Cancer patients with venous thromboembolism: Diagnostic and prognostic value of elevated D-dimers.

BACKGROUND: D-dimer testing is known to have a high sensitivity at simultaneously low specificity, resulting in nonspecific elevations in a variety of conditions. METHODS: This retrospective study sought to assess diagnostic and prognostic features of D-dimers in cancer patients referred to the emergency department for suspected pulmonary embolism (PE) and deep vein thrombosis (DVT). In total, 526 patients with a final adjudicated diagnosis of PE (n = 83) and DVT (n = 69) were enrolled, whereas 374 patients served as the comparative group, in which venous thromboembolism (VTE) has been excluded. RESULTS: For the identification of VTE, D-dimers yielded the highest positive predictive value of 96% (95% confidence interval (CI), 85-99) at concentrations of 9.9 mg/L and a negative predictive value of 100% at .6 mg/L (95% CI, 97-100). At the established rule-out cut-off level of .5 mg/L, D-dimers were found to be very sensitive (100%) at a moderate specificity of nearly 65%. Using an optimised cut-off value of 4.9 mg/L increased the specificity to 95% for the detection of life-threatening VTE at the cost of moderate sensitivities (64%). During a median follow-up of 30 months, D-dimers positively correlated with the reoccurrence of VTE (p = .0299) and mortality in both cancer patients with VTE (p < .0001) and without VTE (p = .0008). CONCLUSIONS: Although D-dimer testing in cancer patients is discouraged by current guidelines, very high concentrations above the 10-fold upper reference limit contain diagnostic and prognostic information and might be helpful in risk assessment, while low concentrations remain useful for ruling out VTE.

Myocardial tissue changes detected by cardiac MRI in a patient with suspected systemic sarcoidosis.

BACKGROUND: The role of cardiac magnetic resonance imaging in the early management of chronic cardiac inflammatory conditions is growing. Our case enlightens the benefit of quantitative mapping in the monitoring and treatment guidance in systemic sarcoidosis. CASE PRESENTATION: We report about a 29-year-old man with an ongoing dyspnea and bihilar lymphadenopathy, suggesting sarcoidosis. Cardiac magnetic resonance showed high mapping values, but no scarring. In follow-ups, cardiac remodeling was noted; cardioprotective treatment normalized cardiac function and mapping markers. Definitive diagnosis was achieved in extracardiac lymphatic tissue during a relapse. CONCLUSION: This case shows the role that mapping markers can play in the detection and treatment at early stage of systemic sarcoidosis.

Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease.

BACKGROUND: In patients with stable angina, two strategies are often used to guide revascularization: one involves myocardial-perfusion cardiovascular magnetic resonance imaging (MRI), and the other involves invasive angiography and measurement of fractional flow reserve (FFR). Whether a cardiovascular MRI-based strategy is noninferior to an FFR-based strategy with respect to major adverse cardiac events has not been established. METHODS: We performed an unblinded, multicenter, clinical-effectiveness trial by randomly assigning 918 patients with typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test to a cardiovascular MRI-based strategy or an FFR-based strategy. Revascularization was recommended for patients in the cardiovascular-MRI group with ischemia in at least 6% of the myocardium or in the FFR group with an FFR of 0.8 or less. The composite primary outcome was death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. The noninferiority margin was a risk difference of 6 percentage points. RESULTS: A total of 184 of 454 patients (40.5%) in the cardiovascular-MRI group and 213 of 464 patients (45.9%) in the FFR group met criteria to recommend revascularization (P = 0.11). Fewer patients in the cardiovascular-MRI group than in the FFR group underwent index revascularization (162 [35.7%] vs. 209 [45.0%], P = 0.005). The primary outcome occurred in 15 of 421 patients (3.6%) in the cardiovascular-MRI group and 16 of 430 patients (3.7%) in the FFR group (risk difference, -0.2 percentage points; 95% confidence interval, -2.7 to 2.4), findings that met the noninferiority threshold. The percentage of patients free from angina at 12 months did not differ significantly between the two groups (49.2% in the cardiovascular-MRI group and 43.8% in the FFR group, P = 0.21). CONCLUSIONS: Among patients with stable angina and risk factors for coronary artery disease, myocardial-perfusion cardiovascular MRI was associated with a lower incidence of coronary revascularization than FFR and was noninferior to FFR with respect to major adverse cardiac events. (Funded by the Guy's and St. Thomas' Biomedical Research Centre of the National Institute for Health Research and others; MR-INFORM ClinicalTrials.gov number, NCT01236807.).

