Hyperemic Microvascular Resistance Research Articles

Coronary circulatory indices in non-infarct related vascular territories in a porcine acute myocardial infarction model

Abstract Background There has been debate on the reliability of fractional flow reserve (FFR) or resting pressure-derived indices in non-IRA of patients with acute ST-segment elevation myocardial infarction. Purpose This study aimed to evaluate temporal changes of coronary hemodynamic and physiologic indices in non-infarct related artery (non-IRA), which might be affected by adjacent infarcted myocardium, using an experimental animal model of acute myocardial infarction (AMI). Methods In Yorkshire swine, acute myocardial infarction was simulated with selective balloon occlusion at left circumflex artery (LCX) as IRA for 30 minutes. Non-IRA stenosis was created using bare metal stent implantation in left anterior descending artery (LAD) 4 weeks before the experiments. Serial changes of systemic hemodynamics, coronary pressure, and Doppler-derived coronary flow velocity were measured in a non-occluded LAD as non-IRA from baseline, balloon occlusion of LCX, and 15 minutes after reperfusion of LCX. Results Among the 6 experimental subjects, the median diameter stenosis of non-IRA was 33.9% (Q1-Q3: 21.7%-46.1%). During balloon occlusion of IRA, there were transient significant changes in both resting and hyperemic aortic pressure (Pa), distal coronary pressure (Pd), averaged peak velocity (APV), trans-stenotic pressure gradient (PG), and microvascular resistance of non-IRA (all P values<0.020). After reperfusion of IRA, the resting APV (P=0.002) and resting trans-stenotic PG (P=0.004) were significantly increased and resting microvascular resistance (P=0.004) was significantly decreased than those in baseline phase. However, the hyperemic APV (P=0.479), hyperemic trans-stenotic PG (P=0.778), and hyperemic microvascular resistance (P=0.816) were not significantly different compared with those in the baseline phase. After reperfusion, the FFR in non-IRA was not significantly different (0.94±0.01 vs. 0.93±0.01, P=0.353), while the CFR (1.93±0.07 vs. 1.36±0.07, P=0.025) and resting Pd/Pa (0.98±0.01 vs. 0.94±0.01, P=0.017) were significantly lower than baseline values. Conclusions In a porcine AMI model, occlusion of IRA induced significant changes of systemic hemodynamics and coronary circulatory indices of non-IRA. However, after reperfusion of IRA, FFR did not change significantly, while resting Summarizing Figure Funding Acknowledgement Type of funding source: Other. Main funding source(s): 1. Philips/Volcano, 2. Bio & Medical Technology Development Program of the National Research Foundation of the Korean government

Multiparametric evaluation of coronary flow predicts long-term outcome in heart transplantation: from coronary flow velocity reserve to its newly introduced companion

Abstract Background Coronary microvascular dysfunction (CMD) leads to a worse prognosis in heart transplantation (HT) patients. Coronary flow velocity reserve (CFVR) estimates the physiologic impact of allograft disease on the coronary circulation. Purpose Our aim was to determine the prognostic role of CFVR and its companion (CFVRC) on long-term survival of HT patients with a follow-up of 28 years. Methods 134 HT patients, surviving at least 5 years after HT, with normal systolic ventricular function and no evidence of angiographic allograft vasculopathy or symptoms/signs of rejection were included. The enrolled population underwent echocardiographic evaluation of microvascular function by the assessment of both the ratio of hyperemic to rest diastolic peak velocity (DPVh and DPVr). These measurements yield CFVR and its associated companion, defined as CFVRC = √{(DPVr)2 + (DPVh)2}, as well as basal and hyperemic coronary microvascular resistance (BMR and HMR). A CFVR≤2.5 was considered abnormal; the median value of DPVh (75 cm/s) and CFVRC (80 cm/s) were utilized to dichotomize the population. Results Based on CFVR and DPVh, HT patients can be assigned to four groups: group 1 (n=32), discordant with preserved CFVR (3.1±0.4); group 2 (n=60), concordant with preserved CFVR (3.4±0.5); group 3 (n=31), concordant with impaired CFVR (1.8±0.3) and group 4 (n=11), discordant with impaired CFVR (2.0±0.2). Survival for each patient group is presented in the Figure (panel A). Specifically, survival was similar in group 1 when compared to group 3 (p=0.8), but significantly lower when compared to group 2 (p=0.03). Therefore, a normal CFVR (>2.5) may not be able to predict the unfavourable long-term outcome. CFVR in fact is an incomplete dimensionless ratio; if the paired velocities are low with high BMR and HMR (group 1), the use of CFVR alone may miss some events, that are yet captured by CFVRC. Differences between survivors and no survivors are presented in the Table. At multivariable survival analysis, CMD, DPVh<75 cm/s, CFVRC<80 cm/s were independent predictors of mortality in HT patients. Consequently, we evaluated the added role of the CMD, DPVh<75 cm/s and CFVRC<80 cm/s to prognostic models including the clinical (Figure, panel B) predictors of mortality. The inclusion of CFVRC<80 cm/s to model with clinical predictors of mortality permitted better prediction of survival in HT patients, compared to only adding CMD or DPVh<75 cm/s. Conclusions This study is the first to demonstrate that the CFVR alone, even representing a determinant of survival in long-term HT patients, is not sufficient to completely predict long-term survival in HT patients. In comparison to CMD and DPVh, the CFVRC provides a significant improvement in survival prediction in long-term HT patients. Thus, the proposed multiparametric approach offers a more comprehensive evaluation of prognosis in HT patients, just by applying available data without the need to perform additional measurements. Funding Acknowledgement Type of funding source: None

