AIP Conference Proceedings 2193, 040008 (2019); https://doi.org/10.1063/1.5139370 2193, 040008
© 2019 Author(s).
Centella asiatica as a potential plaque stabilizer: Future preventive therapy for cardiovascular disease
Cite as: AIP Conference Proceedings 2193, 040008 (2019); https://doi.org/10.1063/1.5139370 Published Online: 10 December 2019
Nindya P. B. S. Utami, and Siti Farida
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Centella asiatica as a Potential Plaque Stabilizer: Future Preventive Therapy for Cardiovascular Disease
Nindya P. B. S. Utami
1)and Siti Farida
2,a)1Undergraduate Student, Faculty of Medicine, Universitas Indonesia, Jl Salemba Raya No 6, Senen, Central Jakarta 10430 Indonesia
2Department of Medical Pharmacy, Faculty of Medicine, Universitas Indonesia, Jl Salemba Raya No 6, Senen, Central Jakarta 10430 Indonesia
a)Corresponding author: siti.farida@ui.ac.id
Abstract. WHO states that cardiovascular disease (CVD) is the cause of 31% of deaths worldwide, reaching 17.7 million deaths per year. Causes of CVD, including smoking, unbalanced food intake, low physical activity, and excessive alcohol consumption. The common pathophysiology of CVD is the formation of atherosclerotic plaques. It begins with endothelial dysfunction that is closely related to diabetes mellitus (DM). Existing treatment focus on preventing the formation of atherosclerotic plaques by lowering blood cholesterol levels and blood viscosity. It prevents the formation of shear strength that can damage the endothelial layer. Centella asiatica (CA) is a well-known herb used as an oxidative-stress remedy.
Literature review was conducted by searching two journal databases, PubMed and Ebscohost. The search was carried out using Boolean Operator as follows: cardiovascular AND therapy AND "Centella asiatica". Sources are not year-limited and include animal studies, randomized-controlled trial reports or related reviews. Based on the literature review, various studies are linking the protective effect of CA on CVD. Ramachandran et al. conducted an in vivo study by using mice with DM. Lipid profiles of DM mice were given asiatic acid shifted towards normalcy, which reduces the risk of atherosclerotic plaque formation. Cesarone et al. conducted Randomized Controlled Trial (RCT) studies by using the group given CA therapy for 12 months. The study showed an increase in Gray-Scale median (GSM) parameters and an improvement in the texture of atherosclerotic plaques, which showed the formation of a stable with low risk for thrombus.
Luzzi et al. conducted RCT study on high-oxidative stress asymptomatic patients given Pycnogenol and CA extract. It showed an increase in the stability of atherosclerotic plaque as indicated by an increase in plaque density, a decrease in the number and size of plaques. These results indicate the potential of CA as a good preventive cardiovascular therapy.
Keywords: cardiovascular disease, Centella asiatica, prevention
INTRODUCTION
WHO states that cardiovascular disease (CVD) is the cause of 31% of deaths worldwide. Annually, the mortality rate caused by CVD reaches 17.7 million deaths per year, with more than 75% of deaths occur in low-middle income countries. CVD has a broad spectrum of disease, with 85% of all CVD deaths are due to heart attack and strokes.
There are several risk factors of CVD as follows: smoking, unbalanced food intake, low physical activity, and excessive alcohol consumption [1].
The common pathophysiology of CVD is the formation of atherosclerotic plaques. Atherosclerotic plaque formation begins with endothelial dysfunction that is closely related to diabetes mellitus (DM). Endothelial dysfunction leads to deposition of low-density lipoprotein, which later ingested by a local macrophage. Local macrophage which ingested LDL later become foam cells. The continuing process of plaque deposition will lead to a bigger plaque size with an unstable surface. Shear strength, which is formed by blood flow, tends to destroy the surface layer of existing plaque and leads to the formation of thromboembolism. Existing treatment focus on preventing the
formation of atherosclerotic plaques by lowering blood cholesterol levels and blood viscosity. It prevents the formation of shear strength that can damage the endothelial layer [2].
Centella asiatica (CA) is a perennial herb that belongs to Umbellifere/Apiceae family. CA is commonly found in tropical and subtropical areas with altitude reaching 1800 m. CA contains triterpenoids such as asiaticoside and asiatic acid. Both molecules were proven to have several clinical efficacies. Asiaticoside found in CA is proven to stimulate collagen synthesis, angiogenesis, and prevent chronic inflammation in the wound-healing process. In the vein insufficiency case, asiaticoside is proven to stabilize connective tissue through the formation of hyaluronic and chondroitin sulphate [3].
