Monika Rech

Hartfalen blijft een van de belangrijkste doodsoorzaken wereldwijd ondanks de verbeterde behandeling van cardiovasculaire ziekten. Therapieën die hartfalen behandelen richten zich op het bestrijden van de symptomen en niet op de oorzaak. Ook beïnvloeden alle hartfalen therapieën de functie van eiwitten, terwijl we sinds kort weten dat het grootste deel van ons DNA, 80%, afgeschreven wordt in niet-eiwit coderende genproducten. Deze genproducten, die niet-coderende RNAs worden genoemd, beïnvloeden de functies van de "traditionele" eiwitten. Het is daarom aannemelijk dat niet-coderende RNAs een therapeutische goudmijn vormen. In mijn proefschrift, getiteld “Unraveling metabolic mechanisms in heart failure: microRNAs as part of the puzzle”, ofwel “Het ontrafelen van metabole mechanismen in hartfalen: microRNAs als deel van de puzzel”, ging ik op zoek naar nieuwe niet-coderende RNA-mechanismen in hartfalen. Ik heb me gericht op een specifieke klasse niet-coderend RNA, die van de microRNAs. MicroRNAs zijn kleine RNA moleculen die specifiek binden aan bepaalde eiwit-coderende RNAs, en microRNAs remmen hierbij de omzetting van deze eiwit-coderende RNAs in eiwit.

Er is nog niet veel bekend over de rol van microRNAs in hartmetabolisme. Een verstoring van hartmetabolisme wordt als een van de mechanismen gezien die ten grondslag liggen aan de ontwikkeling van hartfalen. Echter, hoe deze verstoring optreedt en hoe we het hartmetabolisme kunnen verbeteren, is nog grotendeels onbekend. Tijdens mijn promotieonderzoek heb ik 1) nieuwe protocollen ontwikkeld voor de bestudering van hartmetabolisme in celkweek, en 2) twee microRNAs in het lab bestudeerd die een rol hebben in de regulering van hartmetabolisme. Deze resultaten staan beschreven in mijn proefschrift. De belangrijkste bevindingen zijn: 1) de invloed van omgevingsfactoren op het hartmetabolisme wordt snel “vergeten” als de omgevingsfactoren wegvallen; 2) dat ontsteking en de regulering van ontstekingsactiviteit door ons kandidaat-microRNA bijdraagt aan het verstoren van hartmetabolisme en aan hartfalen; 3) dat bij het toepassen van medicijnen, waaronder microRNA remmers, voor de behandeling van een metabole ziekte als diabetes, rekening gehouden moet worden met de effecten van deze medicijnen op het hartmetabolisme en de nadelige gevolgen hiervan voor de hartfunctie.

Dit proefschrift focust zich daarom op het begrijpen van basale moleculaire mechanismen in hartfalen, zonder de klinische behoeften uit het oog te verliezen; het vinden van nieuwe therapeutische en diagnostische targets voor de behandeling van hartfalen.

Valorization Addendum

Socio-economic relevance

Heart failure is the leading cause of death worldwide and is an enormous burden in terms of public health 1,2. Addressing it should be considered a global health priority. At present, approximately 26 million people worldwide are living with heart failure. In Europe, over 1 million hospitalisations due to heart failure are reported annually. Beside its impact on mortality rates, heart failure severely affects the quality of life of patients and places great stresses on caregivers and healthcare systems 3. Demands on healthcare services, in particular, are predicted to increase dramatically over the next decade as patient numbers rise as a result of ageing populations and detrimental lifestyles 4. Though clinical management has remarkably improved in the last decade, leading to reduced mortality, the incidence of cardiac disease remains tremendously high. While the research community is striving to find new therapeutic strategies to treat heart failure, we still fail to understand the pathophysiological mechanisms that lead to cardiac dysfunction. Fundamental research is vital for understanding heart failure pathophysiology with the goal of finding novel therapeutic targets and improving quality of life. MicroRNAs are small molecules that control and can affect gene expression in our body. They were considered as junk RNA until 10 years ago but since then they have been unmasked as powerful regulators of most biological processes. The understanding of how microRNA could contribute to the development of heart failure may provide novel inputs to treat this disease and will have high relevance to society.

In this thesis I provide evidence for the important role of specific microRNAs during health and during development of heart failure. MicroRNAs have a realistic potential as therapeutic targets. This fundamental and translational research is part of the road towards individualized therapy, providing treatment targeted to the cause of the disease instead of the more general treatment of the symptoms.

