Transcoronary Gradients of Mechanosensitive MicroRNAs as Predictors of Collateral Development in Chronic Total Occlusion.

Background and Objectives: In this present study, we investigated the impact of mechanosensitive microRNAs (mechano-miRs) on the collateral development in 126 chronic total occlusion (CTO) patients, selected from 810 undergoing angiography. Materials and Methods: We quantified the collateral blood supply using the collateral flow index (CFI) and assessed the transcoronary mechano-miR gradients. Results: The patients with favorable collaterals had higher CFI values (0.45 ± 0.02) than those with poor collaterals (0.38 ± 0.03, p < 0.001). Significant differences in transcoronary gradients were found for miR-10a, miR-19a, miR-21, miR-23b, miR-26a, miR-92a, miR-126, miR-130a, miR-663, and let7d (p < 0.05). miR-26a and miR-21 showed strong positive correlations with the CFI (r = 0.715 and r = 0.663, respectively), while let7d and miR-663 were negatively correlated (r = -0.684 and r = -0.604, respectively). The correlations between cytokine gradients and mechano-miR gradients were also significant, including Transforming Growth Factor Beta with miR-126 (r = 0.673, p < 0.001) and Vascular Endothelial Growth Factor with miR-10a (r = 0.602, p = 0.002). A regression analysis highlighted the hemoglobin level, smoking, beta-blocker use, miR-26a, and miR-663 as significant CFI determinants, indicating their roles in modulating the collateral vessel development. Conclusions: These findings suggest mechanosensitive microRNAs as predictive biomarkers for collateral circulation, offering new therapeutic perspectives for CTO patients.

Angiographic Coronary Slow Flow Is Not a Valid Surrogate for Invasively Diagnosed Coronary Microvascular Dysfunction.

BACKGROUND: Ischemia with no obstructive coronary arteries is frequently caused by coronary microvascular dysfunction (CMD). Consensus diagnostic criteria for CMD include baseline angiographic slow flow by corrected TIMI (Thrombolysis In Myocardial Infarction) frame count (cTFC), but correlations between slow flow and CMD measured by invasive coronary function testing (CFT) are uncertain. OBJECTIVES: The aim of this study was to investigate relationships between cTFC and invasive CFT for CMD. METHODS: Adults with ischemia with no obstructive coronary arteries underwent invasive CFT with thermodilution-derived baseline coronary blood flow, coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). CMD was defined as abnormal CFR (<2.5) and/or abnormal IMR (≥25). cTFC was measured from baseline angiography; slow flow was defined as cTFC >25. Correlations between cTFC and baseline coronary flow and between CFR and IMR and associations between slow flow and invasive measures of CMD were evaluated, adjusted for covariates. All patients provided consent. RESULTS: Among 508 adults, 49% had coronary slow flow. Patients with slow flow were more likely to have abnormal IMR (36% vs 26%; P = 0.019) but less likely to have abnormal CFR (28% vs 42%; P = 0.001), with no difference in CMD (46% vs 51%). cTFC was weakly correlated with baseline coronary blood flow (r = -0.35; 95% CI: -0.42 to -0.27), CFR (r = 0.20; 95% CI: 0.12 to 0.28), and IMR (r = 0.16; 95% CI: 0.07-0.24). In multivariable models, slow flow was associated with lower odds of abnormal CFR (adjusted OR: 0.53; 95% CI: 0.35 to 0.80). CONCLUSIONS: Coronary slow flow was weakly associated with results of invasive CFT and should not be used as a surrogate for the invasive diagnosis of CMD.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study.

BACKGROUND: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk. METHODS AND RESULTS: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high-sensitivity C-reactive protein [hsCRP], interleukin-1b, and high-sensitivity cardiac troponin T [hs-cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs-cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs-cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs-cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64, P=0.6) or hs-cTnT. A correlation was observed between a reduction in hsCRP and interleukin-1b with a reduction in hs-cTnT. CONCLUSIONS: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin-1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02714881.

Establishment of nonobstructive coronary microcirculatory disorders in rabbits using three established methods and a comparative study.

