The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy.

The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We investigate here the role of mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. Mst2(-/-) mice showed no alteration in cardiomyocyte proliferation. However, Mst2(-/-) mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of MST2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the prohypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (Yes-associated protein) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human MST2 gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart.

Multiparametric cardiovascular magnetic resonance surveillance of acute cardiac allograft rejection and characterisation of transplantation-associated myocardial injury: a pilot study.

BACKGROUND: Serial surveillance endomyocardial biopsies are performed in patients who have recently undergone heart transplantation in order to detect acute cardiac allograft rejection (ACAR) before symptoms occur, however the biopsy process is associated with a number of limitations. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterize graft recovery following transplantation. METHODS: All patients receiving a heart transplant at a single UK centre over a period of 25 months were approached within one month of transplantation. Multiparametric CMR was prospectively performed on the same day as biopsy on four separate occasions (6 weeks, 10 weeks, 15 weeks and 20 weeks post-transplant). CMR included assessment of global and regional ventricular function, myocardial tissue characterization (T1 mapping, T2 mapping, extracellular volume, LGE) and pixel-wise absolute myocardial blood flow quantification. CMR parameters were compared with biopsy findings. As is standard, grade 2R or higher ACAR was considered significant. RESULTS: 88 CMR-matched biopsies were performed in 22 patients. Eight (9%) biopsies in 5 patients demonstrated significant ACAR. Significant ACAR was associated with a reduction in circumferential strain (-12.7±2.5% vs. -13.7±3.6%, p=0.047) but there was considerable overlap between groups. Whilst trends were observed between ACAR and proposed CMR markers of oedema, particularly after adjusting for primary graft dysfunction, differences were not significant. Significant improvements were seen in markers of graft structure and contractility, oedema and microvascular function over the period studied, although few parameters normalised. CONCLUSIONS: This study provides novel insight into the myocardial injury associated with transplantation, and its recovery, however multiparametric CMR was not able to accurately detect ACAR during the early phase post-transplantation.

Voxel-wise quantification of myocardial blood flow with cardiovascular magnetic resonance: effect of variations in methodology and validation with positron emission tomography.

BACKGROUND: Quantitative assessment of myocardial blood flow (MBF) from cardiovascular magnetic resonance (CMR) perfusion images appears to offer advantages over qualitative assessment. Currently however, clinical translation is lacking, at least in part due to considerable disparity in quantification methodology. The aim of this study was to evaluate the effect of common methodological differences in CMR voxel-wise measurement of MBF, using position emission tomography (PET) as external validation. METHODS: Eighteen subjects, including 9 with significant coronary artery disease (CAD) and 9 healthy volunteers prospectively underwent perfusion CMR. Comparison was made between MBF quantified using: 1. Calculated contrast agent concentration curves (to correct for signal saturation) versus raw signal intensity curves; 2. Mid-ventricular versus basal-ventricular short-axis arterial input function (AIF) extraction; 3. Three different deconvolution approaches; Fermi function parameterization, truncated singular value decomposition (TSVD) and first-order Tikhonov regularization with b-splines. CAD patients also prospectively underwent rubidium-82 PET (median interval 7 days). RESULTS: MBF was significantly higher when calculated using signal intensity compared to contrast agent concentration curves, and when the AIF was extracted from mid- compared to basal-ventricular images. MBF did not differ significantly between Fermi and Tikhonov, or between Fermi and TVSD deconvolution methods although there was a small difference between TSVD and Tikhonov (0.06 mL/min/g). Agreement between all deconvolution methods was high. MBF derived using each CMR deconvolution method showed a significant linear relationship (p<0.001) with PET-derived MBF however each method underestimated MBF compared to PET (by 0.19 to 0.35 mL/min/g). CONCLUSIONS: Variations in more complex methodological factors such as deconvolution method have no greater effect on estimated MBF than simple factors such as AIF location and observer variability. Standardization of the quantification process will aid comparison between studies and may help CMR MBF quantification enter clinical use.

Development and validation of the ASGARD risk score for safe monitoring in asymptomatic nonsevere aortic stenosis.

