Clinical Vascular Research

«Man is as old as his vessel.» (R. Virchow, 1821–1902)

Clinical Vascular Research Team (from left to right): Dr. Thomas Haider, Dr. Delia Nebunu, Dr. Leonie Kreysing, Prof. Dr. Andreas Flammer, Anne-Marieke Vegter, Dr. Matthias Nägele, Prof. Dr. Isabella Sudano, Dr. Sander Trenson.

Vessels connect heart, brain and hand

Vessels connect our entire body. This is also how we understand our research: For two decades now, our research group has been pursuing this integrative approach. We do not regard the heart as an isolated structure, but as a vital team player in a complex network of vessels that spans the entire body and connects all organs. For us, clinical research always means teamwork at its heart: heart failure and prevention specialists work closely with study coordinators and postdocs across the disciplines of physiology, endocrinology, rheumatology, ophthalmology, and neurology.

However, the most important concern of our interdisciplinary clinical research team remains the good and professional relationship with our patients. Our subjects trust us to provide them with good treatment in every respect. Their willingness to participate in studies involving vascular function measurements, data submission, biomaterial and randomization to innovative therapies allows us to find relevant answers to open scientific questions – or to raise new questions.

The football field-sized organ endothelium, which lines all our vessels from the inside, is the central object of our research. Humans have large vessels (macrovessels), such as the brachial artery, and very small vessels (microvessels), such as the vessels in the back of the eye (retinal vessels). The core of our research is to combine gold standard methods of vascular function measurement with new and innovative approaches to investigation. This provides us with new perspectives on the different parts of our vascular bed and allows us to explore their role in health, risk, disease and therapy.

Measurement of vascular function

Endothelial function can now be clinically assessed in several ways and has become a potentially important parameter for early detection of atherosclerotic vascular changes and for estimating the risk of later cardiovascular disease. Measurement of endothelium-dependent vasodilation can be performed invasively and noninvasively. Invasive methods include, for example, intracoronary infusion of acetylcholine followed by quantitative coronary angiography. Practical potential outside the cath lab is mainly with noninvasive methods: Flow-mediated dilatation (FMD) of the brachial artery (Fig. 2) , skin microcirculation by Doppler laser and especially retinal vessel analysis (RVA, Fig. 1.).

Structurally, we assess vessels e.g. with pulse wave analysis (PWA; Fig.3) as a measure of arterial stiffness and with the ocular fundus assessment in the context of RVA (arterio-venous vessel ratio, AVR). Sonographic assessment of carotid intima-media thickness is also used for comprehensive phenotyping of vascular function.

The eye as a window to the heart

The dynamic retinal vessel analysis of RVA allows us to gain completely new insights in an almost amazingly simple way: the eye as a window to the heart (Fig. 4).

Fig. 4: Illustration dynamic retinal vessel analysis.

The method is based on high-resolution video recordings with computer-based measurement of the blood vessels of the ocular fundus before and after the application of flicker light. Flicker light increases the oxygen demand of the retina, which is compensated by dilation of the associated vessels. This dilation is mediated in large part by nitric oxide (NO), a central messenger of healthy endothelial cells. Thus, insufficient dilation of retinal vessels is a sign of endothelial dysfunction of small vessels (microvascular dysfunction).

Currently, the Clinical Vascular Research team is using DVA to study endothelial function in heart failure and in classical risk factors. Thus, in an observational study, endothelial function in small vessels in the eye is compared with endothelial function in the upper arm and vascular stiffness in patients with heart failure, subjects with cardiovascular risk factors, and healthy controls. We were able to demonstrate for the first time microvascular damage in heart failure using dynamic functional analysis of retinal vessels and publish highly (Nagele, Barthelmes et al. 2018). We identified hypercholesterolemia as an important risk factor that can lead to microvascular dysfunction (Nagele, Barthelmes et al. 2018). It was also shown that in the progression of coronary artery disease to ischemic cardiomyopathy, retinal microvascular dysfunction increases progressively (Barthelmes, Nagele et al. 2019). Thus, retinal vascular function reflects the continuum of progressive vascular damage. Through this, the method could be very useful for characterization of different cardiac disease, initial risk stratification, as well as for assessment of therapeutic success in patients with cardiovascular risk factors or disease. In the ongoing observational study, we are therefore currently looking in more detail at the vascular profile of, for example, heart failure patients with preserved systolic ventricular function (HFpEF).

Drugs can improve – or worsen – vascular function

One focus of the research group is to test the cardiac safety of commonly prescribed drugs. Among other things, the effect of paracetamol, a commonly used painkiller, on blood pressure and endothelial function in patients with coronary heart disease was investigated. It was shown that paracetamol is not without cardiovascular side effects as assumed, but can increase blood pressure (Sudano, Flammer et al. 2010). Furthermore, the effects of polyphenol series substances (dark chocolate, pycnogenol) on endothelial function were investigated in patients with heart failure or coronary artery disease on vascular function. We were able to show that both pycnogenol and dark chocolate can improve endothelial function in these patients and thus presumably counteract the development of atherosclerosis (Flammer, Hermann et al. 2007).

