Myocardial T1 and T2 mapping at 3?T: reference values,influencing factors and implications

Background

Myocardial T₁ and T₂ mapping using cardiovascular magnetic resonance (CMR) are promising to improve tissue characterization and early disease detection. This study aimed at analyzing the feasibility of T₁ and T₂ mapping at 3 T and providing reference values.

Methods

Sixty healthy volunteers (30 males/females, each 20 from 20–39 years, 40–59 years, 60–80 years) underwent left-ventricular T₁ and T₂ mapping in 3 short-axis slices at 3 T. For T₂ mapping, 3 single-shot steady-state free precession (SSFP) images with different T₂ preparation times were acquired. For T₁ mapping, modified Look-Locker inversion recovery technique with 11 single shot SSFP images was used before and after injection of gadolinium contrast. T₁ and T₂ relaxation times were quantified for each slice and each myocardial segment.

Results

Mean T₂ and T₁ (pre-/post-contrast) times were: 44.1 ms/1157.1 ms/427.3 ms (base), 45.1 ms/1158.7 ms/411.2 ms (middle), 46.9 ms/1180.6 ms/399.7 ms (apex). T₂ and pre-contrast T₁ increased from base to apex, post-contrast T₁ decreased. Relevant inter-subject variability was apparent (scatter factor 1.08/1.05/1.11 for T₂/pre-contrast T₁/post-contrast T₁). T₂ and post-contrast T₁ were influenced by heart rate (p < 0.0001, p = 0.0020), pre-contrast T₁ by age (p < 0.0001). Inter- and intra-observer agreement of T₂ (r = 0.95; r = 0.95) and T₁ (r = 0.91; r = 0.93) were high. T₂ maps: 97.7% of all segments were diagnostic and 2.3% were excluded (susceptibility artifact). T₁ maps (pre-/post-contrast): 91.6%/93.9% were diagnostic, 8.4%/6.1% were excluded (predominantly susceptibility artifact 7.7%/3.2%).

Conclusions

Myocardial T₂ and T₁ reference values for the specific CMR setting are provided. The diagnostic impact of the high inter-subject variability of T₂ and T₁ relaxation times requires further investigation.     

Endogenous assessment of chronic myocardial infarction with T1ρ-mapping in patients

Background

Detection of cardiac fibrosis based on endogenous magnetic resonance (MR) characteristics of the myocardium would yield a measurement that can provide quantitative information, is independent of contrast agent concentration, renal function and timing. In ex vivo myocardial infarction (MI) tissue, it has been shown that a significantly higher T_1ρ is found in the MI region, and studies in animal models of chronic MI showed the first in vivo evidence for the ability to detect myocardial fibrosis with native T_1ρ-mapping. In this study we aimed to translate and validate T_1ρ-mapping for endogenous detection of chronic MI in patients.

Methods

We first performed a study in a porcine animal model of chronic MI to validate the implementation of T_1ρ-mapping on a clinical cardiovascular MR scanner and studied the correlation with histology. Subsequently a clinical protocol was developed, to assess the feasibility of scar tissue detection with native T_1ρ-mapping in patients (n = 21) with chronic MI, and correlated with gold standard late gadolinium enhancement (LGE) CMR. Four T_1ρ-weighted images were acquired using a spin-lock preparation pulse with varying duration (0, 13, 27, 45 ms) and an amplitude of 750 Hz, and a T_1ρ-map was calculated. The resulting T_1ρ-maps and LGE images were scored qualitatively for the presence and extent of myocardial scarring using the 17-segment AHA model.

Results

In the animal model (n = 9) a significantly higher T_1ρ relaxation time was found in the infarct region (61 ± 11 ms), compared to healthy remote myocardium (36 ± 4 ms) . In patients a higher T_1ρ relaxation time (79 ± 11 ms) was found in the infarct region than in remote myocardium (54 ± 6 ms). Overlap in the scoring of scar tissue on LGE images and T_1ρ-maps was 74%.

Conclusion

We have shown the feasibility of native T_1ρ-mapping for detection of infarct area in patients with a chronic myocardial infarction. In the near future, improvements on the T_1ρ -mapping sequence could provide a higher sensitivity and specificity. This endogenous method could be an alternative for LGE imaging, and provide additional quantitative information on myocardial tissue characteristics.     

Soluble platelet-endothelial cell adhesion molecule-1, a biomarker of ventilator-induced lung injury

Introduction

Endothelial cell injury is an important component of acute lung injury. Platelet-endothelial cell adhesion molecule-1 (PECAM1) is a transmembrane protein that connects endothelial cells to one another and can be detected as a soluble, truncated protein (sPECAM1) in serum. We hypothesized that injurious mechanical ventilation (MV) leads to shedding of PECAM1 from lung endothelial cells resulting in increasing sPECAM1 levels in the systemic circulation.

Methods

We studied 36 Sprague–Dawley rats in two prospective, randomized, controlled studies (healthy and septic) using established animal models of ventilator-induced lung injury. Animals (n = 6 in each group) were randomized to spontaneous breathing or two MV strategies: low tidal volume (V_T) (6 ml/kg) and high-V_T (20 ml/kg) on 2 cmH₂O of positive end-expiratory pressure (PEEP). In low-V_T septic animals, 10 cmH₂O of PEEP was applied. We performed pulmonary histological and physiological evaluation and measured lung PECAM1 protein content and serum sPECAM1 levels after four hours ventilation period.

