Comparison of diagnostic algorithms in clinically suspected viral myocarditis: agreement between cardiac magnetic resonance, endomyocardial biopsy and troponin T.

AIMS: Myocardial inflammation is increasingly detected non-invasively by tissue mapping with cardiovascular magnetic resonance (CMR). Intraindividual agreement with endomyocardial biopsy (EMB) or marker of myocardial injury, high-sensitive troponin (hs-cTnT) in patients with clinically suspected viral myocarditis not understood. METHODS AND RESULTS: Prospective multicentre study of consecutive patients with clinically suspected myocarditis who underwent blood testing for hs-cTnT, CMR and EMB as a part of diagnostic work-up. EMB was considered positive based on immunohistological criteria in line with the ESC definitions. CMR diagnoses employed tissue mapping using sequence-specific cut-off for native T1 and T2 mapping; active inflammation was defined as T1≥2SD and T2≥2SD above the mean of normal range. Hs-cTnT of greater than 13.9ng/1 was considered significant. A total of 114 patients (age (mean±SD) 54±16, 65% males) were included, of which 79(69%) had positive EMB-criteria, 64(56%) CMR criteria, and a total of 58 (51%) positive troponin. Agreement between EMB and CMR diagnostic criteria was poor (CMR vs. ESC: AUCs: 0.51 (0.39-0.62)). The agreement between the significant hs-cTnT rise and CMR-based diagnosis of myocarditis was good (AUC: 0.84 (0.68-0.92); p<0.001), but poor for EMB (0.50 (0.40-0.61). Hs-cTnT was significantly associated with native T1 and T2, hs-CRP and NT-pro BNP (r=0.37, r=0.35, r=0.30, r=0.25 p<0.001), but not immunohistochemical criteria or viral presence. CONCLUSIONS: In clinically suspected viral myocarditis, all diagnostic approaches reflect the pathophysiological elements of myocardial inflammation, however the differing underlying drivers only partially overlap. The EMB and CMR diagnostic algorithms are neither interchangeable in terms of interpretation of myocardial inflammation nor in their relationship with myocardial injury.

Epicardial fat volume is associated with primary coronary slow-flow phenomenon in patients with severe aortic stenosis undergoing transcatheter valve implantation.

BACKGROUND: Primary coronary slow flow (CSF) is defined as delayed opacification of the distal epicardial vasculature during coronary angiography in the absence of relevant coronary artery stenoses. Microvascular disease is thought to be the underlying cause of this pathology. Epicardial fat tissue (EFT) is an active endocrine organ directly surrounding the coronary arteries that provides pro-inflammatory factors to the adjacent tissue by paracrine and vasocrine mechanisms. The aim of the present study was to investigate a potential association between EFT and primary CSF and whether EFT can predict the presence of primary CSF. METHODS: Between 2016 and 2017, n = 88 patients with high-grade aortic stenosis who were planned for transcatheter aortic valve implantation (TAVI) were included in this retrospective study. EFT volume was measured by pre-TAVI computed tomography (CT) using dedicated software. The presence of primary CSF was defined based on the TIMI frame count from the pre-TAVI coronary angiograms. RESULTS: Thirty-nine of 88 TAVI patients had CSF (44.3%). EFT volume was markedly higher in patients with CSF (142 ml [IQR 107-180] vs. 113 ml [IQR 89-147]; p = 0.009) and was strongly associated with the presence of CSF (OR 1.012 [95%CI 1.002-1.021]; p = 0.014). After adjustment, EFT volume was still an independent predictor of CSF (OR 1.016 [95%CI 1.004-1.026]; p = 0.009). CONCLUSION: Primary CSF was independently associated with increased EFT volume. Further studies are needed to validate this finding and elucidate whether a causal relationship exists.

Comparison of First-generation and Third-generation Dual-source Computed Tomography for Detecting Coronary Artery Disease in Patients Evaluated for Transcatheter Aortic Valve Replacement.

