Hyperemic Microvascular Resistance Research Articles

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

AbstractBackground and AimsMeasurement 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.MethodsThirty 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 πDQCA2/4 (0.5 × APV) and hMVRIQCA as distal coronary pressure divided by CBFQCA during maximal hyperemia.ResultsThe 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.ConclusionsComparative evaluation of MR in coronary branches with varying vessel diameters requires vessel diameter to be accounted for.

Non-hyperaemic coronary flow velocity acceleration indices correlate with hyperaemic microvascular resistance in patients with INOCA

Abstract Background Coronary microvascular dysfunction (CMD) is associated with an overall worse prognosis. While the diagnosis and endo-typing of CMD currently rely on hyperaemic physiological indices, the search for accurate non-hyperaemic techniques continues. Flow velocity acceleration pattern is mechanistically associated with changes in shear stress, endothelial function, arterial stiffness and pressure in pulsatile flow systems (1-3). Purpose We aim to interrogate whether resting flow velocity acceleration indices correlate with hyperaemic microvascular resistance (HMR) in patients with Ischemia and no obstructive coronary artery disease (INOCA). Methods In 21 Patients with INOCA (all of whom had presented with typical angina pectoris, had no significant epicardial stenoses but positive myocardial perfusion scan test for ischemia) invasive physiological assessment was performed by means of intracoronary Doppler. Hyperaemia was induced with intracoronary adenosine administration. Coronary flow reserve (CFR) and HMR were calculated per their definitions. Flow velocity acceleration indices were derived from the first derivative of the averaged resting flow velocity waveforms with respect to time. We have defined 6 wave peaks of interest in all patients (peak diastolic acceleration (initial prominent peak with ventricular relaxation, referred as A), early diastolic deceleration (B), early re-acceleration wave (C), peak presystolic deceleration (seen just before initial systolic acceleration peak, J), initial systolic acceleration peak (X) and pre-diastolic deceleration nadir (Z)) and calculated the ratios between them as well as adjusted them with respect to resting mean flow velocity (Figure 1). Results The mean age was 59 ± 8 years and the majority of the study group was female (%81). Cardiovascular risk factors were common amongst the study group.All patients had CFR < 2.5. Mean CFR and HMR were 2.05 ± 0.32 and 2.20 ± 0.60 mmHg.cm.sec-1 respectively. Raw C peak magnitude was significantly correlated with APVh (rho:-0.457 p:0.037) and HMR (rho:0.612 p:0.004). Adjusting the C magnitudes with APVb at patient level yielded better correlations (APVh rho:-0.496 p:0.022 ; HMR:0.642 p:0.002). The ratio between diastolic reacceleration peak (C) and presystolic peak deceleration (J), C/J , adjusted with the APVb ((C/J)/APVb) showed the most pronounced correlation with HMR (rho: 0.758 p < 0.001) (unadjusted C/J – HMR rho: 0.718 p<0.001)(Figure 2). Conclusion(s) Acceleration characteristics of resting coronary flow velocity correlate with hyperaemic microvascular resistance indicating structurally impaired coronary microcirculation, hence their utilisation may aid developing non-hyperaemic physiological markers for coronary microvascular dysfunction in patients with INOCA.Derived Acceleration WaveformsCorrelations between HMR and C/J Ratio

The integration of angio-IMR, QFR and FFR for the detection of ischemia

Abstract Background Fractional flow reserve (FFR) and quantitative flow ratio (QFR) are important tools to assess coronary-specific ischemia, but ischemia may be obscured in the presence of coronary microvascular dysfunction (CMD). Wire free angiography based index of microcirculatory resistance (angio-IMR) might aid in identifying ischemic territories with normal FFR or QFR. Purpose First we sought to validate angio-IMR against invasive resistance indices and [15O]H2O positron emission tomography (PET) derived resistance. Secondly, we investigated whether angio-IMR can help identifying ischemic vessels with normal FFR/QFR. Methods In this PACIFIC 1 and 2 sub study symptomatic patients underwent [15O]H2O PET and invasive coronary angiography with routine three vessel FFR. Invasive hyperemic microvascular resistance (HMR) and IMR were measured in a sub set of patients. A FFR/QFR ≤0.80 and hyperemic myocardial blood flow (hMBF) ≤2.3 ml/min/g were considered ischemic. Microvascular resistance on PET was defined as the ratio of mean distal coronary pressure to MBF. Angio-IMR, QFR and PET analyses were performed by core labs blinded to invasive angiography results. Results Among 259 patients (mean age 61 ± 9 years, 188 (73%) male) 494 vessels were included. Invasive IMR and or HMR were measured in 95 vessels. Angio-IMR did not correlate with invasive HMR/IMR for the right coronary artery (RCA) but correlated weakly with invasive HMR (r=0.39, p=0.03) and moderately (r=0.48, p<0.01) with invasive IMR for the left coronary artery (LCA). The RCA was excluded for further analysis. A very weak correlation between angio-IMR and PET resistance was observed (r=0.17, p<0.01). Territories with ischemia and a normal FFR showed a higher angio-IMR than ischemic territories with reduced FFR (31.3 ± 13.8 vs 22.2 ± 10.3, p<0.01). The same was observed after stratification by QFR/PET results (34.3 ± 15.5 vs 23.9 ± 9.9, p<0.01). Results remained consistent after stratification for diameter stenosis percentage. Conclusions A weak to moderate correlation was found between angio-IMR and invasive resistance indices for the LCA. In territories with an ischemic perfusion angio-IMR was higher in those with a normal FFR/QFR compared to patients with a reduced FFR/QFR. Integration of FFR/QFR and angio-IMR might lead to superior vessel-specific ischemia detection.

