The two special issues of Frontiers in Cardiovascular Medicine devoted to the association of lipids and inflammation are significant collections in consideration of atherosclerosis. Arterial diseases, both macro and micro, represent the most prevalent health issues related to morbidity and mortality. Macrovascular disease leads to the most common cause of death and sustained disability. Heart attacks have remained the number one cause of mortality in the United States for over a century. Ischemic strokes are the fifth leading cause of death and the most common cause of severe long-term disability (1). Microvascular disease is prevalent and emerging as the primary etiology of chronic diseases of aging, including dementia (2). Such disease is responsible for Americans outliving their health by 13 years (3). The underlying pathology for both types of vascular disease is atherosclerosis (4). Pathogenesis of arterial disease depends on the development of chronic inflammation created by sustained activation of immunity from lipids (5). This review will discuss reducing oxidative stress as a measure to make this chronic situation addressable and surmountable.

The pathogenesis of atherosclerosis begins with trapping lipoproteins in the intima during extravasation from the arterial lumen (6). Lipoproteins up to 70 nm can pass through endothelial cells via transcytosis. Therefore, all lipoproteins except the largest very-low-density lipoproteins (VLDL) and chylomicrons can enter the arterial wall from the lumen in a healthy state. These particles diffuse through the wall and efflux on the adventitial side. The critical factor in forming an atheroma is the retention of migrating lipoproteins in the intima. This entrapment occurs via electrostatic forces between apolipoprotein B (apoB) and polysaccharide chains in proteoglycans (7). The captured lipoproteins become aggregated and oxidized.

The resulting ox-LDL activates the immune system stimulating endothelial dysfunction (ED). A critical component of the pathogenesis of atherosclerosis is ED (8). The ox-LDL stimulates innate immunity in endothelial cells through toll-like receptors (TLRs). Stimulation of TLRs results in intracellular chemical reactions which activate nuclear factor-kappa B (NF-kB). As a result, the cell nucleus produces inflammatory cytokines such as interleukin 1 beta, interleukin 6, interleukin 18, and tumor necrosis factor alpha. In addition, NF-kB increases the inflammasome nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3). One crucial function of NLRP3 is the assembly of caspase 1. The cytokines IL-1 beta and IL-18 require cleavage by caspase-1 to become functional. There is an accompanying increase in mitochondrial reactive oxygen species (ROS) which has a bidirectional relationship with NLRP3. The mitochondrial and inflammasome activity increases and preserves the OS. These multiple reactions of inflammation contribute significantly to ED (9). Lectin-like receptors for ox-LDL in the endothelium upregulate the production of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule, which recruit monocytes into the intima. The lipid-proteoglycan complexes get phagocytized via scavenger receptors, leading to foam cell formation (10). The foam cells will coalesce into fatty streaks and subsequent atheroma. Accumulating evidence indicates endothelial shear stress and autophagy also play a critical role in the endothelial dysfunction of atherosclerosis (11). Regardless of the evolving science about the mechanisms of ED, continued retention of lipoproteins will perpetuate ED leading to chronic inflammation and ongoing pathogenesis of atherosclerosis (12).

Preventing and halting atherosclerosis requires eliminating apoB and its associated LDL-C from getting trapped in the intima. The retention would cease if proteoglycans were absent within the intima. Proteoglycans originate from contractile smooth muscle cells (cSMCs) in the media, which get genetically transformed into migratory secretory smooth muscle cells (msSMCs). The msSMCs then move into the deep layer of the intima and produce proteoglycans (13). There are numerous triggers for the formation of msSMCs, but the most prominent is platelet-derived growth factor (PDGF). Therefore, inhibiting PDGF could significantly reduce atherogenesis (14). Oxidative stress (OS) is the primary stimulus to activate platelets (15). Activated platelets produce PDGF (16). Therefore, minimizing OS would significantly reduce the trapping of apolipoprotein B in the intima. Decreasing this first step in forming an atheroma would mitigate the association between lipids and chronic inflammation and impair the pathogenesis of atherosclerosis.