METHODS
A literature review was conducted by searching two journal databases, PubMed and Ebscohost. The search was carried out using Boolean Operator as follows: cardiovascular AND therapy AND "Centella asiatica". Sources are not year-limited and include animal studies, RCT reports, or related reviews. From database searching, authors got 22 articles from PubMed and nine articles Ebscohost. Inclusion criteria for appropriate studies include animal studies, RCT reports or related review. From those articles, authors get seven studies that were appropriate with the objectives of this literature review.
FIGURE 1. A search query for assessing database.
RESULTS AND DISCUSSION
Based on the literature review, the authors get seven studies that are relevant to our objectives. The first study was a study by Belcaro et al. that demonstrated the effect of TFCA in repairing the capillary permeability of venous hypertension patients [4]. The second study was an in vivo study conducted by Ramachandran et al. that showed the profile of mice with DM. Lipid profiles of DM mice that were given asiatic acid shifted towards normalcy. It reduces the risk of atherosclerotic plaque formation [5]. The third study by Incandela et al. showed that the triterpenoid fraction of Centella asiatica (TFCA) was effective in repairing venous wall changes in chronic venous hypertension and protecting venous endothelium [6]. TFCA is the association of three terpenic compounds found in CA: asiaticoside, asiatic acid and et al. acid. TFCA is known to perform this function through connective tissue modulation, improving the synthesis of collagen and protein and stimulate collagen remodeling. In chronic venous hypertension, metabolic alteration of connective tissue was found and resulted in reduced collagen and an elastic component due to an increase in the lysosomal enzyme [6]. TFCA can improve the synthesis of collagen by modulating the metabolism of two amino acid, proline, and alanine which are essential for collagen synthesis and remodeling. By improving the synthesis of collagen and protein, TFCA can modulate fibroblast work on the vein wall. The ability of TFCA in remodeling stimulating collagen is assessed as a possible mechanism of action of TFCA in remodeling echolucent plaques at carotid and femoral bifurcation. Administration of moderate dosage in vitro and in vivo is proven to stimulate the
effect of collagen synthesis, while higher dosage is proven to inhibit the synthesis of collagen and acid mucopolysaccharides [6].
The fourth study was carried out by Cesarone et al. This study used three experimental groups that were given treatment as follows: group A consist of 30 diabetic patients treated with TFCA 60 mg twice daily, group B consist of 10 diabetic patients treated with placebo, and group C consist of 10 diabetic patients treated with antidiabetic treatment only [6]. At the beginning of treatment, baseline characteristics of three experimental groups are not significantly different. The mean duration of diabetes among groups is 11,4 (8-18) years, 10,3 (6-18) years, and 11,1 (6-18) years consecutively for group A (treated 60 mg TFCA, twice daily), B (treated placebo, twice daily), and C (without treatment) [7].
In measuring the performance of the microcirculatory model, five parameters were quantified [7]:
Resting skin flux (RF), performed using laser doppler and classified as microangiopathy with value <1,5 flux units.
Venoarterial response (VAR), performed using laser doppler and classified as microangiopathy with a value < 50%.
Partial pressure of oxygen
Partial pressure of carbon dioxide
Rate of ankle swelling (RAS)
The treatment was given for six months and parameters were measured in the third and sixth months after the administration of therapy. The results of measuring these parameters can be seen in Table 1.
TABLE 1. The microcirculatory parameter after 3 and 6 months of treatment in groups A, B, and C.
Laser Doppler
Output (mV) PCO2 PO2
RAS*
RF VAR (mmHg) (mmHg)
Baseline
Group A 953±215 61±24 40±4 59±5 1.79±0.05
Group B 955±205 63±14 41±5 60±6 1.8±0.09
Group C 942±220 60±6.5 39±6 61±6 1.75±0.05
3 Months
Group A 885±187 204±93 36±1 63±4
Group B 959±204 68±18 41±5 60±5
Group C 955±201 66±16 41±4 59.6±6
6 Months
Group A 855±244 222±190 35±1 65±1 1.59±0.04
Group B 942±221 52±127 39±4 39±4 1.83±0.09
Group C 978±207 71±156 40±5 40±5 1.76±0.1
*RAS (rate of ankle swelling) in mL/min per 100 mL of tissue per minute
Based on these results, it is known that the VAR value in group A dropped significantly (p < 0.05). The reduction of VAR was also assessed based on the percent decrease in resting flow at standing, where the percent ratio decreased at the beginning of therapy, after three months of therapy, and after six months of therapy had the following figures:
6%, 23%, and 25%, respectively. In normal subjects, it is known that VAR will decrease > 30% when standing. The oxygen partial pressure in group A is also known to have a value similar to baseline characteristic, when compared with groups B and C, both of them decrease (p < 0.05). The partial pressure of carbon dioxide is known to have a significant decrease in group A (p < 0.05). Meanwhile, the rate of ankle swelling parameter was known to experience a significant decrease when compared to day 0 until and after six months of receiving TFCA therapy [7].
