Through the multidimensional looking glass: Novel perspectives on heart failure

Heart failure is a deadly chronic cardiovascular disease which affects millions of people worldwide. The rapid increase of new heart failure cases globally urges a necessary shift in the current approaches. This thesis underscored the importance of broadening the perspectives of scientific research in heart failure: by adding the dimension of time (4D) – in terms of circadian rhythms and daily fluctuations – and by using advanced 3D in vitro models that adequately recapitulate native human myocardium, we gained novel insights into this deadly disease. We showed that circadian rhythms can indeed be used to improve clinical interventions, diagnosis and prognosis of heart failure patients, and offered an overview of sources suitable to study these rhythms both in human health and disease. We showed the importance of taking timing into account when measuring prognostic biomarker sST2 concentration as well as pinpointed the optimal time of day to measure pulmonary artery pressures with CardioMEMS sensors. Furthermore, we characterized circadian rhythmicity in heart failure patients and showed that the rhythmic expression of the main endocrine products of the central clock, melatonin and cortisol, is dampened when compared to the healthy controls, thus opening exciting opportunities to develop new interventions targeting the circadian clock. Lastly, we designed a mechanically tunable 3D in vitro model of human cardiac fibrosis to study its mechanistic properties, as well as for it to serve as a tissue-specific drug testing platform. Overall, with the work in this thesis, we set the stage for novel dimensions of diagnostic, prognostic and therapeutic approaches in heart failure.