Maximal Hyperemia Research Articles

The impact of AAOCA anatomical characteristics in coronary blood supply

Abstract Background Impact of AAOCA in coronary blood flow and myocardial perfusion is an unknown field although it is well-accepted that the anomaly is one of the leading causes of sudden death during effort. The risk factors for AAOCA are the anatomical characteristics of the abnormal vessel, such as the presence of intramural (IM) segment, the ostium shape, and the take-off angle. Purpose We aim to evaluate the impact of AAOCA anatomical risk profile in the blood flow using the thermodilution technique, an accurate and reproducible method used to investigate coronary physiology. Methods This is a single-centre prospective study that included AAOCA subjects who underwent invasive thermodilution functional coronary assessment. We divided patients into two groups according to the anatomical risk profile: a) ischemic risk (IR): concomitant presence of IM segment, take-off angle<45°, and slit-like/oval shape ostium, or a IM length>10 mm; b) no-ischemic risk (no-IR): absence of IM segment, take-off angle>45°, round ostium. We obtained coronary functional measures using the thermodilution method. We measured the absolute flow, and coronary resistance at rest and maximal hyperemia. Data were reported as median and IQR and we used Wilcoxon signed-rank test for paired data in the rest vs. hyperaemia comparison. Results We included 28 AAOCA pts (22 male, 6 female, median age: 48.6 (IQR: 18.9) ) that were 20 anomalies of the right coronary and 8 of the left. Symptomatic subjects (n=16) presented with angina (n=12), syncope (n=1), presyncope (n=1), fatigue (n=1), and dyspnea associated with arrhythmia (n=1). The IR group (26 pts; R-AAOCA=24, L-AAOCA=2) has an IM segment with a median length of 10 mm (IQR: 5.5), a median take-off angle of 28° and the ostium was slit-like (n=16), oval (n=10), and round (n=1). The no-IR group consisted of 9 (R-AAOCA=3, L-AAOCA=6), median take-off angle of 69° and the ostium was oval (n=1), and round (n=8). The absolute flow and coronary resistance at rest of the IR group did not have significant differences compared to no-IR. Hyperemia determines an increment of coronary flow in both groups although the IR had a 2.9 fold increase and the no-IR as 3.5 fold increase compared to rest. In particular, the absolute flow of the IR group was significantly lower compared to the no-IR group (185 vs. 330 mL/min, p=0.012) and there was a greater coronary resistance (419 vs. 268 mmHg/(mL/min), p=0.027), as shown in Fig. 1. Conclusions Anatomical risk factors of AAOCA, such as IM take-off angle and ostium morphology, have a negative impact on the coronary blood supply that is reduced when compared to AAOCA without such anatomical features. Such impact can be revealed also at rest using the thermodilution method that induces maximal coronary vasodilatation that is the natural coronary response to physical effort. Further studies are needed to validate benefit of functional assessment in AAOCA risk stratification.

Assessment of coronary microvascular function with absolute coronary fl ow measurements

Abstract Background Reliable assessment of microvascular function is essential, both in research setting and clinical practice. New techniques, such as continuous coronary thermodilution, are very promising and could revolutionize the field. However, there is a need for proper validation before widespread use is possible. Purpose The goals of this study were: 1. to validate the potential of saline infusion to generate maximum hyperemia in vivo. 2. to validate absolute blood flow (ABF) measured with continuous coronary thermodilution at higher (40-50 ml/min) infusion speeds 3. To assess the safety of higher infusion speeds. Methods Fourteen closed-chest sheep underwent ABF measurements with increasing saline infusion speeds with and without adenosine. Another seven open-chest sheep underwent these measurements with epicardial doppler flow probes on both the left anterior descending artery and left circumflex coronary artery. Maximal hyperemia was defined as maximal flow after 45 seconds of proximal occlusion. The principles of laboratory animal care and all national regulations were followed. Results 20 ml/min of saline infusion induced lower hyperemic coronary flow (140 vs 191 ml/min, p=0.0165) and lower coronary flow reserve (CFR) (1.82 vs 3.21, p= <0.0001) than coronary occlusion. In contrast, 30 ml/min resulted in flow (196 vs 192 ml/min, p=0.8292) and CFR (2.77 vs 3.21, p=0.1107) that were not different from post-occlusion. There was a significant flow overestimation bias (Bland-Altman: Bias ± SD: -73.09 ± 30.52, 95% Limits of agreement: -132.9 to -13.27) with 40-50ml/min of saline. Occasionally, higher saline infusion rates resulted in ischemic ECG-changes and ventricular fibrillation (9.5% at 50 ml/min). Conclusions Continuous saline infusion of 30ml/min, but not 20 ml/min, induced maximal hyperemia. ABF measured with saline infusion speeds of 40-50 ml/min was not accurate nor safe, and should therefore be avoided.