Cardiac biomarkers in chronic kidney disease are independently associated with myocardial edema and diffuse fibrosis by cardiovascular magnetic resonance.

BACKGROUND: High sensitivity cardiac troponin T (hs-cTnT) and NT-pro-brain natriuretic peptide (NT-pro BNP) are often elevated in chronic kidney disease (CKD) and associated with both cardiovascular remodeling and outcome. Relationship between these biomarkers and quantitative imaging measures of myocardial fibrosis and edema by T1 and T2 mapping remains unknown. METHODS: Consecutive patients with established CKD and estimated glomerular filtration rate (eGFR) < 59 ml/min/1.73 m2 (n = 276) were compared to age/sex matched patients with eGFR ≥ 60 ml/min/1.73 m2 (n = 242) and healthy controls (n = 38). Comprehensive cardiovascular magnetic resonance (CMR) with native T1 and T2 mapping, myocardial ischemia and scar imaging was performed with venous sampling immediately prior to CMR. RESULTS: Patients with CKD showed significant cardiac remodeling in comparison with both healthy individuals and non-CKD patients, including a stepwise increase of native T1 and T2 (p < 0.001 between all CKD stages). Native T1 and T2 were the sole imaging markers independently associated with worsening CKD in patients [B = 0.125 (95% CI 0.022-0.235) and B = 0.272 (95% CI 0.164-0.374) with p = 0.019 and < 0.001 respectively]. At univariable analysis, both hs-cTnT and NT-pro BNP significantly correlated with native T1 and T2 in groups with eGFR 30-59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2 groups, with associations being stronger at lower eGFR (NT-pro BNP (log transformed, lg10): native T1 r = 0.43 and r = 0.57, native T2 r = 0.39 and r = 0.48 respectively; log-transformed hs-cTnT(lg10): native T1 r = 0.23 and r = 0.43, native T2 r = 0.38 and r = 0.58 respectively, p < 0.001 for all, p < 0.05 for interaction). On multivariable analyses, we found independent associations of native T1 with NT-pro BNP [(B = 0.308 (95% CI 0.129-0.407), p < 0.001 and B = 0.334 (95% CI 0.154-0.660), p = 0.002 for eGFR 30-59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2, respectively] and of T2 with hs-cTnT [B = 0.417 (95% CI 0.219-0.650), p < 0.001 for eGFR < 29 ml/min/1.73 m2]. CONCLUSIONS: We demonstrate independent associations between cardiac biomarkers with imaging markers of interstitial expansion, which are CKD-group specific. Our findings indicate the role of diffuse non-ischemic tissue processes, including excess of myocardial fluid in addition to diffuse fibrosis in CKD-related adverse remodeling.

Sub-segmental quantification of single (stress)-pass perfusion CMR improves the diagnostic accuracy for detection of obstructive coronary artery disease.

BACKGROUND: Myocardial perfusion with cardiovascular magnetic resonance (CMR) imaging is an established diagnostic test for evaluation of myocardial ischaemia. For quantification purposes, the 16 segment American Heart Association (AHA) model poses limitations in terms of extracting relevant information on the extent/severity of ischaemia as perfusion deficits will not always fall within an individual segment, which reduces its diagnostic value, and makes an accurate assessment of outcome data or a result comparison across various studies difficult. We hypothesised that division of the myocardial segments into epi- and endocardial layers and a further circumferential subdivision, resulting in a total of 96 segments, would improve the accuracy of detecting myocardial hypoperfusion. Higher (sub-)subsegmental recording of perfusion abnormalities, which are defined relatively to the normal reference using the subsegment with the highest value, may improve the spatial encoding of myocardial blood flow, based on a single stress perfusion acquisition. OBJECTIVE: A proof of concept comparison study of subsegmentation approaches based on transmural segments (16 AHA and 48 segments) vs. subdivision into epi- and endocardial (32) subsegments vs. further circumferential subdivision into 96 (sub-)subsegments for diagnostic accuracy against invasively defined obstructive coronary artery disease (CAD). METHODS: Thirty patients with obstructive CAD and 20 healthy controls underwent perfusion stress CMR imaging at 3 T during maximal adenosine vasodilation and a dual bolus injection of 0.1 mmol/kg gadobutrol. Using Fermi deconvolution for blood flow estimation, (sub-)subsegmental values were expressed relative to the (sub-)subsegment with the highest flow. In addition, endo-/epicardial flow ratios were calculated based on 32 and 96 (sub-)subsegments. A receiver operating characteristics (ROC) curve analysis was performed to compare the diagnostic performance of discrimination between patients with CAD and healthy controls. Observer reproducibility was assessed using Bland-Altman approaches. RESULTS: Subdivision into more and smaller segments revealed greater accuracy for #32, #48 and # 96 compared to the standard #16 approach (area under the curve (AUC): 0.937, 0.973 and 0.993 vs 0.820, p < 0.05). The #96-based endo-/epicardial ratio was superior to the #32 endo-/epicardial ratio (AUC 0.979, vs. 0.932, p < 0.05). Measurements for the #16 model showed marginally better reproducibility compared to #32, #48 and #96 (mean difference ± standard deviation: 2.0 ± 3.6 vs. 2.3 ± 4.0 vs 2.5 ± 4.4 vs. 4.1 ± 5.6). CONCLUSIONS: Subsegmentation of the myocardium improves diagnostic accuracy and facilitates an objective cut-off-based description of hypoperfusion, and facilitates an objective description of hypoperfusion, including the extent and severity of myocardial ischaemia. Quantification based on a single (stress-only) pass reduces the overall amount of gadolinium contrast agent required and the length of the overall diagnostic study.

