Collection of Atherosclerosis research papers: A comprehensive systematic review paper on Endothelial Dysfunction mechanisms and treatments.

Atherosclerosis research paper collection:

A comprehensive systematic review paper on Endothelial Dysfunction mechanisms and treatments

Abstract:

Background: Endothelial dysfunction is the earliest detectable stage of atherosclerosis, characterized by impaired nitric oxide (NO) bioavailability, increased LDL permeability in endothelial cells, inflammation, and pathophysiologic effects on endothelial cells, making way for the following stages of atherosclerosis. It plays a critical role in the initiation and progression of cardiovascular disease.

Objective: This review systematically evaluates the pathophysiological mechanisms underlying endothelial dysfunction and explores known pharmacological interventions aimed at restoring endothelial function.

Methods: A systematic review of existing literature was conducted following PRISMA guidelines. Studies investigating endothelial dysfunction and its unique inhibition of mechanisms. Statins, ACE inhibitors and Calcium channel blockers were investigated in clinical and experimental studies with their accordance of biological mechanisms in endothelial dysfunction.

Results: Statins have demonstrated significant benefits in improving endothelial function beyond lipid-lowering effects, primarily through increased NO production and reduced oxidative stress. ACE inhibitors mitigate endothelial dysfunction by lowering blood pressure and allowing for vasodilation. Calcium channel blockers show clinical significance by allowing relaxation of endothelial cells and VSMCs. Emerging treatments such as NO donors and endothelial progenitor cell-based therapies present promising avenues for intervention.

Conclusion: Endothelial dysfunction serves as a critical target for early cardiovascular intervention. Current pharmacological therapies, particularly statins, ACE inhibitors, and calcium channel blockers show efficacy in improving endothelial health, but limitations exist in long-term clinical outcomes. Further research can find specific treatments for each symptom of endothelial dysfunction rather than generalized atherosclerotic treatments.

Introduction on Endothelial dysfunction:

Atherosclerosis, otherwise known as arteriosclerosis is defined as the buildup of plaque made out of fats, cholesterol and other substances in and on the artery walls [1]. This accumulation of plaque restricts blood flow (ischemia) over time which can lead to a myocardial infarction (heart attack). Additionally, this buildup of plaque can lead to a blood clot or thrombosis when ruptured. Atherosclerosis is not specific to only the heart, however subdivides into several other diseases including Coronary Artery Disease (CAD/ CHD) which is the most common form of atherosclerosis, in summary, atherosclerosis serves as an underlying cause of several more specific cardiovascular diseases. Although specific data on atherosclerosis is limited, the effect of atherosclerosis is seen in broader cardiovascular data collections. For instance, in 2022, heart disease remained the leading cause of death in the United States, accounting for 702,880 deaths. In this number, CHD (Coronary heart disease) caused 371,506 deaths in 2022, CHD remains the most common form of heart disease and atherosclerosis [2]. Around every 40 seconds, someone in the US experiences a myocardial infarction which stems from a form of atherosclerosis called CAD [2]. Atherosclerosis is divided into 4 major stages including endothelial dysfunction, lipoprotein accumulation, oxidative stress, and arterial calcification. [4], [5], [6], [7]. This research paper will focus solely on endothelial dysfunction and its role in atherosclerosis. The complex interplay of endothelial dysfunction as well as discussion for treatments, inhibition and the potential for future studies will be discussed in this paper. Understanding the mechanisms attributed to each stage of atherosclerosis is necessary to pioneer a new treatment or inhibition method. A systematic review of endothelial dysfunction is necessary to evaluate known treatments for atherosclerosis and CAD in general by dividing atherosclerosis into 4 stages and assessing the most effective pharmaceutical treatments for atherosclerosis to develop a foundation where future treatments with the help of technology will come with ease. Finally, the objective of this systematic review is to analyze how modern pharmacological strategies target key mechanisms in endothelial dysfunction progression.

