Increase In Myocardial Blood Flow Research Articles

Позитронная эмиссионная томография с рубидием-82 в исследованиях перфузии миокарда

This review considers literature sources on myocardial perfusion studies using positron emission tomography with rubidium-82. The history of the development of the method, the protocols of the study, the dissymmetric data are analyzed, and comparisons are made with other positron emitters that are used in clinical practice and research to study myocardial blood supply. The use of PET/CT with rubidium-82 makes it possible to obtain valuable diagnostic information and it allows to measure myocardial blood directly and make a separate assessment of the coronary arteries function. Due to the fact that the production of rubidium-82 does not require an on-site cyclotron and a radiochemical laboratory, this method of imaging is more accessible than other positron emitters used for the same purpose. Also, the study is not associated with significant discomfort for the patient, since the full stress/rest imaging protocol requires less than half an hour. However, the use of rubidium-82 has a number of drawbacks, including the relatively low sharpness of the resulting image due to the high energy of the emitting positrons. Also there is a necessity for a mathematical correction of the roll-off phenomenon, which is a decrease in radiopharmaceutical extraction with an increase in myocardial blood flow. Due to the short half-life period, the provision of stress tests with ergometers is difficult. It needed to use pharmacological stress tests. In addition, usage of rubidium-82 is characterized by a high cost both due to the expensive production of the parent isotope, strontium-82, and the need for frequent replacement of generators – on average, 11 to 13 times a year.

Improved regional myocardial blood flow and flow reserve after coronary revascularization as assessed by serial 15O-water positron emission tomography/computed tomography.

Myocardial perfusion imaging without and with quantitative myocardial blood flow (MBF) and myocardial flow reserve (MFR) plays an important role in the diagnosis and risk stratification of patients with stable coronary artery disease (CAD). We aimed to quantify the effects of coronary revascularization on regional stress MBF and MFR and to determine whether the presence of subendocardial infarction was associated with these changes. Forty-seven patients with stable CAD were prospectively enrolled. They underwent 15O-water positron emission tomography at baseline and 6 months after optimal medical therapy alone (n = 16), percutaneous coronary intervention (PCI) (n = 18), or coronary artery bypass grafting (CABG) (n = 13). Stenosis of ≥50% diameter was detected in 98/141 vessels (70%). The regional MFR was significantly increased from baseline to follow-up [1.84 (interquartile range, IQR 1.28-2.17) vs. 2.12 (IQR 1.69-2.63), P < 0.001] in vessel territories following PCI or CABG due to an increase in the stress MBF [1.33 (IQR 0.97-1.67) mL/g/min vs. 1.64 (IQR 1.38-2.17) mL/g/min, P < 0.001], whereas there was no significant change in the regional stress MBF or MFR in vessel territories without revascularization. A multilevel mixed-effects models adjusted for baseline characteristics, subendocardial infarction assessed by cardiovascular magnetic resonance imaging, and intra-patient correlation showed that the degree of angiographic improvement after coronary revascularization was significantly associated with increased regional stress MBF and MFR (P < 0.05 for all). Coronary revascularization improved the regional stress MBF and MFR in patients with stable CAD. The magnitude of these changes was associated with the extent of revascularization independent of subendocardial infarction.

The impact of prompt gamma compensation on myocardial blood flow measurements with rubidium-82 dynamic PET

BackgroundRubidium-82 myocardial perfusion imaging is a well-established technique for assessing myocardial ischemia. With continuing interest on myocardial blood flow (MBF) and myocardial flow reserve (MFR) measurements, there is a requirement to fully appreciate the impact of technical aspects of the process. One such factor for rubidium-82 is prompt gamma compensation (PGC). This study aims to assess the impact of PGC on MBF and MFR calculated from dynamic Rb-82 data. MethodsDynamic rest and stress images were acquired on a Siemens Biograph mCT and reconstructed with and without PGC in 50 patients (29 male). MBF and MFR were measured in the three main coronary territories as well as globally. ResultsWith PGC, statistically significant reductions in MBF were observed in LAD (−6.9%), LCx (−4.8%), and globally (−6.5%) but only in obese patients. Significant increases in MBF were observed in RCA (+6.4%) in only nonobese patients. In very obese patients, differences of up to 40% in MBF were observed between PGC and non-PGC images. In nearly all cases, similar PGC differences were observed at stress and rest so there were no significant differences in MFR; however, in a small number of very obese patients, differences in excess of 20% were observed. ConclusionPGC results in statistically significant changes in MBF, with the greatest reductions observed in the LAD and LCx territories of obese patients. In most cases, the impact on stress and rest data is of similar relative magnitudes and changes to MFR are small.