PURPOSE: This study compared image quality and evaluability of coronary artery disease (CAD) in routine preparatory imaging for transcatheter aortic valve replacement using 64-slice (first-generation) to 192-slice (third-generation) dual-source computed tomography(DSCT). MATERIALS AND METHODS: The CT data sets of 192 patients (122 women, median age 82 y) without severe renal dysfunction or known CAD were analyzed retrospectively. Half were examined using first-generation DSCT (June 2014 to February 2016) and the other half with third-generation DSCT (April 2016 to April 2017). Per protocol, contrast material (110 [110 to 120] vs. 70 [70 to 70] mL, P <0.001) and radiation dose of multiphasic retrospectively gated thoracic CT angiography (dose-length-product, 1001 [707 to 1312] vs. 727 [474 to 1369] mGy×cm, P <0.001) were significantly lower with third-generation DSCT. Significant CAD was defined as CAD-RADS ≥4 by CT. Invasive coronary angiography served as the reference standard (CAD is defined as ≥70% stenosis or fractional flow reserve ≤0.80). RESULTS: In comparison with first-generation DSCT, third-generation DSCT showed significantly better subjective (3 [interquartile range 2 to 3] vs. 4 [3 to 4.25] on a 5-point scale, P <0.001) and objective image quality (signal-to-noise ratio of left coronary artery 12.8 [9.9 to 16.4] vs. 15.2 [12.4 to 19.0], P <0.001). Accuracy (72.9% vs. 91.7%, P =0.001), specificity (59.7% vs. 88.3%, P <0.001), positive (61.0% vs. 83.3%, P <0.001), and negative predictive value (91.9% vs. 98.2%, P =0.045) for detecting CAD per-patient were significantly better using third-generation DSCT, while sensitivity was similar (92.3% vs. 97.2%, P =0.129). CONCLUSIONS: Coronary artery evaluation with CT angiography before TAVI is feasible in selected patients. Compared with first-generation DSCT, state-of-the-art third-generation DSCT technology is superior for this purpose, allowing for less contrast medium and radiation dose while providing better image quality and improved diagnostic performance.

Epicardial fat volume is associated with preexisting atrioventricular conduction abnormalities and increased pacemaker implantation rate in patients undergoing transcatheter aortic valve implantation.

Epicardial fat tissue (EFT) is a highly metabolically active fat depot surrounding the heart and coronary arteries that is related to early atherosclerosis and adverse cardiac events. We aimed to investigate the relationship between the amount of EFT and preexisting cardiac conduction abnormalities (CCAs) and the need for new postinterventional pacemaker in patients with severe aortic stenosis planned for transcatheter aortic valve implantation (TAVI). A total of 560 consecutive patients (54% female) scheduled for TAVI were included in this retrospective study. EFT volume was measured via a fully automated artificial intelligence software (QFAT) using computed tomography (CT) performed before TAVI. Baseline CCAs [first-degree atrioventricular (AV) block, right bundle branch block (RBBB), and left bundle branch block (LBBB)] were diagnosed according to 12-lead ECG before TAVI. Aortic valve calcification was determined by the Agatston score assessed in the pre-TAVI CT. The median EFT volume was 129.5 ml [IQR 94-170]. Baseline first-degree AV block was present in 17%, RBBB in 10.4%, and LBBB in 10.2% of the overall cohort. In adjusted logistic regression analysis, higher EFT volume was associated with first-degree AV block (OR 1.006 [95% CI 1.002-1.010]; p = 0.006) and the need for new pacemaker implantation after TAVI (OR 1.005 [95% CI 1.0-1.01]; p = 0.035) but not with the presence of RBBB or LBBB. EFT volume did not correlate with the Agatston score of the aortic valve. Greater EFT volume is associated independently with preexisting first-degree AV block and new pacemaker implantation in patients undergoing TAVI. It may play a causative role in degenerative processes and the susceptibility of the AV conduction system.

CMR-derived myocardial strain analysis differentiates ischemic and dilated cardiomyopathy-a propensity score-matched study.

