Adenosine Infusion Research Articles

3D ultrasound coronarography: first proof of concept study on isolated beating rat hearts

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Bettencourt Foundation Background/Introduction We demonstrated recently that Ultrafast ultrasound Doppler imaging can image the intramyocardial coronary circulation in beating hearts of large animals and patients [1]. Yet, ultrasound spatial resolution remains limited by wave physics and coronaries smaller than ∼100 µm could not be imaged. Ultrasound Localization Microscopy (ULM) [2] was recently introduced to tackle this issue and exploit the micrometric localization of microbubble contrast agents at ultrafast frame rate in order to image blood flows in micrometer vessels. Purpose The objective of this work was to demonstrate that 3D ultrafast ultrasound with contrast agents can provide the full 3D mapping of the coronary microcirculation with quantitative flow velocity on a beating rat heart. Methods Acquisitions were performed on ex vivo rat hearts (n = 5) with retrograde perfusion (Langendorff model). A flow of a Krebs–Henseleit solution mixed with a diluted microbubbles solution (0.22%) was perfused at controlled pressure into the coronary arteries (between 5 and 15 mL/min). We used a 32 × 32 elements, 8-MHz matrix-array ultrasound transducer connected to a 1024-channel programmable ultrasound scanner. An ultrafast Doppler imaging sequence consisting of 9 plane waves was transmitted at a PRF of 20 kHz during 270 ms and repeated 40 times. After beamforming and SVD clutter filtering, the microbubbles were localized and tracked in 3D. Flow velocity were mapped at baseline and after infusion of Adenosine (10e-5 µMol) at constant coronary perfusion pressure (120 mm Hg). Eventually, the hearts were fixed using formaldehyde perfusion and imaged by µCT after injection of radio opaque agent. Results We successfully imaged the coronary blood flows of entire rat hearts. It revealed the entire vasculature from large main coronaries arteries (cross section up to 1 mm) to small arterioles (smaller than 40 µm). Coronary flow velocities ranged from [1 – 50] cm/s depending on the arteries diameter. Velocity estimates were validated in vitro in tubes of Ø0.58mm and were in good agreement with theoretical values of a Poiseuille’s flow (relative ratio of 10% for maximum velocities). After Adenosine infusion, perfusion flow rates increased 102% ± 50% (p < 0.05) on average. Eventually, anatomy revealed by 3D ultrasound coronarography was in accordance with the anatomy revealed by the µCT. Conclusion(s) We demonstrated the feasibility of 3D ultrasound coronarography on isolated beating rat hearts. This technique has the potential to become a novel imaging tool to investigate the coronary micro-circulation and quantify non-invasively the Coronary Flow Reserve (CFR). Abstract Figure. Ultrasound coronarography

Noninvasive oxygenation assessment after acute myocardial infarction with breathing maneuvers-induced oxygenation-sensitive magnetic resonance imaging.

The safety profiles when performing stress oxygenation-sensitive magnetic resonance imaging (OS-MRI) have raised concerns in clinical practice. Adenosine infusion can cause side effects such as chest pain, dyspnea, arrhythmia, and even cardiac death. The aim of this study was to investigate the feasibility of breathing maneuvers-induced OS-MRI in acute myocardial infarction (MI). This was a prospective study, which included 14 healthy rabbits and nine MI rabbit models. This study used 3T MRI/modified Look-Locker inversion recovery sequence for native T1 mapping, balanced steady-state free precession sequence for OS imaging, and phase-sensitive inversion recovery sequence for late gadolinium enhancement. The changes in myocardial oxygenation (ΔSI) were assessed under two breathing maneuvers protocols in healthy rabbits: a series of extended breath-holding (BH), and a combined maneuver of hyperventilation followed by the extended BH (HVBH). Subsequently, OS-MRI with HVBH in acute MI rabbits was performed, and the ΔSI was compared with that of adenosine stress protocol. Student's t-test, Wilcoxon rank test, and Friedman test were used to compare ΔSI in different subgroups. Pearson and Spearman correlation was used to obtain the association of ΔSI between breathing maneuvers and adenosine stress. Bland-Altman analysis was used to assess the bias of ΔSI between HVBH and adenosine stress. In healthy rabbits, BH maneuvers from 30 to 50 s induced significant increase in SI compared with the baseline (all p < 0.05). By contrast, hyperventilation for 60 s followed by 10 s-BH (HVBH 10 s) exhibited a comparable ΔSI to that of stress test (p=0.07). In acute MI rabbits, HVBH 10 s-induced ΔSIs among infarcted, salvaged, and the remote myocardial area were no less effectiveness than adenosine stress when performing OS-MRI (r=0.84; p < 0.05). Combined breathing maneuvers with OS-MRI have the potential to be used as a nonpharmacological alternative for assessing myocardial oxygenation in patients with acute MI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

The non-invasive coronary flow reserve predicts exercise capacity in patients undergoing cardiac rehabilitation

