In the last decades, average life expectancy has increased, and consequently elderly patients represent an important proportion of those undergoing coronary angiography and eventually percutaneous coronary intervention. Functional evaluation using fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) is the gold standard for the assessment of intermediate coronary lesions [1]. Notably, these indexes will yield discordant results in about 15% of lesions [2, 3], arising questions about their accuracy in specific settings.

Aging is a well-known risk factor for microvascular dysfunction, secondary to a pro-inflammatory status and several other conditions, such as diabetes, hypertension and left ventricular hypertrophy, which are more prevalent in the elderly and affects vascular compensatory capacity [4, 5, 6].

Recent data confirmed the pivotal role of microcirculation in the vasodilatory response to hyperaemic agents [5, 6, 7, 8], and the influence of a pathological microvascular remodelling on FFR has been already addressed [4]. However, there is another validated hyperaemic index, contrast medium fractional flow reserve (cFFR) [9, 10] which relies on a milder hyperaemia than the one achieved by adenosine [7] and for which the relationship with aging and impaired microcirculation is unknown.

The purpose of our study was to investigate the impact of ageing on the vasodilatory response to different hyperaemic agents (adenosine vs contrast-medium). At the same time, we focused on the relationship between ageing and both hyperaemic (FFR, cFFR) and non- hyperaemic (distal pressure/aortic pressure (Pd/Pa), iFR) pressure-derived coronary physiology indices.

Several technical, clinical, angiographic and hemodynamic factors may influence the output of functional assessment of epicardial stenosis [4, 5, 6]. The presence of microvascular dysfunction represents an important confounder during epicardial physiological assessment [8]. In the present study, we focused on the influence of age on the vasodilatory response to different hyperaemic agents (adenosine versus contrast medium). We have simultaneously analyzed the impact of age on the values of both hyperaemic (FFR and cFFR) and non-hyperaemic indices (Pd/Pa, iFR).

The main results are the following:

-Age appeared to be associated with a decreased hyperaemic response to adenosine, which translates into a higher FFR value;

-Non-hyperemic pressure derived ratios (Pd/Pa, iFR) are confirmed not to be significantly affected by age;

-Contrast medium hyperemia is less affected by age and consequently, cFFR values do not change significantly across the age strata.

We observed an age-dependent reduction in vasodilatory response to adenosine, and we hypothesize that it may be due to an impairment of the vasodilatory capacity of the coronary microcirculation. Aging is a well-known risk factor for microvascular dysfunction, as it induces functional and structural remodelling of all components of the microvascular domain [7, 14].

Age-induced inflammatory state is responsible for endothelial dysfunction and promotes the recruitment of inflammatory cells and cytokine release. As such, older patients experience pathological derangement of vascular and perivascular environment that ultimately leads to impairment of local regulation of microvascular perfusion (by impairing endothelium-mediated, flow-induced arteriolar vasodilation, and angiogenesis) [15, 16]. Moreover, there is a negative impact on oxygen delivery, cellular bioenergetics and scavenging capacity that results in microvascular rarefaction [15, 16, 17, 18]. The direct consequence of these changes is the increase in minimal microvascular resistance under maximal hyperaemia that translates into a partial and progressive loss of coronary reserve [7, 14, 15, 16, 17, 18].

Our results are in line with previous studies reporting a negative correlation between age and coronary flow reserve (CFR), evaluated by thermodilution technique [7, 14].

We identified a modest yet positive correlation between FFR and age, suggesting a potential impact of aging on adenosine-related indices. This connection was reinforced by the observation of higher FFR values in older patients, alongside a notable decline in hyperemic response to adenosine across age groups. Even after adjusting for other significant factors like LAD location and stenosis severity through multivariate regression analysis, advancing age remained linked to both FFR and adenosine-related hyperemia; this was not the case for cFFR and non-hyperemic indices. These diverse strands of evidence affirm this association, addressing initial reservations regarding the perceived weak correlation between age and FFR. The present findings align seamlessly with recent literature on the topic. A study by Faria et al. [13] demonstrated a similar correlation between age and FFR (r = 0.08, p = 0.015) in a small cohort of patients (n = 598).

To the best of our knowledge, this is the first study to show a preserved age-related vasodilatory response to contrast medium injection, with cFFR values being comparable across the age terciles. cFFR is a relatively novel hyperaemic index which uses a contrast medium to induce hyperaemia relying on its osmolality [9, 10]. Contrast-induced hyperaemia has been considered “submaximal” because it is significantly less intense than that induced by adenosine [9, 10], on average conditions cFFR accuracy for disclosing significant lesions was proven in the RINASCI [19] study while other studies documented its superiority to resting Pd/Pa and iFR in predicting FFR [20, 21, 22, 23].

A possible explanation of this different behaviour of adenosine and contrast medium’s hyperaemia across the age spectrum could be related to the physical properties of these agents and also different mechanisms of action, potentially less influenced by intrinsic microvascular dysfunction. While adenosine-induced hyperaemia is principally driven by non-endothelium mediated mechanisms (A2 receptors of smooth muscular cells) dampened by the presence of fibrosis and capillary rarefaction, contrast medium induces hyperaemia by its osmolarity causing the opening of K(ATP) channels in the vascular endothelium and for which the influence of microvascular remodelling is not clear [9, 10].

