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Novel approach to treating pulmonary hypertension

left to right: Prof. Dr. med. Christoph Knosalla, Dr. Mariya Kucherenko, Prof. Dr. med. Wolfgang Kübler (© C.Maier / DHZC)

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Heart failure is already one of the leading causes of death. It affects around four million people in Germany, and the number is rising. In many cases, heart failure also causes abnormally high blood pressure in the lung vessels. This "pulmonary hypertension" in turn often dramatically accelerates the progression of heart failure, often with fatal consequences. In "Nature Communications", scientists from the Charité Hospital in Berlin, Germany, now document decisive progress in understanding this comorbidity - and point the way to a possible therapy for millions of patients worldwide.

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Pulmonary hypertension describes when the pressure in the blood vessels leading from the heart to the lungs is permanently elevated. The disease can have various causes, but in around half of all people with pulmonary hypertension, left heart failure is the underlying cause. In this condition, the heart muscle is too weak to pump the oxygen-rich blood from the left ventricle to the rest of the body.
The chronically elevated blood pressure in the pulmonary circulation puts a strain on the right side of the heart, which pumps the oxygen-poor blood from the body into the pulmonary artery. In the long term, this can lead to heart failure.

Unresolved questions in understanding a common disease

What are the structural changes in the pulmonary arteries of patients with pulmonary hypertension associated with left heart disease (PH-LHD), what role do these changes play in the progression of the disease, and how can they be prevented? How can they possibly be stopped? An international team of researchers led by Prof. Dr. med. Christoph Knosalla from the German Heart Centre of the Charité (DHZC) and Prof. Dr. med. Wolfgang Kübler from the Institute of Physiology at Charité - Universitätsmedizin Berlin, funded by the German Centre for Heart and Circulatory Research (DZHK). The Charité and DZHK scientists have now published their findings in the journal Nature Communications. The first author is Dr. Mariya Kucherenko.

Disturbed balance in the vessel walls

The "extracellular matrix", also known as the "skeleton" of the vessel walls of pulmonary arteries, consists mainly of collagen and elastic fibres. In simple terms, the collagen fibres provide the strength of the vessel wall, while the elastic fibres provide the flexibility - similar to a network of firm tissues and elastic rubber bands. If this balance between elasticity and rigidity is disturbed, the vessel walls can become stiff. In pulmonary arterial hypertension, a rare but serious form of pulmonary hypertension, these pathological changes in the vascular wall have already been described in detail by various research groups, but much less is known about the changes in patients with pulmonary hypertension as a result of left heart disease (PH-LHD). However, this form of the disease is much more common, especially in older people: It is estimated to affect 10% of people over the age of 65.

Groundbreaking findings

Using tissue samples from PH-LHD patients, the research team led by Christoph Knosalla and Wolfgang Kübler was able to identify extensive changes in the extracellular matrix and analyse the underlying cellular processes. According to their findings, the stiffening of the pulmonary artery is initially the result of progressive degradation of elastic fibres, followed by the accumulation of fibrillar collagen within the vessel wall. In particular, the researchers found that the degradation of elastic fibres begins early in the course of the disease - even before the changes in blood pressure in the pulmonary circulation and the stiffening of the arterial wall can be detected in the patients.

First steps towards drug development

In addition, there has already been promising evidence of a possible therapy: The chemical compound pentagalloyl-glucose (PGG; a naturally occurring sugar ester) was able to significantly reduce the degradation of elastin in the laboratory, thus halting or even reversing the hardening of the arteries. In the animal model, the researchers were able to confirm their laboratory results: Targeted administration of PGG nanoparticles normalised lung pressure, prevented progression of pulmonary hypertension and relieved the right ventricle. "With this study, we have taken a major step forward in understanding pulmonary hypertension in left heart failure and, at the same time, point the way to the development of an early therapy," summarises co-study leader Christoph Knosalla. "We now want to deepen these encouraging findings and translate them into diagnostic and therapeutic procedures as quickly as possible. In particular, Knosalla wants to better understand to what extent the remodelling processes in the pulmonary artery can be used to "predict" the severity and course of the disease. "The early and optimal treatment of heart failure is one of the greatest challenges facing cardiovascular medicine in view of the ever-increasing number of people affected. We are delighted that we can make a not inconsiderable contribution to this with our study," says Wolfgang Kübler: "We would like to thank all our collaborators and supporters for this".


Original publication: “Elastin stabilization prevents impaired biomechanics in human pulmonary arteries and pulmonary hypertension in rats with left heart disease”; Nature Communications 14

Scientific contact: Prof. Dr. med. Christoph Knosalla, German Heart Center of the Charité Berlin und Prof. Dr. med. Wolfgang Küble, Institute for Physiology, Charité Berlin

Quelle: press release DHZC