Cost-Effectiveness of Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation in the Australian Health Care System.

BACKGROUND: Heart transplantation is an effective treatment for end-stage congestive heart failure, however, achieving the right balance of immunosuppression to maintain graft function while minimising adverse effects is challenging. Serial endomyocardial biopsies (EMBs) are currently the standard for rejection surveillance, despite being invasive. Replacing EMB-based surveillance with cardiac magnetic resonance (CMR)-based surveillance for acute cardiac allograft rejection has shown feasibility. This study aimed to assess the cost-effectiveness of CMR-based surveillance in the first year after heart transplantation. METHOD: A prospective clinical trial was conducted with 40 orthotopic heart transplant (OHT) recipients. Participants were randomly allocated into two surveillance groups: EMB-based, and CMR-based. The trial included economic evaluations, comparing the frequency and cost of surveillance modalities in relation to quality-adjusted life years (QALYs) within the first year post-transplantation. Sensitivity analysis encompassed modelled data from observed EMB and CMR arms, integrating two hypothetical models of expedited CMR-based surveillance. RESULTS: In the CMR cohort, 238 CMR scans and 15 EMBs were conducted, versus (vs) 235 EMBs in the EMB group. CMR surveillance yielded comparable rejection rates (CMR 74 vs EMB 94 events, p=0.10) and did not increase hospitalisation risk (CMR 32 vs EMB 46 events, p=0.031). It significantly reduced the necessity for invasive EMBs by 94%, lowered costs by an average of AUD$32,878.61, and enhanced cumulative QALY by 0.588 compared with EMB. Sensitivity analysis showed that increased surveillance with expedited CMR Models 1 and 2 were more cost-effective than EMB (all p<0.01), with CMR Model 1 achieving the greatest cost savings (AUD$34,091.12±AUD$23,271.86 less) and utility increase (+0.62±1.49 QALYs, p=0.011), signifying an optimal cost-utility ratio. Model 2 showed comparable utility to the base CMR model (p=0.900) while offering the benefit of heightened surveillance frequency during periods of elevated rejection risk. CONCLUSIONS: CMR-based rejection surveillance in orthotopic heart transplant recipients provides a cost-effective alternative to EMB-based surveillance. Furthermore, it reduces the need for invasive procedures, without increased risk of rejection or hospitalisation for patients, and can be incorporated economically for expedited surveillance. These findings have important implications for improving patient care and optimising resource allocation in post-transplant management.

Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)-based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. METHODS: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. RESULTS: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P=0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P=0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P=0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. CONCLUSIONS: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. REGISTRATION: HREC/13/SVH/66 and HREC/17/SVH/80. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12618000672257.

Native T1 Mapping in the Diagnosis of Cardiac Allograft Rejection: A Prospective Histologically Validated Study.

OBJECTIVES: This study aimed to determine the role of T1 mapping in identifying cardiac allograft rejection. BACKGROUND: Endomyocardial biopsy (EMBx), the current gold standard to diagnose cardiac allograft rejection, is associated with potentially serious complications. Cardiac magnetic resonance (CMR)-based T1 mapping detects interstitial edema and fibrosis, which are important markers of acute and chronic rejection. Therefore, T1 mapping can potentially diagnose cardiac allograft rejection noninvasively. METHODS: Patients underwent CMR within 24 h of EMBx. T1 maps were acquired at 1.5-T. EMBx-determined rejection was graded according to International Society of Heart and Lung Transplant (ISHLT) criteria. RESULTS: Of 112 biopsies with simultaneous CMR, 60 were classified as group 0 (ISHLT grade 0), 35 as group 1 (ISHLT grade 1R), and 17 as group 2 (2R, 3R, clinically diagnosed rejection, antibody-mediated rejection). Native T1 values in patients with grade 0 biopsies and left ventricular ejection fraction >60% (983 ± 42 ms; 95% confidence interval: 972 to 994 ms) were comparable to values in nontransplant healthy control subjects (974 ± 45 ms; 95% confidence interval: 962 to 987 ms). T1 values were significantly higher in group 2 (1,066 ± 78 ms) versus group 0 (984 ± 42 ms; p = 0.0001) and versus group 1 (1,001 ± 54 ms; p = 0.001). After excluding patients with an estimated glomerular filtration rate <50 ml/min/m2, there was a moderate correlation of log-transformed native T1 with high-sensitivity troponin T (r = 0.54, p < 0.0001) and pro-B-type natriuretic peptide (r = 0.67, p < 0.0001). Using a T1 cutoff value of 1,029 ms, the sensitivity, specificity, and negative predictive value were 93%, 79%, and 99%, respectively. CONCLUSIONS: Myocardial tissue characterization with T1 mapping displays excellent negative predictive capacity for the noninvasive detection of cardiac allograft rejection and holds promise to reduce substantially the EMBx requirement in cardiac transplant rejection surveillance.