The benefit of exercise on peripheral muscles is established but the exact role of the coronary microcirculation in exercise capacity after cardiac rehabilitation (CR) is unclear. Our aim was to test the relationship between non-invasive coronary flow reserve (CFR) and exercise capacity in patients undergoing CR after acute myocardial infarction (AMI). CFR was performed by transthoracic Doppler echocardiography in the left anterior descending artery 24 h after angioplasty (CFR1) and after 20 sessions of CR program (at 4 ± 1 months)(CFR2) in 60 consecutive patients (57 ± 11 years, 30% women) with an anterior AMI successfully treated by primary coronary angioplasty. CFR was performed in a modified parasternale view using intravenous adenosine infusion (0.14 mg/kg/min within 2 minutes). CR program consisted of a half hour of fractioned exercise added of a half hour session of general gymnastics and bodybuilding. To test the exercise capacity, symptom limited exercise echocardiography was performed just after the CFR2, in a semi-supine position, starting at 25 watts, with 20-25 watts increments of workload every two minutes. CFR was measured successfully in all patients, and CFR2 was significantly higher than CFR1 (2.9 ± 0.65 vs. 1.9 ± 0.4, P < 0.001). Though CFR1 was correlated to left ventricular systolic function and its improvement at follow-up (all, P < 0.01), CFR2 was independently related to exercise capacity (mean workload 100 ± 30 watts, percent maximal heart rate 83 ± 12%, no ischemia, no new wall motion abnormalities in all tests) after adjusting for age, sex, and body mass index ( r = 0.6, P < 0.01). CFR predicts exercise capacity in patients undergoing a CR program after AMI. The improvement of CFR contributes to cardiac performance.

Abstract 13792: Association of Immunocompromised State With Coronary Microvascular Dysfunction in Patients With Well-controlled HIV

Introduction: Patients with HIV have an elevated risk of cardiovascular disease (CVD) that may be partially driven by inflammation and residual immune dysfunction despite treatment with antiretroviral therapy (ART). Coronary microvascular dysfunction (CMD) is an important pathophysiological link between inflammation, immune dysfunction, and CVD and may provide mechanistic insight into CVD risk among HIV+ patients. Methods: We recruited 3 groups of adults aged 40-80 years free of CVD: HIV with evidence of prior/current immunocompromise (n=17), HIV without immunocompromise (n=19), and HIV- controls. All HIV+ participants were on ART and had suppressed viral loads. All controls were on HIV pre-exposure prophylaxis (PrEP). Immunocompromise was defined as nadir CD4 count &lt;200 cells/μL or current CD4 count &lt;500 cells/μL. Participants underwent Doppler echocardiography with coronary flow velocity measurement in the distal left anterior descending coronary artery at rest and during adenosine infusion. CMD was defined as coronary flow reserve (CFR) &lt; 2.50. Multivariable linear regression models assessed the association of HIV group with CFR. Results: Of 51 individuals who underwent CFR testing, median (IQR) age was 54 (46-58) and 92% were male. CFR was 3.71 (2.90-4.72) in controls, 3.49 (2.52-4.20) in HIV+/ immunocompromise-, and 2.35 (2.12-2.92) in HIV+/ immunocompromise+ (p=0.002). CMD was present in 7% of controls, 21% of HIV+/immunocompromise-, and 53% of HIV+/immunocompromise+ (p= 0.01). Compared with controls, HIV+/immunocompromise+ was significantly associated with lower CFR after multivariable adjustment ( Table ). Conclusions: HIV+ patients with current/prior immunocompromise free of CVD had high prevalence of CMD and had significantly lower CFR compared with controls on PrEP. Future studies should investigate CMD as a possible target for CVD prevention in HIV+ patients, particularly those with a prior or current immunocompromised state.

Abstract 16567: Long-Term Vascular Function in CTO Recanalization. A Randomized Clinical Trial of Ticagrelor vs. Clopidogrel

Background: Coronary vascular function of a chronic coronary total occlusion (CTO) immediately after recanalization is known to be poor and to be partially improved by pre-treatment with loading dose of ticagrelor vs. clopidogrel. It is unknown if this vascular dysfunction is maintained at long-term follow-up and may be improved by 1-year dual antiplatelet therapy (DAPT) with ticagrelor vs. clopidogrel. Methods: The TIGER is a prospective, open-label, two parallel-group controlled clinical trial, which 1:1 randomized 50 CTO patients to pre-PCI loading dose and subsequent 1-year DAPT with ticagrelor vs. clopidogrel. Coronary blood flow (CBF) under stepwise adenosine infusion was assessed after drug loading dose and at follow-up and compared between the two drug groups, adjusting for time of follow-up. Results: Out of 50 patients with index CBF evaluation, 38 (76%) patients underwent angiographic follow-up (23 and 15 at 1 and 3-year, respectively). A higher CBF area under the curve (AUC), already observed after loading dose in ticagrelor vs. clopidogrel group (p=0.027), was maintained at follow-up (AUC 34815.22±24206.06 vs. AUC 22712.47±13768.95; p=0.071). Specifically, whereas high ticagrelor loading dose-related CBF was sustained at follow-up (p=0.933), clopidogrel loading dose-related CBF increased at follow-up (p=0.039). Conclusion: The TIGER trial showed that DAPT with ticagrelor may maintain a higher CBF in a recanalized CTO as compared to clopidogrel, whose treated patients exhibit a lower CBF immediately after PCI with slight increase at follow-up. The clinical value of such sustained higher coronary flow should be evaluated in a larger group of patients.