Coronary flow evaluation in heart transplant patients compared to healthy controls documents the inadequacy of the coronary flow velocity reserve metric

Abstract Background Coronary microvasculopathy has impact on prognosis in heart transplantation (HT). Distinct contributions by functional or structural alterations of coronary microcirculation in HT and their prognostic role have not been fully elucidated. Purpose We aimed to identify the mechanisms of coronary microvascular impairment in HT and their possible prognostic implications by applying a comprehensive analysis in a comparative study. Methods Included were 134 patients, surviving at least 5 years, with normal systolic function and no evidence of allograft vasculopathy or symptoms/signs of rejection. To permit comparison, 50 healthy volunteers without cardiovascular diseases, and matched for age and sex, served as controls. All underwent echocardiographic evaluation of microvascular function by the assessment of rest and hyperemic diastolic peak blood velocity (DPVr and DPVh). These paired data enable calculation of coronary flow velocity reserve (CFVR) and its inherent companion that is based on the quadratic mean: CFVRC = √{(DPVr)2 + (DPVh)2}. Additionally, basal and hyperemic coronary microvascular resistance (BMR and HMR) were estimated. A CFVR ≤2.5 was considered abnormal; the median value of DPVh (75 cm/s) and CFVRC (80 cm/s) were selected as cut-offs to classify patients. Results HT patients can be assigned to four groups, based on their CFVR and DPVh (Figure A): group 1 (n=32), discordant with preserved CFVR (3.1±0.4); group 2 (n=60), concordant with preserved CFVR (3.4±0.5); group 3 (n=31), concordant with impaired CFVR (1.8±0.3) and group 4 (n=11), discordant with impaired CFVR (2.0±0.2). Group 3 represents the structural microvascular remodeling with high HMR, while group 4 represents the functional remodeling with low BMR. Intriguingly, group 1 showed lower DPVr (p<0.0001) and lower DPVh (p<0.0001) than controls (Figure B, upper panel) with lower CFVR (p<0.0001), even if normal, and lower CFVRC (p<0.0001) than controls (Figure B, lower panel). Moreover, both BMR and HMR were higher in group 1 than in controls (5.3±1 vs 4.4±1.2, p=0.001 and 1.5±0.3 vs 1.1±0.2, p<0.0001, respectively), suggesting structural microvascular remodeling. Conversely, group 2 was comparable with controls (Figure B). Clinical characteristics of the different groups are shown in the Table. 13/32 (40.6%) patients in group 1 died in a follow up of 28 years and mortality rate was comparable to group 3 (14/31, 45.2%). However, CFVRC was <80 cm/s in all 13 deaths in group 1, yet being characterized by preserved CFVR (Figure C). Conclusions A normal CFVR could hide detection of microvascular damage with high flow resistance and low flow velocities at rest. This microvasculopathy seems to be secondary to factors unrelated to HT (i.e., less rejections and more often diabetes). Being a dimensionless ratio, CFVR may miss some deaths, yet captured by CFVRC. Thus, the combined use of CFVR and CFVRC provides more complete clinical information on coronary microvasculopathy in HT. Funding Acknowledgement Type of funding source: None

TCT CONNECT-321 Prognostic Impact of Coronary Flow Reserve and Hyperemic Microvascular Resistance on Composite Major Adverse Cardiovascular Events

TCT CONNECT-321 Prognostic Impact of Coronary Flow Reserve and Hyperemic Microvascular Resistance on Composite Major Adverse Cardiovascular Events

Functional coronary angiography in symptomatic patients with no obstructive coronary artery disease.

Patients without obstructive coronary artery disease (CAD) may have epicardial or microvascular dysfunction. The purpose of this study was to characterize patterns of epicardial and microvascular dysfunction in men and women with stable and unstable angina undergoing functional coronary angiography to inform medical therapy. 163 symptomatic patients with ≤50% diameter stenosis and fractional flow reserve (FFR) > 0.8 underwent endothelium-dependent epicardial and microvascular function after intracoronary acetylcholine (10-4 M, 81 mcg over 3minutes). Endothelium-independent function was assessed using coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) after intravenous adenosine (140ug/kg/min). Coronary microvascular dysfunction (CMD) was defined as CFR < 2.5, HMR ≥2, or ≤50% change in coronary blood flow with acetylcholine (CBFACH ). Seventy-two percent had endothelial-dependent epicardial dysfunction (response to ACH: % ∆ in coronary artery diameter and ∆%CBFACH ) and 92% had CMD. Among CMD patients, 65% had CFR < 2.5, 35% had HMR ≥2, and 60% had CBFACH change ≤50%. CFR modestly correlated with HMR (r=-0.38, p < .0001). Among patients with normal CFR, 26% had abnormal epicardial and 20% had abnormal microvascular endothelial dysfunction. Women had a lower CFR (p=.02), higher FFR (p=.03) compared to men. There were no differences in epicardial and microvascular function between patients with stable and unstable angina. In patients with no obstructive CAD: CMD is prevalent, abnormal CFR does not correlate with epicardial or microvascular endothelial dysfunction, women have lower CFR, higher FFR but similar endothelial function compared to men.