Native T1 in discrimination of acute and convalescent stages in patients with clinical diagnosis of myocarditis: a proposed diagnostic algorithm using CMR.

OBJECTIVES: This study investigated whether T1 mapping by cardiac magnetic resonance (CMR) reflects the clinical evolution of disease in myocarditis and supports its diagnosis independently of the disease stages. BACKGROUND: Acute viral myocarditis is characterized by a range of intracellular changes due to viral replication and extracellular spill of debris within days of viral infection. Convalescence may be characterized by a chronic low-grade inflammation leading to ventricular remodelling, but also a complete resolution of myocardial changes. METHODS: Patients with clinical diagnosis of viral myocarditis (N = 165) underwent routine clinical CMR protocol (1.5- and 3.0-T) for assessment of cardiac function and structure, and tissue characterization with T2-weighted imaging and late gadolinium enhancement. T1 mapping was obtained in a mid-ventricular short-axis slice before and >20 min after administration of 0.2 mmol/kg of gadobutrol. RESULTS: Compared with control subjects (n = 40), T1 indexes were increased in patients with myocarditis. Patients with acute symptoms (n = 61) had higher values of T1 indexes compared with patients in clinical convalescence (n = 67). Native T1 is an independent discriminator between health and disease, as well as a discriminator between acute and convalescent stage of the disease. Native T1- was superior to T2-weighted imaging and late gadolinium enhancement with high diagnostic accuracy and positive and negative predictive values. Using pre-defined cutoff values for normal ranges, we demonstrated that acute myocarditis can be independently identified by native T1 of >5 SD above the mean of normal range, whereas convalescence is best defined by either abnormal native T1 (>2 SD) or presence of late gadolinium enhancement. We prospectively tested a new diagnostic algorithm in an independent dataset of patients with clinical diagnosis of myocarditis and achieved similar diagnostic performance. CONCLUSIONS: The new diagnostic algorithm using native T1 can reliably discriminate between health and disease and determine the clinical disease stage in patients with a clinical diagnosis of myocarditis.

Accuracy and clinical outcomes of computed tomography coronary angiography in the presence of a high coronary calcium score.

BACKGROUND: A high coronary calcium burden may adversely affect image quality of CT coronary angiography (CTCA). The ability to rule out clinically significant disease in this setting is uncertain. METHODS: We examined CTCA findings in patients with a calcium score of >600. Utilising a search of death notices, structured patient interview and medical records, downstream investigations, cardiovascular events, revascularisation and mortality were recorded. RESULTS: Sixty patients with a calcium score >600 had CTCA performed on the same day. Coronary disease findings were: mild 28%, moderate 33%, severe 32% and non-diagnostic 7%. During a median 1.75-year follow-up, 31 (53%) of patients underwent further assessment for coronary disease, eight patients (13%) underwent revascularisation and there were two non-cardiovascular and one cardiovascular deaths. No patient with mild or moderate disease at CTCA had subsequently demonstrated ischaemia, was deemed to require PCI or suffered cardiac mortality. The negative predictive value of CTCA for subsequent PCI and all-cause mortality was 97% (100% for cardiac mortality only). The positive predictive value of CTCA for revascularisation or CV death was 42%. CONCLUSION: In patients with an elevated coronary calcium score, a negative CTCA implies an excellent short-term outcome and appears to exclude clinically significant coronary disease.

Four-dimensional image processing of myocardial CT perfusion for improved image quality and noise reduction.

