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


Eur Heart J. 2021;42(43):4431-4441. 

In This Article

Research and Clinical Implications

Research Implications

Impaired flow reserve, the hallmark of CMD, likely leads to impairment of myocardial reserve, which eventually results in HFpEF. Impaired CFR, as measured by the diminished response to adenosine and acetylcholine, has been closely linked to exertional pulmonary arterial wedge pressure in patients with HFpEF.[42] Future research should prospectively assess the dynamic relationship between intracoronary physiology and LV haemodynamics during exercise; this may help untangle the 'cause vs. effect' dilemma that currently plagues our understanding of this intimate relationship. Along with human studies, animal HFpEF models (for instance, using Dahl salt-sensitive rats) may also be useful to understand the longitudinal pathophysiological link between CMD and HFpEF. Once a mechanistic link has been confirmed, the next step would be development of pharmacotherapy targeting specific abnormalities within the pathway. Although the recent 'one size fits all' therapeutic studies targeting the NO–cGMP–PKG pathway have yielded disappointing results, it is conceivable that better disease characterization and endotype-specific therapeutic targets may yield positive outcomes. Informatics and machine-learning techniques may help to identify different endotypes based on statistically clustered clinical and biological characteristics.

Furthermore, a better understanding of the mechanistic link between CMD and HFpEF may provide further therapeutic targets for the CMD–HFpEF endotype, which target the subendocardial ischaemia pathway. Finally, development of risk prediction scores, using invasive and non-invasive parameters of coronary microvascular function, may allow clinicians to predict the likelihood of patients developing CMD–HFpEF.

Clinical Implications

Once the diagnosis of CMD has been confirmed, aggressive pharmacotherapy should be commenced with the primary aim of ameliorating microvascular dysfunction and the secondary aim of preventing, or delaying, the onset of CMD–HFpEF. Small studies have demonstrated improvement of CFR with angiotensin converting enzyme inhibitors and statins.[43] Longitudinal studies are needed to assess whether this treatment strategy prevents the development of HFpEF in patients with CMD. To this effect, routine non-invasive monitoring of systemic microvascular function, via peripheral endothelial assessment or non-invasive coronary flow velocity reserve measurement, may permit focused titration of prognostic and anti-ischaemic therapy in patients with CMD.

After the disappointing results of renin–angiotensin–aldosterone system inhibitors and beta-blockers in patients with HFpEF, the scientific community turned to agents that could modulate the NO–cGMP–PKG pathway. However, despite initial positive outcomes from pre-clinical and pilot studies, none of these drugs have demonstrated favourable outcomes in large trials. The study results and the potential reasons behind the neutral outcomes are illustrated in Figure 4.[44–50]

Figure 4.

Results of therapeutic trials targeting the nitric oxide–cyclic Guanosine Monophosphate–protein kinase G pathway. (A) Summarizes the pilot data (or pre-clinical data), clinical trial data and the potential reasons for neutral outcomes, whilst (B) highlights the specific intracellular pathways that each of the novel agents act on. None of these trials met their primary endpoints. However, all of these trials are plagued by specific and generic trial design limitations. The treatment arm of CAPACITY-HFpEF and SOCRATES-PRESERVED trials lasted for only 12 weeks, which may not have been long enough to lead to sustained improvements in the study endpoints. The patient cohort recruited in the CAPACITY-HFpEF and VITALITY-HFpEF trials may represent a 'healthier' cohort that is not representative of the 'real-world' patient cohort. In the CAPACITY-HFpEF study, only 20% of patients had elevated filling pressures and a majority of patients had New York Heart Association II symptoms. Attenuation of cyclic Guanosine Monophosphate levels in patients with HFpEF is due to the loss of upstream nitric oxide rather than an excessive breakdown of cyclic Guanosine Monophosphate.31 It is, therefore, not unexpected that attempting to augment cyclic Guanosine Monophosphate by inhibiting its breakdown did not lead to clinically meaningful improvements in patients' haemodynamics or exercise capacity in the RELAX trial. Furthermore, whilst the agents used in these trials target the nitric oxide–cyclic Guanosine Monophosphate–protein kinase G pathway, none of the trials directly studied physiological endpoints of impaired vascular function, such as peripheral or coronary endothelial function. Additionally, the physical functioning endpoints (6-min walk distance and change in peak VO2) may not be able to discriminate among effective therapies because patients with HFpEF usually suffer from multiple comorbidities and their impaired physical functioning may be multifactorial in nature. BP, blood pressure; cGMP, cyclic Guanosine Monophosphate; DM, diabetes mellitus; GTP, Guanosine Triphosphate; HFpEF, heart failure with preserved ejection fraction; HTN, hypertension; KCCQ: Kansas City Cardiomyopathy Questionnaire; LAV, left atrial volume; NO, nitric oxide; PA, pulmonary artery; PKG, protein kinase G; sGC, soluble Guanylate Cyclase; 6MWD, 6-min walk distance.

It is now increasingly recognized that HFpEF is a heterogeneous condition comprising distinct endotypes, which have vastly disparate underlying pathophysiology. Therefore, a 'one size fits all' approach is unlikely to yield positive therapeutic outcomes. Coronary microvascular disease–HFpEF is a distinct HFpEF endotype, with impaired CFR and ensuing subendocardial ischaemia and impaired lusitropy being at the centre of its pathogenesis. None of the aforementioned therapeutic trials reported patients' flow reserve (in response to adenosine or acetylcholine) or stipulated an impaired flow reserve in their inclusion criteria. Therefore, it is conceivable that a large percentage of patients recruited in these studies did not have the CMD–HFpEF endotype. Furthermore, although the agents used in these trials theoretically potentiate the NO–cGMP–PKG pathway, none of them ameliorate the subendocardial ischaemia that is fundamental to the development of CMD–HFpEF. Future therapeutic studies should trial endotype-specific agents to target the underlying pathological pathways.

Finally, long-term follow-up of patients with CMD–HFpEF is required to track the natural trajectory of this disease process.

Figure 5 summarizes the future research and clinical implications of the CMD–HFpEF mechanistic link.

Figure 5.

Clinical and research implications of the coronary microvascular disease–heart failure with preserved ejection fraction mechanistic link.