Towards standardized postprocessing of global longitudinal strain by feature tracking - OptiStrain CMR-FT study.

BACKGROUND: Left ventricular global longitudinal strain (GLS) with cardiovascular magnetic resonance (CMR) is an important prognostic biomarker. Its everyday clinical use is limited due to methodological and postprocessing diversity among the users and vendors. Standardization of postprocessing approaches may reduce the random operator-dependent variability, allowing for comparability of measurements despite the systematic vendor-related differences. METHODS: We investigated the random component of variability in GLS measurements by optimization steps which incrementally improved observer reproducibility and agreement. Cine images in two-, three- and four-chamber-views were serially analysed by two independent observers using two different CMR-FT softwares. The disparity of outcomes after each series was systematically assessed after a number of stepwise adjustments which were shown to significantly reduce the inter-observer and intervendor bias, resulting standardized postprocessing approach. The final analysis was performed in 44 subjects (ischaemic heart disease n = 15, non-ischaemic dilated cardiomyopathy, n = 19, healthy controls, n = 10). All measurements were performed blind to the underlying group allocation and previous measurements. Inter- and intra-observer variability were tested using Bland-Altman analyses, intra-class correlation coefficients (ICCs) and coefficients of variation (CVs). RESULTS: Compared to controls, mean GLS was significantly lower in patients, as well as between the two subgroups (p < 0.01). These differences were accentuated by standardization procedures, with significant increase in Cohen's D and AUCs. The benefit of standardization was also evident through improved CV and ICC agreements between observers and the two vendors. Initial intra-observer variability CVs for GLS parameters were 7.6 and 4.6%, inter-observer variability CVs were 11 and 4.7%, for the two vendors, respectively. After standardization, intra- and interobserver variability CVs were 3.1 and 4.3%, and 5.2 and 4.4%, respectively. CONCLUSION: Standardization of GLS postprocessing helps to reduce the random component of variability, introduced by inconsistencies of and between observers, and also intervendor variability, but not the systematic inter-vendor bias due to differences in image processing algorithms. Standardization of GLS measurements is an essential step in ensuring the reliable quantification of myocardial deformation, and implementation of CMR-FT in clinical routine.

High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory cardiovascular involvement in systemic lupus erythematosus.

BACKGROUND: Cardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR). METHODS AND RESULTS: This is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p<0.01). In SLE, hs-TropT was significantly and independently associated with native T2, followed by the models including native T1 and aortic stiffness (Χ2 0.462, p<0.01). There were no relationships between hs-TropT and age, gender, CV risk factors, duration of systemic disease, cardiac structure or function, or late gadolinium enhancement. CONCLUSIONS: Patients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement. TRIAL REGISTRATION NUMER: NCT02407197; Results.

T1 Mapping in Characterizing Myocardial Disease: A Comprehensive Review.