To compare the merits and drawbacks of three approaches for establishing a rabbit model of nonobstructive coronary microcirculatory disease, namely, open thoracic subtotal ligation of coronary arteries, ultrasound-guided cardiac microsphere injection, and sodium laurate injection. New Zealand rabbits were allocated to four groups: a normal group (Blank group), an Open-chest group (Open-chest), a microsphere group (Echo-M), and a sodium laurate group (Echo-SL), each comprising 10 rabbits. The rabbits were sacrificed 24 h after the procedures, and their echocardiography, stress myocardial contrast echocardiography, pathology, and surgical times were compared. The results demonstrated varying degrees of reduced cardiac function in all three experimental groups, the Open-chest group exhibiting the most significant decline. The myocardial filling in the affected areas was visually analyzed by myocardial contrast echocardiography, revealing sparse filling at rest but more after stress. Quantitative analysis of perfusion parameters (ß, A, MBF) in the affected myocardium showed reduced values, the Open-chest group having the most severe reductions. No differences were observed in stress myocardial acoustic imaging parameters between the Echo-M and Echo-SL groups. Among the pathological presentations, the Open-chest model predominantly exhibited localized ischemia, while the Echo-M model was characterized by mechanical physical embolism, and the Echo-SL model displayed in situ thrombosis as the primary pathological feature. Inflammatory responses and collagen deposition were observed in all groups, with the severity ranking of Open-chest > Echo-SL > Echo-M. The ultrasound-guided intracardiac injection method used in this experiment outperformed open-chest surgery in terms of procedural efficiency, invasiveness, and maneuverability. This study not only optimizes established cardiac injection techniques but also offers valuable evidence to support clinical investigations through a comparison of various modeling methods.

Intracoronary electrocardiogram detects coronary microvascular dysfunction and ischemia in patients with no obstructive coronary arteries disease.

BACKGROUND: Coronary microvascular dysfunction (CMD) is the leading cause of ischemia with no obstructive coronary arteries disease (INOCA) disease. Diagnosis of CMD relies on surrogate physiological indices without objective proof of ischemia. OBJECTIVES: Intracoronary electrocardiogram (icECG) derived hyperemic indices may accurately and objectively detect CMD and reversible ischemia in related territory. METHODS: INOCA patients with proven ischemia by myocardial perfusion scan (MPS) and completely normal coronary arteries underwent simultaneous intracoronary electrophysiological (icECG) and physiological (intracoronary Doppler) assessment in all 3 coronary arteries during rest and under adenosine induced hyperemia. RESULTS: Sixty vessels in 21 patients were included in the final analysis. All patients had at least one vessel with abnormal CFR. 41 vessels had CMD (CFR < 2.5), of which 26 had increased microvascular resistance (structural CMD, HMR > 1.9 mmHg.cm-1.s) and 15 vessels had CMD (CFR < 2.5) with normal microvascular resistance (functional CMD, HMR <= 1.9 mmHg.cm-1.s). Only one-third of the patients (n = 7) had impaired CFR < 2.5 in all 3 epicardial arteries. Absolute ST shift between hyperemia and rest (∆ST) has shown the best diagnostic performance for ischemia (cut-off 0.10 mV, sensitivity: 95%, specificity: 72%, accuracy: 80%, AUC: 0.860) outperforming physiological indices (CFR: 0.623 and HMR: 0.653 DeLong's test P = .0002). CONCLUSIONS: In INOCA patients, CMD involves coronary artery territories heterogeneously. icECG can accurately detect CMD causing perfusion abnormalities in patients with INOCA outperforming physiological CMD markers, by demonstrating actual ischemia instead of predicting the likelihood of inducible ischemia based on violated surrogate thresholds of blunted flow reserve or increased minimum microvascular resistance. CONDENSED ABSTRACT: In 21 INOCA patients with coronary microvascular dysfunction (CMD) and myocardial perfusion scan proved ischemia, hyperemic indices of intracoronary electrocardiogram (icECG) have accurately detected vessel-specific CMD and resulting perfusion abnormalities & ischemia, outperforming invasive hemodynamic indices. Absolute ST shift between hyperemia and rest (∆ST) has shown the best classification performance for ischemia in no Obstructive Coronary Arteries (AUC: 0.860) outperforming Doppler derived CMD indices (CFR: 0.623 and HMR: 0.653 DeLong's test P = .0002).icECG can be used to diagnose CMD causing perfusion defects by demonstrating actual reversible ischemia at vessel-level during the initial CAG session, obviating the need for further costly ischemia tests. CLINICALTRIALS: GOV: NCT05471739.

Myocardial perfusion in cardiac amyloidosis.

