Atherosclerosis: The Road Ahead

This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

Role of Oxidative Modifications in Atherosclerosis

The human ATP-binding cassette (ABC) transporter superfamily

Immune responses participate in every phase of atherosclerosis. There is increasing evidence that both adaptive and innate immunity tightly regulate atherogenesis. Although improved treatment of hyperlipidaemia reduces the risk for cardiac and cerebral complications of atherosclerosis, these remain among the most prevalent of diseases and will probably become the most common cause of death globally within 15 years. This Review focuses on the role of immune mechanisms in the formation and activation of atherosclerotic plaques, and also includes a discussion of the use of inflammatory markers for predicting cardiovascular events. We also outline possible future targets for prevention, diagnosis and treatment of atherosclerosis.

The immune response in atherosclerosis: a double-edged sword

The ATP-binding cassette (ABC) transporter superfamily contains membrane proteins that translocate a variety of substrates across extra- and intra-cellular membranes. Genetic variation in these genes is the cause of or contributor to a wide variety of human disorders with Mendelian and complex inheritance, including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response. Conservation of the ATP-binding domains of these genes has allowed the identification of new members of the superfamily based on nucleotide and protein sequence homology. Phylogenetic analysis is used to divide all 48 known ABC transporters into seven distinct subfamilies of proteins. For each gene, the precise map location on human chromosomes, expression data, and localization within the superfamily has been determined. These data allow predictions to be made as to potential functions or disease phenotypes associated with each protein. In this paper, we review the current state of knowledge on all human ABC genes in inherited disease and drug resistance. In addition, the availability of the complete Drosophila genome sequence allows the comparison of the known human ABC genes with those in the fly genome. The combined data enable an evolutionary analysis of the superfamily. Complete characterization of all ABC from the human genome and from model organisms will lead to important insights into the physiology and the molecular basis of many human disorders.

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized by absence of plasma high-density lipoprotein (HDL) and deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes. Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors. In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts, which have a reduced in vitro growth rate. The TD locus has been mapped to chromosome 9q31. Here we present evidence that TD is caused by mutations in ABC1, encoding a member of the ATP-binding cassette (ABC) transporter family, located on chromosome 9q22-31. We have analysed five kindreds with TD and identified seven different mutations, including three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the understanding of cellular HDL metabolism and reverse cholesterol transport, and its association with premature cardiovascular disease.

The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease


 
 
 Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Bundesministerium für Bildung und Forschung.
 
 
 
 Cardiovascular diseases (CVD) remain the most common cause of death, although mortality due to CVD in Germany has decreased continuously over the past 20 years. The reasons for this decline are manifold. Besides the identification of risk factors, the application of algorithms for risk stratification, and the promotion of preventive means, the improvement in treatment strategies was of crucial importance [1, 2]. The ABC-CHD risk model combines novel biomarkers such as N-terminal pro-B-natriuretic peptide (NT-proBNP) and cardiac troponin T (hs-cTnT) with conventional factors in a unifying risk score which has been shown to reliably assess risk for CV mortality in patients with chronic coronary syndrome (CCS) [3]. However, data from the tertiary prevention setting, comparing its performance during different time periods, are scarce.
 
 
 
 This study aimed to describe the characteristics and mortality of two cohorts of patients with CCS with identical study designs recruited in the same rehabilitation clinics approximately 10 years apart.
 
 
 
 The KAROLA cohorts included patients with CCS participating in an inpatient cardiac rehabilitation programme in Germany (KAROLA-I: 1999/2000, KAROLA-II: 2009-2011) [details in 4]. Blood samples and information on sociodemographic factors, lifestyle, and medical treatment were collected at baseline, at the end of rehabilitation, and after 1-year follow-up. A biomarker-based risk model (ABC-CHD model) [3] and Cox regression analysis were used to predict cardiovascular (CV) and non-CV mortality risk during 10 years of follow-up.
 
 
 
 We included 1130 patients from KAROLA-I (mean age 58.7 years, 84.4% men) and 860 from KAROLA-II (mean age 60.4 years, 83.4% men). Patients in the KAROLA-I cohort had significantly higher concentrations of CV biomarkers and fewer patients were taking CV medications, except for statins. The ABC-CHD model which also included age, current smoking, history of diabetes, peripheral arterial disease, as well as hs-cTNT, NT-proBNP, and LDL-cholesterol provided a higher estimate of CV death risk for patients in the KAROLA-I cohort (mean 3-year risk, 3.8%) than for patients in the KAROLA-II cohort (mean 3-year risk, 2.7%, p for difference <0.001). After 10 years of follow-up, 91 (8.1%) patients in KAROLA-I and 45 (5.2%) in KAROLA-II had died from a CV event. Non-CV mortality was quite similar among the two cohorts. Notably, when statin medication upon discharge was included as an exposure variable in the Cox model that included age, sex, biomarkers, and clinical variables for the combined analysis with both cohorts, the HR for CV mortality was 0.54 (95% CI 0.31-0.93) in patients taking high-potency statins compared with patients not on statin medication.
 
 
 
 Advances in disease management including pharmacological treatment over the past 20 years may have led to modest improvement of long-term prognosis of patients with CCS.


/pdf/comparison-of-medical-care-and-long-term-mortality-in-two-8j7l58ns.pdf

Comparison of medical care and long-term mortality in two cohorts of patients 10 years apart with chronic coronary syndrome

Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high. 

https://doi.org/10.1016/j.athplu.2023.06.001

Harry W. Hahmann

Papers

The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease

Comparison of medical care and long-term mortality in two cohorts of patients 10 years apart with chronic coronary syndrome

The German CaRe high registry for familial hypercholesterolemia – Sex differences, treatment strategies, and target value attainment