Safety and efficacy of a hyperaemic agent, intracoronary nicorandil 4mg, for invasive physiological assessments during fractional flow reserve measurement

Abstract Background Fractional flow reserve (FFR) is one of most reliable index for the determining the functional severity coronary artery stenosis. Adenosine is the most commonly used agent for maximal hyperaemia. However, adenosine can cause chest discomfort, bronchial hyper-reactivity, and atrioventricular block. The aim of this study is to evaluate the safety and efficacy of intracoronary nicorandil as an alternative hyperaemic agent for FFR. Methods and results We enrolled consecutive 82 patients (87 lesions) who underwent FFR measurement in our center from Nov. 2018. We compared three groups; intravenous infusion of adenosine (150 μg/kg/min); and adenosine added intracoronary nicorandil 2mg; and intracoronary nicorandil 4mg. Mean FFR value was 0.83±0.09, 0.82±0.09, 0.82±0.08, There was a strong correlation among three groups (R2&amp;gt;0.9). Mean cyclic change in FFR was 0.026±0.023, 0.019±0.010, 0.016±0.014, respectively, cyclic change was smallest in intracoronary nicorandil 4mg group (vs ATP; p&amp;lt;0.001, vs ATP + nicorandil 2mg; p&amp;lt;0.001). By Wilcoxon test, mean FFR value of nicorandil 4mg was significant lower than ATP (p=0.0021), and equal to ATP + nicorandil 2mg (p=0.98). Conclusions Intracoronary nicorandil 4mg is a simple, safe, and effective way to induce steady-state hyperaemia for FFR. Figure 1 Funding Acknowledgement Type of funding source: None

Clinical implications of coronary artery morphology of patients with ischemia and non-obstructive coronary artery disease (INOCA) -An intracoronary OCT study-

Abstract Introduction Ischemia and non-obstructive coronary artery disease (INOCA), including microvascular spasm (MVS) and epicardial spasm, has recently attracted much attention, for which in vivo imaging evaluation for coronary artery morphology is warranted for better understanding of this disorder. Besides the improved diagnostic accuracy of optical coherence tomography (OCT) for coronary plaques, we have recently demonstrated its capability for in vivo visualization of coronary adventitial vasa vasorum (VV) and the enhanced VV formation in patients with epicardial spasm. Purpose We aimed to examine OCT-delineated morphological characteristics in patients with INOCA in vivo. Methods A total of 335 consecutive INOCA patients, who underwent pharmacological spasm provocation tests, lactate sampling, and OCT imaging over the entire length of the left anterior descending (LAD) coronary arteries, were enrolled at our institute over 68 months from April 2013. They were classified into 4 groups; control with non-cardiac chest pain, MVS, diffuse spasm (DS), or focal spasm (FS) (Fig. 1A). MVS was diagnosed when negative lactate extraction ratio (coronary orifice &amp;lt; coronary sinus) was detected despite the absence of epicardial spasm during the spasm provocation test. DS was defined as epicardial spasm induced in more than 2 coronary segments in LAD, and FS as epicardial spasm in one segment. Quantitative analyses for adventitial inflammation and atherosclerotic changes were performed by calculating VV density and %area stenosis (AS) on OCT (Fig. 1B, E). Furthermore, index of microcirculatory resistance (IMR), a marker of microvascular disorder with a cut-off value of ≥25, was measured during intravenous infusion of adenosine, which was then correlated with VV densities in the MVS and DS groups. Coronary plaque with a necrotic core was classified as fibroatheroma (FA), and the number of OCT frames with internal VV (IVV) in the atheroma was counted. Results VV density was significantly higher in MVS as compared with the controls (Fig. 1B). DS was most prevalent in INOCA (Fig. 1A) with highest VV density (Fig. 1B). Patients with IMR≥25 were predominantly distributed with a gradual increase in the MVS, DS, and FS groups, but none in the controls (Fig. 1C). Importantly, there was a significant positive correlation between VV densities and IMR in the MVS and DS groups (Fig. 1D). In addition, FS had the largest plaque size and showed the highest prevalence of FA and IVV (Fig. 1E–G). Conclusions These results indicate that MVS and DS are characterized by vasomotion abnormalities associated with adventitial inflammation and microvascular disorder, while FS by vulnerable atherosclerotic phenotype, suggesting that OCT may be useful for screening high-risk populations in INOCA. Figure 1 Funding Acknowledgement Type of funding source: None