Association between index of microcirculatory resistance and patients' characteristics, coronary computed tomography findings, and the sensor location

Abstract Background The index of microcirculatory resistance (IMR) has been widely used for the assessment of microcirculatory function and the detection of the territory with microvascular dysfunction. For measuring coronary physiological indices including IMR, a pressure/temperature sensor-tipped guidewire is recommended to be located distally to the target lesion, however the determinants of IMR including wire location other than the hyperemic microvascular resistance itself are still undetermined. Purpose This study aimed to clarify the determining factors including coronary computed tomography angiography (CCTA) findings, wire position and vessel anatomy and its effect on IMR values. Methods We retrospectively investigated 121 intermediate left anterior descending artery lesions in chronic coronary syndrome patients in our institutional physiological registry (July 2020 to Aug 2022). All patients underwent preprocedural CCTA and coronary physiological assessment with pressure/temperature sensor-tipped guidewire during invasive coronary angiography or percutaneous coronary intervention (PCI). We placed the wire as far distal as practical for the assessment of physiological indices. Under adenosine-induced hyperemia, the wire was pulled manually to the guide catheter and its pullback length was recorded. CCTA assessment included qualitative lesion morphology assessment (spotty calcification, low attenuation plaque, napkin ring sign) and quantitative plaque analysis (remodeling index). Epicardial fat volume is also measured with the proprietary semi-automated software. The predicting factors for IMR was investigated. Result In a total cohort, IMR was 20.40 (14.07-29.92), and the prevalence of IMR>25 was 36 %. On linear regression analysis, patient characteristics including age and gender were not significant predictors for IMR. CCTA-based high risk plaque features (Spotty calcification, low attenuation plaque and napkin ring sign) were also not associated with IMR. In univariable and multivariable linear regression analysis, wire pullback length, remodeling index and epicardial fat volume were significant predictors for IMR (β 1.369 [0.223-2.515, p=0.020, β 6.651 [1.486-11.815], p=0.012, and β 0.055 [0.008-0.103], p=0.023, respectively). Conclusion Wire location (length form the coronary ostium), remodeling index and epicardial fat volume affects IMR values. Caution should be exercised for the interpretation of IMR values in consideration of these factors.

The left main coronary artery (LMCA) physiology study: comprehensive clinical haemodynamic evaluation of physiology and pathophysiology

Abstract Background & Purpose At present, physiological evaluation of left main coronary artery (LMCA) disease is based on the assumption that pressure-based indices are agnostic to the vessel being assessed. We conducted mechanistic studies to determine whether pressure-based indices in the left anterior descending (LAD) and left circumflex (LCx) arteries are different and if so, the basis of this discrepancy, in patients with normal coronary arteries (LMCA Physiology Study) and in those with isolated LMCA disease (LMCA Pathophysiology Study). Methods Patients with exertional angina were prospectively enrolled after baseline investigation of computed tomography or invasive angiography and those with left ventricular impairment were excluded. Eligibility for the Physiology Study required the absence of epicardial disease on angiography and/or fractional flow reserve or significant coronary microvascular disease (LAD coronary flow reserve (CFR) <2.0). Simultaneous intracoronary pressure and Doppler measurements were performed in the LAD and LCx arteries, at rest and adenosine mediated hyperaemia. A subset also underwent 3-Tesla quantitative stress perfusion cardiac magnetic resonance imaging. Eligibility for the Pathophysiology Study required isolated LMCA disease, which was verified physiologically by pressure wire pullback according to predefined criteria of 1) ≥80% of total FFR arising from the left main coronary artery disease and 2) ≤0.05 FFR gradient distal to the left main coronary artery disease in both vessels. A paired 2-tailed test for significance was performed for all analyses. The protocols were approved by the UK National research ethics committee. Results 71 patients were prospectively enrolled, 28 in the Physiology Study and 43 in the Pathophysiology Study (Table 1). In the LMCA Physiology Study, CFR was higher and hyperaemic microvascular resistance (hMR) lower in the LAD compared to the LCx. In the LMCA Pathophysiology Study, the contribution to total FFR of downstream disease was negligible and comparable in both branches. Moreover, hyperaemic, and non-hyperaemic pressure-based indices were all significantly lower in the LAD, compared to the LCx. In addition, CFR was higher and hMR lower in the LAD compared to the LCx. Correlations are outlined in Figure 1. Differences in pressure-derived measurements remained after correction for the influence of hydrostatic pressures. However, when adjusted for subtended myocardial mass, there was no significant difference in invasive hemodynamic indices or quantitative perfusion analysis-derived myocardial perfusion reserve index. Conclusions Commonly used indices of stenosis severity are not agnostic to the vessel assessed due to differences in myocardial mass and microvascular resistances. The need for vessel-specific thresholds has significant implications on LMCA disease assessment and potentially, interpretation of the existing evidence base on physiological assessment of non-LMCA disease.Table 1Figure 1