OS occurs when reactive oxygen species (ROS) are abundant relative to antioxidants. Mild OS can be beneficial. However, moderately or severely elevated levels of oxidants damage cellular components such as proteins, lipids, and nucleic acids. Such injury impairs cellular function and may cause apoptosis (17). Adenosine triphosphate (ATP), the primary cellular energy source, is formed from oxidant reactions. Mitochondria produce the majority of ATP and ~90% of ROS. Other cellular elements, including cytoplasm, cell membrane, endoplasmic reticulum, and peroxisome, generate a minor amount of ROS. To maintain homeostasis, all of these cellular elements generate antioxidants (18). The mechanisms responsible for ROS production are complex, as are the mechanisms for antioxidant formation, and the explanatory science is still evolving (19, 20). Despite this, the science is definitive that OS is a significant facilitator of chronic degenerative pathologies (21). Mitochondrial therapy is being investigated for many chronic disease pathologies, including atherosclerosis, due to the pivotal role of mitochondria in OS (22, 23).

This review will analyze OS as the critical link between lipids, inflammation, and atherosclerosis. CV risk factors, both known and emerging, will be examined through the lens of OS. The discussion will be about managing these conditions and the judicial use of therapeutic options to stop OS. Reducing OS would result in sustainable prevention and halting of arterial disease. This paper will examine results from a real-world clinic using such a comprehensive approach. Stopping OS (SOS) is paramount in breaking the association between lipids and chronic inflammation. SOS is vital in achieving arterial wellness.

In this section, known and evolving CV risk factors will be addressed through the lens of causing OS prior to the OS generated by lipoproteins retained in the intima. Any risk factor that produces such OS will enhance the trapping of lipoproteins and increase the chance of a chronic association between lipids and inflammation. This chronicity is due to an ongoing atherogenic process. Adequate management of CV risk factors will assuage OS, decreasing PDGF. As a result, msSMCs production will decrease, yielding the opportunity to halt atherogenesis (24).

Stopping oxidative stress (SOS) requires clinical management of all the discussed modifiable traditional and non-traditional CV risk factors. Those issues are remnant lipoproteins, hypertension, smoking, weight, diet, physical activity, insulin resistance, sleep, psychosocial, periodontal disease, other chronic infections, autoimmune disease, gut dysbiosis, vitamin D, and air pollution. This type of healthcare requires a holistic approach along with interdisciplinary collaboration. OS is the common denominator of the risk factors, making them interrelated (see Figure 1). For example, OS is at the root of insulin resistance pathogenesis which leads to T2DM. Therefore, it is no surprise that the above risk factors are associated with an increased risk of new-onset diabetes (55–64, 179–182). Accomplishing SOS demands comprehensive, integrated healthcare. Numerous frequently used drugs impact OS either directly or indirectly (183). This review analyzes many of these agents used to help manage CV risk through the lens of directly mitigating OS.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have evolved as a cornerstone medication to reduce CV risk. These drugs, better known as statins, are recommended in guidelines with benefits greatly outweighing harm (184). When examined through the perspective of OS, these agents excel. Within hours statins progressively reduce OS (185). Elevated NADPH-oxidase expression and activity create OS. A critical substance in the assembly and activity of NADPH-oxidase is Rac1, a guanosine triphosphatase. Stains decrease mevalonate, which results in a reduction in Rac1. The reduction in mevalonate causes a decrease in geranyl-geranyl-pyrophosphate (GGPP). Less GGPP causes increased expression of endothelial nitric oxide synthetase (eNOS). Statins help activate eNOS via phosphorylation. ENOS enhances the restoration of oxidative balance (186). As a significant bonus, statins increase the concentration of two powerful antioxidants, glutathione peroxidase and superoxide dismutase (187). This SOS effect of statins would reduce the PDGR-driven cSMC transformation. Chen and colleagues demonstrated this effect of statins (188). The biomarker lipoprotein-associated phospholipase A-2 (PLAC2) increases during the pathogenesis of atherosclerosis (189). The reduction in PLAC2 in the statin trail LIPID accounted for most of the statin benefit (190). It is conceivable that statins primarily mitigate CV risk via directly reducing OS.

