Understanding and preventing atherosclerosis: from bench to bedside

I got nothing out of this, lots of big words but nothing that clearly states what needs to be done. Whom the fuck was this written for? 

Understanding and preventing atherosclerosis: from bench to bedside

Thomas F Lüscher, MD, FESC

European Heart Journal, Volume 40, Issue 4, 21 January 2019, Pages 323–327, https://doi.org/10.1093/eurheartj/ehz001

Published:

21 January 2019

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For the podcast associated with this article, please visithttps://academic.oup.com/eurheartj/pages/Podcasts.
Atherosclerosis is the underlying process of chronic and acute coronary syndromes, as well as of certain forms of stroke and peripheral artery disease. Atherosclerotic plaques which are the culprits of the disease process develop over decades, leaving enough room for early preventive measures. As outlined in the special article entitled ‘The Year in Cardiology 2018: prevention’ by Željko Reiner from the University Hospital Center Zagreb, Croatia and colleagues,¹ several large-scale studies in cardiovascular prevention have been published in 2018, in particular on novel approaches for dyslipidaemia such as PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition^2–5 and on the impact of SGLT2 (sodium-glucose co-transporter-2) inhibition in diabetics.^6,7 Moreover, the 2018 European Guidelines on Arterial Hypertension redefined optimal blood pressure for younger and elderly hypertensives.⁸
Positive results of trials on the efficacy and safety of advanced renal denervation in hypertension have further expanded the therapeutic spectrum in such patients. Disappointingly, the use of aspirin in primary prevention does not have a favourable risk–benefit ratio,^9–12 whereas in patients with atherosclerotic cardiovascular disease at very high risk, the addition of low-dose factor Xa inhibition to aspirin can provide a net clinical benefit.¹³ New data on inflammation as a treatment target in high-risk patients further expanded secondary prevention in cardiovascular patients.
Prevention should start as early as possible.¹⁴ Unhealthy lifestyles, in particular smoking and alcohol use,¹⁵ exert unfavourable effects on the vasculature already in adolescence, as outlined in the article ‘Early vascular damage from smoking and alcohol in teenage years: the ALSPAC study’ by Marietta Charakida and colleagues from King’s College London in the UK.¹⁶ They determined the impact of smoking and alcohol on arterial stiffness in 1266 participants at 13, 15, and 17 years of age. Interestingly, current smokers had a higher pulse wave velocity compared with non-smokers, and higher smoking exposure was associated with higher pulse wave velocity compared with non-smokers (Figure 1). However, participants who stopped smoking had a similar pulse wave velocity to never smokers. High-intensity drinkers also had increased pulse wave velocity, with an additive effect of smoking and alcohol. Thus, smoking exposure even at low levels and intensity of alcohol use were associated individually and together with increased arterial stiffness, a known measure of vascular age. What public health strategies would be required to prevent adoption of these habits in adolescence and to preserve or restore arterial health are outlined in an Editorial by Thomas Münzel from the Johannes Gutenberg Universität in Mainz, Germany.¹⁷

Figure 1

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The combined effect of smoking over a lifetime and intensity of drinking on arterial stiffness. The combination of high-intensity drinking with lifetime smoking exposure is shown. Pulse wave velocity measurements are expressed as mean values and 95% confidence intervals around the mean on the x-axis. The participants who had ‘high’ drinking intensity and ‘high’ smoking exposure had the highest pulse wave velocity compared with the ‘low lifetime smoking exposure’ and ‘low drinking intensity’. *P < 0.05 (from Charakida M, Georgiopoulos G, Dangardt F, Chiesa ST, Hughes AD, Rapala A, Davey Smith G, Lawlor D, Finer N, Deanfield JE. Early vascular damage from smoking and alcohol in teenage years: the ALSPAC study. See pages 345--353).

PCSK9 loss-of-function genetic variants are associated with lower LDL-cholesterol,¹⁸ but also with higher plasma glucose levels and increased risk of type 2 diabetes mellitus.¹⁹ Giuseppe Norata and colleagues from the University of Milan in Italy investigated the molecular mechanisms underlying this association in their article entitled ‘PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor’.²⁰ To that end, wild-type mice were compared with PCSK9 knockout, LDL-receptor knockout, PCSK9/LDL receptor double knockout, as well as liver-selective PCSK9 knockout mice. Glucose clearance was impaired in PCSK9 knockout mice fed a standard or a high-fat diet compared with controls, while insulin sensitivity was unaffected. Interestingly, PCSK9 knockout mice exhibited larger islets with increased accumulation of cholesteryl esters, paralleled by increased intracellular levels of insulin and decreased plasma insulin and C-peptide levels. This was reverted in PCSK9/LDL receptor double knockout mice, implying that the LDL receptor is the PCSK9 target responsible for the phenotype. Further studies in liver-selective PCSK9 knockout mice, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver-derived PCSK9, the principal target of monoclonal antibodies, does not impact beta cell function and insulin secretion. Thus, locally produced PCSK9 controls pancreatic LDL receptor expression perhaps thereby limiting cholesterol overload of beta cells (Figure 2), a novel and potentially clinically important finding that is further discussed in an interesting Editorial by Francesco Paneni from the University Zurich in Switzerland.²¹