Primary versus iatrogenic (post-PCI) coronary microvascular dysfunction: a wire-based multimodal comparison

BackgroundAlthough there are studies examining each one separately, there are no data in the literature comparing the magnitudes of the iatrogenic, percutaneous coronary intervention (PCI)-induced, microvascular dysfunction (Type-4 CMD) and...

Changes in microvascular resistance following percutaneous coronary intervention - From the ILIAS global registry

BackgroundMicrovascular resistance (MR) has prognostic value in acute and chronic coronary syndromes following percutaneous coronary intervention (PCI), however anatomic and physiologic determinants of the relative changes of MR and its association to target vessel failure (TVF) has not been investigated previously. This study aims to evaluate the association between changes in MR and TVF. MethodsThis is a sub-study of the Inclusive Invasive Physiological Assessment in Angina Syndromes (ILIAS) registry which is a global multi-centre initiative pooling lesion-level coronary pressure and flow data. ResultsPaired pre-post PCI haemodynamic data were available in n = 295 vessels out of n = 828 PCI treated patients and of these paired data on MR was present in n = 155 vessels. Vessels were divided according to increase vs. decrease % in microvascular resistance following PCI (ΔMR % ≤ 0 vs. ΔMR > 0%). Decreased microvascular resistance ΔMR % ≤ 0 occurred in vessels with lower pre-PCI fractional flow reserve (0.67 ± 0.15 vs. 0.72 ± 0.09 p = 0.051), coronary flow reserve (1.9 ± 0.8 vs. 2.6 ± 1.8 p < 0.0001) and higher hyperemic microvascular resistance (2.76 ± 1.3 vs. 1.62 ± 0.74 p = 0.001) and index of microvascular resistance (24.4 IQ (13.8) vs. 15. 8 IQ (13.2) p = 0.004). There was no difference in angiographic parameters between ΔMR % ≤ 0 vs. ΔMR > 0%. In a cox regression model ΔMR % > 0 was associated with increased rate of TVF (hazard ratio 95% CI 3.6 [1.2; 10.3] p = 0.018). ConclusionIncreased MR post-PCI was associated with lesions of less severe hemodynamic influence at baseline and higher rates of TVF at follow-up.

Particularities of coronary physiology in patients with atrial fibrillation: insights from combined pressure and flow indices measurements.

Symptoms suggestive of myocardial ischemia are frequently encountered in patients with atrial fibrillation (AF) even in the absence of obstructive coronary artery disease. Nevertheless, an in-depth characterisation of coronary physiology in patients with AF is currently lacking. We aim to provide an insight into the characteristics of coronary physiology in AF, by performing simultaneous invasive measurements of coronary flow- and pressure- indices in a real-life population of patients with AF and indication of coronary angiography. This is a prospective open label study including patients with permanent or persistent AF and indication of coronary angiography showing intermediate coronary stenosis requiring routine physiological assessment (n = 18 vessels from 14 patients). We measured FFR (fractional flow reserve), and Doppler-derived coronary flow indices, including CFR (coronary flow reserve) and HMR (hyperaemic microvascular resistance). From the analysed vessels, 18/18 vessels (100%) presented a pathological CFR (<2.5), indicative of coronary microvascular dysfunction (CMD), and 3/18 (17%) demonstrated obstructive epicardial coronary disease (FFR ≤ 0.8). A large proportion of vessels (15/18; 83%) showed discordant FFR/CFR with preserved FFR and low CFR. 47% of the coronary arteries in patients with AF and non-obstructive epicardial coronary disease presented structural CMD (HMR ≥ 2.5 mmHg/cm/s), and were associated with high BMR and an impaired response to adenosine. Conversely, vessels from patients with AF and non-obstructive epicardial coronary disease with functional CMD (HMR < 2.5 mmHg/cm/s) showed higher bAPV. The permanent AF subpopulation presented increased values of HMR and BMR compared to persistent AF, while structural CMD was more often associated with persistent symptoms at 3 months, taking into account the limited sample size of our study. Our findings highlight a systematically impaired CFR in patients with AF even in the absence of obstructive epicardial coronary disease, indicative of CMD. In addition, patients with AF presented more prevalent structural CMD (HMR ≥ 2.5 mmHg/cm/s), characterized by reduced hyperaemic responses to adenosine, possibly interfering with the FFR assessment.