BACKGROUND: Image noise and multiple sources of artifact may affect the accurate interpretation of myocardial CT perfusion (CTP) studies. Although artifact within the image is often time dependent, tissue characteristics remain unchanged irrespective of cardiac phase. OBJECTIVE: We assessed a new technique of 4-dimensional, spatiotemporal analysis, using redundant time domain information within additional phase acquisitions to reduce CTP image noise. METHODS: Four-dimensional analysis was assessed in a static phantom and in 10 CTP studies with invasive fractional flow reserve (FFR) correlation. For each voxel within the CTP study the distribution of local Hounsfield values was measured in both time and space with the use of a customized program within MATLAB software. These values were filtered to eliminate those likely to represent noise or rapidly changing beam hardening artifact. All CTP images were acquired within a single heartbeat with 320 detector-row CT. Image noise was quantified as the SD of voxel values within myocardial segments. Contrast was measured between normal and abnormal vascular territories as assessed by FFR. RESULTS: The mean image noise within the unprocessed CTP images was 30 HU (range, 23-42 HU). After 4-dimensional filtering the mean image noise was 22 HU (range, 15-29 HU). The mean reduction in image noise was 28% (P < 0.001). The mean contrast between normally perfused and ischemic segments was not significantly changed. The mean increase in contrast-to-noise ratio between ischemic territories and the myocardial average was 52% (P < 0.001). CONCLUSION: Four-dimensional analysis of CTP significantly reduces image noise and may assist in the assessment of myocardial perfusion studies.

Defining the mid-diastolic imaging period for cardiac CT - lessons from tissue Doppler echocardiography.

BACKGROUND: Aggressive dose reduction strategies for cardiac CT require the prospective selection of limited cardiac phases. At lower heart rates, the period of mid-diastole is typically selected for image acquisition. We aimed to identify the effect of heart rate on the optimal CT acquisition phase within the period of mid-diastole. METHODS: We utilized high temporal resolution tissue Doppler to precisely measure coronary motion within diastole. Tissue-Doppler waveforms of the myocardium corresponding to the location of the circumflex artery (100 patients) and mid-right coronary arteries (50 patients) and the duration and timing of coronary motion were measured. Using regression analysis an equation was derived for the timing of the period of minimal coronary motion within the RR interval. In a validation set of 50 clinical cardiac CT examinations, we assessed coronary motion artifact and the effect of using a mid-diastolic imaging target that was adjusted according to heart rate vs a fixed 75% phase target. RESULTS: Tissue Doppler analysis shows the period of minimal cardiac motion suitable for CT imaging decreases almost linearly as the RR interval decreases, becoming extinguished at an average heart rate of 91 bpm for the circumflex (LCX) and 78 bpm for the right coronary artery (RCA). The optimal imaging phase has a strong linear relationship with RR duration (R2 = 0.92 LCX, 0.89 RCA). The optimal phase predicted by regression analysis of the tissue-Doppler waveforms increases from 74% at a heart rate of 55 bpm to 77% at 75 bpm. In the clinical CT validation set, the optimal CT acquisition phase similarly occurred later with increasing heart rate. When the selected cardiac phase was adjusted according to heart rate the result was closer to the optimal phase than using a fixed 75% phase. While this effect was statistically significant (p < 0.01 RCA/LCx), the mean effect of heart-rate adjustment was minor relative to typical beat-to-beat variability and available precision of clinical phase selection. CONCLUSION: High temporal resolution imaging of coronary motion can be used to predict the optimal acquisition phase in cardiac CT. The optimal phase for cardiac CT imaging within mid-diastole increases with increasing heart rate although the magnitude of change is small.

Maternal hemodynamics influence fetal hemodynamics in normal and hypertensive pregnancy.

OBJECTIVES: This observational case-control study aims to test whether there is a relationship between maternal systemic hemodynamics, maternal renin-angiotensin system and fetal hemodynamics in normal and hypertensive pregnancy. STUDY DESIGN: Four groups of non-pregnant women (n=18), pregnant controls (n=25), women with gestational hypertension (n=21) and preeclampsia (n=10) were included. MAIN OUTCOME MEASURES: Maternal echocardiography parameters, plasma renin and aldosterone were correlated with fetal Doppler parameters in third trimester pregnancy. RESULTS: Higher maternal mean arterial pressure and total peripheral vascular resistance were associated with lower fetal middle cerebral artery pulsatility index (PI) (r=-.51, p<0.01 and r=-.49, p<0.01, respectively); mean arterial pressure correlated negatively with ductus venosus PI (r=-.35, p=0.01); higher maternal plasma aldosterone levels were associated with lower maternal uterine artery resistance (r=-0.33, p=0.03). CONCLUSIONS: It seems that maternal hemodynamics influence fetal hemodynamics with protective adaptation in fetal cerebral and ductus venosus blood flow observed as maternal blood pressure and vascular resistance increase.