Age alters peripheral vascular endothelial function without affecting coronary flow reserve in healthy volunteers

Abstract Background Age is a key risk factor contributing to vascular endothelial dysfunction. Whether the impact of ageing is uniform on various vascular beds is unknown. Endothelial function is classically evaluated by the brachial flow mediated dilatation (FMD) after a brief occlusion which mainly involves nitric oxide (NO) production. However, FMD measurement, requiring highly trained technicians, has been shown to be associated with a high degree of variability. Endothelial function could be also assessed by cutaneous iontophoresis combined with Laser Doppler. By contrast to FMD, this method is easily done by nurses and shows less variability. In parallel, myocardial imaging allows measurement of coronary flow reserve (CFR) coupled with an adenosine challenge leading to both a NO release and a modulation of potassium channels. Purpose The aim of this study was to determine the impact of ageing on vasodilation of peripheral (cutaneous) and coronary blood vessels in healthy volunteers. Methods This prospective single German center study enrolled 75 healthy non-smoking normotensive volunteers, taking no medication. They were divided into three age-subgroups (n=25/group): 18–30, 50–59, and 60–70 years (women: 54, 27 and 23%, respectively). All subjects underwent clinical and laboratory evaluation. Peripheral endothelial function, expressed in cutaneous blood flow (delta CBF), was assessed through cutaneous microcirculation dilation by the non-invasive method using Laser Doppler Speckle Contrast Imaging (LSCI, Perimed) coupled with iontophoresis to locally deliver 125 nmoles of acetylcholine (Ach). The CFR was determined by cardiac magnetic resonance (CMR) coupling with an intravenous infusion of adenosine at 140 μg/kg/min for at least 3 minutes. Results Age was associated with a 23% reduction of peripheral endothelial function (delta CBF, p=0.005) in the elderly group (60–70y) vs. the younger one (18–30y) (median: 56.4 vs. 73.6). By contrast, calculated CFR was unchanged (median: 4.1 vs. 4.2, p=0.38). No relationship was observed between peripheral endothelial function (delta CBF) and CFR (r=0.01, p&amp;gt;0.97) in healthy volunteers. Conclusion In healthy volunteers, ageing is associated with a progressive peripheral but not with a coronary vascular dysfunction. This suggests that the impact of age on endothelial dysfunction depends on different vascular beds. Peripheral endothelial function assessment does not predict coronary vascular function in healthy volunteers. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Servier

Continuous intracoronary versus standard intravenous infusion of adenosine for fractional flow reserve assessment: the HYPEREMIC trial.

The aim of this study was to evaluate the accuracy of a continuous intracoronary (IC) adenosine infusion, administered through the novel HYPEREM™IC over-the-wire microcatheter, to measure fractional flow reserve (FFR). The HYPEREMIC trial was a randomised, non-inferiority, crossover study in which patients with intermediate coronary lesions were enrolled for sequential pressure wire studies. FFR was measured using intravenous (IV) (140-180 mcg/kg/min) versus continuous non-weight-adjusted IC (360 mcg/min) adenosine. Patients were randomised and blinded to the order in which they received the adenosine, separated by a washout period. The primary endpoint was the mean hyperaemic FFR. Forty-one patients were enrolled at three UK sites between June and November 2016. The mean (standard deviation) FFR was 0.82 (±0.09) after IC versus 0.84 (±0.09) after IV adenosine. The difference of -0.02 (95% confidence interval [CI]: -0.03 to -0.01) confirmed the non-inferiority (margin <0.05) of IC to IV adenosine. Intracoronary adenosine was associated with a shorter mean time to maximal hyperaemia (difference -44 [95% CI: -59 to -29] seconds; p<0.0001). Chest discomfort was reported in 32/41 (78.0%) patients during IV adenosine versus 12/41 (29.3%) patients during IC adenosine. Continuous IC adenosine was a reliable, faster and better tolerated method of achieving maximal hyperaemia compared to IV adenosine.

Stimulation of the hepatic arterial buffer response using exogenous adenosine: hepatic rest/stress perfusion imaging.

