
==== Front
Circ Cardiovasc Interv
Circ Cardiovasc Interv
HCV
Circulation. Cardiovascular Interventions
1941-7640
1941-7632
Lippincott Williams & Wilkins Hagerstown, MD

39053911
CIRCCVINT2023013830D
00006
10.1161/CIRCINTERVENTIONS.124.013830
3
10007
10058
10092
10132
Original Articles
Coronary Physiologic Assessment and Imaging
Change in Pd/Pa: Clinical Implications for Predicting Future Cardiac Events at Deferred Coronary Lesions
https://orcid.org/0000-0002-5162-4783
Murai Kota MD, PhD murai.kota11@ncvc.go.jp

https://orcid.org/0000-0001-6307-5593
Kataoka Yu MD, PhD
https://orcid.org/0000-0002-0558-9323
Kiyoshige Eri PhD, MHS, RN kiyoshige.eri@ncvc.go.jp

https://orcid.org/0000-0002-8961-2390
Iwai Takamasa MD, PhD iwai.takamasa06@ncvc.go.jp

https://orcid.org/0009-0000-0710-0870
Sawada Kenichiro MD, PhD sawada.kenichiro@ncvc.go.jp

Matama Hideo MD h.matama@ncvc.go.jp

Miura Hiroyuki MD hmiura@ncvc.go.jp

https://orcid.org/0000-0002-1393-4270
Honda Satoshi MD, PhD satoshi.honda@ncvc.go.jp

https://orcid.org/0000-0002-2706-4317
Fujino Masashi MD, PhD fujinom@ncvc.go.jp

Yoneda Shuichi MD, PhD yonedashuichi1976@ncvc.go.jp

Nakao Kazuhiro MD, PhD knakao1031@ncvc.go.jp

Takagi Kensuke MD, PhD takagi.kensuke@ncvc.go.jp

https://orcid.org/0000-0003-4162-2036
Otsuka Fumiyuki MD, PhD fotsuka@ncvc.go.jp

https://orcid.org/0000-0002-9009-7234
Asaumi Yasuhide MD, PhD asaumiya@ncvc.go.jp

https://orcid.org/0000-0002-0639-0949
Nishimura Kunihiro MD, PhD, MPH knishimu@ncvc.go.jp

https://orcid.org/0000-0001-5372-4932
Noguchi Teruo MD, PhD tnoguchi@ncvc.go.jp

Department of Cardiovascular Medicine (K.M., Y.K., T.I., K.S., H. Matama, H. Miura, S.H., M.F., S.Y., K. Nakao, K.T., F.O., Y.A., T.N.), National Cerebral and Cardiovascular Center, Osaka, Japan.
Department of Preventive Medicine and Epidemiology (E.K., K. Nishimura), National Cerebral and Cardiovascular Center, Osaka, Japan.
Correspondence to: Yu Kataoka, MD, PhD, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 6-1, Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan. Email yu.kataoka@ncvc.go.jp
25 7 2024
9 2024
17 9 e013830e013830
12 2 2024
3 7 2024
© 2024 The Authors.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Circulation: Cardiovascular Interventions is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

BACKGROUND:

Cardiovascular events still occur at intermediate stenosis with fractional flow reserve (FFR) ≥0.81, underscoring the additional measure to evaluate this residual risk. A reduction in distal coronary artery pressure/aortic pressure (Pd/Pa) from baseline to hyperemia (ie, change in Pd/Pa) reflects lipidic burden within vessel walls. We hypothesized that this physiological measure might stratify the risk of future cardiac events at deferrable lesions.

METHODS:

Lesion- (899 intermediate lesions) and patient-based (899 deferred patients) analyses in those with FFR ≥0.81 were conducted to investigate the association between change in Pd/Pa and target lesion failure (TLF) and major adverse cardiac events at 7 years, respectively.

RESULTS:

The occurrence of TLF and major adverse cardiac events was 6.7% and 13.4%, respectively. The incidence of target lesion–related nonfatal myocardial infarction was 0.6%. Lesions with TLF had a greater change in Pd/Pa (0.11±0.03 versus 0.09±0.04; P=0.002), larger diameter stenosis (51.0±9.2% versus 46.4±12.4%; P=0.048), and smaller FFR (0.84 [0.82–0.87] versus 0.86 [0.83–0.90]; P=0.02). Change in Pd/Pa (per 0.01 increase) predicted TLF (odds ratio, 1.16 [95% CI, 1.05–1.28]; P=0.002) and major adverse cardiac event (odds ratio, 1.08 [95% CI, 1.01–1.16]; P=0.03). Lesions with change in Pd/Pa ≥0.10 had 2.94- and 1.85-fold greater likelihood of TLF (95% CI, 1.30–6.69; P=0.01) and major adverse cardiac event (95% CI, 1.08–3.17; P=0.03), respectively. Lesions with FFR ≤0.85 had a substantially higher likelihood of TLF when there is a change in Pd/Pa ≥0.10 (12.4% versus 2.9%; hazard ratio, 3.60 [95% CI, 1.01–12.80]; P=0.04). However, change in Pd/Pa did not affect TLF risk in lesions with FFR ≥0.86 (3.8% versus 3.7%; hazard ratio, 0.56 [95% CI, 0.06–5.62]; P=0.62).

