number is ITMCTR2024000028.
Sample size estimation
According to the literature about the medication effect in preventing ISR occurrence,22 the rate of the experimental group was 0.0364, while the rate of the control group was 0.2640. The two-tailed alpha was 0.05, beta was 0.2, and the sample size ratio of the two groups was set as 1:1. The sample size was calculated as 43 cases in the experimental group and 43 cases in the control group. A total of 86 cases needed to be enrolled.
Patient source
According to the diagnosis, 86 patients were initially enrolled in the group according to the sample size estimation. After screening by inclusion and exclusion criteria, a preliminary selection was made of 60 patients who underwent PCI surgery diagnosed with CHD with TCM syndrome of Qi stagnation and blood stasis, which were included for group allocation. These patients were enrolled at Guangdong Provincial Hospital of Traditional Chinese Medicine between 2020 and December 2021, and were divided into two groups of 30 cases each, a basic medication group for preventing and treating CHD (control group) and RSD Treatment group combined with basic medication (RSD group). The demographic data and underlying diseases (e.g., hypertension, hyperglycemia, hyperlipidemia) were collected as baseline characteristics.
Group treatments
For the control group, basic medication treatment typically includes antiplatelet, lipid-lowering, heart rate control, and controlling high blood pressure or high blood sugar. For the RSD group, RSD granules were taken orally (15 g Radix Salviae, 10 g sandalwood, and 10 g sand kernel, decocted in water and taken twice a day for 5 days). Both groups maintained basic medication after discharge.
Diagnostic criteria
The diagnostic criteria for CHD in patients and the standard for PCI followed the 2019 guidelines for PCI in China.
Inclusion and exclusion criteria
Criteria for inclusion were a diagnosis of CHD that met the criteria for PCI, the ability to complete follow-up, and voluntary participation with the signing of an informed consent form. Criteria for exclusion are abnormal mental consciousness, inability to cooperate, or unstable vital signs, relevant drug contraindications or allergies, or participation in other clinical trials within the past month. Patients over 85 years of age, pregnant, or planning to become pregnant, lactating women, or infants were also excluded.
Criteria for abscission
Firstly, patients who withdrew from the trial without experiencing adverse reactions or poor efficacy. Secondly, Patients lost to follow-up.
Criteria for termination
Firstly, the investigators believed that it was medically necessary to terminate the trial for the participants. Secondly, patients could voluntarily withdraw from the trial. Thirdly, those who experienced severe adverse reactions and could not continue treatment.
Patient follow-up and primary and secondary outcomes
Patients were followed up for 1 year after discharge. The primary outcome was the post-PCI restenosis rate. The secondary outcome was the incidence of newly developed stenosis. All outcomes were monitored for about 1 year after the PCI procedure. Restenosis and newly developed stenosis were detected by angiography or coronary computed tomography.
Safety index and monitoring of adverse reactions
We collected safety indicators related to hematology, including aspartate aminotransferase (referred to as AST), alanine aminotransferase (ALT), creatinine (referred to as Cr), and the international normalized ratio (INR) both before and after treatment. We closely monitored patients for adverse reactions during treatment. Any adverse reactions were observed, addressed if necessary, and promptly recorded.
Statistical analysis
Collected data were analyzed with SPSS (v26.0; IBM Corp., Armonk, NY USA) and R (v3.6.2, http://www.r-project.org ) software. Continuous data were reported as means ± SD and tested for normal distribution using the Kolmogorov-Smirnov test. If the continuous data followed a normal distribution, Student’s t-test for independent samples was used for comparison between the two groups. Otherwise, a Mann-Whitney U test was used. Categorical variables were reported as frequency and proportion (%) and intergroup comparisons were performed with the chi-square test with or without continuity correction or Fisher’s exact test. A p-value < 0.05 was considered statistically significant.
Results
Demographic characteristics of subjects
A total of 60 patients were initially enrolled based on the criteria. Two patients were lost to follow-up and the remaining 58 completed follow-up and were included in the final analysis. No significant differences were observed in demographic characteristics, including sex, age, diagnostic subtype, and comorbidities, between the control group (n = 28) and the RSD group (n = 30) (Table 1).