Electronic Cigarettes Impair Human Coronary Endothelial Function

Electronic (e‐) cigarettes are claimed—but unproven—to be less harmful than standard tobacco cigarettes, which are well known to impair coronary endothelial function and constitute a major cardiovascular risk factor. To determine whether e‐cigarettes cause impairment in human coronary endothelial function, we compared effects of tobacco cigarette smoking and e‐cigarette use to blunt the normal increase in myocardial blood flow (MBF) quantified by contrast enhanced echocardiography perfusion imaging, induced by the exercise pressor reflex (post‐handgrip forearm vascular occlusion). The exercise pressor reflex is a reproducible stimulus to endothelial‐dependent coronary vasodilation while also increasing coronary sympathetic vasoconstrictor drive. The coronary endothelial function testing was performed in healthy young adult cigarette smokers (n=5) and age‐matched e‐cigarette users (n=8), ages 21–38 years: a) after overnight smoking/vaping abstinence; and b) immediately after smoking one Camel‐filtered cigarette or one standard use (15 puffs in 7 minutes) of a popular tank‐style e‐cigarette (Evod: battery 3.7 volts, nicotine content 18 mg). During tobacco abstinence in the young cigarette smokers, the exercise pressor reflex increased mean arterial pressure (MAP) by 21.6 ± 4 mmHg (mean ± SE) and increased MBF by 66 ± 20% over baseline (p&lt;0.05), the latter indicating endothelial‐dependent vasodilation in the human coronary microcirculation. As expected, the MBF failed to increase when the exercise pressor reflex was elicited immediately after cigarette smoking (Δ MBF −2 ± 24%, p=n.s.), indicating acute impairment in coronary endothelial function. The surprising new findings of this study are that MBF also failed to increase and tended to decrease by −45 ± 20% (p=n.s.) when the exercise pressor reflex was elicited immediately after acute e‐cigarette use and by −16 ± 10% (p=n.s.) even when elicited during vaping abstinence (despite comparable mean reflex increases in MAP of 21.1 and 21.6 mm Hg, respectively). Thus, our data to date suggest that, in contrast to what has been widely assumed, e‐cigarette use in young adults causes an impairment in coronary endothelial function that appears to be more persistent than with traditional tobacco cigarettes. Further research is warranted to determine if specific oxidant nanoparticles in e‐cigarette vapor mediate the impaired coronary endothelial function.Support or Funding InformationFunded by Tobacco Related Disease Research Program; ClinicalTrials.gov NCT02612701This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A prostacyclin agonist and an omental flap increased myocardial blood flow in a porcine chronic ischemia model

ObjectiveWe hypothesized that therapeutic efficacy may be augmented by a combination of placing a sheet immersed in ONO-1301SR, a slow-release synthetic prostacyclin agonist-inducing multiproangiogenic cytokines, over the left ventricle and a pedicled omental flap in a chronic myocardial infarct heart. MethodsA minipig chronic myocardial infarction was generated by placing an ameroid constrictor ring around the left anterior descending artery for 4 weeks. The minipigs were then assigned into 4 groups of 6 each: sham, omental flap only, ONO-1301SR only, and ONO-1301SR combined with an omental flap (combined). Four weeks after treatment, therapeutic efficacy was evaluated histologically and via several modalities used in the clinical setting. ResultsIn an angiogram and pressure wire study, the combined group induced development of collateral arteries to decrease the resistance and increase the flow reserve of microvasculature in the left circumflex territory. In a 13N-ammonia positron emission tomography study, the combined group displayed a prominent increase in myocardial blood flow and myocardial flow reserve in the left circumflex territory, particularly at the infarct-border region. Consequently, the combined group showed greater regional cardiac function in the left circumflex territory particularly at the infarct-border region, contributing to a greater global ejection fraction with a smaller left ventricular endosystolic volume. Pathologically, attenuated fibrosis, nonswollen myocytes, and upgraded capillary density and proangiogenic cytokines were prominent in the combined group. ConclusionsONO-1301SR combined with a pedicled omental flap synergistically promoted myocardial angiogenesis, leading to function recovery in a porcine chronic myocardial infarction model.

