Basal Microvascular Resistance　― Another Invasively Measured Physiological Index for Predicting Future Heart Failure Events ―

From the beginning of coronary angioplasty by Grüntzig et al,¹ an invasive coronary physiological assessment has been performed and has rapidly advanced to date.² Coronary pressure and flow (or velocity), as an absolute value or surrogate, can be invasively measured during cardiac catheterization to estimate coronary resistance, and this coronary physiological assessment with pressure, flow, and resistance plays a crucial role in detecting obstructive and nonobstructive myocardial ischemia, stratifying cardiovascular risks, and guiding the decision for coronary revascularization.³ Over the past few decades, several invasive coronary physiological indices have been developed (Table). Fractional flow reserve (FFR) is the invasive standard for assessing myocardial ischemia caused by epicardial coronary artery disease (CAD), and nonhyperemic pressure ratios, such as instantaneous wave-free ratio,⁴ are guideline-recommended alternatives to FFR.⁵ Recent clinical interest in patients with ischemia and nonobstructive CAD has gained considerable momentum globally, facilitating invasive diagnostic procedures to evaluate coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), both of which are guideline-recommended indices for assessing coronary microvascular dysfunction (CMD).⁶ Using an invasive thermodilution method, CFR is calculated as the ratio of hyperemic and resting mean transit time (Tmn), a surrogate of coronary blood flow, and IMR is defined as a product of hyperemic Tmn and distal coronary pressure. More recently, the resistive reserve ratio (RRR) and the microvascular resistance reserve (MRR) have been proposed to specifically evaluate CMD, particularly for coronary microvascular dilation capacity (i.e., functional CMD).^7–9 However, CFR, RRR, and MRR as a ratio using physiological indices at rest and hyperemia may have inherent limitations, which cannot independently assess resting and hyperemic conditions. IMR is specifically designed to evaluate microvascular resistance during hyperemia, excluding the influence of variable resting coronary microvascular resistance under different conditions. To date, the pathological significance of the resting state of the microvasculature has not yet been sufficiently explored.

Table.

Key Physiological Indices Invasively Assessed in the Catheterization Laboratory

Physiological index	Definition	Cutoff value	Feature	Strength	Limitation
Resting Pd/Pa	(Pd/Pa) at rest	≤0.92	Simple index for epicardial CAD	No need for dedicated analytic software	Not established for guiding revascularization
FFR	(Pd/Pa) at hyperemia	≤0.80	Specific index for epicardial CAD	Guideline-recommended invasive standard	Need for hyperemia as compared with NHPRs
NHPR	(Pd/Pa) at rest within a specific timing	≤0.89	Specific index for epicardial CAD	Alternative to FFR with no need for hyperemia	Less robust clinical evidence than FFR
CFR	Resting Tmn/hyperemic Tmn	<2.0–2.5	Reflecting coronary epicardial and microvascular capacity	Strong predictor of adverse outcomes	Influenced by conditions and hemodynamics
b-IMR	(Pd * Tmn) at rest	≤47.1a	Reflecting baseline microvascular resistance	Potential for predicting HF-related outcomes	Not established yet
IMR	(Pd * Tmn) at hyperemia	≥25	Reflecting hyperemic microvascular resistance	Guideline-recommended invasive index for INOCA	Relatively wide variation with technical caveats
RRR	(Pd * Tmn at rest)/ (Pd * Tmn at hyperemia)	(<2.6–3.5)b	Specific index for microvascular dilatory capacity	Potentially greater prognostic ability than CFR	Influenced by conditions and hemodynamics
MRR	(CFR/FFR) * (resting Pa/hyperemic Pa)c	(<2.1–3.0)b	Potentially more specific index for microvascular function	Reproducible and operator-independentd	Need for dedicated equipmentd