Intracoronary nicardipine to induce hypaeremia

Abstract Background Several pharmacological agents and routes of administration have been used to induce transient maximal hyperaemia, but most suffer from shortcomings that limit their clinical usage. Nicardipine, a dihydropyridine calcium channel blocker, has been proposed as a coronary hyperaemic agent with the advantage of not causing any adverse effects. Purpose We compared intracoronary (IC) nicardipine with IC papaverine for obtaining fractional flow reserve (FFR) and pullback pressure gradient (PPG). Methods and results This is a prospective, single-center study enrolling stable patients presenting with intermediate coronary artery disease (CAD) undergoing invasive functional assessment. The lowest FFR, duration of the hyperemic plateau, and PPG were assessed after IC nicardipine (400 µg to the left coronary or 300 µg to the right coronary artery) and IC papaverine (12 mg to the left coronary artery and 8 mg to the right coronary artery). Results Overall, 107 patients with 108 vessels (216 FFR and 216 PPG paired measurements) were analyzed. The correlation in FFR between nicardipine and papaverine was r = 0.95 (95% CI 0.92 to 0.96, p < 0.001) with a mean difference of 0.02 FFR units (limit of the agreement [LOA]: -0.04 to 0.08). Similarly, the correlation in PPG between nicardipine and papaverine was r = 0.86 (95% CI 0.71 to 0.93, p < 0.001) with a mean difference of 0.01 PPG units (limit of the agreement [LOA]: -0.14 to 0.17). The hyperaemic plateau was significantly longer with nicardipine (101.4 ± 62.1 s nicardipine vs 41.5 ± 14.3 s papaverine, p < 0.001). No significant differences were observed in the magnitude of changes in blood pressure and heart rate (p=NS). No complications occurred with the administration of IC nicardipine or papaverine. Conclusion FFR and PPG values obtained following nicardipine administration exhibited excellent agreement with those obtained using papaverine. Moreover, the hyperaemic response induced by nicardipine led to a significantly prolonged steady state in comparison to papaverine. Given its widespread availability, cost-effectiveness, safety profile and frequent utilization in clinical settings, nicardipine emerges as the optimal vasodilator for coronary physiology testing.FFR by Nicardipine vs PapaverinePPG by Nicardipine vs Papaverine

Evaluation of Intravenous Versus Intracoronary Adenosine in Coronary Reactivity Testing

Coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) obtained through coronary bolus thermodilution are used to assess and treat patients with angina and no obstructive coronary artery disease. Previous studies demonstrate comparable results assessing epicardial ischemia by fractional flow reserve using intravenous (IV) or intracoronary (IC) adenosine. It is unknown if there is a similarity between IC and IV hyperemia with adenosine when performing coronary reactivity testing (CRT). We reviewed CRT data and baseline demographics in a cohort of patients who underwent CRT for ischemia and no obstructive coronary artery disease. We evaluated CFR and IMR in patients whereby maximal hyperemia was obtained by both IC and IV means using linear regression, one-way analysis of variance, Wilcoxon, and Bland-Altman analysis. We assessed 62 patients with a median age of 60.5 years (50 to 67), and 72% were females. The average CFR with IC adenosine was 3.12 (2.31 to 4.06) and 2.71 (2.0 to 3.88) with IV adenosine, with an R2 value of 0.50 (p <0.0001). The average IMR with IC adenosine was 28.23 (16.24 to 50.72) and 22.27 (14.79 to 37.0) with IV adenosine, with an R2 value of 0.33 (p <0.0001). Average intra-method variability between IC and IV adenosine was nonsignificant (p = 0.31 for CFR and p = 0.55 for IMR). Bland-Altman analysis showed reasonable agreement between IV and IC adenosine for CFR and IMR with slightly higher values using IC adenosine. Therefore, in CRT with bolus thermodilution, CFR and IMR values obtained with IC adenosine correlate well with those obtained with IV adenosine. This presents a potential alternative to IV adenosine for bolus thermodilution CRT.

Aortic versus distal pressure for derivation of hyperaemic microvascular resistance: From the ILIAS registry

BackgroundIn patients with angina and non-obstructive coronary arteries (ANOCA), intracoronary function testing typically involves assessing the minimal microvascular resistance. This can be derived from the coronary flow and the distal pressure (Pd) during maximal hyperaemia. Theoretically, in ANOCA patients, resistance and pressure have minimal impact along the epicardial vessel, suggesting the possibility of deriving hyperaemic microvascular resistance (HMR) using aortic pressure (Pa) instead of Pd, but this has not been studied previously. Methods and resultsData from the ILIAS registry, a global multicentre registry pooling lesion-level coronary pressure and flow data, were used to compare HMR calculated with Pa versus Pd. A total of N = 1321 evaluated vessels were included. The study population consisted predominantly of men (68 %) with a mean age of 62 ± 10 years, and stable anginal symptoms (93 %). The overall correlation between HMR calculated with Pa and with Pd was good (Pearson's correlation coefficient: 0.84, p ≤0.005). The Bland-Altman plot showed a mean difference between HMR based on Pa and Pd of 0.53 (limits of agreements ±1.35). An adjusted Bland-Altman showed that the difference between HMR based on Pa and Pd was significantly related to the functional severity of the epicardial lesion (R2 = 0.71, coef.: −4.5, p < 0.005). In patients with a FFR >0.80 there were no considerable outliers, and with a FFR <0.80 outliers increased significantly. ConclusionsIn ANOCA patients, defined by a FFR above 0.80, HMR can be accurately measured with aortic pressure instead of distal pressure. However, in patients with a FFR below 0.80, there is a significant difference between HMR measured with Pa and Pd.