Diagnostic value of global myocardial perfusion reserve assessment based on coronary sinus flow measurements using cardiovascular magnetic resonance in addition to myocardial stress perfusion imaging.

Myocardial perfusion reserve (MPR) is defined as the maximal possible increase in myocardial blood flow (MBF) above baseline conditions. Global MBF can be measured non-invasively by means of coronary sinus flow velocity encoded cine (VENC) cardiovascular magnetic resonance (CMR). We aimed to explore the relationship between global MBF/MPR and the extent and severity of coronary artery disease (CAD) in patients referred for CAD work-up by adenosine-stress CMR. Fifty-eight patients with suspected obstructive CAD underwent both adenosine-stress CMR and invasive coronary angiography. In addition to standard cine- and late gadolinium enhancement (LGE)-imaging, first-pass myocardial perfusion imaging (MPI) and coronary sinus flow measurements (VENC) were performed at rest and during peak stress (after 140 µg/kg/min adenosine), respectively. Nineteen young patients with a very low CAD pre-test probability and normal adenosine-stress CMR formed the control group. Fifty-nine percent (n = 34) of the study group showed segmental, adenosine-induced myocardial perfusion defects compared to none of the control group (P < 0.001). Global MPR was lower in the study group compared to the control group: 2.3 (1.5-3.1) vs. 3.1 (2.0-4.3), P = 0.016. The SYNTAX score was higher in the study group patients with an impaired MPR (<2) compared to those with a preserved MPR (3.0 vs. 16.0, P = 0.01)-mainly due to higher prevalence of proximal epicardial stenoses (60% vs. 27%, P = 0.02) and multi-vessel disease (56% vs. 24%, P = 0.017). The diagnostic yield of stress CMR for the diagnosis of CAD (>50% stenosis) increased from 65to 88% when global MPR assessment was considered in addition to MPI (P = 0.025). Global MBF and MPR values correlate with the anatomical extent and complexity of CAD and increase the diagnostic yield of non-invasive stress CMR in the work-up of CAD. CMR-based MBF and MPR measurements may play a future role in the evaluation of the total ischaemic burden-particularly in patients with multi-vessel disease.

Assessment of segmental myocardial blood flow and myocardial perfusion reserve by adenosine-stress myocardial arterial spin labeling perfusion imaging.

To determine the feasibility of measuring increases in myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) on a per-segment basis using arterial spin labeled (ASL) magnetic resonance imaging (MRI) with adenosine vasodilator stress in normal human myocardium. Myocardial ASL scans at rest and during adenosine infusion were incorporated into a routine 3T MR adenosine-induced vasodilator stress protocol and were performed in 10 healthy human volunteers. Myocardial ASL was performed using single-gated flow-sensitive alternating inversion recovery (FAIR) tagging and balanced steady-state free precession (bSSFP) imaging at 3T. A T2 -prep blood oxygen level-dependent (BOLD) SSFP sequence was used to concurrently assess segmental myocardial oxygenation with BOLD signal intensity (SI) percent change in the same subjects. There was a statistically significant difference between MBF measured by ASL at rest (1.75 ± 0.86 ml/g/min) compared to adenosine stress (4.58 ± 2.14 ml/g/min) for all wall segments (P < 0.0001), yielding a per-segment MPR of 3.02 ± 1.51. When wall segments were divided into specific segmental myocardial perfusion territories (ie, anteroseptal, anterior, anterolateral, inferolateral, inferior, and inferoseptal), the differences between rest and stress regional MBF for each territory remained consistently statistically significant (P < 0.001) after correcting for multiple comparisons. This study demonstrates the feasibility of measuring MBF and MPR on a segmental basis by single-gated cardiac ASL in normal volunteers. Second, this study demonstrates the feasibility of performing the ASL sequence and T2 -prepared SSFP BOLD imaging during a single adenosine infusion. 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:413-420.

