Percutaneous coronary intervention (PCI) is currently the standard of care for flow-limiting coronary lesions associated with myocardial ischemia [1,2,3]. However, estimation of the hemodynamic relevance in intermediate coronary lesions (50–70% diameter stenosis) is a daily clinical challenge. Fractional flow reserve (FFR) was established as a diagnostic tool to assess the functional relevance of intermediate coronary stenosis, and FFR-guided PCI is associated with a lower events rate and incidence of urgent revascularization [2, 4,5,6,7,8]. However, recent studies have shown that there is an anatomic–functional mismatch in up to two thirds of cases of “intermediate” coronary stenosis estimated by angiography that may lead to incorrect treatment decisions [5]. In addition, FFR-guided PCI has only been validated in patients with stable coronary artery disease and has not yet been verified for specific conditions such as heart failure or microvascular dysfunction [5,6,7,8]. Thus, an increased left ventricular end-diastolic pressure that influences coronary flow may have an impact on the FFR assessment, which uses a guidewire to measure blood pressure within a coronary artery [9]. Moreover, diabetes mellitus, which is associated with microvascular dysfunction and impaired vasodilatory capacity, results in increased microvascular resistance that also may influence the FFR assessment. These aspects have not been considered in the assessment and validation of FFR in previous trials [10].

Therefore, the aim of the present study was to examine the influence of specific patient comorbidities on FFR values and the frequency of PCI in patients with intermediate coronary artery stenosis.

Methods

Patients and treatment

A total of 652 patients with coronary artery disease for whom FFR was conducted between January 2014 and December 2017 and who had intermediate coronary diameter stenosis (50–70%) assessed by angiography were included in this retrospective study. All patients who were included in the present study underwent FFR assessment. Clinical history, physical examination, and laboratory test results were assessed for all patients. Physical examination and echocardiography were performed within the routine clinical work-up. In the present study, specific cardiovascular comorbidities were treated according to the current guidelines of the European Society of Cardiology (ESC) at a maximal tolerated dose with consideration of contraindications [11,12,13,14,15,16].

Assessment of FFR was carried out using the FFR-System OPTIS Integrated System, Abbott Inc. (San Francisco, CA, USA) and was performed according to standard clinical practice at maximal hyperemia induced by intravenous adenosine following a standardized, body weight-adapted protocol (140–160 μg/kg/min). Fractional flow reserve-guided PCI was performed in lesions only if the FFR was considered pathological under maximal hyperemia (FFR < 0.80). Influencing factors were defined as acute coronary syndrome (ACS), heart failure with reduced ejection fraction (HFrEF: LVEF ≤ 30%), heart failure with preserved ejection fraction, diabetes mellitus, chronic kidney disease defined as a glomerular filtration rate (GFR) <45 ml/min−1, atrial fibrillation (AF), and left ventricular hypertrophy (LVH). Acute coronary syndrome was diagnosed and treated according to the current guidelines of the ESC [13]. Accordingly, patients with ST-elevation infarction were referred directly to the catheter laboratory for invasive diagnostics and treatment [11]. In addition, patients with non-ST-elevated acute coronary syndrome (NSTE-ACS) were diagnosed on the basis of clinical conditions, echocardiographic criteria, and laboratory results considering cardiac biomarkers (troponin‑I, creatine kinase, creatine kinase-MB; [14]). Patients at high risk were referred for invasive coronary angiography within 24 h. Patients at intermediate risk were referred for invasive diagnostics within 72 h [14]. Patients with cardiogenic shock, life-threatening ventricular arrhythmias, or hemodynamic instability were not included in the present study. Heart failure with preserved ejection fraction (HFpEF) was defined by the presence of elevated BNP plasma values and echocardiographic criteria related to diastolic dysfunction (E/e′ > 13) [13]. Left ventricular hypertrophy was defined by echocardiography on the basis of a thickness of the posterior wall and septum >12 mm in diastole [16].

Exclusion criteria were defined as left main stenosis (diameter stenosis >50%), serial stenosis within the target vessel, and bypass graft on the target vessel. All clinical parameters and FFR values were assessed retrospectively for all patients with intermediate coronary stenosis between January 2014 and December 2017. Approval for the study was obtained from the institutional review board of the University of Giessen (99/13). The investigation conforms to the principles outlined in the Declaration of Helsinki.