Estimation of Microvascular Dysfunction by Using 13N-Ammonia Positron Emission Tomography with Quantitative Myocardial Blood Flow Analysis in Chronic Coronary Syndrome.

Although coronary artery disease (CAD) is characterized by epicardial atherosclerosis and microvascular disease, the importance of evaluating microvascular dysfunction has not been sufficiently recognized in clinical practice. We estimated microvascular disease severity by assessing hyperemic microvascular resistance (MVR), as determined by absolute quantification of myocardial blood flow (MBF) with 13N-ammonia positron emission tomography-myocardial perfusion imaging (PET-MPI). We retrospectively collected data for 23 CAD patients who underwent both stress/rest PET-MPI and invasive coronary angiography (CAG) with fractional flow reserve (FFR) measurement. Among 30 vessels for which FFR measurement was performed, 13 had a low FFR (FFR ≤0.75). For each patient, myocardial segments of a standard 17-segment model were assigned to the stenotic myocardial area perfused by the FFR-measured vessel and a reference normal-perfusion area based on PET-MPI and the coronary distribution on CAG. Hyperemic MVR was calculated by using the formula, hyperemic MVR = hyperemic mean blood pressure × FFR/hyperemic MBF of the stenotic vessel. A strong negative correlation was observed between hyperemic MVR and hyperemic MBF in the reference normal-perfusion area (R = -0.758, P<0.001). Microvascular disease severity in chronic CAD can be estimated by hyperemic MBF of the normal-perfusion area with 13N-ammonia PET-MPI.

Coronary Microcirculation: The Next Frontier in the Management of STEMI

Although the widespread adoption of timely invasive reperfusion strategies over the last two decades has significantly improved the prognosis of patients with ST-segment elevation myocardial infarction (STEMI), up to half of patients after angiographically successful primary percutaneous coronary intervention (PCI) still have signs of inadequate reperfusion at the level of coronary microcirculation. This phenomenon, termed coronary microvascular dysfunction (CMD), has been associated with impaired prognosis. The aim of the present review is to describe the collected evidence on the occurrence of CMD following primary PCI, means of assessment and its association with the infarct size and clinical outcomes. Therefore, the practical role of invasive assessment of CMD in the catheterization laboratory, at the end of primary PCI, is emphasized, with an overview of available technologies including thermodilution- and Doppler-based methods, as well as recently developing functional coronary angiography. In this regard, we review the conceptual background and the prognostic value of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), hyperemic microvascular resistance (HMR), pressure at zero flow (PzF) and angiography-derived IMR. Finally, the so-far investigated therapeutic strategies targeting coronary microcirculation after STEMI are revisited.

Impact of the downstream myocardial mass on values of coronary microvascular resistance.

The assessment of hyperemic microvascular resistance (HMR) may be dependent on the assessment location in the coronary artery and the amount of partial myocardial mass (PMM) distal to the assessment locations. The aim of this study was to investigate the differences in HMR values between the distal and proximal sites in the same coronary arteries as well as the relationship between HMR and PMM. Twenty-nine vessels from 26 patients who had undergone intracoronary physiological assessments including Doppler flow velocity at the distal third part and the proximal third part in the same vessels were assessed. The mean values of HMR and PMM at the distal sites were 2.08 ± 0.75 mmHg/cm/sec and 22.2 ± 10.4g, respectively. At the proximal sites, the values of HMR and PMM were 1.19 ± 0.33 mmHg/cm/sec and 59.9 ± 18.3g, respectively. All HMR values at the distal sites were significantly higher than those at the proximal sites (p &lt; 0.001). Smaller PMM at the distal sites was significantly associated with higher HMR (r=-0.544, p=0.002) and was the strongest factor affecting the HMR values (p=0.009), while this relationship was not observed at the proximal sites (r=-0.262, p=0.17). The impact of PMM on HMR was diminished at assessment locations where PMM was greater than 35 g. In conclusion, a small amount of downstream myocardial mass could be related to high HMR values. The assessment location around the proximal coronary artery with over 35 g of myocardium would be appropriate to assess HMR because it minimizes the influence of the assessment location.

Coronary wave energy to predict functional recovery in patients with ischemic left ventricular dysfunction