Bempedoic acid (BA) lowers cholesterol in a similar manner to statins. It inhibits ATP-citrate lyase (ACL), a catalyst necessary to form acetyl-CoA. Less production of acetyl-CoA causes decreased formation of HMG-CoA. Thus, it acts upstream from statins to inhibit HMG-CoA production. Just like statins, this will decrease mevalonate formation, which should result in the activation of eNOS, helping to restore oxidative balance. BA theoretically has the potential to lower remnant cholesterol since acetyl-CoA activity can lead to increased TG (191). However, studies have shown no significant decrease in TG levels to date (192–195). BA has not been investigated for its ability to increase antioxidants. No data is available evaluating BA's effect on PLAC2. BA does carry a warning of increasing uric acid. There currently is no CV outcome data, albeit some is expected later this year with the CLEAR trial (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated with Bempedoic Acid). The medication requires prior authorization, and the cost is a concern (196). It remains to be determined if BA is an effective agent to reduce OS.

Because triglyceride (TG) reduction independent of LDL-C lowers CV risk, lipid-lowering agents beyond statins are frequently required (197). TGs are a surrogate representation of remnant cholesterol, which natively creates OS. Therefore, any therapy that lowers TG will directly lower OS. The question is; do any of these therapies directly reduce OS by other mechanisms? Fibrates decrease the progression of atherosclerosis and reduce CV risk (198). However, the evidence does not support that fibrates reduce OS beyond what would be expected from lowering TG (199). Numerous studies confirm that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly lower TG and CV risk (200–202). In addition to PCSK9 inducing LDL receptor degradation, it activates NADPH oxidase promoting OS. Therefore, PSCK9-inhibitors (PCSK9-I) may reduce OS beyond reducing TG. Accumulating evidence suggests PCSK9-I may reduce CV risk via SOS (203).

Niacin, the water-soluble vitamin B3, is the oldest and one of the most effective agents to affect all lipoproteins favorably (204). In an in vitro study utilizing human aortic endothelial cells, niacin inhibited ROS production by angiotensin II (205). Seventeen subjects with an insulin resistance type dyslipidemia demonstrated that 2 grams of niacin a day for 3 months significantly reduced TG and OS (206). However, the degree of reduction in OS in that study may have been due to the lowering of TG. Niacin is a precursor for nicotinamide adenine dinucleotide (NAD⁺). Recently it was discovered that NAD⁺ is a co-substrate for the sirtuin family of deacetylases which help maintain mitochondrial homeostasis. The benefits of niacin may primarily be related to its influence on the NAD⁺/sirtuin-axis (207). In vitro and in vivo trials have confirmed that niacin reduces OS (208). Whether or not the mechanism for this reaches beyond its effect on TG is not established.

Omega 3 fatty acids (FAs) are an effective therapy for TG (209). A meta-analysis evaluating the effect of omega 3 FAs vs. placebo on the oxidative stress biomarker malondialdehyde (MDA) concluded a significant decrease in MDA with omega 3 FAs. The analysis also showed significantly increased activity of the antioxidant enzyme glutathione peroxidase (GPx). The conclusion was that omega 3 FAs reduce OS. It was noted in the analysis that the change in MDA seemed to be due to the improvement in the lipid profile (210). The evidence indicates that the benefit of SOS with omega 3 FAs is due to a reduction in TG. In summary, all TG-lowering agents SOS, but the only one that does so beyond the lipid effect, maybe PCSK9 inhibitors.