AIMS: Current guidelines recommend serial echocardiography at minimum 1-2 year intervals for monitoring patients with nonsevere aortic valve stenosis (AS), which is costly and often clinically inconsequential.We aimed to develop and test whether the biomarker-based ASGARD risk score (Aortic Valve Stenosis Guarded by Amplified Risk Determination) can guide the timing of echocardiograms in asymptomatic patients with nonsevere AS. METHODS: The development cohort comprised 1,093 of 1,589 (69%) asymptomatic patients with mild-to-moderate AS who remained event-free one year after inclusion into the SEAS trial. Cox regression landmark analyses with a 2-year follow-up identified the model (ASGARD) with the lowest Akaike information criterion for association to AS-related composite outcome (heart failure hospitalization, aortic valve replacement, or cardiovascular death). Fine-Gray analyses provided cumulative event rates by ASGARD score quartiles. The ASGARD score was internally validated in the remaining 496 patients (31%) from the SEAS-cohort and externally in 71 asymptomatic outpatients with nonsevere AS from six Copenhagen hospitals. RESULTS: The ASGARD score comprises updated measurements of heart rate and age- and sex-adjusted N-terminal pro-brain natriuretic peptide upon transaortic maximal velocity (Vmax) from the previous year. The ASGARD score had high predictive accuracy across all cohorts (external validation: area under the curve: 0.74 [95% CI, 0.62-0.86]), and similar to an updated Vmax measurement. An ASGARD score ≤50% was associated with AS-related event rates ≤5% for a minimum of 15 months. CONCLUSION: The ASGARD score could provide a personalized and safe surveillance alternative to routinely planned echocardiograms, so physicians can prioritize echocardiograms for high-risk patients.

In this study, we developed and examined the potential of the novel ASGARD risk score to tailor personalized follow-up intervals for diagnostic heart scans, incorporating updated heart rate and blood marker measurements along with the heart scan data from the previous year. Patients with the ASGARD risk score within the lowest 50% had a low annual risk of aortic valve-related events (less than 5%) for a minimum of 15 months.In clinical settings, the ASGARD score could provide a personalized and safe monitoring alternative to routine heart scans, prioritizing the diagnostic heart scans for high-risk patients.

Association of high-sensitivity troponin T with outcomes in asymptomatic non-severe aortic stenosis: a post-hoc substudy of the SEAS trial.

Background: High-sensitivity Troponin T (hsTnT), a biomarker of cardiomyocyte overload and injury, relates to aortic valve replacement (AVR) and mortality in severe aortic stenosis (AS). However, its prognostic value remains unknown in asymptomatic patients with AS. We aimed to investigate if an hsTnT level >14 pg/mL (above upper limit of normal 99th percentile) is associated with echocardiographic AS-severity, subsequent AVR, ischaemic coronary events (ICE), and mortality in asymptomatic patients with non-severe AS. Methods: In this post-hoc sub-analysis of the multicentre, randomised, double-blind, placebo-controlled SEAS trial (ClinicalTrials.gov, NCT00092677), we included asymptomatic patients with mild to moderate-severe AS. We ascertained baseline and 1-year hsTnT concentrations and examined the association between baseline levels and the risk of the primary composite endpoint, defined as the first event of all-cause mortality, isolated AVR (without coronary artery bypass grafting (CABG)), or ICE. Multivariable regressions and competing risk analyses examined associations of hsTnT level >14 pg/mL with clinical correlates and 5-year risk of the primary endpoint. Findings: Between January 6, 2003, and March 4, 2004, a total of 1873 patients were enrolled in the SEAS trial, and 1739 patients were included in this post-hoc sub-analysis. Patients had a mean (SD) age of 67.5 (9.7) years, 61.0% (1061) were men, 17.4% (302) had moderate-severe AS, and 26.0% (453) had hsTnT level >14 pg/mL. The median hsTnT difference from baseline to 1-year was 0.8 pg/mL (IQR, -0.4 to 2.3). In adjusted linear regression, log(hsTnT) did not correlate with echocardiographic AS severity (p = 0.36). In multivariable Cox regression, a hsTnT level >14 pg/mL vs. hsTnT ≤14 pg/mL was associated with an increased risk of the primary composite endpoint (HR, 1.41; 95% CI, 1.18-1.70; p = 0.0002). In a competing risk model of first of the individual components of the primary endpoint, a hsTnT level >14 pg/mL was associated with ICE risk (HR 1.71; 95% CI, 1.23-2.38; p = 0.0013), but not with isolated AVR (p = 0.064) or all-cause mortality (p = 0.49) as the first event. Interpretation: hsTnT level is within the reference range (≤14 pg/mL) in 3 out of 4 non-ischaemic patients with asymptomatic mild-to-moderate AS and remains stable during a 1-year follow-up regardless of AS-severity. An hsTnT level >14 pg/mL was mainly associated with subsequent ICE, which suggest that hsTnT concentration is primarily a risk marker of subclinical coronary atherosclerotic disease. Funding: Merck & Co., Inc., the Schering-Plough Corporation, the Interreg IVA program, Roche Diagnostics Ltd., and Gangstedfonden. Open access publication fee funding provided by prof. Olav W. Nielsen and Department of Cardiology, Bispebjerg University Hospital, Denmark.