Abstract Background Invasive coronary angiography and non-invasive viability testing are the cornerstones of diagnosing and managing ischemic left ventricular dysfunction. At present there is no single test which serves both needs but, if developed, could revolutionise investigation of this condition. Coronary wave intensity analysis (cWIA) interrogates both contractility and microvascular physiology of the subtended myocardium [1,2] and therefore has the potential to fulfil this goal. Objectives We hypothesized that cWIA measured during coronary angiography would predict functional recovery with a similar accuracy to late gadolinium enhanced cardiac magnetic resonance imaging (LGE-CMR). Methods Patients with a left ventricular ejection fraction ≤40% and extensive coronary disease were enrolled. cWIA, fractional flow reserve and microvascular resistance were assessed with a simultaneous coronary Doppler and pressure-sensing guidewire during cardiac catheterization at rest, during hyperaemia and during low-dose dobutamine stress. Viability was assessed using LGE-CMR. Regional left ventricular function was assessed at baseline and 6-month follow up after optimization of medical therapy +/− revascularization, using transthoracic echocardiography. The primary outcome was regional functional recovery. Results Forty participants underwent baseline physiology, LGE-CMR and thirty had echocardiography at baseline and 6 months; 21/42 territories demonstrated functional recovery. Resting backward compression wave energy was significantly greater in recovering than non-recovering territories (−5240±3772 vs. −1873±1605 W m–2 s–1, p=0.099, Figure 1), and had comparable diagnostic accuracy to CMR (area under the curve 0.812 vs. 0.757, p=0.649, Figure 2); a threshold of −2500 W mm–2 s–1 had 86% sensitivity and 76% specificity at predicting recovery. Backward expansion wave energy did not predict recovery. FFR was numerically higher in recovering territories (0.81±0.17 vs. 0.71±0.16, p=0.058), whilst hyperaemic microvascular resistance did not differentiate recovering from non-recovering territories (1.97±0.73 vs. 2.29±1.00, p=0.287). The likelihood of functional recovery was similar in revascularised and non-revascularised territories (15/29 vs. 6/13 respectively, p=0.739). Low-dose dobutamine stress increased the energy of all waves, but did not improve the accuracy of cWIA in predicting recovery. In a regression model, resting backward compression wave energy and optimization of medical therapy predicted functional recovery; fractional flow reserve and hyperemic microvascular resistance did not. Conclusions Backward compression wave energy has similar accuracy to LGE-CMR in the prediction of functional recovery. cWIA has the potential to revolutionise the management of ischaemic left ventricular dysfunction, in a manner analogous to the effect of fractional flow reserve on the management of stable angina. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The British Heart Foundation Clinical Research Training Fellowship

Sex-differences in prevalence and outcomes of the different endotypes of chronic coronary syndrome – analysis from the multi-center international ILIAS Registry

Abstract Introduction Guideline-directed management of chronic coronary syndrome (CCS) remains focused on obstructive causes of angina, and is based on established therapies derived from studies predominantly including men. This occurs despite documented higher mortality from cardiovascular causes in women compared to men, which is hypothesized to be related to a higher prevalence of coronary microvascular dysfunction (CMD) in women. However, data on the relationship between sex, the different endotypes of CCS, and related sex-specific clinical outcomes are limited. Purpose This study aimed to investigate the relationship between sex and the different endotypes of CCS, as well as sex-specific clinical outcomes of CCS endotypes. Method In patients with stable angina undergoing coronary angiography, the following invasive coronary hemodynamics were characterized: fractional flow reserve (FFR; &amp;lt;0.80 considered abnormal), coronary flow reserve (CFR; &amp;lt;2.0 considered abnormal) and microcirculatory resistance (MR) (hyperemic microvascular resistance; &amp;gt;2.5mmHg/cm/sec or index of microvascular resistance &amp;gt;25 considered abnormal). Patients were stratified into three groups: 1) hemodynamically significant obstructive coronary artery disease (oCAD) (FFR abnormal or a severe coronary stenosis requiring revascularization), 2) no-obstructive coronary artery disease but with CMD (FFR normal, but abnormal CFR and/or MR), or 3) no-obstructive coronary artery disease and no CMD (FFR normal, and normal CFR and MR). We assessed the prevalence of the CCS endotypes across sex, and sex-specific cardiovascular outcomes over a follow-up of 7 years defined as the composite endpoint of death or acute myocardial infarction. Results Amongst a total of 1987 included patients, 1435 (72.2%) were men and 552 (27.8%) were women. oCAD occurred in 904 (45.5%) patients, which was significantly more prevalent in men (48.9% (701/1435) of men vs. 36.8% (203/552) of women, p&amp;lt;0.001). In contrast, CMD was significantly more prevalent in women (19.6% (281/1435) of men vs. 24.1% (133/552) of women, p=0.031). Across the population, either oCAD or CMD occurred in 68.4% of men versus 60.9% of women (p=0.002). There were no sex-specific differences in cardiovascular outcomes across CCS entities (Figure 1). Conclusion In patients evaluated for CCS who underwent clinically indicated coronary angiography and physiological assessment, men were more likely to have oCAD and women were more likely to be classified as CMD. There were no sex-related differences in the prognosis associated with the individual CCS endotypes. Therefore, pathophysiological changes in the coronary circulation potentially underlying angina pectoris are similarly prevalent in men and women, but the high incidence of CMD in women makes women prone to underdiagnosis if no additional physiological measurements are assessed. Funding Acknowledgement Type of funding sources: None.