Pd/Pa fluctuation with continuous ATP administration indicates inaccurate FFR measurement caused by insufficient hyperemia.

Continuous intravenous adenosine triphosphate (ATP) administration is the standard method for inducing maximal hyperemia in fractional flow reserve (FFR) measurements. Several cases have demonstrated fluctuations in the ratio of mean distal coronary pressure to mean arterial pressure (Pd/Pa) value during ATP infusion, which raised our suspicions of FFR value inaccuracy. This study aimed to investigate our hypothesis that Pd/Pa fluctuations may indicate inaccurate FFR measurements caused by insufficient hyperemia. We examined 57 consecutive patients with angiographically intermediate coronary lesions who underwent fractional flow reverse (FFR) measurements in our hospital between November 2016 and September 2018. Pd/Pa was measured after continuous ATP administration (150μg/kg/min) via a peripheral forearm vein for 5min (FFRA); and we analyzed the FFR value variation in the final 20s of the 5min, defining 'Fluctuation' as variation range > 0.03. Then, 2mg of nicorandil was administered into the coronary artery during continued ATP infusion, and the Pd/Pa was remeasured (FFRA+N). Fluctuations were observed in 23 of 57 patients. The cases demonstrating discrepancies of > 0.05 between FFRA and FFRA+N were observed more frequently in the fluctuation group than in the non-fluctuation group (12/23 vs. 1/34; p < 0.0001). The discrepancy between FFRA and FFRA+N values was smaller in the non-fluctuation group (mean difference ± SD; -0.00026 ± 0.04636 vs. 0.02608 ± 0.1316). Pd/Pa fluctuation with continuous ATP administration could indicate inaccurate FFR measurements caused by incomplete hyperemia. Additional vasodilator administration may achieve further hyperemia when Pd/Pa fluctuations are observed.

Prognostic Value of Microvascular Resistance Reserve Measured Immediately After PCI in Stable Coronary Artery Disease.

Microvascular resistance reserve (MRR) has been proposed as a specific metric to quantify coronary microvascular function. The long-term prognostic value of MRR measured in stable patients immediately after percutaneous coronary intervention (PCI) is unknown. This study sought to determine the prognostic value of MRR measured immediately after PCI in patients with stable coronary artery disease. This study included 502 patients with stable coronary artery disease who underwent elective PCI and coronary physiological measurements, including pressure and flow estimation using a bolus thermodilution method after PCI. MRR was calculated as coronary flow reserve divided by fractional flow reserve times the ratio of mean aortic pressure at rest to that at maximal hyperemia induced by hyperemic agents. An abnormal MRR was defined as ≤2.5. Major adverse cardiac events (MACEs) were defined as a composite of all-cause mortality, any myocardial infarction, and target-vessel revascularization. During a median follow-up of 3.4 years, the cumulative MACE rate was significantly higher in the abnormal MRR group (12.5 versus 8.3 per 100 patient-years; hazard ratio 1.53 [95% CI, 1.10-2.11]; P<0.001). A higher all-cause mortality rate primarily drove this difference. On multivariable analysis, a higher MRR value was independently associated with lower MACE and lower mortality. When comparing 4 subgroups according to MRR and the index of microcirculatory resistance, patients with both abnormal MRR and index of microcirculatory resistance (≥25) had the highest MACE rate. An abnormal MRR measured immediately after PCI in patients with stable coronary artery disease is an independent predictor of MACE, particularly all-cause mortality.

Optimization of Absolute Coronary Blood Flow Measurements to Assess Microvascular Function: In Vivo Validation of Hyperemia and Higher Infusion Speeds.