Different Microcirculation Response Between Culprit and Non‐Culprit Vessels in Patients With Acute Coronary Syndrome

BackgroundThis study investigated whether the microvascular dysfunction differed between culprit and non‐culprit vessels in patients with acute coronary syndrome who underwent percutaneous coronary intervention.Methods and ResultsIn 115 prospectively recruited patients, after successful percutaneous coronary intervention, culprit and non‐culprit intracoronary hemodynamic measurements were performed and repeated at 6‐month follow‐up. 13N‐ammonia positron emission tomography was performed at 6‐month follow‐up visit to determine absolute myocardial blood flow. The resistance values of each vessel were calculated using the coronary pressure data and the myocardial blood flow values obtained from 13N‐ammonia positron emission tomography data. We compared the measurements between culprit and non‐culprit vessels and assessed changes in microvascular dysfunction during the study period. In 334 vessels (115 culprit and 219 non‐culprit), the culprit vessel group showed a lower fractional flow reserve and coronary flow reserve than the non‐culprit vessel group at baseline and 6‐month follow‐up, respectively. The value of index of microcirculatory resistance was different between the 2 groups in the baseline but not at 6‐month follow‐up. The microvascular resistance at rest and hyperemic microvascular resistance were not different between the 2 groups, but resistance to stenosis was higher in the culprit vessel group, under both resting and hyperemic status (P=0.02 and P<0.01, respectively). In the culprit vessel analysis, the fractional flow reserve and index of microcirculatory resistance decreased whereas coronary flow reserve increased (P<0.01 for all) at 6‐month follow‐up. However, there was no change in index of microcirculatory resistance, coronary flow reserve, and fractional flow reserve from baseline to 6‐month follow‐up in the non‐culprit vessel analysis.ConclusionsThe observed microvascular dysfunction in acute coronary syndrome is limited to the culprit vessel territory in the acute phase, which is relatively recovered in the chronic phase and there is no out‐of‐culprit territory involvement.RegistrationURL: https://www.clini​caltr​ials.gov; Unique identifier: NCT04169516.

Coronary Circulatory Indexes in Non-Infarct-Related Vascular Territories in a Porcine Acute Myocardial Infarction Model

ObjectivesThe aim of this study was to evaluate temporal changes in coronary hemodynamic and physiological indexes in the non-infarct-related artery (IRA), which might be affected by adjacent infarcted myocardium, using an experimental animal model of acute myocardial infarction. BackgroundThere has been debate on the reliability of fractional flow reserve and resting pressure-derived indexes, including instantaneous wave-free ratio, in the non-IRA in patients with acute ST-segment elevation myocardial infarction. MethodsIn Yorkshire swine, acute myocardial infarction was simulated with selective balloon occlusion at the left circumflex coronary artery as the IRA for 30 min. Non-IRA stenosis was created using bare-metal stent implantation in the left anterior descending coronary artery 4 weeks before the experiments. Serial changes in systemic hemodynamic status, coronary pressure, and Doppler-derived coronary flow velocity were measured in a nonoccluded left anterior descending coronary artery as the non-IRA from baseline, balloon occlusion of the left circumflex coronary artery, and 15 min after reperfusion of the left circumflex coronary artery. ResultsAmong the 6 experimental subjects, the median diameter stenosis of the non-IRA was 33.9% (interquartile range: 21.7% to 46.1%). During balloon occlusion of the IRA, there were transient significant changes in both resting and hyperemic aortic pressure, distal coronary pressure, averaged peak velocity, transstenotic pressure gradient, and microvascular resistance of the non-IRA (p < 0.020 for all). After reperfusion of the IRA, the resting averaged peak velocity (p = 0.002) and resting transstenotic pressure gradient (p = 0.004) were significantly increased and resting microvascular resistance (p = 0.004) was significantly decreased compared with their values in the baseline phase. However, the hyperemic averaged peak velocity (p = 0.479), hyperemic transstenotic pressure gradient (p = 0.778), and hyperemic microvascular resistance (p = 0.816) were not significantly different compared with those in the baseline phase. After reperfusion, fractional flow reserve in the non-IRA was not significantly different (0.94 ± 0.01 vs. 0.93 ± 0.01; p = 0.353), while coronary flow reserve (1.93 ± 0.07 vs. 1.36 ± 0.07; p = 0.025) and instantaneous wave-free ratio (0.97 ± 0.01 vs. 0.93 ± 0.01; p = 0.001) were significantly lower than baseline values. ConclusionsIn a porcine model of acute myocardial infarction, occlusion of the IRA induced significant changes in systemic hemodynamic status and coronary circulatory indexes of the non-IRA. However, after reperfusion of the IRA, fractional flow reserve did not change significantly, whereas coronary flow reserve and instantaneous wave-free ratio showed significant changes compared with baseline values.