Cardiovascular magnetic resonance provides insights into myocardial structure and function noninvasively, with high diagnostic accuracy and without ionizing radiation. Myocardial tissue characterization in particular gives cardiovascular magnetic resonance a prime role among all the noninvasive cardiovascular investigations. Late gadolinium enhancement imaging is an established method for visualizing replacement scar, providing diagnostic and prognostic information in a variety of cardiac conditions. Late gadolinium enhancement, however, relies on the regional segregation of tissue characteristics to generate the imaging contrast. Thus, myocardial pathology that is diffuse in nature and affecting the myocardium in a rather uniform and global distribution is not well visualized with late gadolinium enhancement. Examples include diffuse myocardial inflammation, fibrosis, hypertrophy, and infiltration. T1 mapping is a novel technique allowing to diagnose these diffuse conditions by measurement of T1 values, which directly correspond to variation in intrinsic myocardial tissue properties. In addition to providing clinically meaningful indices, T1-mapping measurements also allow for an estimation of extracellular space by calculation of extracellular volume fraction. Multiple lines of evidence suggest a central role for T1 mapping in detection of diffuse myocardial disease in early disease stages and complements late gadolinium enhancement in visualization of the regional changes in common advanced myocardial disease. As a quantifiable measure, it may allow grading of disease activity, monitoring progress, and guiding treatment, potentially as a fast contrast-free clinical application. We present an overview of clinically relevant technical aspects of acquisition and processing, and the current state of art and evidence, supporting its clinical use.

Society for Cardiovascular Magnetic Resonance (SCMR) expert consensus for CMR imaging endpoints in clinical research: part I - analytical validation and clinical qualification.

Cardiovascular disease remains a leading cause of morbidity and mortality globally. Changing natural history of the disease due to improved care of acute conditions and ageing population necessitates new strategies to tackle conditions which have more chronic and indolent course. These include an increased deployment of safe screening methods, life-long surveillance, and monitoring of both disease activity and tailored-treatment, by way of increasingly personalized medical care. Cardiovascular magnetic resonance (CMR) is a non-invasive, ionising radiation-free method, which can support a significant number of clinically relevant measurements and offers new opportunities to advance the state of art of diagnosis, prognosis and treatment. The objective of the SCMR Clinical Trial Taskforce was to summarizes the evidence to emphasize where currently CMR-guided clinical care can indeed translate into meaningful use and efficient deployment of resources results in meaningful and efficient use. The objective of the present initiative was to provide an appraisal of evidence on analytical validation, including the accuracy and precision, and clinical qualification of parameters in disease context, clarifying the strengths and weaknesses of the state of art, as well as the gaps in the current evidence This paper is complementary to the existing position papers on standardized acquisition and post-processing ensuring robustness and transferability for widespread use. Themed imaging-endpoint guidance on trial design to support drug-discovery or change in clinical practice (part II), will be presented in a follow-up paper in due course. As CMR continues to undergo rapid development, regular updates of the present recommendations are foreseen.

Diagnostic and prognostic significance of cardiovascular magnetic resonance native myocardial T1 mapping in patients with pulmonary hypertension.

BACKGROUND: Native T1 may be a sensitive, contrast-free, non-invasive cardiovascular magnetic resonance (CMR) marker of myocardial tissue changes in patients with pulmonary artery hypertension. However, the diagnostic and prognostic value of native T1 mapping in this patient group has not been fully explored. The aim of this work was to determine whether elevation of native T1 in myocardial tissue in pulmonary hypertension: (a) varies according to pulmonary hypertension subtype; (b) has prognostic value and (c) is associated with ventricular function and interaction. METHODS: Data were retrospectively collected from a total of 490 consecutive patients during their clinical 1.5 T CMR assessment at a pulmonary hypertension referral centre in 2015. Three hundred sixty-nine patients had pulmonary hypertension [58 ± 15 years; 66% female], an additional 39 had pulmonary hypertension due to left heart disease [68 ± 13 years; 60% female], 82 patients did not have pulmonary hypertension [55 ± 18; 68% female]. Twenty five healthy subjects were also recruited [58 ±4 years); 51% female]. T1 mapping was performed with a MOdified Look-Locker Inversion Recovery (MOLLI) sequence. T1 prognostic value in patients with pulmonary arterial hypertension was assessed using multivariate Cox proportional hazards regression analysis. RESULTS: Patients with pulmonary artery hypertension had elevated T1 in the right ventricular (RV) insertion point (pulmonary hypertension patients: T1 = 1060 ± 90 ms; No pulmonary hypertension patients: T1 = 1020 ± 80 ms p < 0.001; healthy subjects T1 = 940 ± 50 ms p < 0.001) with no significant difference between the major pulmonary hypertension subtypes. The RV insertion point was the most successful T1 region for discriminating patients with pulmonary hypertension from healthy subjects (area under the curve = 0.863) however it could not accurately discriminate between patients with and without pulmonary hypertension (area under the curve = 0.654). T1 metrics did not contribute to prediction of overall mortality (septal: p = 0.552; RV insertion point: p = 0.688; left ventricular free wall: p = 0.258). Systolic interventricular septal angle was a significant predictor of T1 in patients with pulmonary hypertension (p < 0.001). CONCLUSIONS: Elevated myocardial native T1 was found to a similar extent in pulmonary hypertension patient subgroups and is independently associated with increased interventricular septal angle. Native T1 mapping may not be of additive value in the diagnostic or prognostic evaluation of patients with pulmonary artery hypertension.

