Received: 1 February 2019 
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  Revised: 9 February 2019 
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  Accepted: 10 February 2019
DOI: 10.1111/apha.13265
E X AC TA
Listen to your physiologist!
Aristotle (384‐322 BC), a Greek philosopher, presented in
one of his earliest work in the fourth century BC an accurate
and universal description of the human cardiovascular sys-
tem. Aristotle laid the foundation of modern evidence‐based
medicine, concluding there cannot be a scientific conclu-
sion which is drawn from a single person or an individual
alone: “Individuum est ineffabile” (The individual cannot be
grasped).1 Nowadays, diseases of the cardiovascular system
(CVD) are the leading cause of illness and death worldwide,
except on the African continent,2 while at the same time
modern clinical medicine sees a paradigm shift towards in-
dividual, personalized treatment refining the standards set by
evidence‐based guidelines.
The overall strategy to fight CVD begins by global car-
diovascular risk assessment and translates to the clinic by the
effort to reduce CVD risk factors. Here, the physician aims
on controlling risk factors such as systolic blood pressure,
cholesterol blood level, adipositas or smoking, either by med-
ication or by motivating the patient to change his life style.3
However, we need basic research for developing novel ther-
apeutic options to target the underlying pathological mecha-
nisms of CVD. In fact, in most cases, the underlying cause
of the cardiovascular events is atherosclerosis and many re-
search projects aim on stabilizing plaques or directly treating
arterial inflammation.4
Physiology, by nature, focusses on function and interac-
tion in biological systems. For clinical practice, the physiol-
ogist's holistic view of the human organism is very valuable
to successfully translate bench results to the bedside. Given
both the significant differences between individual vascular
provinces and their multiple local and systemic interactions,
cardiovascular medicine is indeed an interdisciplinary field.
Only a comprehensive knowledge of the complex inter-
actions within biological systems as well as the impact of in-
dividual differences will pave the way for novel therapeutic
strategies.
Two millennia later, physiologists confirm modern‐day
theories in in vivo studies with careful, conscious interpre-
tation, and thereby cross borders between countries, cultures
and disciplines.5 Hence, all physicians, surgeons, researchers
and inventors out there: Listen to your physiologist!
Cardiovascular physiology and pathophysiology have
been a main focus of physiological research for years, owing
at least in part to the above‐mentioned relevance of CVD with
regard to public health worldwide. Prior articles in this series
© 2019 Scandinavian Physiological Society.     1 of 4
Acta Physiologica. 2019;225:e13265. wileyonlinelibrary.com/journal/apha |
https://doi.org/10.1111/apha.13265
have highlighted the indispensability of effective risk factor
management and health education. Herein, we will focus on
recent research results with potential impact on the develop-
ment of therapeutic options.
Endothelial cell (EC) dysfunction acts as a major mile-
stone on the way to CVD.6 The vascular endothelium, that is,
the inner lining of the mammalian vascular system, not only
acts as a barrier and metabolic interface, but also co‐regu-
lates vascular tone. Endothelial dysfunction is measurable to
a certain degree, but has not yet made it into clinical practice
as a relevant diagnostic tool.7 A disturbed balance between
vasodilating, antimitogenic and antithrombogenic factors
(endothelium‐derived relaxing factors) on the one hand and
vasoconstricting, prothrombotic and proliferative substances
(endothelium‐derived contracting factors) on the other hand
is commonly used to define endothelial dysfunction.8
Park et al9 recently reported how mitochondria‐derived
free radicals are responsible for an impaired endothelium‐de-
pendent vasodilator responses in skeletal muscle feed arteries
of older, otherwise healthy individuals. Beyond the immedi-
ate results and in relation to other studies in different vascular
provinces, the results indicate how age‐dependent changes in
vascular reactivity may differ among resistance arteries of
haemodynamically important vascular beds.10
Other recently described factors involved in EC dysfunc-
tion are soluble epoxide hydrolase, a bifunctional enzyme
whose encoding gene EPHX2 is associated with familial
hypercholesterolaemia, regulated via its epigenetic regula-
tor Jarid1b (KDM5B),11,12 and interferon‐induced protein 35
(IFI35), which had previously been described as an inflam-
matory mediator.13
Micro RNAs, first described in Caenorhabditis elegans in
1993, are non‐coding RNA molecules of approximately 22
nucleotides, involved in RNA silencing and post‐transcrip-
tional regulation of gene expression. Interestingly, Alexandru
et al14 describe how, in a rodent model, healthy donor micro-
particles carrying miRNA ameliorate EC dysfunction on the
progenitor level, thus strengthening the link between miRNA
regulation and CVD pathophysiology.
Wang et al15 recently observed a novel link between de-
creased stress‐related autophagy and endothelial dysfunction
in atherosclerosis, mediated by miR‐214‐3p.16
Atherosclerotic vascular lesions, in general, underlie
CVD. While at first a mere calcification and build‐up mech-
anism was blamed, we know today that atherosclerosis is far
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more complex. Peripheral artery disease (PAD) is referred
to as atherosclerotic narrowing of the arterial vessels of the
extremities, and the aorta. In its most severe form, supply
areas of occluded vessels are insufficient perfused and am-
putation of limbs can be necessary. Observed in its entirety,
the major cause and problem of PAD is shared by all ath-
erosclerotic disease, such as the occlusion of vessels in the
heart (coronary artery disease), and brain (cerebrovascular
disease).