Left ventricular (LV) longitudinal, circumferential, and radial motion can be measured using feature tracking of cardiac magnetic resonance (CMR) images. The aim of our study was to detect differences in LV mechanics between patients with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) who were matched using a propensity score-based model. Between April 2017 and October 2019, 1224 patients were included in our CMR registry, among them 141 with ICM and 77 with DCM. Propensity score matching was used to pair patients based on their indexed end-diastolic volume (EDVi), ejection fraction (EF), and septal T1 relaxation time (psmatch2 module L Feature tracking provided six parameters for global longitudinal, circumferential, and radial strain with corresponding strain rates in each group. Strain parameters were compared between matched pairs of ICM and DCM patients using paired t tests. Propensity score matching yielded 72 patients in each group (DCM mean age 58.6 ± 11.6 years, 15 females; ICM mean age 62.6 ± 13.2 years, 11 females, p = 0.084 and 0.44 respectively; LV-EF 32.2 ± 13.5% vs. 33.8 ± 12.1%, p = 0.356; EDVi 127.2 ± 30.7 ml/m2 vs. 121.1 ± 41.8 ml/m2, p = 0.251; native T1 values 1165 ± 58 ms vs. 1167 ± 70 ms, p = 0.862). There was no difference in global longitudinal strain between DCM and ICM patients (- 10.9 ± 5.5% vs. - 11.2 ± 4.7%, p = 0.72), whereas in DCM patients there was a significant reduction in global circumferential strain (- 10.0 ± 4.5% vs. - 12.2 ± 4.7%, p = 0.002) and radial strain (17.1 ± 8.51 vs. 21.2 ± 9.7%, p = 0.039). Our data suggest that ICM and DCM patients have inherently different myocardial mechanics, even if phenotypes are similar. Our data show that GCS is significantly more impaired in DCM patients. This feature may help in more thoroughly characterizing cardiomyopathy patients.

Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68+, CD163+ and CD206+ macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure.

Does the severity of low-gradient aortic stenosis classified by computed tomography-derived aortic valve calcification determine the outcome of patients after transcatheter aortic valve implantation (TAVI)?

OBJECTIVES: Aortic valve calcification (AVC) determined by computed tomography has emerged as a complementary measure of aortic stenosis (AS) severity and as a predictor of adverse events. Thus, AVC can guide further treatment decisions in patients with low-gradient AS (LG-AS). We compared the symptomatic and prognostic outcome of patients with low vs. high AVC after transcatheter aortic valve implantation (TAVI). METHODS: Patients with an aortic valve area index ≤ 0.6 cm2/m2 and a mean pressure gradient (MPG) < 40 mmHg were classified as low-flow, low-gradient AS (LFLG-AS; stroke volume index [SVI] ≤ 35 ml/m2, left ventricular ejection fraction [LVEF] < 50%, n = 173), paradoxical LFLG-AS (pLFLG-AS, SVI ≤ 35 ml/m2, LVEF ≥ 50%, n = 233), or normal-flow, low-gradient AS (NFLG-AS, SVI > 35 ml/m2, LVEF ≥ 50%, n = 244); patients with MPG ≥ 40 mmHg (n = 1142) served as controls. Patients were further categorized according to published AVC thresholds. RESULTS: Demographic characteristics and cardiovascular risk were not different between patients with high vs. low AVC in any of the subgroups. Patients with low AVC had a lower MPG. Symptom improvement at 30 days was observed in the majority of patients but was less pronounced in LFLG-AS patients with low vs. those with high AVC. Kaplan-Meier 1-year survival curves were identical between patients with low and high AVC in all three LG-AS groups. CONCLUSIONS: The severity of LG-AS based on AVC has no impact on 1-year prognosis once TAVI has been performed. KEY POINTS: • Aortic valve calcification (AVC) determined by computed tomography has emerged as a complementary measure of aortic stenosis (AS) severity and is of prognostic value in selected patients. • Patients with inconsistent echocardiographic measures can be classified as having severe or nonsevere AS by the computed tomography-derived AVC score. • The prognostic value of AVC in patients with low-gradient AS is abrogated after correction of afterload by TAVI.

Diagnostic value of cardiovascular magnetic resonance in comparison to endomyocardial biopsy in cardiac amyloidosis: a multi-centre study.

