Continuous Thermodilution Research Articles

Minimal coronary microvascular resistance: agreement between continuous and bolus thermodilution

Abstract Background Continuous thermodilution quantifies absolute microvascular resistance (Rµ, Woods units), the quintessential metric of microvascular function. Rµ is minimal during hyperaemia (Rµ,hyper) with increased Rµ,hyper suggestive of microvascular dysfunction. Bolus thermodilution measures the index of microcirculatory resistance (IMR), a dimensionless surrogate of Rµ,hyper. Purpose We compared Rµ,hyper measured by continuous thermodilution (invasive Rµ,hyper) with the gold standard [15O]H2O positron emission tomography (PET Rµ,hyper), and explored the correlation between invasive Rµ,hyper and uncorrected IMR. Methods The accuracy of invasive Rµ,hyper was assessed in a cohort of 24 patients in which both invasive and PET Rµ,hyper were measured (cohort 1). For both techniques, Rµ,hyper was assessed in both the left anterior descending artery (LAD) and the circumflex artery (LCX), corresponding to 46 measurement of Rµ,hyper in total (LAD=24, LCX=22). Agreement between invasive Rµ,hyper and IMR was evaluated in a cohort of 250 patients with angina and non-obstructive coronary arteries (ANOCA) evaluated in 3 European centres (cohort 2). All measurements in this cohort were performed in the LAD, with patients randomly assigned in a 1:1 ratio to undergo either bolus or continuous thermodilution first. Both techniques were performed by the same operator during the same procedure with a strict interval of 5 minutes between techniques. Results In cohort 1, invasive Rµ,hyper exhibited a strong correlation with PET Rµ,hyper (r=0.86 [95% CI 0.76-0.92], p<0.001), with excellent absolute agreement (ICC 0.82 [95% CI 0.70-0.90], p<0.001) (Figure 1). Furthermore, Passing-Bablok regression analysis found no significant systematic (intercept A: 54.53 [95% CI -18.95 to 120.96]) or proportional (slope B: 0.90 [95% CI 0.71 to 1.15]) bias between invasive Rµ,hyper and PET Rµ,hyper. However, in cohort 2, invasive Rµ,hyper exhibited no significant correlation with IMR (r=0.11 [95% CI -0.01 to 0.23], p=0.08) (Figure 2). Conclusion Invasive Rµ,hyper derived from continuous thermodilution exhibited excellent agreement with non-invasive Rµ,hyper measured by [15O]H2O PET, the current standard of reference. However, IMR exhibited no significant correlation with invasive Rµ,hyper in patients with stable coronary syndromes.Figure 1.PET vs invasive Rµ,hyperFigure 2.Invasive Rµ,hyper vs IMR

Simplification of coronary continuous thermodilution

Abstract Background Continuous coronary thermodilution with saline permits the accurate measurement of volumetric blood flow (Q) and absolute microvascular resistance. However, this requires repositioning of the temperature sensor by the operator to measure the entry temperature of the saline infusate, denoted as Ti. Purpose We evaluated if Ti could be predicted based upon known parameters without compromising the accuracy of calculated Q. This would significantly simplify the technique and render it completely operator independent. Methods In a derivation cohort of 371 patients with Q measured both at rest and during hyperaemia, multivariate linear regression was used to derive an equation for the prediction of Ti. Agreement of standard Q (calculated with measured Ti) and simplified Q (calculated with predicted Ti) was assessed in a validation cohort of 120 patients that underwent repeat Q measurements. The accuracy of simplified Q was assessed in a second validation cohort of 23 patients with [15O]H2O positron emission tomography (PET)-derived Q measurements. Results Simplified Q exhibited strong agreement with standard Q (r=0.94 [95% CI 0.93-0.95], ICC 0.94 [95% CI 0.92-0.95], both p<0.001) (Figure 1). Simplified Q exhibited excellent agreement with PET-derived Q (r=0.86 [95% CI 0.75-0.92], ICC=0.84 [95% CI 0.72-0.91], both p<0.001) (Figure 2). Compared with standard Q, there was no statistically significant difference between correlation coefficients (p=0.29) or standard deviations of absolute differences with PET-derived Q (p=0.85). Conclusion Assessing volumetric coronary flow by continuous thermodilution with predicted Ti instead of measured Ti does not compromise its accuracy when compared to [15O]H2O PET. It significantly simplifies the technique and renders absolute coronary flow measurements completely operator independent.Figure 1.AgreementFigure 2.Accuracy

Assessment of structural and functional microvascular dysfunction using microvascular resistance reserve versus invasive exercise stress testing