Reliable assessment of coronary microvascular function is essential. Techniques to measure absolute coronary blood flow are promising but need validation. The objectives of this study were: first, to validate the potential of saline infusion to generate maximum hyperemia in vivo. Second, to validate absolute coronary blood flow measured with continuous coronary thermodilution at high (40-50 mL/min) infusion speeds and asses its safety. Fourteen closed-chest sheep underwent absolute coronary blood flow measurements with increasing saline infusion speeds at different dosages under general anesthesia. An additional 7 open-chest sheep underwent these measurements with epicardial Doppler flow probes. Coronary flows were compared with reactive hyperemia after 45 s of coronary occlusion. Twenty milliliters per minute of saline infusion induced a significantly lower hyperemic coronary flow (140 versus 191 mL/min; P=0.0165), lower coronary flow reserve (1.82 versus 3.21; P≤0.0001), and higher coronary resistance (655 versus 422 woods units; P=0.0053) than coronary occlusion. On the other hand, 30 mL/min of saline infusion resulted in hyperemic coronary flow (196 versus 192 mL/min; P=0.8292), coronary flow reserve (2.77 versus 3.21; P=0.1107), and coronary resistance (415 versus 422 woods units; P=0.9181) that were not different from coronary occlusion. Hyperemic coronary flow was 40.7% with 5 mL/min, 40.8% with 10 mL/min, 73.1% with 20 mL/min, 102.3% with 30 mL/min, 99.0% with 40 mL/min, and 98.0% with 50 mL/min of saline infusion when compared with postocclusive hyperemic flow. There was a significant bias toward flow overestimation (Bland-Altman: bias±SD, -73.09±30.52; 95% limits of agreement, -132.9 to -13.27) with 40 to 50 mL/min of saline. Occasionally, ischemic changes resulted in ventricular fibrillation (9.5% with 50 mL/min) at higher infusion rates. Continuous saline infusion of 30 mL/min but not 20 mL/min induced maximal hyperemia. Absolute coronary blood flow measured with saline infusion speeds of 40 to 50 mL/min was not accurate and not safe.

Changes in Cardiac Electrical Biomarker in Response to Coronary Arterial Occlusion: An Experimental Observation.

Cardiac electrical biomarker (CEB), an indicator of ischaemia-induced change in myocyte polarity, has been proposed for diagnosis of acute coronary syndrome. However, effect of coronary occlusion on CEB has not been demonstrated. CEB was acquired before (CEB0), during maximal adenosine hyperaemia (CEBhyp), balloon inflations (CEBmax) and 1 (CEB1h), 2 (CEB2h) and 3 (CEB3h) h after percutaneous coronary intervention along with pre- and post-procedural troponin-I. CEB of subjects with non-cardiac chest pain without risk factors was used as controls (CEBc). "Late recovery" (LR) of CEB was defined as CEB3h > median-CEB0. CEB was recorded in 75 patients undergoing stenting (group 1) including 8 with FFR < 0.8 (group 1a), 25 with FFR ≥ 0.8 (group 2) and 49 controls. In group 1, CEB0 (median, IQR) was higher than CEBc (48.0; 29.5-88.3 vs 30.0; 17.0-44.0; p < 0.001). CEBmax (185; 105.0-331.0) was higher than CEB0 (p < 0.0001). CEB1h (78.0; 31.5-143.8; p < 0.0001) and CEB2h (63.0; 31.5-114.3; p = 0.039) were higher than CEB0 while CEB3h (54.0; 24.3-94.8, p = 0.152) was similar. LR occurred in 50.7% patients. CEBmax predicted LR (OR 1.01, 95% CI 1.00-1.01, p < 0.001) (AUC 0.759, p < 0.001). CEB0 in group 1a and group 2 were similar (p = 0.524). CEBhyp was higher than CEB0 in group 1a (126.0, 109.5-266.0 vs 47.5, 20.5-73.5; p = 0.016) and group 2 (44.0, 27.8-104.8 vs 39.0, 24.0-90.3; p = 0.014). CEBhyp was higher in group 1a than 2 (p = 0.039). CEBhyp (AUC 0.75, p = 0.017) accurately predicted FFR < 0.8. Coronary arterial occlusion increases CEB that retains a "memory" of the ischaemic event. CEBhyp was higher only when FFR was ischaemic and accurately identified FFR < 0.8.

CT-derived Fractional Flow Reserve: How, When, and Where to use this Novel Cardiac Imaging Tool.

Fractional flow reserve computed tomography (FFRCT) is a novel imaging modality. It utilizes computational fluid dynamics analysis of coronary blood flow obtained from CCTA images to estimate the decrease in pressure across coronary stenosis during the maximum hyperemia. The FFRCT can serve as a valuable tool in the assessment of coronary artery disease (CAD). This non-invasive option can be used as an alternative to the invasive fractional Flow Reserve (FFR) evaluation, which is presently considered the gold standard for evaluating the physiological significance of coronary stenoses. It can help in several clinical situations, including Assessment of Acute and stable chest pain, virtual planning for coronary stenting, and treatment decision-making. Although FFRCT has demonstrated potential clinical applications as a non-invasive imaging technique, it is also crucial to acknowledge its limitations in clinical practice. As a result, it is imperative to meticulously evaluate the advantages and drawbacks of FFRCT individually and contemplate its application in combination with other diagnostic examinations and clinical data.

Catheter-based examination for pulmonary microcirculatory function in patients with pulmonary hypertension.