AIMS: Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage. The aims of this study were to assess the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment. METHODS AND RESULTS: Ninety-three patients with cardiac amyloidosis (CA) (light-chain amyloidosis n = 42, transthyretin amyloidosis n = 51) and 97 without CA (three-vessel coronary disease [3VD] n = 47, unobstructed coronary arteries n = 26, healthy volunteers [HV] n = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-four myocardial biopsies and three explanted hearts with CA were analysed histopathologically. Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA: 1.04 ± 0.51 ml/min/g, 3VD: 1.35 ± 0.50 ml/min/g, unobstructed coronary arteries: 2.92 ± 0.52 ml/min/g, HV: 2.91 ± 0.73 ml/min/g; CA vs. 3VD p = 0.011, CA vs. unobstructed coronary arteries p < 0.001, CA vs. HV p < 0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p < 0.05). Biopsies demonstrated abnormal vascular endothelial growth factor staining in cardiomyocytes and endothelial cells, which may be related to hypoxia conditions. Amyloid infiltration in intramural arteries was associated with severe lumen reduction and severe reduction in capillary density. CONCLUSION: Cardiac amyloidosis is associated with severe inducible myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where in addition to systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.

Myocardial Blood Flow Determination From Contrast-Free Magnetic Resonance Imaging Quantification of Coronary Sinus Flow.

BACKGROUND: Determination of myocardial blood flow (MBF) with MRI is usually performed with dynamic contrast enhanced imaging (MBFDCE ). MBF can also be determined from coronary sinus blood flow (MBFCS ), which has the advantage of being a noncontrast technique. However, comparative studies of MBFDCE and MBFCS in large cohorts are lacking. PURPOSE: To compare MBFCS and MBFDCE in a large cohort. STUDY TYPE: Prospective, sequence-comparison study. POPULATION: 147 patients with type 2 diabetes mellitus (age: 56+/-12 years; 106 male; diabetes duration: 12.9+/-8.1 years), and 25 age-matched controls. FIELD STRENGTH/SEQUENCES: 1.5 Tesla scanner. Saturation recovery sequence for MBFDCE vs. phase-contrast gradient-echo pulse sequence (free-breathing) for MBFCS . ASSESSMENT: MBFDCE and MBFCS were determined at rest and during coronary dilatation achieved by administration of adenosine at 140 µg/kg/min. Myocardial perfusion reserve (MPR) was calculated as the stress/rest ratio of MBF values. Coronary sinus flow was determined twice in the same imaging session for repeatability assessment. STATISTICAL TESTS: Agreement between MBFDCE and MBFCS was assessed with Bland and Altman's technique. Repeatability was determined from single-rater random intraclass and repeatability coefficients. RESULTS: Rest and stress flows, including both MBFDCE and MBFCS values, ranged from 33 to 146 mL/min/100 g and 92 to 501 mL/min/100 g, respectively. Intraclass and repeatability coefficients for MBFCS were 0.95 (CI 0.90; 0.95) and 5 mL/min/100 g. In Bland-Altman analysis, mean bias at rest was -1.1 mL/min/100 g (CI -3.1; 0.9) with limits of agreement of -27 and 24.8 mL/min/100 g. Mean bias at stress was 6.3 mL/min/100 g (CI -1.1; 14.1) with limits of agreement of -86.9 and 99.9. Mean bias of MPR was 0.11 (CI: -0.02; 0.23) with limits of agreement of -1.43 and 1.64. CONCLUSION: MBF may be determined from coronary sinus blood flow, with acceptable bias, but relatively large limits of agreement, against the reference of MBFDCE . LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Relation of Thrombolysis in Myocardial Infarction Frame Count to Invasively Measured Coronary Physiologic Indexes.

In the international guidelines, higher thrombolysis in myocardial infarction frame count (TFC) is indicated as evidence of coronary microvascular dysfunction (CMD). However, the association of TFC with invasively measured coronary physiologic parameters such as coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) remains unclear. Patients without significant epicardial coronary lesions underwent invasive coronary physiologic assessment using a thermodilution method in the left anterior descending artery. Corrected TFC (cTFC) was evaluated on coronary angiography. The cut-off values of CFR and IMR were defined as ≤2.0 and >25, and patients with abnormal CFR and/or IMR were defined as having CMD. This study aimed to assess whether cTFC >25, a cut-off value in the guidelines, was diagnostic of the presence of CMD. Of the 137 patients, 34 (24.8%) and 32 (23.3%) had cTFC >25 and CMD, respectively. The rate of CMD was not significantly different between patients with and without cTFC >25. cTFC was weakly correlated with at rest and hyperemic mean transit time and IMR, whereas no significant correlation was observed between cTFC and CFR. The receiver operating characteristic curve analysis showed the poor diagnostic ability of cTFC for abnormal CFR and IMR and the presence of CMD. In conclusion, in patients without epicardial coronary lesions, cTFC as a continuous value and with the cut-off value of 25 was not diagnostic of abnormal CFR and IMR and the presence of CMD. Our results did not support the use of cTFC in CMD evaluation.