4‐HNE modified TRPV1 dysfunction leads to loss of capsaicin‐mediated eNOS activity and microvascular dysfunction

Our lab has previously demonstrated enhanced 4‐hydroxynonenal (4‐HNE) post‐translational modification (PTM) of TRPV1 decreases TRPV1 functional expression and contributes to microvascular dysfunction in diabetes. Furthermore, recent studies have shown TRPV1 activation elicits eNOS activation and NO production. Accordingly, we hypothesize that the enhanced 4‐HNE‐mediated PTM of TRPV1 contributes to diabetic microvascular dysfunction in db/db mice via decreased eNOS activation and resultant signaling. Contrast echocardiography demonstrated that 4‐HNE decreased capsaicin mediated increases in myocardial blood flow and decreased capsaicin‐mediated relaxation in isolated coronary microvessels. TRPV1 functional analysis using calcium imaging revealed blunted capsaicin‐mediated calcium influx in the presence of 4‐HNE in isolated mouse coronary endothelial cells (MCECs). Finally, 4‐HNE treatment of MCECs decreased eNOS phosphorylation at Ser1197 leading to decreased measure in capsaicin‐mediated nitrate production. Single point mutation, of a pore region cysteine residue 621, rescued channel activity and preserved capsaicin‐mediated eNOS phosphorylation and NO production. These data suggest that TRPV1 is targeted by redox‐active substances that directly modulate channel activity at numerous sites in diabetes to decrease TRPV1 functional expression and contribute to microvascular dysfunction. The results obtained demonstrate a signaling pattern aberrant in TRPV1 regulation of vascular control in diabetes.

Abstract 12519: Age Impacts the Interpretation of Myocardial Blood Flow Values in Cardiac PET/CT

Introduction: Quantitative myocardial blood flow (MBF) obtained via Rb82 PET/CT using regadenoson provides the ability to assess ischemia through analysis of stress MBF and coronary flow reserve (CFR), the augmentation of flow expressed as a stress/rest ratio. It is unknown to what extent, if any, age-related changes in arteries (i.e. arterial stiffening, atherosclerosis) impact MBF and, thus, the interpretation of ischemia. Hypothesis: MBF values change as a function of age and impact PET interpretation. Methods: Patients who underwent PET/CT from May 2013 to April 2015 with normal perfusion images and no history of PCI or CABG were included (n=3329, 1720 women, 1498 men). Rest MBF, stress MBF, and CFR) (mL/min/g) were recorded in all vessels separated by gender and by age &lt;60 or ≥60. Analysis was conducted on individual vessels and global estimates were calculated averaging all vessels. Estimated average median differences between age &lt;60 and ≥60 were adjusted for traditional cardiovascular risk factors (BMI, smoking, diabetes, hypertension, hyperlipidemia, family history). Results: Effects of Age on Global MBF Adjusted for Traditional Risk Factors Conclusions: In patients ≥60 years of age with normal perfusion imaging, rest MBF increases, stress MBF decreases, and the resultant CFR is decreased, all statistically significant. This may reflect a higher fixed level of vasodilation in older vessels at rest and a more limited ability to vasodilate with stress independent of other CV risk factors. Given the increasing use of PET/CT for ischemia assessment, it is important to recognize expected MBF changes with age to decrease false positive studies and unwarranted invasive testing.