Mechanisms of atherosclerotic lesion development and
progression are far from understood. Recently, Liu and co-
workers have described the mechanisms by which the neu-
ropeptide cortistatin counteracts vascular calcification.17,18
Zhao et al19 describe how CCN family member 1, an ECM‐as-
sociated protein involved in intercellular signalling, interferes
with physiological cholesterol metabolism and aggravates
atherosclerosis. Despite its underlying principle of vascular
occlusion, hypoperfusion and ischaemic organ failure, CVD
characteristics differ between vascular beds. Both cerebral20
and cardiac arteries21 differ significantly in vasomotor func-
tion, CVD development and progression.
Plaques are not static, and while mammalian organisms
respond with regenerative efforts to restore blood flow, the
individual capacity for vascular regeneration is highly vari-
able. Here, the regeneration process relevant for the resto-
ration of vascular inflow is referred to as arteriogenesis. In
the presence of an artery occlusion, pre‐existing small col-
lateral vessels (arterioles) develop into much larger arter-
ies (biological bypasses) that have the potential to allow a
certain level of perfusion distal to the blockage.22 Regularly
performed physical exercise has been shown to improve ar-
teriogenesis; however, CVD patients are severely limited in
performing active exercise.23
Physical activity is beneficial in CVD, both in primary
and secondary prevention. Numerous studies have aimed at
elucidating the underlying mechanisms, for example, long‐
term high‐level endurance training in young female athletes
is associated with potentially favourable peripheral artery ad-
aptation,24 which provides a new perspective on risk factor
management to counteract the CVD risk brought about by a
sedentary lifestyle.
Exercise may induce heritable epigenetic modifications
that augment transcriptional programmes protective of
CVD,25 while p53‐mediated adaptations to chronic exercise
training26 have implications for a multitude of cellular func-
tions, including their regenerative potential.
Individual shear rate therapy (ISRT) has shown to enhance
regenerative vascular remodelling (arteriogenesis), increases
quality of life and improves endothelial function.23,27 ISRT is
regarded as non‐invasive treatment option for PAD patients
and simulates exercise (passive exercise). In PAD, exercise,
together with a passive shear rate (ISRT) therapy regimen,
increases peripheral blood mononuclear cell telomerase
activity, thus enhancing the regenerative potential of immune
cells and vascular tissues.28,29
Individual or personalized therapies are frequently re-
ferred to as precision medicine. Precision medicine is an
emerging approach for disease treatment and prevention,
and takes into account individual variability in patient genes,
anatomy and lifestyle.30 A personalized medicine describes
the disease at a higher resolution by clinical or genomic tech-
nologies to enable more precise targeting of subgroups of pa-
tients with new therapies.31
Treatment strategies that affect one person might not
necessarily be beneficial for another person, which is well
known in training were personalized supervised exercise
programs (active or passive) show strong results for preven-
tion and recovery from CVDs. A good example for a per-
sonalized therapeutic concept is provided by the continuous
development of Antepulsation from ISRT (passive training).
Before Antepulsation therapy, individual angioarchitecture
is evaluated by high‐definition ultrasound, and the relative
pulse wave index (RPSI) will be assessed in the calf arteries.
RPSI was shown to correlate with arterial development and
the highest RPSI is considered the value at which therapeu-
tic regenerative arteriogenesis can be maximized.32
Later, Antepulsation is performed by cuffs that are
wrapped around patients legs, which are inflated in the early
diastole of each cardiac cycle ECG triggered (from hip to
leg)—thereby enhancing arterial pulse wave velocity in the
distal direction. The Antepulsation method described here is
conducted to deliver individual treatment pressures (between
120 mm Hg and 180 mm Hg cuff pressure), and for continu-
ous monitoring in order to achieve the best therapeutic effect.
In contrast to enhanced external counterpulsation
(EECP), were patients are treated with pressure between
250‐300 mm Hg, Antepulsation uses low cuff‐pressures. It was
shown that a generalized high pressure concept (EECP) needs
to be reconsidered since it may result in side effects and may
decreased arterial flow velocity in the lower limb and brain.33,34
In summary, there is increasing awareness of the neces-
sity of understanding the underlying mechanisms of vascular
biology in order to provide sustained healing for CVDs. The
physiologist is the scientist that combines the basic knowl-
edge about, for example angiology with the complexity of the
pathology of CVDs. Physiologists understand that the same
treatment is not necessarily result‐based for all patients. The
pattern of concomitant diseases, the varying causes of the
diseases, the individual vessel architecture and the genetic
background affect the further course of the diseases. There
must be a coherent approach to research and individualized
treatment concepts. Antepulsation is a prime example of
‘more is not necessarily better’. Instead individual parame-
ters need to be considered to calculate optimum treatment
parameters. Hence, please do not pressure me, but listen to
your physiologist!
EXACTA
CO N F LIC T OF IN T E R E ST
None.
ORCID
Philipp Hillmeister  https://orcid.org/0000-0003-1749-2315
Philipp Hillmeister1
Ivo Buschmann1
Anja Bondke Persson2
1 tween autophagy and endothelial cell dysfunction in atherosclero-
Department for Angiology, Brandenburg Medical School,
Campus Clinic Brandenburg, DAZB Deutsches Angiologie
Zentrum Brandenburg-Berlin, Brandenburg an der Havel,
Germany
2
Charité– Universitätsmedizin Berlin, Corporate Member
of Freie Universität Berlin, Humboldt‐Universität zu Berlin,
and Berlin Institute of Health, Berlin, Germany
Email: p.hillmeister@klinikum-brandenburg.de
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