Table 1Comparison of the baseline characteristics of the study groups
| Variable | Control, n = 28 | RSD, n = 30 | p |
|---|
| Basic inflammation | | | |
| Sex | | | 0.425 |
| Female | 7 (25.0) | 4 (13.3) | |
| Male | 21 (75.0) | 26 (86.7) | |
| Age | 61.2 (11.9) | 61.7 (12.4) | 0.888 |
| Days in hospital | 10.0 (7.00; 11.2) | 7.00 (7.00; 10.0) | 0.055 |
| Diagnosis | | | 0.656 |
| Angina | 22 (78.6) | 21 (70.0) | |
| MI | 6 (21.4) | 9 (30.0) | |
| Comorbidity | | | |
| Hypertension | 20 (71.4) | 16 (53.3) | 0.251 |
| DM | 10 (35.7) | 14 (46.7) | 0.562 |
| Hyperlipidemia | 14 (50.0) | 21 (70.0) | 0.198 |
| Comorbidities, n | | | 0.663 |
| 0 | 6 (21.4) | 3 (10.0) | |
| 1 | 9 (32.1) | 11 (36.7) | |
| 2 | 8 (28.6) | 8 (26.7) | |
| 3 | 5 (17.9) | 8 (26.7) | |
Baseline vessel stenosis characteristics before PCI
Before examining the effect of RSD, we compared the baseline characteristics of vessel stenosis between the control group and the RSD group prior to PCI. The location of vessel stenosis was divided into proximal, mid, and distal, and no significant differences in stenotic vessel characteristics were observed between the two groups (p > 0.05). The degree of stenosis was also calculated as a percentage of occlusion area, and differentiation was made based on whether the occlusion was complete or not. No significant differences were found between the two groups (p > 0.05). When comparing the number of vessels in a narrow state before PCI, no statistically significant differences were found (p > 0.05). (Table 2).
Table 2Characteristics of stenotic vessels in the study groups
| Variable | Control, n = 28 | RSD, n = 30 | p |
|---|
| Location of stenosis |
| LAD | | | 0.266 |
| none | 1 (3.57) | 3 (10.0) | |
| proximal | 12 (42.9) | 9 (30.0) | |
| middle | 13 (46.4) | 18 (600) | |
| distant | 2 (7.14) | 0 (0.00) | |
| LCX | | | 0.501 |
| none | 6 (21.4) | 8 (26.7) | |
| proximal | 7 (25.0) | 7 (23.3) | |
| middle | 9 (32.1) | 5 (16.7) | |
| distant | 6 (21.4) | 10 (33.3) | |
| RCA | | | 0.221 |
| none | 3 (10.7) | 3 (10.0) | |
| proximal | 11 (39.3) | 5 (16.7) | |
| middle | 10 (35.7) | 13 (43.3) | |
| distant | 4 (14.3) | 9 (30.0) | |
| Vessels in stenosis in % | | | |
| LAD | 90.0 (77.5; 95.0) | 85.0 (58.8; 90.0) | 0.349 |
| LCX | 80.0 (50.0; 90.0) | 67.5 (7.50; 98.8) | 0.771 |
| RCA | 85.0 (63.8; 91.2) | 82.5 (52.5; 95.0) | 0.969 |
| Total occlusion | 17 (60.7) | 14 (46.7) | 0.419 |
| Stenotic vessels, n | | | 0.809 |
| 0 | 1 (3.57) | 1 (3.33) | |
| 1 | 3 (10.7) | 3 (10.0) | |
| 2 | 3 (10.7) | 6 (20.0) | |
| 3 | 21 (75.0) | 20 (66.7) | |
Characteristics of implanted stent features during PCI
The characteristics of stents implanted during PCI were compared as they could affect the prognosis of future restenosis. No significant statistical differences were found between the two groups (p > 0.05) in stent diameter, length, or the number of stents implanted during PCI (Table 3). These results suggest that the baseline characteristics of the control group and RSD group in terms of vascular stenosis and stent characteristics implanted during PCI were similar, and when combined with the demographic characteristics of the subjects, indicate that the baseline of these two groups was comparable.
