Microvascular resistance reserve: impact on health status and myocardial perfusion after revascularization in chronic coronary syndrome.

BACKGROUND AND AIMS: The microvascular resistance reserve (MRR) is a novel invasive index of the microcirculation, which is independent of epicardial stenoses, and MRR has both diagnostic and prognostic implications. This study investigates whether MRR is associated with health status outcomes by revascularization in patients with moderate coronary stenoses. METHODS: Consecutive patients with stable chest pain and moderate (30-90% diameter) stenoses on invasive coronary angiography (n=222) underwent invasive physiology assessment. Revascularization was performed by guideline recommendations. At baseline and follow-up, health status and myocardial perfusion were assessed by Seattle Angina Questionnaire (SAQ) and positron emission tomography. The primary endpoint was freedom from angina at follow-up with secondary endpoints including changes in health status by SAQ domains and myocardial perfusion by MRR and revascularization status. Low MRR was defined as ≤3.0. RESULTS: Freedom from angina occurred in 38/173 patients. In multivariate analyses, MRR was associated with freedom from angina at follow-up (odds ratio 0.860, 95% confidence interval 0.740-0.987). By MRR and revascularization groups, patients with normal MRR who did not undergo revascularization, and patients with abnormal MRR who underwent revascularization, improved health status of angina frequency (mean difference SAQ angina frequency score 8.5 [3.07-13.11] and 13.5 [2.82-23.16], respectively). For both groups, health status of physical limitation (mean difference in SAQ physical limitation score 9.7 [4.79-11.93] and 8.7 [0.53-13.88], respectively) and general health status (mean difference in SAQ summary score 9.3 [5.18-12.50] and 10.8 [2.51-17.28], respectively) also improved. Only patients with abnormal MRR who underwent revascularization improved myocardial perfusion. CONCLUSIONS: In patients with moderate coronary stenoses, MRR seems to predict symptomatic and perfusion benefit of revascularization.

The pressure-derived microvascular resistance reserve and its correlation to Doppler MRR measurement-a proof of concept study.

Background: Microvascular resistance reserve (MRR) is a recently introduced specific index of coronary microcirculation. MRR calculation can utilize parameters deriving from coronary flow reserve (CFR) assessment, provided that intracoronary pressure data are also available. The previously proposed pressure-bounded CFR (CFRpb) defines the possible CFR interval on the basis of resting and hyperemic pressure gradients in the epicardial vessel, however, its correlation to the Doppler wire measurement was reported to be rather poor without the correction for hydrostatic pressure. Purpose: We aimed to determine the pressure-bounded coronary MRR interval with hydrostatic pressure correction according to the previously established equations of CFRpb adapted for the MRR concept. Furthermore, we also aimed to design a prediction model using the actual MRR value within the pressure-bounded interval and validate the results against the gold-standard Doppler wire technique. Methods: Hydrostatic pressure between the tip of the catheter and the sensor of the pressure wire was calculated by height difference measurement from a lateral angiographic view. In the derivation cohort the pressure-bounded MRR interval (between MRRpbmin and MRRpbmax) was determined solely from hydrostatic pressure-corrected intracoronary pressure data. The actual MRR was calculated by simple hemodynamic equations incorporating the anatomical data of the three-dimensionally reconstructed coronary artery (MRRp-3D). These results were analyzed by regression analyses to find relations between the MRRpb bounds and the actual MRRp-3D. Results: In the derivation cohort of 23 measurements, linear regression analysis showed a tight relation between MRRpbmax and MRRp-3D (r 2 = 0.74, p < 0.0001). Using this relation (MRRp-3D = 1.04 + 0.51 × MRRpbmax), the linear prediction of the MRR was tested in the validation cohort of 19 measurements against the gold standard Doppler wire technique. A significant correlation was found between the linearly predicted and the measured values (r = 0.54, p = 0.01). If the area stenosis (AS%) was included to a quadratic prediction model, the correlation was improved (r = 0.63, p = 0.004). Conclusions: The MRR can be predicted reliably to assess microvascular function by our simple model. After the correction for hydrostatic pressure error, the pressure data during routine FFR measurement provides a simultaneous physiological assessment of the macro- and microvasculature.

The Influence of Epicardial Resistance on Microvascular Resistance Reserve.

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. OBJECTIVES: The 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. METHODS: In 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. 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 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). CONCLUSIONS: MRR, 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.

The Impact of Microvascular Resistance Reserve on the Outcome of Patients With STEMI.