Evidence indicates that blood pressure medications reduce CV risk regardless of a hypertensive diagnosis. Healthcare providers should focus communication on the benefit of these agents on CV risk rather than the blood pressure benefit (211). Renin-angiotensin-aldosterone system (RAAS) medications have been considered a cornerstone for individuals with CVD (212). RAAS agents have pleiotropic effects beyond blood pressure reduction (213). RAAS therapy can double the antioxidant extracellular superoxide dismutase (EC-SOD) concentration. The change in EC-SOD partially explains the reduction in OS by RAAS medications (214). The main feature of RAAS agents is to reduce the effects on angiotensin II (AngII) either by reducing the production of AngII or blocking the receptor to activate AngII. AngII activates NADPH oxidase, which leads to increased ROS and OS (215). Amlodipine is a frequently used agent in individuals with CV risk. Amlodipine is known to reduce the progression of atherosclerosis. One mechanism by which it accomplishes this is inhibition of cSMC transformation and migration (216). Utilizing nitrotyrosine as a marker of OS, Kim and colleagues demonstrated therapy with amlodipine and a RAAS agent, and each significantly lowered the level after 24 weeks. The authors concluded that amlodipine reduces OS (217). Beta-blockers have a prominent role in managing CV risk. Carvedilol significantly reduced OS as measured by thiobarbituric acid-reactive substances (TBARS) (218). In vitro data have shown that carvedilol reduces ROS production by mitochondria (219). In a study of 44 patients with essential hypertension, multiple biomarkers, including the ferric-reducing ability of plasma (FRAP), glutathione/oxidized glutathione, malondialdehyde, and plasma 8-isoprostane, were used to assess OS. Twenty-three patients received carvedilol 12.5 mg/d, and twenty-one received nebivolol 5 mg/d for 12 weeks. All four biomarkers of OS improved significantly with carvedilol. There were no significant changes with nebivolol (220). These beneficial effects on the pathogenesis of atherosclerosis of the above three major classes of blood pressure medications were assessed in a comprehensive review of multiple strategies to manage hypertension (221). A significant reason the hypertensive medications amlodipine, carvedilol, and RAAS agents reduce CV risk is related to directly reducing OS.

Insulin resistance (IR), a CV risk factor, frequently requires medication therapy regardless of T2DM status. Hyperglycemia which results from IR, generates OS by multiple mechanisms (222). Therefore, any medication utilized to reduce IR and hyperglycemia will reduce OS. The question is, do any of them directly reduce OS by mechanisms other than reducing hyperglycemia. The alpha-glucosidase, dipeptidyl peptidase-4 inhibitors, and sulfonylurea agents have shown that they reduce OS (223–225). However, there is no evidence that the mechanism responsible reaches beyond reducing hyperglycemia. Metformin activates adenosine monophosphate-activated protein kinase (AMPK) (226). This activation leads to the expression of the antioxidant genes for the production of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) (227). The increase in these agents enhances the antioxidant system, reducing ROS (228). Activation of AMPK also maintains the cSMC phenotype (229). The mechanism of activating AMPK will reduce the initial step in the pathogenesis of atherosclerosis and is a mechanism separate from reducing hyperglycemia. Thiazolidinediones (TZD), glucagon-like peptide-1s (GLP-1), and sodium-glucose cotransporter 2 inhibitors (SGLT-2) also activate AMPK (230–232). The TZD pioglitazone also destroys SMCs, which have transformed into msSMCs (233). These actions are a significant benefit in shutting down the pathogenesis of atherosclerosis. Indeed, pioglitazone has excellent studies showing it has a positive effect on mitigating the progression of atherosclerosis in IR patients regardless of diabetic status (234–237). In summary, all antidiabetic drugs SOS. Metformin, GLP-1, SGLT-2, and TZD agents do so by effects outside of mitigating hyperglycemia. The best medication for SOS appears to be pioglitazone with its unique ability to cause apoptosis of msSMCs.