A device that can evaluate human pulmonary microcirculation is currently unavailable. This study aimed to establish a novel approach for assessing pulmonary microcirculation in patients with pulmonary hypertension (PH). We used a guidewire embedded with temperature and pressure sensors to measure the following pulmonary microcirculatory function indicators: pulmonary flow reserve, pulmonary index of microcirculatory resistance (PIMR), and pulmonary resistive reserve ratio. Adenosine was administered to patients to induce hyperemia in the pulmonary artery for assessment. The correlation between these indicators and various parameters, including serum biomarkers, hemodynamic and respiratory functions, and exercise capacity, were examined. The procedure was performed in 19 patients with moderate PH, without major complications. The minimum effective adenosine dosage for maximal hyperemia, without severe side effects, was 150 μg∙kg-1∙min-1. Multivariate stepwise analysis revealed a positive correlation between the hyperemic PIMR and serum uric acid (p < 0.001) and N-terminal probrain natriuretic peptide levels (p = 0.014). Therefore, this catheter-based method offers an effective means to assess pulmonary microcirculatory function in patients with PH, and the optimal dose of adenosine for this evaluation was 150 μg∙kg-1∙min-1.

Reduced response to regadenoson with increased weight: An artificial intelligence–based quantitative myocardial perfusion study

BackgroundThere is conflicting evidence regarding the response to a fixed dose of regadenoson in patients with high body weight. The aim of this study was to evaluate the effectiveness of regadenoson in patients with varying body weights using novel quantitative cardiovascular magnetic resonance (CMR) perfusion parameters in addition to standard clinical markers. MethodsConsecutive patients with typical angina and/or risk factors for coronary artery disease (N = 217) underwent regadenoson stress CMR perfusion imaging using a dual-sequence quantitative protocol with perfusion parameters generated from an artificial intelligence (AI)–based algorithm. CMR was performed on 1.5T scanners using a standard 0.4 mg injection of regadenoson. A cohort of consecutive patients undergoing adenosine stress perfusion (N = 218) was used as a control group. ResultsAn inverse association of myocardial perfusion reserve and weight (mean decrease −0.05 per 10 kg increase, 95% confidence interval [CI] −0.009/−0.0001, P = 0.045) was noted in the regadenoson group but not in patients stressed with adenosine (P = 0.77). Adjusted logistic regression analysis revealed a 10 kg increase resulted in 36% increased odds for inadequate stress response (odds ratio [OR] = 1.36, 95% CI 1.10–1.69, P = 0.005). Moreover, a significant interaction (OR = 1.09, 95% CI 1.02–1.16, P = 0.012) between stressor type (regadenoson vs adenosine) and weight was noted. This was also confirmed in the propensity-matched subgroup (P = 0.024) and was not attenuated after adjustment (P = 0.041). Body surface area (BSA) (P = 0.006) but not body mass index (P = 0.055) was differentially associated with inadequate response conditional to the stressor used, and this association remained significant after adjustment for confounders (P = 0.025). Patients in the highest quartile of weight (>93 kg) or BSA (>2.06 m2) had substantially increased odds for inadequate response with regadenoson (OR = 8.19, 95% CI 2.04–32.97, P = 0.003 for increased weight and OR = 7.75, 95% CI 1.93–31.13, P = 0.004 for increased BSA). Both weight and BSA had excellent discriminative ability for inadequate regadenoson response (receiver operating characteristic area under curves 0.84 and 0.83, respectively). ConclusionUsing quantitative perfusion CMR in patients undergoing pharmacological stress with regadenoson, we found an inverse relationship between patient weight and both clinical response and myocardial perfusion parameters. A fixed-dose bolus approach may not be adequate to induce maximal hyperemia in patients with increased weight. Weight-adjusted stressors, such as adenosine, may be considered instead in patients with body weight >93 kg and BSA >2.06 m2.

Coronary microvascular resistance comparison of coronary arteries with and without considering vascular diameter: A retrospective, single-center study.

Measurement of coronary microvascular resistance (MR) is essential for diagnosing nonocclusive coronary artery ischemia, but whether coronary branches of different diameters can be similarly assessed using hyperemic microvascular resistance index (hMVRI) calculated from average peak velocity (APV) remains unclear. We investigated the relationship between coronary arteries of different diameters and hMVRI. Thirty patients with suspected angina pectoris and nonobstructive coronary stenosis with fractional flow reserve >0.8 underwent evaluation of all coronary arteries using a Doppler velocity and pressure-equipped guidewire. Quantitative coronary angiography (QCA) was used to analyze vessel diameter (DQCA). Coronary blood flow (CBFQCA) was calculated as πDQCA 2/4 (0.5 × APV) and hMVRIQCA as distal coronary pressure divided by CBFQCA during maximal hyperemia. The hMVRI was significantly higher for the right coronary artery than for the left anterior descending artery, but no significant differences between arteries were seen for CBFQCA and hMVRIQCA. Although the correlation between CBFQCA and APV was weak, CBFQCA divided into three groups according to DQCA showed very strong correlations with APV. Slopes of the straight line between APV and CBFQCA for small-, middle-, and large-diameter groups were 0.48, 0.30, and 0.21, respectively, with slope decreasing as diameter increased. Comparative evaluation of MR in coronary branches with varying vessel diameters requires vessel diameter to be accounted for.