The diagnosis and treatment of women with recurrent cardiac ischemia and normal coronary arteries.

Cardiac disease is the leading cause of death in women. Among women with recurrent chest pain, abnormal electrocardiograms, and/or stress tests who undergo coronary angiography, as many as 50% have normal or <50% coronary artery obstructive disease. Pharmacologic stress assessment of coronary artery flow reserve in these women frequently demonstrates an inability to increase blood flow to >2.5 times normal flow. Contributory factors include abnormal epicardial or microvascular reactivity, microvascular remodeling or rarefaction, autonomic dysfunction, or coronary plaque rupture/erosion. Assessment is necessary of serum biomarkers and coronary artery flow reserve, fractional flow reserve, microvascular resistance, and epicardial/microvascular spasm. Aggressive treatment of women with positive tests is necessary because these women have an increased incidence of recurrent chest pain, repeated hospitalizations and coronary angiograms, and cardiac death.

Developing and evaluating a chronic ischemic cardiomyopathy in swine model by rest and stress CMR.

A large animal model of chronic coronary artery disease (CAD) is crucial for the understanding the underlying pathophysiological processes of chronic CAD and consequences for cardiac structure and function. The goal of this study was to develop a chronic model of CAD in a swine model and to evaluate the changes of myocardial structure, myocardial motility, and myocardial viability during coronary stenosis. A total of 30 swine (including 24 experimental animals and 6 controls) were enrolled. The chronic ischemia model was constructed by using Ameroid constrictor in experimental group. The 24 experimental animals were further divided into 4 groups (6 animals in each group) and were sacrificed at 1, 2, 3 and 4 weeks after operation for pathological examination, respectively. Cardiac magnetic resonance (CMR) was performed preoperatively and weekly postoperatively until sacrificed both in experimental and control group. CMR cine images, rest/adenosine triphosphate (ATP) stress myocardial contrast perfusion and LGE were performed and analyzed. The rest wall thickening (WT) score was calculated from rest cine images. The MPRI (myocardial perfusion reserve index) and MPR (myocardial perfusion reserve) were calculated based on rest and stress perfusion images. Pathology staining including triphenyltetrazolium chloride, HE and picrosirus red staining were performed after swine were sacrificed and collagen volume fraction (CVF) was calculated. The time to formation of ischemic, hibernating, and infarcted myocardium was recorded. In experimental group, from 1w to 4w after surgery, the rest WT score decreased gradually from 35.2 ± 2.0%, 32.0 ± 2.9% to 30.5 ± 3.0% and finally 29.06 ± 1.78%, p < 0.001. Left ventricular ejection fraction was gradually impaired after modeling (58.9 ± 12.6%, 56.3 ± 10.1%, 55.3 ± 9.0%, 53.8 ± 9.9%, respectively). And the MPR and MPRI also decreased stepwise with extent of surgery time (MPRI dropped from 2.1 ± 0.4, 2.0 ± 0.2 to 1.8 ± 0.3 and finally 1.7 ± 0.1, p = 0.004; MPR dropped from 2.3 ± 0.4, 2.1 ± 0.2 to 1.9 ± 0.4 and finally 1.8 ± 0.1, p < 0.001). Stronger associations between MPR, MPRI and CVF were paralleled lower wall thickening scores in fibrosis-affected areas. The ischemic myocardium was first appeared in the first week after surgery (involving ten segments), hibernated myocardium was first appeared in the second week after surgery (involving seventeen segments). LGE was first appeared in eight swine in the third weeks after surgery (16 segments). At 4w after surgery, average 9.6 g scar tissue was found among 6 swine. At the same time, histological analysis established the presence of fibrosis and ongoing apoptosis in the infarcted area. In conclusion, our study provided valuable insights into the pathophysiological processes of chronic CAD and its consequences for cardiac structure and function in a large animal model through combining myocardial motion and stress perfusion.

Improved reproducibility for myocardial ASL: Impact of physiological and acquisition parameters.