A chronic association between lipids and inflammation develops with active pathogenesis of atherosclerosis. The first step in the pathogenesis involves trapping apolipoprotein B (apo B), which contains all the vascularly harmful cholesterol, in the intima. The contained cholesterol particles become oxidized and generate inflammation. The inflammation comes from activating the immune system to remove the oxidized particles from the arterial wall. The innate immune system initially responds by generating inflammatory cytokines and monocyte chemoattractant proteins affecting the endothelium. Subsequently, monocytes are captured on the endothelium and penetrate the intima. Macrophages are formed from those monocytes to digest the oxidized lipids. The adaptive immune system responds with effector T cells stimulated by antigens such as oxidized lipoproteins (238). If the trapping continues, the macrophages become engorged, becoming foam cells. In addition, SMCs may also become engorged with oxidized lipoproteins contributing to the mass of foam cells (239). If the process continues, the foam cells coalesce into fatty streaks and form atheroma. Active pathogenesis of atherosclerosis produces substances such as oxidized LDL and matrix metalloproteinase-2, which also contribute to the transformation of cSMCs (240). The three essential elements involved in the pathogenesis of atherosclerosis are apoB, endothelial permeability, and binding of lipoproteins in the intima (241). Individual analysis of these three components is helpful when attempting to end the chronic association between lipids and inflammation.

Would solely focusing on apoB stop the chronic association between lipids and inflammation? Excellent health requires cholesterol and fat. Cholesterol is a vital hormone ingredient, now recognized as an essential regulator of innate immunity (242). Fat is also an essential ingredient for health (243). Their transport to cells depends on apoB. Therefore, extreme reduction or elimination of this component is not feasible. It is only harmful when it gets trapped in the intima or if it contains high levels of remnant cholesterol. If there is no retention of apoB in the intima, an individual could have high levels with low CV risk. The converse would also be true. If there is the retention of apoB in the intima, an individual could have low levels with high CV risk. There is evidence congruent with retention being the critical determinant for arterial disease. One study found that about half of the 231,986 people with coronary artery disease had low levels of apoB (244). Studies also demonstrate that the absolute risk for atherosclerosis in many people with high apoB is low, albeit the relative risk might be twice that of subjects with low apoB (245). The main factor determining the number of lipoproteins retained in the intima is the number of proteoglycans available to bind apoB. The quantity of apoB diffusing through the arterial wall far exceeds the quantity trapped in the intima (7). Thus, reducing the plasma apo B concentration will decrease the intimal retention to some degree, but it will not prevent it. As long as there is the intimal binding of apoB regardless of apoB concentration, there will be a persistent association between lipids and inflammation.

Would focus on endothelial permeability and the responsible immune milieu end the chronic lipid inflammatory association? The immune activation and subsequent endothelial response are mechanisms to maintain arterial wellness. Interfering with this process might reduce inflammation enough to lower the risk of an underlying atheroma creating a thrombus from endothelial rupture or erosion. CV event risk in patients with known arterial disease was lowered with the medication canakinumab, which inhibits the proinflammatory cytokine interleukin-1β. Such action, however, does not halt the intimal binding of apoB. Continuation of the pathogenesis of atherosclerosis was evident, with a significant number of patients receiving canakinumab requiring hospitalization for unstable angina (246). The immune reaction and resultant inflammation are designed to restore wellness. Should the unhealthy retention of apoB continue, the chronic association between lipoproteins and inflammation will remain.

Stopping the binding of apoB in the intima would end the chronic association between lipids and inflammation. Proteoglycans have a protein core with negatively charged glycosaminoglycan chains. ApoB carries a positive charge. This electrostatic force traps the lipoproteins (247). These binding proteoglycans are produced by msSMCS which originate from cSMCs. The change occurs in the medial layer, and the msSMCs move into the deep layer of the intima. Proteoglycans are then secreted into the intima. SMCs are the first cells seen in the intima in locations destined to develop atherosclerosis (13). Prevention of the cSMC transformation would halt the binding. The chronic lipid inflammatory association would stop, as would the pathogenesis of atherosclerosis.