Association of Annual N-Terminal Pro-Brain Natriuretic Peptide Measurements With Clinical Events in Patients With Asymptomatic Nonsevere Aortic Stenosis: A Post Hoc Substudy of the SEAS Trial.

IMPORTANCE: Recent studies have questioned the presumed low-risk status of patients with asymptomatic nonsevere aortic stenosis (AS). Whether annual N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements are useful for risk assessment is unknown. OBJECTIVE: To assess the association of annual NT-proBNP measurements with clinical outcomes in patients with nonsevere AS. DESIGN, SETTING, AND PARTICIPANTS: Analysis of annual NT-proBNP concentrations in the multicenter, double-blind Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) randomized clinical trial was performed. SEAS was conducted from January 6, 2003, to April 1, 2008. Blood samples were analyzed in 2016, and data analysis was performed from February 10 to October 10, 2021. SEAS included 1873 patients with asymptomatic AS not requiring statin therapy with transaortic maximal flow velocity from 2.5 to 4.0 m/s and preserved ejection fraction. This substudy included 1644 patients (87.8%) with available blood samples at baseline and year 1. EXPOSURES: Increased age- and sex-adjusted NT-proBNP concentrations at year 1 and a 1.5-fold or greater relative NT-proBNP concentration change from baseline to year 1. Moderate AS was defined as baseline maximal flow velocity greater than or equal to 3.0 m/s. MAIN OUTCOMES AND MEASURES: Aortic valve events (AVEs), which are a composite of aortic valve replacement, cardiovascular death, or incident heart failure due to AS progression, were noted. Landmark analyses from year 1 examined the association of NT-proBNP concentrations with outcomes. RESULTS: Among 1644 patients, 996 were men (60.6%); mean (SD) age was 67.5 (9.7) years. Adjusted NT-proBNP concentrations were within the reference range (normal) in 1228 of 1594 patients (77.0%) with NT-proBNP values available at baseline and in 1164 of 1644 patients (70.8%) at year 1. During the next 2 years of follow-up, the AVE rates per 100 patient-years for normal vs increased adjusted NT-proBNP levels at year 1 were 1.39 (95% CI, 0.86-2.23) vs 7.05 (95% CI, 4.60-10.81) for patients with mild AS (P < .01), and 10.38 (95% CI, 8.56-12.59) vs 26.20 (95% CI, 22.03-31.15) for those with moderate AS (P < .01). Corresponding all-cause mortality rates were 1.05 (95% CI, 0.61-1.81) vs 4.17 (95% CI, 2.42-7.19) for patients with mild AS (P < .01), and 1.60 (95% CI, 0.99-2.57) vs 4.78 (95% CI, 3.32-6.87) for those with moderate AS (P < .01). In multivariable Cox proportional hazards regression models, the combination of a 1-year increased adjusted NT-proBNP level and 1.5-fold or greater NT-proBNP level change from baseline was associated with the highest AVE rates in both patients with mild AS (hazard ratio, 8.12; 95% CI, 3.53-18.66; P < .001) and those with moderate AS (hazard ratio, 4.05; 95% CI, 2.84-5.77; P < .001). CONCLUSIONS AND RELEVANCE: The findings of this study suggest that normal NT-proBNP concentrations at 1-year follow-up are associated with low AVE and all-cause mortality rates in patients with asymptomatic nonsevere AS. Conversely, an increased 1-year NT-proBNP level combined with a 50% or greater increase from baseline may be associated with high AVE rates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00092677.