T1 and T2 Mapping in Recognition of Early Cardiac Involvement in Systemic Sarcoidosis.

Purpose To determine whether quantitative tissue characterization with T1 and T2 mapping supports recognition of myocardial involvement in patients with systemic sarcoidosis. Materials and Methods Fifty-three consecutive patients with a biopsy-proven extracardiac diagnosis of systemic sarcoidosis (21 men; median age, 45 years; interquartile range, 22 years) and 36 normotensive previously healthy control subjects (14 men; median age, 43 years; interquartile range, 18 years) underwent cardiovascular magnetic resonance imaging, which was performed to assess cardiac function and late gadolinium enhancement, and T1 and T2 mapping. A follow-up substudy was performed in 40 patients (mean follow-up interval, 144 days ± 35 [standard deviation]); of these 40 patients, 18 underwent anti-inflammatory treatment for systemic symptoms. Binary logistic regression and receiver operating characteristic curve analyses were used to assess discrimination between health and disease; Wilcoxon signed rank test was used to assess the effect of treatment. Results When compared with control subjects, patients had higher ventricular volume, higher myocardial native T1 and T2, and lower longitudinal strain and ejection fraction (P < .05 for all). Myocardial native T1 and T2 had higher discriminatory accuracy (area under the receiver operating characteristic curve [AUC]: 0.96 and 0.89, respectively) for separation between control subjects and patients when compared with the standard diagnostic criteria (AUC < 0.67). Native T1 was the independent discriminator between health and disease (specificity, 90%; sensitivity, 96%; accuracy, 94%). There was a significant reduction of native T1 and T2 in the patients who underwent treatment (z score: -3.72 and -2.88; P < .01) but not in the patients who did not (z score, -1.42 and -1.38; P > .15). Conclusion Quantitative myocardial tissue characterization with T1 and T2 mapping may enable noninvasive recognition of cardiac involvement and activity of myocardial inflammation in patients with systemic sarcoidosis. Future studies will be performed to confirm their role in risk stratification and guidance of clinical management. © RSNA, 2017 Online supplemental material is available for this article.

High-throughput gadobutrol-enhanced CMR: a time and dose optimization study.

BACKGROUND: Reducing time and contrast agent doses are important goals to provide cost-efficient cardiovascular magnetic resonance (CMR) imaging. Limited information is available regarding the feasibility of evaluating left ventricular (LV) function after gadobutrol injection as well as defining the lowest dose for high quality scar imaging. We sought to evaluate both aspects separately and systematically to provide an optimized protocol for contrast-enhanced CMR (CE-CMR) using gadobutrol. METHODS: This is a prospective, randomized, single-blind cross-over study performed in two different populations. The first population consisted of 30 patients with general indications for a rest CE-CMR who underwent cine-imaging before and immediately after intravenous administration of 0.1 mmol/kg body-weight of gadobutrol. Quantitative assessment of LV volumes and function was performed by the same reader in a randomized and blinded fashion. The second population was composed of 30 patients with indication to late gadolinium enhancement (LGE) imaging, which was performed twice at different gadobutrol doses (0.1 mmol/kg vs. 0.2 mmol/kg) and at different time delays (5 and 10 min vs. 5, 10, 15 and 20 min), within a maximal interval of 21 days. LGE images were analysed qualitatively (contrast-to-noise ratio) and quantitatively (LGE%-of-mass). RESULTS: Excellent correlation between pre- and post-contrast cine-imaging was found, with no difference of LV stroke volume and ejection fraction (p = 0.538 and p = 0.095, respectively). End-diastolic-volume and end-systolic-volume were measured significantly larger after contrast injection (p = 0.008 and p = 0.001, respectively), with a mean difference of 3.7 ml and 2.9 ml, respectively. LGE imaging resulted in optimal contrast-to-noise ratios 10 min post-injection for a gadobutrol dose of 0.1 mmol/kg body-weight and 20 min for a dose of 0.2 mmol/kg body-weight. At these time points LGE quantification did not significantly differ (0.1 mmol/kg: 11% (16.4); 0.2 mmol/kg: 12% (14.5); p = 0.059), showing excellent correlation (ICC = 0.957; p < 0.001). CONCLUSION: A standardized CE-CMR rest protocol giving a dose of 0.1 mmol/kg of gadobutrol before cine-imaging and performing LGE 10 min after injection represents a fast low-dose protocol without significant loss of information in comparison to a longer protocol with cine-imaging before contrast injection and a higher dose of gadobutrol. This approach allows to reduce examination time and costs as well as minimize contrast-agent exposure.