BACKGROUND: Microvascular resistance reserve (MRR) can characterize coronary microvascular dysfunction (CMD); however, its prognostic impact in ST-segment elevation myocardial infarction (STEMI) patients remains undefined. OBJECTIVES: This study sought to investigate the prevalence of CMD in STEMI patients and to elucidate the prognostic performance of MRR. METHODS: This prospective cohort study enrolled 210 STEMI patients with multivessel disease who underwent successful revascularization and returned at 3 months for coronary physiology assessments with bolus thermodilution. The prevalence of CMD (MRR <3) and the association between MRR and major adverse cardiovascular and cerebrovascular events (MACCEs) at 12 months were investigated. RESULTS: The median age of patients was 65 years, and 59.5% were men. At the 3-month follow-up, 56 patients (27%) had CMD (MRR <3.0). The number of MACCEs at 12 months was higher in patients with vs without CMD (48.2% vs 11.0%; P < 0.001). MRR was independently associated with 12-month MACCEs (HR: 0.45 per unit increase; 95% CI: 0.31-0.67; P < 0.001) and with stroke, heart failure, and poorer recovery in left ventricular systolic function. The areas under the receiver-operating characteristic curves for predicting MACCEs at 12 months with fractional flow reserve, coronary flow reserve (CFR), the index of microvascular resistance (IMR), and MRR were 0.609, 0.762, 0.781, and 0.743, respectively. The prognostic performance of CFR, IMR, and MRR were all comparable. CONCLUSIONS: The novel parameter MRR is a prognostic marker of MACCEs in STEMI patients with a comparable performance to CFR and IMR. (Impact of TMAO Serum Levels on Hyperemic IMR in STEMI Patients [TAMIR]; NCT05406297).

Prognostic Implications of Microvascular Resistance Reserve in Symptomatic Patients With Intermediate Coronary Stenosis.

BACKGROUND: Microvascular resistance reserve (MRR) is a novel index reflecting coronary microcirculatory function, irrespective of epicardial coronary artery stenosis. There is limited evidence regarding whether MRR can be an independent prognostic tool in patients with stable ischemic heart disease (IHD). OBJECTIVES: The aim of this study was to evaluate clinical outcomes according to MRR in patients with stable IHD accompanied with or without significant epicardial coronary artery stenosis. METHODS: The present study included 547 consecutive patients undergoing systematic echocardiographic and invasive physiological assessment for suspected stable IHD. Significant epicardial coronary artery stenosis was defined as fractional flow reserve (FFR) ≤0.80. Coronary microvascular dysfunction (CMD) was defined as MRR ≤3.0. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure. RESULTS: Among the study group, 172 patients (31.4%) had FFR ≤0.80, and 200 patients (36.6%) had CMD defined by MRR ≤3.0. MRR showed no significant correlation with FFR (R = -0.031; P = 0.469), but it was significantly correlated with the index of microcirculatory resistance (R = -0.353; P < 0.001), N-terminal pro-B-type natriuretic peptide (R = -0.296; P < 0.001), left ventricular filling pressure (E/e' ratio) (R = -0.224; P < 0.001), and diastolic dysfunction grade (P < 0.001). During a median follow-up period of 3.3 years (Q1-Q3: 2.0-4.5 years), MRR was significantly associated with MACE risk (HR: 1.23 per 1-U decrease; 95% CI: 1.12-1.36; P < 0.001). CMD defined by MRR ≤3.0 was associated with an increased MACE risk for both FFR >0.80 (41.0% vs 26.0%; adjusted HR: 1.59; 95% CI: 1.07-2.35; P = 0.021) and FFR ≤0.80 (34.7% vs 14.8%; adjusted HR: 2.32; 95% CI: 1.12-4.82; P = 0.024). CONCLUSIONS: Decreased MRR was associated with the presence of cardiac diastolic dysfunction as well as increased left ventricular filling pressure. The presence of CMD defined by MRR was independently associated with the risk for a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure in patients with stable IHD, irrespective of significant epicardial coronary artery stenosis. (Prognostic Impact of Cardiac Diastolic Function and Coronary Microvascular Function [DIAST-CMD]; NCT05058833).

Measuring Absolute Coronary Flow and Microvascular Resistance by Thermodilution: JACC Review Topic of the Week.

Diagnosing coronary microvascular dysfunction remains challenging, primarily due to the lack of direct measurements of absolute coronary blood flow (Q) and microvascular resistance (Rµ). However, there has been recent progress with the development and validation of continuous intracoronary thermodilution, which offers a simplified and validated approach for clinical use. This technique enables direct quantification of Q and Rµ, leading to precise and accurate evaluation of the coronary microcirculation. To ensure consistent and reliable results, it is crucial to follow a standardized protocol when performing continuous intracoronary thermodilution measurements. This document aims to summarize the principles of thermodilution-derived absolute coronary flow measurements and propose a standardized method for conducting these assessments. The proposed standardization serves as a guide to ensure the best practice of the method, enhancing the clinical assessment of the coronary microcirculation.