In vivo validation of intra-coronary absolute flow measurements and comparison of reliability between different microvascular indices and the microvascular resistance reserve

Abstract Background Coronary microvascular dysfunction plays a major role in patients with cardiac ischemia without flow limiting epicardial coronary stenosis, takotsubo cardiomyopathy, aortic valve stenosis and heart failure with preserved ejection fraction. In clinical practice, the index of microvascular resistance (IMR) and coronary flow reserve (CFR), and more recently the absolute coronary blood flow (ABF), absolute coronary resistance (ACR) and the microvascular resistance reserve (MRR) are used as parameters to measure resistance and flow using continuous coronary thermodilution. Purpose Firstly, to validate ABF measured with continuous coronary thermodilution in vivo against epicardial doppler-measured flow. Secondly, to assess reliability and reproducibility in-vivo of different microvascular indices. Methods For the purpose of this study coronary measurements were conducted in two large animal models and in patients, all with the appropriate ethical committee approval. For the first part of the study, fourteen sheep underwent repeated paired measurements of ABF and ACR (with use of continuous thermodilution) with different saline infusion speeds, as well as IMR, CFR and MRR in multiple coronary vessels. Seven additional sheep underwent these measurements while having simultaneous measurements with epicardial coronary flow probes (gold standard) in an open-chest model. The epicardial flow probes were placed on the proximal left anterior descending and circumflex artery. Maximal hyperemia was induced with adenosine (CFR and IMR) or infusion of saline at a rate of 30ml/min (ABF, ACR and MRR). For the second part of the study, in 41 patients receiving routine microvascular assessment, IMR and CFR measurements were duplicated by a single operator, after re-calibration, to assess the reproducibility of the measurement. The combined animal and human data resulted in the analysis of 408 coronary measurements made in 88 coronary vessels during 65 heart catheterizations. Results In sheep, ABF measured with continuous thermodilution (with saline infusion speeds from 5ml/min to 30ml/min) was accurate when compared with epicardial flow measurements. (Table 1, Fig 1A) Notably, the continuous thermodilution measurement had the tendency to slightly overestimate ABF. (Table 1, Fig 1B) The two methods were equivalent within 15% (Two one-sided test: mean difference: -8.73%; 95% CI: -14.40 to -3.06%, p= 0.016). When comparing test-retest reproducibility between the indices, CFR performed the worst while ACR and MRR performed the best. MRR had a significantly better reproducibility than the IMR. (Table 1, Fig 1C). Conclusion ABF can accurately be determined by continuous coronary thermodilution. MRR and ACR have a significantly superior reliability and reproducibility compared to IMR and CFR. Unlike ACR, MRR is not vessel or territory-size dependent and is therefore the index of choice for future research and clinical assessment of the microcirculation.

Changes in cardiac electrical biomarker with hyperaemic stress: an experimental perspective

Abstract Background "Cardiac electrical biomarker" (CEB) is a numerical index measured by the Vectraplex ECG (vECG) System with Vectraplex AMI software that measures changes in the cardiac electrical field vectors from dipolar to multipolar during myocardial ischemia. CEB performs well in detecting NSTEMI and STEMI against physician adjudicated diagnosis. Purpose To assess changes in CEB during adenosine stress induced ischaemia. Method Thirty-three patients, in the VECTRA-PCI trial, with normal surface ECG (sECG) had CEB measured before (CEB0), at maximal hyperaemia (CEBh)) and 1-(CEB1), 2-(CEB2) and 3-(CEB3) hours after standard fractional flow reserve (FFR) assessment using intravenous adenosine. vECGs were adjudicated for quality by 2 blinded observers. vECGs with artefacts and arrhythmias were discarded and CEBs from best traces were analysed. Forty-nine individuals with non-cardiac chest pain, without past medical history or risk factors for CAD, on no medications, normal ECGs, normal blood profile acted as controls. CEBs (median, IQR) were compared using appropriate tests. Results FFR was normal (&amp;gt;/=0.80) (nFFR) in 25 and ischaemic (&amp;lt;0.80) (iFFR) in 8 patients. CEB0 in nFFR and iFFR groups were similar to each other (p=0.785) (Fig 1) and to controls (30.0; IQR 17.0-44.0, vs nFFR: p=0.057, vs iFFR: p=0.241). Compared to CEB0, CEBh was higher in nFFR (p=0.014) (Fig 1A) and iFFR (p=0.016) groups (Fig 1B). CEBh in iFFR (126.0; 109.5-216.0) higher than nFFR (44.0; 27.8-104.8), (p=0.039). In nFFR group, CEB1, 2 and 3, though numerically lower, were statistically similar to CEBh and CEB0 (Fig 1A) suggesting quick recovery. In iFFR group CEB1 was similar to and CEB2 and 3 were lower than CEBh (Fig 1B) suggesting a slower recovery of CEB. Both CEBh and change from CEB0 to CEBh (δCEB0-h), but not CEB0, predicted ischaemic FFR with similar accuracy (p=0.570) (Fig 2). CEBh &amp;gt;96 and δCEB0-h &amp;gt;28 had similar sensitivity of 87.5% with specificity of 68% and 80% respectively. Conclusion Obstructive coronary atheroma is associated with higher CEB than non-obstructive atheroma under hyperaemic stress. Both CEBh and δCEB0-h accurately predict ischaemic FFR with higher specificity of δCEB0-h. This is the first study to measure CEB changes with hyperaemic stress in patients with coronary artery disease and could have potential for wider clinical application. Figure 1. Changes in the CEB during and after hyperaemic stress in patients with normal (A) and ischaemic (B) FFR. Figure 2. Area under the ROC curve to determine the diagnostic accuracy of pre-procedural CEB, hyperaemic CEB and change in CEB from baseline to hyperaemia in determining ischaemic FFR.Fig 1. Changes in CEB with stress.Fig 2. CEB for ischaemic FFR