Materials and Methods:

This study evaluated published clinical data from databases such as PubMed, Google Scholar, ClinicalTrials.gov to examine published peer-review studies and human clinical trials to assess the biomechanical effects of known treatments for endothelial dysfunction. It also adhered to the standards outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [8].

3.1: Literature Search Strategy

A comprehensive search strategy was implemented to find accredited sources such as CDC, WHO, and other electronic databases such as PubMed, Google Scholar, ClinicalTrials.gov were used to isolate potential clinical trials and/ or experimental trials of a given pharmaceutical treatment. Free-text keywords related to "endothelial dysfunction treatments," "statins," "ACE inhibitors," and "calcium channel blockers".

The mechanism of action of each treatment was also researched with its biological effect on endothelial dysfunction.

3.2: Study Selection Criteria

The selection process was conducted in accordance with the PRISMA guidelines. Independent reviewers screened titles and abstracts to identify viability of articles in accordance with the. The full texts of the selected articles were independently evaluated by the same reviewer to determine their eligibility for inclusion in the meta-analysis or experimental research of a large sample size.

The inclusion criteria were as follows: Study types including; (1) Clinical trials (randomized controlled trials, cohort studies), (2) Systematic reviews & meta-analyses, (3) In-vitro or mechanistic studies with direct relevance to human atherosclerosis. Publication dating as followed; 2005–2025 (Ensure the study reflects current pharmaceutical strategies). Population specifics including; (4) Studies involving human participants diagnosed with atherosclerosis or at high cardiovascular risk, (5) Studies that explore age-related differences in treatment responses. Interventions which analyzed pharmaceutical interventions targeting endothelial dysfunction (4.1)

The exclusion criteria were as follows: (1) Animal studies; Unless they provide direct translational relevance to human pathophysiology. (2) In-vitro studies without human application; Studies focusing purely on cell cultures or animal models without clear clinical implications. (3) Case Reports, Opinion Pieces, or Editorials. (4) Studies with small sample sizes (<100 participants), unless the study is incredibly novel and pinpoints the mechanism of action of the pharmaceutical treatment. Interventions including: (1) Surgical or interventional procedures (e.g., stenting, bypass surgery), (2) Alternative or herbal medicine studies without clinical validation and rigorous human clinical trials, (3) Studies published before 2005 and studies not in English.

3.3: Data Extraction & Analysis

A data extraction method was used to collect relevant information from selected papers and studies. An independent reviewer extracted data including relevance of the abstract, sample Size (Age, Gender, Comorbidities, Inclusion/Exclusion Criteria), treatment used (Drug Name, Dosage, Duration, Mechanism of Action), Atherosclerosis Stage Targeted (Endothelial Dysfunction, Lipoprotein Transport, Oxidative Stress, Calcification), outcome measures (Primary ones including LDL-C Reduction, Inflammatory Markers (CRP, IL-1β), Arterial Plaque Reduction and secondary ones including Cardiovascular Events, Adverse Effects, Mortality Reduction). This data was put through a PRISMA flowchart [8] for study selection and it was synthesized to identify patterns, trends, and gaps in the current literature. The studies were assessed through qualitative (comparisons in treatment effectiveness) and quantitative measures (treatment trend and analysis).

Pathophysiology of Endothelial dysfunction (ED) & Targeted Treatments

4.1 Endothelial Dysfunction & Early-Stage Interventions

Endothelial dysfunction and plaque formation are the initial biological mechanisms of atherosclerosis and atherosclerotic plaque development. Before getting into the specifics of endothelial dysfunction, it is crucial to understand what endothelial cells are and their role in the human body. Endothelial cells (ECs) regulate several key processes such as including vascular tone, wound healing, reactive oxygen species, shear stress response, and inflammation [10]. In addition to EC dysfunction, early atherosclerosis is characterized by early fatty streak development, and it begins as early as childhood, during which time low-density lipoprotein (LDL) cholesterol particles accumulate in the arterial intima [10], however this section is exclusive to understanding how endothelial dysfunction sets the platform for later atherosclerotic pathways. Abnormalities in the peptides such as nitric oxide, endothelin-1, and prostacyclin were detected in early onset EC dysfunction [10].