Reference values for intracoronary Doppler flow velocity-derived hyperaemic microvascular resistance index

BackgroundInvasive assessments of microvascular function are rapidly becoming an integral part of physiological assessment in chronic coronary syndromes. ObjectiveWe aimed to establish a reference range for Doppler flow velocity-derived hyperaemic microvascular resistance index (HMR) in a cohort of angina with no significant epicardial coronary obstruction (ANOCA) patients with no structural pathophysiological alterations in the coronary circulation. MethodsThe reference population consisted of ANOCA patients undergoing invasive coronary vasomotor function assessment who had a coronary flow reserve (CFR) >2.5, and had either (1) tested negatively for spasm provocation (n = 12) or (2) tested positively with only angina at rest (n = 29). A reference range for HMR was established using a non-parametric method and correlations with clinical characteristics were determined using a spearman rank correlation analysis. ResultsIn 41 patients median HMR amounted to 1.6 mmHg/cm/s [Q1, Q3: 1.3, 2.2 mmHg/cm/s]. The reference range for HMR that is applicable to 95% of the population was 0.8 mmHg/cm/s (90% CI: 0.8–1.0 mmHg/cm/s) to 2.7 mmHg/cm/s (90% CI: 2.6–2.7 mmHg/cm/s). No significant correlations were found between HMR and clinical characteristics. ConclusionIn this reference population undergoing invasive coronary vasomotor function testing, the 90% confidence interval of the HMR upper limit of normal ranges from 2.6 to 2.7 mmHg/cm/s. A > 2.5 mmHg/cm/s HMR threshold can be used to identify abnormal microvascular resistance in daily clinical practice.

Presence of Coronary Endothelial Dysfunction, Coronary Vasospasm, and Adenosine-Mediated Vasodilatory Disorders in Patients With Ischemia and Nonobstructive Coronary Arteries.

Coronary function testing in patients with ischemia and nonobstructive coronary arteries (INOCA) commonly includes assessment of adenosine-mediated vasodilation and acetylcholine spasm provocation. The purpose of this study was to evaluate the diagnostic value of additional endothelial function testing for the diagnosis of vasomotor dysfunction in patients with INOCA. In this retrospective cohort study, we included patients with INOCA who underwent clinically indicated comprehensive coronary function testing. Endothelial dysfunction was defined as a <50% increase in coronary blood flow, determined by Doppler flow, and/or epicardial vasoconstriction compared to baseline, in response to low-dose acetylcholine. Coronary artery spasm (CAS) was defined as vasospastic angina or microvascular angina in response to coronary high-dose acetylcholine. An impaired adenosine-mediated vasodilation was defined as a coronary flow reserve <2.5 and/or hyperemic microvascular resistance ≥2.5. Among all 110 patients, 79% had endothelial dysfunction, 62% had CAS, and 29% had an impaired adenosine-mediated vasodilation. Endothelial dysfunction was present in 80% of patients who tested positively for CAS and/or an impaired adenosine-mediated vasodilation. Endothelial function testing increases the diagnostic yield of coronary function testing that only incorporates adenosine testing and spasm provocation by 17% to 92%. Of patients with normal adenosine-mediated vasodilation and no inducible CAS, 68% had endothelial dysfunction. Concomitant endothelial dysfunction was prevalent in the vast majority of patients with INOCA with inducible CAS and/or an impaired adenosine-mediated vasodilation. In patients with INOCA without inducible CAS and normal adenosine-mediated vasodilation, two-thirds had endothelial dysfunction. These results indicate the relevance to perform endothelial function testing in patients with INOCA in view of its therapeutic implication.

Coronary Flow Evaluation in Heart Transplant Patients Compared to Healthy Controls Documents the Superiority of Coronary Flow Velocity Reserve Companion as Diagnostic and Prognostic Tool.

BackgroundDistinct contributions by functional or structural alterations of coronary microcirculation in heart transplantation (HT) and their prognostic role have not been fully elucidated. We aimed to identify the mechanisms of coronary microvascular dysfunction (CMD) in HT and their prognostic implications.Methods134 patients, surviving at least 5 years after HT, without evidence of angiographic vasculopathy or symptoms/signs of rejection were included. 50 healthy volunteers served as controls. All underwent the assessment of rest and hyperemic coronary diastolic peak flow velocity (DPVr and DPVh) and coronary flow velocity reserve (CFVR) and its inherent companion that is based on the adjusted quadratic mean: CCFVR = √{(DPVr)2 + (DPVh)2}. Additionally, basal and hyperemic coronary microvascular resistance (BMR and HMR) were estimated.ResultsBased on CFVR and DPVh, HT patients can be assigned to four endotypes: endotype 1, discordant with preserved CFVR (3.1 ± 0.4); endotype 2, concordant with preserved CFVR (3.4 ± 0.5); endotype 3, concordant with impaired CFVR (1.8 ± 0.3) and endotype 4, discordant with impaired CFVR (2.0 ± 0.2). Intriguingly, endotype 1 showed lower DPVr (p < 0.0001) and lower DPVh (p < 0.0001) than controls with lower CFVR (p < 0.0001) and lower CCFVR (p < 0.0001) than controls. Moreover, both BMR and HMR were higher in endotype 1 than in controls (p = 0.001 and p < 0.0001, respectively), suggesting structural microvascular remodeling. Conversely, endotype 2 was comparable to controls. A 13/32 (41%) patients in endotype 1 died in a follow up of 28 years and mortality rate was comparable to endotype 3 (14/31, 45%). However, CCFVR was < 80 cm/s in all 13 deaths of endotype 1 (characterized by preserved CFVR). At multivariable analysis, CMD, DPVh < 75 cm/s and CCFVR < 80 cm/s were independent predictors of mortality. The inclusion of CCFVR < 80 cm/s to models with clinical indicators of mortality better predicted survival, compared to only adding CMD or DPVh < 75 cm/s (p < 0.0001 and p = 0.03, respectively).ConclusionA normal CFVR could hide detection of microvasculopathy with high flow resistance and low flow velocities at rest. This microvasculopathy seems to be secondary to factors unrelated to HT (less rejections and more often diabetes). The combined use of CFVR and CCFVR provides more complete clinical and prognostic information on coronary microvasculopathy in HT.