The hepatic arterial buffer response is a mechanism mediated by adenosine whereby hepatic arterial perfusion (HAP) increases when portal flow decreases, and is implicated in liver disease. The first study aim was to measure HAP in patients undergoing myocardial perfusion imaging (MPI), thus developing hepatic arterial rest/stress perfusion imaging (HAPI). The second aim was to compare adenosine-induced changes in splenic perfusion (SP) and HAP with corresponding changes in myocardial blood flow (MBF). Patients had MPI with 82Rb PET/CT using adenosine (n = 45) or regadenoson (n = 33) for stressing. SP and HAP were measured using a first-pass technique that gives HAP rather than total hepatic perfusion. Renal perfusion (RP) was also measured. Mean MBF and HAP increased after both adenosine ([stress-rest]/rest 1.1 and 0.8) and regadenoson (1.4 and 0.6), but the respective changes did not correlate. After adenosine, SP (- 0.48) and RP (- 0.26) both decreased. The change in SP correlated positively with the change in MBF (r = 0.36; p = 0.015) but did not correlate with change in HAP. After regadenoson, SP (0.2) and RP (0.2) both increased. The changes in SP correlated with the changes in MBF (r = 0.39; p = 0.025) and HAP (r = 0.39; p = 0.02). Changes in RP correlated with changes in HAP (r = 0.51; p = 0.0008) but not MBF. Resting SP (r = 0.32; p = 0.004), but not resting HAP, correlated with hepatic fat burden. Adenosine-induced change in HAP also correlated with hepatic fat (r = 0.29; p = 0.05). HAPI could be a useful new hepatic function test. Neither splenic 'switch-off' nor hepatic arterial 'switch-on' identifies adequacy of stress in MPI. • This article describes a new method for assessing arterial perfusion of the liver and its capacity to respond to an infusion of adenosine, a substance that normally 'drives' hepatic arterial flow. • Hepatic arterial flow increased in response to adenosine, sometimes dramatically. Adenosine is already used clinically to stimulate myocardial blood flow in patients with suspected coronary disease, but the increase in flow did not correlate with the corresponding increase in hepatic arterial flow. • Analogous to the use of adenosine in the myocardium, the increase in hepatic arterial flow in response to adenosine has the potential to be a new clinically useful method for the evaluation of hepatic arterial haemodynamics in liver disease.

Differences between gap-related persistent conduction and carina-related persistent conduction during radiofrequency pulmonary vein isolation.

BackgroundDuring pulmonary vein isolation (PVI), nonisolation after initial encircling of the pulmonary veins (PVs) may be due to gaps in the initial ablation line, or alternatively, earliest PV activation may occur on the intervenous carina and ablation within the wide‐area circumferential ablation (WACA) circle is needed to eliminate residual conduction. This study investigated prognostic implications and predictors of gap‐related persistent conduction (gap‐RPC) and carina‐related persistent conduction (carina‐RPC) during PVI.Methods and ResultsTwo hundred fourteen atrial fibrillation (AF) patients (57% paroxysmal, 61% male, mean age 62 ± 9 years) undergoing first contact force‐guided radiofrequency PVI were studied. Preprocedural cardiac computed tomography imaging was used to assess left atrial and PV anatomy. PVI was assessed directly after initial WACA circle creation, after a minimum waiting period of 30 minutes, and after adenosine infusion. Persistent conduction was targeted for additional ablation and classified as gap‐RPC or carina‐RPC, depending on the earliest activation site. The 1‐year AF recurrence rate was higher in patients with gap‐RPC (47%) compared to patients without gap‐RPC (28%; P = .003). No significant difference in 1‐year recurrence rate was found between patients with carina‐RPC (37%) and patients without carina‐RPC (31%; P = .379). Multivariate analyses identified paroxysmal AF and WACA circumference as independent predictors of gap‐RPC, whereas carina width and WACA circumference correlated with carina‐RPC.ConclusionsGap‐RPC is associated with increased AF recurrence risk after PVI, whereas carina‐RPC does not predict AF recurrence. Moreover, gap‐RPC and carina‐RPC have different correlates and may thus have different underlying mechanisms.

Assessment of Semi-automated Computed Tomographic Measures of Segmental Perfusion Defects in a Swine Model (Sus scrofa) of Intermediate Coronary Lesions.

Computed tomographic myocardial perfusion (CTP) imaging is a tool that shows promise in emergent settings for defining the hemodynamic significance of coronary artery disease. In this study, we examined the accuracy with which the transmural perfusion ratio (TPR) derived through semiautomated CTP analysis reflected segmental perfusion defects associated with intermediate coronary artery lesions in swine. Lesions (diameter stenosis, 65% ± 11%) of the left anterior descending coronary artery (LAD) were created in 10 anesthetized female swine (weight, 47.5 ± 1.9 kg) by using a pneumatic occlusion device implanted on the LAD. Occluder inflation pressures were adjusted to maintain fractional flow reserve (FFR, 74.3 ± 1.7) during adenosine infusion (140ug/kg/min). Static CTP imaging using a stress-rest protocol and segmental TPR derived from semiautomated CT perfusion software was compared with microsphere-derived TPR (mTPR) by using a 16-segment model and polar mapping. Intermediate LAD stenosis was verified through multiplanar coronary CT angiography. Receiver operating characteristic analysis identified an optimal threshold for segmental perfusion defects for intermediate lesions (TPR threshold, ≤0.80); however, the area under the receiver operating characteristic curve was 0.58, and the overall accuracy was 63%. At this threshold, the sensitivity and specificity were 65% and 61%, and the positive and negative predictive values were 61% and 65%, respectively. Although CTP-TPR illustrated segmental perfusion defects with intermediate lesions, the disparity between CTP-TPR and mTPR measures of segmental perfusion suggests that further advances in analysis software may be necessary to improve the localization of segmental defects for intermediated lesions.