Results

High-V_T MV caused severe lung injury in healthy and septic animals, and decreased lung PECAM1 protein content (P < 0.001). Animals on high-V_T had a four- to six-fold increase of mean sPECAM1 serum levels than the unventilated counterpart (35.4 ± 10.4 versus 5.6 ± 1.7 ng/ml in healthy rats; 156.8 ± 47.6 versus 35.6 ± 12.6 ng/ml in septic rats) (P < 0.0001). Low-V_T MV prevented these changes. Levels of sPECAM1 in healthy animals on high-V_T MV paralleled the sPECAM1 levels of non-ventilated septic animals.

Conclusions

Our findings suggest that circulating sPECAM1 may represent a promising biomarker for the detection and monitoring of ventilator-induced lung injury.     

Two repetition time saturation transfer (TwiST) with spill-over correction to measure creatine kinase reaction rates in human hearts

Background

Phosphorus saturation transfer (ST) magnetic resonance spectroscopy can measure the rate of ATP generated from phosphocreatine (PCr) via creatine kinase (CK) in the human heart. Recently, the triple-repetition time ST (TRiST) method was introduced to measure the CK pseudo-first-order rate constant k_f in three acquisitions. In TRiST, the longitudinal relaxation time of PCr while γ-ATP is saturated, T₁`, is measured for each subject, but suffers from low SNR because the PCr signal is reduced due to exchange with saturated γ-ATP, and the short repetition time of one of the acquisitions. Here, a two-repetition time ST (TwiST) method is presented. In TwiST, the acquisition with γ-ATP saturation and short repetition time is dropped. Instead of measuring T<sub>1</sub>`, an intrinsic relaxation time T₁ for PCr, T₁^intrinsic, is assumed. The objective was to validate TwiST measurements of CK kinetics in healthy subjects and patients with heart failure (HF).

Methods

Bloch equation simulations that included the effect of spillover irradiation on PCr were used to derive formulae for T₁^intrinsic and k_f measured by both TRiST and TwiST methods. Spillover was quantified from an unsaturated PCr measurement used in the current protocol for determining PCr and ATP concentrations. Cardiac TRiST and TwiST data were acquired at 3 T from 12 healthy and 17 HF patients.

Results

Simulations showed that both k_f measured by TwiST and T₁^intrinsic require spill-over corrections. In human heart at 3 T, the spill-over corrected T₁^intrinsic = 8.4 ± 1.4 s (mean ± SD) independent of study group. TwiST and TRiST k_f measurements were the same, but TwiST was 9 min faster. Spill-over corrected TwiST k_f was 0.33 ± 0.08 s⁻¹ vs. 0.20 ± 0.06 s⁻¹ in healthy vs HF hearts, respectively (p < 0.0001).

Conclusion

TwiST was validated against TRiST in the human heart at 3 T, generating the same results 9 min faster. TwiST detected significant reductions in CK k_f in HF compared to healthy subjects, consistent with prior 1.5 T studies using different methodology.

Electronic supplementary material

The online version of this article (doi:10.1186/s12968-015-0175-4) contains supplementary material, which is available to authorized users.     

Evaluation of diastolic function by three-dimensional volume tracking of the mitral annulus with cardiovascular magnetic resonance: comparison with tissue Doppler imaging

Background

Measurement of mitral annulus (MA) dynamics is an important component of the evaluation of left ventricular (LV) diastolic function; MA velocities are commonly measured using tissue Doppler imaging (TDI). This study aimed to examine the clinical potential of a semi-automated cardiovascular magnetic resonance (CMR) technique for quantifying global LV diastolic function, using 3D volume tracking of the MA with conventional cine-CMR images.

Methods

124 consecutive patients with normal ejection fraction underwent both clinically indicated transthoracic echocardiography (TTE) and CMR within 2 months. Interpolated 3D reconstruction of the MA over time was performed with semi-automated atrioventricular junction (AVJ) tracking in long-axis cine-CMR images, producing an MA sweep volume over the cardiac cycle. CMR-based diastolic function was evaluated, using the following parameters: peak volume sweep rates in early diastole (PSR_E) and atrial systole (PSR_A), PSR_E/PSR_A ratio, deceleration time of sweep volume (DT_SV), and 50% diastolic sweep volume recovery time (DSVRT₅₀); these were compared with TTE diastolic measurements.

Results

Patients with TTE-based diastolic dysfunction (n = 62) showed significantly different normalized MA sweep volume profiles compared to those with TTE-based normal diastolic function (n = 62), including a lower PSR_E (5.25 ± 1.38 s⁻¹ vs. 7.72 ± 1.7 s⁻¹), a higher PSR_A (6.56 ± 1.99 s⁻¹ vs. 4.67 ± 1.38 s⁻¹), a lower PSR_E/PSR_A ratio (0.9 ± 0.44 vs. 1.82 ± 0.69), a longer DT_SV (144 ± 55 ms vs. 96 ± 37 ms), and a longer DSVRT₅₀ (25.0 ± 11.0% vs. 15.6 ± 4.0%) (all p < 0.05). CMR diastolic parameters were independent predictors of TTE-based diastolic dysfunction after adjusting for left ventricular hypertrophy, hypertension, and coronary artery disease. Good correlations were observed between CMR PSR_E/PSR_A and early-to-late diastolic annular velocity ratios (e′/a′) measured by TDI (r = 0.756 to 0.828, p < 0.001).

Conclusions

3D MA sweep volumes generated by semi-automated AVJ tracking in routinely acquired CMR images yielded diastolic parameters that were effective in identifying patients with diastolic dysfunction when correlated with TTE-based variables.     