BACKGROUND: Cardiac amyloidosis (CA) is an infiltrative disease characterised by accumulation of amyloid deposits in the extracellular space of the myocardium-comprising transthyretin (ATTR) and light chain (AL) amyloidosis as the most frequent subtypes. Histopathological proof of amyloid deposits by endomyocardial biopsy (EMB) is the gold standard for diagnosis of CA. Cardiovascular magnetic resonance (CMR) allows non-invasive workup of suspected CA. We conducted a multi-centre study to assess the diagnostic value of CMR in comparison to EMB for the diagnosis of CA. METHODS: We studied N = 160 patients characterised by symptoms of heart failure and presence of left ventricular (LV) hypertrophy of unknown origin who presented to specialised cardiomyopathy centres in Germany and underwent further diagnostic workup by both CMR and EMB. If CA was diagnosed, additional subtyping based on EMB specimens and monoclonal protein studies in serum was performed. The CMR protocol comprised cine- and late-gadolinium-enhancement (LGE)-imaging as well as native and post-contrast T1-mapping (in a subgroup)-allowing to measure extracellular volume fraction (ECV) of the myocardium. RESULTS: An EMB-based diagnosis of CA was made in N = 120 patients (CA group) whereas N = 40 patients demonstrated other diagnoses (CONTROL group). In the CA group, N = 114 (95%) patients showed a characteristic pattern of LGE indicative of CA. In the CONTROL group, only 1/40 (2%) patient showed a "false-positive" LGE pattern suggestive of CA. In the CA group, there was no patient with elevated T1-/ECV-values without a characteristic pattern of LGE indicative of CA. LGE-CMR showed a sensitivity of 95% and a specificity of 98% for the diagnosis of CA. The combination of a characteristic LGE pattern indicating CA with unremarkable monoclonal protein studies resulted in the diagnosis of ATTR-CA (confirmed by EMB) with a specificity of 98% [95%-confidence interval (CI) 92-100%] and a positive predictive value (PPV) of 99% (95%-CI 92-100%), respectively. The EMB-associated risk of complications was 3.13% in this study-without any detrimental or persistent complications. CONCLUSION: Non-invasive CMR shows an excellent diagnostic accuracy and yield regarding CA. When combined with monoclonal protein studies, CMR can differentiate ATTR from AL with high accuracy and predictive value. However, invasive EMB remains a safe invasive gold-standard and allows to differentiate CA from other cardiomyopathies that can also cause LV hypertrophy.

Challenges of recognizing bicuspid aortic valve in elderly patients undergoing TAVR.

Recognition of bicuspid aortic valve (BAV) may be challenging in elderly patients with heavily calcified aortic valves undergoing transcatheter aortic valve replacement (TAVR). In this subset, the diagnostic value of pre-procedural echocardiography in clinical routine is unknown. From a total of 2583 patients undergoing TAVR in our center, we determined the rate of BAV detected by routine echocardiography as documented in the medical records. Pre-procedural multidetector computed tomography (MDCT) images were retrospectively analyzed for the presence of BAV and served as reference standard. Using MDCT criteria, BAV was found in 235 (9.1%) (age 80.1 years [interquartile range 76.4; 83.4], 44.3% female). Of these, only 27/235 (11.5%) had been identified as BAV according to echocardiography reports, whereas 6/2348 (0.3%) with TAV had been wrongly diagnosed as BAV (p < 0.001; sensitivity 11.5%, specificity 99.7%). Correct diagnosis of BAV by echocardiography was more likely when transesophageal echocardiography was available (odds ratio (OR) 5.12 [95% confidence interval (CI) 2.22; 11.80]; p < 0.001) and the reader was experienced (OR 5.28 [95% CI 1.55; 18.04]; p = 0.008). Furthermore, correct diagnosis of BAV was more likely in bicommissural-type BAV (OR 2.22 [95% CI 0.90; 5.48]; p = 0.08), whereas heavy aortic valve calcification lead to misdiagnosis (OR 0.39 [95% CI 0.14; 1.06]; p = 0.07). In elderly patients with severe aortic stenosis that are candidates for TAVR, the presence of BAV may be considerably underestimated when relying solely on routine echocardiography. This underlines the value of MDCT for the screening of BAV in this patient population.

Case report of severe PCR-confirmed COVID-19 myocarditis in a European patient manifesting in mid January 2020.