Coronary vasomotor function in infarcted and remote myocardium after primary percutaneous coronary intervention

ObjectiveIn patients with acute myocardial infarction (AMI), coronary vasomotor function is impaired in the myocardial territory supplied by the culprit artery and in remote myocardium supplied by angiographically normal vessels....

Flow-mediated dilation: An evolving method.

Endothelial dysfunction embodies roles of precursor and perpetuator of systemic atherosclerotic disease. Identifying and quantifying its impact would therefore provide insight on the genesis of atherosclerosis initiation and progression. However, endothelial dysfunction comprises a broad spectrum of impaired functionsdranging from vascular tone regulation to plaque stabilizing propertiesdand available clinical methods effectively estimate only singular aspects of the underlying condition. Functionally, vasomotor regulation reflects endothelial function and its regulation occurs at the macrovascular [1] and microvascular [2] levels. Substantial evidence indicates that impairment in vasomotor function signalizes subsequent atherosclerotic disease [3e5] and recurrence of cardiovascular events [6,7]. However, this discriminator is not an effective surrogate indicator in all populations [2,8]. Some studies suggest that microvascular dysfunction predicts risk more reliably in healthier and younger populations as opposed to patients with established systemic, macrovascular atherosclerosis [9]. Flow mediated dilation methods (FMD) provide a surrogate endpoint to evaluate the potential dilatatory response of a conduit (macrovascular) artery stimulated by reactive hyperemia. This observed response generally mimics the increase in myocardial blood flow to accommodate local metabolic demands, known as coronary flow reserve [10,11]. Arterial flow and vessel wall shear stress variables (stimulus for FMD) are not traditionally assessed;

TRPV1 residues vital to protection against 4‐HNE modification, preservation of channel activity and microvascular function

We previously demonstrated enhanced 4-hydroxynonenal (4-HNE) post-translational modification (PTM) of TRPV1 decreases TRPV1 functional expression and contributes to microvascular dysfunction in diabetes. Accordingly, we hypothesized that manipulation of residues associated with 4-HNE PTM would preserve TRPV1 function and restore vascular integrity. 4-HNE decreased capsaicin mediated increases in myocardial blood flow and capsaicin-mediated relaxation in isolated coronary microvessels. TRPV1 functional analysis using electrophysiology revealed blunted capsaicin-mediated currents in the presence of 4-HNE which were reversed by the reactive carbonyl species scavenger aminoguanidine (AGD). Using computational biology, we identified three probable residues, previously identified to be important for oxidative modification, as potential sites for 4-HNE modification. The corresponding residues, C616, C621 and C634, were mutated to alanine (individually and in combination) and subsequently we examined the effects of 4-HNE on TRPV1 currents induced by capsaicin via electrophysiology. The mutation of the three pore cysteine (individually or in combination) abrogated the effects of 4-HNE on capsaicin-mediated currents. These data suggest that TRPV1 is targeted by redox-active substances that directly modulate channel activity at numerous sites in diabetes to decrease TRPV1 functional expression and contribute to microvascular dysfunction. The results obtained demonstrate an optimal redox state is critical for a properly functioning TRPV1 channel.

Abnormal myocardial blood flow in children with mild/moderate aortic stenosis.

To quantify myocardial blood flow in infants and children with mild or moderate aortic stenosis using adenosine-infusion cardiac magnetic resonance. It is unclear whether asymptomatic children with mild/moderate aortic stenosis have myocardial abnormalities. In addition, cardiac magnetic resonance-determined normative myocardial blood flow data in children have not been reported. We studied 31 infants and children with either haemodynamically normal hearts (n=20, controls) or mild/moderate aortic stenosis (n=11). The left ventricular myocardium was divided into six segments, and the change in average segmental signal intensity during contrast transit was used to quantify absolute flow (ml/g/minute) at rest and during adenosine infusion by deconvolution of the tissue curves with the arterial input of contrast. In all the cases, adenosine was well tolerated without complications. The mean pressure gradient between the left ventricle and the ascending aorta was higher in the aortic stenosis group compared with controls (24 versus 3 mmHg, p<0.001). Left ventricular wall mass was slightly higher in the aortic stenosis group compared with controls (65 versus 50 g/m², p<0.05). After adenosine treatment, both the absolute increase in myocardial blood flow (p<0.0001) and the hyperaemic flow significantly decreased (p<0.001) in children with mild/moderate aortic stenosis compared with controls. Abnormal myocardial blood flow in children with mild/moderate aortic stenosis may be an important therapeutic target.