CONCLUSIONS:

Despite deferrable FFR values, lesions and patients with a change in Pd/Pa ≥0.10 had higher cardiovascular risk. Change in Pd/Pa might help stratify lesion- and patient-level risks of future cardiac events in those with FFR ≥0.81.

arterial pressure
coronary artery disease
coronary stenosis
fractional flow reserve, myocardial
vasodilation
OPEN-ACCESSTRUE
SDCT
==== Body
pmcWHAT IS KNOWN

Cardiovascular events subsequently occur in ≈10% of coronary lesions deferred based on fractional flow reserve values.

A recent near-infrared spectroscopy imaging study reported that not only fractional flow reserve but also change in distal coronary artery pressure/aortic pressure (Pd/Pa; defined as a reduction in distal coronary artery pressure/aortic pressure from baseline to hyperemia) are associated with the extent of lipidic plaque materials, which suggests that change in Pd/Pa might be an additional measure for predicting future outcomes at deferrable lesions.

WHAT THE STUDY ADDS

Lesions with subsequent target lesion failure more likely presented with greater change in Pd/Pa (0.11±0.03 versus 0.09±0.04; P=0.002), larger diameter stenosis (51.0% versus 46.4%; P=0.04), and smaller fractional flow reserve (0.84 [0.82–0.87] versus 0.86 [0.83–0.90]; P=0.02).

During the 7-year observational period, lesions with changes in Pd/Pa ≥0.10 had a higher likelihood of experiencing lesion-level target lesion failure and patient-level major adverse cardiac events.

Our findings suggest that change in Pd/Pa is another physiological measure for stratifying lesion- and patient-level risks of future cardiac events at intermediate stenosis with fractional flow reserve ≥0.81.

Fractional flow reserve (FFR) reflecting distal coronary artery pressure/aortic pressure (Pd/Pa) during hyperemia is a guideline-recommended method to evaluate the functional severity of coronary artery stenosis. Revascularization for coronary lesions is deferrable if its FFR is over 0.80.1–3 However, recent studies have reported that ≈10% of deferred lesions have subsequent cardiac events,4,5 suggesting the need to further stratify the risk of future cardiac events in coronary lesions with FFR ≥0.81.

Physiological coronary measures have been reported to be associated with plaque components.6–8 We recently used near-infrared spectroscopy imaging to quantitatively measure lipidic plaque materials associated with future cardiac events.9,10 In that analysis, lower Pd/Pa during hyperemia (ie, FFR) was associated with a greater accumulation of lipidic content within vessel walls.11 Furthermore, a larger reduction of Pd/Pa in response to hyperemic agents (ie, change in Pd/Pa) was another independent contributor to more lipidic plaque features. Because the presence of lipidic plaque is associated with subsequent cardiac outcomes, the degree of change in Pd/Pa from rest to hyperemia might stratify the risk of future cardiac events.

A previous study using virtual histology-intravascular ultrasound demonstrated an association between necrotic core materials and coronary endothelial dysfunction.12 Furthermore, another study employing near-infrared spectroscopy imaging showed that patients with endothelial dysfunction have more accumulation of lipidic content within vessel walls than those without.13 This vascular endothelial abnormality at lipid-rich plaques could impair vasodilation in epicardial arteries, thereby causing a larger change in Pd/Pa.14 Based on these findings and mechanistic insights, we hypothesized that change in Pd/Pa might help identify coronary lesions associated with a higher risk of cardiac events despite FFR ≥0.81. The current study sought to elucidate whether a change in Pd/Pa could predict future cardiovascular events in deferred lesions with FFR ≥0.81.

METHODS

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Subjects

The current study retrospectively investigated 2559 patients who had undergone coronary angiography and subsequent FFR measurement for intermediate stenosis at our institute from January 1, 2012, to August 31, 2022 (Figure 1). Intermediate stenosis was defined as a lesion with diameter stenosis between 25% and 75% on quantitative coronary angiography. We excluded the following patients: 1434 patients whose revascularization was performed due to FFR ≤ 0.80, 218 patients whose revascularization was deferred despite FFR ≤0.80, 5 patients with missing data on change in Pd/Pa, and 3 patients whose FFR was measured in a bypass graft. The remaining 899 patients with FFR ≥0.81 whose revascularization was deferred were included in the current analysis (Figure 1). The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. This study protocol was approved by the institutional review board of the National Cerebral and Cardiovascular Center (M24-055-10). The subjects gave informed consent.

Figure 1. Study flowchart. A total of 899 patients whose revascularization was deferred with fractional flow reserve (FFR) ≥0.81 were included in the current analysis. Pd/Pa indicates distal coronary artery pressure/aortic pressure; and TLF, target lesion failure.

Quantitative Coronary Angiography Analysis

The current study included quantitative coronary angiography analysis (Qangio XA, Medis, Leiden, the Netherlands).15 Analyzed variables included minimum lumen diameter, reference lumen diameter, diameter stenosis, area stenosis, lesion length, and distance from the ostium to the target lesion (ie, the distance between the ostium of the vessel and the site of the minimum lumen diameter for target lesions).16

FFR and Change in Pd/Pa Measurement

The target vessel was defined as the coronary artery that underwent FFR measurement. The target lesion was defined as the coronary segment presenting with the most severe stenosis within the target vessel. If a patient had multiple target vessels with FFR data, the vessel with the largest change in Pd/Pa was selected.

