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4 Current andEmerging Therapies forAtherosclerosis
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The potential cardiovascular benets of this agent have been further demonstrated
via reports of favourable effects on plaque imaging and are being evaluated in large
prospective studies. Cannakinumab is an interleukin-1β antagonist, thought to play
a role in modulating inammasome activity. A large cardiovascular outcomes trial of
statin-treated patients with elevated CRP levels demonstrated that administration of
canakinumab reduced the incidence of cardiovascular events, albeit with a predictable excess in infection [80]. In parallel, a reduction in lung cancer was observed,
underscoring the signicant burden of smoking related lung disease in patients with
clinically manifest atherosclerotic disease. The ndings of this study provide the
rst, large scale validation that specically targeting inammation can have a protective benet in terms of reducing residual risk beyond statin therapy.
81
4.10 Obesity Targeted Therapies
The rising global prevalence of cardiometabolic risk factors parallels the spread of
abdominal obesity. Efforts to curb obesity have the potential to reduce both associated risk factors, but more importantly cardiovascular complications. When introduced at an early stage in life, weight loss has been demonstrated to result in
regression of early changes within the vessel wall. The benets on cardiovascular
risk in older individuals has proven more challenging to demonstrate. While improving the cardiac risk factor prole, weight loss strategies have not yet proven to
reduce cardiovascular event rates in large outcomes trials. This is further supported
by use of a range of pharmacological agents, specically designed to achieve weight
loss, in which a lack of clinical benet, and in some circumstances, an excess in
adverse events has been observed. Whether the weight loss and observed improvement in risk factor prole with GLP-1 receptor agonists produces clinical benet in
the setting of overweight or obesity, but not diabetes, remains to be determined in
clinical trials. An additional approach involves the use of surgical interventions for
extreme levels of obesity. While use of lap band techniques have not proven to be
successful. More extensive techniques involving Roux-en-Y gastric bypass or
sleeve gastrectomy produce robust and durable metabolic benets, which may have
a greater potential to translate to less cardiovascular events [81].
Beyond its effects on conventional metabolic risk factors, obesity is also associated with an excess rate of sleep disordered breathing [82]. Numerous reports have
demonstrated an increase in cardiovascular risk with worsening degrees of obstructive sleep apnoea. A range of mechanisms may underscore this association leading
to potentially an increase in atherosclerotic, heart failure and arrhythmia related
events. While there is considerable interest in the potential role for sleep apnoea
targeted interventions to reduce vascular events, the one large outcomes trial performed to date in this space failed to demonstrate a reduction in cardiovascular risk
[83]. Whether specic triage of patients and dedicated efforts to promoting greater
adherence to therapy during the night results in a greater chance of success remains
to be determined.
82
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A. J. Nelson and S. J. Nicholls
4.11 Cardiac Rehabilitation
With a large body of evidence supporting both lifestyle and pharmacologic
approaches to secondary prevention of atherosclerotic cardiovascular disease, there
has been increasing interest in the provision of rehabilitation services to patients,
particularly in the early weeks following an acute ischaemic event. This has the
potential to reinforce information for patients about living with cardiovascular disease and the rationale for ongoing compliance with preventive therapies. Such clinics have proven to result in greater adherence with therapy, better risk factor control
and several reports of potential reductions in recurrent clinical events [84, 85]. More
efforts are required to determine how to maximise a patient’s chance of attending
and completing these programs, which are likely to be achieved by offering services
in a range of formats and attempts to integrate digital technologies into the long
term monitoring of a patient’s risk factor control.
4.12 Conclusion
Atherosclerotic cardiovascular disease continues to present a major challenge throughout the world. While advances in lifestyle and pharmacologic approaches have made
a substantial impact in reducing risk, many patients are either not offered the full
complement of established therapies or their adherence with these approaches declines
over time. There are ongoing efforts to develop new therapies and to maximise use of
established approaches in the patients that are most likely to benet from their use.
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of the American College of Cardiology Task Force on Expert Consensus Decision
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A. J. Nelson and S. J. Nicholls
Further Reading
Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, et al. Rivaroxaban with
or without aspirin in patients with stable peripheral or carotid artery disease: an international,
randomised, double-blind, placebo-controlled trial. Lancet. 2018;391:219–29. https://doi.
org/10.1016/S0140-6736(17)32409-1.
Das SR, Everett BM, Birtcher KK, Brown JM, Cefalu WT, Januzzi JL Jr, etal. 2018 ACC expert
consensus decision pathway on novel therapies for cardiovascular risk reduction in patients
with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American
College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol.
2018;72:3200–23.
Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, etal. Rivaroxaban
with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319–30.
https://doi.org/10.1056/NEJMoa1709118.
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, etal. 2018 AHA/ACC/
AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the man-
agement of blood cholesterol: a report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082–e143.
https://doi.org/10.1161/CIR.0000000000000625.
Nicholls SJ, Nelson AJ.HDL and cardiovascular disease. Pathology. 2019;51:142–7. https://doi.
org/10.1016/j.pathol.2018.10.017.
