Feasibility, safety and effectiveness in measuring microvascular resistance with regadenoson

AIM: The study aims to test whether simultaneous measurement of fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) is feasible, safe and effective during regadenoson-induced hyperemia. METHODS AND RESULTS: FFR, CFR and IMR were measured simultaneously during regadenoson (Rapiscan 400 μg) -induced hyperemia in 50 patients with stable coronary artery disease with a SYNTAX score of <22. Simultaneous measurement of FFR, CFR and IMR was technically feasible in all cases (50/50). No side effects occurred and even patients fulfilling classical contraindications for the use of adenosine (10/50) could be included. Regadenoson-induced hyperemia remained stable after maximal pressure drop for more than 35 sec as measured by systemic aortic and distal coronary pressure. There was a significant drop in transit mean time from baseline to hyperemia of more than 50% (1.0 ± 0.6 s vs. 0.4 ± 0.2 s, p < 0.01). Patients' mean IMR value was 23.4, and IMR values above 75th percentile significantly correlated with metformin demanding diabetes mellitus with OR 21.76 and nicotine abuse with OR 10.28. CONCLUSION: A single intravenous regadenoson bolus via peripheral line increases coronary blood flow without harmful systemic side effects enabling interventionists to simultaneously assess FFR, CFR and IMR in patients with stable coronary artery disease.

Keywords: Coronary artery disease; regadenoson; coronary hyperemia; coronary blood flow

Abbreviations

• AMI

• acute myocardial infarction

• AV

• atrioventricular

• ECG

• electrocardiography

• CAD

• coronary artery disease

• CCS

• Canadian Cardiovascular Society

• CI

• confidence interval

• CFR

• coronary flow reserve

• CMR

• cardiac magnetic resonance

• COPD

• chronic obstructive pulmonary disease

• FFR

• fractional flow reserve

• IMR

• index of microcirculatory resistance

• i.c.

• intracoronary

• i.v.

• intravenous

• LCA

• left coronary artery

• LCX

• left circumflex artery
• Pa
• proximal aortic pressure
• Pd
• distal arterial pressure

• MVO

• microvascular obstruction

• NSTEMI

• non ST-elevation myocardial infarction

• NYHA

• New York Heart Association

• OR

• odds ratio

• PCI

• percutaneous coronary intervention

• PET

• positron emission tomography

• RCA

• right coronary artery

• STEMI

• ST-elevation myocardial infarction

• Tmn

• transit mean time

1 Introduction

Fractional flow reserve (FFR), coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) provide mortality relevant information about coronary macro- and microcirculation [[1]].

The gold standard to induce coronary hyperemia for measurement of FFR, CFR and IMR is adenosine. However, adenosine needs continuous central venous infusion or intracoronary delivery [[1]] and provokes additional biological effects due to its unspecific action on all adenosine receptors [[3]]. In contrast, the specific A2a-receptor agonist, regadenoson, has been shown to dilate coronary arteries, thus enabeling FFR measurements, and can be administered as a simple bolus of 4 ml via peripheral vein [[4]]. It has already been shown that regadenoson provides comparable values for invasive FFR and non-invasive myocardial perfusion reserve in single photon emissions computer tomography (SPECT) compared to adenosine [[4], [6]]. However, it is debated whether regadenoson induces stable and persistent hyperemia [[4]], as this would be required for simultaneous measurement of FFR, CFR and IMR while using the thermodilution method for CFR and IMR.

The hypothesis of the present study was that simultaneous measurement of FFR, CFR and IMR is feasible, safe and effective after regadenoson-induced hyperemia in patients with stable coronary artery disease and a SYNTAX score <22 undergoing a transradial procedure.

2 Methods

2.1 Study population

The ethical board of Heinrich Heine University Düsseldorf approved the present study (study reference 5701R; registration ID 2016095585). All participants signed informed consent. The study complies with the declaration of Helsinki.