FFR measurement was performed as previously described.17 Briefly, after the coronary artery was cannulated with a 5F guide catheter, a pressure-monitoring guidewire (PressureWire Certus, Aeris, or X, Abbott Vascular, Santa Clara, CA; Optowire, Zeon Medical, Tokyo, Japan; or COMET, Boston Scientific, Marlborough, MA) was advanced to the most distal site of the target vessel. Following the measurement of Pd/Pa at rest, hyperemia was induced by the administration of intravenous adenosine 5’-triphosphate at the rate of 180 μg/kg per minute. In patients with contraindications to the use of adenosine 5’-triphosphate, intracoronary nicorandil 2 mg was used instead.18 After a hyperemic state was achieved, Pd/Pa was measured again (ie, FFR). Change in Pd/Pa was calculated using the following formula11 (Figure 2): change in Pd/Pa=Pd/Pa at rest−Pd/Pa during hyperemia.

Figure 2. Change in distal coronary artery pressure/aortic pressure (Pd/Pa). A, Physiological assessment was performed for intermediate stenosis (diameter stenosis, 48%) in the mid-left anterior descending artery. B and C, Pd/Pa decreased from 0.95 to 0.84 during hyperemia. The change in Pd/Pa was 0.11. FFR indicates fractional flow reserve.

All procedural decisions, including the selection of which lesion or vessel in which to measure FFR, pressure-monitoring guidewire, and hyperemic agent, were made according to the discretion of the individual operator.

Outcomes

The primary outcome was the occurrence of a target lesion failure (TLF), which was defined as the composite of target lesion–related nonfatal myocardial infarction and ischemia-driven target lesion revascularization.4,19,20 The primary outcome was evaluated in a lesion-based analysis (899 target lesions). The secondary outcome was a patient-oriented major adverse cardiac event (MACE), which included the composite of cardiac death, nonfatal myocardial infarction, ischemia-driven unplanned revascularization, and hospitalization due to unstable or progressive angina.4,19–21 The secondary outcome was evaluated in a patient-based analysis (899 patients). The definition of each outcome is summarized in the Supplemental Methods.

Study patients were followed in our institution’s outpatient clinic, by a general practitioner, or both every 1–3 months. Testing to evaluate for myocardial ischemia was conducted according to each physician’s discretion. Clinical follow-up data were collected from medical records from hospital discharge up to 7 years after FFR measurement. All outcomes were adjudicated by independent physicians who were unaware of the clinical characteristics of the study participants (K.M. and Y.K.).

Statistical Analysis

Normally distributed variables were expressed as mean±SD. Nonnormally distributed variables were expressed as medians (25th–75th percentiles). Categorical data were expressed as numbers (%). Comparisons of normally distributed variables were performed with the Student t test. Nonnormally distributed variables were compared using the Mann-Whitney U test. Categorical variables were analyzed using the χ2 test or the Fisher exact test, as appropriate. The time-to-event rate was based on Kaplan-Meier estimates. Logistic regression analysis was used to evaluate the association between change in Pd/Pa with clinical outcomes. To test the ability of change in Pd/Pa to differentiate target lesions with and without subsequent TLF, receiver operating characteristic analysis was performed to generate a C statistic and determine the optimal change in Pd/Pa threshold for identifying subsequent TLF. The time-to-event rate was compared using a Cox proportional hazard model with adjustment for other clinical or lesion characteristics that might affect the occurrence of cardiovascular events. These include age, gender, estimated glomerular filtration rate, diameter stenosis for TLF, diabetes, low-density lipoprotein cholesterol level, and left ventricular ejection fraction in addition to these factors for MACE.4,22,23 The assumption of proportionality was assessed by the Schoenfeld residuals, and all Cox proportional hazards models satisfied the proportional hazards assumption. To evaluate the ability of change in Pd/Pa to predict TLF at various FFR values, the same analysis was performed separately for lesions divided by the median value of FFR. All statistical tests were 2-sided. P<0.05 was regarded as statistically significant. Analyses were performed with SPSS software, version 27 (IBM Corporation, Armonk, NY) and R, version 4.2.3 (The R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Occurrence of TLF and MACE

During the observational period with a median follow-up of 1144 (567–1949) days, the incidence of TLF was 6.7%. Only 2 target lesion–related nonfatal myocardial infarctions (0.6%) occurred during the observation period. Ischemia-driven target lesion revascularization was required in 6.7% of lesions analyzed (Table S1A). MACE was observed in 13.4% of the entire study population. The prevalence of cardiac death, nonfatal myocardial infarction, ischemia-driven unplanned revascularization, and hospitalization due to unstable or progressive angina was 2.3%, 2.2%, 11.4%, and 2.1%, respectively (Table S1B).

Baseline Clinical Demographics of the Study Patients

Study patients were stratified into 2 groups by TLF status. Table 1 summarizes the comparison of clinical demographics between the 2 groups (Table 1). The study population was predominantly male (71%) and had a high prevalence of hypertension (77%), dyslipidemia (75%), and type 2 diabetes (34%). Chronic coronary syndrome was the presenting condition in 87% of patients. Acute coronary syndrome was the presenting condition in 13% of patients. With regard to the use of guideline-recommended medications, patients with TLF were more likely to have received aspirin and a β-blocker (Table 1), whereas the use of statins (96% versus 88%; P=0.16) and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (64% versus 61%; P=0.71) did not differ between 2 groups. With these medical therapies, there were no significant differences in lipid or glycemic profiles (Table 1).

