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.

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.

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.

Prevalence and prognostic impact of nonischemic late gadolinium enhancement in stress cardiac magnetic resonance.

AIM: To assess the prevalence and prognostic significance of NI-LGE in patients undergoing stress-CMR. METHODS: Stress-CMR with either dipyridamole or adenosine was performed in 283 patients (228 men, 81%) including perfusion imaging, wall motion evaluation and LGE. Follow-up was completed in all enrolled patients (median time: 1850 days; interquartile range: 1225-2705 days). Composite endpoint included cardiac death, ventricular tachycardia, myocardial infarction, stroke, hospitalization for cardiac cause and coronary revascularization performed beyond 90 days from stress-CMR scans. RESULTS: One hundred and twelve patients (40%) had negative LGE (no-LGE), 140 patients (49%) I-LGE and 31 patients (11%) NI-LGE. Twenty-five events occurred in the no-LGE group, 68 in I-LGE and 11 in the NI-LGE group. On survival curves, patients with NI-LGE had worse prognosis than patients with no-LGE regardless of the presence of inducible perfusion defects. No significant prognostic differences were found between I-LGE and NI-LGE. CONCLUSION: NI-LGE can be detected in 11% of patients during stress-CMR providing a diagnosis of nonischemic cardiac disease. Patients with NI-LGE have worse prognosis than those with no-LGE.

Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19).

IMPORTANCE: Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide. Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown. OBJECTIVE: To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness. DESIGN, SETTING, AND PARTICIPANTS: In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020. EXPOSURE: Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription-polymerase chain reaction on swab test of the upper respiratory tract. MAIN OUTCOMES AND MEASURES: Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained. Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor-matched patients (n = 57). RESULTS: Of the 100 included patients, 53 (53%) were male, and the mean (SD) age was 49 (14) years. The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days. Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization. At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (greater than 3 pg/mL) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (greater than 13.9 pg/mL) in 5 patients (5%). Compared with healthy controls and risk factor-matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, and raised native T1 and T2. A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), or pericardial enhancement (n = 22). There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1119 [1092-1150] ms vs 1141 [1121-1175] ms; P = .008) and hsTnT (4.2 [3.0-5.9] pg/dL vs 6.3 [3.4-7.9] pg/dL; P = .002) but not for native T2 mapping. None of these measures were correlated with time from COVID-19 diagnosis (native T1: r = 0.07; P = .47; native T2: r = 0.14; P = .15; hsTnT: r = -0.07; P = .50). High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.33; P < .001) and native T2 mapping (r = 0.18; P = .01). Endomyocardial biopsy in patients with severe findings revealed active lymphocytic inflammation. Native T1 and T2 were the measures with the best discriminatory ability to detect COVID-19-related myocardial pathology. CONCLUSIONS AND RELEVANCE: In this study of a cohort of German patients recently recovered from COVID-19 infection, CMR revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis. These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.

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.

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.

CMR imaging biosignature of cardiac involvement due to cancer-related treatment by T1 and T2 mapping.

BACKGROUND: Cancer-related treatment is associated with development of heart failure and poor outcome in cancer-survivors. T1 and T2 mapping by cardiovascular magnetic resonance (CMR) may detect myocardial injury due to cancer-related treatment. METHODS: Patients receiving cancer-related treatment regimes underwent screening of cardiac involvement with CMR, either within 3 months (early Tx) or >12 months (late Tx) post-treatment. T1 and T2 mapping, cardiac function, strain, ischaemia-testing, scar-imaging and serological cardiac biomarkers were obtained. RESULTS: Compared to age/gender matched controls (n = 57), patients (n = 115, age (yrs): median(IQR) 48(28-60), females, n = 60(52%) had reduced left ventricular ejection fraction (LV-EF) and strain, and higher native T1 and T2. The early Tx group (n = 52) had significantly higher native T1, T2 and troponin levels compared to the late Tx group, indicating myocardial inflammation and oedema (p < 0.01). On the contrary, late Tx patients showed raised native T1, increased LV-end-systolic volumes, reduced LV-EF and deformation, and elevated NT-proBNP, suggesting myocardial fibrosis and remodelling (p < 0.05). Prospective validation of these results in an independent cohort of patients with similar treatment regimens (n = 25) and longitudinal assessments revealed high concordance of CMR imaging signatures of early and late cardiac involvement. CONCLUSIONS: Native T1 and T2 mapping can be valuable in detecting and monitoring of cardiac involvement with cancer-related treatment, providing distinct biosignatures of early inflammatory involvement (raised native T1 and T2) and interstitial fibrosis and remodelling (raised native T1 but not T2), respectively. Our findings may provide an algorithm allowing to identify susceptible myocardium to potentially guide cardio-protective treatment measures.

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 and T2 mapping in myocarditis: seeing beyond the horizon of Lake Louise criteria and histopathology.

