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Challenges and Opportunities in Atherosclerosis

Challenges and Opportunities in Atherosclerosis

Rusanov, S. Y. (2022)

Abstract

The article is presented in the form of a review and analysis of the literature, which additionally helps to reveal the mechanisms of the pathogenesis of the development of atherosclerosis in humans. A contemporary vision is refuted that animal models of atherosclerosis are completely similar to the two types of human atherosclerotic lesions. The use of incorrect information about the etiology and pathogenesis of atherosclerotic lesions in humans reduces and even completely interferes with the possibility to carry out effective treatment and prevention of cardiovascular diseases associated with atherosclerosis. The two types of human atherosclerotic plaques have very different characteristics compared to atherosclerotic plaques in animals. They have a completely different etiology, pathogenesis, have a completely different appearance and location relative to the artery wall, have a different structure of the fibrous cap, a different pathway of LDL and macrophages, a different location of lipid core, a different way and time of arterial occlusion, a different type of endothelial dysfunction, they interact in totally different way with the walls of the artery and still have many additional differences that make both human atherosclerotic lesions completely different from atherosclerotic lesion in animals. Types IV atherosclerotic lesions consist of one lipid core with molten extracellular lipid. Type V atherosclerotic lesions type is a long, concentric, soft, strong, elastic, yellow, uniform structure. Due to the large number of inconsistencies between atherosclerotic lesions in animals and the two types of atherosclerotic lesions in humans, it is neither possible nor reasonable to use animal models to study the development of atherosclerotic lesions in humans. The plaques appear in the lumen of the artery in just a few days, in places of a sharp narrowing of the artery caused by hyperstimulation of the nervous system. The plaques consist of LDL, which were glued together with fibrin filaments. It also doesn’t allow to detect a very simple mechanism accountable for the pathological increase in LDL levels in people who do not have genetic abnormalities. This mechanism proposed by the author is described in the first article dedicated to the type V atherosclerotic lesions (“Cylindrical cholesterol plaque”).

Sabbah, M. (2023)

Abstract

The early detection of atherosclerosis has been the interest of researchers in order to prevent diseases progression. And, most of cases diagnosed with atherosclerosis in late stages resulted of subjective ways of diagnosis in the healthcare sector.

Consequently, in order to help cardiologists diagnose atherosclerosis in early stages with an objective, fast and accurate way, we are proposing a machine learning model based on autoencoders that enables atherosclerosis detection from MRI images of murine subjects.

This novel way of automated system consists of applying various image processing techniques on the input MRI images. Then, after training, testing and validation it will be capable of classifying the images as atherosclerotic or not based on a specific threshold for the reconstruction error calculated from the autoencoders’ output.

An autoencoder is a feed-forward neural network that has its input neurons equal to the output neuron. The classification works by comparing the reconstructed images to the original input images and evaluating loss between them. Since the autoencoder is trained on healthy images, reconstruction error of the healthy images would be low while that of atherosclerotic subjects would be higher. By setting a threshold for the loss, we can classify the images as healthy or atherosclerotic.

The pre-processing of these images was made using a Block Matching 3D (BM3D) filter to remove the noise in the images prior to application of a Contrast Limited Adaptive Histogram Equalization (CLAHE) to enhance the contrast. The next step included introducing the dataset into the autoencoder to start training on the healthy images, after increasing the images number with augmentation.

The results showed a reconstruction loss of 0.018 while using the stacked architecture of the autoencoder and 0.0366 when using the convolutional autoencoder architecture.

Borges, S., Mendonça, M., Sousa, J., Serrão, M., Santos, M., Temtem, M., Sá, D., Sousa, F., Henriques, E., Borges, S., Freitas, S., Rodrigues, M., Guerra, G., Drumond, A., Sousa, A., & Palma Reis, R. (2023)

Abstract

Introduction: Identifying markers to discriminate high and low-risk individuals better is essential. Coronary Calcium Score (CAC) is an established marker of subclinical atherosclerosis. Epicardial Adipose Tissue (EAT), a new imaging biomarker, has shown considerable interest in the scientific community.