Impaired glucose tolerance and insulin resistance in heart failure: underrecognized and undertreated?

BACKGROUND: A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear. METHODS AND RESULTS: The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR. CONCLUSIONS: We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients.

Left ventricular filling and diastolic myocardial deformation in chronic primary mitral regurgitation.

AIMS: Chronic primary mitral regurgitation (MR) results in enhanced filling of the left ventricle (LV) during early diastole. Filling is impaired with the onset of LV systolic dysfunction, due to increased myocardial stiffness and reduced restoring forces. We investigated echocardiographic parameters of early diastolic function in relation to LV systolic function. METHODS AND RESULTS: Early diastolic transmitral flow and tissue Doppler velocities, propagation velocity of early filling (V(p)), and early diastolic strain rates (SR-E) were measured in 30 patients with chronic degenerative MR and 30 age-matched controls. MR subjects were further subdivided into group 1 (14 subjects) if they had well compensated LV, and group 2 (16 subjects) if they had one or more of the following: functional limitation (> NYHA class I), LV end-systolic diameter >or=4.0 cm, and LV ejection fraction

Left atrial function and deformation in chronic primary mitral regurgitation.

AIMS: To study global and regional left atrial (LA) mechanics in chronic primary mitral regurgitation (MR) with echocardiography. METHODS AND RESULTS: LA volumes during reservoir, conduit, and contractile phases were measured in 27 MR patients and 25 controls. LA ejection fraction (EF) and ejection force were calculated. Reservoir (SR-R), conduit (SR-C), and contractile phase (SR-A) strain rates, and reservoir phase strain were obtained. LA volumes were higher in MR in all phases. In MR, ejection force was increased (21.5 vs. 12.3 kdynes, P = 0.001); reservoir phase strain (32.91 +/- 14.26%), SR-R (2.65 +/- 0.87), SR-C (-2.02 +/- 0.58), and SR-A (-2.55 +/- 1.31 s(-1)) were increased (23.14 +/- 7.96%, 1.62 +/- 0.53, -1.29 +/- 0.59, -1.98 +/- 0.65 s(-1), in controls, respectively, P < or = 0.004). Regional deformation correlated with corresponding volumetric parameters. Despite enhanced SR-A in MR, LA EF was unchanged (31.34 vs. 29.23%, P = ns), and LA contractile tissue velocity (A') was reduced (-5.39 +/- 1.95 vs. -6.91 +/- 1.80 cm/s, P = 0.006). The LA contractile contribution to left ventricular filling was significantly reduced in MR. CONCLUSION: LA deformation is increased in all phases in MR. Unchanged LA EF and reduced A' may reflect the reduced contractile contribution to left ventricular filling.

Promoter polymorphism of the matrix metalloproteinase 3 gene is associated with regurgitation and left ventricular remodelling in mitral valve prolapse patients.