Pathophysiology of Endothelial dysfunction:

The primary pathophysiologic effects attributed to endothelial dysfunction are reduced vasodilation, a proinflammatory state, and prothrombotic properties [10], [11]. In addition, reduced vasodilatory responses are most seen in endothelial dysfunction arising due to reduced nitric oxide generation, oxidative excess, and reduced production of hyperpolarizing factor [11].

Endothelial cells regulate vascular tone [12]:

ECs regulate vascular tone through nitric oxide (NO), prostacyclin (PGI2) and endothelium derived hyperpolarizing factor (EDHF) or vasoconstrictive factors such as thromboxane (TXA2) and endothelin-1 (ET-1).

NO is formed through nitric oxide synthase (NOS). NO has three isoforms including nNOS (NO is used as a neuronal messenger that regulates synaptic neurotransmitter release, iNOS (activates macrophages, guiding them to an area of injury), eNOS (which produces nitric oxide in the vasculature)

Prostacyclin and Thromboxane A2 play a role in endothelial dysfunction, their production is done via COX-1 and COX-2, COX 1 is normally expressed in endothelial cells, however COX-2 is expressed only during endothelial injury or expressed due to proinflammatory cytokines released by lymphocytes like macrophages due to the activation of iNOS. It is essential to note that when NO is reduced, prostacyclin (PGl2) plays a role in vasodilation. However, once Thromboxane A2 is formed (TxA2), TxA2 binds to thromboxane-proteinoid (TP) receptors, causing platelet aggregation. In addition to platelet aggregation, TxA2 upregulates the levels of Calcium (Ca2+) levels on smooth muscle and ECs leading to vasoconstriction.

Endothelin-1 is a vasoconstrictor which is expressed in the body in three isoforms, ET-1, ET-2, and ET-3, however endothelial cells only release ET-1. ET-1 also plays along with reduced NO and reduced PGl2 during endothelial dysfunction. In terms of inflammation, ET-1, when bonded to its ET-a receptors, activates macrophages, increases neutrophil-vessel wall interactions, and elevates free radical concentrations, all of which lead to ED [13]. Therefore, inhibition of ET-1 to ET-a binding can have anti-atherosclerotic effects which will be examined later.

Endothelium-derived hyperpolarizing factor (EDHF) makes the resting membrane potential of underlying smooth muscle more negative (hyperpolarization). Hyperpolarization of the smooth muscle cells and endothelial cells arise from a rapid efflux from [K]+, leading to higher periods of relaxation and vasoconstriction. in the case of hyperpolarization, both NO and PGl2 are reduced, not allowing for adequate vasodilation.

Endothelial dysfunction and inflammation [14]:

As mentioned above, endothelial dysfunction and inflammation can be connected through iNOS with the migration of macrophages to an injury site [12]. More than disruptions in maintaining vascular tone, inflammation in endothelial dysfunction can arise from tissue injury or infection, leading to morphological and functional modifications. The processes of morphology and function are triggered by inflammatory cytokines such as TNF-a (tumor-necrosis factor alpha), ILs (interleukins), and pattern recognition receptor activation (PRR) after detection of a pathogen.

To begin, NLRP3 Inflammasomes are a major inflammatory response as a result of a pro-inflammatory cytokine. “NLRP3 inflammasome activation can be the outcome of various signals, namely ion fluxes, mitochondrial dysfunction, and ROS overproduction” [14]. “The inflammatory and pro-coagulant effects of endothelial cells are mediated by the NF-κB signaling” [14]. The relation between NF-κB and endothelial dysfunction can be noted by the release of inflammatory mediators that modulate smooth muscle cell activation. Other molecules such as NOX send pro-inflammatory mediators to the endothelial cell. Shear stress on ECs lead to a series of immune responses.