Purpose: Study the impact of EAT volume in discrimination and reclassification of cardiovascular events when added to CAC score. Investigate whether EAT volume is a good prognosis marker in an asymptomatic population.

Methods: A cohort of 1024 individuals without coronary disease were selected and followed prospectively during an extended period. CAC score was evaluated by cardiac tomography. Quantification of EAT was performed through a semi-automated technique (TeraRecon Aquarius Workstation). Pearson’s or Spearman’s correlations identified EAT-associated parameters. Harrel C-statistics assessed the discriminative ability for events. Categorical free Net Reclassification Improvement (cfNRI) and Integrated Discrimination Index (IDI) reclassified the individuals. Kaplan-Meier evaluated cardiovascular disease prognosis, and Cox regression identified variables independently associated with cardiovascular events.

Results: EAT volume was significantly correlated with age, body mass index, non-high-density lipoprotein (HDL) cholesterol, triglycerides, systolic and diastolic blood pressure, and inversely with HDL cholesterol. CAC score and EAT had a C-Statistic of 0.737 (0.651 – 0.823) and 0.662 (0.564-0.760), respectively. When EAT was added to CAC, it increased to 0.777 (0.681 – 0.873) and 60% of the participants were better reclassified (NRI=60%). Higher EAT volume displayed the worst prognosis (p=0.006) and was associated, independently, with cardiovascular events, even after adjusting for risk factors and CAC score (p=0.021).

Conclusions: EAT may be an essential imaging marker of subclinical atherosclerosis and a potential therapeutic target for primary prevention. Reducing EAT volume with adequate measures (physical exercise, proper diet, pharmacological interventions) could decrease atherosclerosis and improve outcomes.

Morales-Villegas, E., Castillo-Núñez Y., & Badimon, J. (n.d.). 

Abstract

Aim and scope: This review is intended to update the knowledge, but above all, to understand the difference between “normal” level vs. biological level of LDL cholesterol (LDL-C) and the physiology of the metabolism of lipoproteins with apoprotein B100 (LP-apoB100). Such medical knowledge is fundamental before introducing to the world of dyslipidemia, atherosclerosis, and pharmacotherapeutics.

Unfortunately, the teaching of the enunciated concepts -as a starting point for basic knowledge- is frequently mixed with multiple related topics, among them: the pathophysiology analysis of LP-apoB100 metabolism, that is, of dyslipidemias; the description of transgenic animal models for their study; Mendelian randomization studies of the correlation between certain genetic patterns or single nucleotide polymorphism with specific dyslipidemias and atherosclerotic cardiovascular disease (ASCVD), the study at different levels of atherosclerosis -main consequence of the abnormal metabolism of LP-apoB100- and finally, the treatment of atherogenic dyslipidemias, atherosclerosis, and ASCVD.

Hence, teaching these concepts is complex, and therefore, also the learning by the non-specialist physician of these priority chapters in modern medicine. This review is premised on the following sentence: “LP-apoB100 were not created by nature to cause atherosclerosis”.

In this contemporary review we will analyze current knowledge on: the physiological value of LP-apoB100 with an emphasis on LDL, metabolism of LP-apoB100 (assembly and secretion of VLDL by the hepatocyte, circulatory transformation of VLDL to IDL, circulatory/hepatic transformation of IDL to LDL and hepatobiliary elimination of LDL) and finally LDL oxidation and elimination by reverse transport.

As Goldstein and Brown anticipated in the 1970s: “only by understanding the metabolism of LP-apoB100 will we be able to develop drugs to treat hypercholesterolemia and reduce its implicit atherosclerotic cardiovascular risk.”