PURPOSE: To investigate and mitigate the influence of physiological and acquisition-related parameters on myocardial blood flow (MBF) measurements obtained with myocardial Arterial Spin Labeling (myoASL). METHODS: A Flow-sensitive Alternating Inversion Recovery (FAIR) myoASL sequence with bSSFP and spoiled GRE (spGRE) readout is investigated for MBF quantification. Bloch-equation simulations and phantom experiments were performed to evaluate how variations in acquisition flip angle (FA), acquisition matrix size (AMS), heart rate (HR) and blood T 1 $$ {\mathrm{T}}_1 $$ relaxation time ( T 1 , B $$ {\mathrm{T}}_{1,B} $$ ) affect quantification of myoASL-MBF. In vivo myoASL-images were acquired in nine healthy subjects. A corrected MBF quantification approach was proposed based on subject-specific T 1 , B $$ {\mathrm{T}}_{1,B} $$ values and, for spGRE imaging, subtracting an additional saturation-prepared baseline from the original baseline signal. RESULTS: Simulated and phantom experiments showed a strong dependence on AMS and FA ( R 2 $$ {R}^2 $$ >0.73), which was eliminated in simulations and alleviated in phantom experiments using the proposed saturation-baseline correction in spGRE. Only a very mild HR dependence ( R 2 $$ {R}^2 $$ >0.59) was observed which was reduced when calculating MBF with individual T 1 , B $$ {\mathrm{T}}_{1,B} $$ . For corrected spGRE, in vivo mean global spGRE-MBF ranged from 0.54 to 2.59 mL/g/min and was in agreement with previously reported values. Compared to uncorrected spGRE, the intra-subject variability within a measurement (0.60 mL/g/min), between measurements (0.45 mL/g/min), as well as the inter-subject variability (1.29 mL/g/min) were improved by up to 40% and were comparable with conventional bSSFP. CONCLUSION: Our results show that physiological and acquisition-related factors can lead to spurious changes in myoASL-MBF if not accounted for. Using individual T 1 , B $$ {\mathrm{T}}_{1,B} $$ and a saturation-baseline can reduce these variations in spGRE and improve reproducibility of FAIR-myoASL against acquisition parameters.

Changes in myocardial blood flow in a canine model of left sided breast cancer radiotherapy.

BACKGROUND: Left-sided breast cancer patients receiving adjuvant radiotherapy are at risk for coronary artery disease, and/or radiation mediated effects on the microvasculature. Previously our laboratory demonstrated in canines with hybrid 18FDG/PET a progressive global inflammatory response during the initial one year following treatment. In this study, the objective is to evaluate corresponding changes in perfusion, in the same cohort, where resting myocardial blood flow (MBF) was quantitatively measured. METHOD: In five canines, Ammonia PET (13NH3) derived MBF was measured at baseline, 1-week, 1, 3, 6 and 12-months after cardiac external beam irradiation. MBF measurements were correlated with concurrent 18FDG uptake. Simultaneously MBF was measured using the dual bolus MRI method. RESULTS: MBF was significantly increased at all time points, in comparison to baseline, except at 3-months. This was seen globally throughout the entire myocardium independent of the coronary artery territories. MBF showed a modest significant correlation with 18FDG activity for the entire myocardium (r = 0.51, p = 0.005) including the LAD (r = 0.49, p = 0.008) and LCX (r = 0.47, p = 0.013) coronary artery territories. CONCLUSION: In this canine model of radiotherapy for left-sided breast cancer, resting MBF increases as early as 1-week and persists for up to one year except at 3-months. This pattern is similar to that of 18FDG uptake. A possible interpretation is that the increase in resting MBF is a response to myocardial inflammation.

Coronary artery bypass grafting transiently improves myocardial flow reserve in patients with impaired left ventricular function.