Comparison of cardiovascular magnetic resonance characteristics and clinical consequences in children and adolescents with isolated left ventricular non-compaction with and without late gadolinium enhancement

Background

Although cardiovascular magnetic resonance (CMR) is showing increasingly diagnostic potential in left ventricular non-compaction (LVNC), relatively little research relevant to CMR is conducted in children with LVNC. This study was performed to characterize and compare CMR features and clinical outcomes in children with LVNC with and without late gadolinium enhancement (LGE).

Methods

A cohort of 40 consecutive children (age, 13.7 ± 3.3 years; 29 boys and 11 girls) with isolated LVNC underwent a baseline CMR scan with subsequent clinical follow-up. Short-axis cine images were used to calculate left ventricular (LV) ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), myocardial mass, ratio of non-compacted-to-compacted myocardial thickness (NC/C ratio), and number of non-compacted segments. The LGE images were analyzed to assess visually presence and patterns of LGE. The primary end point was a composite of cardiac death and heart transplantation.

Results

The LGE was present in 10 (25 %) children, and 46 (27 %) segments were involved, including 23 non-compacted segments and 23 normal segments. Compared with LGE- cohort, LGE+ cohort had significantly lower LVEF (23.8 ± 10.7 % vs. 42.9 ± 16.7 %, p < 0.001) and greater LVEDV (169.2 ± 65.1 vs. 118.2 ± 48.9 mL/m², p = 0.010), LVESV (131.3 ± 55.5 vs. 73.3 ± 46.7 mL/m², p = 0.002), and sphericity indices (0.75 ± 0.19 vs. 0.60 ± 0.20, p = 0.045). There were no differences in terms of number and distribution of non-compacted segments, NC/C ratio, and myocardial mass index between LGE+ and LGE- cohort. In the LGE+ cohort, adverse events occurred in 6 patients compared to 2 events in the LGE- cohort. Kaplan-Meier analysis showed a significant difference in outcome between LGE+ and LGE- cohort for cardiac death and heart transplantation (p = 0.011).

Conclusions

The LGE was present in up to one-fourth of children with LVNC, and the LGE+ children exhibited a more maladaptive LV remodeling and a higher incidence of cardiovascular death and heart transplantation.     

Better lactate clearance associated with good neurologic outcome in survivors who treated with therapeutic hypothermia after out-of-hospital cardiac arrest

Introduction

Several methods have been proposed to evaluate neurological outcome in out-of-hospital cardiac arrest (OHCA) patients. Blood lactate has been recognized as a reliable prognostic marker for trauma, sepsis, or cardiac arrest. The objective of this study was to examine the association between initial lactate level or lactate clearance and neurologic outcome in OHCA survivors who were treated with therapeutic hypothermia.

Methods

This retrospective cohort study included patients who underwent protocol-based 24-hour therapeutic hypothermia after OHCA between January 2010 and March 2012. Serum lactate levels were measured at the start of therapy (0 hours), and after 6 hours, 12 hours, 24 hours, 48 hours and 72 hours. The 6 hour and 12 hour lactate clearance were calculated afterwards. Patients’ neurologic outcome was assessed at one month after cardiac arrest; good neurological outcome was defined as Cerebral Performance Category one or two. The primary outcome was an association between initial lactate level and good neurologic outcome. The secondary outcome was an association between lactate clearance and good neurologic outcome in patients with initial lactate level >2.5 mmol/l.

Results

Out of the 76 patients enrolled, 34 (44.7%) had a good neurologic outcome. The initial lactate level showed no significant difference between good and poor neurologic outcome groups (6.07 ±4 .09 mmol/L vs 7.13 ± 3.99 mmol/L, P = 0.42), However, lactate levels at 6 hours, 12 hours, 24 hours, and 48 hours in the good neurologic outcome group were lower than in the poor neurologic outcome group (3.81 ± 2.81 vs 6.00 ± 3.22 P <0.01, 2.95 ± 2.07 vs 5.00 ± 3.49 P <0.01, 2.17 ± 1.24 vs 3.86 ± 3.92 P <0.01, 1.57 ± 1.02 vs 2.21 ± 1.35 P = 0.03, respectively). The secondary analysis showed that the 6-hour and 12-hour lactate clearance was higher for good neurologic outcome patients (35.3 ± 34.6% vs 6.89 ± 47.4% P = 0.01, 54.5 ± 23.7% vs 25.6 ± 43.7% P <0.01, respectively). After adjusting for potential confounding variables, the 12-hour lactate clearance still showed a statistically significant difference (P = 0.02).

Conclusion

The lactate clearance rate, and not the initial lactate level, was associated with neurological outcome in OHCA patients after therapeutic hypothermia.     

T2 mapping of the heart with a double-inversion radial fast spin-echo method with indirect echo compensation

Background

The abnormal signal intensity in cardiac T₂-weighted images is associated with various pathologies including myocardial edema. However, the assessment of pathologies based on signal intensity is affected by the acquisition parameters and the sensitivities of the receiver coils. T₂ mapping has been proposed to overcome limitations of T₂-weighted imaging, but most methods are limited in spatial and/or temporal resolution. Here we present and evaluate a double inversion recovery radial fast spin-echo (DIR-RADFSE) technique that yields data with high spatiotemporal resolution for cardiac T₂ mapping.

Methods

DIR-RADFSE data were collected at 1.5 T on phantoms and subjects with echo train length (ETL) = 16, receiver bandwidth (BW) = ±32 kHz, TR = 1RR, matrix size = 256 × 256. Since only 16 views per echo time (TE) are collected, two algorithms designed to reconstruct highly undersampled radial data were used to generate images for 16 time points: the Echo-Sharing (ES) and the CUrve Reconstruction via pca-based Linearization with Indirect Echo compensation (CURLIE) algorithm. T₂ maps were generated via least-squares fitting or the Slice-resolved Extended Phase Graph (SEPG) model fitting. The CURLIE-SEPG algorithm accounts for the effect of indirect echoes. The algorithms were compared based on reproducibility, using Bland-Altman analysis on data from 7 healthy volunteers, and T₂ accuracy (against a single-echo spin-echo technique) using phantoms.