Another conceivable explanation could be related to the desensitization phenomena. Previous studies revealed a reduction of adenosine’s effect in elderly patients [24, 25]. Experimental models have shown greater local release of adenosine in the coronary microcirculation of older animals, leading to a reduction of expression of adenosine receptors and limiting the effectiveness of an exogenous administration [26]. This was not documented for contrast medium.

Furthermore, the presence of age-related diseases such as diabetes and hypertension, could contribute to microvascular dysfunction, particularly affecting adenosine-induced hyperemia. Histopathological examinations in diabetic animals have unveiled various coronary vessel abnormalities, including arteriolar thickening, perivascular connective tissue accumulation, capillary microaneurysms, and reduced capillary density [27]. These findings culminate in impaired coronary vasodilation upon administration of exogenous adenosine, suggesting a potential connection between compromised metabolic vasodilation and diabetes mellitus [27]. Similarly, studies on left ventricular hypertrophy have shown an inverse correlation between capillary density and hypertrophy severity, associated with impaired adenosine-induced flow augmentation [4, 5, 6].

Differences in the sensitivity to adenosine can provide further clues into the discordance phenomenon. Recent studies showed that discordance between FFR and cFFR is observed in about 10–15% of patients [2]. In the rare case of discordance between FFR and cFFR, the former is reliable and more accurately predict worse outcomes [26]. Specifically, our group has previously demonstrated that FFR+/cFFR- patients showed a prognosis similar to FFR-/cFFR- patients while FFR-/cFFR+ patients showed a prognosis similar to FFR+/cFFR+ patients [28].

In the present study, we described a significant reduction of positive discordance (defined as FFR $\le$0.8 and cFFR $\ge$0.83) and increasing age suggesting that aging may be one of the most important factors associated with FFR-cFFR discrepancy. Conversely, non-hyperaemic indices, such as Pd/Pa and iFR, appeared to be unrelated to aging, in line with the recently reported observations [13].

Our findings suggest for the first time a similar behaviour between hyperaemic (cFFR) and non-hyperaemic indices (iFR, Pd/Pa) in patients with possible impairment in microcirculation, such as older aged groups.

Overall, in this particular setting, cFFR could be considered to incorporate the best characteristic of the most important hyperemic (FFR) and non-hyperemic (iFR, Pd/Pa) indices, in that it still allows some assessment of residual vasodilatory capacity without compromising accuracy.

The present analysis was based on retrospective data from PROPHET-FFR and MEMENTO studies and our conclusions are mainly hypothesis-generating rather than hypothesis testing. However, there was a clear biological and clinical rationale for performing this analysis, as the microcirculatory modifications associated with age had been previously described. Another limitation might be the lack of an invasive assessment of the microvascular resistance, which would have provided a more comprehensive insight into this condition.

Aging seems to be associated with a decreased vasodilatory response of the microcirculation to adenosine administration. This was not observed for contrast medium-induced hyperaemia. FFR showed a weak and positive correlation with age probably leading to elevated FFR values while cFFR didn’t change across the age spectrum. This fact may influence the degree of concordance between these two hyperaemic indices in terms of functional stenosis classification. Between hyperaemic indexes, cFFR is less affected by age.

Elderly patients present higher FFR values due to an impaired response to adenosine. However, cFFR values and hyperaemic response to contrast-medium are not influenced by patient age. cFFR may be considered a more reliable and reproducible index than FFR in the evaluation of epicardial stenosis in this setting.

CAD, coronary artery disease; ACS, acute coronary syndrome; CCS, chronic coronary syndromes; NSTE- ACS, non-ST segment elevation acute coronary syndromes; STE-ACS, ST segment elevation acute coronary syndromes; EF, ejection fraction; CKD, chronic kidney disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; FFR, fractional flow reserve; cFFR, contrast fractional flow reserve; iFR, instantaneous wave-free ratio; LAD, left anterior descending; RCA, right coronary artery; LCx, left circumflex; Pa, aortic pressure; Pd, distal pressure.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

AML: conception and design, analysis and interpretation of data, drafting and revising critically the manuscript for important intellectual content and final approval; DG: conception and design, analysis and interpretation of data, drafting the manuscript; GZ, PC, SM, FDG, GA, AV, EP, ER, CA: collection, analysis and interpretation of data, drafting the manuscript; FB, CT, RMR, SBB, DF, NA, LR and FC: interpretation of data for the work, important intellectual contribution and final approval of the manuscript submitted. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The studies involving human participants were reviewed and approved by local ethics committees and conformed to the Declaration of Helsinki. The patients/participants provided their written informed consent to participate. (PROPHET-FFR study, this study was approved by the Fondazione Policlinico Universitario A. Gemelli IRCCS of Rome Ethics Committee, approval number: 3237).

Not applicable.

The authors thank the Italian Ministry of Health for the funding within the “Ricerca corrente 2021” project.

AML. received speaking honoraria from Abbott, Menarini, Bruno, Bayer, Medtronic and Daiichi Sankyo; CT, FB. received speaker’s fees from Abbott, Medtronic, and Abiomed. SBB has received investigation grants and consulting honoraria from Abbott and investigation grants from Volcano/Philips. NA has received consulting honoraria from Abbott, Boston Scientific and Shockwave Medical. LR has received investigation speaker fees from Boston Scientific, Abbott vascular, Philips/Volvano. Antonio Maria Leone is serving as one of the Editorial Board members and Guest Editors of this journal. We declare that Antonio Maria Leone had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Ezra Abraham Amsterdam. The other authors have no conflicts of interest.