Vascular SMCs are subject to phenotypic change. The mechanisms resulting in transformation are complex. The plasticity of a SMC depends on its anatomic location, embryonic origin, maturity, and subtype. Most research has focused on the contractile phenotype and the synthetic phenotype. The genetic transformation involves the activation and suppression of SMC genes. PDGF can induce transformation, which is mediated by multiple mechanisms (248). One of those mechanisms was elucidated recently. A DNA-modifying enzyme ten-eleven translocation-2 (TET2) is a master epigenetic regulator of cSMC transformation (249). MicroRNA-22-3p (miR-22-3p) activates TET2 to transform cSMCs. Circular mitogen-activated protein kinase 5 (circMAP3K5) acts like a sponge for miR-22-3p. This reduction in the availability of miR-22-3p decreases the genetic transformation of cSMCs. In an in vivo mouse model, circMAP3K5 inhibited SMC-induced intimal hyperplasia. PDGF significantly reduces the expression of circMAP3K5 in human coronary artery SMCs (250). This reduction would lead to an increase in cSMC transformation to msSMCs. We have discussed numerous ways in which to minimize PDGF. The purpose of reducing PDGF is to reduce the creation of msSMCs.

Transformation of cSMCs into msSMCs can occur by other mechanisms. Angiopoietins are present in SMCs. They can influence genetic transformation. An increase in angiopoietin 2 (Angpt2) relative to angiopoietin 1 (Angpt1) in human aortic SMCs caused a transformation to migratory SMCs. The high-risk periodontal pathogen Porphyromonas gingivalis stimulated the Angpt2/Angpt1 ratio shift. The authors concluded that this mechanism links periodontal disease to atherosclerosis (95). Periodontal disease should be addressed as a CV risk factor. Protein kinase C (PKC) enhances the conversion of cSMCs to msSMCs. Insulin resistance activates PKC. Activated PKC also reduces nitric oxide and increases endothelial-1, increasing cSMC transformation (251). The solution is to minimize insulin resistance. Thromboxane A2 (TXA2) activates yes associated protein 1 (YAP)/WW-domain-containing transcription regulator 1 (TAZ), which causes more transformation of cSMCs to msSMCs (252). TXA2 is mainly synthesized via cyclooxygenase (COX)-1 in activated platelets. Urinary thromboxane B2 (TXB2) is a surrogate biomarker for TXA2 production. TXB2 is an independent risk factor for CV mortality. The authors suggest that TXB2 measurement could help guide the use of low-dose aspirin (253). Despite aspirin use, TXB2 levels can be elevated. Numerous health conditions can cause this. They include cigarette smoking, T2DM, HTN, obesity, and systemic lupus erythematosus. Any issue which causes OS activates platelets which increases the levels of TXA2, leading to higher TXB2 (254). To accomplish minimization of TXA2 requires managing all the CV risk factors causing OS and judicial use of low-dose aspirin.

Atherosclerosis and the accompanying chronic association of lipids and inflammation is arguably the most common and devastating human ailment. Researchers have noted preventing the seeding of msSMCs into the intima as a potential solution to halt the pathogenesis of atherosclerosis (13, 255, 256). Utilization of the science presented in this paper provides a clinical path to reduce the production of msSMCs by SOS. That achievement in an individual could eliminate chronic inflammation associated with lipids. More importantly, it could establish arterial health minimizing the risk for end-stage macrovascular diseases such as myocardial infarction and ischemic stroke. Most importantly, it would minimize the risk of developing chronic microvascular diseases of aging such as dementia, heart failure, renal failure, erectile dysfunction, peripheral arterial disease, and eye conditions like macular degeneration.