Abstract Background Coronary microvascular dysfunction is an heterogenous entity with structural dysfunction present in about 60% of cases. Although Coronary Flow Reserve (CFR) is commonly used for diagnosis, this index is nonspecific to the microvasculature. The effectiveness of the recently introduced Microvascular Resistance Reserve (MRR) and absolute microvascular resistance (Rµ) in identifying microvascular dysfunction endotypes remains uncertain. Objective To evaluate whether MRR and hyperemic Rµ assessment are effective in dichotomizing functional and structural microvascular dysfunction as compared with Rµ and coronary blood flow (Q) monitoring during exercise. Methods Rµ and MRR were first assessed using continuous thermodilution with saline infusion at 10 mL/min (rest) and 20 mL/min (hyperemia) in the left anterior descending artery of consecutive patients with Angina and Non-Obstructive Coronary Arteries. An MRR<2.3 was considered the cutoff for coronary microvascular dysfunction. Q and Rµ were assessed during subsequent stress testing with an incremental workload of 30 watts every two minutes, using a dedicated supine cycling ergometer. Results Coronary microvascular dysfunction was observed in 36.6% of the participants with suspected Angina with Non-Obstructive Coronary Artery disease (11 out of 30). Median hyperemic Rµ was 561 [381; 684] Wood Unit (WU) among patients with microvascular dysfunction. Participants with structural dysfunction (MRR<2.3 and hyperemic Rµ>561WU), had a resting Rµ similar to participants without CMD (1286±410 versus 1231±291 WU) but exhibited both impaired reduction of Rµ (139 [64; 288] versus 191 [74; 317] WU per 30 watts) and increase of Q during exercise (20 [1; 37.5] versus 52 [15.5; 92.0] mL/min per 30 watts). Patients with functional dysfunction (MRR<2.3 and hyperemic Rµ<561WU) had lower resting Rµ (672±219 WU) and higher resting Q (152±39 versus 84±24 mL/min) with a similar increase of Q during exercise (55 [30.5; 103.0] than participants without CMD. Mean N-terminal pro B-type natriuretic peptide level was higher in the structural group (425±563 ng/L) as compared to the functional and normal groups (86±10 ng/L and 50±80 ng/L respectively). Conclusion The use of MRR combined to hyperemic Rµ, derived from continuous intracoronary thermodilution, enables the assessment of coronary microvascular dysfunction with an accurate distinction between functional and structural endotypes.Microvascular hemodynamic adaptationNTpBNP level

Absolute coronary flow and microvascular resistance before and after TAVR

Abstract Purpose This study aims to investigate microcirculatory changes, both at rest and during hyperemia, using continuous intracoronary thermodilution, before TAVR, immediately post-TAVR, and at 6-month follow-up. Methods We included consecutive patients with high-gradient AS undergoing TAVR with non-obstructive coronary artery disease in the left anterior descending artery (LAD). Absolute coronary flow (Q) and microvascular resistance (R) were measured in the LAD using continuous intracoronary thermodilution at rest (Qrest) and during hyperemia (Qhyper) before and after TAVR, as well as at 6-month follow-up. Echocardiography and cardiac computed tomography (CCT) were used to quantify total myocardial mass and LAD-specific mass. Regional myocardial perfusion (QN) was calculated by dividing absolute coronary flow by the subtended myocardial mass. Results In 51 patients, absolute flow and microvascular resistance were assessed at rest and during hyperemia before and after TAVR. The mean age was 84.1 ± 5.0 years, and 35 participants were male (68.6%). Measurements were also obtained 6 months after TAVR in 20 (39%) patients. Overall, there were no significant changes in resting and hyperemic flow and resistance before and after TAVR (Qrest 68 [55-88] mL/min vs 69 [54 – 92] mL/min, p=0.776; Qhyper 158 [129 – 200] mL/min vs 172 [132, 216] mL/min, p=0.449, before and after TAVR, respectively). Consequently, coronary flow reserve (CFR) and microvascular resistance reserve (MRR) remained unchanged. At 6 months, there were no significant changes in flow and resistance both at rest and during hyperemia compared to baseline (Qrest: 72 [63-84] vs 83 [59-108] mL/min, p=0.658; Qhyper: 181 [158-200] vs 194 [167-222] mL/min, p=0.492; pre-TAVR and at 6 months follow-up, respectively), resulting in unchanged CFR and MRR. However, at follow-up, there was a noteworthy reduction in left ventricular mass of approximately 13% (from 201.9 ± 37.9g to 175.1 ± 46.6 g, p<0.001), leading to an increase in hyperemic perfusion (QN,hyper: 0.86 [0.69-1.06] vs 1.20 [0.99-1.32] mL/min/g, p=0.008; pre-TAVR and follow-up, respectively), but not in resting perfusion (QN, rest: 0.34 [0.30-0.48] vs 0.47 [0.36-0.67] mL/min/g, p=0.06). Conclusion Immediately after TAVR, there are no changes in absolute coronary flow and coronary flow reserve. Over time, LV remodeling is associated with increased hyperemic perfusion, indicating that, in the context of the observed pathophysiological changes in coronary microcirculation in AS patients after TAVR, the reverse LV remodeling has a more significant impact than the acute LV unloading achieved by valve replacement itself.

