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Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical Abstract), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.

Mutations in the RMRP-gene, encoding the lncRNA component of the RNase MRP complex, are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in RMRP RNA lead to skeletal dysplasia. Since chondrogenic differentiation of the growth plate is required for development of long bones, we hypothesized that RMRP RNA plays a pivotal role in chondrogenic differentiation. Expression of Rmrp RNA and RNase MRP protein subunits was detected in the murine growth plate and during the course of chondrogenic differentiation of ATDC5 cultures, where Rmrp RNA expression was found to be correlated with chondrocyte hypertrophy. Genetic interference with Rmrp RNA expression in ATDC5 cultures caused a deregulation of chondrogenic differentiation, with a prominent impact on hypertrophy and changes in pre-rRNA processing and rRNA levels. Promoter reporter studies showed that Rmrp RNA expression responds to chondrogenic morphogens. Chondrogenic trans-differentiation of cartilage-hair hypoplasia fibroblasts was impaired with a pronounced impact on hypertrophic differentiation. Together, our data show that RMRP RNA expression is regulated during different stages of chondrogenic differentiation and indicate that RMRP RNA may play a pivotal role in chondrocyte hypertrophy, with potential consequences for CHH pathobiology.