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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
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
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 plaques
26
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 Netherlands
27
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 p66Shc 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.