Table 3Characteristics of stents placed in stenotic vessels in the study groups
| Variable | Control, n = 28 | RSD, n = 30 | p |
|---|
| Stent diameter in mm | | | |
| LAD | 1.31 (0.00; 3.00) | 0.00 (0.00; 2.87) | 0.794 |
| LCX | 0.00 (0.00; 0.00) | 0.00 (0.00; 0.00) | 0.708 |
| RCA | 0.00 (0.00; 3.31) | 0.00 (0.00; 2.72) | 0.246 |
| Stent length in mm | | | |
| LAD | 9.00 (0.00; 32.6) | 0.00 (0.00; 23.8) | 0.264 |
| LCX | 0.00 (0.00; 0.00) | 0.00 (0.00; 0.00) | 0.575 |
| RCA | 0.00 (0.00; 28.0) | 0.00 (0.00; 29.5) | 0.750 |
| Stents, n | | | 0.684 |
| 1 | 15 (53.6) | 18 (60.0) | |
| 2 | 12 (42.9) | 10 (33.3) | |
| 3 | 1 (3.57) | 2 (6.67) | |
Effects of RSD on restenosis in culprit vessels after PCI
Restenosis severity was assessed by dividing the degree of stenosis into less than or more than 50% of the arterial lumen area, and calculating the number of restenosis cases for each vessel. The left circumflex artery (LCX) had the lowest severity of restenosis. Statistical analysis revealed no significant difference in restenosis percentage between the control group and the RSD group for all three arteries (p > 0.05). Further statistical analysis of restenosis types for each vessel also showed similar results, with no significant difference found between the two groups for any individual artery (p > 0.05). A comparison of the number of restenotic vessels did not show statistical significance (p > 0.05) (Table 4). These data suggest that RSD did not show any significant effect on improving post-PCI restenosis.
Table 4Characteristics of vessels in restenosis after PCI in the study groups
| Variable | Control, n = 28 | RSD, n = 30 | p |
|---|
| Restenosis, % | | | |
| LAD | 0.00 (0.00 ;0.00) | 0.00 (0.00; 0.00) | 0.301 |
| LCX | 0.00 (0.00; 0.00) | 0.00 (0.00; 0.00) | - |
| RCA | 0.00 (0.00; 0.00) | 0.00 (0.00; 0.00) | 0.122 |
| Vessels in restenosis, n | | | 0.707 |
| 0 | 26 (92.9) | 25 (83.3) | |
| 1 | 2 (7.14) | 5 (16.7) | |
| Restenosis type | | | |
| LAD | | | 0.483 |
| 0 | 27 (96.4) | 30 (100) | |
| 3 | 1 (3.57) | 0 (0.00) | |
| LCX | | | – |
| 0 | 28 (100) | 30 (100) | |
| RCA | | | 0.096 |
| 0 | 27 (96.4) | 25 (83.3) | |
| 1 | 0 (0.00) | 4 (13.3) | |
| 2 | 0 (0.00) | 1 (3.33) | |
| 4 | 1 (3.57) | 0 (0.00) | |
Effects of RSD on neostenosis in nonculprit vessels after PCI
As RSD did not significantly affect restenosis, we investigated the impact of RSD on newly developed stenosis after PCI, which we refer to as new stenosis. We compared this with the baseline and post-PCI stenosis of the blood vessels. The results showed that there was no significant difference in the percentage of new stenosis between the control group and the RSD group in these three arteries (p > 0.05). We also calculated the number of nonprimary vessel stenoses that increased after PCI, and found no significant difference between the control group and the RSD group (p > 0.05) (Table 5). These data suggest that RSD therapy did not reduce the incidence of new stenosis in nonprimary vessels following PCI.