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.

Cycling coupled to intra-coronary thermodilution to evaluate angina with non-obstructive coronary artery disease

Abstract BACKGOUND Patients with Angina and Non-Obstructive Coronary Artery disease (ANOCA) face misdiagnosis and inadequate treatment. A new continuous thermodilution method enables assessment of absolute coronary blood flow (Q) and microvascular resistance (Rµ). The effectiveness of saline-induced hyperemia in capturing exercise-induced coronary flow regulation remains unknown. OBJECTIVE To describe Q and Rµ adaptation during exercise and to explore the correlation between Coronary Flow Reserve (CFR) derived from saline and exercise-induced hyperemia, as well as Microvascular Resistance Reserve (MRR). Methods Q, Rµ, CFR and MRR were first assessed using continuous thermodilution with saline infusion at 10 mL/min (rest) and 20 mL/min (hyperemia) in the left anterior descending artery, followed by subsequent stress testing using a dedicated supine cycling ergometer. The microvascular parameters were assessed during incremental workload of 30 watts every two minutes. CFRsaline<2.5 was considered the cutoff for coronary microvascular dysfunction. A minimal sample size of 29 participants was required to detect a hypothesized Spearman coefficient correlation r=0.5 between CFRsaline and CFRexercise using a 80% power and 5% significance level test. Results Coronary microvascular dysfunction was observed in 53.3% of the participants with suspected ANOCA (16 out of 30). During cycling, participants with coronary microvascular dysfunction had a lower reduction in Rµ (-109 [32; 286] versus -202 [102; 379] WU per 30 watts, p<0.01) and a lower ability to increase coronary flow (7 [30.5; 103.0] versus 21 [5.8; 45.0] mL/min per 30 watts, p=0.01) compared with those without coronary microvascular dysfunction. In the overall population, average CFRsaline and CFRexercise were 2.70±0.90 and 2.85±1.54, respectively (p=0.46) with an agreement classification of 83.3%. A good correlation between the two techniques was observed for both CFR (Spearman coefficient r=0.73, p<0.0001) and MRR (r=0.76, p<0.0001). Monitoring of CFR and Rµ during exercise unmasked functional coronary microvascular dysfunction priorly labeled as normal by saline induced hyperemia in 13.3% of the study population. These individuals had a moderate and late decrease of Rµ during the early stages of exercise, with a plateau up to 75% of their theoretical workload. Conclusion Participants with coronary microvascular dysfunction demonstrated compromised CFR due to impaired reduction of Rµ during physical workload. Saline-induced hyperemia provided a valid surrogate for exercise physiology independently of the absolute level of CFR and MRR, although exercise provided more granularity to evaluate hemodynamic adaptation among participants with functional dysfunction.

The influence of epicardial resistance on Microvascular Resistance Reserve (MRR)

Abstract Background The optimal index of microvascular function should be specific for the microvascular compartment. Yet, coronary flow reserve (CFR), despite being widely used to diagnose coronary microvascular dysfunction (CMD), is influenced by both epicardial and microvascular resistance. Conversely, microvascular resistance reserve (MRR) adjusts for fractional flow reserve (FFR), and thus is theoretically independent of epicardial resistance. Purpose We tested the hypothesis that MRR, unlike CFR, is not influenced by increasing epicardial resistance, and thus is a more specific index of microvascular function. Methods In a cohort of 16 patients that had undergone proximal left anterior descending artery stenting, we created four grades of artificial stenosis (no stenosis, mild, moderate, and severe) using a coronary angioplasty balloon inflated to different degrees within the stent. For each stenosis grade, we calculated CFR and MRR using continuous thermodilution (64 measurements of each) in order to assess their response to changing epicardial resistance. Results Graded balloon inflation resulted in a significant sequential decrease in mean FFR (no stenosis: 0.82 ±0.05; mild: 0.72 ±0.04; moderate: 0.61 ±0.05; severe: 0.48 ±0.09, p<0.001). This translated into a linear decrease in mean hyperaemic coronary flow (no stenosis: 170.5 ±66.8 ml/min; mild: 149.8 ±58.8 ml/min; moderate: 124.4 ±53.0 ml/min; severe: 94.0 ±45.2 ml/min, p<0.001) (Figure 1). CFR exhibited a marked linear decrease with increasing stenosis (no stenosis: 2.5 ±0.9; mild: 2.2 ±0.8; moderate: 1.8 ±0.7; severe: 1.4 ±0.6), corresponding to a decrease of 0.3 for a decrease in FFR of 0.1 (p<0.001). Conversely, MRR exhibited a minimal decrease across all stenosis grades (no stenosis: 3.0 ±1.0; mild: 3.0 ±1.0; moderate: 2.9 ±1.0; severe: 2.8 ±1.0), corresponding to a decrease of just 0.05 for a decrease in FFR of 0.1 (p<0.001) (Figure 1). Conclusion MRR, unlike CFR, is minimally influenced by epicardial resistance, and thus should be considered the most specific index of microvascular function.Figure 1.Absolute blood flow (Q) vs FFRFigure 2.MRR/CFR vs FFR