Target groups

The focus of this thesis is on the pathophysiology of heart failure as a consequence of metabolic syndrome and/or hypertension. The content of this thesis is relevant to the scientific community, to Pharma companies, to public institutes that will set up and run clinical trials to improve treatments for patients. In addition to the scientific/academic community, the ultimate and most important target groups of this thesis are the patients with hypertensive heart disease, metabolic heart failure, heart failure with preserved and reduced ejection fraction, and those who are at risk of developing heart failure. Importantly, since non-coding RNAs regulate the molecular mechanisms of all life processes, the findings in this thesis are transferrable and applicable to other diseases. The microRNAs described in this thesis are most likely also involved in other disease settings. For example, the identification of microRNAs involved in the regulation of mitochondrial function and insulin sensitivity, like miR-103/107 described in this thesis, is of interest of the general community of patients with metabolic syndrome, type 2 diabetes, neurodegenerative disorders, endothelial dysfunction, chronic obstructive pulmonary disease and aging.

Science communication

Despite the burden that heart failure imposes on society, the awareness of the disease is sometimes still limited. Even after heart failure has developed, premature deaths could be prevented if patients were taught to recognize the symptoms. Public awareness campaigns have great potential to improve outcomes for patients with heart failure and ultimately to save lives. Patient education programs could have a dramatic effect on improving outcomes and on prevention. Where needed, access to end-of-life care and support for all patients, families, and caregivers should form part of a high-quality service.

It is crucial to maintain and encourage international collaborative research to fully understand the underlying pathophysiology of heart failure. Research will ultimately lead to new therapies for improved clinical outcomes of patients with all types of heart failure. However, the more we understand about the underlying pathophysiology of heart failure, the more becomes clear that the treatment should be heading for both inside and outside the heart. For this reason, cardiologists and other specialists are projected to closely communicate for the treatment strategies of heart failure patients.

Activity and products

The basic research conducted in this thesis was performed at the department of Cardiology at the Cardiovascular Research Institute Maastricht (CARIM). The department has recognized expertise in investigating molecular mechanisms and specifically non-coding RNAs in complex models of heart failure. The acquired knowledge and the implementation of a new model for studying heart failure in vivo, will directly contribute to the expertise of the researchers involved, allowing them to further advance the understanding of the molecular mechanisms of heart failure. Moreover, the results described in this thesis will be documented and implemented in original scientific articles that will enable scientists and clinicians worldwide to build on the presented research data. The articles are or will be submitted to internationally well-recognized peer-reviewed journals where they are or will be accessible globally to the scientific community. In addition, knowledge obtained from these studies is currently communicated in the setting of international conferences by means of posters and oral presentations.

Innovation

In this thesis we studied the role of specific microRNAs in complex models of metabolic and hypertensive heart failure. One major challenge for developing therapeutic targets for heart failure and especially heart failure with preserved ejection fraction (HFpEF) is the fact that most animal models fall short of capturing the complexity of the human disease, and human data remain limited. Here we established a mouse model for studying the main risk factors predisposing to HFpEF, namely, hypertension, obesity and pre-diabetes. The development of diagnostic and therapeutic tools such as microRNA-like molecules for heart failure depends on the comprehensive knowledge of the pathophysiological mechanisms underlying this disease. This thesis contributes to a better understanding of the mechanisms that lead to cardiac disease during hypertension, obesity and diabetes, conditions that often co-exist in Western society. Promisingly, the concept of microRNA therapeutics is rapidly developing for a variety of diseases. There are currently a number of companies investing in RNA-based therapeutics that are highly specific and stable in vivo. We describe the role of microRNAs miR-103/107 and miR-155 in the heart. Although we demonstrated that the microRNAs studied in this thesis are involved in the regulation of cardiac function and metabolism, there are further steps that need to be taken. For instance, future research will have to confirm our findings in larger animal models to make a first translation to clinical applications. After successful translation these microRNAs can become targets for pharmaceutical companies in order to determine the dosage, tissue targeting, and side effects.

Continuing research is essential if we aim at addressing the unmet needs in caring for patients with heart failure. New therapies are required for patients with types of heart failure such as HFpEF for which current treatments relieve symptoms but do not address the disease. Besides, more affordable therapies are desperately necessary in the economically developing world. International collaborative research focusing on understanding the causes and treatment of heart failure worldwide has the potential to benefit tens of millions of people. It is time to make a difference by confronting the heavy burden of heart failure on society.