Table 1. Clinical Characteristics of the Study Participants at Baseline

Angiographic and Physiological Measures of Analyzed Target Lesions

Table 2 summarizes the angiographic and physiological measures. Target lesions with TLF were more likely to have greater diameter stenosis (51.0% versus 46.4%; P=0.04). While Pd/Pa at rest was similar between the 2 groups, FFR was significantly smaller in target lesions with TLF compared with those without TLF (0.84 versus 0.86; P=0.02). Furthermore, a larger change in Pd/Pa was observed in lesions with TLF (0.11 versus 0.09; P=0.002).

Table 2. Characteristics of Target Lesions

Association Between Change in Pd/Pa With TLF and MACE

Logistic regression analysis showed that change in Pd/Pa (per 0.01 increase) is a predictor of TLF (odds ratio, 1.16 [95% CI, 1.05–1.28]; P=0.002) and MACE (odds ratio, 1.08 [95% CI, 1.01–1.16]; P=0.03; Table 3). Receiver operating characteristic analysis revealed a change in Pd/Pa ≥0.10 as the cutoff value for predicting subsequent TLF (C statistic, 0.67; sensitivity, 68%; and specificity, 62%; Figure 3). Figure 4 illustrates the distribution of FFR and change in Pd/Pa ≥0.10. A total of 353 lesions (39%) exhibited a change in Pd/Pa ≥0.10.

Table 3. Association Between Change in Pd/Pa (per 0.01 Increase) and Clinical Outcome

Figure 3. Receiver operator characteristic analysis for change in distal coronary artery pressure/aortic pressure in predicting target lesion failure.

Figure 4. Distribution of fractional flow reserve (FFR) and change in distal coronary artery pressure/aortic pressure (Pd/Pa) ≥0.10.

Characteristics of study subjects and target lesions stratified by change in Pd/Pa of 0.10 are summarized in Tables S2 and S3. Patients with target lesions presenting with change in Pd/Pa ≥0.10 were younger (70.8±9.9 versus 73.9±9.7 years; P<0.001). A higher proportion of them were male (77% versus 67%; P<0.001; Table S2). Target lesions with change in Pd/Pa ≥0.10 were more common in the right coronary artery (32% versus 19%) and less common in the left anterior descending artery (50% versus 62%) than those with change in Pd/Pa <0.10 (P<0.001). Greater diameter stenosis (48.1±11.5% versus 45.5±12.7%; P=0.002) and area stenosis (71.7±12.2% versus 68.7±14.3%; P=0.001) and shorter lesion length (13.3±7.6 versus 14.7±8.2 mm; P=0.006) were observed in lesions with change in Pd/Pa ≥0.10 compared with those with change in Pd/Pa <0.10. On physiological analysis, target lesions with change in Pd/Pa ≥0.10 had higher Pd/Pa at rest (0.96±0.03 versus 0.95±0.04; P<0.001) and smaller FFR (0.83 [0.82–0.76] versus 0.88 [0.85–0.92]; P<0.001) than those with change in Pd/Pa <0.10 (Table S3). After adjusting for age, gender, estimated glomerular filtration rate, and diameter stenosis, target lesions with change in Pd/Pa ≥0.10 were associated with a 2.94-fold greater likelihood of experiencing TLF (95% CI, 1.30–6.69; P=0.01; Figure 5A). A similar relationship was observed in lesions located within the left anterior descending artery (adjusted hazard ratio (HR), 3.62 [95% CI, 1.04–12.61]; P=0.04). In nonleft anterior descending artery lesions, there was a trend toward higher risk of TLF in association with change in Pd/Pa ≥0.10, but this did not meet statistical significance (adjusted HR, 2.34 [95% CI, 0.79–6.93]; P=0.13). While the occurrence of target lesion–related nonfatal myocardial infarction did not differ between those with and without change in Pd/Pa ≥0.10 (P=0.88), ischemia-driven target lesion revascularization occurred more frequently in target lesions with change in Pd/Pa ≥0.10 than in those without (Figure S1A and S1B).

Figure 5. Comparison of outcomes in patients stratified by a change in distal coronary artery pressure/aortic pressure (Pd/Pa) of 0.10. A, Target lesion failure (TLF). B, Major adverse cardiac event (MACE).

Patient-based analysis demonstrated that those with change in Pd/Pa ≥0.10 more frequently experienced MACE (18.9% versus 8.7%; adjusted HR, 1.85 [95% CI, 1.08–3.17]; P=0.03; Figure 5B). Figure S2 illustrates the occurrence of each MACE component in patients with or without change in Pd/Pa ≥0.10. The higher occurrence of MACE in lesions with change in Pd/Pa>0.10 was mainly driven by ischemia-driven unplanned revascularization (17.1% versus 6.4%; adjusted HR, 2.26 [95% CI, 1.19–4.32]; P=0.01).

