Heart failure with preserved ejection fraction (HFpEF), a well-recognised growing health problem accounting for approximately half of all HF patients, is still without completely defined mechanistic background(s) (1). After a decade of failures and disappointments of the clinical trials that tested drug effectiveness for HFpEF, only recently promising data have emerged (2). The concept of endotyping HFpEF (identifying the distinct underlying pathophysiological mechanism) and phenotyping HFpEF patients might be a promising way to go, considering heterogenous HFpEF pathophysiology and diversity of HFpEF patients (1, 3).
Coronary microvascular disfunction (CMD), assessed invasively and non-invasively, is present in approximately two thirds of HFpEF patients and associated with systemic endothelial dysfunction and haemodynamic markers of HF severity (4). Additionally, among patients without epicardial CAD investigated for chest pain and/dyspoea (i.e., microvascular angina) CMD strongly influenced future risk for HFpEF hospitalisation (5). The potential (causal) link between CMD and HFpEF emerged, postulating CMD as the core pathophysiological component for HFpEF development. Since myocardial stiffening and fibrosis are structural and functional hallmarks of HFpEF, repetitive microvascular ischaemia/reperfusions due to CMD (with consequent myocardial injury and fibrosis) and enhanced pro-hypertrophic (and profibrotic) signalling due to diminished endothelial nitric oxide bioavailability in the milieu of chronic microvascular inflammation were proposed as driving forces for HFpEF development. Basically, this paradigm was foundation for the paper of Kanagala et al (6).
Kanagala et al., corroborate the high incidence of CMD, assessed by multiparametric cardiac MR (CMR) with perfusion imaging, in a large prospective observational cohort study of symptomatic HFpEF patients. CMD, defined as myocardial perfusion reserve (MPR) <2 was present in 70% of patients with HFpEF versus 48% of control subjects (p= 0.014). Furthermore, the independent association between CMD and all-cause mortality or hospitalisation for HF in HFpEF patients was found for: 1 SD increase of CMD, HR for combined events was approximately 0.6 after adjustment for clinical, blood and imaging parameters. However, the authors did not find significant linear correlation between MPR and diffuse fibrosis (assessed by extracellular volume – ECV and indexed ECV - iECV). Also, there was no difference in MPR between HFpEF patients with and without focal non-infarction fibrosis.
This study strongly supports the prognostic importance of CMD in HFpEF, but argues against (perhaps too simplified) an intuitively conceptualised chain of events (chronic CMD inducing myocardial fibrosis leads to HFpEF). Interestingly, the study identified some other CMD correlates in HFpEF patients (age, HR, diastolic BP, Hb, urea, creatinine, eGFR, BNP, usage of loop diuretics and non-invasive estimate of LV filling pressure - E/e prim).
Several things should be commented regarding this important study. First, although the MPR is widely recognised as a non-invasive standard for CMD assessment it reflexes one aspect of the coronary microcirculation - an endothelium independent vasodilatation, predominantly determined by microvascular structural changes (microvascular remodeling, rarefaction, etc.), and strongly influenced by the haemodynamic status at the time of the MPR assessment. In contrast to the commented study, in most other studies investigating MPR in HFpEF, myocardial blood flow at rest was increased, with the limited ability to be increased more in response to endothelium independent vasodilator (adenosine), resulting in reduced MPR. In the commented study myocardial blood flow at rest was as in control group (normal), whereas the driving force of reduced MPR was impaired hyperaemic myocardial blood flow. This warrants further explanations (perhaps earlier stage of HFpEF in commented study). Second, new CMR techniques for quantitative myocardial perfusion are available, offering more precises MPR assessment. Third, increased ECV is not ultimate histological diagnosis of interstitial fibrosis, although it correlates nicely with biopsy proven fibrosis in certain HFpEF patients. The new CMR techniques (mapping) are now available for more reliable cardiac fibrosis quantification. Fourth, invasive CMD testing in HFpEF patients pointed that several (at least four) potential mechanisms/ endotypes underlying CMD in HFpEF (7). Consequently, there is hight uncertainty which of these CMDs endotypes might be a cause, and which of these might be a consequence of HFpEF and/or at which stage of HFpEF development. At this moment it is also vague whether SGLT2 inhibitor(s) proved to be effective HFpEF patients, works through CMD improvement and whether this potential effect depends on the HFpEF phenotype /endotype/stage.
Well-designed prospective studies investigating distinct subtypes of HFpEF patients with comprehensive CMD assessment (orientated towards invasive coronary physiology) might provide better insight into CMD mechanisms in HFpEF, (potential) causal relation between CMD and HFpEF and more clearly define therapeutic target(s) for both entities (that seems to be in the constant interplay). Until then the enigma whether CMD is a servant or master of HFpEF remains (as it is still in many other diseases in the cardio-vascular continuum).