A total of 50 patients with SYNTAX-score <22 were recruited from the cardiological outpatient clinic of Heinrich-Heine-University Düsseldorf. All patients screened for the study had routinely been scheduled for cardiac catheterization in accordance with current guidelines [[7]]. They were enrolled for the study, if there was an indication for FFR measurement due to a coronary artery stenosis of unclear hemodynamic relevance. Patients with hemodynamic instability, severe hypotension, acute myocardial ischemia or AV block II-III were excluded. FFR, CFR and IMR measurements were performed in all 50 enrolled patients. No central venous access was necessary, since all patients received regadenoson via peripheral line or additionally received adenosine intracoronarily. The parameters FFR, CFR and IMR were collated in 1 coronary artery per patient.

2.2 Coronary angiography and measurement of FFR, CFR and IMR

Coronary angiography was performed via radial access in all patients according to standard techniques and protocols. A 6F guiding catheter without side holes was advanced into the respective coronary ostium. A peripheral line was placed on the patient's back of the hand.

All measurements were performed after diagnostic angiography. A pressure-temperature sensor guide wire (PressureWiretrademark Certustrademark, St. Jude Medical, Inc.) was used for the simultaneous measurement of FFR, CFR and IMR. A RadiAnalyzer Xpresstrademark control unit was used to store, display and calculate all measurements recorded by the guide wire. Pressure and temperature were carefully calibrated after 200 μg of nitroglycerin was administered intracoronarily for relaxation of the macrovasculature. The pressure wire was introduced into the target coronary artery after equilibration and advanced towards the distal part of the vessel. Hyperemia for measurements of FFR, CFR and IMR was achieved by administration of 400 μg regadenoson via peripheral line as 4 ml bolus followed by a flush of 10 ml NaCl, once.

For assessment of regadenoson-induced systemic hyperemia, aortic mean pressure was continuously recorded. Recording usually lasted 180 seconds. For inter-patient comparability, we normalized aortic mean pressures in Fig. 2 to the initial value before administration of regadenoson. For assessment of regadenoson-induced coronary hyperemia, distal coronary pressure was extracted from the RadiAnalyzer Software at baseline and after the onset of patient symptoms.

We performed FFR measurements with adenosine intracoronarily (200 μg for LCA and 100 μg for RCA) before regadenoson administration in a subset of patients (09/50) in order to compare the coronary hyperemic effect induced by adenosine with that induced by regadenoson in our set-up. When distal arterial pressure (Pd) returned to baseline values after adenosine-mediated hyperemia [[9]], regadenoson was injected in these patients.

CFR and IMR were determined via thermodilution method: After gently flushing the catheter with saline for optimal thermodilution curves, three manual intracoronary bolus injections of 3 ml saline each at room temperature were conducted at rest and the mean value of these three measurements was calculated (Tmnr). In case of implausible values or error messages, measurements could be selectively repeated. During regadenoson-induced hyperemia, this procedure was repeated for generation of hyperemic transit mean time (Tmnh). In parallel, the prevailing proximal aortic (Pa) and Pd were recorded and RadiAnalyzer Xpresstrademark control unit automatically calculated FFR as Pd/Pa. Using the derived Pd and transit mean times under hyperemia, we calculated apparent IMR as Pd×Tmnh. All IMR values were also corrected by Yong's formula (IMRcorr = Pa×Tmnh×([1.35×Pd/Pa]– 0.32) to adjust for the influence of collateral flow [[10]]. All previously described measurements were performed during one cycle of regadenoson-induced hyperemia.

2.3 Statistical analysis

Categorical variables are presented as numbers and relative frequencies (percentages), and continuous variables as means and standard deviations or median with interquartile range (first, third quartiles). All data were analyzed on a per-patient basis. For the comparison of transit mean times at rest and after regadenoson-induced hyperemia, a Student's t-test was used. Correlation of FFR values meausured by means of regadenoson and adenosine-induced hyperemia was checked by means of simple linear regression.

All statistical analyses were performed in SPSS, version 18.0 (SPSS Inc., Chicago, Illinois).