BACKGROUND: Viral genesis is the most common cause of myocarditis. COVID-19-associated myocarditis seems to be a notable extrapulmonary manifestation, which may result in the need for a different treatment. There has been no positive polymerase chain reaction (PCR) testing of SARS-CoV-2 in heart specimens, thus far. CASE SUMMARY: A 48-year-old male patient presented with fever, dyspnoea, and haemoptysis. Laboratory findings showed highly elevated inflammatory and cardiac damage markers. Thoracic computed tomography (CT) revealed bilateral, patchy peripheral ground-glass opacities with a crazy-paving pattern, focal consolidations, and mild pleural effusions. Cardiac imaging with echocardiography and magnetic resonance imaging (MRI) detected a reduced biventricular function. MRI additionally showed myocardial oedema and late gadolinium enhancement. Lung and heart biopsies were performed, revealing alveolitis with necrosis and acute lymphocytic myocarditis. Testing for usual cardiotropic viruses was negative, and no aspects of vasculitis or granuloma could be found. Due to fulfilling the criteria, the patient was diagnosed with rheumatic vasculitis. Treatment with cyclophosphamide and steroids was initiated. Later, the patient reported a history of travel to Tyrol in mid January. Consequently, PCR testing for SARS-CoV-2 was performed, which was positive in the heart specimen. Immunosuppressive treatment was discontinued. During a follow-up visit at the end of April, the patient's recovery was stable. DISCUSSION: In COVID-19 infections, myocardial inflammation can be present as an extrapulmonary manifestation. Positive PCR testing confirms myocardial invasion of the virus. Imaging and laboratory studies correlate with the histopathological findings, and thus should be performed in COVID-19 patients who are suspicious for myocarditis. Supportive treatment with steroids may be useful in these patients.

The ACURATE neo Transcatheter Heart Valve: A Comprehensive Analysis of Predictors of Procedural Outcome.

OBJECTIVES: The aim of this study was to perform a comprehensive analysis of factors that affect procedural outcomes of transcatheter aortic valve replacement using the ACURATE neo prosthesis (Symetis/Boston, Ecublens, Switzerland). BACKGROUND: Predictors of procedural outcomes using the ACURATE neo prosthesis are poorly understood. METHODS: A total of 500 patients underwent transfemoral aortic valve replacement with the ACURATE neo prosthesis. Device landing zone calcification was stratified as severe, moderate, or mild. Anatomic and procedural predictors of second-degree or greater paravalvular leakage and permanent pacemaker implantation were assessed. RESULTS: Post-procedural second-degree or greater paravalvular leakage was more frequent with increasing device landing zone calcification (mild 0.8% vs. moderate 5.0% vs. severe 13.0%; p < 0.001), whereas permanent pacemaker implantation was independent of device landing zone calcification. More severe periannular calcification (odds ratio [OR]: 1.007; 95% confidence interval [CI]: 1.003 to 1.010; p < 0.001), less oversizing (OR: 0.867; 95% CI: 0.773 to 0.971; p = 0.014), the presence of annular plaque protrusions (OR: 2.756; 95% CI: 1.138 to 6.670; p = 0.025), and aortic movement of the delivery system after full deployment (OR: 5.593; 95% CI: 1.299 to 24.076; p = 0.02), and sinotubular junction height (OR: 1.156; 95% CI: 1.007 to 1.328; p = 0.04) independently predicted second-degree or greater paravalvular leakage. Predictors of permanent pacemaker implantation were pre-existing right bundle branch block (OR: 3.122; 95% CI: 1.261 to 7.731; p = 0.01) and more oversizing (OR: 1.111; 95% CI: 1.009 to 1.222; p = 0.03). CONCLUSIONS: Successful transcatheter aortic valve replacement using the ACURATE neo device predominantly depends on careful patient selection with appropriate oversizing and taking into account the individual anatomy and calcium distribution of the aortic root.

Comparison of outcomes using balloon-expandable versus self-expanding transcatheter prostheses according to the extent of aortic valve calcification.

BACKGROUND: Device landing zone (DLZ) calcification is an important determinant of procedural success in transcatheter aortic valve implantation (TAVI). OBJECTIVE: To evaluate the impact of DLZ calcification on procedural outcome with different types of transcatheter heart valves (THVs). METHODS: Aortic valve calcium density (AVCdens) was determined by non-contrast-enhanced computed tomography in 1232 patients undergoing transfemoral TAVI. We stratified the outcome data according to the extent of AVCdens (mild, moderate, severe) and compared balloon-expandable (BE) with self-expanding (SE) THV. Moreover, THVs were subdivided according to their radial force (BE: high; SEmod: moderate; SElow: low). RESULTS: With BE THV, PVR ≥2° (2.1 vs. 7.9%; p < 0.001), post-dilatation (12.3 vs. 36.6%; p < 0.001), malpositioning (8.4 vs. 13.0%; p = 0.01), device embolization (0.4 vs. 2.6%; p = 0.004), and the need for a second valve (1.2 vs. 3.6%; p = 0.01) were less frequent than with SE devices, but mean transaortic gradients at discharge were higher [12.0 mmHg (8.0-15.0) vs. 9.0 mmHg (6.0-11.0); p < 0.001], and aortic root injury was more frequent (2.7 vs. 0.8%; p = 0.01). In cases of severe calcification, differences between BE and SE THV regarding PVR, post-dilatation, and hemodynamics were mostly pronounced, followed by patients with moderate AVCdens. In cases with low AVCdens, the best outcomes with respect to PVR, pacemaker implantation, and hemodynamics were achieved with SElow THV. CONCLUSIONS: In severe and moderate DLZ calcification, BE devices may have advantages, whereas in mild DLZ calcification, SElow THV showed the most favorable profile.