Currently, the team is investigating the role of endothelial function as a potential marker for the success of new heart failure therapies. In this context, we are currently investigating vascular function under valsartan/sacubtril (Entresto®) versus valsartan alone (VASCEND-LCZ). A recommendation for valsartan/sacubitril has already been included in the guidelines due to clear improvements in prognosis and rehospitalization rates. We help explain why valsartan/sacubitril shows such promise. In addition to new drugs, non-drug therapies are increasingly used in modern medicine. For example, cardiac resynchronization therapy (CRT) can significantly improve heart failure. The support of the SNSF enables us to investigate the effect of this cardiac resynchronization therapy on vascular function in more detail.

In addition to vascular function, another project supported by the SNSF focuses on sympathetic nerve activity. The aim of the OPIOVASC study is to investigate the vascular and sympathetic effects of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis compared to healthy subjects. We have already used this combination of measurement methods in previous studies. We showed that patients with Takotsubo syndrome had impaired endothelial function and increased sympathetic nervous system activity compared with controls. This study highlights the potentially central role of stress and stress processing in the development of this disease (Naegele, Flammer et al. 2016).

Against stress, chocolate-dark chocolate-helps. After our results on the benefit of dark chocolate on vascular function (Flammer, Hermann et al. 2007) were published under some media attention, we are currently continuing the investigation of polyphenol-like substances in a catheter study. We are testing the effect of a flavonoid drink (contained in dark chocolate) on coronary vessels in patients already suffering from cardiac disease.

Blood volume as an important link of the cardiovascular system

Blood is the transport medium within the vascular network of our body and transports vital oxygen, nutrients and messenger substances (hormones) but also metabolic end products as well as cells of the immune system and coagulation. The blood volume of a human being is on average about 5 liters. It is composed of about 60% fluid, the blood plasma, and about 40% solid components, mainly blood cells. It is regulated by various organs and hormonal systems such as the renin-angiotensin-aldosterone system (RAAS). Diseases of the cardiovascular system, such as heart failure, can lead to a pathologically altered blood volume status. Volume overload (hypervolemia) is the most common reason for decompensation of the cardiovascular system in heart failure and not infrequently leads to hospitalization and the use of dehydrating medications (diuretics). Conversely, anemia, a reduction in red blood cell mass, is relatively commonly observed in heart failure. Anemia is associated with an increased risk of disease and mortality. Maintaining a physiological blood volume (euvolemia) is thus of central importance in the therapy of heart failure. Indirect methods of determining volume status, such as clinical signs of volume overload (e.g., neck vein congestion signs), are relatively imprecise and nonspecific in this regard. Therefore, accurate and reliable determination of blood volume using quantitative measurement methods plays an essential role. Measurement of blood volume using the carbon monoxide rebreathing method (CORB, Fig. 5) is a non-invasive, safe and easy-to-use method for determining blood volume and its components (e.g. plasma volume, total hemoglobin mass, red blood cell volume). Using this method, we recently demonstrated that heart failure patients with preserved left ventricular ejection fraction (HFpEF) may have reduced blood volume compared with healthy individuals of the same age, which was reflected, among other things, by increased activity of blood volume-regulating hormone systems (Montero, Haider et al. 2019). Here, the reduced blood volume was due to reduced red blood cell volume (RBCV), which may contribute to reduced oxygen-carrying capacity with impaired exercise capacity. In another comparative study, we also demonstrated that even a single hemodialysis session leads to an altered response of the small vessels of the ocular fundus (mainly the venules) to flicker light (Montero, Haider et al. 2020). Currently, we are investigating in a prospective observational study (BLOVO-CVD1) the blood volume status and its role with respect to vascular function in heart failure patients compared to patients with cardiovascular risk factors and healthy subjects of the same age. Furthermore, we are investigating the role of blood volume in patients with refractory hypertension in a cross-disciplinary collaboration project (HYRENE). In the future, we also want to increasingly evaluate blood volume status in acute heart failure with the ambitious goal of establishing blood volume measurement to determine current volume status and to monitor and manage drainage therapy in routine heart failure clinical practice. In addition, we will also evaluate the effects of new volume-regulating drugs such as the SGLT2 inhibitors on volume as well as vascular status in clinically stabilized heart failure patients after acute decompensated heart failure (ADHF) as part of the DAPA-VOLVO project.

Fig. 5: Non-invasive measurement of blood volume using the carbon monoxide rebreathing (CO-RB) method and the use of a fully automated meter (OpCO, Detalo Health).