Finally, chronic inflammatory diseases are characterized by a significant inflammatory burden, the overexpression of inflammatory cytokines. For example, rheumatoid arthritis, the presence of endothelial dysfunction is frequently present [15]. In another instance, the correlation between reduced NO production for vasodilation and inflammation is seen in cases of psoriasis.

Endothelial dysfunction and thrombosis [14]:

In healthy conditions, endothelial cells can produce antithrombin molecules to inhibit cell coagulation, however endothelial dysfunction leads to a shift in EC phenotype, leading to higher levels of coagulation within the endothelium, these activated ECs can express active tissue factor on the cell surface thereby initiating the extrinsic pathway of coagulation. In cases of severe bacterial and viral infections, thrombosis in endothelium is widely prevalent without a true known explanation.

Risk Factors for Endothelial dysfunction:

There are several risk factors for endothelial dysfunction which can also be seen in cardiovascular diseases. In addition to the risk factors below, there are several others which all contribute to endothelial dysfunction in their respective ways, most notably, vasoconstriction and inflammation.

Diabetes and endothelial dysfunction:

Several overlaps are present on the effect of diabetes in endothelial dysfunction and oxidative stress. In terms of endothelial dysfunction, hyperglycemia leads to intracellular changes by a series of redox reactions. Type 1 diabetes (insulin-dependent diabetes mellitus) has been linked to “poor endothelial cell-dependent vasodilation and increased blood levels of von Willebrand factor (vWF), thrombomodulin, selectin, plasminogen activator inhibitor, type IV collagen, and tissue plasminogen activator (t-PA)” [16]. Type 2 diabetes is linked to an impairment in NO release [16]. Higher levels of endothelin-1 (above) have been noted in type 2 diabetes and hence, has been linked toward vascular impairment and endothelial dysfunction.

Hypertension and endothelial dysfunction [16], [17]:

Persistent hypertension exposes the endothelium to excessive mechanical stress, leading to structural damage and dysfunction. This stress disrupts the balance between vasodilators such nitric oxide, NO and vasoconstrictors such as endothelin-1, without adequate NO release and upregulation of endothelin-1, hypertension lasts, promoting vasoconstriction and increasing vascular resistance. In addition to an impact on NO production, Hypertension reduces NO bioavailability due to increased oxidative stress and activation of enzymes like NADPH oxidase, which generate reactive oxygen species (ROS), tying together oxidative stress as a result of endothelial dysfunction.

Endothelial dysfunction to LDL cholesterol permeability:

Damage to the endothelial barrier leads to circulating LDL (low density lipoproteins) to circulate and reach the intima of blood vessels. After binding to proteoglycans, LDL begins to accumulate. [18]. The higher levels of circulating cholesterol in the blood lead to factors such as hypertension, driving endothelial dysfunction again. The accumulation of cholesterol and its role in atherosclerosis will be discussed more in 4.2 and 4.3 when discussing the role of LDL oxidation.

Targeted treatments for Endothelial Dysfunction:

Known medications for endothelial dysfunction are ACE inhibitors (inhibits conversion of angiotensin I to angiotensin II), statins (to reduce cholesterol biosynthesis, and calcium channel blockers (inducing vascular endothelial relaxation).