Physiological Stratification of Patients With Angina Due to Coronary Microvascular Dysfunction

BackgroundCoronary microvascular dysfunction (CMD) is defined by diminished flow reserve. Functional and structural CMD endotypes have recently been described, with normal and elevated minimal microvascular resistance, respectively. ObjectivesThis study determined the mechanism of altered resting and maximal flow in CMD endotypes. MethodsA total of 86 patients with angina but no obstructive coronary disease underwent coronary pressure and flow measurement during rest, exercise, and adenosine-mediated hyperemia and were classified as the reference group or as patients with CMD by a coronary flow reserve threshold of 2.5; functional or structural endotypes were distinguished by a hyperemic microvascular resistance threshold of 2.5 mm Hg/cm/s. Endothelial function was assessed by forearm blood flow (FBF) response to acetylcholine, and nitric oxide synthase (NOS) activity was defined as the inverse of FBF reserve to NG-monomethyl-L-arginine. ResultsOf the 86 patients, 46 had CMD (28 functional, 18 structural), and 40 patients formed the reference group. Resting coronary blood flow (CBF) (24.6 ± 2.0 cm/s vs. 16.6 ± 3.9 cm/s vs. 15.1 ± 4.7 cm/s; p < 0.001) and NOS activity (2.27 ± 0.96 vs. 1.77 ± 0.59 vs. 1.30 ± 0.16; p < 0.001) were higher in the functional group compared with the structural CMD and reference groups, respectively. The structural group had lower acetylcholine FBF augmentation than the functional or reference group (2.1 ± 1.8 vs. 4.1 ± 1.7 vs. 4.5 ± 2.0; p < 0.001). On exercise, oxygen demand was highest (rate−pressure product: 22,157 ± 5,497 beats/min/mm Hg vs. 19,519 ± 4,653 beats/min/mm Hg vs. 17,530 ± 4,678 beats/min/mm Hg; p = 0.004), but peak CBF was lowest in patients with structural CMD compared with the functional and reference groups. ConclusionsFunctional CMD is characterized by elevated resting flow that is linked to enhanced NOS activity. Patients with structural CMD have endothelial dysfunction, which leads to diminished peak CBF augmentation and increased demand during exercise. The value of pathophysiologically stratified therapy warrants investigation.

Acute alterations in glucose homeostasis impact coronary microvascular function in patients presenting with ST-segment elevation myocardial infarction.

BackgroundMicrovascular dysfunction in the setting of ST-segment myocardial infarction (STEMI) is thought to be related to stress-related metabolic changes, including acute glucose intolerance. The aim of this study was to assess the relationship between admission glucose levels and microvascular function in non-diabetic STEMI patients.Methods92 consecutive patients with a first anterior-wall STEMI treated with primary percutaneous coronary intervention (PPCI) were enrolled. Blood glucose levels were determined immediately prior to PPCI. After successful PPCI, at 1‑week and 6‑month follow-up, Doppler flow was measured in culprit and reference coronary arteries to calculate coronary flow velocity reserve (CFVR), baseline (BMR) and hyperaemic (HMR) microvascular resistance.ResultsThe median admission glucose was 8.3 (7.2–9.6) mmol/l respectively 149.4 mg/dl [129.6–172.8] and was significantly associated with peak troponin T (standardised beta coefficient [std beta] = 0.281; p = 0.043). Multivariate analysis revealed that increasing glucose levels were significantly associated with a decrease in reference vessel CFVR (std beta = −0.313; p = 0.002), dictated by an increase in rest average peak velocity (APV) (std beta = 0.216; p = 0.033), due to a decreasing BMR (std beta = −0.225; p = 0.038) in the acute setting after PPCI. These associations disappeared at follow-up. These associations were not found for the infarct-related artery.ConclusionElevated admission glucose levels are associated with impaired microvascular function assessed directly after PPCI in first anterior-wall STEMI. This influence of glucose levels is an acute phenomenon and contributes to microvascular dysfunction through alterations in resting flow and baseline microvascular resistance.

Model-based analysis of the sensitivities and diagnostic implications of FFR and CFR under various pathological conditions.