Numerous health issues are known to create arterial inflammation. These conditions included physical inactivity, lipids, smoking, hypertension, poor diet, obesity, insulin resistance, periodontal disease, other chronic infections, obstructive sleep apnea, psychosocial, vitamin D deficiency, gut dysbiosis, autoimmune diseases, and air pollution. Optimal clinical management of these health conditions has been proposed to halt atherosclerosis (257). In 2015, a retrospective analysis of data from a clinic utilizing the above approach was published. The study found that such individualized care positively affected the atherosclerotic disease process. The study evaluated the change in carotid intima-media thickness (cIMT) and carotid plaque during 8 years of clinical management of 576 patients. Baseline demographics revealed a mean age of 55.5 years, mean BMI of 27.5 kg/m², 39% female, 36% current or former smokers, 73% insulin resistant, 89% hyperlipidemia, 58% hypertensive, 34% Framingham Risk Score of >10% and 100% White. Carotid plaque was present in 85% of the patients. Coronary artery disease, as defined by coronary calcification or history of coronary event or intervention, was present in 25% of subjects. Eight years of therapy to improve all non-optimal health issues that created arterial inflammation resulted in a significant regression of cIMT and quantity of carotid plaque. There was also a significant reduction in Lp-PLA2, a biomarker that indicates active pathogenesis of atherosclerosis, as mentioned earlier in this paper. These results indicated not only halting arterial disease but also regressing the disease. In addition, no CV events occurred in any 576 patients (258). This information supports that knowledge regarding the causes of arterial inflammation can be translated into actual practice to stop the arterial disease.

Halting and regressing atherosclerosis theoretically should be beneficial. However, three prospective studies utilizing sophisticated imaging of arterial disease with MRI of carotids, near-infrared spectroscopy, and optical coherence tomography of the coronaries demonstrated that the lipid-richness of the plaque is the significant predictor of CV events (259–261). A retrospective study examined carotid plaque morphology changes in patients receiving multifactorial CV risk reduction treatment in the prevention clinic referenced in the above paragraph. The cohort consisted of 324 patients treated for 5 years with baseline characteristics very similar to the population of 576 patients mentioned above. At baseline, 53% of subjects had at least one lipid-rich plaque. At the end of 5 years, no patients had any lipid-rich plaque. The authors concluded that comprehensive, evidence-based management in a community-based prevention clinic benefits vulnerable plaque (262). These results indicate that clinicians can shut down and stabilize atherosclerosis with comprehensive management of health conditions causing OS and inflammation.

There are strengths in the above real-world evidence (RWE). Such evidence is increasing in importance. RWE can better mimic a patient's actual clinical situation. This reflection would include compliance with advice, number of illnesses, and magnitude of multiple treatments in an individual patient. RWE has obvious financial benefits compared to randomized clinical trials (RCT). Many unanswered questions in medicine which involve multiple variable interventions in an individual patient are not feasible to answer in RCT. RWE can also potentially generate answers faster than RCT. The expediency is especially true if the therapies are approved, making recruitment for an RCT more difficult (263). RWE is not limited to initiation by an investigator or dependent upon corporate sponsorship, which can introduce bias (264). It is now recognized that RWE is seriously needed to bolster the knowledge deficiency between RCTs and evidence-based, innovative management of complex diseases (265).

Let us examine some strengths of the RWE presented above, indicating halting and stabilizing of arterial disease. The outcome measurement of cIMT is robust. The same company performed all of the cIMT tests. Their sonographers and readers undergo routine testing for accuracy. There is a strong correlation between cIMT and atherosclerosis histology. The systemic presence of arterial disease is also correlated with cIMT. CV event risk is correlated with the change in cIMT. CV event risk decreases 12% for each 0.010 mm yearly reduction in cIMT progression (266). The RWE showed regression of cIMT instead of simply slowing progression. Identifying subclinical atherosclerosis with carotid plaque was clinically valuable in determining comprehensiveness and management goals. The presence of atherosclerosis is conditio sine qua non for risk of having a CV event (267). Finding atheroma in “healthy” subjects enhances patient management decisions (268). Subclinical carotid plaque is strongly associated with heart attack and stroke risk. Such identification should reclassify an individual's risk for a CV event (269). Identifying subclinical arterial disease is a cornerstone of the prevention clinic. This investigation allowed the migration to a ternary classification of CV prevention. Primary prevention care was provided to patients without any arterial disease. Secondary prevention was delivered to individuals with subclinical arterial disease. Tertiary prevention was given to subjects who proved they had arterial disease with interventions or events. This classification aided therapy decisions such as low-dose aspirin (270). The high degree of management compliance is partially attributed to the patient's visualization of the plaque (271). The cIMT testing enhanced care, and the follow-up results proved that atherosclerosis's pathogenesis could be halted in an actual healthcare clinic.

