Why do we care about coronary microvascular dysfunction and heart failure with preserved ejection fraction: addressing knowledge gaps for evidence-based guidelines

This editorial refers to ‘Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF’^†, by S.J. Shah et al., on page 3439.

There is increasing documentation that coronary microvascular dysfunction (CMD)-related subendocardial ischaemia contributes to left ventricular remodeling, diastolic and systolic dysfunction, and subsequent heart failure with preserved ejection fraction (HFpEF).¹ To date, prevalence of microvascular dysfunction in heart failure with preserved ejection fraction (PROMIS-HFpEF) (n=202) is the largest prospective, multicentre study (Scandinavia, USA, and Singapore) evaluating coronary flow reserve (CFR), a diagnostic measure of CMD, in subjects with known HFpEF.² In this study, 75% of the subjects had evidence of CMD, defined as CFR < 2.5 measured by adenosine stress transthoracic Doppler echocardiography. The investigators found that low CFR is associated with elevated N-terminal pro b-type natriuretic peptide (NTproBNP), and abnormal cardiac structure and function including left atrial and right ventricular (RV) dysfunction. Shah et al. also report that low CFR is associated with peripheral endothelial dysfunction, as measured by reactive hyperemia index (RHI). While other studies have reported peripheral vascular dysfunction in patients with HFpEF,³ the PROMIS-HFpEF investigators are the first to document an association with CFR. Specifically, low CFR is more strongly associated with low RHI in obesity, suggesting that HFpEF is a systemic vascular disorder that potentially impacts other organs.

The PROMIS-HFpEF study comes at a critical juncture to address key knowledge gaps that adversely impact women, the majority of CMD and HFpEF victims; indeed, 55% of the study sample are women. We and others have conducted multiple pharmacological probe trials for CMD with observed benefit only with angiotensin converting enzyme inhibitors (ACE-Is) and alpha–beta-blockers,⁴ while therapeutic HFpEF trials to date including ACE-Is, angiotensin receptor blockers (ARBs), digoxin, aldosterone antagonists, phosphodiesterase type 5 inhibitor (PDE5 inhibitor), and nitrates have not demonstrated benefit in HFpEF, with the exception of one small study evaluating the beta-blocker propranolol.⁵ These findings suggest that while identification of CMD in HFpEF may be an important link, targeting CMD alone as a therapeutic HFpEF target may prove ineffective, e.g. prior established endothelial therapies (statins and ACE-I) trials in HFpEF have failed. New hypotheses and approaches to mechanistic understanding are needed to address remaining knowledge gaps, and to design clinical trials for evidence-based HFpEF guidelines.

Our and other investigations to date suggest that risk factor conditions (hypertension, obesity, dyslipidaemia, dysglycaemia, oestrogen loss, inactivity etc.) promote a pro-inflammatory, pro-oxidative state, rendering the coronary microvasculature and myocardium vulnerable to: (i) adverse left ventricular (LV) remodeling, (ii) subendocardial ischaemia, (iii) focal and diffuse fibrosis, (iv) cardiac steatosis, and (iv) vascular stiffness⁴. Based on these observations, we propose that CMD plays a critical role in initiating pre-HFpEF, and LV and RV dysfunction in patients with ischaemia and no obstructive coronary arteries (INOCA).⁶ We further hypothesize that this syndrome is associated with a microvascular-related ischaemia–myocardial dysfunctional state, characterized by abnormal diastolic and systolic function, which may progress to HFpEF. That these conditions lead to actual myocardial damage is evidenced by a recent study⁷ showing that CMD is associated with increases in high-sensitivity cardiac troponin (hs-cTnI), and that hs-cTnI elevations predict future HFpEF.⁸ However, how CMD-related ischaemic damage contributes to HFpEF development is an important knowledge gap. Investigations identifying specific mechanistic pathways are therefore critically needed if we are going to make any therapeutic advancements.