Estimation of the vascular resistance amplifier in the renal vascular bed in conscious hypertensive rabbits: comparison with the total peripheral vasculature

ObjectivesThe vascular amplifier in hypertension is a result of structural changes in resistance arteries. We estimated the vascular amplifier hypertensive:normotensive (H:N) ratio in the renal bed compared with the total peripheral bed in conscious rabbits during infusion of vasoconstrictor and vasodilator stimuli. MethodsRabbits were subjected to bilateral renal cellophane wrap or sham operation. A perivascular ultrasonic flow probe was implanted on the left renal artery to measure renal blood flow. A catheter was inserted into the thoracic aorta for agonist administration. Blood pressure, heart rate and renal blood flow were measured on three separate days in conscious rabbits with intact effectors, ganglionic block or neurohumoral block. Dose-response curves were constructed to intra-arterial infusion of noradrenaline, angiotensin II, adenosine and acetylcholine. ResultsResting renal vascular resistance in hypertensive rabbits was markedly decreased by ganglionic block and further by neurohumoral block. With effectors intact, ganglionic block or neurohumoral block, the H:N ratio for renal vascular resistance was 2.32, 1.72 or 1.72, respectively. The ratio was generally maintained during the infusion of constrictor and dilator drugs although distortions occurred at higher concentrations of constrictor or dilator drugs. ConclusionsEstimation of the renal resistance amplifier in renal wrap hypertension with neurohumoral block accords with our earlier estimates of the total peripheral resistance amplifier (1.79). This vascular resistance amplifier is consistent with a decrease in internal radius through structural remodelling in the renal vascular bed as is reflected in the total arterial circulation in hypertension.

Heart Rate-Independent 3D Myocardial Blood Oxygen Level-Dependent MRI at 3.0 T with Simultaneous 13N-Ammonia PET Validation.

Background Despite advances, blood oxygen level-dependent (BOLD) cardiac MRI for myocardial perfusion is limited by inadequate spatial coverage, imaging speed, multiple breath holds, and imaging artifacts, particularly at 3.0 T. Purpose To develop and validate a robust, contrast agent-unenhanced, free-breathing three-dimensional (3D) cardiac MRI approach for reliably examining changes in myocardial perfusion between rest and adenosine stress. Materials and Methods A heart rate-independent, free-breathing 3D T2 mapping technique at 3.0 T that can be completed within the period of adenosine stress (≤4 minutes) was developed by using computer simulations, ex vivo heart preparations, and dogs. Studies in dogs were performed with and without coronary stenosis and validated with simultaneously acquired nitrogen 13 (13N) ammonia PET perfusion in a clinical PET/MRI system. The MRI approach was also prospectively evaluated in healthy human volunteers (from January 2017 to September 2017). Myocardial BOLD responses (MBRs) between normal and ischemic myocardium were compared with mixed model analysis. Results Dogs (n = 10; weight range, 20-25 kg; mongrel dogs) and healthy human volunteers (n = 10; age range, 22-53 years; seven men) were evaluated. In healthy dogs, T2 MRI at adenosine stress was greater than at rest (mean rest vs stress, 38.7 msec ± 2.5 [standard deviation] vs 45.4 msec ± 3.3, respectively; MBR, 1.19 ± 0.08; both, P < .001). At the same conditions, mean rest versus stress PET perfusion was 1.1 mL/mg/min ± 0.11 versus 2.3 mL/mg/min ± 0.82, respectively (P < .001); myocardial perfusion reserve (MPR) was 2.4 ± 0.82 (P < .001). The BOLD response and PET MPR were positively correlated (R = 0.67; P < .001). In dogs with coronary stenosis, perfusion anomalies were detected on the basis of MBR (normal vs ischemic, 1.09 ± 0.05 vs 1.00 ± 0.04, respectively; P < .001) and MPR (normal vs ischemic, 2.7 ± 0.08 vs 1.7 ± 1.1, respectively; P < .001). Human volunteers showed increased myocardial T2 at stress (rest vs stress, 44.5 msec ± 2.6 vs 49.0 msec ± 5.5, respectively; P = .004; MBR, 1.1 msec ± 8.08). Conclusion This three-dimensional cardiac blood oxygen level-dependent (BOLD) MRI approach overcame key limitations associated with conventional cardiac BOLD MRI by enabling whole-heart coverage within the standard duration of adenosine infusion, and increased the magnitude and reliability of BOLD contrast, which may be performed without requiring breath holds. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Almeida in this issue.