Acute hemodynamic effect of oral ketones in patients with acutely decompensated heart failure and low cardiac output syndrome: a prospective randomized study.

Abstract Background Preliminary studies showed positive inotropic effect of mild ketosis in patients with heart failure with reduced ejection fraction (HFrEF). Purpose To evaluate the acute hemodynamic effect of oral administration of beta-hydroxybutyrate (OHB) in patients with HFrEF and low cardiac output syndrome. Methods Patients with acutely decompensated HFrEF treated with inotropic therapy were randomized (1:1) to enteral bolus of OHB (25g of OHB monoester in 65 ml of solution; H.V.M.N Ketone Ester, H.V.M.N, USA) administered three times with 3-hour intervals or to euvolemic placebo. The serum concentration of OHB, biochemical markers, and invasive hemodynamics (Swan-Ganz catheter with continuous thermodilution) were repeatedly measured before and during 24 hours after administration of OHB. The primary endpoint was the maximum change in cardiac index (CI). Results The study included 20 patients with decompensated HFrEF (age: 57 ± 8 years; left ventricular ejection fraction: 21 ± 4%; non-ischemic cardiomyopathy: 16 [80%], median INTERMACS class: 3 [IQR 2 - 4]), who were treated with milrinone (0.5 ± 0.1 ug/kg/min, n=18) or levosimendan (0.1 ug/kg/min up to 25 mg, n=2). Patients in the OHB group (n = 10) did not differ from the placebo group (n = 10) in baseline clinical, biochemical, hemodynamic or echocardiographic characteristics. Baseline OHB concentration was normal (<0.6 mmol/L) in all patients. Administration of OHB increased serum concentration from 0.3 ± 0.2 mmol/L to a maximum of 2.4 ± 0.7 mmol/L (<0.001). Concentrations of OHB peaked at 1.5 ± 0.5 hours after administration of each OHB drink, and the maximum concentration was achieved at 4.1 ± 2.5 hours (Figure 1). No changes in OHB concentration were observed in the placebo group. In both study groups, there was a significant increase of CI at 3 hours compared to baseline, but the increase was significantly greater in the OHB group (OHB: 3.2 ± 0.6 vs. 2.1 ± 0.4 L/min/m2; placebo: 2.3 ± 0.4 vs. 2.0 ± 0.3 L/min/m2; both p<0.001 compared to baseline; p < 0.001 for OHB vs. placebo at 3 hours). The maximum relative increase of CI was 60 ± 24% in the OHB group (p <0.001) and 18 ± 8% in the placebo group (p< 0.01). The change of CI correlated with the change of OHB concentration in the OHB group (r = 0.58, p<0.001) but not in the placebo group (r = 0.1, p = 0.3). The changes in CI were not related to heart rate or concentration of norepinephrine, which did not change significantly throughout the study in both groups. Conclusion Oral administration of OHB leads to a significant temporary increase in myocardial contractility. This novel therapeutic concept might be a promising adjunction to inotropic support in patients with decompensated HFrEF.

Absolute coronary blood flow across different endotypes of ANOCA.