Prevalence of myocardial crypts in a large retrospective cohort study by cardiovascular magnetic resonance.

BACKGROUND: Myocardial crypts are discrete clefts or fissures in otherwise compacted myocardium of the left ventricle (LV). Recent reports suggest a higher prevalence of crypts in patients with hypertrophic cardiomyopathy (HCM) and also within small samples of genotype positive but phenotype negative relatives. The presence of a crypt has been suggested to be a predictor of gene carrier status. However, the prevalence and clinical significance of crypts in the general population is unclear. We aimed to determine the prevalence of myocardial crypts in a large cohort of subjects using clinical cardiovascular magnetic resonance (CMR). METHODS: Consecutive subjects referred for clinical CMR during a 12-month period (n = 1020, age 52.6 ± 17, males: 61%) were included. Crypts were defined as >50% invagination into normal myocardium and their overall prevalence, location and shape was investigated and compared between different patient groups. RESULTS: The overall prevalence of crypts was 64/1020 (6.3%). In a predefined 'normal' control group the prevalence was lower (11/306, 3.6%, p = 0.031), but were equally prevalent in ischemic heart disease (12/236, 5.1%, p = n/s) and the combined non-ischemic cardiomyopathy (NICM) groups (24/373; 6.4%, p = n/s). Within the NICM group, crypts were significantly more common in HCM (9/76, 11.7%, p = 0.04) and hypertensive CM subjects (3/11, 27%, p = 0.03). In patients referred for CMR for family screening of inherited forms of CM, crypts were significantly more prevalent (10/41, 23%, p < 0.001), including a smaller group with a first degree relative with HCM (3/9, 33%, p = 0.01). CONCLUSION: Myocardial crypts are relatively common in the normal population, and increasingly common in HCM and hypertensive cardiomyopathy. Crypts are also more frequently seen in normal phenotype subjects referred because of a family history of an inherited cardiomyopathy and HCM specifically. It is uncertain what the significance of crypts are in this group, and because of variability in the imaging protocols used and their relative frequency within the normal population, should not be used to clinically stratify these patients. Prospective studies are required to confirm the clinical significance of myocardial crypts, as their significance remains unclear.

Reference values for healthy human myocardium using a T1 mapping methodology: results from the International T1 Multicenter cardiovascular magnetic resonance study.

BACKGROUND: T1 mapping is a robust and highly reproducible application to quantify myocardial relaxation of longitudinal magnetisation. Available T1 mapping methods are presently site and vendor specific, with variable accuracy and precision of T1 values between the systems and sequences. We assessed the transferability of a T1 mapping method and determined the reference values of healthy human myocardium in a multicenter setting. METHODS: Healthy subjects (n=102; mean age 41 years (range 17-83), male, n=53 (52%)), with no previous medical history, and normotensive low risk subjects (n=113) referred for clinical cardiovascular magnetic resonance (CMR) were examined. Further inclusion criteria for all were absence of regular medication and subsequently normal findings of routine CMR. All subjects underwent T1 mapping using a uniform imaging set-up (modified Look- Locker inversion recovery, MOLLI, using scheme 3(3)3(3)5)) on 1.5 Tesla (T) and 3 T Philips scanners. Native T1-maps were acquired in a single midventricular short axis slice and repeated 20 minutes following gadobutrol. Reference values were obtained for native T1 and gadolinium-based partition coefficients, λ and extracellular volume fraction (ECV) in a core lab using standardized postprocessing. RESULTS: In healthy controls, mean native T1 values were 950±21 msec at 1.5 T and 1052±23 at 3 T. λ and ECV values were 0.44±0.06 and 0.25±0.04 at 1.5 T, and 0.44±0.07 and 0.26±0.04 at 3 T, respectively. There were no significant differences between healthy controls and low risk subjects in routine CMR parameters and T1 values. The entire cohort showed no correlation between age, gender and native T1. Cross-center comparisons of mean values showed no significant difference for any of the T1 indices at any field strength. There were considerable regional differences in segmental T1 values. λ and ECV were found to be dose dependent. There was excellent inter- and intraobserver reproducibility for measurement of native septal T1. CONCLUSION: We show transferability for a unifying T1 mapping methodology in a multicenter setting. We provide reference ranges for T1 values in healthy human myocardium, which can be applied across participating sites.