Transfemoral aortic valve implantation using a self-expanding transcatheter heart valve without pre-dilation.

BACKGROUND: The aim of the present study was to investigate whether transfemoral implantation of the Acurate neo transcatheter heart valve without pre-dilation is feasible. METHODS: Between December 2014 and December 2016, 294 patients were treated with the Acurate neo prosthesis at our center. Of these, 72 cases were performed without pre-dilation. The decision to omit pre-dilation was at the discretion of the operator, preferably in the case of mild to moderate aortic valve calcification (AVC). Propensity matching (1:1) resulted in 48 cases in each group. Main outcomes of interest were device success according to VARC-2 criteria, residual aortic regurgitation (AR) ≥ 2°, and rate of post-dilation. RESULTS: Median [IQR] age in patients without pre-dilation was 82.7 years [78.6­85.6], STS score was 4.6% [3.4­6.1], and AVC-score was 1436 AU [1043­1682] with mild and moderate AVC in 63.9% and 36.1% of cases, respectively. Device success was achieved in 94.4% of cases, post-dilation was necessary in 26.4%, and one (1.4%) patient had moderate AR. In the matched population, there were no differences regarding device success, rate of AR ≥ 2°, need for post-dilation, and post-procedural mean gradient, but the group without pre-dilation had shorter procedure (34.0 min [27.0­38.8] vs. 43.0 min [34.3­52.0]; p < 0.001) and fluoroscopy times (7.4 min [5.7­9.0] vs. 9.9 min [7.9­13.5]; p < 0.001). CONCLUSION: In select patients with mild to moderate AVC, transfemoral implantation of the Acurate neo without pre-dilation is feasible and safe. This allows for a straightforward procedure that may be performed without rapid pacing in the majority of cases.

Cyclic changes in area- and perimeter-derived effective dimensions of the aortic annulus measured with multislice computed tomography and comparison with metric intraoperative sizing.

AIMS: Multislice computed tomography (MSCT) is recommended for annular sizing prior to transcatheter aortic valve implantation (TAVI), but it remains unclear whether systolic or diastolic reconstructions should be used and whether the effective annular diameter should be derived by area or perimeter. In this study these different approaches were compared with intraoperative sizing. METHODS: In 52 patients who were evaluated but deemed unsuitable for TAVI, the annulus was measured during conventional surgery using metric sizers (AnnOp) and compared with MSCT measurements (cross-sectional diameter derived by area [AnnAsys, AnnAdia; AnnAmean = (AnnAsys + AnnAdia)/2] and perimeter (AnnPsys, AnnPdia) in systole and diastole). Furthermore, TAVI was simulated based on AnnOp and the impact of the various MSCT approaches on sizing strategy was determined. RESULTS: The best agreement with AnnOp [mean difference (limits of agreement)] was shown for AnnAmean [0.03 mm (-1.9 to 1.96)], whereas the strongest deviation was noted for AnnPsys [-1.08 mm (-3.01 to 0.86)]. Mean differences between systole and diastole were significant but small: 0.82 mm (3.5 %) for area- and 0.81 mm (3.3 %) for perimeter-derived measurements. Simulation of TAVI revealed the least change of strategy for AnnAmean (76.9 %) as compared with AnnPsys (53.8 %); between AnnAsys and AnnAdia sizing would have been deviant in 17.3 % due to relatively large intraindividual cyclic differences. CONCLUSIONS: AnnAmean demonstrated the best agreement with AnnOp, whereas perimeter-derived measurements were somewhat overestimated. Despite a negligible average difference between systolic and diastolic annular values, in a subset of patients the intraindividual cyclic variability was relatively large and potentially of clinical impact.

Release kinetics of inflammatory biomarkers in a clinical model of acute myocardial infarction.