Change in Pd/Pa ≥0.10, FFR, and TLF Risk

Further analysis was conducted to evaluate whether the risk of TLF associated with a change in Pd/Pa ≥0.10 differed in association with FFR. Target lesions were stratified according to the median value of FFR (0.86; Figure 6). The prevalence of change in Pd/Pa ≥0.10 in lesions with FFR between 0.81 and 0.85 and FFR ≥0.86 was 74% and 29%, respectively. Among lesions with FFR between 0.81 and 0.85, change in Pd/Pa ≥0.10 was significantly associated with the occurrence of TLF (12.4% versus 2.9%; adjusted HR, 3.60 [95% CI, 1.01–12.80]; P=0.04). In contrast, among lesions with FFR ≥0.86, the risk of TLF was not necessarily elevated even when a change in Pd/Pa was ≥0.10 (3.8% versus 3.7%; adjusted HR, 0.56 [95% CI, 0.06–5.62]; P=0.62). Figure 7 illustrates 2 representative cases.

Figure 6. Relationship between change in distal coronary artery pressure/aortic pressure (Pd/Pa) and target lesion failure (TLF) stratified by the median value of fractional flow reserve (FFR, 0.86). HR indicates hazard ratio.

Figure 7. Representative cases. A, A 70-year-old gentleman with silent myocardial ischemia underwent coronary angiography, which revealed intermediate stenosis in the proximal segment of the left circumflex artery (LCX) with diameter stenosis of 46% (arrowhead). His low-density lipoprotein cholesterol (LDL-C) level was 99 mg/dL while on statin therapy. B and C, Distal coronary artery pressure/aortic pressure (Pd/Pa) decreased substantially, from 0.95 at rest to 0.82 during hyperemia. The change in Pd/Pa was 0.13. Revascularization was deferred due to fractional flow reserve (FFR) ≥0.81. D, Two years later, stress scintigraphy showed new ischemia in the lateral wall region. Subsequent coronary angiography revealed progression of the LCX stenosis, with diameter stenosis of 81% (arrowhead). Revascularization with a drug-eluting stent was performed. E, An 80-year-old gentleman with angina pectoris had intermediate stenosis in the proximal segment of LCX with a diameter stenosis of 69% (arrowhead). His LDL-C level was 66 mg/dL while on statin therapy. F and G, Pd/Pa at baseline and during hyperemia was 0.92 and 0.84, respectively. The change in Pd/Pa was 0.08. Revascularization was deferred. The clinical course has been uneventful for 6 years.

DISCUSSION

Cardiac events still occur in FFR-guided deferrable lesions, but clinical approaches for identifying high-risk deferred lesions have not been established yet. In the current study analyzing coronary lesions with FFR ≥0.81, the risk of lesion- and patient-related cardiac events increased when their change in Pd/Pa was ≥0.10. In particular, ischemia-driven coronary revascularization was more frequently required in those with change in Pd/Pa ≥0.10 despite a high prevalence of antithrombotic and statin therapy. These findings indicate the importance of change in Pd/Pa when stratifying future risks of cardiac events in lesions and patients with FFR ≥0.81.

Change in Pd/Pa can be considered a coronary physiological measure that reflects the degree of vascular response through the process of hyperemia. Previous intravascular imaging studies have demonstrated that lipid-rich coronary lesions have an impaired response to vasodilatory agents due to endothelial dysfunction.12,13,24 Because these vasodilatory agents act on epicardial arteries and resistance arteries, lipid-rich lesions might not sufficiently dilate during hyperemia, resulting in relatively more severe stenosis.14 These mechanisms could account for a larger reduction in Pd/Pa through hyperemia (ie, a larger change in Pd/Pa) in lipidic plaques, which potentially reflects the presence of more severe endothelial dysfunction. Considering that both endothelial dysfunction and lipidic plaque accumulation are associated with subsequent cardiovascular events, these findings suggest that changes in Pd/Pa can help predict future cardiac events.9,10,25,26

In addition, the current study elucidated that coronary lesions with a change in Pd/Pa ≥0.10 are shorter and have larger diameter stenosis. These results are consistent with previous studies that showed that focal lesions have larger diameter stenosis and greater reduction of Pd/Pa after hyperemia.27,28 In another imaging study, focal stenosis more frequently presented with unstable plaque features compared with diffuse lesions.16 Mechanistically, focal stenosis causes disturbances in laminar flow and produces low wall shear stress, thereby leading to plaque progression and inflammation.29,30 These morphological features could account for the current observations about the association between changes in Pd/Pa and future cardiac events.

Furthermore, in the current analysis, target lesions with a change in Pd/Pa ≥0.10 were physiologically characterized by larger Pd/Pa at rest and smaller FFR. Feher et al31 reported that coronary artery stenosis with preserved perfusion pressure at rest is associated with constriction of microvessels driven by compensatory autoregulation of coronary flow. Analyzed lesions with a change in Pd/Pa ≥0.10 might be associated with these features of the microcirculation pertinent to compensatory autoregulation. One recent observational study reported that these physiological characteristics are associated with a larger increase in coronary flow during hyperemia.28 Considering that pressure gradients depend on the amount of blood flow,32 increasing coronary flow could lead to a greater reduction of Pd/Pa during hyperemia, ultimately leading to smaller FFR in target lesions with a change in Pd/Pa ≥0.10. Given a higher risk of subsequent coronary events in lesions with low FFR, even deferred lesions,5 the coronary microcirculation and compensatory autoregulation of coronary flow might contribute to the present finding that a larger change in Pd/Pa is associated with a higher occurrence of cardiac events (Figure S3).

