Age‐related changes in the coronary microcirculation influencing the diagnostic performance of invasive pressure‐based indices and long‐term patient prognosis

Abstract Objectives Investigate age‐related changes in coronary microvascular function, its effect on hyperemic and non‐hyperemic indices of stenosis relevance, and its prognostic implications. Background Evidence assessing the effect of age on fractional flow reserve (FFR), resting mean distal intracoronary pressure/mean aortic pressure (Pd/Pa), and microcirculatory function remains scarce. Methods This is a post hoc study of a large prospective international registry (NCT03690713) including 1134 patients (1326 vessels) with coronary stenoses interrogated with pressure and flow guidewires. Age‐dependent correlations with functional indices were analyzed. Prevalences of FFR, resting Pd/Pa, and coronary flow reserve (CFR) classification agreement were assessed. At 5 years follow‐up, the relation between resting Pd/Pa, CFR, and their age‐dependent implications on FFR‐guided percutaneous coronary intervention (PCI) deferral (deferred if FFR > 0.80) were investigated using vessel‐oriented composite outcomes (VOCO) composed of death, myocardial infarction, and repeated revascularization. Results Age correlated positively with FFR (r = 0.08, 95% confidence interval [CI]: 0.03 to 0.13, p =  0.005), but not with resting Pd/Pa (r = −0.03, 95% CI:−0.09 to 0.02, p = 0.242). CFR correlated negatively with age (r = −0.15, 95% CI: −0.21 to −0.10, p < 0.001) due to a significant decrease in maximal hyperemic flow in older patients. Patients over 60 years of age with FFR‐guided deferred‐PCI abnormal resting Pd/Pa or abnormal CFR had increased risk of VOCO (hazard ratio [HR]: 2.10, 95% CI: 1.15 to 4.36, p = 0.048; HR: 2.46, 95% CI:1.23 to 4.96, p = 0.011; respectively). Conlusions Aging is associated with decrease in microcirculatory vasodilation, as assessed with adenosine‐based methods like CFR. In patients older than 60 years in whom PCI is deferred according to FFR > 0.80, CFR and resting Pd/Pa have an incremental value in predicting future vessel‐oriented patient outcomes.

Conlusions: Aging is associated with decrease in microcirculatory vasodilation, as assessed with adenosine-based methods like CFR. In patients older than 60 years in whom PCI is deferred according to FFR > 0.80, CFR and resting Pd/Pa have an incremental value in predicting future vessel-oriented patient outcomes. The same is true for nonhyperemic indices, which recently have gained large attention as an alternative to guide PCI due to a number of advantages over FFR in the assessment of coronary stenoses.

A recent analysis of the A Denosine Vasodilator Independent
Stenosis Evaluation II study found that patient age has an impact on pressure-derived indices. For the same coronary stenosis severity, FFR values increase in older patients, while instantaneous wave-free ratio (iFR) values remain constant throughout the age spectrum. 3 However, solid evidence outlining the mechanisms behind age-related differences in intracoronary pressure-based indices, as well as its potential impact on outcomes and clinical decision making, is still missing.
The purpose of our study was to investigate, based on intracoronary pressure and flow measurements, the impact of aging on pressure-derived coronary physiology and microcirculatory indices and the influence of this effect on clinical outcomes in a large cohort of patients.

| Study population
This study is based on a post hoc analysis of a large prospective international registry (International Collaboration of Comprehensive Physiologic Assessment, NCT03690713) that has already served as a basis for several publications. [4][5][6][7][8][9] Key exclusion criteria included patients with hemodynamic instability, severe left ventricular systolic dysfunction (ejection fraction < 40%), left main stenosis, surgical grafts, contraindications to adenosine, and severe vessel tortuosity or calcification. In all enrolling centers, invasive angiography was performed as clinically indicated and according to local practice. All the enrolled patients underwent invasive intracoronary pressure and flow measurements, including FFR, coronary flow reserve (CFR), and the hyperemic index of coronary microcirculatory resistance (IMR) for at least one coronary artery. From this registry, we selected patients with stable angina or acute coronary syndrome (ACS) who had coronary stenosis (at least 30% diameter lesion by quantitative assessment) in one or more major epicardial vessels or its branches suitable for PCI. In patients with ACS, noninfarct-related arteries with significant angiographical lesions were interrogated in a second procedure. The patients were followed-up during 5 years for the patient and vessel-orientated outcomes. Individual patient data for pooled analysis were collected using standardized spreadsheets. The study protocol was authorized by institutional review boards or ethics committees at corresponding centers. All patients were granted written informed consent.