RATIONALE: Inflammation in the setting of acute myocardial infarction (MI) has been linked to risk stratification; however, the release kinetics of inflammatory biomarkers in patients with acute MI has been difficult to establish. OBJECTIVE: The aim of this study was to determine the kinetics of changes in the levels of several biomarkers specifically linked to inflammation after transcoronary ablation of septal hypertrophy, a procedure that mimics acute MI. METHODS AND RESULTS: We analyzed release kinetics of C-reactive protein, high-sensitivity C-reactive protein, interleukin-6, soluble CD40 ligand, and peripheral blood leukocyte subsets in patients (n=21) undergoing transcoronary ablation of septal hypertrophy. Blood samples were collected before transcoronary ablation of septal hypertrophy and at various times after transcoronary ablation of septal hypertrophy. Serum levels of C-reactive protein were increased at 24 hours (1.0 mg/dL [interquartile range [IQR], 0.7-1.75] versus 0.2 mg/dL [IQR, 0.1-1.05] at baseline [BL]; P<0.001), whereas high-sensitivity C-reactive protein increased as early as 8 hours (2.68 mg/L [IQR, 1.23-11.80] versus 2.17 mg/L [IQR, 1.15-5.06] at BL; P=0.002). Interleukin-6 was significantly increased at 45 minutes (2.59 pg/mL [IQR, 1.69-5.0] versus 1.5 pg/mL [IQR, 1.5-2.21] at BL; P=0.002), and soluble CD40 ligand was significantly decreased at 60 minutes (801.6 pg/mL [IQR, 675.0-1653.5] versus 1750.0 pg/mL [IQR, 1151.0-2783.0] at BL; P=0.016). Elevated counts of polymorphonuclear neutrophils were detectable at 15 minutes, with a significant increase at 2 hours (6415 cells/µL [IQR, 5288-7827] versus 4697 cells/µL [IQR, 2892-5620] at BL; P=0.004). Significant monocytosis was observed at 24 hours (729 cells/µL [IQR, 584-1344] versus 523 cells/µL [IQR, 369-701] at BL; P=0.015). CONCLUSIONS: Interleukin-6 and neutrophil granulocytes showed a continuous rise at all prespecified time points after induction of MI. Our results provide valuable additional evidence of the diagnostic value of inflammatory biomarkers in the setting of early acute MI.

Sham surgery and inter-individual heterogeneity are major determinants of monocyte subset kinetics in a mouse model of myocardial infarction.

AIMS: Mouse models of myocardial infarction (MI) are commonly used to explore the pathophysiological role of the monocytic response in myocardial injury and to develop translational strategies. However, no study thus far has examined the potential impact of inter-individual variability and sham surgical procedures on monocyte subset kinetics after experimental MI in mice. Our goal was to investigate determinants of systemic myeloid cell subset shifts in C57BL/6 mice following MI by developing a protocol for sequential extensive flow cytometry (FCM). METHODS AND RESULTS: Following cross-sectional multiplex FCM analysis we provide for the first time a detailed description of absolute quantities, relative subset composition, and biological variability of circulating classical, intermediate, and non-classical monocyte subsets in C57BL/6 mice. By using intra-individual longitudinal measurements after MI induction, a time course of classical and non-classical monocytosis was recorded. This approach disclosed a significant reduction of monocyte subset dispersion across all investigated time points following MI. We found that in the current invasive model of chronic MI the global pattern of systemic monocyte kinetics is mainly determined by a nonspecific inflammatory response to sham surgery and not by the extent of myocardial injury. CONCLUSIONS: Application of sequential multiplexed FCM may help to reduce the impact of biological variability in C57BL/6 mice. Furthermore, the confounding influence of sham surgical procedures should always be considered when measuring monocyte subset kinetics in a murine model of MI.

Release kinetics of early ischaemic biomarkers in a clinical model of acute myocardial infarction.

