Untangling the Pathophysiologic Link Between Coronary Microvascular Dysfunction and Heart Failure With Preserved Ejection Fraction

Aish Sinha; Haseeb Rahman; Andrew Webb; Ajay M. Shah; Divaka Perera

Disclosures

Eur Heart J. 2021;42(43):4431-4441. 

In This Article

Pathophysiological Links Between Coronary Microvascular Disease and Heart Failure With Preserved Ejection Fraction

Impaired Lusitropy

Whilst the significance of impaired NO pathways is well established in the development of CMD, eNOS dysfunction is also thought to play a central role in the pathogenesis of HFpEF.[29] A systemic inflammatory state, induced by cardiovascular risk factors, leads to increased endothelial production of reactive oxygen species.[30] Reactive oxygen species, such as superoxide ions, react with NO to form peroxynitrite. Peroxynitrite oxidizes the eNOS cofactor tetrahydrobiopterin (BH4), which results in eNOS uncoupling and reduced NO production and bioavailability, which, in turn, leads to reduced cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG) activity. Protein kinase G is involved in titin phosphorylation; titin is a cytoskeletal protein that acts as a bidirectional spring and is responsible for early diastolic recoil and late diastolic distensibility of cardiomyocytes. Therefore, titin hypophosphorylation makes cardiomyocytes less compliant.[31] The impaired NO–cGMP–PKG axis leads to heightened diastolic stiffness through hypophosphorylation of titin in cardiomyocytes, leading to impaired lusitropy and LV diastolic reserve (Graphical Abstract).

Furthermore, an up-regulation of inducible nitric oxide synthase (iNOS) has also been implicated in the pathogenesis of HFpEF.[32] Pharmacological eNOS inhibition, in a murine model of HFpEF, enhanced iNOS activity. This led to dysregulation of protein quality control, resulting in accumulation of misfolded proteins, which ultimately resulted in cardiomyocyte dysfunction and impaired lusitropy. Importantly, pharmacological inhibition of iNOS improved lusitropy and exercise intolerance in this model of HFpEF.[32]

Subendocardial Ischaemia

Mechanistic studies have consistently demonstrated that patients with HFpEF have an inability to adequately augment their myocardial blood flow (MBF) and oxygen delivery during stress. Patients with HFpEF and NOCAD demonstrate a higher LV external work, MVO2 and MBF at rest but blunted rise in these indices during dobutamine-induced stress, compared to control subjects.[33] Although myocardial oxygen extraction is enhanced, the rise in MBF (supply) is inadequate to meet the change in LV external work (demand) in patients with HFpEF. The myocardial oxygen supply:demand mismatch is associated with limitations in LV systolic and diastolic reserve, alongside the inability to adequately increase cardiac output during exercise, which can lead to sufficient ischaemia to cause elevation in high-sensitivity troponin T levels.[34] Patients with HFpEF have reduced phosphocreatine:ATP ratio during exercise,[35] which may explain the impaired LV diastolic reserve as ATP is required during diastole for the detachment of the myosin head from actin and for the extrusion of intracellular calcium ions. Reduced ATP production, due to inadequate myocardial perfusion, will likely lead to incomplete diastolic relaxation due to diastolic cross-bridge cycling. Whilst these data suggest that subendocardial ischaemia, due to attenuated augmentation of MBF during stress, may be pathogenetic in HFpEF, it is not clear whether this precedes the changes in myocardial reserve or is caused by the latter. A vicious cycle has been proposed, whereby attenuated oxygen delivery impairs myocyte relaxation, which promotes heightened myocardial tension and increased oxygen consumption demands.[36,37]

In summary, cardiovascular risk factors, such as hypertension, diabetes mellitus, and hyperlipidaemia, lead to a systemic inflammatory state, which leads to endothelial dysfunction through eNOS uncoupling. Coronary endothelial dysfunction, clinically diagnosed as an inability to augment CBF by ≥50% in response to acetylcholine, leads to impaired lusitropy through the NO–cGMP–PKG pathway. Impaired lusitropy may potentiate subendocardial ischaemia, both leading to impaired myocardial reserve and HFpEF. Coronary microvascular disease, which may represent a later stage in the coronary microvascular dysfunction spectrum than endothelial dysfunction, leads to subendocardial ischaemia through the impaired ability of the VSM to relax in response to appropriate stimuli. This may potentiate impaired lusitropy and lead to impaired myocardial reserve and HFpEF (Graphical abstract).

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