Although fractional flow reserve (FFR) and coronary flow reserve (CFR) are both frequently used to assess the functional severity of coronary artery stenosis, discordant results of diagnosis between FFR and CFR in some patient cohorts have been reported. In the present study, a computational model was employed to quantify the impacts of various pathophysiological factors on FFR and CFR. In addition, a hyperemic myocardial ischemic index (HMIx) was proposed as a reference for comparing the diagnostic performances of FFR and CFR. Obtained results showed that CFR was more susceptible than FFR to the influence of many pathophysiological factors unrelated to coronary artery stenosis. In particular, the numerical study proved that increasing hyperemic coronary microvascular resistance significantly elevated FFR while reducing CFR despite fixed severity of coronary artery stenosis, whereas introducing aortic valve disease only caused a significant decrease in CFR with little influence on FFR. These results provided theoretical evidence for explaining some clinical observations, such as the increased risk of discordant diagnostic results between FFR and CFR in patients with increased hyperemic microvascular resistance, and significant increase in CFR after surgical relief of severe aortic valve disease. When evaluated with respect to the predictive value for hyperemic myocardial ischemia, the performance of FFR was found to be considerably compromised in the presence of severe coronary vasodilation dysfunction or aortic valve disease, whereas the relationship between CFR and HMIx remained relatively stable, suggesting that CFR may be a more reliable indicator of myocardial ischemia under complex pathophysiological conditions.

The Relationship of Capillary Blood Flow Assessments with Real Time Myocardial Perfusion Echocardiography to Invasively Derived Microvascular and Epicardial Assessments

The basis for abnormal microvascular flow responses to demand stress in coronary artery disease (CAD) is affected by resistance changes at both the epicardial stenosis level and within the downstream capillary network. We hypothesized that abnormal microvascular perfusion (MVP) responses during demand stress in patients with intermediate coronary stenoses occur when fractional flow reserve (FFR) across the epicardial stenosis is normal, because of increased microvascular resistance. In 49 coronary arteries of 41 patients with intermediate stenoses (40%-80%) who were referred for both coronary angiography and demand stress MVP assessment, invasive coronary hemodynamics were obtained across the stenosis to measure FFR, coronary flow reserve (CFR), and hyperemic microvascular resistance (HMR) during adenosine infusion. MVP in each coronary artery territory (CAT) during demand stress was evaluated by an independent expert reviewer blinded to clinical and angiographic data. Thirty-four of the 49 CATs with intermediate stenoses exhibited abnormal MVP. Although the sensitivity of MVP was high for detecting abnormal FFR (100%), FFR<0.8 was observed in only 15 of the 34 vessels that exhibited abnormal MVP (positive predictive value 44%). However, HMR was abnormal in 32 of 34 vessels (94%) with abnormal MVP (positive predictive value, 94%). Although abnormal MVP has high sensitivity for detecting abnormal FFR, MVP is frequently abnormal when FFR is normal. In a large percentage of these patients, invasive assessments of microvascular resistance are abnormal.

Temporal Changes in Coronary Hyperemic and Resting Hemodynamic Indices in Nonculprit Vessels of Patients With ST-Segment Elevation Myocardial Infarction

Percutaneous coronary intervention (PCI) of nonculprit vessels among patients with ST-segment elevation myocardial infarction (STEMI) is associated with improved clinical outcome compared with culprit vessel-only PCI. Fractional flow reserve (FFR) and coronary flow reserve are hyperemic indices used to guide revascularization. Recently, instantaneous wave-free ratio was introduced as a nonhyperemic alternative to FFR. Whether these indices can be used in the acute setting of STEMI continues to be investigated. To assess the value of hemodynamic indices in nonculprit vessels of patients with STEMI from the index event to 1-month follow-up. This substudy of the Reducing Micro Vascular Dysfunction in Revascularized STEMI Patients by Off-target Properties of Ticagrelor (REDUCE-MVI) randomized clinical trial enrolled 98 patients with STEMI who had an angiographic intermediate stenosis in at least 1 nonculprit vessel. Patient enrollment was between May 1, 2015, and September 19, 2017. After successful primary PCI, nonculprit intracoronary hemodynamic measurements were performed and repeated at 1-month follow-up. Cardiac magnetic resonance imaging was performed from 2 to 7 days and 1 month after primary PCI. The value of nonculprit instantaneous wave-free ratio, FFR, coronary flow reserve, hyperemic index of microcirculatory resistance, and resting microcirculatory resistance from the index event to 1-month follow-up. Of 73 patients with STEMI included in the final analysis, 59 (80.8%) were male, with a mean (SD) age of 60.8 (9.9) years. Instantaneous wave-free ratio (SD) did not change significantly (0.93 [0.07] vs 0.94 [0.06]; P = .12) and there was no change in resting distal pressure/aortic pressure (mean [SD], 0.94 [0.06] vs 0.95 [0.06]; P = .25) from the acute moment to 1-month follow-up. The FFR decreased (mean [SD], 0.88 [0.07] vs 0.86 [0.09]; P = .001) whereas coronary flow reserve increased (mean [SD], 2.9 [1.4] vs 4.1 [2.2]; P < .001). Hyperemic index of microcirculatory resistance decreased and resting microcirculatory resistance increased from the acute moment to follow-up. The decrease in distal pressure from rest to hyperemia was smaller at the acute moment vs follow-up (mean [SD], 10.6 [11.2] mm Hg vs 14.1 [14.2] mm Hg; P = .05). This blunted acute hyperemic response correlated with final infarct size (ρ, -0.29; P = .02). The resistive reserve ratio was lower at the acute moment vs follow-up (mean [SD], 3.4 [1.7] vs 5.0 [2.7]; P < .001). In the acute setting of STEMI, nonculprit coronary flow reserve was reduced and FFR was augmented, whereas instantaneous wave-free ratio was not altered. These results may be explained by an increased hyperemic microvascular resistance and a blunted adenosine responsiveness at the acute moment that was associated with infarct size.