Intracoronary continuous thermodilution is a novel technique to quantify absolute true coronary flow and microvascular resistance. However, few data are available in patients with angina with non-obstructive coronary arteries (ANOCA). This study aimed to investigate the diagnostic potential of hyperaemic absolute coronary flow (Qmax) and absolute microvascular resistance (Rμ,hyper) among different ANOCA endotypes, and to determine the correlation between continuous - and bolus - thermodilution indexes. A total of 222 patients were scheduled for clinically indicated coronary function testing (CFT), of whom 120 patients were included in this analysis. These patients underwent CFT including acetylcholine (ACh) provocation testing and microvascular function assessment using both bolus and continuous thermodilution. CFT was negative (CFT-) in 32 (26.7%) patients. Endothelium-dependent dysfunction (ACh+) was present in 63 (52.5%) patients, and coronary microvascular dysfunction (CMD) identified at bolus thermodilution (CMD+) was present in 62 (51.7%) patients. Patients with a positive CFT (CFT+) showed significantly lower Qmax and higher Rμ,hyper values as compared to CFT-. Qmax was significantly lower in CMD+ versus CMD- patients (0.174 vs 0.222 L/min; p=0.04) but did not differ in patients with or without a positive ACh test (0.198 vs 0.219 L/min; p=0.86). The prevalence of a CFT+ is high in a selected ANOCA population. In our study, Qmax and Rμ,hyper were associated with a positive CFT. Qmax was associated with the presence of microvascular dysfunction but not with a positive acetylcholine test. The novel continuous thermodilution method can provide further insights into ANOCA endotypes.

Simplification of continuous intracoronary thermodilution.

Continuous intracoronary thermodilution with saline allows for the accurate measurement of volumetric blood flow (Q) and absolute microvascular resistance (Rμ). However, this requires repositioning of the temperature sensor by the operator to measure the entry temperature of the saline infusate, denoted as Ti. We evaluated whether Ti could be predicted based on known parameters without compromising the accuracy of calculated Q. This would significantly simplify the technique and render it completely operator independent. In a derivation cohort of 371 patients with Q measured both at rest and during hyperaemia, multivariate linear regression was used to derive an equation for the prediction of Ti. Agreement between standard Q (calculated with measured Ti) and simplified Q (calculated with predicted Ti) was assessed in a validation cohort of 120 patients that underwent repeat Q measurements. The accuracy of simplified Q was assessed in a second validation cohort of 23 patients with [15O]H2O positron emission tomography (PET)-derived Q measurements. Simplified Q exhibited strong agreement with standard Q (r=0.94, confidence interval [CI]: 0.93-0.95; intraclass correlation coefficient [ICC] 0.94, CI: 0.92-0.95; both p<0.001). Simplified Q exhibited excellent agreement with PET-derived Q (r=0.86, CI: 0.75-0.92; ICC=0.84, CI: 0.72-0.91; both p<0.001). Compared with standard Q, there were no statistically significant differences between correlation coefficients (p=0.29) or standard deviations of absolute differences with PET-derived Q (p=0.85). Predicting Ti resulted in an excellent agreement with measured Ti for the assessment of coronary blood flow. It significantly simplifies continuous intracoronary thermodilution and renders absolute coronary flow measurements completely operator independent.

Absolute coronary flow and microvascular resistance before and after transcatheter aortic valve implantation.

Severe aortic stenosis (AS) is associated with left ventricular (LV) remodelling, likely causing alterations in coronary blood flow and microvascular resistance. We aimed to evaluate changes in absolute coronary flow and microvascular resistance in patients with AS undergoing transcatheter aortic valve implantation (TAVI). Consecutive patients with AS undergoing TAVI with non-obstructive coronary artery disease in the left anterior descending artery (LAD) were included. Absolute coronary flow (Q) and microvascular resistance (Rμ) were measured in the LAD using continuous intracoronary thermodilution at rest and during hyperaemia before and after TAVI, and at 6-month follow-up. Total myocardial mass and LAD-specific mass were quantified by echocardiography and cardiac computed tomography. Regional myocardial perfusion (QN) was calculated by dividing absolute flow by the subtended myocardial mass. In 51 patients, Q and R were measured at rest and during hyperaemia before and after TAVI; in 20 (39%) patients, measurements were also obtained 6 months after TAVI. No changes occurred in resting and hyperaemic flow and resistance before and after TAVI nor after 6 months. However, at 6-month follow-up, a notable reverse LV remodelling resulted in a significant increase in hyperaemic perfusion (QN,hyper: 0.86 [interquartile range {IQR} 0.691.06] vs 1.20 [IQR 0.99-1.32] mL/min/g; p=0.008; pre-TAVI and follow-up, respectively) but not in resting perfusion (QN,rest: 0.34 [IQR 0.30-0.48] vs 0.47 [IQR 0.36-0.67] mL/min/g; p=0.06). Immediately after TAVI, no changes occurred in absolute coronary flow or coronary flow reserve. Over time, the remodelling of the left ventricle is associated with increased hyperaemic perfusion.