3 Results

3.1 General characteristics of the study population

50 patients with SYNTAX-score <22 undergoing a transradial coronary angiography were enrolled for the study and Table 1 shows their general characteristics. Mean age of the population was 67.5 ± 11.6 years. The majority (72%) of patients was male. On average, the patients presented clinically with NYHA 1.9 ± 0.9 and CCS 2.4 ± 1.4. Approximately one third of patients showed signs of ischemia in exercise electrocardiography, -echocardiography or SPECT. With regard to cardiovascular risk factors, the majority of the patients had hypertension (79%) and more than half a previous PCI (58%), even 41% out of them in the vessel of measurement. A significant part of the population suffered from diabetes mellitus (44%), hyperlipidemia (46%) or had nicotine consumption (33%) in their medical history. The mean BMI was 28 ± 4.8, with 22% of the population being obese per definition [[11]]. More than a third (40%) of patients was taking two or more vasoactive medications for lowering blood pressure.

Table 1 General characteristics of the study population (n = 50)

Demographics
Age, y	67.5 ± 11.6
Female	14 (28%)
Clinical presentations
NYHA class	1.9 ± 0.9; 2 (1;3)
CCS class	2.4 ± 1.4; 2 (0;3)
Cardiovascular risk factors
Hypertension	38 (79%)
Diabetes mellitus	21 (44%)
Hyperlipidemia	22 (46%)
Nicotine	16 (33%)
BMI	28 ± 4.8
Obesity	11 (22%)
Previous PCI	29 (58%)
Vasoactive medications
β-blocker	40 (80%)
Nitrates	7 (14%)
Calcium antagonists	16 (32%)
Ranolazine	5 (10%)
Dihydralazine	1 (2%)
α2-agonists	3 (6%)
α1-antagonists	1 (2%)
Patients with two or more vasoactive medications	20 (40%)
Contraindications against adenosine
Asthma/COPD	9 (18%)
Atrioventricular block	1 (2%)

Values are mean ± SD, median (interquartile ranges, 25th– 75th), or n (%). NYHA = New York Heart Association; CCS = Canadian Cardiovascular Society; BMI = Body mass index; PCI = Percutaneous coronary intervention; COPD = Chronic obstructive pulmonary disease. *Obesity was defined as body mass index ≥ 25 kg/m2.

The general characteristics of vessels and physiological parameters of the investigated study population are presented in Table 2. FFR, CFR and IMR were measured in left main stem (n = 1), LAD (n = 27), in LCX (n = 6) and RCA (n = 16).

Table 2 General characteristics of vessels and physiological parameters (n = 50)

Measured vessel location
Left anterior descending artery	27 (54%)
Left circumflex artery	6 (12%)
Left coronary artery main stem	1 (2%)
Right coronary artery	16 (32%)
Coronary physiological indices
FFR	0.86 ± 0.09
IMR	25.2 (15.9; 40.3)
IMRcorr	23.4 (15.7; 40.3)
CFR	2.5 ± 1.2
Tmnr	0.9 ± 0.6
Tmnh	0.4 ± 0.2
Pa rest	97.6 ± 14.7
Pa hyp	83.4 ± 20.1
Pd rest	83.2 ± 14.7
Pd hyp	70.3 ± 19.9

Values are mean ± SD, median (interquartile ranges, 25th– 75th), or n (%). FFR = Fractional flow reserve; IMR = Index of microcirculatory resistance; IMRcorr = calculated IMR with Yong's formula (IMRcorr = Pa×Tmnh×([1.35×Pd/Pa]– 0.32). CFR = Coronary flow reserve; Tmnr = Transit mean time at rest; Tmnh. = Transit mean time under hyperemia; Pa rest = aortic pressure at rest; Pa hyp = aortic pressure at under hyperemia; Pd rest = distal coronary pressure at rest; Pd hyp = distal coronary pressure under hyperemia.