BACKGROUND AND AIMS: Mitral valve prolapse (MVP) is common and highly variable in its severity, but the factors underlying this variability are unclear. In this study, we tested the hypothesis that polymorphic variations in Matrix Metalloproteinase (MMP) genes might be predictors of left ventricular (LV) remodelling and severity of regurgitation in MVP. METHODS AND RESULTS: 70 MVP patients and 75 normal subjects were studied. We performed comprehensive echocardiography and analyzed promoter polymorphisms in the MMP-1 and MMP-3 genes. The MMP-3 -1612 5A/6A polymorphism showed strong associations with indices of mitral regurgitation and LV remodelling: Patients with 5A/5A allele had more pronounced remodelling and more severe mitral regurgitation than patients with the 6A/6A or 5A/6A alleles. We then cloned and sequenced 2 kb fragments of MMP-3 promoter from patients with 5A/5A and 6A/6A genotypes and found 4 different sets of promoter haplotypes. Promoter analysis showed that higher promoter activity was related to a more severe phenotype and that the haplotype variants had a more dominant role in determining the activity. CONCLUSIONS: Our data identifies the MMP-3 promoter haplotype as a novel marker of an adverse disease course in MVP, suggesting the presence of genetic determinants for the severity of MVP.

Identification of the Asymptomatic Patient With Severe Mitral Regurgitation: Discrepancy Between Research and Clinical Practice.

Organic mitral regurgitation (MR) is a common disorder, and because of the increase in population and its aging, the occurrence of MR is steadily increasing. Current guideline recommendations on the management of asymptomatic severe MR are conflicting and based solely on registries or nonrandomized trials in expert heart valve clinics, resulting in a lack of evidence for the best treatment strategy. In this review, we will evaluate the latest evidence on diagnostic approaches and treatment strategies for asymptomatic patients without a clear indication for surgical intervention. Implications for management in daily practice are discussed, including an update on the diagnostic approaches that are currently available for the evaluation of MR. For optimal care, it is important that every severe MR patient, including the unidentified patient, is referred to a specialized heart team and is assessed on an individual basis according to the guideline recommendations, experience of the surgical center, and the patient's characteristics and preferences. Screening and diagnostic approaches need to be performed on the basis of standardized protocols and strict criteria. In addition, specialized valve centers must meet the surgical criteria to guarantee high reparability rates in asymptomatic patients. Awareness among cardiologists and cardiothoracic surgeons, improved guidelines adherence, and a systematic approach, including strict criteria in the management of asymptomatic patients with severe organic MR, will ensure reliable and applicable results in research and daily clinical practice.

Total Center Percutaneous Coronary Intervention Volume and 30-Day Mortality: A Contemporary National Cohort Study of 427 467 Elective, Urgent, and Emergency Cases.

BACKGROUND: The relationship between procedural volume and prognosis after percutaneous coronary intervention (PCI) remains uncertain, with some studies finding in favor of an inverse association and some against. This UK study provides a contemporary reassessment in one of the few countries in the world with a nationally representative PCI registry. METHODS AND RESULTS: A nationwide cohort study was performed using the national British Cardiovascular Intervention Society registry. All adult patients undergoing PCI in 93 English and Welsh NHS hospitals between 2007 and 2013 were analyzed using hierarchical modeling with adjustment for patient risk. Of 427 467 procedures (22.0% primary PCI) in 93 hospitals, 30-day mortality was 1.9% (4.8% primary PCI). 87.1% of centers undertook between 200 and 2000 procedures annually. Case mix varied with center volume. In centers with 200 to 399 PCI cases per year, a smaller proportion were PCI for ST-segment-elevation myocardial infarction (8.4%) than in centers with 1500 to 1999 PCI cases per year (24.2%), but proportionally more were for ST-segment-elevation myocardial infarction with cardiogenic shock (8.4% versus 4.3%). For the overall PCI cohort, after risk adjustment, there was no significant evidence of worse, or better, outcomes in lower volume centers from our own study, or in combination with results from other studies. For primary PCI, there was also no evidence for increased or decreased mortality in lower volume centers. CONCLUSIONS: After adjustment for differences in case mix and clinical presentation, this study supports the conclusion of no trend for increased mortality in lower volume centers for PCI in the UK healthcare system. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT02184949.

Cardiac amyloidosis.