Direct wire pacing during measurement of fractional flow reserve: A randomized proof-of-concept noninferiority crossover trial.

Adenosine administration for fractional flow reserve (FFR) measurement may induce heart pauses. To assess the accuracy and tolerability of direct wire pacing (DWP) during measurement of FFR. Adults with at least one intermediate coronary artery stenosis (40%-80%) were consecutively enrolled between June 2021 and February 2022 in this randomized, noninferiority, crossover trial (NCT04970082) carried out in France. DWP was applied (DWP) or not (standard method) through the pressure guidewire used for FFR measurement during adenosine-induced maximal hyperaemia. Subjects were randomly assigned to the allocation sequence (DWP first or standard first). A 2-minute washout period was observed between the two FFR measurements performed for each stenosis. The primary endpoint was the reproducibility of FFR measurements between methods. A total of 150 focal lesions, presented by 94 subjects, were randomized (ratio: 1:1). The FFR values obtained with each method were nearly identical (R = 0.98, p = 0.005). The mean FFR difference of 0.00054 (95% confidence interval: 0.004 to 0.003) showed the noninferiority of FFR measurement with DWP vs. that with the standard method. Higher levels of chest discomfort were reported with DWP than with the standard method (0.61 ± 0.84 vs. 1.05 ± 0.89, p < 0.001), and a correlation was observed between the electrical sensations reported with DWP and chest discomfort (p < 0.001). Pauses (n = 20/148 lesions) were observed with the standard method, but did not correlate with chest discomfort (p = 0.21). No pauses were observed with DWP. DWP during FFR measurement resulted in accurate and reproducible FFR values, and eliminated the pauses induced by adenosine.

Patient-specific modeling of blood flow in the coronary arteries

Patient-specific models of blood flow in the coronary arteries have entered clinical practice worldwide to aid in the diagnosis and management of heart disease. This technology leverages modern AI-based image segmentation methods to extract the geometry of the coronary arteries from noninvasive computed tomography volumetric imaging, computational physiology methods to define boundary conditions and computational fluid dynamic techniques to compute coronary artery flow and pressure. The methods described herein have been used to compute the fractional flow reserve (FFR) in the coronary arteries, namely the ratio of pressure in a coronary artery to the reference aortic pressure under conditions of maximum hyperemia induced by the intravenous administration of a vasodilator to mimic increased coronary artery blood flow as occurs during physical activity. The fractional flow reserve derived from coronary computed tomography angiography (CCTA) using patient-specific models of coronary artery blood flow is referred to as FFRCT and has been validated against invasive measurements using pressure wires in several hundred patients and subsequently evaluated in clinical trials in several thousand patients. Patient-specific models of coronary artery blood flow can be used to predict outcomes of coronary artery revascularization procedures, to identify patients at risk of having a heart attack, and to model tissue perfusion of the microcirculation by coupling with emerging models of cardiac function. This paper provides a state-of-the-art review of computational methods for, and applications of, quantifying blood flow in patient-specific models of the coronary arteries.

Coronary microcirculatory dysfunction can be assessed by positive dicrotic wave and amplitude index on resting distal coronary pressure waveform, a newly developed index.