Infections May Cause Arterial Inflammation, Atherosclerosis, Myocarditis and Cardiovascular Disease

Ravnskov, U., Alabdulgader, A., & McCully, K. S. (2023)

Abstract

Effective prevention and treatment of atherosclerosis and cardiovascular disease (CVD), the commonest cause of death in most countries, is still lacking. For many years we have studied the cholesterol hypothesis and found that there are many contradictions to this hypothesis. For instance, no trial has shown exposure response; the lipid values are not associated with degree of atherosclerosis, and people with high LDL-C live just as long or longer than people with low LDL-C. These facts together with the observation that inflammation is a common finding in atherosclerotic arteries have probably contributed to the hypothesis that CVD may be caused by inflammation. However, several trials with anti-inflammatory drugs have shown that such treatment increases the risk of CVD. Therefore, a relevant hypothesis is whether it is infections which cause the inflammation and whether CVD may be caused by infections because many human observations and animal experiments are in accordance with this idea. As cholesterol-lowering treatment is ineffective and may cause serious side effects, we believe that future research should elucidate the importance of infections in the etiology of CVD. A relevant method would be to perform a blood culture on all patients with an acute AMI and if it is positive, to treat the patient with an appropriate antibiotic.

Sergey, R. (2023). 

Abstract

An analysis of scientific literature, photo and video materials showed that plaques in humans are completely different from plaques in animals and the «contemporary official description» of AS. They differ in appearance, lack of inflammation of the walls of the artery, clinical manifestations, complications. It has also been found that «true» plaque has nothing to do with the first four types of atherosclerosis in humans. It was necessary to understand how in the lumen of a healthy artery a strong, elastic, yellow, homogeneous plaque in the form of a hollow cylinder – a «cylindrical plaque» – appears very quickly? As a result, the «Hydrodynamic Theory» was proposed, which answers all the complex questions related to the appearance, aging and destruction of «true» plaques in humans. It describes the etiology, pathogenesis, clinical manifestations, classification, complications, methods of treatment and prevention of «cylindrical» plaques that cause heart attacks and strokes in humans.

Karpouzas, G., Ormseth, S. R., Hernández, E., & Budoff, M. J. (2023)

Abstract

Methods. The sample included 144 patients with complete biomarker data who underwent plaque evaluation with coronary computed tomography angiography; 95 were re-imaged within 6.9±0.3 years. Presence of >5 segments with plaque or coronary artery calcium >100 constituted extensive disease; lesions rendering >50% stenosis were considered obstructive. The Framingham 2008 cardiovascular risk score was included in all models.

Results. Hs-cTnI added to the cardiovascular risk score increased area-under-the curve (AUC) from 0.710 to 0.729 and improved prediction accuracy for baseline plaque presence [Net Reclassification Improvement =0.538 (95% confidence interval 0.143-0.895)] and Integrated Discrimination Improvement (IDI) =0.035 (0.001-0.128). In contrast, a-b2GPI-IgA did not, and the combination offered no added benefit over hs-cTnI alone. While hs-cTnI alone did not predict plaque progression, a-b2GPI-IgA presence did (p=0.005), especially in patients with >median hs-cTnI (p=0.015). In patients with >median hs-cTnI, adding a-b2GPI-IgA to a cardiovascular risk score model predicting progression from non-extensive/non-obstructive to extensive/obstructive plaque increased AUC from 0.796 to 0.878 and improved model precision [IDI=0.277 (0.011-0.946)].

Conclusion. High hs-cTnI significantly improved prediction of baseline plaque presence and may trigger an initial non-invasive coronary atherosclerosis evaluation. A-b2GPI-IgA presence may justify a follow-up interrogation in patients with non-extensive, non-obstructive plaque at baseline.

Rusanov, S. Y. (2022b)

Abstract

The “contemporary official” description of AS, according to the generally accepted theory, should completely coincide with vascular lesions in an animal and vascular lesions in humans. A study of AS in humans and animals has shown that humans have two separate types of lesions that are completely unrelated. Both species have their own characteristics (etiology, pathogenesis, appearance), which are completely different from each other. Lesions in humans also do not coincide with lesions in animals. The “contemporary” type of AS differs both from AS in animals and AS in humans, but at the same time creates the illusion of “identity” of these processes. In practice, the “contemporary” look cannot be found in the vessels of animals and humans. This article analyzes how the “contemporary” type of atherosclerotic lesion appeared, and how, for 100 years, the “contemporary” type could create an imitation of the “similarity” of completely different processes.