Table 5Comparison of the number of vessels in neostenosis after PCI in the study groups
| Variable | Control, n = 28 | RSD, n = 30 | p |
|---|
| Neostenosis, % | | | |
| LAD | 0.00 (0.00; 0.00) | 0.00 (0.00; 0.00) | 0.446 |
| LCX | 0.00 (0.00; 0.00) | 0.00 (0.00; 0.00) | 0.676 |
| RCA | 0.00 (0.00; 0.00) | 0.00 (0.00; 7.50) | 0.469 |
| Vessels in neostenosis, n | | | 0.400 |
| 0 | 17 (60.7) | 13 (43.3) | |
| 1 | 8 (28.6) | 11 (36.7) | |
| 2 | 3 (10.7) | 6 (20.0) | |
Multifactor logistic regression analysis for ISR or neostenosis incidence
As differences of the RSD treatment-associated reduction in ISR or neostenosis incidence after PCI were not significant, we analyzed the factors that may have affected the occurrence of ISR or neostenosis. Although multifactor logistic regression analysis of the ISR incidence did not find any significantly associated factors (Table 6), the diagnosis of MI/angina (p = 0.031), average stent length (p = 0.010) and ALT (p = 0.027) were found to be significantly associated with neostenosis occurrence (Table 7).
Table 6Multifactor logistic regression analysis of ISR occurrence
| Variable | B | SE | Wals | p | Exp (B) |
|---|
| Sex | −478.535 | 34,037.470 | 0.000 | 0.989 | 0.000 |
| Age | 13.437 | 947.063 | 0.000 | 0.989 | 6.850E+5 |
| Days in hospital | −5.477 | 5,584.037 | 0.000 | 0.999 | 0.004 |
| MI/angina | 121.665 | 100,330.728 | 0.000 | 0.999 | 6.893E+52 |
| Hypertension | −39.138 | 5,474.732 | 0.000 | 0.994 | 0.000 |
| DM | 81.574 | 85,987.229 | 0.000 | 0.999 | 2.673E+35 |
| Hyperlipidemia | −14.845 | 125,004.392 | 0.000 | 1.000 | 0.000 |
| AST | 0.852 | 355.185 | 0.000 | 0.998 | 2.343 |
| ALT | 0.043 | 742.722 | 0.000 | 1.000 | 1.044 |
| Cr | −3.551 | 2,408.717 | 0.000 | 0.999 | 0.029 |
| INR | −643.202 | 33,927.690 | 0.000 | 0.985 | 0.000 |
| Vessels in stenosis, # | −25.3 | 24,559.627 | 0.000 | 0.999 | 0.000 |
| Average stent diameter | −41.076 | 27,394.159 | 0.000 | 0.999 | 0.000 |
| Average stent length | −53.152 | 1,960.253 | 0.001 | 0.978 | 0.000 |
| Stent, # | 264.242 | 11,905.468 | 0.000 | 0.982 | 5.736E+114 |
Table 7Multifactor logistic regression analysis of neostenosis occurrence
| Variable | B | SE | Wals | p | Exp (B) |
|---|
| Sex | 0.255 | 0.992 | 0.066 | 0.797 | 1.290 |
| Age | 0.054 | 0.039 | 1.839 | 0.175 | 1.055 |
| Days in hospital | −0.007 | 0.100 | 0.005 | 0.941 | 0.993 |
| MI/angina | 4.021 | 1.864 | 4.652 | 0.031* | 55.760 |
| Hypertension | −0.257 | 0.837 | 0.094 | 0.759 | 0.773 |
| DM | −0.921 | 0.952 | 0.936 | 0.333 | 0.398 |
| Hyperlipidemia | 0.407 | 0.900 | 0.205 | 0.651 | 1.503 |
| AST | 0.006 | 0.010 | 0.339 | 0.561 | 1.006 |
| ALT | 0.071 | 0.032 | 4.866 | 0.027* | 1.073 |
| Cr | 0.007 | 0.012 | 0.402 | 0.526 | 1.007 |
| INR | 0.379 | 2.069 | 0.034 | 0.855 | 1.461 |
| Stenotic vessels, n | 0.323 | 0.544 | 0.353 | 0.552 | 1.381 |
| Average stent diameter | −1.965 | 1.949 | 1.016 | 0.313 | 0.140 |
| Average stent length | 0.528 | 0.205 | 6.653 | 0.010* | 1.695 |
| Stent, # | −0.380 | 0.771 | 0.243 | 0.622 | 0.684 |
Between-group comparison of common clinical indicators
To evaluate the efficacy of treatment to common clinical indicators that were closely related to CHD and ISR occurrence, we compared the indicators before and after treatment in the two groups, including body weight, systolic/diastolic blood pressure (SBP/DBP), low-density lipoprotein (LDL)-cholesterol, and hemoglobin A1c (HbA1c). The results showed there were no significant changes in these indicators in the two groups either before or after treatment (p > 0.05) (Table 8).