Statistical analysis

All data for continuous variables are expressed as mean ± SD or as median and interquartile range, as appropriate. Categorical variables are reported as number and percentage. After testing for normal distribution, values were compared using the unpaired Student’s t test or Mann–Whitney test, as appropriate. Fisher’s exact test or a chi-squared test was used for categorical variables with nominal scales. Intergroup comparisons were made using the Mann–Whitney test. Multivariate stepwise logistic regression analysis was applied to identify independent factors at a level of p < 0.05. Adjusted odds ratios with 95% confidence intervals were used to quantify the independent factors. For all statistical analyses, the statistical software SPSS 24.0 (Statistical Package for the Social Sciences, Chicago, IL, USA) for Windows was used.

Results

A total of 652 patients (493 men [75.6%], mean age 67 ± 10 years) were included in the present study. Patient baseline characteristics are shown in Table 1. Invasive diagnostics and PCI were performed using the radial access in 463 patients (71%). In this study, a total of 808 lesions (left anterior descending artery [LAD]: 418 [51.7%], left circumflex artery [LCX]: 212 [26.2%], and right coronary artery [RCA]: 178 [22.1%]) with coronary diameter stenosis of 50–70% were assessed by FFR (Table 2 and 3). In one patient, a coronary dissection occurred that was caused by the FFR wire.

Table 1 Patients characteristics
Full size table
Table 2 Procedural characteristics
Full size table
Table 3 Procedural characteristics
Full size table

A subset of patients was classified as having HFrEF (n = 77 [11.8%]) or HFpEF (n = 397 [60.9%]) according to the left ventricular ejection fraction and diastolic function assessed by echocardiography (Table 4). Left ventricular hypertrophy was diagnosed in 311 (47.7%) patients, and ACS was determined in 267 (40.9%; NSTE-ACS: 263 [30.3%], STEMI: 4 [0.6%]) (Table 4).

Table 4 Patients comorbidities
Full size table

Pathological values for FFR (≤0.80) obtained immediately before PCI were most frequently observed in the LAD (n = 168/418; 40.2%) followed by the RCA (n = 37/178; 20.8%) and the LCX (n = 22/212; 10.4%). In lesions with 50% diameter stenosis the FFR was pathological in 7.5% of cases (19/254); for 60% diameter stenosis, the FFR was pathological in 21.2% of cases (61/288); and for 70% diameter stenosis, the FFR was pathological in 55.3% of cases (147/266; Fig. 1).

Fig. 1
figure 1

Pathological fractional flow reserve (FFR) results in 50%, 60%, and 70% diameter stenosis. Pathological values for FFR (≤0.80) were most frequent in the left anterior descending artery (LAD; n = 93/235; 39.6%) followed by the right coronary artery (RCA; n = 27/90; 30%), and the left circumflex artery (LCX; n = 12/103; 11.7%)

Full size image

The results from the subgroup analysis showed that the presence of comorbidities including NSTE-ACS (26.1% vs. 29.5% in the entire cohort; p = 0.29), HFrEF (26.0% vs. 28.4%, p = 0.90), HFpEF (27.2% vs. 30.3%; p = 0.75), diabetes mellitus (24.8% vs. 29.9%; p = 0.18), chronic kidney disease (26.8% vs. 28.5%; p = 0.14), AF (25% vs. 29%; p = 0.19), and LVH (33.4% vs. 25.4%; p = 0.35) was not associated with the occurrence of pathological FFR values (Fig. 2a–c).

Fig. 2
figure 2

Results from the subgroup analysis showed that the presence of comorbidities, including a diabetes mellitus, chronic kidney disease (CKD), and atrial fibrillation, b systolic and diastolic heart failure and left ventricular (LV) hypertrophy, and c acute coronary syndrome (ACS), was not associated with the occurrence of pathological fractional flow reserve (FFR) values. HFpEF heart failure with preserved ejection fraction, HFrEF heart failure with reduced ejection fraction, NSTEMI non-ST-elevation myocardial infarction, UA unstable angina

Full size image

Discussion

In the present study the measurement of FFR was confirmed to be a safe and feasible method of evaluating coronary artery stenosis in routine clinical practice. Pathological values for FFR were most often observed in the LAD, followed by the RCA and LCX. Furthermore, the FFR values obtained before PCI were not influenced by the presence of comorbidities such as heart failure, diabetes mellitus, and LVH, which confirms the validity of the method in a broad spectrum of patients with cardiovascular disease.