| Coronary angiography
Coronary angiography was performed according to standard practice. Angiographic views were obtained after the administration of intracoronary nitrates (100 or 200 µg). Quantitative coronary angiography (QCA) was performed using validated software (CAAS II, Pie Medical Imaging) and quantitative parameters were obtained including percent diameter stenosis, minimal luminal diameter, reference-vessel size, and lesion length (median [Q1, Q3]).

| Coronary physiology
Physiology measurements were obtained after coronary angiography.
In cases where PCI was performed, preinterventional measurements were used for analysis. The measurement protocols for FFR, CFR, and IMR were standardized among the enrolling centers. Coronary arteries were engaged with a 5-7 F guide catheter without side holes. Intracoronary nitrates were administrated before each measurement. A pressure wire (St. Jude Medical) was introduced and positioned at the distal segment of the target vessel and mean aortic pressure (Pa) and mean distal intracoronary pressure (Pd) were obtained. Mean transit time (T mn ) was derived after obtaining three thermodilution curves by injecting 4 ml of saline at room temperature. Hyperemia was induced following intravenous infusion of adenosine (140 µg/kg/min) and hyperemic Pa, Pd, and T mn were measured during sustained hyperemia. FFR was calculated as the lowest Pd/Pa ratio average of three consecutive beats during stable hyperemia. Hemodynamic severity was defined as FFR ≤ 0.80 and PCI was recommended as stated by societal recommendations. 10 CFR was calculated as resting T mn /hyperemic T mn. 5

| Age and pressure-derived indices relationship
Age correlations with invasive physiological indices were assessed.
The patients were then stratified into two groups according to the 60 years-old cut-off, based on research reporting important differences in hyperemic flow and myocardial perfusion reserve after vasodilator administration starting from that age. 1
Age correlations with microvascular resistance indices were in line with findings described above. CFR and RRR both correlated negatively with age (r = −0.15, 95% CI: −0.21 to −0.10, p < 0.001; Figure 1C and r = −0.19, 95% CI: −0.24 to −0.14, p < 0.001; Figure 1D, respectively). The same correlations with age and the above-mentioned indices were maintained even in the absence of angiographically significant stenosis (<50%)-Supporting Information: Table 1. Importantly, as shown in Figure 2 and Supporting Information:   Table 3). Figure 4 shows the agreement/discordance relationship between FFR and resting Pd/Pa and FFR and CFR, in terms of functional stenosis relevance, per age group (below or above 60 years old). The older group had higher prevalence of discordance due to high FFR (8.9% vs. 13.4%; p = 0.047). Interestingly, no significant differences in the prevalence of discordance due to abnormal resting Pd/Pa were found, although a nonsignificant trend toward decrement with age was noted (9.9% vs. 7.9%, p = 0.244). Similarly, older patients had higher prevalence of discordance due to abnormal CFR (15.7% vs.

| Effect of aging on the agreement between hyperemic and nonhyperemic indices of stenoses relevance
12.5%, p = 0.047). Supporting Information: Table 4 shows the tendency for increased discordance between FFR > 0.80 and resting Pd/Pa ≤ 0.92 associated with aging and abnormal CFR. Supporting Information: Table 5 illustrates a model to predict this discordance using generalized estimating equations, showing independent contributions from both older age and CFR.