Table 8Comparison of the clinical indicators common to the study groups
| Variable | Control, n = 28 | RSD, n = 30 | p |
|---|
| Weight in kg | | | |
| Before treatment | 68.9 (14.8) | 71.0 (10.3) | 0.580 |
| After treatment | 68.5 (13.4) | 70.4 (12.6) | 0.605 |
| SBP in mmHg | | | |
| Before treatment | 137 (18.4) | 129 (15.3) | 0.090 |
| After treatment | 135 (19.9) | 131 (17.1) | 0.463 |
| DBP in mmHg | | | |
| Before treatment | 79.0 (75.5; 90.5) | 75.5 (72.2; 80.0) | 0.087 |
| After treatment | 79.0 (71.5; 91.5) | 80.0 (73.5; 84.8) | 0.801 |
| LDL in mmol/L | | | |
| Before treatment | 2.98 (1.07) | 2.91 (1.14) | 0.821 |
| After treatment | 1.93 (1.66; 2.17) | 1.98 (1.42; 2.39) | 0.892 |
| HbA1c, % | | | |
| Before treatment | 6.10 (5.90; 7.60) | 6.20 (5.73; 6.80) | 0.248 |
| After treatment | 6.20 (5.93; 7.30) | 6.00 (5.90; 6.90) | 0.477 |
Safety index in hematology
To assess the safety of renal sympathetic denervation for the treatment of coronary artery stenosis and restenosis, we measured hematological parameters such as AST, ALT, Cr, and INR to evaluate liver and kidney function and coagulation. Comparison of these hematological parameters before and after treatment did not reveal any significant differences between the control group and the RSD group (p > 0.05) (Table 9), indicating that RSD had a good safety profile in clinical treatment.
Table 9Comparison of the hematological indicators in the study groups
| Variable | Control, n = 28 | RSD, n = 30 | p |
|---|
| Before treatment | | | |
| AST | 19.9 (16.8; 27.3) | 24.6 (18.2; 42.7) | 0.075 |
| ALT | 16.9 (12.8; 27.2) | 27.5 (16.3; 45.1) | 0.083 |
| Cr | 77.2 (72.2; 90.7) | 81.2 (66.0; 95.4) | 0.791 |
| INR | 0.98 (0.95; 1.03) | 0.94 (0.90; 1.00) | 0.117 |
| After treatment | | | |
| AST | 17.2 (15.2; 25.9) | 20.0 (15.7; 23.4) | 0.570 |
| ALT | 19.7 (13.3; 31.0) | 20.5 (13.9; 32.6) | 0.779 |
| Cr | 79.5 (73.9; 93.1) | 81.3 (72.2; 93.0) | 0.870 |
| INR | 0.92 (0.91; 0.95) | 0.94 (0.90; 0.97) | 0.737 |
Adverse reactions
In clinical treatment, there were no observed adverse reactions or serious adverse reactions associated with RSD in either the control group or the RSD group. Together with the hematological indicators, these results indicate that RSD was safe for the treatment of CHD.