Coronary pressure-derived FFR is the current standard of care for the functional assessment of lesion severity for patients with intermediate-grade stenosis (50–70% stenosis) without evidence of ischemia in noninvasive testing or for those with multivessel disease [4, 6,7,8, 10]. Interestingly, the hemodynamic relevance, as defined by FFR ≤ 0.80, correlates poorly with diameter stenosis by visual estimation [5, 6]. Thus, in the FAME Study (Fractional Flow Reserve versus Angiography for Multivessel Evaluation), in only 35% of the cases of 50–70% diameter stenosis was the stenosis hemodynamically relevant, and in 20% of the cases of 71–90% stenosis the FFR finding was negative [8]. These results are consistent with our findings in the present study. Valid estimation of intermediate coronary stenosis is an advantage in routine clinical practice, and, importantly, a potential misjudgment is of prognostic relevance.

Assessment of FFR is applied routinely irrespective of specific patient characteristics such as systolic or diastolic heart failure, diabetes mellitus-related microvascular disease, AF, or ACS; however, FFR has not been validated under all of these conditions since such patients were excluded in previous randomized controlled trials [4, 8, 17, 18]. In the present study, pathological FFR values were most frequently documented in the LAD followed by the RCA and the LCX. This observation might be partly explained by factors such as the mass of the myocardial territory that is supplied by the epicardial coronary vessel and the amount of collateral blood flow. Importantly, this order of FFR values was also confirmed for all degrees of diameter stenosis in the present study.

Considering a possible impact of myocardial mass and microvascular circulation on FFR values, patient comorbidities such as diabetes mellitus, LVH, and heart failure may influence FFR; however, such potential confounders were not considered in previous trials [4, 5, 8, 9, 17, 18]. The validity of FFR measurements is associated with the vasodilatory capacity of the coronary system, and thus the presence of microvascular dysfunction may affect the required maximal hyperemia. In particular, patients with diabetes mellitus are characterized by microvascular dysfunction and impaired vasodilatory capacity with increased microvascular resistance [10]. Therefore, diabetic patients may display an abnormal response to coronary vasodilators used in FFR assessment, and FFR interpretation is still controversial in this specific cohort [10, 19,20,21]. In the present study, there were no differences between patients with and without type two diabetes mellitus in the frequency of pathological FFR values among patients with intermediate coronary stenosis. Thus, our findings suggest that FFR measurement conducted under maximal hyperemia is a valid method for assessing coronary hemodynamic properties in patients with diabetes mellitus. The presence of LVH in a subgroup of patients likewise did not influence the frequency of pathological FFR values, suggesting that LVH also has a negligible impact on FFR assessment. Nevertheless, the results of the present study have to be validated in a larger trial of FFR measurements that takes the aspect of microvascular dysfunction into account.

In heart failure patients, the increased left ventricular end-diastolic pressure influences the coronary blood flow and may thus impact FFR assessment [9]. In previous randomized controlled trials, patients with reduced left ventricular function were excluded, and therefore FFR assessment was also not validated in these patients [4, 5, 8,9,10]. However, in the present study, FFR values obtained in patients with intermediate coronary stenosis under maximal hyperemia were not more frequently pathological in patients with systolic (HFrEF) or diastolic (HFpEF) heart failure compared with patients having a normal systolic or diastolic left ventricular function. Therefore, the results of the present study confirm the validity of FFR assessment in heart failure patients.

Acute coronary syndrome, with extended catecholamine secretion and ischemic injury, is associated with microvascular dysfunction that may influence FFR assessment [22,23,24]. Current evidence, however, suggests that FFR assessment is also valid in patients with NSTE-ACS, and it is used under this specific condition in routine clinical practice [22,23,24]. The evidence from previous trials was supported by results from the present study [22,23,24]. Thus, there were no differences in the frequency of pathological FFR values between patients with NSTE-ACS and those with stable coronary artery disease. Further larger-scale studies will be necessary to confirm the results of the present study in patients with ACS.

Limitations

The results of the present study were based on a retrospective analysis and are therefore exploratory in nature. This must be considered as a major limitation of the present study. No additional invasive measurements of vasodilatory capacity with increased microvascular resistance were made in addition to FFR analysis in patients with diabetes mellitus. Further prospective studies are required to confirm the results of the present study.

Conclusion

The present study demonstrates that fractional flow reserve (FFR) measurement is a valid and reliable method of evaluating coronary artery stenosis in routine clinical practice. Pathological FFR values were most frequently documented in the left anterior descending artery followed by the right coronary artery and the left circumflex artery. The results also indicate that the presence of heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, diabetes mellitus, atrial fibrillation, and left ventricular hypertrophy does not influence FFR values; thus, measurement of FFR is valid in assessing the indication for percutaneous coronary intervention in patients with these comorbidities.