Results

Both reconstruction algorithms generated in vivo images with high spatiotemporal resolution and showed good reproducibility. Mean T₂ difference between repeated measures and the coefficient of repeatability were 0.58 ms and 2.97 for ES and 0.09 ms and 4.85 for CURLIE-SEPG. In vivo T₂ estimates from ES were higher than those from CURLIE-SEPG. In phantoms, CURLIE-SEPG yielded more accurate T₂s compared to reference values (error was 7.5-13.9% for ES and 0.6-2.1% for CURLIE-SEPG), consistent with the fact that CURLIE-SEPG compensates for the effects of indirect echoes. The potential of T₂ mapping with CURLIE-SEPG is demonstrated in two subjects with known heart disease. Elevated T₂ values were observed in areas of suspected pathology.

Conclusions

DIR-RADFSE yielded TE images with high spatiotemporal resolution. Two algorithms for generating T₂ maps from highly undersampled data were evaluated in terms of accuracy and reproducibility. Results showed that CURLIE-SEPG yields T₂ estimates that are reproducible and more accurate than ES.     

Incremental value of cardiovascular magnetic resonance over echocardiography in the detection of acute and chronic myocardial infarction

Background

Although echocardiography is used as a first line imaging modality, its accuracy to detect acute and chronic myocardial infarction (MI) in relation to infarct characteristics as assessed with late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) is not well described.

Methods

One-hundred-forty-one echocardiograms performed in 88 first acute ST-elevation MI (STEMI) patients, 2 (IQR1-4) days (n = 61) and 102 (IQR92-112) days post-MI (n = 80), were pooled with echocardiograms of 36 healthy controls. 61 acute and 80 chronic echocardiograms were available for analysis (53 patients had both acute and chronic echocardiograms). Two experienced echocardiographers, blinded to clinical and CMR data, randomly evaluated all 177 echocardiograms for segmental wall motion abnormalities (SWMA). This was compared with LGE-CMR determined infarct characteristics, performed 104 ± 11 days post-MI. Enhancement on LGE-CMR matched the infarct-related artery territory in all patients (LAD 31%, LCx 12% and RCA 57%).

Results

The sensitivity of echocardiography to detect acute MI was 78.7% and 61.3% for chronic MI; specificity was 80.6%. Undetected MI were smaller, less transmural, and less extensive (6% [IQR3-12] vs. 15% [IQR9-24], 50 ± 14% vs. 61 ± 15%, 7 ± 3 vs. 9 ± 3 segments, p < 0.001 for all) and associated with higher left ventricular ejection fraction (LVEF) and non-anterior location as compared to detected MI (58 ± 5% vs. 46 ± 7%, p < 0.001 and 82% vs. 63%, p = 0.03). After multivariate analysis, LVEF and infarct size were the strongest independent predictors of detecting chronic MI (OR 0.78 [95%CI 0.68-0.88], p < 0.001 and OR 1.22 [95%CI0.99-1.51], p = 0.06, respectively). Increasing infarct transmurality was associated with increasing SWMA (p < 0.001).

Conclusions

In patients presenting with STEMI, and thus a high likelihood of SWMA, the sensitivity of echocardiography to detect SWMA was higher in the acute than the chronic phase. Undetected MI were smaller, less extensive and less transmural, and associated with non-anterior localization and higher LVEF. Further work is needed to assess the diagnostic accuracy in patients with non-STEMI.     

Cardiac-respiratory self-gated cine ultra-short echo time (UTE) cardiovascular magnetic resonance for assessment of functional cardiac parameters at high magnetic fields

Background

To overcome flow and electrocardiogram-trigger artifacts in cardiovascular magnetic resonance (CMR), we have implemented a cardiac and respiratory self-gated cine ultra-short echo time (UTE) sequence. We have assessed its performance in healthy mice by comparing the results with those obtained with a self-gated cine fast low angle shot (FLASH) sequence and with echocardiography.

Methods

2D self-gated cine UTE (TE/TR = 314 μs/6.2 ms, resolution: 129 × 129 μm, scan time per slice: 5 min 5 sec) and self-gated cine FLASH (TE/TR = 3 ms/6.2 ms, resolution: 129 × 129 μm, scan time per slice: 4 min 49 sec) images were acquired at 9.4 T. Volume of the left and right ventricular (LV, RV) myocardium as well as the end-diastolic and -systolic volume was segmented manually in MR images and myocardial mass, stroke volume (SV), ejection fraction (EF) and cardiac output (CO) were determined. Statistical differences were analyzed by using Student t test and Bland-Altman analyses.

Results

Self-gated cine UTE provided high quality images with high contrast-to-noise ratio (CNR) also for the RV myocardium (CNR_{blood-myocardium} = 25.5 ± 7.8). Compared to cine FLASH, susceptibility, motion, and flow artifacts were considerably reduced due to the short TE of 314 μs. The aortic valve was clearly discernible over the entire cardiac cycle. Myocardial mass, SV, EF and CO determined by self-gated UTE were identical to the values measured with self-gated FLASH and showed good agreement to the results obtained by echocardiography.