Automation of intracoronary continuous thermodilution for absolute coronary flow and microvascular resistance measurements.

Microvascular resistance reserve (MRR) as derived from continuous intracoronary thermodilution specifically quantifies microvasculature function. As originally described, the technique necessitates reinstrumentation of the artery and manual reprogramming of the infusion pump when performing resting and hyperemic measurements. To simplify and to render this procedure operator-independent, we developed a fully automated method. The aim of the present study is to validate the automated procedure against the originally described one. For the automated procedure, an infusion pump was preprogrammed to allow paired resting-hyperemic thermodilution assessment without interruption. To validate the accuracy of this new approach, 20automated measurements were compared to those obtained in the same vessels with conventional paired resting-hyperemic thermodilution measurements (i.e., with a sensor pullback at each infusion rate and manual reprogramming of the infusion pump). A close correlation between the conventional and the automated measuring technique was found for resting flow (Qrest : r = 0.89, mean bias = 2.52; SD = 15.47), hyperemic flow (Qhyper : r = 0.88, mean bias = -2.65; SD = 27.96), resting microvascular resistance (Rμ-rest : r = 0.90, mean bias = 52.14; SD = 228.29), hyperemic microvascular resistance Rμ-hyper : r = 0.92, mean bias = 12.95; SD = 57.80), and MRR (MRR: r = 0.89, mean bias = 0.04, SD = 0.59). Procedural time was significantly shorter with the automated method (5'25″ ± 1'23″vs. 4'36″ ± 0'33″, p = 0.013). Continuous intracoronary thermodilution-derived measurements of absolute flow, absolute resistance, and MRR can be fully automated. This further shortens and simplifies the procedure when performing paired resting-hyperemic measurements.

Prognostic significance of severe coronary microvascular dysfunction post-PCI in patients with STEMI: A systematic review and meta-analysis.

Coronary microvascular dysfunction (CMVD) is common and associated with poorer outcomes in patients with ST Segment Elevation Myocardial Infarction (STEMI). The index of microcirculatory resistance (IMR) and the index of hyperemic microvascular resistance (HMR) are both invasive indexes of microvascular resistance proposed for the diagnosis of severe CMVD after primary percutaneous coronary intervention (pPCI). However, these indexes are not routinely assessed in STEMI patients. Our main objective was to clarify the association between IMR or HMR and long-term major adverse cardiovascular events (MACE), through a systematic review and meta-analysis of observational studies. We searched Medline, PubMed, and Google Scholar for studies published in English until December 2020. The primary outcome was a composite of cardiovascular death, non-cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and rehospitalization for heart failure occurring after at least 6 months following CMVD assessment. We identified 6 studies, reporting outcomes in 1094 patients (mean age 59.7 ± 11.4 years; 18.2% of patients were women) followed-up from 6 months to 7 years. Severe CMVD, defined as IMR > 40 mmHg or HMR > 3mmHg/cm/sec was associated with MACE with a pooled HR of 3.42 [2.45; 4.79]. Severe CMVD is associated with an increased risk of long-term adverse cardiovascular events in patients with STEMI. Our results suggest that IMR and HMR are useful for the early identification of severe CMVD in patients with STEMI after PCI, and represent powerful prognostic assessments as well as new therapeutic targets for clinical intervention.

Gradual Versus Abrupt Reperfusion During Primary Percutaneous Coronary Interventions in ST-Segment-Elevation Myocardial Infarction (GUARD).