Statins and endothelial dysfunction:
Statins have an effect on reducing endothelial dysfunction by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) and therefore inhibiting cholesterol biosynthesis [19]. Medications such as Atorvastatin, Rosuvastatin, and Pravastatin have large clinical significance in reducing LDL-Cholesterol and improving endothelial function. A clinical statin study, [21] showed great success in the inhibition of enzyme HMG-CoA reductase, with a clinical study performed on 258 patients directly with the use of the statin name, pravastatin. Patients that underwent statin treatment had a significantly greater reduction of HMG-CoA enzyme. Additionally, the statin group of 258 patients had a restenosis rate and repeat endothelial dysfunction of 25.4%. The same study showed that pravastatin might have anti-inflammatory effects on CRP protein (C-reactive protein). In this study, patients given pravastatin had a 16.9% reduction rate out of a sample size of 865 patients, showing how statin can have an anti-inflammatory along with LDL-C reduction rates. A similar study to pravastatin used atorvastatin in a sample population of cigarette and non-cigarette smokers [22]. Atorvastatin increased flow-mediated vasodilation in cigarette smokers from 8.0±0.6% to 10.5±1.3%. Atorvastatin administration decreased total and LDL cholesterol levels similarly in cigarette smokers and healthy controls by 123±30 mg/dL and LDL cholesterol to 58 mg/dL in healthy groups and 137±42 mg/dL (P=0.023) and LDL to 55±30 mg/dL (P=0.003) [22] in smokers. Such data shows the vasodilating effects of statins by increasing endothelial-dependent vasodilation, leading to how endothelial dysfunction arises from lower NO production, however, is then improved by LDL-C reduction in the endothelium and upregulation of NO. In summary, study [22] shows how statins play a role in both preserving endothelial function and in maintaining and lowering oxidative stress due to LDL accumulation.

ACE Inhibitors and endothelial dysfunction:

ACE inhibitors block the conversion of angiotensin I to angiotensin II, angiotensin II is a known potent vasoconstrictor, increasing blood pressure, which drives endothelial dysfunction. By reducing the levels of angiotensin II, ACE inhibitors promote vasodilation through the increased availability of bradykinin (a peptide that enhances nitric oxide production, which helps in the relaxation of blood vessels and improved endothelial function). Clinical evidence below shows how ACE inhibitors such as ramipril and captopril can improve endothelial function in patients with early stage atherosclerosis, and more specifically, endothelial dysfunction [23].

[24] Used a study design with patients 18 years or older with shows signs of coronary artery disease. This was a randomized study that aims at studying the effect of the ACE-inhibitor perindopril (8mg/day) on morbidity and mortality in over 333 patients with stable coronary artery disease without clinical heart failure [24]. Out of the 333 patients given perindopril, The mean change in FMD (flow mediated vasodilatation) between baseline and 36 months was 0.91% (SD 3.77). Since this study examined the vasodilation effects of ACE inhibitors, the average FMD over a 6 month period was 15% in perindopril groups, showing the effect of ACE inhibitors and its relation of NO production. Another clinical study sampled 1,129 patients, with 805 patients given Angiotensin converting enzyme inhibitors (ACEIs) [30]. This study showed the 1.26% improval rate of FMD in treatment groups across 11 clinical studies. In 4 other clinical trials in the same source, ACEIs had a 2.51% increase in FMD when compared to calcium channel blockers.

Calcium channel blockers and endothelial dysfunction:

In more specificity, this paper will investigate the role of calcium channel blocker, Amlodipine. Calcium channel blockers are a well known remedy of hypertension by blocking voltage dependent calcium channels in vascular smooth muscle cells to induce relaxation and hence lower blood pressure. Because of lowered calcium release induced contraction and lowered blood pressure, amlodipine is associated with improved endothelial function [25]. To understand the effectiveness of amlodipine, this section looks at meta-analysis of [26] and [27]. [27] Stated how S-amlodipine significantly lowered levels of inflammatory markers and significantly increased eNOS and NO levels. S-amlodipine uses OPG to block RANK/RANKL interaction as well as downregulate miR-155 to improve vascular endothelial and vascular smooth muscle cell function. [28] Showed the use of Nifedipine and its restoration on endothelial function in CAD patients. Out of a population pool of 454 patients, 226 patients were evaluable for the intention-to-treat analysis of changes in endothelial function and/or changes in plaque volume. In patients treated with nifedipine, blood pressure was lower than on placebo by 5.8/2.1 mmHg, around a 5.8% decrease compared to placebo groups. Nifedipine lowered LDL by 4.8% in treated groups. Over a period of up to two years, nifedipine significantly improved coronary endothelial function compared to placebo