Secemsky EA, Yeh RW, Kereiakes DJ, Cutlip DE, Steg PG, Massaro JM, etal. Extended duration
dual antiplatelet therapy after coronary stenting among patients with peripheral arterial disease:
a subanalysis of the dual antiplatelet therapy study. JACC Cardiovasc Interv. 2017;10:942–54.
https://doi.org/10.1016/j.jcin.2017.02.013.
Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, etal.
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for
the prevention, detection, evaluation, and management of high blood pressure in adults:
a report of the American College of Cardiology/American Heart Association Task Force
on Clinical Practice Guidelines. Circulation. 2018;138:e484–594.
CIR.0000000000000596.
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https://doi.org/10.1161/
Chapter 5
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Pathophysiology ofAngiogenesis andIts
Role inVascular Disease
NathanK.P.Wong, EmmaL.Solly, ChristinaA.Bursill, JoanneT.M.Tan,
andMartinK.C.Ng
Key Learning Points
Angiogenesis is the process of new blood vessel formation from pre-existing
•
vessels that is critical for growth and development and in response to tissue isch-
aemia such as that seen during a myocardial infarction or in peripheral artery
disease.
• Uncontrolled angiogenesis is a key contributor to the development and progres-
sion of malignant cancers and atherosclerotic plaque formation. Angiogenesis-
associated diseases are the leading causes of mortality and morbidity worldwide.
Impaired angiogenic responses underpin the mechanisms associated with diabe-
tes- and age-related vascular complications.
• The intricate balance between desirable physiological angiogenesis and unwanted
pathological angiogenesis involves the regulation of a suite of signalling
Joanne T.M. Tan and Martin K.C. Ng contributed equally to this work.
N. K. P. Wong
South Australian Health and Medical Research Institute, Adelaide, SA, Australia
The University of Sydney, Sydney, NSW, Australia
E. L. Solly
South Australian Health and Medical Research Institute, Adelaide, SA, Australia
The University of Adelaide, Adelaide, SA, Australia
C. A. Bursill · J. T. M. Tan (
South Australian Health and Medical Research Institute, Adelaide, SA, Australia
The University of Sydney, Sydney, NSW, Australia
The University of Adelaide, Adelaide, SA, Australia
e-mail: Joanne.Tan@sahmri.com
M. K. C. Ng
The University of Sydney, Sydney, NSW, Australia
Royal Prince Alfred Hospital, Sydney, NSW, Australia
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_5
*)
89© Springer Nature Switzerland AG 2020
90
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pathways, regulatory factors and cell-to-cell interactions. Physiological angio-
genesis is primarily mediated by the hypoxia transcription factor HIF-1α while
pathological angiogenesis is driven by the inammatory transcription factor
NFκB. Numerous angiogenic mediators can be driven by both hypoxia and
inammation.
N. K. P. Wong et al.
5.1 Introduction
The human circulatory system is comprised of a complex branching network of
blood vessels designed to transport oxygen and nutrients to cells, remove waste
products and facilitate immune surveillance. Given its diverse functions, this vascular network must be responsive and capable of adapting to a range of tissue microenvironments, stressors and changing metabolic demands. In the physiologic state,
this is achieved through dynamic yet highly coordinated processes of blood vessel
growth and remodelling, which are under the balanced control of both stimulating
and inhibiting factors. In disease states, however, these processes are frequently
dysregulated, with inadequate, excessive or abnormal vessel growth potentially
leading to a broad range of clinical pathologies [1].
Angiogenesis refers to the process in which new blood vessels, in particular capillaries, are formed from the pre-existing vascular network. Angiogenesis is distinguished from vasculogenesis, which refers to the assembly of a primary vascular
plexus, typically in the developing embryo, that arises de novo from the differentiation of mesoderm-derived precursors called angioblasts [2]. Recent decades of
research have begun to reveal some of the cellular and molecular mechanisms that
underpin the contribution of angiogenesis to the pathophysiology of vascular diseases. Pro-angiogenic stimuli activate endothelial cells (ECs) to detach from their
basement membranes, then migrate and proliferate to form branching tubular structures, driving the sprouting of new capillaries from the primary plexus [2, 3]. Further
remodelling involves the recruitment of mural cells such as vascular smooth muscle
cells (VSMCs) and pericytes, as well as the laying down of extracellular matrix
(ECM) to provide structural stability and facilitate vessel maturation [3]. This process continues until pro-angiogenic cues subside or are inhibited, at which point
vessel growth becomes quiescent and anti-angiogenic factors predominate.
It is well recognised that angiogenesis is a critical process in normal postnatal
growth and development. It is crucial in providing nourishment to granulation tissue
during wound healing, as well as in the formation of collateral vessels as part of an
adaptive response to vascular occlusion and ischaemia [
angiogenesis plays an important role in conditions such as ischaemic heart disease,
peripheral arterial disease (PAD), delayed wound healing and ischaemic stroke.
Conversely, excessive pathological angiogenesis driven by inammation is a key
contributor to the development and progression of malignant cancers, atherosclerotic plaques, proliferative retinal disease and inammatory arthritides, as well as
many other pathologies [5]. A detailed and holistic understanding of the factors
4]. The failure of adequate
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