BackgroundIntramyocardial edema and hemorrhage are key pathological mechanisms in the development of reperfusion‐related microvascular damage in ST‐segment–elevation myocardial infarction. These processes may be facilitated by abrupt restoration of intracoronary pressure and flow triggered by primary percutaneous coronary intervention. We investigated whether pressure‐controlled reperfusion via gradual reopening of the infarct‐related artery may limit microvascular injury in patients undergoing primary percutaneous coronary intervention.Methods and ResultsA total of 83 patients with ST‐segment–elevation myocardial infarction were assessed for eligibility and 53 who did not meet inclusion criteria were excluded. The remaining 30 patients with totally occluded infarct‐related artery were randomized to the pressure‐controlled reperfusion with delayed stenting (PCRDS) group (n=15) or standard primary percutaneous coronary intervention with immediate stenting (IS) group (n=15) (intention‐to‐treat population). Data from 5 patients in each arm were unsuitable to be included in the final analysis. Finally, 20 patients undergoing primary percutaneous coronary intervention who were randomly assigned to either IS (n=10) or PCRDS (n=10) were included. In the PCRDS arm, a 1.5‐mm balloon was used to achieve initial reperfusion with thrombolysis in myocardial infarction grade 3 flow and, subsequently, to control distal intracoronary pressure over a 30‐minute monitoring period (MP) until stenting was performed. In both study groups, continuous assessment of coronary hemodynamics with intracoronary pressure and Doppler flow velocity was performed, with a final measurement of zero flow pressure (primary end point of the study) at the end of a 60‐minute MP. There were no complications associated with IS or PCRDS. PCRDS effectively led to lower distal intracoronary pressures than IS over 30 minutes after reperfusion (71.2±9.37 mm Hg versus 90.13±12.09 mm Hg, P=0.001). Significant differences were noted between study arms in the microcirculatory response over MP. Microvascular perfusion progressively deteriorated in the IS group and at the end of MP, and hyperemic microvascular resistance was significantly higher in the IS arm as compared with the PCDRS arm (2.83±0.56 mm Hg.s.cm−1 versus 1.83±0.53 mm Hg.s.cm−1, P=0.001). The primary end point (zero flow pressure) was significantly lower in the PCRDS group than in the IS group (41.46±17.85 mm Hg versus 76.87±21.34 mm Hg, P=0.001). In the whole study group (n=20), reperfusion pressures measured at predefined stages in the early reperfusion period showed robust associations with zero flow pressure values measured at the end of the 1‐hour MP (immediately after reperfusion: r=0.782, P<0.001; at the 10th minute: r=0.796, P<0.001; and at the 20th minute: r=0.702, P=0.001) and peak creatine kinase MB level (immediately after reperfusion: r=0.653, P=0.002; at the 10th minute: r=0.597, P=0.007; and at the 20th minute: r=0.538, P=0.017). Enzymatic myocardial infarction size was lower in the PCRDS group than in the IS group with peak troponin T (5395±2991 ng/mL versus 8874±1927 ng/mL, P=0.006) and creatine kinase MB (163.6±93.4 IU/L versus 542.2±227.4 IU/L, P<0.001).ConclusionsIn patients with ST‐segment–elevation myocardial infarction, pressure‐controlled reperfusion of the culprit vessel by means of gradual reopening of the occluded infarct‐related artery (PCRDS) led to better‐preserved coronary microvascular integrity and smaller myocardial infarction size, without an increase in procedural complications, compared with IS.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT02732080.

Comparison of Doppler Flow Velocity and Thermodilution Derived Indexes of Coronary Physiology.

ObjectivesThe aim of this study was to compare Doppler flow velocity and thermodilution-derived indexes and to determine the optimal thermodilution-based diagnostic thresholds for coronary flow reserve (CFR).BackgroundThe majority of clinical data and diagnostic thresholds for flow-based indexes are derived from Doppler measurements, and correspondence with thermodilution-derived indices remain unclear.MethodsAn international multicenter registry was conducted among patients who had coronary flow measurements using both Doppler and thermodilution techniques in the same vessel and during the same procedure.ResultsPhysiological data from 250 vessels (in 149 patients) were included in the study. A modest correlation was found between thermodilution-derived CFR (CFRthermo) and Doppler-derived CFR (CFRDoppler) (r2 = 0.36; P < 0.0001). CFRthermo overestimated CFRDoppler (mean 2.59 ± 1.46 vs 2.05 ± 0.89; P < 0.0001; mean bias 0.59 ± 1.24 by Bland-Altman analysis), the relationship being described by the equation CFRthermo = 1.04 × CFRDoppler + 0.50. The commonly used dichotomous CFRthermo threshold of 2.0 had poor sensitivity at predicting a CFRDoppler value <2.5. The optimal CFRthermo threshold was 2.5 (sensitivity 75.54%, specificity 81.25%). There was only a weak correlation between hyperemic microvascular resistance and index of microvascular resistance (r2 = 0.19; P < 0.0001), due largely to variation in the measurement of flow by each modality. Forty-four percent of patients were discordantly classified as having abnormal microvascular resistance by hyperemic microvascular resistance (≥2.5 mm Hg · cm−1 · s) and index of microvascular resistance (≥25).ConclusionsCFR calculated by thermodilution overestimates Doppler-derived CFR, while both parameters show modest correlation. The commonly used CFRthermo threshold of 2.0 has poor sensitivity for identifying vessels with diminished CFR, but using the same binary diagnostic threshold as for Doppler (<2.5) yields reasonable diagnostic accuracy. There was only a weak correlation between microvascular resistance indexes assessed by the 2 modalities.