Recently, the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter) reported that 13.0% of 5-year target vessel failures occurred in deferrable patients with 0.81 ≤ FFR ≤0.85, suggesting they have a residual risk for cardiac events.5 In the current study, coronary lesions with FFR between 0.81 and 0.85 had a considerably higher risk of subsequent TLF when its change in Pd/Pa was >0.10. Our previous near-infrared spectroscopy imaging study revealed that both lower FFR and larger changes in Pd/Pa are associated with more lipidic plaque material.11 Even in lesions with deferrable FFR values, the presence of these 2 physiological abnormalities might synergistically reflect a substantial amount of lipid-rich material, which ultimately worsens future outcomes. Currently, lesions with FFR >0.81 are deferrable. However, the current findings indicate that lesions presenting with a change in Pd/Pa ≥0.10 are still at high risk and potentially require additional therapy. As shown in the tables, lesions with a large change in Pd/Pa were more likely to be focal or stenotic and have preserved microcirculation. Lesions with a large change in Pd/Pa might benefit from percutaneous coronary intervention with stent implantation. Future studies are needed to elucidate whether percutaneous coronary intervention could improve cardiovascular outcomes in those with a change in Pd/Pa ≥0.10. On the other hand, the frequency of TLF was low (3.7%–3.8%) in those with FFR ≥0.86, and the change in Pd/Pa ≥0.10 did not affect their TLF risk. The detailed mechanism behind this finding remains to be determined. However, even in deferrable lesions, higher FFR is associated with more stable plaque features.33 In addition, as shown in Figure 4, lesions presenting with change in Pd/Pa ≥0.10 were mainly deferrable lesions with FFR ≤0.85, which indicates a lower frequency of change in Pd/Pa ≥0.10 in those with FFR ≥0.86. Given the association between lipidic plaque features and these 2 physiological abnormalities, the form of atherosclerotic disease in deferrable lesions with FFR ≥0.86 might be more likely delipidated. Therefore, the effect of concomitant change in Pd/Pa ≥0.10 might be small. Future studies are needed to identify another measure for predicting the risk of future cardiac events in lesions with FFR ≥0.86.

Several caveats should be considered when interpreting the current findings. First, this was a single-center observational study that included a relatively small number of cardiovascular events. Second, the C statistic for change in Pd/Pa in predicting TLF was modest. Third, the association between change in Pd/Pa and lipidic burden has been reported only in FFR-positive lesions. Future studies are needed to investigate this association in FFR-negative lesions. Fourth, the occurrence of TLF and MACE was mainly driven by ischemia-driven target lesion revascularization and unplanned ischemia–driven revascularization, respectively. Due to the retrospective nature of this study, selection bias cannot be excluded. The number of deaths and nonfatal myocardial infarctions was small; therefore, the current study did not have enough power to investigate the relationship between change in Pd/Pa ≥0.10 and these hard cardiac events.

In conclusion, the current study measured change in Pd/Pa, the difference between Pd/Pa at rest and during hyperemia, in lesions with FFR ≥0.81. Lesions with TLF were more likely to have a greater change in Pd/Pa. Receiver operating characteristic analysis demonstrated 0.10 as a cutoff for predicting TLF (C statistic, 0.67; sensitivity, 68%; and specificity, 62%). During an observational period of up to 7 years, lesion-based analyses demonstrated that change in Pd/Pa ≥0.10 predicted TLF. In addition, a change in Pd/Pa ≥0.10 elevated the risk of patient-oriented MACE. These clinical end points were mainly driven by revascularization. Change in Pd/Pa is potentially a physiological measure for risk stratification of future cardiac events in lesions and patients with deferrable FFR values.

ARTICLE INFORMATION

Acknowledgments

The authors would like to acknowledge cardiology medical fellows and co-medical staff members (Sayaka Watanabe, Shintaro Kobayashi, and Tomoyu Kondo) for their support in measuring fractional flow reserve (change in distal coronary artery pressure/aortic pressure [Pd/Pa]) during coronary angiography. They also thank Ms Tomoko Nishimura, Ms Yuko Yoshioka, and Ms Emi Kanai for their excellent assistance.

Sources of Funding

This study was supported by the Naohiko Miyata-Asahi Intecc Foundation for Medical Technology and Research; the Fukuda Foundation for Medical Technology; the Shimadzu Science Foundation; the Astellas Foundation for Research on Metabolic Disorders; and the Japan Society for the Promotion of Science, KAKENHI (grant JP 23K15178).

Disclosures

Dr Murai received honoraria from Abbott, Terumo, Amgen, Astellas, Zeon Medical, and Boehringer Ingelheim and support for attending meetings from OrbusNeich. Dr Kataoka received research support from Nipro and Abbott and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda, and Daiichi Sankyo. Dr Otsuka received a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and honoraria from Abbott, Amgen, Astellas, BioPharma, Bayer, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Kowa, Nipro, Novartis, Otsuka, Pfizer, Sanofi, Takeda, and Terumo. The other authors report no conflicts.

Supplemental Material

Supplemental Methods

Tables S1–S3

Figures S1–S3

Supplementary Material

Nonstandard Abbreviations and Acronyms

FFR fractional flow reserve

HR hazard ratio

MACE major adverse cardiac event

Pd/Pa distal coronary artery pressure/aortic pressure

TLF target lesion failure

Presented at the 32nd Annual Meeting of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT2024), Sapporo, Japan, July 25–27, 2024.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCINTERVENTIONS.124.013830.