TCT-518 First-in-Man Use of Continuous Thermodilution Derived FFR and Absolute Flow in Physiological Assessment of Peripheral Arterial Disease

TCT-518 First-in-Man Use of Continuous Thermodilution Derived FFR and Absolute Flow in Physiological Assessment of Peripheral Arterial Disease

Vascular Remodeling in Coronary Microvascular Dysfunction.

Approximately half of the patients with angina and nonobstructive coronary artery disease (ANOCA) have evidence of coronary microvascular dysfunction (CMD). This study aims to characterize patients with ANOCA by measuring their minimal microvascular resistance and to examine the pattern of vascular remodeling associated with these measurements. The authors prospectively included patients with ANOCA undergoing continuous thermodilution assessment. Lumen volume and vessel-specific myocardial mass were quantified using coronary computed tomography angiography (CTA). CMD was defined as coronary flow reserve<2.5 and high minimal microvascular resistance as >470 WU. A total of 153 patients were evaluated; 68 had CMD, and 22 of them showed high microvascular resistance. In patients with CMD, coronary flow reserve was 1.9 ± 0.38 vs 3.2 ± 0.81 in controls (P< 0.001). Lumen volume was significantly correlated with minimal microvascular resistance (r =-0.59 [95%CI:-0.45 to-0.71]; P< 0.001). In patients with CMD and high microvascular resistance, lumen volume was 40% smaller than in controls (512.8 ± 130.3mm3 vs 853.2 ± 341.2mm3; P< 0.001). Epicardial lumen volume assessed by coronary CTA was independently associated with minimal microvascular resistance (P< 0.001). The predictive capacity of lumen volume from coronary CTA for detecting high microvascular resistance showed an area under the curve of 0.79 (95%CI: 0.69-0.88). Patients with CMD and high minimal microvascular resistance have smaller epicardial vessels than those without CMD. Coronary CTA detected high minimal microvascular resistance with very good diagnostic capacity. Coronary CTA could potentially aid in the diagnostic pathway for patients with ANOCA.

Development and validation of a novel angiography-derived index of absolute coronary blood flow and resistance.

Intracoronary continuous thermodilution has been recently proposed as an invasive method to quantify absolute coronary flow (Qabs) and resistance (Rabs) in vivo. The aim of the present study is to develop and validate of a novel pressure-wire- and microcatheter-free surrogate of coronary flow and resistance derived from a standard coronary angiogram. Angiography derived coronary flow (Qangio) and resistance (Rangio) was prospectively validated in a two-center cohort of patients from Oxford Heart Centre and the Essex Cardiothoracic Centre. Qabs and Rabs were measured during resting and hyperemic conditions with continuous thermodilution using the Rayflow microcatheter. Qangio and Rangio were computed from the diagnostic coronary angiogram in a blinded fashion in resting and hyperemic conditions. A total of 62 patients and 115 vessels were included in the present analysis. The median Qabs at rest was 75ml/min (53-95) and 151ml/min (105-203) during hyperemia; Qangio at rest was 84ml/min (66-108) and 154ml/min (115-195) during hyperemia. There was a strong correlation between Qabs and Qangio (R = 0,72; p < 0.001, R = 0,86; p < 0.001 respectively) with satisfactory interclass correlation (0.841, 95% CI 0.509-0.957; p = 0.0003). The median Rabs was 1111 mmHg/(L/min) (830-1581.4) at rest and 454 mmHg/(L/min) (348-610) during hyperemia; angiographic resistance (Rangio) was 937.4 mmHg/(L/min) (695.4-1261.9) at rest and 492.4 mmHg/(L/min) (406-697) during hyperemia. There was a strong correlation between Rabs and Rangio in both conditions (R = 0,81; p < 0.001 and R = 0,78; p < 0.001 respectively). The was a good correlation between absolute coronary flow reserve (CFR) and angiography-derived CFR (R = 0,61; p < 0.001) and between absolute microvascular resistance reserve (MRR) and angiography-derived MRR (R = 0,49; p < 0.001).

Changes in absolute coronary flow and microvascular resistance during exercise in patients with ANOCA.