Conclusions

Self-gated UTE allows for robust measurement of cardiac parameters of diagnostic interest. Image quality is superior to self-gated FLASH, rendering the method a powerful alternative for the assessment of cardiac function at high magnetic fields.     

Pulmonary artery to aorta ratio for the detection of pulmonary hypertension: cardiovascular magnetic resonance and invasive hemodynamics in heart failure with preserved ejection fraction

Background

Previous work indicates that dilatation of the pulmonary artery (PA) itself or in relation to the ascending aorta (PA:Ao ratio) predicts pulmonary hypertension (PH). Whether these results also apply for heart failure with preserved ejection fraction (HFpEF) is unknown.In the present study we evaluated the diagnostic and prognostic power of PA diameter and PA:Ao ratio on top of right ventricular (RV) size, function, and septomarginal trabeculation (SMT) thickness by cardiovascular magnetic resonance (CMR) in HFpEF.

Methods and Results

159 consecutive HFpEF patients were prospectively enrolled. Of these, 111 underwent CMR and invasive hemodynamic evaluation.By invasive assessment 64 % of patients suffered from moderate/severe PH (mean pulmonary artery pressure (mPAP) ≥30 mmHg). Significant differences between groups with and without moderate/severe PH were observed with respect to PA diameter (30.9 ± 5.1 mm versus 26 ± 5.1 mm, p < 0.001), PA:Ao ratio (0.93 ± 0.16 versus 0.78 ± 0.14, p < 0.001), and SMT diameter (4.6 ± 1.5 mm versus 3.8 ± 1.2 mm; p = 0.008). The strongest correlation with mPAP was found for PA:Ao ratio (r = 0.421, p < 0.001). By ROC analysis the best cut-off for the detection of moderate/severe PH was found for a PA:Ao ratio of 0.83.Patients were followed for 22.0 ± 14.9 months. By Kaplan Meier analysis event-free survival was significantly worse in patients with a PA:Ao ratio ≥0.83 (log rank, p = 0.004). By multivariable Cox-regression analysis PA:Ao ratio was independently associated with event-free survival (p = 0.003).

Conclusion

PA:Ao ratio is an easily measureable noninvasive indicator for the presence and severity of PH in HFpEF, and it is related with outcome.     

A randomized,cross‐over trial of metoprolol succinate formulations to evaluate PK and PD end points for therapeutic equivalence

There are limited comparison data throughout the dosing interval for generic versus brand metoprolol extended‐release (ER) tablets. We compared the pharmacokinetics (PKs) and pharmacodynamics of brand name versus two generic formulations (drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (T _max) in adults with hypertension. Participants were randomized to equal drug doses (50–150 mg/day) administered in one of two sequences (brand‐drug1‐brand‐drug2 or brand‐drug2‐brand‐drug1) and completed 24‐h PK, digital heart rate (HR), ambulatory blood pressure (BP), and HR studies after taking each formulation for greater than or equal to 7 days. Metoprolol concentrations were determined by liquid chromatography tandem mass spectrometry, with noncompartmental analysis performed to obtain PK parameters in Phoenix WinNonlin. Heart rate variability (HRV) low‐to‐high frequency ratio was determined per quartile over the 24‐h period. Thirty‐six participants completed studies with the brand name and at least one generic product. Among 30 participants on the 50 mg dose, the primary PK end points of area under the concentration‐time curve and C _max were similar between products; T _max was 6.1 ± 3.6 for the brand versus 3.5 ± 4.9 for drug 1 (p = 0.019) and 9.6 ± 3.2 for drug 2 (p < 0.001). Among all 36 participants, 24‐h BPs and HRs were similar between products. Mean 24‐h HRV low‐to‐high ratio was also similar for drug 1 (2.04 ± 1.35), drug 2 (1.86 ± 1.35), and brand (2.04 ± 1.77), but was more sustained over time for the brand versus drug 1 (drug × quartile interaction p = 0.017). Differences in T _max between metoprolol ER products following repeated doses may have implications for drug effects on autonomic balance over the dosing interval.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Data from single dose pharmacokinetic studies in healthy volunteers were used to establish the bioequivalence of generic metoprolol extended‐release (ER) products. WHAT QUESTION DID THIS STUDY ADDRESS? This study examined whether generic metoprolol ER formulations maintain their therapeutic effects throughout the dosing interval. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Following repeated doses, autonomic balance, as assessed by the ratio of low‐to‐high frequency heart rate variability (HRV), was more sustained throughout the dosing interval with the brand name product compared to a generic formulation with a differing time to maximum concentration. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These data suggest that HRV should be further evaluated as a pharmacodynamic measure for therapeutic equivalence.     

Feature tracking compared with tissue tagging measurements of segmental strain by cardiovascular magnetic resonance

Background

Left ventricular segmental wall motion analysis is important for clinical decision making in cardiac diseases. Strain analysis with myocardial tissue tagging is the non-invasive gold standard for quantitative assessment, however, it is time-consuming. Cardiovascular magnetic resonance myocardial feature-tracking (CMR-FT) can rapidly perform strain analysis, because it can be employed with standard CMR cine-imaging. The aim is to validate segmental peak systolic circumferential strain (peak SCS) and time to peak systolic circumferential strain (T2P-SCS) analysed by CMR-FT against tissue tagging, and determine its intra and inter-observer variability.

Methods

Patients in whom both cine CMR and tissue tagging has been performed were selected. CMR-FT analysis was done using endocardial (CMR-FT_endo) and mid-wall contours (CMR-FT_mid). The Intra Class Correlation Coefficient (ICC) and Pearson correlation were calculated.