Pilot study evaluating the role of cardiac magnetic resonance imaging in monitoring adjuvant trastuzumab therapy for breast cancer.

AIM: To explore the incidence of subclinical cardiotoxicity in women treated with adjuvant trastuzumab in the early breast cancer setting using cardiac magnetic resonance imaging (cMRI). METHODS: The cardiac function and myocardial tissue characteristics of 25 women who had completed adjuvant trastuzumab therapy greater than 6 months previously was evaluated using MRI and comparing this with symptoms and routine echocardiography. RESULTS: Evidence of myocardial tissue damage was seen in two women in the absence of functional change or previous cardiac symptoms. CONCLUSION: Tissue characterization using cMRI may provide a useful tool in defining trastuzumab induced cardiotoxicity.

A method for coronary artery calcium scoring using contrast-enhanced computed tomography.

BACKGROUND: Limitations to the coronary calcium score include its requirement for noncontrast imaging and radiation exposure that approaches current methods for contrast-enhanced CT angiography. OBJECTIVES: We sought to derive and validate a method of measuring the coronary artery calcium score (CACS) from standard contrast-enhanced CT, obviating the need for a second non-contrast calcium scan. METHODS: The volume of intramural calcium of >320 HU in major coronary vessels was measured in 90 contrast-enhanced and traditional non-contrast calcium scan pairs. An empiric conversion factor was derived to convert the small voxel contrast-enhanced calcium volume to an Agatston calcium score. The accuracy of this technique was then prospectively validated in 120 consecutive patients undergoing clinical calcium scans and contrasted-enhanced coronary CT. Eleven patients were excluded from analysis because of the prespecified criteria of excessive noise in the contrast-enhanced CT or total coronary artery occlusion. RESULTS: The Pearson correlation of the contrast scan-derived calcium score with the measured CACS was r2 = 0.99. With standard CACS risk bands, agreement of the contrast-enhanced calcium score estimate with the measured CAC by quadratic weighted κ was 0.96. The 95% limits of agreement (Agatston units) were given by ±(3.2 + 0.14 × CACS + 4.44 mean square root of CACS). Inter-observer and intra-observer reliability with the intraclass correlation was 0.99. CONCLUSION: The calcium score can be accurately measured from contrast-enhanced cardiac CT scans with the use of a Hounsfield unit threshold of 320.

Granulocyte colony stimulating factor in chronic angina to stimulate neovascularisation: a placebo controlled crossover trial.

BACKGROUND: Experimental studies demonstrate that granulocyte colony stimulating factor (G-CSF) promotes neovascularisation and confers cardioprotection. OBJECTIVE: To assess the efficacy of repeated low dose G-CSF plus exercise on myocardial ischaemia in patients with severe chronic ischaemic heart disease. METHODS: 18 patients with Canadian Cardiovascular Society class III-IV angina completed a randomised, double blind, crossover study of dose adjusted G-CSF versus placebo. Exercise was commenced 6 weeks prior and continued for the duration of the study. G-CSF or placebo was administered daily for 5 consecutive days at fortnightly intervals for three cycles, followed by crossover after 6 weeks. Primary outcome was myocardial perfusion by cardiac magnetic resonance imaging (MRI). Secondary outcomes were: Seattle Angina and Utility Based Quality of Life Heart Questionnaire (SAQ/UBQ-H), Exercise Stress Test (EST) and quantification of endothelial progenitor cells (EPC) by flow cytometry and angiogenic cytokines by immunoassay. RESULTS: Compared with placebo, G-CSF had no effect on myocardial ischaemia by cardiac MRI, EST or SAQ/UBQ-H, despite effective EPC mobilisation (peak fold increase: CD34+ =19, CD34+ CD133+ = 37, CD34+ vascular endothelial growth factor receptor 2 (VEGFR-2)+ = 5, CD34+ CD133+ VEGFR-2+ = 3; all p<0.05 vs. placebo). Plasma levels of stromal cell derived factor 1, angiopoietin 1, interleukin 8 and tumour necrosis factor α decreased after a symptom limited EST while vascular endothelial growth factor and platelet derived growth factor remained unchanged. All cytokines were unchanged following G-CSF. Seven troponin I positive events occurred with G-CSF compared with three with placebo (p=0.289). High sensitivity C reactive protein and N terminal prohormone brain natriuretic peptide increased with G-CSF (both p<0.01 vs. placebo). CONCLUSION: In patients with chronic ischaemic heart disease, G-CSF mobilises EPCs but does not improve myocardial perfusion or angina. G-CSF increases plasma levels of adverse prognostic cardiac biomarkers. Clinical trial registration information Australian New Zealand Clinical Trials Registry: http://www.anzctr.org.au. Unique identifier: ACTRN012607000354482.