Improvement of Fractional Flow Reserve after Percutaneous Coronary Intervention Does Not Necessarily Indicate Increased Coronary Flow.

Coronary flow is expected to increase by epicardial lesion modification after successful percutaneous coronary intervention (PCI) in stable angina. According to the concept of fractional flow reserve (FFR), the improvement in FFR after PCI reflects the extent of coronary flow increase. However, this theory assumes that hyperaemic microvascular resistance does not change after PCI, which is being refuted in recent studies. The authors quantitated regional absolute coronary blood flow (ABF) before and after PCI using a thermodilution method and compared it with FFR in 28 patients with stable coronary artery disease who had undergone successful PCI. Although FFR indicated changes in ABF, with a mean difference of -5.5 ml/min, there was no significant relationship between individual changes in FFR and in ABF (R=0.27, p=0.16). The discrepancy was partly explained by changes in microvascular resistance following PCI. These results suggest that changes in FFR do not necessarily indicate an increase in absolute coronary blood flow following PCI in individual patients, although they could be correlated in a cohort level.

Coronary flow reserve is related to the extension and transmurality of myocardial necrosis and predicts functional recovery after acute myocardial infarction

Few studies have examined the effect of transmurality of myocardial necrosis on coronary microcirculation. The aim of this study was to examine the influence of cardiac magnetic resonance-derived (GE-MRI) structural determinants of coronary flow reserve (CFR) after anterior myocardial infarction (STEMI), and their predictive value on regional functional recovery. Noninvasive CFR and GE-MRI were studied in 37 anterior STEMI patients after primary coronary angioplasty. The wall motion score index in the left descending anterior coronary artery territory (A-WMSI) was calculated at admission and follow-up (FU). Recovery of regional left ventricular (LV) function was defined as the difference in A-WMSI at admission and FU. The necrosis score index (NSI) and transmurality score index (TSI) by GE-MRI were calculated in the risk area. Baseline (BMR) and hyperemic (HMR) microvascular resistance, arteriolar resistance index (ARI), and coronary resistance reserve (CRR) were calculated at the Doppler echocardiography. Bivariate analysis indicated that the CPK and troponin I peak, heart rate, NSI, TSI, BMR, the ARI, and CRR were related to CFR. Multivariable analysis revealed that TSI was the only independent determinant of CFR. The CFR value of >2.27, identified as optimal by ROC analysis, was 77% specific and 73% sensitive with accuracy of 76% in identifying patients with functional recovery. Preservation of microvascular function after AMI is related to the extent of transmurality of myocardial necrosis, is an important factor influencing regional LV recovery, and can be monitored by noninvasive CFR.

Relationship between FFR, CFR and coronary microvascular resistance - Practical implications for FFR-guided percutaneous coronary intervention.

ObjectiveThe aim was threefold: 1) expound the independent physiological parameters that drive FFR, 2) elucidate contradictory conclusions between fractional flow reserve (FFR) and coronary flow reserve (CFR), and 3) highlight the need of both FFR and CFR in clinical decision making. Simple explicit theoretical models were supported by coronary data analyzed retrospectively.MethodologyFFR was expressed as a function of pressure loss coefficient, aortic pressure and hyperemic coronary microvascular resistance. The FFR-CFR relationship was also demonstrated mathematically and was shown to be exclusively dependent upon the coronary microvascular resistances. The equations were validated in a first series of 199 lesions whose pressures and distal velocities were monitored. A second dataset of 75 lesions with pre- and post-PCI measures of FFR and CFR was also analyzed to investigate the clinical impact of our hemodynamic reasoning.ResultsHyperemic coronary microvascular resistance and pressure loss coefficient had comparable impacts (45% and 49%) on FFR. There was a good concordance (y = 0.96 x − 0.02, r2 = 0.97) between measured CFR and CFR predicted by FFR and coronary resistances. In patients with CFR < 2 and CFR/FFR ≥ 2, post-PCI CFR was significantly >2 (p < 0.001), whereas it was not (p = 0.94) in patients with CFR < 2 and CFR/FFR < 2.ConclusionThe FFR behavior and FFR-CFR relationship are predictable from basic hemodynamics. Conflicting conclusions between FFR and CFR are explained from coronary vascular resistances. As confirmed by our results, FFR and CFR are complementary; they could jointly contribute to better PCI guidance through the CFR-to-FFR ratio in patients with coronary artery disease.