Coronary Artery Disease Assessment via On-Site CT Fractional Flow Reserve in Patients Undergoing Transcatheter Aortic Valve Replacement.

Purpose To examine the clinical feasibility of workstation-based CT fractional flow reserve (CT-FFR) for coronary artery disease (CAD) evaluation during preprocedural planning in patients undergoing transcatheter aortic valve replacement (TAVR). Materials and Methods In this retrospective single-center study, 434 patients scheduled for TAVR between 2018 and 2020 were screened for study inclusion; a relevant proportion of patients (35.0% [152 of 434]) was not suitable for evaluation due to insufficient imaging properties. A total of 112 patients (mean age, 82.1 years ± 6.7 [SD]; 58 [52%] men) were included in the study. Invasive angiography findings, coronary CT angiography results, and Agatston score were acquired and compared with on-site CT-FFR computation for evaluation of CAD and prediction of major adverse cardiovascular events (MACE) within a 24-month follow-up. Results Hemodynamic relevant CAD, as suggested by CT-FFR of 0.80 or less, was found in 41 of 70 (59%) patients with stenosis of 50% or more. MACE occurred in 23 of 112 (20.5%) patients, from which 14 of 23 had stenoses with CT-FFR of 0.80 or less (hazard ratio [HR], 3.33; 95% CI: 1.56, 7.10; P = .002). CT-FFR remained a significant predictor of MACE after inclusion in a multivariable model with relevant covariables (HR, 2.89; 95% CI: 1.22, 6.86; P = .02). An Agatston score of 1000 Agatston units or more (HR, 2.25; 95% CI: 0.98, 5.21; P = .06) and stenoses of 50% or more determined via invasive angiography (HR, 0.94; 95% CI: 0.41, 2.17; P = .88) were not significant predictors of MACE. Conclusion Compared with conventional CAD markers, CT-FFR better predicted adverse outcomes after TAVR. A relevant portion of the screened cohort, however, was not suitable for CT-based CAD evaluation. Keywords: CT, Transcatheter Aortic Valve Implantation/Replacement (TAVI/TAVR), Cardiac, Coronary Arteries, Outcomes Analysis © RSNA, 2024 See also the commentary by Weir-McCall and Pugliese in this issue.

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts.

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.

Proteomics analysis of cardiac extracellular matrix remodeling in a porcine model of ischemia/reperfusion injury.

BACKGROUND: After myocardial ischemia, extracellular matrix (ECM) deposition occurs at the site of the focal injury and at the border region. METHODS AND RESULTS: We have applied a novel proteomic method for the analysis of ECM in cardiovascular tissues to a porcine model of ischemia/reperfusion injury. ECM proteins were sequentially extracted and identified by liquid chromatography tandem mass spectrometry. For the first time, ECM proteins such as cartilage intermediate layer protein 1, matrilin-4, extracellular adipocyte enhancer binding protein 1, collagen α-1(XIV), and several members of the small leucine-rich proteoglycan family, including asporin and prolargin, were shown to contribute to cardiac remodeling. A comparison in 2 distinct cardiac regions (the focal injury in the left ventricle and the border region close to the occluded coronary artery) revealed a discordant regulation of protein and mRNA levels; although gene expression for selected ECM proteins was similar in both regions, the corresponding protein levels were much higher in the focal lesion. Further analysis based on >100 ECM proteins delineated a signature of early- and late-stage cardiac remodeling with transforming growth factor-ß1 signaling at the center of the interaction network. Finally, novel cardiac ECM proteins identified by proteomics were validated in human left ventricular tissue acquired from ischemic cardiomyopathy patients at cardiac transplantation. CONCLUSION: Our findings reveal a biosignature of early- and late-stage ECM remodeling after myocardial ischemia/reperfusion injury, which may have clinical utility as a prognostic marker and modifiable target for drug discovery.