Dynamic Changes in ST Segment Resolution After Myocardial Infarction and the Association with Microvascular Injury on Cardiac Magnetic Resonance Imaging.

BACKGROUND: persistent ST elevation after reperfused ST elevation myocardial infarction (STEMI) is believed to be related to poor microvascular perfusion. Cardiac magnetic resonance imaging (CMR) can evaluate microvascular obstruction (MVO) and intramyocardial haemorrhage (IMH) both of which represent severe microvascular damage, have independent prognostic value and are dynamic and evolving over the first 48hours after reperfusion. The aim of this study was to assess whether the development of MVO or IMH has an impact upon ST segment resolution. METHODS: patients undergoing primary percutaneous coronary intervention (PCI) for STEMI had serial 12 lead electrocardiograms (ECG) from one hour after PCI until discharge. Persistent single lead maximal residual ST elevation (maxSTE) at each time point was calculated. ST segment deterioration (re-elevation) was calculated on each ECG until discharge compared with one hour post PCI ECG. CMR was performed within seven days post infarct utilising T2 weighted imaging to evaluate culprit artery area at risk (AAR) and IMH. Gadolinium delayed enhancement CMR quantified infarct size and MVO. RESULTS: in the 41 patients studied 58% had MVO and 41% had IMH. ST segment deterioration was more common in those with MVO or IMH (p=0.03 and p=0.008 respectively). MaxSTE was higher at each time point after PCI in those with MVO but only became statistically significant after 24hours. The measurement of maxSTE at 48 or 72hours after revascularisation provided the best correlation with the combination of infarct size, AAR, MVO and intramyocardial haemorrhage. CONCLUSION: microvascular injury as defined on CMR is associated with dynamic changes and persistence of ST segment elevation in the first 72hours after reperfusion.

Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses.

AIMS: Neuregulin-1 (NRG-1) plays a critical role in the adaptation of the heart to injury, inhibiting apoptosis and inducing cardiomyocyte proliferation. We have shown previously that rhNRG-1 improves cardiac function and survival in animal models of cardiomyopathy. Here we report the first human study aimed at exploring the acute and chronic haemodynamic responses to recombinant human NRG-1 (beta(2a) isoform; rhNRG-1) in patients with stable chronic heart failure (CHF). METHODS AND RESULTS: Fifteen patients (age, 60 ± 2; NYHA II:III, 9:6; left ventricular ejection fraction (LVEF) <40%) on optimal medical therapy for CHF, received a rhNRG-1 infusion daily for 11 days. Acute and chronic haemodynamic, structural and biochemical effects were determined by serial right heart catheterization, cardiac magnetic resonance (CMR), echocardiography and measurement of neurohumoral indices. Acutely, cardiac output increased by 30% during a 6 h rhNRG-1 infusion (P < 0.01). Pulmonary artery wedge pressure and systemic vascular resistance decreased 30 and 20%, respectively, at 2 h (P < 0.01). A 47% reduction in serum noradrenaline, a 55% reduction in serum aldosterone and a 3.6-fold increase in N-terminal prohormone brain natriuretic peptide levels were concurrently observed (P < 0.001). These acute haemodynamic effects were sustained, as demonstrated by the 12% increase in LVEF from 32.2 ± 2.0% (baseline) to 36.1 ± 2.3% (mean ± SE, P < 0.001) at 12 weeks. The therapy was well tolerated. CONCLUSION: rhNRG-1 appears to produce favourable acute and chronic haemodynamic effects in patients with stable CHF on optimal medical therapy. Randomized controlled trials of rhNRG-1 in cardiac disease are thus warranted. Clinical Trial Registration Information The trial was registered with the Australian New Zealand Clinical Trials Registry, anzctr.org.au Identifier: ACTRN12607000330448.