3.2 Feasibility of simultaneous measurement of FFR, CFR and IMR during regadenoson-induced hy...

Three Tmn values were recorded under non-hyperemic and under hyperemic conditions and expressed as mean value. Under non-hyperemic condition, Tmn calculation was repeated in 20/50 patients. The measurement was repeated once in 15/20 patients and twice in 5/20 patients. Common reasons for repetitive measurements were too slow injection time and too low amplitude of the thermodilution curve. These problems could be solved by repositioning the guiding catheter. Under hyperemia no error messages occurred while conducting thermodilution curves. Hyperemic conditions are shown in Fig. 1: after injection of regadenoson there was an intermittent increase of aortic mean pressure (on average +5%) during the first 24 ± 13 seconds (period "S") accompanied by symptom onset. After 54 ± 17 seconds (period "M"), recordings displayed a maximal and comparable drop of aortic mean and mean distal coronary (Pd) pressure (28 ± 10% vs. 28 ± 17%). Mean distal coronary pressure (Pd) of the population was significantly lower during regadenoson-induced hyperemia than during resting conditions (70 ± 20 mmHg vs. 83 ± 15 mmHg, p <  0.001). As can be seen in Fig. 1, after maximal pressure drop at 30 seconds the slope of the mean aortic pressure curve remained flat with a slope of smaller than 0.3 for further 35 seconds. During this period of flat slope cold saline was injected, which took 20 ± 2 seconds (period "I"). Even after the end of period "I", in 30% of patients aortic mean pressure did not rise back to baseline values during the full remaining recorded time (period "R"). In 70% of patients, aortic mean pressure did not reach baseline values during further 45 ± 34 seconds.

Graph: Fig. 1 Regadenoson induces stable hyperemia in systemic and coronary circulation. (A) Aortic mean pressure (black) and distal coronary pressure Pd (red) normalized to 100 % in the course of time after peripheral regadenoson injection (in seconds). S: time to symptom onset (24 ± 13 s). M: time to maximal systemic blood pressure effect (54 ± 17 s). I: duration of three times cold saline injection (20 ± 2 s). R: duration of systemic blood pressure effect (not reaching baseline values). PD: pressure drop. ΔP: maximal decrease of aortic mean pressure (28 ± 10%). (B) The slope of the normalized aortic mean pressure curve in the course of time (in seconds). Given are the difference quotients of each corresponding data point.

3.3 Safety of CFR and IMR measurement during regadenoson-induced hyperemia

As can be seen in Table 1, one fifth of our study collective had contraindications for the use of adenosine, in terms of relevant bronchoconstrictive lung disease or atrioventricular block 2–3° (Table 1). After administration of regadenoson via peripheral line we could not document any regadenoson-induced atrioventricular block and dyspnoea occurred in only 5 % of patients (Fig. 2A). 80% of the patients complained about chest discomfort after regadenoson injection. Additionally, we could document side effects like flush in 9 %, headache in 7 % and nausea in 6 % of patients (Fig. 2A).

Graph: Fig. 2 Side effect profile of regadenoson (A) and correlation between FFR values under intravenously regadenoson- and intracoronarily adenosine-induced hyperemia (B). (A) Regadenoson does not induce harmful systemic side effects. *Relevant bradycardia was defined as symptomatic bradycardia with <30 beats per minute for at least 10 secs. (B) In a subset of 9 patients, coronary hyperemia was achieved by intracoronary adenosine, thereafter hyperemia was induced in the same patient with regadenoson intravenously. FFR values derived from regadenoson correlate to FFR values derived by adenosine (linear correlation of R2 = 0,9883).

3.4 Effectiveness of measuring CFR and IMR during regadenoson-induced hyperemia

To ensure that hyperemic effects of regadenoson can be compared with the effects of adenosine in our setup we performed FFR measurements in 9/50 patients after intracoronary adenosine delivery and intravenous regadenoson bolus thereafter. Figure 2 B shows that FFR measurement, performed by means of regadenoson-induced hyperemia, significantly correlates with FFR measurement, which was carried out by intracoronarily given adenosine (R2 = 0.9883 with p <  0.01).

As can be seen in Fig. 3, there was a significant drop in Tmn from baseline to hyperemia of more than 50% (1.0 ± 0.6 vs. 0.4 ± 0.2, p <  0.01) indicating a sufficient increase of coronary blood flow. However, there was only one patient with a drop of less than 10% in Tmn and therefore a CFR close to 1.

Graph: Fig. 3 Effect of hyperemia on transit mean time. Transit mean time (Tmn) at rest and after hyperemia induction by regadenoson. Given are mean values of 3 technical replicates and their individual decline after hyperemia.

3.5 Distribution of FFR and IMR values

Table 2 displays that mean FFR of the study population was 0.86±0.09, median IMRcorr was 23.4, and median apparent IMR of 25.2 only slightly higher. Only 11/50 patients had an FFR ≤ 0.8 (Fig. 4), whereas more than half of the study population showed an IMR >23 (n  = 26) and even nearly one third an IMR >40 (n = 13). Concerning IMR values, we could observe two peaks in the distribution of IMR in our study population: one peak at IMR 15.4±4.2, the other peak at IMR 40.2 ± 10.0 (Fig. 4).