BACKGROUND: Myocardial flow reserve (MFR) derived from 13N-ammonia positron emission tomography is an index used to evaluate ischemic cardiomyopathy and predict the prognosis of patients with coronary artery disease (CAD). This study aimed to evaluate the short-term changes in MFR in patients who underwent coronary artery bypass grafting (CABG). In addition, as a reference, we showed the changes in MFR in the percutaneous coronary intervention (PCI) and optimal medical therapy (OMT) patient groups. METHODS: To determine the short-term effects of CABG in CAD with left ventricular dysfunction, myocardial blood flow (MBF) and MFR were measured before and after CABG. Additionally, we showed changes in MBF and MFR of the PCI and OMT patient groups during treatment. RESULTS: We observed that resting MBF did not significantly increase from baseline to post-CABG (0.84 ± 0.32 vs. 0.83 ± 0.23, P = 0.958); however, stress MBF increased significantly from baseline to post-CABG (1.23 ± 0.64 vs. 1.49 ± 0.42, P < 0.001). The global MFR increased significantly from baseline to post-CABG (1.49 ± 0.42 mL/g/min vs. 1.91 ± 0.51 mL/g/min, P < 0.001). Additionally, stress and resting ejection fraction (EF) significantly increased (stress EF: 42 ± 18.7% vs. 50.9 ± 18%, P = 0.005; resting EF: 45.8 ± 19.5% vs. 52.1 ± 19.4%, P = 0.031). CONCLUSIONS: This study demonstrated that CABG significantly improved MFR in a short period of time with left ventricular dysfunction. These findings suggest that epicardial coronary artery patency restores myocardial microcirculatory dysfunction in the short term.

Long-term impact of myocardial inflammation on quantitative myocardial perfusion-a descriptive PET/MR myocarditis study.

PURPOSE: Whether myocardial inflammation causes long-term sequelae potentially affecting myocardial blood flow (MBF) is unknown. We aimed to assess the effect of myocardial inflammation on quantitative MBF parameters, as assessed by 13N-ammonia positron emission tomography myocardial perfusion imaging (PET-MPI) late after myocarditis. METHODS: Fifty patients with a history of myocarditis underwent cardiac magnetic resonance (CMR) imaging at diagnosis and PET/MR imaging at follow-up at least 6 months later. Segmental MBF, myocardial flow reserve (MFR), and 13N-ammonia washout were obtained from PET, and segments with reduced 13N-ammonia retention, resembling scar, were recorded. Based on CMR, segments were classified as remote (n = 469), healed (inflammation at baseline but no late gadolinium enhancement [LGE] at follow-up, n = 118), and scarred (LGE at follow-up, n = 72). Additionally, apparently healed segments but with scar at PET were classified as PET discordant (n = 18). RESULTS: Compared to remote segments, healed segments showed higher stress MBF (2.71 mL*min-1*g-1 [IQR 2.18-3.08] vs. 2.20 mL*min-1*g-1 [1.75-2.68], p < 0.0001), MFR (3.78 [2.83-4.79] vs. 3.36 [2.60-4.03], p < 0.0001), and washout (rest 0.24/min [0.18-0.31] and stress 0.53/min [0.40-0.67] vs. 0.22/min [0.16-0.27] and 0.46/min [0.32-0.63], p = 0.010 and p = 0.021, respectively). While PET discordant segments did not differ from healed segments regarding MBF and MFR, washout was higher by ~ 30% (p < 0.014). Finally, 10 (20%) patients were diagnosed by PET-MPI as presenting with a myocardial scar but without a corresponding LGE. CONCLUSION: In patients with a history of myocarditis, quantitative measurements of myocardial perfusion as obtained from PET-MPI remain altered in areas initially affected by inflammation. CMR = cardiac magnetic resonance; PET = positron emission tomography; LGE = late gadolinium enhancement.

A simplified method to correct saturation of arterial input function for cardiac magnetic resonance first-pass perfusion imaging: validation with simultaneously acquired PET.