Figure 2

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Impact of Pcsk9 deficiency on β-cell function. PCSK9 produced and released from δ cells controls low-density lipoprotein receptor expression in β cells. Pcsk9 deficiency results in increased expression of low-density lipoprotein receptor in β cells, thus leading to increased accumulation of cholesterol esters which impact glucose-stimulated insulin secretion, resulting in hyperglycaemia and impaired glucose tolerance observed (from Da Dalt L, Ruscica M, Bonacina F, Balzarotti G, Dhyani A, Di Cairano E, Baragetti A, Arnaboldi L, De Metrio S, Pellegatta F, Grigore L, Botta M, Macchi C, Uboldi P, Perego C, Catapano AL, Norata GD. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. See pages 357–368).

Atherosclerosis is a chronic inflammatory disease with subendothelial infiltration of white blood cells,^22,23 uptake of modified lipids by monocytes, and increased local levels of cyto- and chemokines.^24,25 Activated T cells are prominent in atherosclerosis plaques²⁶ and negatively regulated by E3-ligase Casitas B-cell lymphoma-B (CBL-B) which is expressed in macrophages. In their article entitled ‘Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8⁺ T cell-mediated macrophage death’, Esther Lutgens and colleagues from the University of Amsterdam in The Netherlands²⁷ report lower expression of CBL-B in advanced human atherosclerotic plaques and is inversely correlated with the necrotic core area. Of note, Cblb/Apoe double knockout mice exhibited increased plaque area. Plaques contained fewer macrophages due to increased apoptosis, had larger necrotic cores, and contained more CD8⁺ T cells. Cblb/Apoe double knockout macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. CBL-B deficiency increased the number of CD8⁺ T cells, which were protected against apoptosis and Treg-mediated suppression. Interferon-γ and granzyme B production was also enhanced in Cblb/Apoe double knockout CD8⁺ T cells, which provoked macrophage killing. Depletion of CD8⁺ T cells in Cblb/Apoe double knockout bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8⁺ T cells. Thus, CBL-B expression in human plaques decreases with atherosclerosis progression. CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8⁺ T-cell activation and CD8⁺ T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques.
Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity,²⁸ but the underlying molecular mechanisms remain poorly understood. The adaptor p66^Shc is emerging as a key molecule for ROS generation and vascular damage.²⁹ In their article ‘Interplay among H3K9-editing enzymes SUV39H1, JMJD2C, and SRC-1 drives p66^Shc transcription and vascular oxidative stress in obesity’, Francesco Cosentino and colleagues from the University Hospital Solna in Stockholm, Sweden investigated whether epigenetic regulation of p66^Shc contributes to obesity-related vascular disease.³⁰ ROS-driven endothelial dysfunction was observed in visceral fat arteries isolated from obese subjects as compared with lean controls. Gene profiling of chromatin-modifying enzymes in visceral fat arteries revealed a significant dysregulation of methyltransferase SUV39H1, demethylase JMJD2C, and acetyltransferase SRC-1 in obese as compared with control subjects. This was associated with reduced di-(H3K9me2) and tri-methylation (H3K9me3) as well as acetylation (H3K9ac) of histone 3 lysine 9 (H3K9) on the p66^Shc promoter. Reprogramming SUV39H1, JMJD2C, and SRC-1 in isolated endothelial cells and aortas from obese mice suppressed p66^Shc-derived ROS, restored nitric oxide levels, and rescued endothelial dysfunction. Consistently, in vivo editing of chromatin remodellers blunted obesity-related vascular p66^Shc expression. SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment to the p66^Shc promoter as its overexpression in obese mice erased H3K9-related changes on the p66^Shc promoter while SUV39H1 genetic deletion in lean mice reproduced obesity-induced H3K9 remodelling and p66^Shc transcription. Thus, this represents a novel epigenetic mechanism underlying endothelial dysfunction in obesity. Targeting SUV39H1 may attenuate oxidative transcriptional programmes and thus prevent vascular disease in obese individuals.
This issue is complemented by Discussion Forum contributions. In their contribution ‘Effect of statins on measures of coagulation: potential role of low-density lipoprotein receptors’, Francesco Paciullo and colleagues from the Universita degli Studi di Perugia in Italy comment on a recently published paper ‘Rosuvastatin use improves measures of coagulation in patients with venous thrombosis’ by Joseph Biedermann and colleagues from Erasmus MC in Rotterdam, The Netherlands.^31,32 Joseph Biedermann and Willem Lijfering respond to the comments by Paciullo et al. in their own response.³³ In another Discussion Forum ‘Is the PURE study pure fiction?’ Edward Archer and colleagues from EvolvingFX in Lake Worth, USA discuss the recently published paper entitled ‘Diet and nutrition after the PURE study’ by Sanjay Sharma and colleagues from St George’s University of London in the UK.^34,35
The editors hope that readers of this issue of the European Heart Journal will find it of interest.