Results

10 healthy volunteers, 10 left bundle branch block (LBBB) and 10 hypertrophic cardiomyopathy patients were selected. With CMR-FT all 480 segments were analyzable and with tissue tagging 464 segments.Significant differences in mean peak SCS values of the total study group were present between CMR-FT_endo and tissue tagging (-23.8 ± 9.9% vs -13.4 ± 3.3%, p < 0.001). Differences were smaller between CMR-FT_mid and tissue tagging (-16.4 ± 6.1% vs -13.4 ± 3.3%, p = 0.001). The ICC of the mean peak SCS of the total study group between CMR-FT_endo and tissue tagging was low (0.19 (95%-CI-0.10-0.49), p = 0.02). Comparable results were seen between CMR-FT_mid and tissue tagging. In LBBB patients, mean T2P-SCS values measured with CMR-FT_endo and CMR-FT_mid were 418 ± 66 ms, 454 ± 60 ms, which were longer than with tissue tagging, 376 ± 55 ms, both p < 0.05. ICC of the mean T2P-SCS between CMR-FT_endo and tissue tagging was 0.64 (95%-CI-0.36-0.81), p < 0.001, this was better in the healthy volunteers and LBBB group, whereas the ICC between CMR-FT_mid and tissue tagging was lower.The intra and inter-observer agreement of segmental peak SCS with CMR-FT_mid was lower compared with tissue tagging; similar results were seen for segmental T2P-SCS.

Conclusions

The intra and inter-observer agreement of segmental peak SCS and T2P-SCS is substantially lower with CMR-FT_mid compared with tissue tagging. Therefore, current segmental CMR-FT_mid techniques are not yet applicable for clinical and research purposes.     

Some characteristics of hyperglycaemic crisis differ between patients with and without COVID-19 at a safety-net hospital in a cross-sectional study

ObjectiveTo compare patients with DKA, hyperglycaemic hyperosmolar syndrome (HHS), or mixed DKA-HHS and COVID-19 [COVID (+)] to COVID-19-negative (−) [COVID (−)] patients with DKA/HHS from a low-income, racially/ethnically diverse catchment area.MethodsA cross-sectional study was conducted with patients admitted to an urban academic medical center between 1 March and 30 July 2020. Eligible patients met lab criteria for either DKA or HHS. Mixed DKA-HHS was defined as meeting all criteria for either DKA or HHS with at least 1 criterion for the other diagnosis.ResultsA total of 82 participants were stratified by COVID-19 status and type of hyperglycaemic crisis [26 COVID (+) and 56 COVID (−)]. A majority were either Black or Hispanic. Compared with COVID (−) patients, COVID (+) patients were older, more Hispanic and more likely to have type 2 diabetes (T2D, 73% vs 48%, p < .01). COVID(+) patients had a higher mean pH (7.25 ± 0.10 vs 7.16 ± 0.16, p < .01) and lower anion gap (18.7 ± 5.7 vs 22.7 ± 6.9, p = .01) than COVID (−) patients. COVID (+) patients were given less intravenous fluids in the first 24 h (2.8 ± 1.9 vs 4.2 ± 2.4 L, p = .01) and were more likely to receive glucocorticoids (95% vs. 11%, p < .01). COVID (+) patients may have taken longer to resolve their hyperglycaemic crisis (53.3 ± 64.8 vs 28.8 ± 27.5 h, p = .09) and may have experienced more hypoglycaemia <3.9 mmol/L (35% vs 19%, p = .09). COVID (+) patients had a higher length of hospital stay (LOS, 14.8 ± 14.9 vs 6.5 ± 6.0 days, p = .01) and in-hospital mortality (27% vs 7%, p = .02).DiscussionCompared with COVID (−) patients, COVID (+) patients with DKA/HHS are more likely to have T2D. Despite less severe metabolic acidosis, COVID (+) patients may require more time to resolve the hyperglycaemic crisis and experience more hypoglycaemia while suffering greater LOS and risk of mortality. Larger studies are needed to examine whether differences in management between COVID (+) and (−) patients affect outcomes with DKA/HHS.     

Extracellular volume quantification in isolated hypertension - changes at the detectable limits?

Background

Diffuse myocardial fibrosis (DMF) is important in cardiovascular disease, however until recently could only be assessed by invasive biopsy. We hypothesised that DMF measured by T1 mapping is elevated in isolated systemic hypertension.

Methods

In a study of well-controlled hypertensive patients from a specialist tertiary centre, 46 hypertensive patients (median age 56, range 21 to 78, 52 % male) and 50 healthy volunteers (median age 45, range 28 to 69, 52 % male) underwent clinical CMR at 1.5 T with T1 mapping (ShMOLLI) using the equilibrium contrast technique for extracellular volume (ECV) quantification. Patients underwent 24-hours Automated Blood Pressure Monitoring (ABPM), echocardiographic assessment of diastolic function, aortic stiffness assessment and measurement of NT-pro-BNP and collagen biomarkers.

Results

Late gadolinium enhancement (LGE) revealed significant unexpected underlying pathology in 6 out of 46 patients (13 %; myocardial infarction n = 3; hypertrophic cardiomyopathy (HCM) n = 3); these were subsequently excluded. Limited, non-ischaemic LGE patterns were seen in 11 out of the remaining 40 (28 %) patients. Hypertensives on therapy (mean 2.2 agents) had a mean ABPM of 152/88 mmHg, but only 35 % (14/40) had left ventricular hypertrophy (LVH; LV mass male > 90 g/m²; female > 78 g/m²). Native myocardial T1 was similar in hypertensives and controls (955 ± 30 ms versus 965 ± 38 ms, p = 0.16). The difference in ECV did not reach significance (0.26 ± 0.02 versus 0.27 ± 0.03, p = 0.06). In the subset with LVH, the ECV was significantly higher (0.28 ± 0.03 versus 0.26 ± 0.02, p < 0.001).