Discussion of Endothelial dysfunction

Endothelial dysfunction is the earliest detectable stage of atherosclerosis, and leads to atherosclerotic plaque development. The primary indicators of endothelial dysfunction (ED) are reduced nitric oxide availability which leads to vasoconstriction, commonly, a fatty streak development caused by higher LDL levels allows for lipoprotein transport which is typically seen in stage 2 of atherosclerosis. Endothelial dysfunction also is commonly associated with vascular inflammation due to a migration of macrophages because of the release of iNOS (due to lowered NO availability). This vascular inflammation can also be explained due to a release of inflammatory cytokines such as tumor necrosis factor alpha, interleukins, and pattern recognition by macrophages and lymphocytes. Endothelial dysfunction also can lead to a shift of endothelial/ vascular smooth muscle phenotype. With all of the markers of endothelial dysfunction above, the chances of a plaque rupture in atherosclerosis becomes higher, leading to a thrombosis.

This paper discussed the known treatments of endothelial dysfunction through the understanding of mechanism of action, clinical trials, and experimental research. Statins, ACE inhibitors, and calcium channel blockers are known and effective treatments of endothelial dysfunction. Statins inhibit LDL- cholesterol biosynthesis. ACE inhibitors block the conversion of angiotensin I to the potent vasoconstrictor, angiotensin II. Finally, calcium channel blockers have an important role in the medical field to ensure vasodilation and to relax vascular smooth muscle cell (VSMC) contraction. However, apart from these, new and upcoming treatments such as NO donors and endothelial progenitor cell therapy, offer potential future treatment avenues.

In terms of statins and endothelial dysfunction, this paper investigated the role of Pravastatin as a medication to inhibit HMG-CoA enzyme (conversion of cholesterol and plaque accumulation). A clinical study used a sample size of 258 patients, proving the recurring rate of endothelial dysfunction as being lowered by 25.4%. Another medication, atorvastatin showed not only anti-LDL accumulation effects on the endothelium, however, showed anti-inflammatory effects of statins. This statin increased flow-mediated vasodilation in cigarette smokers from 8.0±0.6% to 10.5±1.3%, and lowered LDL to 55±30 mg/dL. Statins also have vasodilating effects of statins by increasing endothelial-dependent vasodilation, leading to how endothelial dysfunction arises from lower NO production, however, is then improved by LDL-C reduction in the endothelium and upregulation of NO. Some trials suggest high-dose statins improve endothelial health independent of cholesterol levels as well as improving vascular tone as seen in the results section. In terms of the biological role Statins have on endothelial dysfunction, Increase NO Production: Statins upregulate endothelial nitric oxide synthase (eNOS) and downregulate iNOS to lower inflammation and migration of macrophages to the injury site by increasing its expression and preventing its degradation, leading to enhanced NO bioavailability. Endothelial dysfunction ties into stage 3 of atherosclerosis, and statins inhibit HMG-CoA reductase, statins reduce isoprenoid intermediates that activate NADPH oxidase, decreasing reactive oxygen species (ROS) that degrade NO, hence connecting this mechanism of action to both NO production and oxidative stress. Finally, studies above show Statin’s anti-inflammatory properties by inhibiting NF-κB activation and lowering pro-inflammatory cytokines (e.g., TNF-α, IL-6).

ACE inhibitors prevent the production of angiotensin II to lower vascular inflammation and ROS production. The clinical study examined this paper using a sample size of 333 of which half were given the ACE inhibitor, perindopril, and showed 15% FMD effects (flow mediated vasodilation) after 36 months. This study essentially showed the increased production of NO under ACE inhibitors, making ACE inhibitors a widely accessible treatment for those with hypertension. Another published study, with the use of 1,129 patients and over the course of 11 clinical trials, again showed the great effect that ACE inhibitors (ACEIs, angiotensin converting enzyme inhibitors) have on lowering FMD. This study drew a comparison between ACEIs and calcium channel blockers, allowing for further clinical studies and experimental studies to pinpoint the mechanism of action of ACE inhibitors as lowering hypertension through increasing FMD. The biological mechanisms of ACE inhibitors and statins can be tied together by how ACE inhibitors prevent angiotensin II (Ang II) formation, reducing Ang II-mediated vasoconstriction and oxidative stress while increasing bradykinin levels, which enhances eNOS activation. This mechanism of action can allow further research and developments to create a hybrid drug between statins and ACE inhibitors since both enhance eNOS bioavailability. In addition, ACE inhibitors, by blocking Angiotensin II formation, reduce endothelial stiffness and reactive oxidative species (ROS).