For Sources of Funding and Disclosures, see page 815.
==== Refs
REFERENCES

1. Lawton JS Tamis-Holland JE Bangalore S Bates ER Beckie TM Bischoff JM Bittl JA Cohen MG DiMaio JM Don CW . 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145 :e18–e114. doi: 10.1161/CIR.0000000000001038 34882435
2. Neumann FJ Sousa-Uva M Ahlsson A Alfonso F Banning AP Benedetto U Byrne RA Collet JP Falk V Head SJ ; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40 :87–165. doi: 10.1093/eurheartj/ehy394 30165437
3. Yamagishi M Tamaki N Akasaka T Ikeda T Ueshima K Uemura S Otsuji Y Kihara Y Kimura K Kimura T ; Japanese Circulation Society Working Group. JCS 2018 guideline on diagnosis of chronic coronary heart diseases. Circ J. 2021;85 :402–572. doi: 10.1253/circj.CJ-19-1131 33597320
4. Cho YK Hwang J Lee CH Kim IC Park HS Yoon HJ Kim H Han SW Hur SH Kim KB . Influence of anatomical and clinical characteristics on long-term prognosis of FFR-guided deferred coronary lesions. JACC Cardiovasc Interv. 2020;13 :1907–1916. doi: 10.1016/j.jcin.2020.05.040 32819479
5. Kuramitsu S Matsuo H Shinozaki T Horie K Takashima H Terai H Kikuta Y Ishihara T Saigusa T Sakamoto T ; J-CONFIRM Investigators. Five-year outcomes after fractional flow reserve-based deferral of revascularization in chronic coronary syndrome: final results from the J-CONFIRM registry. Circ Cardiovasc Interv. 2022;15 :e011387. doi: 10.1161/CIRCINTERVENTIONS.121.011387 35130711
6. Gaur S Ovrehus KA Dey D Leipsic J Botker HE Jensen JM Narula J Ahmadi A Achenbach S Ko BS . Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemia-causing lesions. Eur Heart J. 2016;37 :1220–1227. doi: 10.1093/eurheartj/ehv690 26763790
7. Park HB Heo R Ó Hartaigh B Cho I Gransar H Nakazato R Leipsic J Mancini GBJ Koo BK Otake H . Atherosclerotic plaque characteristics by CT angiography identify coronary lesions that cause ischemia: a direct comparison to fractional flow reserve. JACC Cardiovasc Imaging. 2015;8 :1–10. doi: 10.1016/j.jcmg.2014.11.002 25592691
8. Usui E Yonetsu T Kanaji Y Hoshino M Yamaguchi M Hada M Fukuda T Sumino Y Ohya H Hamaya R . Optical coherence tomography-defined plaque vulnerability in relation to functional stenosis severity and microvascular dysfunction. JACC Cardiovasc Interv. 2018;11 :2058–2068. doi: 10.1016/j.jcin.2018.07.012 30336810
9. Waksman R Di Mario C Torguson R Ali ZA Singh V Skinner WH Artis AK Cate TT Powers E Kim C ; LRP Investigators. Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study. Lancet. 2019;394 :1629–1637. doi: 10.1016/S0140-6736(19)31794-5 31570255
10. Erlinge D Maehara A Ben-Yehuda O Botker HE Maeng M Kjoller-Hansen L Engstrom T Matsumura M Crowley A Dressler O ; PROSPECT II Investigators. Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study. Lancet. 2021;397 :985–995. doi: 10.1016/S0140-6736(21)00249-X 33714389
11. Murai K Kataoka Y Nakaoku Y Nishimura K Kitahara S Iwai T Nakamura H Hosoda H Hirayama A Matama H . The association between the extent of lipidic burden and delta-fractional flow reserve: analysis from coronary physiological and near-infrared spectroscopic measures. Cardiovasc Diagn Ther. 2021;11 :362–372. doi: 10.21037/cdt-20-1024 33968615
12. Lavi S Bae JH Rihal CS Prasad A Barsness GW Lennon RJ Holmes DR Jr Lerman A . Segmental coronary endothelial dysfunction in patients with minimal atherosclerosis is associated with necrotic core plaques. Heart. 2009;95 :1525–1530. doi: 10.1136/hrt.2009.166017 19497916
13. Choi BJ Prasad A Gulati R Best PJ Lennon RJ Barsness GW Lerman LO Lerman A . Coronary endothelial dysfunction in patients with early coronary artery disease is associated with the increase in intravascular lipid core plaque. Eur Heart J. 2013;34 :2047–2054. doi: 10.1093/eurheartj/eht132 23569198
14. Lupi A Buffon A Finocchiaro ML Conti E Maseri A Crea F . Mechanisms of adenosine-induced epicardial coronary artery dilatation. Eur Heart J. 1997;18 :614–617. doi: 10.1093/oxfordjournals.eurheartj.a015305 9129891
15. Suzuki N Asano T Nakazawa G Aoki J Tanabe K Hibi K Ikari Y Kozuma K . Clinical expert consensus document on quantitative coronary angiography from the Japanese Association of Cardiovascular Intervention and Therapeutics. Cardiovasc Interv Ther. 2020;35 :105–116. doi: 10.1007/s12928-020-00653-7 32125622