Graph: Fig. 4 Distribution of fractional flow reserve (FFR) and index of microcirculatory resistance (IMRcorr) frequencies (A) and classification of patients according to the cut-off values of FFR and IMRcorr (B). Cut-offs: FFR≤0.80, and IMRcorr: according to (9).

In a multivariate analysis the relationship between patients' characteristics (sex, age, obesity, hypertension, metformin demanding diabetes mellitus, smoking and RCA location) and IMR values was investigated (Table 3). The multivariate generalized estimating equation model identified a significant correlation between metformin demanding diabetes mellitus (OR 21.76, 95% CI 1.7–278.11, p = 0.02) and smoking (OR 10.28, 95% CI 1.1–96, p = 0.04) with increased IMR values above the 75th percentile. Obesity and hypertension failed to reach the level of significance (obesity: OR 0.16, 95% CI 0.02–1.33, p = 0.09; hypertension: OR 4.31, 95% CI 0.58–31.79, p = 0.15). No association with increased IMR was documented for sex (OR 2.8, 95% CI 0.36–21.93, p = 0.32), age (OR 0.97, 95% CI 0.9–1– 05. p = 0.45) and coronary territory (RCA: OR 3.13, 95 % CI 0.55–17.89, p = 0.2).

Table 3 Multivariate analysis of predictors for high IMR*

	All variables			Variable selection
	OR	95% CI	p	OR	95% CI	p
Sex	2.80	0.36–21.93	0.32
Age	0.97	0.9–1.05	0.45
Obesity	0.16	0.02–1.33	0.09	0.19	0.03–1.22	0.08
Hypertension	4.31	0.58–31.79	0.15	4.85	0.77–30.64	0.09
Metformin-demanding DM	21.76	1.7–278.11	0.02	14.73	1.6–132.32	0.02
Smoking	10.28	1.1–96	0.04	8.50	1.22–59.17	0.03
RCA	3.13	0.55–17.89	0.2

*according to (9). IMR: index of microcirculatory resistance. OR: odds ratio. CI: confidence interval. p: probability. DM: diabetes mellitus. RCA: right coronary artery.

4 Discussion

The main findings of the present study are, that (i) simultaneous assessment of FFR, CFR and IMR was feasible in all 50 cases, (ii) regadenoson easily and effectively increases coronary flow by means of 50% reduction in transit mean time with a consecutive drop in systemic and coronary pressure and (iii) hyperemia was stable and long-lasting to obtain 3 thermodilution curves for measurement of Tmn at hyperemia, (iv) and no AV-Block or bronchospasm occurred after regadenoson injection.

4.1 Feasibility of simultaneous measurement of FFR, CFR and IMR during regadenoson-induced hy...

The advantages of regadenoson in terms of ease of use for inducing hyperemia have been described for non-invasive stress tests and for invasive FFR measurements [[12]]. Our study data show that after achievement of full hyperemia, indicated by maximal decrease of coronary and aortic mean pressure, the slope of the mean aortic pressure curve remained flat for more than 30 seconds. This was sufficient for a comprehensive measurement of FFR, CFR and IMR without time constraints in all patients. Stability and also duration of regadenoson-induced hyperemia was comparable to literature [[14]]. It has already been shown that regadenoson induced a very similar reduction of Pd as was observed with intravenous adenosine in NSTEMI patients (pressure drop of 16.6±12.8% vs. 13.9%) [[15]]. Indeed, technical problems occurred in 20/50 cases under baseline conditions (too low temperature amplitude or a too slow injection time), but could be solved easily by repositioning the guiding catheter. Under hyperemia no error occurred. Summarizing, simultaneous measurement of FFR, CFR and IMR during regadenoson-induced hyperemia is technically feasible.