BACKGROUND: First-pass perfusion imaging in magnetic resonance imaging (MRI) is an established method to measure myocardial blood flow (MBF). An obstacle for accurate quantification of MBF is the saturation of blood pool signal intensity used for arterial input function (AIF). The objective of this project was to validate a new simplified method for AIF estimation obtained from single-bolus and single sequence perfusion measurements. The reference MBF was measured simultaneously on 13N-ammonia positron emission tomography (PET). METHODS: Sixteen patients with clinically confirmed myocardial ischemia were imaged in a clinical whole-body PET-MRI system. PET perfusion imaging was performed in a 10-min acquisition after the injection of 10 mCi of 13N-ammonia. The MRI perfusion acquisition started simultaneously with the start of the PET acquisition after the injection of a 0.075 mmol/kg gadolinium contrast agent. Cardiac stress imaging was initiated after the administration of regadenoson 20 s prior to PET-MRI scanning. The saturation part of the MRI AIF data was modeled as a gamma variate curve, which was then estimated for a true AIF by minimizing a cost function according to various boundary conditions. A standard AHA 16-segment model was used for comparative analysis of absolute MBF from PET and MRI. RESULTS: Overall, there were 256 segments in 16 patients, mean resting perfusion for PET was 1.06 ± 0.34 ml/min/g and 1.04 ± 0.30 ml/min/g for MRI (P = 0.05), whereas mean stress perfusion for PET was 2.00 ± 0.74 ml/min/g and 2.12 ± 0.76 ml/min/g for MRI (P < 0.01). Linear regression analysis in MBF revealed strong correlation (r = 0.91, slope = 0.96, P < 0.001) between PET and MRI. Myocardial perfusion reserve, calculated from the ratio of stress MBF over resting MBF, also showed a strong correlation between MRI and PET measurements (r = 0.82, slope = 0.81, P < 0.001). CONCLUSION: The results demonstrated the feasibility of the simplified AIF estimation method for the accurate quantification of MBF by MRI with single sequence and single contrast injection. The MRI MBF correlated strongly with PET MBF obtained simultaneously. This post-processing technique will allow easy transformation of clinical perfusion imaging data into quantitative information.

Left Ventricular Mechano-Energetic Efficiency Identifies an Early Impairment of Myocardial Blood Flow in Arterial Hypertension.

BACKGROUND: Arterial hypertension causes cardiac functional and structural alterations. In hypertensive patients without flow-limiting epicardial coronary artery disease, we investigated possible relationships between positron emission tomography/computed tomography-derived myocardial blood flow (MBF) and echocardiographic parameters of left ventricular (LV) performance, including mechano-energetic efficiency indexed for myocardial mass (MEEi). METHODS: Seventy-eight hypertensive patients without flow-limiting epicardial coronary artery disease underwent echocardiography, including MEEi computation, and cardiac positron emission tomography/computed tomography with assessment of MBF/mass ratio at rest and after stress and myocardial flow reserve. The lowest MEEi tertile (MEEi<0.031 mL/s/g) was compared to the merged second and third tertiles (MEEi≥0.031). RESULTS: Patients in the lowest MEEi tertile were older, had higher systolic blood pressure and body mass index. They also had higher prevalence of LV hypertrophy, whereas lower resting and stress MBF/mass ratio. MEEi was significantly correlated with both resting (r=0.51; P<0.0001) and hyperemic (r=0.54; P<0.0001) MBF/mass ratios, whereas it was not related to myocardial flow reserve. Delta of MBF/mass ratio was lower in the lowest MEEi tertile than in the highest (P<0.0001). In separate multiple linear regression models, after adjusting for sex, systolic blood pressure, body mass index, prevalence of LV hypertrophy, left atrial volume index, and diuretic therapy, the association between LV MEEi and both hyperemic (beta coefficient=0.44; P=0.003) and resting (beta coefficient=0.35; P=0.008) MBF/mass ratio remained significant. CONCLUSIONS: In hypertensive patients without flow-limiting epicardial coronary artery disease, low values of MEEi could detect an early LV dysfunction involving an impairment of both resting and hyperemic MBF/mass ratios. MEEi has the advantage of simpler detection, cheaper costs than positron emission tomography/computed tomography, and a lack of radiation exposure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02211365.

Ticagrelor Treatment is Associated With Increased Coronary Flow Reserve in Survivors of Myocardial Infarction.

BACKGROUND: The pleiotropic action of ticagrelor, with effects in addition to platelet inhibition, has been shown to improve endothelial function in patients with coronary artery disease. These positive effects are possibly adenosine mediated. This study investigated the association of ticagrelor therapy and coronary artery flow reserve in survivors of myocardial infarction (MI). METHODS: This was an exploratory, cross-sectional, open substudy of PROFLOW. High-risk individuals with a history of MI were identified. Coronary flow reserve (CFR) was measured non-invasively in the left anterior descending artery using transthoracic Doppler echocardiography. Coronary flow velocity was measured at rest and at maximal flow after induction of hyperaemia by intravenous infusion of adenosine at 140 µg/kg/min. Patients receiving ticagrelor (n=75) were compared with those not receiving ticagrelor (n=506), using simple and multiple linear regression models. Most patients in both groups were treated with aspirin (97% in the ticagrelor and 94% in the non-ticagrelor group). Adjustment for traditional risk factors was conducted. RESULTS: The mean age at study inclusion was 68.5±6.8 years, and most patients were male (81.8%). The simple linear regression analysis showed ticagrelor treatment to be significantly associated with increased CFR: ticagrelor 2.95±0.76 (mean±SD), non-ticagrelor 2.70±0.77, (coefficient 0.25; 95% CI 0.063-0.438; p=0.009). This association was significant in two of the three multiple linear regression models with increasing numbers of variables: Model 1 (0.28; 0.06-0.50; p=0.014), Model 2 (0.26; 0.03-0.48; p=0.025), and borderline significant in Model 3 (0.21; -0.01 to 0.43; p=0.058). CONCLUSIONS: Ticagrelor treatment was associated with increased CFR in this high-risk population. Increased CFR may be a clinically important therapeutic effect of ticagrelor in addition to platelet inhibition.