Value of serum pregnancy-associated plasma protein A for predicting cardiovascular events among patients presenting with cardiac chest pain.

BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A) has been suggested as a candidate marker for the identification of unstable plaques in coronary arteries. We assessed the value of PAPP-A for predicting short-term cardiovascular events in a large cohort of patients presenting with cardiac chest pain. METHODS: We included consecutive patients who presented to a teaching hospital in Germany with chest pain of cardiac origin confirmed by coronary angiography. We analyzed PAPP-A levels from serum samples drawn within 30 minutes after arrival in the emergency department or in the catheterization laboratory. Patients were followed for 90 days or until death for major adverse cardiovascular events, defined as the combined outcome of stent thrombosis, myocardial (re)infarction, ischemic stroke or cardiovascular-related death. RESULTS: A total of 2568 patients (mean age [± standard deviation (SD)] 68 ± 11 years; 74% male) presented with cardiac chest pain: 55% had stable angina and 45% had acute coronary syndrome. The PAPP-A levels ranged from 4 to 2154 mIU/L (median 14.0 mIU/L, interquartile range 9.3-25.2 mIU/L). Major adverse cardiovascular events occurred in 203 patients (7.9%). The mean PAPP-A level was higher among patients who had an event than among those who did not (62 ± 156 v. 21 ± 23 mIU/L, p < 0.001). In a multivariable analysis, PAPP-A remained a significant independent predictor of the primary outcome within 90 days (hazard ratio per 1 SD increase in PAPP-A level 1.96, 95% confidence interval 1.74-2.21). The optimal prognostic cutoff value was a PAPP-A level of 34.6 mIU/L. INTERPRETATION: Higher levels of serum PAPP-A were independently associated with an increased short-term risk of cardiovascular events in patients presenting with cardiac chest pain. Further studies are required to validate the use of PAPP-A in routine clinical practice to predict future cardiovascular events.

Standardization of T1 measurements with MOLLI in differentiation between health and disease--the ConSept study.

BACKGROUND: T1 imaging based on pixel-wise quantification of longitudinal relaxation has the potential to differentiate between normal and abnormal myocardium. The accuracy of T1 measurement has not been established nor systematically tested in the presence of health and disease. METHODS: Intra-observer, inter-observer and inter-study reproducibility of T1 imaging was assessed in subjects with left ventricular hypertrophy (LVH, n = 25) or dilated cardiomyopathy (DCM, n = 43). Thirty-eight subjects with low-pretest likelihood of cardiomyopathy served as a control group. T1 values were acquired in a single mid-ventricular short axis slice using modified Look-Locker imaging prior and after the application of gadolinium contrast at 1.5 and 3 T. Analysis was performed with regions of interest (ROI) placed conservatively within the septum or to include the whole short axis (SAX) myocardium. RESULTS: Intra-observer, inter-observer and inter-study repeated measurements within the septum showed smaller mean differences and narrower 95% confidence intervals than repeated short axis ROI measurements. Native T1 values were higher in septal ROIs compared with SAX values at both field strengths (1.5 T: 976 ± 37 vs. 952 ± 41, p < 0.01; 3 T: 1108 ± 67 vs. 1087 ± 60, p < 0.01). Native T1 values revealed significant mean differences between controls and patients with LVH for both septal (1.5 T: 26 ± 9, p < 0.01; 3 T: 50 ± 13, p < 0.01) and SAX ROIs (1.5 T: 19 ± 11, p < 0.05; 3 T: 47 ± 19, p < 0.05) with greater differences observed at 3 T versus 1.5 T field strength. Native T1 values revealed significant mean differences between controls and patients with DCM for septal ROI (1.5 T: 29 ± 15, p < 0.05; 3 T: 55 ± 16, p < 0.01) at both 1.5 T and 3 T, but only for SAX ROIs at 3 T (49 ± 17, p < 0.01). There were no significant differences in post-contrast T1 values or partition coefficient (λ) between controls and patients. CONCLUSION: Conservative septal ROI T1 measurement is a robust technique with excellent intra-observer, inter-observer and inter-study reproducibility for native and post-contrast T1 value and partition coefficient measurements. Moreover, native septal T1 values reveal the greatest difference between normal and abnormal myocardium, which is independent of geometrical alterations of cardiac chamber and wall thickness. We propose the use of native T1 measurements using conservative septal technique as the standardized approach to distinguish health from disease assuming diffuse myocardial involvement.