Sex and age differences in the association of heart rate responses to adenosine and myocardial ischemia in patients undergoing myocardial perfusion imaging

BackgroundIn light of growing cardiovascular mortality rates observed in young women, sexual dimorphism in cardiac autonomic nervous control is gaining increasing attention. Heart rate responses to adenosine mirror autonomic activity and may carry important prognostic information. Methods and ResultsHemodynamic changes during adenosine stress were retrospectively analysed in a propensity-matched cohort of 1932 consecutive patients undergoing myocardial perfusion single-photon-emission computed tomography (MPI-SPECT). Heart rate (HR) and systolic blood pressure (SBP) increased during adenosine infusion (P < 0.001). The increase in SBP and HR (heart rate reserve, HRR), was significantly more pronounced in women compared with men (P < 0.05). Patients ≤ 55 years had a higher HRR compared with patients > 55 years (46.8% vs 37.5%, P = 0.015). Women ≤ 55 years with a reversible perfusion defect on MPI-SPECT exhibited the highest HRR (89.2%), while age-matched men showed a blunted HR response to adenosine (26.4%, P = 0.01). Accordingly, age and an interaction term of female sex and increased HRR were identified as significant predictors of myocardial ischemia in a multiple regression analysis (OR 1.4, 95% CI 1.02-1.9, P = 0.038). ConclusionHRR during adenosine infusion is influenced by age and sex. Our data suggest a stronger, sympathetic-driven, hemodynamic response to adenosine in younger women with myocardial ischemia.

Individual Lesion-Level Meta-Analysis Comparing Various Doses of Intracoronary Bolus Injection of Adenosine With Intravenous Administration of Adenosine for Fractional Flow Reserve Assessment.

Intravenous infusion of adenosine is considered standard practice for fractional flow reserve (FFR) assessment but is associated with adverse side-effects and is time-consuming. Intracoronary bolus injection of adenosine is better tolerated by patients, cheaper, and less time-consuming. However, current literature remains fragmented and modestly sized regarding the equivalence of intracoronary versus intravenous adenosine. We aim to investigate the relationship between intracoronary adenosine and intravenous adenosine to determine FFR. We performed a lesion-level meta-analysis to compare intracoronary adenosine with intravenous adenosine (140 µg/kg per minute) for FFR assessment. The search was conducted in accordance to the Preferred Reporting for Systematic Reviews and Meta-Analysis statement. Lesion-level data were obtained by contacting the respective authors or by digitization of scatterplots using custom-made software. Intracoronary adenosine dose was defined as; low: <40 µg, intermediate: 40 to 99 µg, and high: ≥100 µg. We collected 1972 FFR measurements (1413 lesions) comparing intracoronary with intravenous adenosine from 16 studies. There was a strong correlation (correlation coefficient =0.915; P<0.001) between intracoronary-FFR and intravenous-FFR. Mean FFR was 0.81±0.11 for intracoronary adenosine and 0.81±0.11 for intravenous adenosine (P<0.001). We documented a nonclinically relevant mean difference of 0.006 (limits of agreement: -0.066 to 0.078) between the methods. When stratified by the intracoronary adenosine dose, mean differences between intracoronary and intravenous-FFR amounted to 0.004, 0.011, or 0.000 FFR units for low-dose, intermediate-dose, and high-dose intracoronary adenosine, respectively. The present study documents clinically irrelevant differences in FFR values obtained with intracoronary versus intravenous adenosine. Intracoronary adenosine hence confers a practical and patient-friendly alternative for intravenous adenosine for FFR assessment.

Rapid-onset vasodilator responses to exercise in humans: Effect of increased baseline blood flow.

What is the central question of this study? What is the effect of an elevated baseline blood flow, induced by high-dose intra-arterial infusion of either adenosine or ATP, on the rapid-onset vasodilatory response to a single forearm muscle contraction? What is the main finding and its importance? The peak response to a single contraction is unaffected by augmented baseline blood flow, and thus, is likely to be attributable to a feedforward vasodilatory mechanism. The hyperaemic responses to single muscle contractions are proportional to exercise intensity, which, in turn, is proportional to tissue metabolic demand. Hence, we tested the hypothesis that the rapid-onset vasodilatory response after a single muscle contraction would be unaffected when baseline blood flow was increased via high-dose intra-arterial infusion of either adenosine (ADO) or ATP. Twenty-four healthy young participants (28±1years) performed a single forearm contraction (20% maximal voluntary contraction) 75min after commencement of a continuous infusion of ADO (n=6), ATP (n=8) or saline (control; n=10). Brachial artery diameter and blood velocity were measured using Doppler ultrasound. Resting forearm vascular conductance (FVC; in millilitres per minute per 100mmHg per decilitre of forearm volume) was significantly higher during ADO (33±17) and ATP infusion (33±17) compared with the control infusion (8±3; P<0.05). The peak FVCs post-contraction during ADO and ATP infusions were significantly greater than during the control infusion (P<0.05), but not different from one another. The peak change in FVC from baseline was similar in all three conditions (control, 14±1; ADO, 24±2; and ATP, 23±6; P=0.15). Total FVC (area under the curve) did not differ significantly between ADO and ATP (333±69 and 440±125); however, total FVC during ATP infusion was significantly greater compared with the control value (150±19; P<0.05). We conclude that the peak response to a single contraction is unaffected by augmented baseline blood flow and is therefore likely to be attributable to a feedforward vasodilatory mechanism.