Pathophysiological Significance of Velocity-Based Microvascular Resistance at Maximal Hyperemia in Peripheral Artery Disease.

Aim: Maximal hyperemic response, leading to examination of microvascular resistance in lower-limb lesions is not well understood. This study aimed to investigate the infrainguinal arterial physiological response through a hyperemic condition and the pathophysiological significance of microvascular resistance in peripheral artery disease.Methods: Sixteen limbs with focal stenosis of the superficial femoral artery (SFA) and 16 control limbs were analyzed. We assessed the fractional flow reserve (FFR), vascular flow reserve (VFR), and hyperemic microvascular resistance (h-MR) of the SFA with a pressure/Doppler flow sensor-tipped combination guidewire before and after endovascular therapy (EVT). Skin perfusion pressure (SPP) on both the dorsal and the plantar sides of the foot was measured at baseline before and after the endovascular procedures.Results: FFR (p < 0.05) and VFR (p < 0.05), but not h-MR, improved after EVT. There was no association between h-MR and FFR or VFR before EVT. h-MR was negatively correlated with the dorsal SPP before EVT (r = −0.589, p < 0.05). h-MR in patients with high h-MR before EVT significantly decreased after EVT (p < 0.05). Patients with high, but not those with low, h-MR before EVT exhibited a significant increase in dorsal and plantar SPP after EVT (p < 0.05, each).Conclusion: EVT for SFA stenosis improved FFR and VFR comprehensively, with no apparent change in h-MR. However, high h-MR before EVT may play a predictive role for limb perfusion improvement associated with h-MR reduction after EVT.

Lower Circulating Omega-3 Polyunsaturated Fatty Acids Are Associated with Coronary Microvascular Dysfunction Evaluated by Hyperemic Microvascular Resistance in Patients with Stable Coronary Artery Disease.

The consumption of omega-3 polyunsaturated fatty acids (PUFAs) reduces the incidence of cardiovascular events and sudden cardiac death. Coronary microvascular dysfunction (CMD) is a predictor of cardiac mortality, but little information is known on the relationship between CMD and omega-3 PUFAs. This study aimed to identify the relationship between the serum levels of omega-3 PUFAs and the CMD evaluated by the hyperemic microvascular resistance index (hMVRI) to assess coronary microvascular function in patients with stable coronary artery disease (CAD).Intracoronary physiological variables (fractional flow reserve (FFR), hMVRI, mean distal coronary pressure (Pd), and average peak velocity (APV)) were measured in 108 patients. These parameters were evaluated in 150 coronary arteries with stenosis of intermediate severity and without significant ischemia (FFR > 0.80). The PUFA levels and atherosclerotic risk factors were also measured. Univariate analysis shows that hMVRI was negatively correlated with eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (β = -0.31, P = 0.001) and EPA (β = -0.25, P = 0.009) and was positively correlated with dihomo-γ-linolenic acid (β = 0.26, P = 0.006). Multivariate regression analysis shows that the EPA/AA ratio was the only independent determinant of hMVRI (β = -0.234, SE = 0.231, P = 0.024). Furthermore, hMVRI decreased significantly from the lowest to highest tertiles of the EPA/AA ratio (P = 0.007). The EPA/AA ratio was positively correlated with APV at hyperemia (β = 0.26, P = 0.008) but not with Pd at hyperemia.A lower serum EPA/AA ratio may cause CMD in patients with stable CAD.

Clinical and coronary haemodynamic determinants of recurrent chest pain in patients without obstructive coronary artery disease — A pilot study

BackgroundCoronary haemodynamic testing frequently identifies abnormal pathophysiological parameters in patients with angina and non-obstructed coronaries on angiography (NoCAD) but the clinical utility of these measures has received limited attention. ObjectiveThis study aims to identify the clinical and coronary haemodynamic determinants of recurrent chest pain at one month in patients with NoCAD. MethodsPatients with angina, NoCAD (<50% stenosis) and normal LV systolic function underwent invasive coronary haemodynamic testing involving: (1) angiographic TIMI frame and opacification rate, (2) microvascular functional measures including coronary flow reserve (CFR) and hyperaemic microvascular resistance (HMR), (3) coronary endothelial function assessment with low dose intracoronary acetylcholine (IC-ACh) infusions (0.18 μg/min & 1.8 μg/min over 2 min), and (4) Provocative spasm testing with high dose IC-ACh boluses (25, 50 and 100 μg). Clinical and health status were assessed at baseline and one month. ResultsIn the 49 NoCAD patients (78% female, mean age of 54 ± 11) undergoing comprehensive coronary haemodynamic testing, 33 (67%) continued to experience chest pain at one month. Determinants of recurrent chest pain on univariate analysis included baseline chest pain status or a HMR > 1.9. Multivariate logistic regression analysis identified frequent angina at baseline (OR: 68.9 [4.1, 1165.0], p = 0.003), previous unstable angina admission (OR: 43.9 [3.5, 547.9], p = 0.003) and a HMR > 1.9 (OR: 15.6 [2.1, 114.0], p = 0.007) as independent predictors of recurrent chest pain. ConclusionIn this small pilot study, an abnormal HMR was the only coronary haemodynamic parameter that was a determinant of ongoing angina at short-term follow-up.