Cardiac rehabilitation improves coronary endothelial function in patients with heart failure due to dilated cardiomyopathy: A positron emission tomography study.

Endothelial dysfunction is common in patients with heart failure and is associated with poor clinical outcome. Cardiac rehabilitation is able to enhance peripheral endothelial function but its impact on coronary vasomotion remains unknown. We aimed to evaluate the effect of cardiac rehabilitation on coronary vasomotion in patients with heart failure. We prospectively enrolled 29 clinically stable heart failure patients from non-ischaemic dilated cardiomyopathy and without coronary risk factors. Myocardial blood flow was quantified using (15)-O water positron emission tomography at rest and during a cold pressor test, before and after 12 weeks of cardiac rehabilitation and optimization of medical therapy. Rest myocardial blood flow was significantly improved after the completion of rehabilitation compared to baseline (1.31 ± 0.38 mL/min/g vs. 1.16 ± 0.41 mL/min/g, p = 0.04). The endothelium-related change in myocardial blood flow from rest to cold pressor test and the percentage of myocardial blood flow increase during the cold pressor test were both significantly improved after cardiac rehabilitation (respectively from -0.03 ± 0.22 mL/min/g to 0.19 ± 0.22 mL/min/g, p < 0.001 and from 101.5 ± 16.5% to 118.3 ± 24.4%, p < 0.001). Left ventricular ejection fraction, plasma levels of brain natriuretic peptide, maximal oxygen consumption and the Minnesota Living with Heart Failure Questionnaire score were also significantly improved. The improvement was not related to uptitration of medical therapy. Coronary endothelial function is altered in patients with heart failure due to non-ischaemic dilated cardiomyopathy. In these patients, cardiac rehabilitation significantly improves coronary vasomotion.

The effect of beta blocker withdrawal on adenosine myocardial perfusion imaging

BackgroundThe effect of beta blockers on myocardial blood flow (MBF) under vasodilators has been studied in several SPECT and PET myocardial perfusion imaging (MPI) studies with divergent results. The present study evaluated the effect of a beta blocker withdrawal on quantitative adenosine MBF and on MPI results. MethodsTwenty patients with beta blockers and CAD history were studied with quantitative adenosine N-13 ammonia PET. The first study was performed under complete medication and the second after beta blocker withdrawal. The PET studies were independently read with respect to MPI result and clinical decision making. ResultsGlobal MBF showed an increase from 180.2 ± 59.9 to 193.6 ± 60.8 mL·minute−1/100 g (P = .02) after beta blocker withdrawal. The segmental perfusion values were closely correlated (R2 = 0.82) over the entire range of perfusion values. An essentially different interpretation after beta blocker discontinuation was found in two cases (10%). ConclusionA beta blocker withdrawal induces an increase in adenosine MBF. In the majority of cases, MPI interpretation and decision making are independent of beta blocker intake. If a temporary beta blocker withdrawal before MPI is not possible or was not realized by the patient, it is appropriate to perform adenosine stress testing without loss of the essential MPI result.

4‐HNE post‐translational modification of TRPV1: implications for diabetic cardiomyopathy (1155.8)