The fifth study was conducted by Incandela et al. for 12 months of observation. This study aims to study randomized controlled trials with 3 groups, namely group A which contains 50 diabetic patients with neuropathy (28 male; 22 female), group B which contains 50 diabetic patients without neuropathy (30 male; 20 female), and 40 healthy controls belonging to group C (20 male; 20 female). This study has a drop rate low-out and compliance of the study subjects was assessed as being good for the therapy given (95% included patients used > 98% prescribed tablets).
The study was conducted for 12 months by assessing the following parameters at the beginning of the study and at the end of the study: RF, VAR, and RAS. In groups A and B, samples were divided into two subgroups with different treatments. One subgroup was given TFCA therapy 60 mg twice daily and the other subgroup was given a placebo.
Observations for 12 months can be seen in Table 2 [8].
Table 2. Comparison of parameters of RF, VAR, RAS, and Scale line of edema before and after treatment Group
RF VAR RAS Scale line of
Edema-swelling Baseline After 12
Months Baseline After 12
Months Baseline After 12
Months Baseline After 12 Months A TFCA 3.4 (1.1) 2.1 (0.3)* 21 (11-56) 29 (12-66)* 2.5 (0.3) 23 (0.4) 8.4 (3) 4.3 (2)*
Placebo 3.3 (1) 3.2 (0.4) 22 (14-58) 18 (8-44) 2.4 (0.3) 1.8 (0.2)* 8.3 (2) 7.5 (3) B TFCA 2.2 (0.5) 1.7 (0.2)* 31 (18-66) 31 (13-55) 2.1 (0.2) 2.3 (0.4) 7 (2) 4 (2)*
Placebo 2.2(0.6) 2.3 (0.5) 32 (19-58) 38 (12-59)* 2.2 (0.2) 1.9 (0.3)* 7 (2) 6.5 (2) C Healthy
Control
1.2 (0.2) 1.3 (0.2) 46 (33-75) 45 (34-67) 1.8 (0.2) 1.8 (0.1) 8.4 (3) 4.3 (2)*
*different significantly compared to inclusion value (p<0,05) RF : Mean (SD); VAR : Median (Min-Max), RAS : Mean (SD)
From the results shown in Table 2, it can be seen that group A decrease in RF and an increase in VAR parameters after getting 12 months of therapy. While the placebo subgroup showed a significant reduction in RAS, which showed worsening of microvascular function. In the B group, RF parameters were reduced after receiving 12 months therapies, whereas in the placebo subgroup there was a decrease in RAS lead to a decrease of microvascular function [8].
In addition to assessing these three parameters, this study also assessed edema-swelling subjectively by using analog scale lines. The results of the comparison of the analog scale line at the beginning of therapy and after 12 months of therapy can be seen in Table 2. The effect of TFCA in decreasing of oedema may improve the conduction of nerve and the nerve ending.
Cesarone et al. and Luzzi et al. conducted two other Randomized Controlled Trial (RCT) studies. Cesarone et al.
demonstrated that in the group given CA therapy for 12 months, there was an increase in Gray-Scale median (GSM) parameters and an improvement in the texture of atherosclerotic plaques, which showed the formation of a stable with low risk for thrombus [9]. Luzzi et al. conducted the study on high-oxidative stress asymptomatic patients given Pycnogenol and CA extract showed an increase in the stability of atherosclerotic plaque as indicated by an increase in plaque density and decrease in the number and size of plaques [10].
CONCLUSION
These results show that CA increases the stability of the plaque, reduce the size and number of the plaque.
Moreover, CA improve the flux, rate of ankle swelling (RAS), and capillary filtration, improve microcirculation.
These results indicate the potential of Centella asiatica as a good preventive therapy for cardiovascular disease.
ACKNOWLEDGMENTS
The publication funding of the article was supported by the PITTA Grand from Directorate of Research and Community Service, Universitas Indonesia, with the number of contract 2131/UN2.R3.1/HKP.05.00/2018.
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