Conclusion

In well-controlled hypertensive patients, conventional CMR discovered significant underlying diseases (chronic infarction, HCM) not detected by echocardiography previously or even during this study. T1 mapping revealed increased diffuse myocardial fibrosis, but the increases were small and only occurred with LVH.     

Infusion of 2.5?meq/min of lactic acid minimally increases CO2 production compared to an isocaloric glucose infusion in healthy anesthetized,mechanically ventilated pigs

Introduction

Blood acidification by lactic acid infusion converts bicarbonate to CO₂. This effect can be exploited to increase the transmembrane PCO₂ gradient of an extracorporeal membrane lung, resulting in a significant increase of extracorporeal CO₂ removal. Lactic acid, however, is an energetic substrate and its metabolism might increase total body CO₂ production (VCO₂), limiting the potential beneficial effects of this technique. The aim of our study was to compare VCO₂ during isocaloric infusion of lactic acid or glucose.

Methods

Six pigs (45 ± 5 kg) were sedated and mechanically ventilated. Estimated caloric needs were 2,300–2,400 Kcal/die (95 to 100 Kcal/h). A sequence of two steps lasting four hours each was performed: 1) Glucose, 97 kcal/h were administered as 50% glucose solution, and 2) Lactic Acid, approximately 48.5 kcal/h were administered as lactic acid and approximately 48.5 kcal/h as 50% glucose solution. This sequence was repeated three times with two-hour intervals. Every hour VCO₂, arterial blood gases and lactate were measured. Blood glucose level was kept constant by titrating an insulin infusion, ventilation was adjusted to maintain arterial PCO₂ at 50 mmHg, a normal value for our animal model.

Results

During Lactic Acid steps VCO₂ increased less than 5% compared to the Glucose steps (282 vs. 269 ml/min, P <0.05); blood glucose did not differ between the two groups (respectively 101 ± 12 vs. 103 ± 8 mg/dl). Arterial lactate was always lower than 3 mmol/L. Arterial pH was lower during Lactic Acid steps (7.422 vs. 7.445, P <0.05).

Conclusions

Replacing 50% of the caloric input with lactic acid increased total CO₂ production by less than 5% compared to an equal caloric load provided entirely by a 50% glucose solution.     

In-vivo quantitative T2 mapping of carotid arteries in atherosclerotic patients: segmentation and T2 measurement of plaque components

Background

Atherosclerotic plaques in carotid arteries can be characterized in-vivo by multicontrast cardiovascular magnetic resonance (CMR), which has been thoroughly validated with histology. However, the non-quantitative nature of multicontrast CMR and the need for extensive post-acquisition interpretation limit the widespread clinical application of in-vivo CMR plaque characterization. Quantitative T₂ mapping is a promising alternative since it can provide absolute physical measurements of plaque components that can be standardized among different CMR systems and widely adopted in multi-centre studies. The purpose of this study was to investigate the use of in-vivo T₂ mapping for atherosclerotic plaque characterization by performing American Heart Association (AHA) plaque type classification, segmenting carotid T₂ maps and measuring in-vivo T₂ values of plaque components.

Methods

The carotid arteries of 15 atherosclerotic patients (11 males, 71 ± 10 years) were imaged at 3 T using the conventional multicontrast protocol and Multiple-Spin-Echo (Multi-SE). T₂ maps of carotid arteries were generated by mono-exponential fitting to the series of images acquired by Multi-SE using nonlinear least-squares regression. Two reviewers independently classified carotid plaque types following the CMR-modified AHA scheme, one using multicontrast CMR and the other using T₂ maps and time-of-flight (TOF) angiography. A semi-automated method based on Bayes classifiers segmented the T₂ maps of carotid arteries into 4 classes: calcification, lipid-rich necrotic core (LRNC), fibrous tissue and recent IPH. Mean ± SD of the T₂ values of voxels classified as LRNC, fibrous tissue and recent IPH were calculated.

Results

In 37 images of carotid arteries from 15 patients, AHA plaque type classified by multicontrast CMR and by T₂ maps (+ TOF) showed good agreement (76% of matching classifications and Cohen’s κ = 0.68). The T₂ maps of 14 normal arteries were used to measure T₂ of tunica intima and media (T₂ = 54 ± 13 ms). From 11865 voxels in the T₂ maps of 15 arteries with advanced atherosclerosis, 2394 voxels were classified by the segmentation algorithm as LRNC (T₂ = 37 ± 5 ms) and 7511 voxels as fibrous tissue (T₂ = 56 ± 9 ms); 192 voxels were identified as calcification and one recent IPH (236 voxels, T₂ = 107 ± 25 ms) was detected on T₂ maps and confirmed by multicontrast CMR.

Conclusions

This carotid CMR study shows the potential of in-vivo T₂ mapping for atherosclerotic plaque characterization. Agreement between AHA plaque types classified by T₂ maps (+TOF) and by conventional multicontrast CMR was good, and T₂ measured in-vivo in LRNC, fibrous tissue and recent IPH demonstrated the ability to discriminate plaque components on T₂ maps.     

Effects of thoracic epidural anesthesia on survival and microcirculation in severe acute pancreatitis: a randomized experimental trial

Introduction

Severe acute pancreatitis is still a potentially life threatening disease with high mortality. The aim of this study was to evaluate the therapeutic effect of thoracic epidural anaesthesia (TEA) on survival, microcirculation, tissue oxygenation and histopathologic damage in an experimental animal model of severe acute pancreatitis in a prospective animal study.

