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 system. Aristotle laid the foundation of modern evidence-based medicine, concluding there cannot be a scientific conclusion 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 individual, personalized treatment refining the standards set by evidence-based guidelines. The overall strategy to fight CVD begins by global cardiovascular 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 medication or by motivating the patient to change his life style.3 However, we need basic research for developing novel therapeutic options to target the underlying pathological mechanisms of CVD. In fact, in most cases, the underlying cause of the cardiovascular events is atherosclerosis and many research projects aim on stabilizing plaques or directly treating arterial inflammation.4 Physiology, by nature, focusses on function and interaction in biological systems. For clinical practice, the physiologist'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 interactions within biological systems as well as the impact of individual differences will pave the way for novel therapeutic strategies. Two millennia later, physiologists confirm modern-day theories in in vivo studies with careful, conscious interpretation, 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 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 development of therapeutic options. Endothelial cell (EC) dysfunction acts as a major milestone 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-regulates 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-dependent vasodilator responses in skeletal muscle feed arteries of older, otherwise healthy individuals. Beyond the immediate 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 dysfunction are soluble epoxide hydrolase, a bifunctional enzyme whose encoding gene EPHX2 is associated with familial hypercholesterolaemia, regulated via its epigenetic regulator Jarid1b (KDM5B),11, 12 and interferon-induced protein 35 (IFI35), which had previously been described as an inflammatory 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-transcriptional regulation of gene expression. Interestingly, Alexandru et al14 describe how, in a rodent model, healthy donor microparticles 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 decreased 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 mechanism was blamed, we know today that atherosclerosis is far 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 amputation of limbs can be necessary. Observed in its entirety, the major cause and problem of PAD is shared by all atherosclerotic 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 coworkers have described the mechanisms by which the neuropeptide cortistatin counteracts vascular calcification.17, 18 Zhao et al19 describe how CCN family member 1, an ECM-associated 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 function, 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 variable. Here, the regeneration process relevant for the restoration of vascular inflow is referred to as arteriogenesis. In the presence of an artery occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (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 arteriogenesis; 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 adaptation,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 functions, 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 referred 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 technologies to enable more precise targeting of subgroups of patients 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 prevention and recovery from CVDs. A good example for a personalized 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 therapeutic 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 continuous 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 necessity 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 knowledge 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 parameters need to be considered to calculate optimum treatment parameters. Hence, please do not pressure me, but listen to your physiologist! None.