Whether saline-induced hyperaemia captures exercise-induced coronary flow regulation remains unknown. Through this study, we aimed to describe absolute coronary flow (Q) and microvascular resistance (Rμ) adaptation during exercise in participants with angina with non-obstructive coronary artery disease (ANOCA) and to explore the correlations between saline- and exercise-derived coronary flow reserve (CFR) and microvascular resistance reserve (MRR). Rμ, Q, CFR and MRR were assessed in the left anterior descending artery using continuous thermodilution with saline infusion at 10 mL/min (rest), 20 mL/min (hyperaemia) and finally at a 10 mL/min infusion rate during stress testing with a dedicated supine cycling ergometer. An incremental workload of 30 watts every two minutes was applied. A saline-derived CFR (CFRsaline) cutoff <2.5 was used to identify coronary microvascular dysfunction (CMD). CFRsaline-defined CMD was observed in 53.3% of the participants (16/30). While cycling, these patients less of an ability to increase Q (7 [interquartile range [IQR] 30.5-103.0] vs 21 [IQR 5.8-45.0] mL/min/30 watts; p=0.01) due to a smaller decrease of Rμ (109 {IQR 32-286} vs 202 [IQR 102-379] Wood units [WU]/30 watts; p<0.01) as compared with the group with normal CFRsaline. In the overall population, CFRsaline and exercise-derived CFR (CFRexercise) were 2.70±0.90 and 2.85±1.54, respectively, with an agreement classification of 83.3%. A good correlation between saline and exercise techniques for both CFR (r=0.73; p<0.0001) and MRR (r=0.76; p<0.0001) was observed. Among participants with normal CFRsaline, 28.7% (4/14) had an impaired CFRexercise <2.5 at the peak of exercise due to a moderate and late decrease of Rμ. Saline-induced hyperaemia provided a valid surrogate for exercise physiology independently of the absolute level of CFR and MRR, although exercise provided more granularity to evaluate adaptation among participants with exercise-related CMD.

Continuous thermodilution and microvascular resistance reserve during the index procedure in acute coronary syndrome without obstructive coronary artery disease: A pilot study.

In 5%-25% of non-ST-elevation acute coronary syndrome (NSTE-ACS) patients, coronary angiography reveals no obstructive coronary arteries (MINOCA). Coronary microvascular disease (CMD) is a potential causal pathophysiological mechanism in these patients and can be diagnosed by continuous thermodilution assessment. Recently, the microvascular resistance reserve (MRR) has been introduced as a novel index to assess the vasodilatory capacity of the microcirculation. However, continuous thermodilution and MRR have never been investigated in the acute setting in MINOCA patients and invasive assessment of the microcirculation in these patients are currently lacking. The objectives of the study were to investigate the incidence of CMD (MRR ≤ 2.7) in patients with MINOCA and to evaluate the feasibility and safety of continuous thermodilution-based assessment during index coronary angiography in the acute setting. This study was a prospective, observational, pilot study investigating coronary physiology in the acute setting in MINOCA patients. Patients admitted with a diagnosis of NSTE-ACS were eligible for inclusion. In total, 19 MINOCA patients were included in this analysis;the mean age was 70 ± 9 years, and 79% were females. CMD was present in 6 patients (32%). Qrest was significantly higher in the MRR ≤ 2.7 group compared to the MRR > 2.7 group (0.076 [0.057-0.100] vs. 0.049 [0.044-0.071] L/min, p = 0.03). Rµ,rest was significantly lower in the MRR ≤ 2.7 group compared to the MRR > 2.7 group (1083 [710-1510] vs. 1563 [1298-1970]WU,p = 0.04). No periprocedural complications or hemodynamic instability have occurred during continuous thermodilution assessment during the index coronary angiography. In patients admitted for MINOCA undergoing immediate coronary angiography, continuous thermodilution assessmentand MRR are feasible and safe in the acute setting, and evidence of functional CMD could be observed in one-third of the MINOCA patients.

Effects of age on microvascular function in patients with normal coronary arteries.

It has been suggested that coronary microvascular function decreases with age, irrespective of the presence of epicardial atherosclerosis. Our aim is to quantitatively investigate the effects of age on microvascular function in patients with normal coronary arteries. In 314 patients with angina with no obstructive coronary artery disease (ANOCA), microcirculatory function was tested using the continuous thermodilution method. In 305 patients, the association between age and both resting and hyperaemic myocardial blood flow (Q), microvascular resistance (Rμ), absolute coronary flow reserve (CFR) and microvascular resistance reserve (MRR) was assessed. In addition, patients were divided into 3 groups to test for differences based on age quartiles (≤52 years [24.9%], 53-64 years [49.2%], ≥65 years [25.9%]). The mean age was 59±9 years with a range from 22 to 79 years. The mean resting Q (Qrest) was not different in the 3 age groups (88±34 mL/min, 82±29 mL/min, and 86±38 mL/min, R2=0.001; p=0.62). A trend towards a decreasing mean hyperaemic Q (Qmax) was observed with increasing age (223±79 mL/min, 209±84 mL/min, 200±80 mL/min, R2=0.010; p=0.083). The mean resting Rμ (Rμ,rest) were 1,204±460 Wood units (WU), 1,260±411 WU, and 1,289±455 WU (p=0.23). The mean hyperaemic Rμ (Rμ,hyp) increased significantly with advancing age (429±149 WU, 464±164 WU, 503±162 WU, R2=0.026; p=0.005). Consequently, MRR decreased with age (3.2±1.2, 3.1±1.0, 2.9±0.9; p=0.038). This trend was present in both the patients with (n=121) and without (n=184) coronary microvascular dysfunction (CMD). There is an age-dependent physiological increase in minimal microvascular resistance and decrease in microvascular function, which is represented by a decreased MRR and is independent of atherosclerosis. The age-dependent decrease in MRR was present in both patients with and without CMD and was most evident in patients with smooth coronary arteries.