Previously our lab has shown TRPV1 ‐dependent regulation of myocardial blood flow (MBF) is disrupted in a db/db mouse model of diabetic cardiomyopathy (DCM). A crucial mechanism behind pathologies seen in diabetes is the imbalance in oxidative stress (OS) leading to increased lipid peroxidation (LPO). The LPO product 4‐hydroxynonenal (4‐HNE) is known to increase oxidative post translational modification (PTM) resulting in altered protein function. Investigation into the implications of this oxidative PTM on TRPV1 has yet to be examined. Accordingly, we hypothesized that 4‐HNE PTM of TRPV1 results in decreased functional expression leading to perfusion impairments in DCM. Initial experiments were performed to evaluate 4‐HNE modification of TRPV1. Pull down experiments on HEK cells constitutively expressing TRPV1, treated with H2O2 (to simulate OS) and 4‐HNE, resulted in increased 4‐HNE modified TRPV1 compared to control with a concomitant decrease in TRPV1 expression. Similar findings were demonstrated in hearts from diabetic animals and controls treated with H2O2 and 4‐HNE. Computer generated modeling identified numerous possible residues capable of undergoing 4‐HNE modification of which several were confirmed using mass spectroscopy. TRPV1 functional analysis using path‐clamp electrophysiology revealed blunted capsaicin‐mediated currents in the presence of 4‐HNE and/or prolonged H2O2 treatment. Similarly, 4‐HNE decreased capsaicin mediated increases in MBF and relaxation in isolated coronary microvessels. These data suggest that increased OS in a diabetic state leads to decreased TRPV1 functional expression resulting in perfusion impairments seen in DCM.

0276: Dynamics of the perfusion reserve during adenosine-induced stress in rats

In clinical routine, myocardial perfusion MRI is generally performed with a stress/rest protocol using adenosine as a short living (10s half-life) stressor. Adenosine allows visualizing ischemic risk zones in the myocardium and is typically injected 3 to 4 minutes prior to stress imaging. To gain insight into perfusion dynamics under stress, we used a non-invasive and fast imaging procedure (cine-ASL) to study the longitudinal effect of a continuous injection of adenosine on myocardial blood flow (MBF) and MBF reserve in rats. MBF and MBF reserve were monitored every 5min following adenosine injection (140μg/kg/min) on 17 healthy Wistar rats at 4.7T. For the Stress group (N=6), adenosine was continuously injected for 40min. For the Stress/Recovery group (N=6), adenosine was injected for 25min and then stopped for the last 15min. Finally, for the Control group (N=7), a saline solution was injected for 40 min. Mean group MBF at rest was 5.4±0.5mL/g/min in a ROI covering the entire myocardium. Mean group MBF data are reported as a function of time after onset of adenosine (Fig). In every studied animal of the 2 first groups subjected to stress, an initial MBF increase was found within the first 5min following adenosine infusion. But, the maximum MBF response to adenosine was always obtained later, between 5-10min, followed by a continuous MBF decrease until 25min. Maximum stress perfusion was 10.8±1.4mL/g/min leading to a reserve of 2.1±0.3, consistent with previously reported study. This study focuses on MBF response dynamics to adenosine. In rats, maximum MBF response to adenosine was found between 5 to 10min. Such dynamic measurements give more detailed insight into rodent coronary reserve and coronary responses to infused vasodilators and may give complementary information on microvascular functional defects in non-ischemic heart disease models.

In vivo characterization of rodent cyclic myocardial perfusion variation at rest and during adenosine-induced stress using cine-ASL cardiovascular magnetic resonance.