INTRODUCTION: Myocarditis and its sequelae remain an unconquered clinical problem, disproportionately affecting the young. Several hurdles beset myocarditis, including non-specific symptoms, heterogeneous clinical presentation, dynamic disease stages, underscored by an absence of an easy diagnostic test or a specific treatment. Areas covered: The current diagnostic means are poorly equipped to counter the challenge; the gold standard by invasive endomyocardial biopsy relies on availability of expert procedural and reading skill. The tissue diagnostic criteria were developed to improve readers agreement with clinical diagnosis, and not based on evidence for differential treatment or improved prognosis. The Lake-Louise Criteria represented a first step towards a non-invasive diagnosis. They require extensive imaging, which is insufficiently robust with poor diagnostic confidence and tissue pathophysiological validation; they similarly lack evidence of improved outcome by guiding clinical management. T1 and T2 mapping are a step-change, providing robust, short and quantifiable imaging application, which can veritably reflect the dynamic and heterogeneous underlying disease. Expert commentary: T1 and T2 mapping harbours a unique potential for an objective non-invasive disease recognition and treatment discovery in myocarditis. These measures should enter independently into clinical experimentation, with a high priority for outcome and therapeutic studies.

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.

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.

Deciphering cardiac involvement in systemic inflammatory diseases: noninvasive tissue characterisation using cardiac magnetic resonance is key to improved patients' care.

INTRODUCTION: Cardiac involvement in systemic inflammatory diseases (SID) has a major impact on patients' morbidity and mortality, yet the pathways to its recognition and management remain poorly established. Areas covered: Overall clinical management in SID patients is primarily guided by systemic symptoms. Cardiovascular disease goes largely undetected, as it evolves through years of a protracted and subclinical course. Despite the increased awareness and insights into the mechanistic role of the inflammatory pathways, clinical management of cardiac involvement continues to rely on diagnostic means, which are frequently insensitive, invasive and rely on radiation exposure. Advanced tissue characterisation with cardiovascular magnetic resonance (CMR) offers an accurate, non-invasive and radiation-free diagnostic method with obvious advantages: it is able to inform on a range of cardiovascular pathophysiology, as well as support safe serial examinations, informing on the disease presence, progress and response to treatment. Expert commentary: We summarise the recent advances in non-invasive imaging, and bridge the novel insights into pathophysiology with future posibilities in diagnosis and manangement of SID patients. We propose an interdisciplinary framework to screening of cardiac involvement in SID using an indepth phenotyping of evolution of cardiovascular disease, to decipher the opportunities to improve patients' cardiac care.

Native T1 and T2 mapping by CMR in lupus myocarditis: Disease recognition and response to treatment.

BACKGROUND: Lupus myocarditis is likely more common than recognized clinically due to non-specific symptoms and lack of reliable non-invasive diagnostic tests. We investigated the role of native T1 and T2 in recognition of active myocardial inflammatory involvement in patients with systemic lupus erythematous (SLE). METHODS: 76 patients with clinically suspected lupus myocarditis (14 males, age: 44±16years) underwent quantitative tissue characterization with native T1 and T2 mapping. Normotensive healthy subjects taking no medication served as controls (n=46). Follow-up CMR studies were performed in a total of 35 subjects of which 14 patients received intensified anti-inflammatory treatment, as guided by SLE disease activity. RESULTS: Compared to controls SLE patients had higher inflammatory markers, LV mass, native T1 and T2 values, and reduced longitudinal strain (p<0.01). In patients with a positive troponin test (n=36; 46%), native T1 and T2 were significantly higher (p<0.01) with otherwise similar proportions of diffuse perimyocardial LGE (33%) and pericardial effusion (32%). Sixty-nine patients (83%) had an abnormal native T1, whereas 51 (71%) met diagnostic criteria for acute myocarditis. Follow-up CMRs revealed significantly greater reduction in native T1 and T2 values in patients with intensified anti-inflammatory treatment (p<0.001) with the greatest change observed within the first follow-up period and plateauing thereafter. Native T1 and T2 were significant predictors of treatment response. CONCLUSIONS: Native T1 and T2 mapping support recognition of lupus myocarditis and reflect the response to anti-inflammatory treatment. Native T1 and T2 mapping may support an effective, noninvasive, radiation- and gadolinium contrast-free screening method for lupus myocarditis.

Advances in Cardiovascular MRI using Quantitative Tissue Characterisation Techniques: Focus on Myocarditis.

Tissue characterisation capabilities are continuing to evolve and proving to be valuable in the non-invasive diagnosis of clinically-heterogeneous manifestations of myocarditis. The authors investigate how cardiovascular magnetic resonance imaging offers an increasingly reliable alternative to invasive biopsy for clinically-stable patients, and how this tool - with further longitudinal study - will improve the overall understanding of the natural course of myocarditis.

T1 mapping in myocarditis - headway to a new era for cardiovascular magnetic resonance.