Discussion
This clinical study aimed to investigate the impact of RSD on coronary stenosis and restenosis, however, our data did not show significant benefits of RSD in preventing the occurrence of restenosis and neostenosis. Many factors can promote the formation of ISR, such as inflammatory state, platelet aggregation, vessel wall damage, thrombosis, and increased cholesterol absorption.22 Stent placement and the number and type of stents implanted can cause mechanical damage.23 Loss or abnormality of endothelial functional integrity can stimulate an inflammatory response in the artery, causing intimal hyperplasia, stenosis, and sclerosis. Drug treatment to prevent restenosis is a common intervention after percutaneous stenting procedures. These medications include antiplatelet agents,24 anticoagulants, anti-inflammatory,25 and antioxidants. However, the continuation of conventional drug therapy after PCI for CHD still cannot completely prevent the formation of ISR for several possible reasons. First, there is a wide variation in the body composition of different individuals who are resistant to conventional drugs,24 and the increase in drug resistance may increase the risk of thrombotic complications after PCI.26 Secondly, patient lifestyle (e.g., smoking) and medication compliance,27 as well as disease comorbidities (e.g., hypertension, diabetes, anemia,28 etc.) may increase the possibility of ISR formation. In addition, stent type, low stent implantation pressure, and multiple stent placement are strongly associated with ISR in patients after PCI.29 One study found that longer stent length and smaller stent diameter are likely it is to increase the incidence of ISR 8–12 months after PCI.29
Studies have shown that RSD is an important prescription for the treatment of cardiovascular diseases. The main mechanisms of action include anticoagulation, anti-inflammation, antioxidation, protection of endothelial cells, reduction of mitochondrial depolarization, reduction of pro-apoptosis and increase of anti-apoptotic proteins, which protect blood vessels, reduce thrombosis, prevent myocardial hypoxia-induced injury and myocardial infarction. Many studies have confirmed that RSD interferes with signaling pathways related to atherosclerosis through various pathways to achieve therapeutic effects.30,31 A network pharmacology analysis showed that RSD has 67 potential active ingredients and 109 therapeutic targets in the treatment of ischemic cardiomyopathy (ICM).21 Another network pharmacology and experimental analysis suggested that RSD had anti-atherosclerotic and endothelial-to-mesenchymal transition activity via the LASP1/PI3K/AKT pathway, providing a possible therapeutic intervention for atherosclerosis.30 RSD mediated therapeutic effects by modulating atherosclerosis-related biological processes and signaling pathways.31 In addition, the monarch Salviae protects the heart from ischemia and reperfusion injury.32 For example, Tanshinone IIA,33 the main lipid-soluble component of Radix Salviae,34 has anti-inflammatory and antioxidant activities. Both the ethanolic extract of Salviae and the aqueous extract of Salviae have blood nourishing and tonic properties. Some clinical studies have also shown that RSD improved the symptoms of CHD, angina pectoris, and slow arrhythmias in cardiac disease. Through its pharmacological mechanism, it reduces the risk of myocardial ischemia and myocardial infarction, and improves cardiac function and myocardial metabolism, etc. RSD is also widely used in the treatment of hypertension, hyperlipidemia, and other diseases.35 The underlying mechanism of ISR development is inflammation triggered by endothelial and vascular injury occurring 6 months after PCI and the appearance of atherosclerosis within the stent in late endothelial hyperplasia. Based on the mechanism of action of RSD and the underlying mechanism of ISR formation, as well as previous relevant basic and clinical studies, we suggest that RSD may prevent the formation of ISR.
Normally, conventional secondary preventive therapy drugs for CHD including DAPT are used to prevent ISR. For the treatment of ISR, the most used intervention is PCI, including cutting balloons, drug-eluting balloons, DES, and excimer laser coronary atherectomy. Some pioneering studies on the preventive medication to ISR showed that thiazolidinedione (TZD) treatment for 6 to 18 months significantly reduced the incidence of ISR, target lesion revascularization, and major adverse cardiovascular events in patients after PCI, and Pioglitazone treatment seems to have more beneficial effects than Rosiglitazone.36 Nevertheless, few studies have shown the efficacy and safety of herbal medicines in preventing ISR incidence. Our data in another study found that RSD combined with remote ischemic preconditioning did not significantly affect angina attack and prognosis of CHD, but decreased the frequency of emergency medications in CHD patients, indicating a therapeutic effect of RSD in CHD. Herein, our data in this study also partially indicate a therapeutic trend of RSD in preventing ISR incidence, although we did not observe the statistical significance. This pilot study will help to design further studies in investigating RSD effects to stenosis in the future.