4.2 Safety of simultaneous measurement of FFR, CFR and IMR during regadenoson-induced hyperem...

We could not document any atrioventricular block after administration of regadenoson, which reflects a high grade of safety in simultaneous measurement of FFR, CFR and IMR during regadenoson-induced hyperemia. As a selective Adenosine 2A receptor agonist, regadenoson has less side effects than adenosine [[16]]. In our study, we could even include patients who fulfill classical contraindications for the use of adenosine in terms of COPD, asthma or atrioventricular block. Thus, regadenoson seems to be a useful alternative to adenosine regarding side effect profile and contraindications. Since cardiovascular disease is a major comorbiditiy in COPD patients [[18]], and even in our study 18% of patients had bronchoconstrictive lung disease, regadenoson-induced hyperemia represents the sole safe method in simultaneous measurement of FFR, CFR and IMR via thermodilution technique.

4.3 Effectiveness of simultaneous measurement of FFR, CFR and IMR and plausibility of measure...

We could show that regadenoson-induced hyperemia is effective in inducing coronary hyperemia, as average Tmn under hyperemia was significantly smaller than transit mean time at rest (0.4 ± 0.2 sec at hyperemia, 1.0 ± 0.6 sec at rest). Additionally, compared to intracoronarily given adenosine, similar FFR values could be acquired in a subset of patients (Fig. 1A). A similar vasodilator effect of regadenoson compared to adenosine was already assessed for FFR measurements and for non-invasive myocardial perfusion reserve assessment [[13], [19], [23]].

The investigated study population was characterized by a low SYNTAX score (<22) and FFR mean value was 0.86 in our study population (only 11/50 patients with FFR≤0.80). Compared to large registries, the present study population was characterized by increased IMR values (Mean IMR corr: 23.4 vs. 16.6) [[23]]. This finding might be explained by higher age (67.5 ± 9.7 vs. 61.1 ± 9.7 years) and a higher frequency of hypertension, nicotine abuse and diabetes mellitus (hypertension 79% vs. 62%; diabetes mellitus: 44% vs. 26%) in our study collective [[23]]. In line with this, a multivariate analysis showed, that metformin demanding diabetes mellitus and nicotine abuse correlated with high IMR values, corresponding to literature and thus indicating reliability of the measured IMR values [[24]].

5 Conclusion

A single intravenous regadenoson bolus reliably increases coronary blood flow without harmful systemic side effects enabling interventionists to simultaneously assess FFR, CFR and IMR by the thermodilution method in patients with stable coronary artery disease undergoing a transradial procedure.

5.1 Study limitations

We did not conduct a direct comparison of regadenoson and intravenous adenosine for assessment of CFR, IMR and maximal pressure drop in the same patient. However, we confirmed in a subgroup of patients (9/50) that FFR values under intracoronarily given adenosine closely correlated to intravenously given regadenoson. Due to the long half-life of regadenoson (terminal half time of 33 to 108 min) [[6]] we could not repeat the measurements after values had returned to baseline.

As a feasibility, safety and effectiveness study the patient population was not sufficiently powered to neither assess correlations between IMR and co-morbidities nor asses the meaning of IMR in terms of clinical outcome.

5.2 Impact on daily practice

The gold standard to induce coronary hyperemia for measurement of FFR, CFR and IMR is adenosine, but it exerts additional biological effects due to its unspecific action on all adenosine receptors. The A2a-receptor agonist, regadenoson, has been shown to dilate coronary arteries and enables FFR measurements, specifically.

The present study demonstrates that regadenoson produces reliably stable conditions of coronary hyperemic blood flow and shows for the first time that simultaneous measurement of FFR, CFR and IMR via thermodilution method during regadenoson-induced hyperemia is feasible, safe and effective.

These preliminary data have to be confirmed in large trials and registries. and also a direct comparison of adenosine and regadenoson in hyperemic effectiveness and its association to comorbidities and prognosis are of great interest.

Ethical standards

The ethical board of Heinrich Heine University Düsseldorf approved the present study (study reference 5701R; registration ID 2016095585). All participants signed informed consent. The study complies with the declaration of Helsinki.

Funding

Grant of DFG (Deutsche Forschungsgemeinschaft); GRL B0-4264/1-1.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Acknowledgments

SFB (CRC 1116).

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By Vera Lachmann; Marc Heimann; Christian Jung; Tobias Zeus; Pablo Emilio Verde; Malte Kelm and Florian Bönner

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