Physiological indices assessed with invasive Doppler methods are excluded because of their current clinical unavailability. ^aReported by Murai et al.^{10 b}Not well established yet. ^cThe formula indicates the mathematically calculated MRR by a bolus thermodilution method, but MRR was originally developed as an index assessed with a continuous-saline thermodilution method using a dedicated microcatheter. ^dFor MRR by a continuous-saline thermodilution method. b-IMR, basal microvascular resistance; CAD, coronary artery disease; CFR, coronary flow reserve; FFR, fractional flow reserve; HF, heart failure; IMR, index of microvascular resistance; INOCA, ischemia with nonobstructive coronary artery disease; MRR, microvascular resistance reserve; NHPR, nonhyperemic pressure ratio; Pa, aortic pressure; Pd, distal coronary pressure; RRR, resistive reserve ratio; Tmn, mean transit time.

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In this issue of the Journal, the study by Murai et al marks a significant advancement by introducing and validating basal microvascular resistance (b-IMR), also known as the “basal resistance index”, as a standalone prognostic marker across a broad spectrum of coronary circulatory indices (Table).¹⁰ Unlike traditional metrics, b-IMR exclusively assesses the resting state of microvascular resistance, which enables a more nuanced understanding of microvascular function, distinguishing it from the physiological stresses induced by hyperemia. In their 2-center, retrospective registry study, 226 patients undergoing bolus thermodilution-based coronary physiological assessments in the left descending coronary artery were enrolled, among whom those with physiologically significant CAD (FFR ≤0.80) were excluded. The study’s primary aim was to evaluate the relationships of b-IMR with clinical variables and outcomes. Importantly, Murai et al assessed 2 different types of clinical outcome events: heart failure-related outcomes (all-cause death and heart failure hospitalization) and atherosclerotic cardiovascular events (cardiovascular death, acute coronary syndrome, coronary revascularization, cerebral infarction, and peripheral vascular events).¹⁰ In their study, patients with lower b-IMR were more likely to be older and anemic and to have inflammation and higher E/e′ on echocardiography.¹⁰ Given that b-IMR strongly correlated with resting Tmn, but was not significantly associated with distal coronary pressure at rest, it is conceivable that a lower b-IMR directly represents higher resting coronary blood flow in patients with such vulnerable characteristics. Murai et al found that a lower b-IMR (≤47.1) was linked to an increased risk of heart failure-related outcomes during a median follow-up of 2 years. Consistent with prior studies, a lower CFR (≤2.5) was associated with higher risks of both heart failure and atherosclerotic events. Notably, b-IMR provided incremental prognostic value for all-cause death and heart failure events beyond CFR, although it did not predict atherosclerotic cardiovascular events. On the other hand, a higher IMR (≥25) correlated with atherosclerotic cardiovascular outcomes, confirming earlier research results.¹¹ These insights are invaluable, underscoring the distinct pathophysiological conditions indicated by hyperemic and resting microvascular resistances. As a critical area of investigation, it remains important to tease out whether b-IMR primarily reflects broad systemic conditions or carries pathological significance as an indicator of microcirculatory dysfunction. Even though Murai et al performed multivariable and sensitivity analyses, the relative and combined predictive values of b-IMR with other indices, such as Tmn at rest, CFR, IMR, RRR, and MRR, are uncertain. Furthermore, it should be noted that reference values for b-IMR have not yet been established. Further studies are essential to define these norms and to validate the clinical relevance of b-IMR across diverse patient populations.

Among the various coronary physiological indices, the report now sheds light on b-IMR, a surrogate of resting coronary microvascular resistance. The authors should be commended for showcasing the prognostic impact of b-IMR on heart failure and death. Perhaps b-IMR will be a part of the armamentarium of interventional cardiologists for estimating patient risk from the perspective of ischemic heart disease, and the road ahead should be paved with future research based on this first step.

Disclosure

Y.K. is a member of Circulation Journal’s Editorial Team and reports research grants from Abbott Medical Japan. Other authors have nothing to disclose concerning this paper.

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