Delineation of epicardial stenosis in patients with microvascular disease using pressure drop coefficient: A pilot outcome study.

AIMTo investigate the patient-outcomes of newly developed pressure drop coefficient (CDP) in diagnosing epicardial stenosis (ES) in the presence of concomitant microvascular disease (MVD).METHODSPatients from our clinical trial were divided into two subgroups with: (1) cut-off of coronary flow reserve (CFR) < 2.0; and (2) diabetes. First, correlations were performed for both subgroups between CDP and hyperemic microvascular resistance (HMR), a diagnostic parameter for assessing the severity of MVD. Linear regression analysis was used for these correlations. Further, in each of the subgroups, comparisons were made between fractional flow reserve (FFR) < 0.75 and CDP > 27.9 groups for assessing major adverse cardiac events (MACE: Primary outcome). Comparisons were also made between the survival curves for FFR < 0.75 and CDP > 27.9 groups. Two tailed chi-squared and Fischer’s exact tests were performed for comparison of the primary outcomes, and the log-rank test was used to compare the Kaplan-Meier survival curves. P < 0.05 for all tests was considered statistically significant.RESULTSSignificant linear correlations were observed between CDP and HMR for both CFR < 2.0 (r = 0.58, P < 0.001) and diabetic (r = 0.61, P < 0.001) patients. In the CFR < 2.0 subgroup, the %MACE (primary outcomes) for CDP > 27.9 group (7.7%, 2/26) was lower than FFR < 0.75 group (3/14, 21.4%); P = 0.21. Similarly, in the diabetic subgroup, the %MACE for CDP > 27.9 group (12.5%, 2/16) was lower than FFR < 0.75 group (18.2%, 2/11); P = 0.69. Survival analysis for CFR < 2.0 subgroup indicated better event-free survival for CDP > 27.9 group (n = 26) when compared with FFR < 0.75 group (n = 14); P = 0.10. Similarly, for the diabetic subgroup, CDP > 27.9 group (n = 16) showed higher survival times compared to FFR group (n = 11); P = 0.58.CONCLUSIONCDP correlated significantly with HMR and resulted in better %MACE as well as survival rates in comparison to FFR. These positive trends demonstrate that CDP could be a potential diagnostic endpoint for delineating MVD with or without ES.

Abnormal coronary vasoreactivity in transient left ventricular apical ballooning (tako-tsubo) syndrome.

The exact etiology and pathophysiologic mechanisms of tako-tsubo syndrome (TTS) remain controversial. To further evaluate the abnormal coronary vasoreactivity and its possible anatomical substrate in TTS. We studied 47 patients (46 women; age 67±12years) who underwent diagnostic cardiac catheterization and evaluation of coronary vasoreactivity by sequential acetylcholine (Ach), nitroglycerine and adenosine testing with angiographic and intracoronary pressure-Doppler flow monitoring. Coronary artery wall morphology was also evaluated by intravascular ultrasound (IVUS) imaging in 45 vessels of 43 patients. Abnormal coronary vasoconstriction to Ach stimulation was elicited in 40 patients (85%) involving the LAD artery and its branches in 39 (83%). Abnormal microvascular function was seen in 39 (83%) patients. Overall, hyperemic microvascular resistance index (HMR) was higher and Doppler coronary flow velocity reserve (CFVR) was lower in the LAD artery territory as compared to the reference territories (2.64±1.23 vs 2.05±0.56; p=0.008 and 1.95±0.7 vs 2.3±0.6; p=0.018, respectively). IVUS revealed no plaque rupture, dissection or thrombosis but occult plaque formation and myocardial bridging were found as a possible anatomical substrate of endothelial dysfunction in 67% and 48.8% patients respectively. A global failure of coronary vasomotor function was demonstrated in most TTS patients. These findings implicate abnormal vasoconstrictive response to the activation of the sympathetic system as a potential mechanism involved in the pathogenesis of myocardial stunning in TTS. Competency in medical knowledge: Abnormal coronary vasoconstriction secondary to endothelial dysfunction may actively contribute to the clinical manifestation of acute coronary syndromes in patients with non-obstructive coronary disease. Translational outlook 1: TTS patients reveal a global failure of vasomotor function with both vasoconstrictive response to acetylcholine and increased hyperemic microvascular resistances in the territory of myocardial stunning. They may also show occult coronary atherosclerosis and myocardial bridging as the anatomic substrates of endothelial dysfunction. Translational outlook 2: The cardiac phenotype of TTS includes a high prevalence of coronary vasomotor disturbances. These findings implicate abnormal vasoconstrictive response to the activation of the sympathetic system as a potential mechanism involved in the pathogenesis of TTS in post-menopausal women. Thus, a systematic evaluation of coronary vasoreactivity could better characterize the syndrome.