| Implications of aging for clinical-decision making based on pressure-derived coronary indices
Overall, at a mean follow-up of 5 years, there were no significant differences in VOCO nor in the individual components of the primary endpoint when comparing patients with below and over 60 years (Table 3 and Supporting Information: Table 6).
However, as shown in Table 4 and Figure 5 deferring PCI according to FFR in the presence of abnormal resting Pd/Pa was associated with a significant lower survival rate compared with normal resting Pd/Pa ( Figure 5). Furthermore, in patients ≥60 years old in whom PCI was deferred based on FFR, the presence of abnormal CFR was associated with a significant lower survival compared with patients with preserved CFR. Of note, this finding was not observed in the younger group.
As shown in Table 4 and Figure 5, discriminating patients with  Figure 6. As shown in Supporting Information:

| DISCUSSION
The main findings of this study are the following: (1)  In our study, we documented a significant decrease in CFR associated with aging, both in the overall study population and in patients in whom PCI was deferred on the grounds of FFR values.
RRR, an index of arteriolar dynamicity, also decreases with age. The dominant mechanism leading to CFR impairment is a progressive decrease in hyperemic flow beyond 60 years of age ( Figure 2). These observations are concordant with previous studies based on position emission tomography, that also identified age 60 years-old as the age over which significant changes in the microcirculation are observed. 1,2 Of note, we failed to reproduce the significant increase in baseline flow that previous studies have shown with aging, as a cause of low CFR, neither a significant increase in the coronary microcirculatory resistance. We also found that CFR correlates strongly with resting Pd/Pa than with FFR. An explanation for this phenomenon can be found in previous studies showing that nonhyperemic indices, such as iFR, correlate better with flow indices than FFR, either by intracoronary Doppler assessment, 14 or by positron emission tomography. 15 Our study also shows how the above-mentioned effect of aging translates into patient outcomes when FFR is used as a tool to defer coronary revascularization. As Figure 6 shows  While the performance of additional CFR measurements on top of FFR measurements seems to contribute to a better risk profile in elderly patients undergoing FFR, it has to be kept in mind that only a minority of catheterization laboratories perform routinely assessment of the coronary microcirculation with either Doppler-or thermodilutiondedicated guidewires. In this regard, our findings provide a unique opportunity to perform such stratification of risk using a conventional pressure guidewire to measure resting Pd/Pa, which has a better sensitivity than FFR to predict abnormal CFR (Figure 3). In this regard, we found that the incremental prognostic value of resting Pd/Pa over FFR in elderly patients is similar to that of CFR ( Figures 5 and 6, Table 4). to clarify which therapeutic attitude should be followed in case of this type of discrepancy between FFR and resting Pd/Pa.

| LIMITATIONS
Our study is limited in that it is a retrospective subgroup analysis of an observational registry. Henceforth, our conclusions are mainly hypothesis generating rather than hypothesis testing. Nevertheless, there is a clear biological and clinical rationale for performing this analysis, as the microcirculatory and epicardial modifications associated with age had been previously described.
Another potential limitation is the absence of consensus in defining "older-age" in the literature. "Elderly" is a definition mainly dependent on ethnical and cultural background, ranging from 55 to 75 years or higher. Nevertheless, our study does not aim to provide a new cut-off for older age. We used the mentioned 60 years old as a separating point based on studies demonstrating that this is when significant changes in resting and hyperemic coronary flows start to appear.

| CONCLUSIONS
Aging is associated with a marked decrease in the vasodilatory response of the microcirculation to adenosine administration, as assessed with CFR. This fact influences the degree of concordance between hyperemic and nonhyperemic indices in terms of functional stenosis classification. In patients older than 60 years in whom PCI is deferred on the grounds of FFR values, both CFR and resting Pd/Pa have an incremental value in predicting future vessel-oriented patient outcomes.

ACKNOWLEDGMENTS
The authors of this study are solely responsible for the design and conduct, all analysis, manuscript drafting and editing, and are responsible for its final contents.