Mixing properties of coronary infusion catheters assessed by in vitro experiments and computational fluid dynamics.

Continuous infusion thermodilution is an established technique for the assessment of absolute coronary blood flow and microvascular resistance due to its proven accuracy and reproducibility. However, for this technique to yield reliable measurements, direct and homogenous mixing of injected saline and blood is mandatory. This study aimed to assess and compare the mixing properties of two different microcatheters, namely the Rayflow® (with sideholes for infusion) and the Finecross® catheter (single end-hole for infusion), which are commonly used in the catheterization laboratory. The study employed three different methods to evaluate the mixing properties of the catheters. Firstly, a qualitative assessment of mixing was performed using ink injections in an in vitro bench model of a coronary artery. Secondly, in analogy to the human catheterization laboratory, mixing properties over the length of the coronary artery were assessed semi-quantitatively by temperature measurements in the bench model. Lastly, a quantitative assessment was performed by 3D computational fluid dynamics, where the standard deviation and entropy ratio of the temperature over the cross-section in the coronary artery model were calculated for both catheters. All three evaluation methods demonstrated that the Rayflow catheter's specific design leads to a more optimal, homogeneous mixture of blood and saline over both the cross-section and length of a coronary vessel, as compared with the standard end-hole catheter.

The Influence of Epicardial Resistance on Microvascular Resistance Reserve

BackgroundThe optimal index of microvascular function should be specific for the microvascular compartment. Yet, coronary flow reserve (CFR), despite being widely used to diagnose coronary microvascular dysfunction (CMD), is influenced by both epicardial and microvascular resistance. Conversely, microvascular resistance reserve (MRR) adjusts for fractional flow reserve (FFR), and thus is theoretically independent of epicardial resistance. ObjectivesThe authors tested the hypothesis that MRR, unlike CFR, is not influenced by increasing epicardial resistance, and thus is a more specific index of microvascular function. MethodsIn a cohort of 16 patients who had undergone proximal left anterior descending artery stenting, we created 4 grades of artificial stenosis (no stenosis, mild, moderate, and severe) using a coronary angioplasty balloon inflated to different degrees within the stent. For each stenosis grade, we calculated CFR and MRR using continuous thermodilution (64 measurements of each) to assess their response to changing epicardial resistance. ResultsGraded balloon inflation resulted in a significant sequential decrease in mean FFR (no stenosis: 0.82 ± 0.05; mild: 0.72 ± 0.04; moderate: 0.61 ± 0.05; severe: 0.48 ± 0.09; P < 0.001). This translated into a linear decrease in mean hyperemic coronary flow (no stenosis: 170.5 ± 66.8 mL/min; mild: 149.8 ± 58.8 mL/min; moderate: 124.4 ± 53.0 mL/min; severe: 94.0 ± 45.2 mL/min; P < 0.001). CFR exhibited a marked linear decrease with increasing stenosis (no stenosis: 2.5 ± 0.9; mild: 2.2 ± 0.8; moderate: 1.8 ± 0.7; severe: 1.4 ± 0.6), corresponding to a decrease of 0.3 for a decrease in FFR of 0.1 (P < 0.001). In contrast, MRR exhibited a negligible decrease across all stenosis grades (no stenosis: 3.0 ± 1.0; mild: 3.0 ± 1.0; moderate: 2.9 ± 1.0; severe: 2.8 ± 1.0), corresponding to a decrease of just 0.05 for a decrease in FFR of 0.1 (P < 0.001). ConclusionsMRR, unlike CFR, is minimally influenced by epicardial resistance, and thus should be considered the more specific index of microvascular function. This suggests that MRR can also reliably evaluate microvascular function in patients with significant epicardial disease.

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.