Cardiac magnetic resonance imaging/magnetic resonance spectroscopy (cMRI/MRS) is a powerful clinical tool that has the potential to non-invasively measure the key pathophysiological endpoints in this cascade linking CMD to HFpEF. In addition to being the most precise and reproducible imaging modality to assess cardiac morphology and global systolic function, cMRI/MRS provides a quantitative platform for the evaluation of regional tissue deformation (strain), myocardial perfusion reserve, bioenergetics, and tissue characteristics (Figure 1). Indeed, cMRI-derived markers are able to assess both the intramyocardial microvascular network and the extravascular myocardium. Consistent with our overarching hypothesis, we reason that chronic ischaemia (impaired flow reserve) related to the dysfunction and/or rarefaction of the intramyocardial microvasculature in CMD leads to repeat bouts of myocardial damage, which in turn is manifested as diffuse interstitial fibrosis, myocyte hypertrophy, and/or myocardial steatosis, ultimately culminating in diastolic and systolic dysfunction with myocardial stiffening, emblematic of HFpEF. Similar to the Doppler left anterior descending (LAD) approach used by Shah et al.,² cMRI-derived myocardial perfusion reserve index is a surrogate measure of impaired coronary reactivity to adenosine and increased microvascular resistance.^9,10 In contrast, however, cMRI enables direct assessment of subendocardial perfusion, a more sensitive measure of microvascular dysfunction/rarefaction. Further, focal fibrosis can be detected using late gadolinium-enhancement cMRI, which, in a recent study of women with INOCA, has been shown to have a prevalence of 8%.¹¹ Moreover, cMRI-derived myocardial T1 is elevated in women with INOCA compared to matched controls, a finding that may be indicative of adverse intramyocardial remodeling including diffuse fibrosis.¹² Finally, in similar INOCA cohorts, myocardial steatosis, along with both subclinical systolic and diastolic dysfunction, have also been detected using cMRS and cMRI, respectively.^13,14 Taken together, cMRI/MRS provides a wide array of pathophysiological endpoints, each representing novel potential treatment targets. Following confirmatory studies, these pathways could be targeted by innovative metabolic, inflammatory, and fibrosis strategies currently being tested in other organ systems, such as non-alcoholic steatohepatitis.

Figure 1.

Potential pathophysiological mechanisms linking CMD to HFpEF. The power of cardiac magnetic resonance imaging/magnetic resonance spectroscopy to define key pathophysiological mechanisms linking coronary microvascular dysfunction-related myocardial ischaemia to heart failure with preserved ejection fraction. Top illustrates traditional invasive measures of CMD (A), and resultant subendocardial ischaemia measured by first-pass perfusion magnetic resonance imaging and altered myocardial bioenergetics measured by ³¹P magnetic resonance spectroscopy (B). (C–E) illustrate three proposed mechanistic pathways linking coronary microvascular dysfunction-related ischaemia to heart failure with preserved ejection fraction, including cardiac steatosis-induced lipotoxicity (C), adverse remodeling (D), and impaired systolic and diastolic function (E). The red arrows indicate directionality (cause and effect), with black question marks highlighting knowledge gaps for investigation. Note both the simple cause–effect relationship in some cases (e.g. ischaemia-related adverse remodeling), as well as more complex relationships involving multiple pathways. Importantly, cardiac magnetic resonance imaging/magnetic resonance spectroscopy is ideally situated to address all of the proposed mechanistic pathways. 2,3-DPG: 2-3-diphosphoglycerate; ATP: adenosine triphosphate; CMD, coronary microvascular dysfunction; cardiac magnetic resonance imaging/spectroscopy, HFpEF, heart failure with preserved ejection fraction; LA, left atrium; LGE, late gadolinium enhancement; LV, left ventricle; PCr, phosphocreatine; RV, right ventricle; TG, triglyceride.

In summary, Shah et al.² have provided an important contribution to our pathophysiological understanding of HFpEF, providing some of the strongest evidence to date of a CMD–HFpEF relationship. Further investigation is now needed to better define the specific mechanisms and temporal relationship, linking CMD-related myocardial ischemia, myocellular damage, and HFpEF. cMRI/MRS may provide the necessary depth and breadth to address these knowledge gaps, improve HFpEF subgroup phenotyping, and identify new treatment targets. Only then can mechanistically supported HFpEF intervention trials be considered, including: (i) anti-ischaemic/scar therapies (intensive statin/ACE-I/ARB combination, alpha–beta-blockers, and nitric oxide-cyclic GMP), (ii) strain/remodeling therapies (sacubitril/valsartan), and/or (iii) anti-fibrotic therapies (galectin 3, peptidyl arginine deiminase type IV inhibitor, stress-activated kinase-1 inhibitor, protein kinase G, and fibroblast growth factor).

Funding

Research reported in this publication was supported by the National Heart, Lung and Blood Institute (NHLBI) under grant numbers N01HV68161, N01HV68162, N01HV-68163, N01HV68164, U01HL64829, U01HL649141, U01HL649241, T32HL69751, R00HL124323; the National Institute on Aging (NIA) under grant number R03AG032631; the National Institute of Child Health and Human Development under grant number K12HD051959; the National Center for Research Resources (NCRR) under grant number M01RR000425; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, The Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc., Laurence Harbor, NJ, the Edythe L. Broad Women’s Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California, and the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, American Heart Association grant 16SDG27260115, and the Harry S. Moss Heart Trust.

Conflict of interest: The authors have no conflicts of interest to disclose.