Endothelium-dependent and independent coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction.

Coronary microvascular inflammation is hypothesized to play a fundamental role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). No study has directly evaluated both endothelium-dependent and independent coronary microvascular function in HFpEF. Consecutive patients with HFpEF undergoing invasive coronary physiologic testing and echocardiography were examined. Endothelial function was quantified by the increase in coronary blood flow in response to intracoronary infusion of acetylcholine (10-6 -10-4 mol/L) using a Doppler flow wire with quantitative angiography. Endothelium-independent coronary microvascular function was assessed by the hyperaemic increase in coronary flow reserve in response to adenosine infusion. Among 162 HFpEF patients (67% women), coronary microvascular function was abnormal in 117 (72%). Isolated endothelium-dependent microvascular dysfunction was present in 47 patients (29%), isolated endothelium-independent microvascular dysfunction in 53 patients (33%), and combined microvascular dysfunction in 17 patients (10%). The presence of coronary microvascular dysfunction was not identifiable from medical co-morbidities or other clinical characteristics. As compared to patients with normal endothelium-independent function, HFpEF patients with endothelium-independent coronary microvascular dysfunction displayed lower diastolic relaxation velocities (7.0± 1.8 vs. 8.4± 2.9cm/s, P= 0.002) and higher estimated filling pressures (E/e' 13.1± 4.1 vs. 9.6± 3.4, P< 0.001). There were no relationships between left ventricular structure, function, or haemodynamics and endothelium-dependent coronary vasodilatation. Endothelium-independent microvascular dysfunction was associated with increased mortality. Coronary microvascular dysfunction is common in patients with HFpEF and is caused equally by endothelium-dependent and independent mechanisms, but the presence of microvascular dysfunction cannot be identified from clinical markers and co-morbidities alone. Patients with HFpEF and endothelium-independent microvascular dysfunction display worse diastolic dysfunction and outcomes.

Adenosine as cardioprotective in off-pump coronary artery bypass grafting

ObjectiveTo assess the effect of adenosine as a cardioprotective drug and its role in attenuating ischemia-reperfusion injury during off-pump coronary artery bypass surgery.BackgroundCardioprotective drugs have long been investigated for use during off-pump coronary artery bypass surgery to attenuate ischemia-reperfusion injury and limit hemodynamic instability. Adenosine has been investigated due to its cardioprotective effect that is mediated through A1 and A3 adenosine receptors. Stimulation of these receptors reproduces the infarct-limiting effect of ischemic preconditioning.MethodsAfter approval of the local ethics committee and informed written consent, fifty patients undergoing elective off-pump coronary artery bypass grafting were prospectively studied. The adenosine group received an infusion of Adenoscan at a rate of 50 μg/kg/min for 15 min. The control group received normal saline at the same rate and volume calculated. Pulmonary artery catheter was introduced through the right internal jugular vein. Cardiac output measurements were obtained. Cardiac index, stroke volume, systemic vascular resistance, pulmonary vascular resistance, right ventricular stroke work index, and left ventricular stroke work index were derived. Hemodynamic measurements were recorded together with blood levels of troponin I and CK-MB fraction to detect perioperative myocardial necrosis. Postoperative duration of mechanical ventilation, ICU stay together with inotropic support quantification using inotropic score were recorded.ResultsFifty patients were included in the study. In the adenosine group, the infusion of adenosine resulted in a significant reduction in mean pulmonary artery pressure after stopping drug infusion (18 ± 2.2 mmHg versus 31 ± 4.1 mmHg). There was a recorded increase in cardiac index in the adenosine group that started 15 min after adenosine infusion and lasted for 12 h postoperatively (p < 0.001). Also, adenosine infusion resulted in a reduction in pulmonary vascular resistance that exceeded the reduction in systemic vascular resistance which resulted in a decrease in pulmonary vascular resistance/systemic vascular resistance ratio (0.14 in adenosine group 15 min after injection versus 0.28 in control group) and (0.11 in adenosine group 12 h postoperatively versus 0.26 in control group). The cTroponin I measured 6 h postoperatively was less in the adenosine group compared with the control group (5.8 ± 2.8 ng/ml versus 16.5 ± 3.9 ng/ml).ConclusionAdenosine infusion during off-pump coronary artery surgery may improve cardiac index, reduce the need for inotropes, and have cardioprotective effect.

Assessment with intracoronary pressure and flow guidewire, at baseline and after intracoronary adenosine infusion, in a patient with Takotsubo syndrome

Assessment with intracoronary pressure and flow guidewire, at baseline and after intracoronary adenosine infusion, in a patient with Takotsubo syndrome