Table 4.

Major limitations and knowledge gaps for MVD in HFpEF.

Limitation	HFpEF is a heterogeneous syndrome and has a variety of diagnostic criteria. This leads to different study populations with different disease stages and clinical phenotypes [5].
	Studies mainly focused on a general pathophysiology for an entire HFpEF population rather than selected phenotypes.
	The microvascular function is a continuum, and there is no clear cut-off value to define microvascular dysfunction in human biology. Nevertheless, studies are often focused on finding cut-off values that can have direct clinical implications. Both quantitative and categorical approaches are needed to improve current knowledge of MVD in HFpEF and could help in evaluating the likelihood of biological causality.
	No gold standard exists to assess MVD. Studies often overgeneralize specific microvascular alterations, which limits study designs and comparability within and between studies.
	MVD is not exclusive to HFpEF. Important drivers and clinical correlates of both (Table 3) need to be accounted for when interpreting study results. This requires larger study populations, which are not available in most of the current literature.
	Intervention studies with a direct or indirect effect on MVD have not selected patients based on those MVD aspects that are targeted with the intervention, limiting causal inference.
Knowledge Gap	Knowledge on causality and underlying mechanisms of MVD and HFpEF is mostly derived from animal models, but their agreement with corresponding human phenotypes needs more research [180].
	Comparable longitudinal data of microvascular function are lacking in healthy individuals, HFpEF development, and adverse disease progression due to heterogeneity in microvascular assessments and HFpEF definitions.
	The role of MVD in specific HFpEF phenotypes remains to be elucidated.
	The similarity and underlying mechanisms of peripheral and coronary MVD in HFpEF deserve more investigation, as similar impairments with the same underlying mechanism could guide future targeted therapies.