Another strength of the RWE involves the monitoring of arterial inflammation. The prevention clinic assessed the adequacy of management of all the causes of arterial inflammation with these biomarkers. The endothelium was judged for the amount of inflammation by the hsCRP and wellness by the microalbumin-creatinine ratio (272, 273). Intimal inflammation and atherogenic activity were checked with lipoprotein-associated phospholipase A2 (Lp-PLA2) (189). Myeloperoxidase (MPO) was monitored since elevations are associated with an increased risk of endothelial rupture and erosion (274). Urinary F2-isoprostane was followed as a marker of oxidative stress (275). Clinically, the patient was judged to have a quiescent atherosclerotic process and low risk for an atherothrombotic event when all the inflammatory biomarkers were in an acceptable range. This approach was successful, albeit without a complete understanding of the reasons. As explained throughout this paper, we know that all the root causes of inflammation being managed in the clinic generate OS, leading to lipoprotein retention in the intima. The trapped lipoproteins then turn on the immune system, which causes the monitored biomarkers of inflammation to increase. With mitigation of OS, the first step in atherosclerosis's pathogenesis is prevented, ending the chronic association of lipids and inflammation. Once the atherosclerotic disease process stops, any existing atheroma has an opportunity to delipidate and shrink. The RWE showing a significant reduction in Lp-PLA2 supports this concept.

One glaring weakness of the RWE is that there was a lack of ethnic diversity. The good news is that from a biological standpoint, the principle of SOS should halt and stabilize arterial disease regardless of ethnicity. Humans are 99.99% identical from a genetic standpoint. There are different frequencies of genetic variants in ethnic groups, but humans are arguably the same race. Discrete human ethnic groups are based on social constructs such as language, neighborhoods, education, income, preferred foods, and physical activity (276). Biological responses to these social differences will affect the degree of OS. Therefore, any study evaluating the RWE in other ethnic populations must accurately assess the environmental and sociocultural issues affecting the risk factors that generate OS (277). Given this, arterial disease can be halted and stabilized in humans.

The RWE presented supports that the chronic association of lipids and inflammation can be interrupted. SOS can halt the pathogenesis of atherosclerosis. Clinically this requires individual patient management of the myriad of conditions that cause OS. Such management necessitates a time-consuming individualized interdisciplinary healthcare approach. An excellent term for such care is arteriology. There is a vast need for arteriologists. The RWE should be bolstered in additional clinics and populations. It would be challenging to design RCTs to strengthen the data due to the need for personalized care manipulating numerous variations in management. The current RWE is logical and anchored in evidence-based therapies. There is a new meaning for the distress code- SOS, which could enhance the lives of millions.

For interested individuals, the prevention clinic with the RWE has a nomenclature for the system of care delivered. It is called the BaleDoneen Method. Instruction in the method is delivered to other healthcare providers in an approved 17-h CME and CE course. The public can learn about the method from two books [Bale, Bradley F., Doneen, Amy L., & Cool, Lisa Collier (2014). Beat the Heart Attack Gene: The Revolutionary Plan to Prevent Heart Disease, Stroke, and Diabetes. Nashville, TN: John Wiley & Sons.; Bale, Bradley F., Doneen, Amy L., & Cool, Lisa Collier (2022). Healthy Heart Healthy Brain: The Personalized Path to Protect Your Memory, Prevent Heart Attacks and Strokes and Avoid Chronic Illness. New York, NY: Little, Brown Spark].

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.