OBJECTIVE: To determine the release kinetics of different biomarkers with potential as novel early ischaemic biomarkers in patients with acute coronary syndrome (ACS); it is difficult to establish the detailed release kinetics in patients with acute myocardial infarction (AMI). METHODS: We analysed the release kinetics of soluble fms-like tyrosine kinase (sFlt-1), ischaemia modified albumin (IMA), and heart-type fatty acid binding protein (hFABP) in patients with hypertrophic obstructive cardiomyopathy who were undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure mimicking AMI. Consecutive patients (n=21) undergoing TASH were included. Blood samples were collected before TASH and 15, 30, 45, 60, 75, 90, and 105 min and 2, 4, 8, and 24 h after TASH. sFlt-1 and hFABP were quantified in serum, and IMA was quantified in plasma using immunoassays. RESULTS: sFLT-1 and hFABP increased significantly 15 min after induction of AMI vs baseline as follows: sFlt-1, 3657.5 ng/L (IQR 2302.3-4475.0) vs 76.0 ng/L (IQR 71.2-88.8) (p<0.001); hFABP, 9.0 ng/mL (IQR 7.0-15.4) vs 4.6 ng/mL (IQR 3.4-7.1) (p<0.001). sFlt-1 demonstrated a continuous decrease after the 15th min. hFABP showed a continuous increase until the 8th hour with a decline afterwards. The IMA concentrations increased significantly 30 min after induction of AMI vs baseline, with values of 26.0 U/mL (IQR 21.8-38.6) vs 15.6 U/mL (IQR 10.1-24.7) (p=0.02), and then decreased after 75 min. CONCLUSIONS: sFlt-1 and hFABP increased very early after induction of myocardial ischaemia, showing different release kinetics. The additional information provided by these findings is helpful for developing their potential combined use with cardiac troponins in patients with suspected AMI.

Neutrophil gelatinase-associated lipocalin (NGAL) for the early detection of contrast-induced nephropathy after percutaneous coronary intervention.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) occurs in up to 13% of patients undergoing percutaneous coronary intervention (PCI). Neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal impairment. We investigated whether increased urinary NGAL concentrations were predictive of CI-AKI within 2 days after PCI or of a higher re-hospitalization rate within 9 months. METHODS: Consecutive patients (n = 128), with stable coronary heart disease and eGFR ≥ 30 mL/min/1.73 m(2), undergoing PCI were included. Venous serum samples for measurement of creatinine, blood urea nitrogen, and cystatin C and urine samples for NGAL measurement were collected 4 hours and 1 and 2 days after contrast medium application. Patients were followed over 9 months to determine clinical endpoints. RESULTS: CI-AKI was observed in 14 patients (10.9%) after PCI. NGAL concentrations before PCI were significantly higher in patients with subsequent CI-AKI (19.8 ng/mL [14.4-35.8] vs. 11.6 ng/mL [5.6-28.2]; p = 0.04). There was no significant difference in NGAL concentrations 4 h after PCI between patients with and without CI-AKI. One day after PCI, NGAL concentrations were significant higher in patients developing CI-AKI (100.1 ng/mL [41.5-129.2] vs. 16.6 ng/mL [9.1-28.1]; p < 0.001). Compared to common biomarkers, NGAL best predicted CI-AKI (AUC 0.939 [95% CI 0.89-0.99; p < 0.001]). The re-hospitalization rate due to progressive renal insufficiency within 9 months was higher in the group with CI-AKI than the group without (4 [28.6%] vs. 4 [3.5%], p < 0.01). CONCLUSION: Urinary NGAL is a biomarker for predicting CI-AKI when measured 1 day after PCI.

Neutrophil gelatinase-associated lipocalin (NGAL) for the early detection of cardiac surgery associated acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a common complication after cardiac surgery. Neutrophil gelatinase-associated lipocalin (NGAL) may be an early biomarker for cardiac surgery-associated (CSA) AKI. We investigated whether increased urinary NGAL concentrations were predictive of AKI within 4 days after surgery and of mortality within 9 months. METHODS: Consecutive patients (n = 141) undergoing major cardiac surgery were included. Creatinine, blood urea nitrogen, cystatin C and urinary NGAL were measured before, 4 hours and 4 days after extracorporeal circulation. RESULTS: AKI was observed in 47 (33.3%) patients. The 4-hour urinary NGAL measurement was an independent predictor of stage 2 and 3 AKI (AUC 0.901; 95% CI 0.81-0.99). Patients with AKI had a higher 9-month mortality rate (19.1% vs. 3.2%; logrank 10.9; P = 0.001; HR 19.8; 95% CI 3.7-107.1). Urinary NGAL was not predictive of mortality within 9 months after surgery. CONCLUSION: Urinary NGAL is a biomarker for very early risk stratification of AKI after cardiac surgery and may be useful as a basis for early interventional strategies to prevent CSA-AKI.