Multifactor logistic regression analysis was used to further screen the factors that might affect ISR or neostenosis incidence. Although multifactor logistic regression analysis for the ISR incidence did not find significantly associated factors, the diagnosis of MI/angina, average stent length, and ALT level was found to be significantly associated with neostenosis occurrence. These data were consistent with previous reports that the patient, stent, and lesion-related predictors were particularly important for predicting stenosis after PCI.37–39
Limitations
The results observed in this pilot study have some limitations. Firstly, the sample size was relatively small, the number of finally enrolled subjects was limited, and it was influenced by individual differences. There is a possibility of sampling bias compared with the overall population, and the trial design needs to be improved. Secondly, the duration of RSD administration in the test group of this study was relatively short. Further study with a longer dosing time is planned to investigate and confirm the clinical efficacy of RSD for ISR prevention. Thirdly, the integrated target effects of the active ingredients of RSD may be different for systemic and local effects, which needs to be improved by researchers in basic experiments and clinical trials.
Future perspectives
The negative result in ISR occurrence in this study may have been associated with the relatively small sample size and short duration of RSD administration. Studies with more patients and prolonged RSD duration will be performed to investigate the RSD effects in regulating stenosis after PCI.
Conclusions
This study was designed to test the additional efficacy of RSD plus conventional treatment for coronary artery restenosis and neostenosis, compared with the conventional treatment given to the control group. Our data showed that although the addition of RSD for a short period did not significantly change restenosis and neostenosis occurrence after PCI, the diagnosis of MI/angina, average stent length, and ALT levels were significantly associated with neostenosis occurrence. This pilot study will provide preliminary evidence for designing further studies to investigate RSD effects to stenosis in the future.
Abbreviations
- AST:
alanine transaminase
- ALT:
alanine transaminase
- CHD:
coronary heart disease
- Cr:
creatinine
- DAPT:
dual antiplatelet therapy
- DES:
drug-eluting stents
- DM:
diabetes mellitus
- ICM:
ischemic cardiomyopathy
- INR:
international normalized ratio
- ISR:
in-stent restenosis
- LAD:
left anterior descending coronary artery
- LCX:
left circumflex coronary artery
- MI:
myocardial infarction
- NA:
neointimal atherosclerosis
- PCI:
percutaneous coronary intervention
- RCA:
right coronary artery
- RSD:
Radix Salviae decoction
Declarations
Ethical statement
This study was carried out in accordance with the recommendations of the 2019 Guidelines for Percutaneous Coronary Intervention in China (Chinese Society of Cardiology). The protocol was approved and registered at the Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (http://183.62.15.51:9081/GZGCP/index.jsp), with the approval registration number BF2022-052. All subjects gave written informed consent in accordance with the Declaration of Helsinki. This study is registered at https://www.chictr.org.cn/index.html. The registration identification number is ITMCTR2024000028.
Data sharing statement
No additional data are available.
Funding
This study was supported by Special Funding for TCM Science and Technology Research of Guangdong Provincial Hospital of Chinese Medicine (No. YN2020QN10, to QL), Zhuhai Medical Science and Technology Research Fund Project (No. ZH24013310210002PWC, to QL), Municipal School (College) Joint Funding Project of Guangzhou Science and Technology Bureau (No. 2060206, to QL), National Natural Science Foundation of China (No. 82274279, to QL), and Guangdong Provincial Bureau of Traditional Chinese Medicine Fund Project (No. 20221360, to QL).
Conflict of interest
The authors declared that there is no conflict of interests in the authorship and publication of this contribution.
Authors’ contributions
Designed the study and finalized the manuscript (QL), collected patient information and constructed the dataset (PZL, PCD, QQL), completed the first version of the manuscript (RYY, QL), finished the manuscript corrections (QL, DWW), and finished the manuscript revisions (QL, AMZ). All authors read and approved the final manuscript