Comparative assessment of coronary physiology using transthoracic pulsed-wave Doppler and myocardial contrast echocardiography in rats.

BACKGROUND: Coronary physiology assessment in rodents by ultrasound is an excellent noninvasive and easy to perform technique, including pulsed-wave Doppler (PWD) and myocardial contrast echocardiography (MCE). Both techniques and the corresponding calculated parameters were investigated in this study at rest as well as their response to pharmacologically induced stress. METHODS: Left ventricular myocardial function was assessed in eight anaesthetised rats using transthoracic echocardiography. Coronary physiology was assessed by both PWD of the left coronary artery and MCE using a bolus method. Measurements were performed at rest and under stimulation with adenosine and dobutamine. Effects of stimulation on the calculated parameters were evaluated and rated by effect size (η2). RESULTS: Changes could be demonstrated by selected parameters of PWD and MCE. The clearest effect in PWD was found for diastolic peak velocity (η2 = 0.58). It increased from 528 ± 110 mm/s (mean ± standard deviation) at rest to 839 ± 342 mm/s (p = 0.001) with adenosine and 1093 ± 302 mm/s with dobutamine (p = 0.001). The most distinct effect from MCE was found for the normalised wash-in rate (η2 = 0.58). It increased from 1.95 ± 0.35% at rest to 3.87 ± 0.85% with adenosine (p = 0.001) and 3.72 ± 1.03% with dobutamine (p = 0.001). CONCLUSION: Induced changes in coronary physiology by adenosine and dobutamine could successfully be monitored using MCE and PWD in anaesthetised rats. Due to the low invasiveness of the measurements, this protocol could be used for longitudinal animal studies.

Coronary Slow Flow Is Not Diagnostic of Microvascular Dysfunction in Patients With Angina and Unobstructed Coronary Arteries.

Background Guidelines recommend that coronary slow flow phenomenon (CSFP), defined as corrected thrombolysis in myocardial infarction frame count (CTFC) >$$ > $$27, can diagnose coronary microvascular dysfunction (CMD) in patients with angina and nonobstructed coronary arteries. CSFP has also historically been regarded as a sign of coronary endothelial dysfunction (CED). We sought to validate the utility of CTFC, as a binary classifier of CSFP and as a continuous variable, to diagnose CMD and CED. Methods and Results Patients with angina and nonobstructed coronary arteries had simultaneous coronary pressure and flow velocity measured using a dual sensor-tipped guidewire during rest, adenosine-mediated hyperemia, and intracoronary acetylcholine infusion. CMD was defined as the inability to augment coronary blood flow in response to adenosine (coronary flow reserve <2.5) and CED in response to acetylcholine (acetylcholine flow reserve ≤1.5); 152 patients underwent assessment using adenosine, of whom 82 underwent further acetylcholine testing. Forty-six patients (30%) had CSFP, associated with lower flow velocity and higher microvascular resistance as compared with controls (16.5±$$ \pm $$6.9 versus 20.2±$$ \pm $$6.9 cm/s; P=0.001 and 6.26±$$ \pm $$1.83 versus 5.36±$$ \pm $$1.83 mm Hg/cm/s; P=0.009, respectively). However, as a diagnostic test, CSFP had poor sensitivity and specificity for both CMD (26.7% and 65.2%) and CED (21.1% and 56.0%). Furthermore, on receiver operating characteristics analyses, CTFC could not predict CMD or CED (area under the curve, 0.41 [95% CI, 0.32%-0.50%] and 0.36 [95% CI, 0.23%-0.49%], respectively). Conclusions In patients with angina and nonobstructed coronary arteries, CSFP and CTFC are not diagnostic of CMD or CED. Guidelines supporting the use of CTFC in the diagnosis of CMD should be revisited.