Some lesions have high resting distal coronary pressure/aortic pressure (Pd/Pa) despite low fractional flow reserve (FFR). This study aimed to assess microcirculatory dysfunction as a possible basal mechanism. Patients were grouped into two according to coffee intake (caffeine 222 mg) before coronary angiography. Through an adenosine-induced Pd/Pa decrease, amplitude index was calculated by dividing the difference between the highest pressure after the inflection point and the minimal diastolic pressure by the pulse pressure on the Pd waveform. In 130 coronary lesions (caffeine group, n = 69; non-caffeine group, n = 61) from 113 patients, the amplitude index through the adenosine-induced Pd/Pa decrease in all lesions was 0.54 ± 0.11 at resting Pd/Pa and 0.44 ± 0.12 at FFR (P < 0.0001). The positive dicrotic wave distribution on a maximal hyperaemia (FFRnicr)-resting Pd/Pa graph was analysed. In lesions with FFRnicr <0.80 on the FFRnicr-resting Pd/Pa graph, the resting Pd/Pa was divided into three zones based on Pd/Pa values: high-remaining, intermediate, and low. The high-remaining zone had a higher amplitude index than the intermediate zone (0.60 ± 0.09 vs. 0.48 ± 0.12; P < 0.005); the low zone lesions had no inflection point (no amplitude index). The high-remaining zone correlated with a larger positive dicrotic wave than the intermediate zone (94 vs. 30%; P < 0.005). Most lesions in the high-remaining zone corresponded to the caffeine group. In severe coronary stenosis, a high-remaining resting Pd/Pa with a high amplitude index or a positive dicrotic wave on the resting Pd waveform suggests microcirculatory dysfunction, such as insufficient arteriolar dilation reactive to myocardial ischaemia. UMIN000046883.

Angiography-based coronary flow reserve: The feasibility of automatic computation by artificial intelligence.

Coronary flow reserve (CFR) has prognostic value in patients with coronary artery disease. However, its measurement is complex, and automatic methods for CFR computation are scarcely available. We developed an automatic method for CFR computation based on coronary angiography and assessed its feasibility. Coronary angiographies from the Corelab database were annotated by experienced analysts. A convolutional neural network (CNN) model was trained for automatic segmentation of the main coronary arteries during contrast injection. The segmentation performance was evaluated using 5-fold cross-validation. Subsequently, the CNN model was implemented into a prototype software package for automatic computation of the CFR (CFRauto) and applied on a different sample of patients with angiographies performed both at rest and during maximal hyperemia, to assess the feasibility of CFRauto and its agreement with the manual computational method based on frame count (CFRmanual). Altogether, 137,126 images of 5913 angiographic runs from 2407 patients were used to develop and evaluate the CNN model. Good segmentation performance was observed. CFRauto was successfully computed in 136 out of 149 vessels (91.3%). The average analysis time to derive CFRauto was 18.1 ± 10.3 s per vessel. Moderate correlation (r = 0.51, p < 0.001) was observed between CFRauto and CFRmanual, with a mean difference of 0.12 ± 0.53. Automatic computation of the CFR based on coronary angiography is feasible. This method might facilitate wider adoption of coronary physiology in the catheterization laboratory to assess microcirculatory function.

Relationship of OCT-defined plaque characteristics with CCTA-derived coronary inflammation and CMR-derived global coronary flow reserve in patients with acute coronary syndrome.

The relationship of layered plaque detected by optical coherence tomography (OCT) with coronary inflammation and coronary flow reserve (CFR) remains elusive. We aimed to investigate the association of OCT-defined layered plaque with pericoronary adipose tissue (PCAT) inflammation assessed by coronary computed tomography angiography (CCTA) and global (G)-CFR assessed by cardiac magnetic resonance imaging (CMR) in patients with acute coronary syndrome (ACS). We retrospectively investigated 88 patients with first ACS who underwent preprocedural CCTA, OCT imaging of the culprit lesion prior to primary/urgent percutaneous coronary intervention (PCI), and postprocedural CMR. All patients were divided into two groups according to the presence and absence of OCT-defined layered plaque at the culprit lesion. Coronary inflammation was assessed by the mean value of PCAT attenuation (-190 to -30 HU) of the three major coronary vessels. G-CFR was obtained by quantifying absolute coronary sinus flow at rest and during maximum hyperemia. CCTA and CMR findings were compared between the groups. In a total of 88 patients, layered plaque was detected in 51 patients (58.0%). The patients with layered plaque had higher three-vessel-PCAT attenuation value (-68.58 ± 6.41 vs. -71.60 ± 5.21 HU, P = 0.021) and culprit vessel-PCAT attenuation value (-67.69 ± 7.76 vs. -72.07 ± 6.57 HU, P = 0.007) than those with non-layered plaque. The patients with layered plaque had lower G-CFR value (median, 2.26 [interquartile range, 1.78, 2.89] vs. 3.06 [2.41, 3.90], P = 0.003) than those with non-layered plaque. The presence of OCT-defined layered plaque at the culprit lesion was associated with high PCAT attenuation and low G-CFR after primary/urgent PCI in patients with ACS. OCT assessment of culprit plaque morphology and detection of layered plaque may help identify increased pericoronary inflammation and impaired CFR, potentially providing the risk stratification in patients with ACS and residual microvascular dysfunction after PCI.