This paper finally examined the role of calcium channel blockers and how the calcium channel blocker, Amlodipine showed great experimental significance by lowering the levels of VSMC contraction, allowing for vasodilation in vessels. This is because it blocks voltage gated calcium channels upon the release of Ca2+ ions by the sarcoplasmic reticulum of contractile muscle cells. Amlodipine also has effects by the downregulation of miR 155, increasing nitric oxide levels, and to block RANK/RANKL pathways. In a clinical trial of Nifedipine, this calcium channel blocker reduced BP and LDL cholesterol levels by 4-5% in treated groups when compared to placebo groups. This shows how calcium channel blockers improve with vascular relaxation through lowering blood pressure, but also lowering LDL-cholesterol, allowing for more experimental data to be collected in this correlation. Calcium channel blockers have their own way of increasing NO availability, and do so by blocking L-type calcium channels, CCBs reduce intracellular calcium in vascular smooth muscle cells, leading to vasodilation and reduced endothelial shear stress. Amlodipine (mentioned above) also decrease NADPH oxidase activity, lowering ROS (reactive oxidative species) production and preventing NO degradation, ROS production plays a crucial role in foam cell creation and lipoprotein transport to further develop atherosclerotic plaques. Therefore, without forming ROS and oxidative LDL species, calcium channel blockers like amlodipine reduce endothelial permeability to LDL cholesterol.

For future research on this stage of atherosclerosis, there are several notable limitations such as how many studies focus on short-term endothelial function without long-term cardiovascular outcome data. Although this paper cited long term clinical trials, endothelial dysfunction has several modes of prevalence, making it necessary to have a wider variety of treatment time-stamps. The traditional markers of endothelial dysfunction such as FMD are useful, but have limited biomolecular significance. However, novel therapies such as the evolution of endothelial NO pathways and stem cell therapies are under investigation.

On a final note of clinical implications of statins, ACE inhibitors and Calcium channel blockers, given that endothelial dysfunction is the precursor of the atherosclerotic plaque formation cascade, early pharmacological interventions could delay or prevent disease progression. There are targeted drugs and treatments for patients with a history of endothelial dysfunction and common risk factors of endothelial dysfunction such as diabetes, smoking, obesity, hypertension, and more. The pathophysiology of these diseases has long lasting effects on the progression of atherosclerosis, with the increase of LDL cholesterol permeability to endothelial cells. In the future, the potential treatments of endothelial dysfunction will remain vast, with the combination of known treatments and the increased use of technology in the medical field.

Conclusion:

Endothelial dysfunction is a fundamental process in the initiation of atherosclerosis, driven by oxidative stress, inflammation, and impaired nitric oxide signaling. Statins, ACE inhibitors, and calcium channel blockers have shown promise in restoring endothelial function. However, remain generalized treatments instead of examining each symptom of endothelial dysfunction.

While current therapies primarily focus on reducing risk factors such as hyperlipidemia and hypertension, the future of endothelial dysfunction treatment may lie in targeted endothelial repair strategies, including endothelial progenitor cell therapy, NO production, and to lower endothelial inflammation. Further clinical trials are needed to determine the efficacy of emerging stem cell and anti-oxidative therapies and establish personalized treatment approaches and strategies for high risk patients.

Recognizing endothelial dysfunction as a key biomarker of cardiovascular disease risk may shift clinical practice toward the early stages of atherosclerosis without the need of later surgical interventions.

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