Comprehensive invasive evaluation of coronary microcirculation in patients with Takotsubo syndrome.

BACKGROUND AND AIMS: The etiology and pathophysiology of Takotsubo syndrome (TTS) remain a matter of debate. In murine models of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion led to the development of TTS. Importantly, TTS was reversible when normal perfusion was restored. However, in clinical practice, the assessment of coronary microcirculation in patients with TTS has primarily relied on non-invasive or indirect, angiography-derived methods. METHODS AND RESULTS: For the first time, we performed invasive microcirculatory assessment, by both validated techniques currently available in the catheterization laboratory, namely intracoronary bolus and continuous thermodilution, in patients with TTS, upon hospital admission and at short term follow-up. Our findings demonstrate that CMD was consistently present in all patients upon hospital admission, as assessed by both techniques. At a median follow-up of 3 months, after the recovery of left ventricular ejection fraction, two third of patients no longer exhibited CMD. CONCLUSIONS: These findings support the hypothesis that an acute and transient worsening in coronary microvascular function plays a pivotal role in the pathophysiology of TTS.

Microvascular resistance reserve: diagnostic and prognostic performance in the ILIAS registry.

AIMS: The microvascular resistance reserve (MRR) was introduced as a means to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting for the influence of concomitant epicardial disease and the impact of administration of potent vasodilators on aortic pressure. This study aimed to evaluate the diagnostic and prognostic performance of MRR. METHODS AND RESULTS: A total of 1481 patients with stable symptoms and a clinical indication for coronary angiography were included from the global ILIAS Registry. MRR was derived as a function of the coronary flow reserve (CFR) divided by the fractional flow reserve (FFR) and corrected for driving pressure. The median MRR was 2.97 [Q1-Q3: 2.32-3.86] and the overall relationship between MRR and CFR was good [correlation coefficient (Rs) = 0.88, P < 0.005]. The difference between CFR and MRR increased with decreasing FFR [coefficient of determination (R2) = 0.34; Coef.-2.88, 95% confidence interval (CI): -3.05--2.73; P < 0.005]. MRR was independently associated with major adverse cardiac events (MACE) at 5-year follow-up [hazard ratio (HR) 0.78; 95% CI 0.63-0.95; P = 0.024] and with target vessel failure (TVF) at 5-year follow-up (HR 0.83; 95% CI 0.76-0.97; P = 0.047). The optimal cut-off value of MRR was 3.0. Based on this cut-off value, only abnormal MRR was significantly associated with MACE and TVF at 5-year follow-up in vessels with functionally significant epicardial disease (FFR <0.75). CONCLUSION: MRR seems a robust indicator of the microvascular vasodilator reserve capacity. Moreover, in line with its theoretical background, this study suggests a diagnostic advantage of MRR over other indices of vasodilatory capacity in patients with hemodynamically significant epicardial coronary artery disease.

Factors Associated with Impaired Resistive Reserve Ratio and Microvascular Resistance Reserve.

Coronary microvascular dysfunction (CMD) is described as an important subset of ischemia with no obstructive coronary artery disease. Resistive reserve ratio (RRR) and microvascular resistance reserve (MRR) have been proposed as novel physiological indices evaluating coronary microvascular dilation function. The aim of this study was to explore factors associated with impaired RRR and MRR. Coronary physiological indices were invasively evaluated in the left anterior descending coronary artery using the thermodilution method in patients suspected of CMD. CMD was defined as a coronary flow reserve <2.0 and/or index of microcirculatory resistance ≥25. Of 117 patients, 26 (24.1%) had CMD. RRR (3.1 ± 1.9 vs. 6.2 ± 3.2, p < 0.001) and MRR (3.4 ± 1.9 vs. 6.9 ± 3.5, p < 0.001) were lower in the CMD group. In the receiver operating characteristic curve analysis, RRR (area under the curve 0.84, p < 0.001) and MRR (area under the curve 0.85, p < 0.001) were both predictive of the presence of CMD. In the multivariable analysis, previous myocardial infarction, lower hemoglobin, higher brain natriuretic peptide levels, and intracoronary nicorandil were identified as factors associated with lower RRR and MRR. In conclusion, the presence of previous myocardial infarction, anemia, and heart failure was associated with impaired coronary microvascular dilation function. RRR and MRR may be useful to identify patients with CMD.

Microvascular resistance reserve in the presence of functionally significant epicardial stenosis and changes after revascularization.