Myocarditis is a major cause of cardiac morbidity and mortality, particularly in young patients. A spectrum of challenges besets this condition, from establishing the diagnosis to effective treatment. Endomyocardial biopsy remains the diagnostic gold standard, despite its invasiveness, low diagnostic yield and a paucity of consequential management pathways. Cardiac magnetic resonance by Lake Louise criteria has contested to become the non-invasive diagnostic alternative by providing confirmation of disease. The advent of T1 mapping now allows a high diagnostic accuracy in confirmation and exclusion of disease, discrimination of stages and activity of disease. Alongside the research into the mechanisms and potential therapeutic targets, cardiac magnetic resonance confidently claims a prime role within a modern diagnostic pathway in clinically stable patients with suspected myocarditis.

Individualized cardiovascular risk assessment by cardiovascular magnetic resonance.

Cardiovascular magnetic resonance (CMR) is gaining clinical importance in preventive medicine. Evidence on diagnostic accuracy and prognostic value, in addition to the development of faster imaging, increased availability of equipment and imaging expertise have led to a wide-spread use of CMR in a growing number of clinical indications. The first part of this review summarizes the role of CMR biomarkers for risk assessment focusing on the patients groups that benefit from the use of CMR. In the second part, the future directions for CMR are discussed and their role in prevention of cardiovascular disease.

Coupling vascular and myocardial inflammatory injury into a common phenotype of cardiovascular dysfunction: systemic inflammation and aging - a mini-review.

The rising epidemic of cardiovascular (CV) disease is fuelled by obesity, hypertension and diabetes and, independently and cumulatively, by an aging population. Extensive research identified immunoinflammatory mechanisms as key drivers in the initiation and progression of the disease, from early asymptomatic stages of vascular and myocardial injury leading to the clinically manifest dysfunction and remodeling in advanced stages. Underlying processes include endothelial dysfunction and extracellular matrix restructuration leading to increased vascular stiffness, as well as myocardial remodeling with dilatation and wall thinning. In this, overproduction of tumor necrosis factor-α, amongst others, contributes to generalized CV injury and dysfunction. Moreover, recent insights into the involvement of innate and adaptive immunity in atherosclerosis have shed light on many interesting parallels with chronic systemic inflammatory conditions, such as rheumatoid arthritis, with aggravated inflammation-induced vascular and myocardial injury. Besides, chronologic age has been identified as a potent, independent risk for reduced CV capacity and a plethora of heart diseases, with other modifiable risk factors acting as accelerators. We discuss the available evidence and propose that characterization of inflammatory CV responses might reveal a distinctive CV inflammatory phenotype. A comprehensive noninvasive bio-signature, comprising immunomic biomarkers and integrated noninvasive imaging, may serve as a potential tool in the early diagnosis and prognostication of CV risk.

Rapid detection of acute kidney injury by plasma and urinary neutrophil gelatinase-associated lipocalin after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with a significant risk of postoperative renal dysfunction. We studied the utility of a novel biomarker in predicting acute kidney injury (AKI) in adult patients undergoing cardiac surgery. METHODS AND RESULTS: Blood and urine were obtained from 50 patients undergoing CPB-requiring surgery. Patients were divided into group A (n=41) with normal creatinine pre-bypass and post-bypass and group B (n=9) who developed an increase in serum creatinine of >0.5 mg/dL within the first 48 hours post CPB. Plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL) was determined at baseline and 2 hours after CPB.Plasma levels of NGAL were higher in patients who developed AKI [214+/-16.7 ng/mL (95% CI 176.9-252.9)] compared with those who did not [149.5+/-13.5 ng/mL (95% CI 122.1-175.7); P=0.035]. Two hours after CPB, there was a significant increase (P=0.0003) in NGAL levels, greater in those patients who developed AKI [476.1+/-41.1 ng/mL (95% CI 380.6-571.6); P=0.0003] compared with those who did not [278.4+/-22 ng/mL (95% CI 233.9-323.0)]. In the AKI group, urinary NGAL increased from 7.13+/-2.30 ng/mL (95% CI 2.5-11.8) to 2924+/-786 ng/mL (95% CI 1110-4739). In the non-AKI group, there was an increase from 1.6+/-0.6 (95% CI 0.3-3.0) to 749+/-179 ng/mL (95% CI 386-1113). The post-CPB levels of urinary NGAL were significantly different in the AKI group (P<0.0001) such that a suitable threshold for use as a diagnostic test could be determined. Receiver operating characteristics were determined for plasma and urinary NGAL with area under the curve (AUC) of 0.80 and 0.96, respectively. For a threshold of 433 ng/mmol creatinine, the test had 90% sensitivity and 78% specificity for the detection of post-CPB renal dysfunction. CONCLUSIONS: Measurement of this novel biomarker in the urine or plasma of patients in the first hours after CPB is predictive of subsequent renal injury. Although the AUC for plasma NGAL seemed inferior to urine, even an AUC of 0.8 as reported compares very favorably to that for other "outstanding" biomarkers (eg, AUCs in the 0.7 range for troponin).