16. Sakai K Mizukami T Leipsic J Belmonte M Sonck J Norgaard BL Otake H Ko B Koo BK Maeng M . Coronary atherosclerosis phenotypes in focal and diffuse disease. JACC Cardiovasc Imaging. 2023;16 :1452–1464. doi: 10.1016/j.jcmg.2023.05.018 37480908
17. De Bruyne B Pijls NH Smith L Wievegg M Heyndrickx GR . Coronary thermodilution to assess flow reserve: experimental validation. Circulation. 2001;104 :2003–2006. doi: 10.1161/hc4201.099223 11673336
18. Jang HJ Koo BK Lee HS Park JB Kim JH Seo MK Yang HM Park KW Nam CW Doh JH . Safety and efficacy of a novel hyperaemic agent, intracoronary nicorandil, for invasive physiological assessments in the cardiac catheterization laboratory. Eur Heart J. 2013;34 :2055–2062. doi: 10.1093/eurheartj/eht040 23396491
19. Stone GW Sabik JF Serruys PW Simonton CA Genereux P Puskas J Kandzari DE Morice MC Lembo N Brown WM 3rd ; EXCEL Trial Investigators. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med. 2016;375 :2223–2235. doi: 10.1056/NEJMoa1610227 27797291
20. Mehta SR Wood DA Storey RF Mehran R Bainey KR Nguyen H Meeks B Di Pasquale G Lopez-Sendon J Faxon DP ; COMPLETE Trial Steering Committee and Investigators. Complete revascularization with multivessel PCI for myocardial infarction. N Engl J Med. 2019;381 :1411–1421. doi: 10.1056/NEJMoa1907775 31475795
21. Kedhi E Berta B Roleder T Hermanides RS Fabris E IJsselmuiden AJJ Kauer F Alfonso F von Birgelen C Escaned J . Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT-FFR trial. Eur Heart J. 2021;42 :4671–4679. doi: 10.1093/eurheartj/ehab433 34345911
22. Go AS Chertow GM Fan D McCulloch CE Hsu CY . Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351 :1296–1305. doi: 10.1056/NEJMoa041031 15385656
23. Navarese EP Robinson JG Kowalewski M Kolodziejczak M Andreotti F Bliden K Tantry U Kubica J Raggi P Gurbel PA . Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA. 2018;319 :1566–1579. doi: 10.1001/jama.2018.2525 29677301
24. Puri R Nicholls SJ Brennan DM Andrews J Liew GY Carbone A Copus B Nelson AJ Kapadia SR Tuzcu EM . Coronary atheroma composition and its association with segmental endothelial dysfunction in non-ST segment elevation myocardial infarction: novel insights with radiofrequency (iMAP) intravascular ultrasonography. Int J Cardiovasc Imaging. 2015;31 :247–257. doi: 10.1007/s10554-014-0545-2 25296909
25. Vanhoutte PM Shimokawa H Feletou M Tang EH . Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol (Oxf). 2017;219 :22–96. doi: 10.1111/apha.12646 26706498
26. Bonetti PO Lerman LO Lerman A . Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23 :168–175. doi: 10.1161/01.atv.0000051384.43104.fc 12588755
27. Mizukami T Sonck J Sakai K Ko B Maeng M Otake H Koo BK Nagumo S Norgaard BL Leipsic J . Procedural outcomes after percutaneous coronary interventions in focal and diffuse coronary artery disease. J Am Heart Assoc. 2022;11 :e026960. doi: 10.1161/JAHA.122.026960 36444858
28. Warisawa T Cook CM Howard JP Ahmad Y Doi S Nakayama M Goto S Yakuta Y Karube K Shun-Shin MJ . Physiological pattern of disease assessed by pressure-wire pullback has an influence on fractional flow reserve/instantaneous wave-free ratio discordance. Circ Cardiovasc Interv. 2019;12 :e007494. doi: 10.1161/CIRCINTERVENTIONS.118.007494 31084237
29. Chatzizisis YS Coskun AU Jonas M Edelman ER Feldman CL Stone PH . Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007;49 :2379–2393. doi: 10.1016/j.jacc.2007.02.059 17599600
30. Shishikura D Sidharta SL Honda S Takata K Kim SW Andrews J Montarello N Delacroix S Baillie T Worthley MI . The relationship between segmental wall shear stress and lipid core plaque derived from near-infrared spectroscopy. Atherosclerosis. 2018;275 :68–73. doi: 10.1016/j.atherosclerosis.2018.04.022 29864607
31. Feher A Sinusas AJ . Quantitative assessment of coronary microvascular function: dynamic single-photon emission computed tomography, positron emission tomography, ultrasound, computed tomography, and magnetic resonance imaging. Circ Cardiovasc Imaging. 2017;10 :e006427. doi: 10.1161/CIRCIMAGING.117.006427 28794138
32. Young DF Cholvin NR Kirkeeide RL Roth AC . Hemodynamics of arterial stenoses at elevated flow rates. Circ Res. 1977;41 :99–107. doi: 10.1161/01.res.41.1.99 862148
33. Lee JM Choi KH Koo BK Park J Kim J Hwang D Rhee TM Kim HY Jung HW Kim KJ . Prognostic implications of plaque characteristics and stenosis severity in patients with coronary artery disease. J Am Coll Cardiol. 2019;73 :2413–2424. doi: 10.1016/j.jacc.2019.02.060 31097161