In the presence of functionally significant epicardial lesions, microvascular resistance reserve (MRR) calculation needs incorporation of collateral flow. Coronary fractional flow reserve (FFRcor ) requiring coronary wedge pressure (Pw ), which is an essential part of the true MRR calculation, is reportedly estimated by myocardial FFR (FFRmyo ) not requiring Pw measurement. We sought to find an equation to calculate MRR without the need for Pw . Furthermore, we assessed changes in MRR after percutaneous coronary intervention (PCI). An equation to estimate FFRcor was developed from a cohort of 230 patients who underwent physiological measurements and PCI. Corrected MRR was calculated using this equation and compared with true MRR in 115 patients of the different set of the validation cohort. True MRR was calculated using FFRcor . FFRcor and FFRmyo showed a strong linear relationship (r2  = 0.86) and an equation was FFRcor  = 1.36 × FFRmyo - 0.34. This equation provided no significant difference between corrected MRR and true MRR in the validation cohort. Pre-PCI lower coronary flow reserve and higher index of microcirculatory resistance were independent predictors of pre-PCI decreased true MRR. True MRR significantly decreased after PCI. In conclusion, MRR can be accurately corrected using an equation for FFRcor estimation without Pw .

Validation of pressure-bounded coronary flow reserve using invasive coronary physiologic assessment.

Coronary flow reserve (CFR) represents entire coronary compensatory capacity. While CFR assessment is recommended to identify patients at an increased risk of cardiovascular events and coronary microvascular dysfunction, invasive CFR measurement is often technically challenging. Although not well validated yet, pressure-bounded CFR (pbCFR) has been proposed as a simple surrogate to estimate impaired CFR. In this study, we evaluated coronary physiological characteristics of low pbCFR using detailed invasive assessment. Invasive physiological assessment including resting ratio of distal coronary pressure to aortic pressure (Pd/Pa), fractional flow reserve (FFR), resting and hyperemic mean transit time, index of microcirculatory resistance (IMR), CFR, resistive reserve ratio, and microvascular resistance reserve (MRR) was performed in 107 patients in the left anterior descending coronary artery. pbCFR was calculated only with resting Pd/Pa and FFR. Patients were divided into low pbCFR and non-low pbCFR groups. Of 107 patients, 50 (46.7%) had low pbCFR. FFR (0.90 ± 0.05 vs. 0.83 ± 0.05, p < 0.001), hyperemic mean transit time (0.27 ± 0.17 vs. 0.21 ± 0.12, p = 0.04), and IMR (20.4 ± 13.2 vs. 15.0 ± 9.1, p = 0.01) were significantly higher in the low pbCFR group than their counterpart. While directly measured CFR did not differ significantly (4.4 ± 2.3 vs. 5.1 ± 2.8, p = 0.18), MRR was lower in the low pbCFR group (5.4 ± 3.0 vs. 6.8 ± 3.8, p = 0.047). The rates of CFR < 2.0 and IMR ≥ 25 were not significantly different between the 2 groups. In conclusion, although CFR did not differ significantly, IMR and MRR were impaired in patients with low pbCFR, suggesting pbCFR as a potential surrogate of coronary microvascular function in clinical practice.

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

AIM: 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. METHODS AND RESULTS: 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, 20 automated 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). CONCLUSION: 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.

Pressure- and 3D-Derived Coronary Flow Reserve with Hydrostatic Pressure Correction: Comparison with Intracoronary Doppler Measurements.

Purpose: To develop a method of coronary flow reserve (CFR) calculation derived from three-dimensional (3D) coronary angiographic parameters and intracoronary pressure data during fractional flow reserve (FFR) measurement. Methods: Altogether 19 coronary arteries of 16 native and 3 stented vessels were reconstructed in 3D. The measured distal intracoronary pressures were corrected to the hydrostatic pressure based on the height differences between the levels of the vessel orifice and the sensor position. Classical fluid dynamic equations were applied to calculate the flow during the resting state and vasodilatation based on morphological data and intracoronary pressure values. 3D-derived coronary flow reserve (CFRp-3D) was defined as the ratio between the calculated hyperemic and the resting flow and was compared to the CFR values simultaneously measured by the Doppler sensor (CFRDoppler). Results: Haemodynamic calculations using the distal coronary pressures corrected for hydrostatic pressures showed a strong correlation between the individual CFRp-3D values and the CFRDoppler measurements (r = 0.89, p < 0.0001). Hydrostatic pressure correction increased the specificity of the method from 46.1% to 92.3% for predicting an abnormal CFRDoppler < 2. Conclusions: CFRp-3D calculation with hydrostatic pressure correction during FFR measurement facilitates a comprehensive hemodynamic assessment, supporting the complex evaluation of macro-and microvascular coronary artery disease.