BackgroundAssessment of cyclic myocardial blood flow (MBF) variations can be an interesting addition to the characterization of microvascular function and its alterations. To date, totally non-invasive in vivo methods with this capability are still lacking. As an original technique, a cine arterial spin labeling (ASL) cardiovascular magnetic resonance approach is demonstrated to be able to produce dynamic MBF maps across the cardiac cycle in rats.MethodHigh-resolution MBF maps in left ventricular myocardium were computed from steady-state perfusion-dependent gradient-echo cine images produced by the cine-ASL sequence. Cyclic changes of MBF over the entire cardiac cycle in seven normal rats were analyzed quantitatively every 6ms at rest and during adenosine-induced stress.ResultsThe study showed a significant MBF increase from end-systole (ES) to end-diastole (ED) in both physiological states. Mean MBF over the cardiac cycle within the group was 5.5 ± 0.6 mL g-1 min-1 at rest (MBFMin = 4.7 ± 0.8 at ES and MBFMax = 6.5 ± 0.6 mL g-1 min-1 at ED, P = 0.0007). Mean MBF during adenosine-induced stress was 12.8 ± 0.7mL g-1 min-1 (MBFMin = 11.7±1.0 at ES and MBFMax = 14.2 ± 0.7 mL g-1 min-1 at ED, P = 0.0007). MBF percentage relative variations were significantly different with 27.2 ± 9.3% at rest and 17.8 ± 7.1% during adenosine stress (P = 0.014). The dynamic analysis also showed a time shift of peak MBF within the cardiac cycle during stress.ConclusionThe cyclic change of myocardial perfusion was examined by mapping MBF with a steady-pulsed ASL approach. Dynamic MBF maps were obtained with high spatial and temporal resolution (6ms) demonstrating the feasibility of non-invasively mapping cyclic myocardial perfusion variation at rest and during adenosine stress. In a pathological context, detailed assessment of coronary responses to infused vasodilators may give valuable complementary information on microvascular functional defects in disease models.

Absolute flow or myocardial flow reserve for the detection of significant coronary artery disease?

We compared the accuracy of quantified myocardial flow reserve and absolute stress myocardial blood flow (MBF) alone in the detection of coronary artery disease (CAD). Myocardial flow reserve, i.e. ratio of stress and rest flow, has been commonly used to detect CAD with many imaging modalities. However, it is not known whether absolute stress flow alone is sufficient for detection of significant CAD. We enrolled 104 patients with moderate (30-70%) pre-test likelihood of CAD without previous myocardial infarction. MBF was measured by positron emission tomography and O-15-water at rest and during the adenosine stress in the regions of the left anterior descending, left circumflex, and right coronary artery. All the patients underwent invasive coronary angiography including the measurement of fractional flow reserve when appropriate. Quantified myocardial flow reserve (optimal cut-off value 2.5) detected significant coronary stenosis with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 81, 87, 66 and 94%, respectively. When compared with flow reserve, absolute MBF at stress (optimal cut-off value of 2.4 mL/min/g) was more accurate in detecting significant coronary stenosis [area under the curve (AUC) 0.94 vs. 0.90, P = 0.02] with sensitivity, specificity, PPV, and NPV of 95% (P = 0.03 vs. flow reserve), 90, 73, and 98%, respectively. An absolute increase of MBF from rest to stress by <1.5 mL/g/min had also similar accuracy in detecting CAD (AUC: 0.95). The results were comparable in patients who did and did not receive i.v. beta-blockers prior imaging. Absolute stress perfusion alone was superior to perfusion reserve in the detection of haemodynamically significant CAD and allows shorter imaging protocols with smaller radiation dose.

Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium

Following coronary artery occlusion growth of collateral vessels can provide an effective blood supply to the dependent myocardium. The ischemia, which results in growth of collateral vessels, recruits an inflammatory response with expression of cytokines and growth factors, upregulation of endothelial nitric oxide (NO) synthase (eNOS) in vascular endothelial cells, and expression of inducible nitric oxide synthase (iNOS) in both vessels and cardiac myocytes. Because NO is a potent collateral vessel dilator, this study examined whether NO derived from iNOS or constitutive NOS regulates myocardial blood flow (MBF) in the collateral region. Nonselective NOS inhibition with N(G)-nitro-l-arginine (LNA) caused vasoconstriction with a significant decrease in MBF to the collateral region during exercise. In contrast, the highly selective iNOS inhibitor 1400W caused a 21 ± 5% increase of MBF in the collateral region. This increase in MBF following selective iNOS blockade was proportionate to an increase in myocardial O2 consumption (MVo2). The results suggest that NO produced by iNOS inhibits MVo2 in the collateralized region, so that the increase in MBF following iNOS blockade was the result of metabolic vasodilation secondary to an increase in MVo2. Thus the coordinated expression of iNOS to restrain MVo2 and eNOS to maintain collateral vasodilation act to optimize the O2 supply-demand relationship and protect the collateralized myocardium from ischemia.