Systemic amyloidosis commonly affects the heart. Indeed, cardiac symptoms may be the first clinical indicator of underlying amyloid deposition. Using two case studies, this article reviews the latest evidence regarding cardiac amyloidosis. The diagnosis of cardiac involvement can be established through imaging with echocardiography and magnetic resonance. Supportive evidence may be gained from biochemical markers such as serum N-terminal probrain natriuretic peptide (NT-proBNP). The main clinical consequences of amyloid deposition are cardiac failure and rhythm disturbances. Attempts to cure the underlying disease process with chemotherapy and/or cardiac and/or liver transplantation have had variable results. Stem-cell transplantation is associated with significant mortality in the context of cardiac involvement. Although newer therapeutic agents are emerging, the overall outlook at this time remains poor.

Can the index of myocardial performance be used to detect acute cellular rejection after heart transplantation?

The index of myocardial performance (IMP), combining systolic and diastolic function, was measured in 50 orthotopic heart transplant recipients to determine if it could be used to detect acute rejection. It was calculated as the sum of the isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) divided by the ejection time. Comparison of intrarecipient changes in Doppler intervals between rejection and nonrejection states demonstrated an increase in IVCT and decrease in IVRT during rejection with no significant change in the IMP. Rejection is likely to be best detected by assessing these parameters independently rather than by measuring the IMP.

Comparison of echocardiographic markers of right ventricular function in determining prognosis in chronic pulmonary disease.

Right ventricular (RV) dysfunction determines prognosis in patients with chronic pulmonary disease. We examined the relative prognostic potential of measures of systolic, diastolic, and global RV function in 87 patients with chronic pulmonary disease. Systolic function was evaluated by measuring RV dimensions, diastolic function by pulsed wave Doppler of the tricuspid flow profile, and global function by the Tei index. After 15.5 months follow-up, 47 patients had died. Univariate analysis demonstrated that both clinical and echocardiographic variables predicted survival. In the multivariate model both RV end-diastolic diameter index and velocity of late diastolic filling were independent predictors of survival. Receiver operator characteristic analysis demonstrated that a composite model combining these 2 measures provided the most powerful prognostic information. Echocardiographic indices of RV function identify patients with pulmonary disease at high risk and provide incremental prognostic information over and above that supplied by clinical data.

Multiparametric cardiovascular magnetic resonance assessment of cardiac allograft vasculopathy.

OBJECTIVES: This study sought to evaluate the diagnostic performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting cardiac allograft vasculopathy (CAV) using contemporary invasive epicardial artery and microvascular assessment techniques as reference standards, and to compare the performance of CMR with that of angiography. BACKGROUND: CAV continues to limit the long-term survival of heart transplant recipients. Coronary angiography has a Class I recommendation for CAV surveillance and annual or biannual surveillance angiography is performed routinely in most centers. METHODS: All transplant recipients referred for surveillance angiography at a single UK center over a 2-year period were prospectively screened for study eligibility. Patients prospectively underwent coronary angiography followed by coronary intravascular ultrasound, fractional flow reserve, and index of microcirculatory resistance. Within 1 month, patients underwent multiparametric CMR, including assessment of regional and global ventricular function, absolute myocardial blood flow quantification, and myocardial tissue characterization. In addition, 10 healthy volunteers underwent CMR. RESULTS: Forty-eight patients were recruited, median 7.1 years (interquartile range: 4.6 to 10.3 years) since transplantation. The CMR myocardial perfusion reserve was the only independent predictor of both epicardial (ß = -0.57, p < 0.001) and microvascular disease (ß = -0.60, p < 0.001) on stepwise multivariable regression. The CMR myocardial perfusion reserve significantly outperformed angiography for detecting moderate CAV (area under the curve, 0.89 [95% confidence interval (CI): 0.79 to 1.00] vs. 0.59 [95% CI: 0.42 to 0.77], p = 0.01) and severe CAV (area under the curve, 0.88 [95% CI: 0.78 to 0.98] vs. 0.67 [95% CI: 0.52 to 0.82], p = 0.05). CONCLUSIONS: CAV, including epicardial and microvascular components, can be detected more accurately using noninvasive CMR-based absolute myocardial blood flow assessment than with invasive coronary angiography, the current clinical surveillance technique.