Grade 3 ischemia on the admission electrocardiogram is associated with severe microvascular injury on cardiac magnetic resonance imaging after ST elevation myocardial infarction.

BACKGROUND: Grade 3 ischemia during ST elevation myocardial infarction (STEMI) is defined as ST elevation with distortion of the terminal portion of the QRS on electrocardiogram (ECG). The aim of this study was to evaluate the effect of ischemic grade on cardiac magnetic resonance (CMR) imaging infarct characteristics such as infarct size, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and myocardial salvage. METHODS: Patients with STEMI treated with primary percutaneous coronary intervention had a 12-lead ECG on presentation for analysis of ischemic grade. Gadolinium-enhanced CMR imaging was performed within 7 days to assess infarct size, MVO, IMH, and myocardial salvage. RESULTS: Of the 37 patients enrolled in the study, grade 3 ischemia was present in 32%. Those with grade 3 ischemia had higher peak troponin I levels (P = .013), more MVO (P < .001), more IMH (P < .001), larger infarct size (P = .025), and less myocardial salvage (P = .012). Regression analysis found that grade 3 ischemia, infarct size, and peak troponin I level were significantly associated with MVO and IMH. CONCLUSION: Grade 3 ischemia on the admission ECG during STEMI is closely associated with the development of severe microvascular damage on CMR imaging.

Reproducibility of adenosine stress cardiovascular magnetic resonance in multi-vessel symptomatic coronary artery disease.

PURPOSE: First-pass perfusion cardiovascular magnetic resonance (CMR) is increasingly being utilized in both clinical practice and research. However, the reproducibility of this technique remains incompletely evaluated, particularly in patients with severe coronary artery disease (CAD). The purpose of this study was to determine the inter-study reproducibility of adenosine stress CMR in patients with symptomatic multi-vessel CAD and those at low risk for CAD. METHODS: Twenty patients (10 with CAD, 10 low risk CAD) underwent two CMR scans 8 +/- 2 days apart. Basal, mid and apical left ventricular short axis slices were acquired using gadolinium 0.05 mmol/kg at peak stress (adenosine, 140 micro/kg/min, 4 min) and rest. Myocardial perfusion was evaluated qualitatively by assessing the number of ischemic segments, and semi-quantitatively by determining the myocardial perfusion reserve index (MPRi) using a normalized upslope method. Inter-study and observer reproducibility were assessed--the latter being defined by the coefficient of variation (CoV), which was calculated from the standard deviation of the differences of the measurements, divided by the mean. Additionally, the percentage of myocardial segments with perfect agreement and inter- and intra-observer MPRi correlation between studies, were also determined. RESULTS: The CoV for the number of ischemic segments was 31% with a mean difference of -0.15 +/- 0.88 segments and 91% perfect agreement between studies. MPRi was lower in patients with CAD (1.13 +/- 0.21) compared to those with low risk CAD (1.59 +/- 0.58), p = 0.02. The reproducibility of MPRi was 19% with no significant difference between patients with CAD and those with low risk CAD (p = 0.850). Observer reproducibility for MPRi was high: inter-observer CoV 9%, r = 0.93 and intra-observer CoV 5%, r = 0.94. For trials using perfusion CMR as an endpoint, an estimated sample size of 12 subjects would be required to detect a two-segment change in the number of ischemic segments (power 0.9, alpha 0.05). CONCLUSIONS: Adenosine stress CMR, by qualitative and semi-quantitative normalized upslope analyses are reproducible techniques in both patients with multi-vessel CAD and those without known CAD. The robust inter-study reproducibility of perfusion CMR supports its clinical and research application.