Methods

In this study, 34 pigs were randomly assigned into 2 treatment groups. After severe acute pancreatitis was induced by intraductal injection of glycodesoxycholic acid in Group 1 (n = 17) bupivacaine (0.5%; bolus injection 2 ml, continuous infusion 4 ml/h) was applied via TEA. In Group 2 (n = 17) no TEA was applied. During a period of 6 hours after induction, tissue oxygen tension (tpO₂) in the pancreas and pancreatic microcirculation was assessed. Thereafter animals were observed for 7 days followed by sacrification and histopathologic examination.

Results

Survival rate after 7 days was 82% in Group 1 (TEA) versus 29% in Group 2: (Control) (P <0.05). Group 1 (TEA) also showed a significantly superior microcirculation (1,608 ± 374 AU versus 1,121 ± 510 AU; P <0.05) and tissue oxygenation (215 ± 64 mmHg versus 138 ± 90 mmHG; P <0.05) as compared to Group 2 (Control). Consecutively, tissue damage in Group 1 was reduced in the histopathologic scoring (5.5 (3 to 8) versus 8 (5.5 to 10); P <0.05).

Conclusions

TEA led to improved survival, enhanced microcirculatory perfusion and tissue oxygenation and resulted in less histopathologic tissue-damage in an experimental animal model of severe acute pancreatitis.     

Assessment of cardiovascular physiology using dobutamine stress cardiovascular magnetic resonance reveals impaired contractile reserve in patients with cirrhotic cardiomyopathy

Background

Liver cirrhosis has been shown to affect cardiac performance. However cardiac dysfunction may only be revealed under stress conditions. The value of non-invasive stress tests in diagnosing cirrhotic cardiomyopathy is unclear. We sought to investigate the response to pharmacological stimulation with dobutamine in patients with cirrhosis using cardiovascular magnetic resonance.

Methods

Thirty-six patients and eight controls were scanned using a 1.5 T scanner (Siemens Symphony TIM; Siemens, Erlangen, Germany). Conventional volumetric and feature tracking analysis using dedicated software (CMR42; Circle Cardiovascular Imaging Inc, Calgary, Canada and Diogenes MRI; Tomtec; Germany, respectively) were performed at rest and during low to intermediate dose dobutamine stress.

Results

Whilst volumetry based parameters were similar between patients and controls at rest, patients had a smaller increase in cardiac output during stress (p = 0.015). Ejection fraction increase was impaired in patients during 10 μg/kg/min dobutamine as compared to controls (6.9 % vs. 16.5 %, p = 0.007), but not with 20 μg/kg/min (12.1 % vs. 17.6 %, p = 0.12). This was paralleled by an impaired improvement in circumferential strain with low dose (median increase of 14.4 % vs. 30.9 %, p = 0.03), but not with intermediate dose dobutamine (median increase of 29.4 % vs. 33.9 %, p = 0.54). There was an impaired longitudinal strain increase in patients as compared to controls during low (median increase of 6.6 % vs 28.6 %, p < 0.001) and intermediate dose dobutamine (median increase of 2.6%vs, 12.6 % p = 0.016). Radial strain response to dobutamine was similar in patients and controls (p > 0.05).

Conclusion

Cirrhotic cardiomyopathy is characterized by an impaired cardiac pharmacological response that can be detected with magnetic resonance myocardial stress testing. Deformation analysis parameters may be more sensitive in identifying abnormalities in inotropic response to stress than conventional methods.     

Relationship between hair shedding and systemic inflammation in COVID-19 pneumonia

Background: A higher risk for COVID-19 infection and severity for men compared to women has been described since the beginning of the pandemic. The role of androgens has been recently highlighted as they control two key steps of coronavirus infection mediated through the transmembrane protease serin 2 (TMPRRS2) and the angiotensin-converting enzyme 2 (ACE2) receptor in the lung tissue. Furthermore, a high incidence of androgenic alopecia among males with COVID-19 disease have been reported.Objective: This study aims to evaluate the telogen effluvium (TE) prevalence and its relationship with clinical and immunologic parameters in a sample of patients consecutively evaluated after recovery from COVID-19 pneumonia in Northern Italy.Methods: Overall 104 patients were recruited within three months from COVID-19 pneumonia recovery; 80 (77%) had been hospitalized in a Respiratory Intensive Care Unit and the remaining ones had been treated at home. The extent of TE was assessed with a visual analogic scale for thick bundle of hairs. Demographic and clinical data and systemic inflammation biomarkers were also evaluated.Results. Thirty-two patients reported a history of TE and their mean TE-VAS score was 5.78 ± 1.72 (range 3–9). Women had about a 5-fold higher risk (odds) of complaining of TE compared to males (OR = 4.69, 95%CI: 1.91, 11.49; p = .001), and the association became stronger when adjusted for COVID-19 severity (hospital admission vs home care: OR = 6.09, 95%CI: 2.34, 15.88; p < .001). Levels of C-reactive protein >1.90 mg/l (OR_adj: 2.43, 95%CI 0.85, 7.05, p = 0.096) or IL 1β > 5 ng/l (OR_adj 4.72, 95%CI: 1.31, 23.19, p = .03) were also significantly associated with TE.Conclusion: This exploratory study raises the hypothesis that hair shedding is more strictly related to the severity of COVID-19 disease and the underlying inflammation rather than to patients'' hormonal status.

KEY MESSAGES

• The presence of Telogen effluvium (TE) was significantly more common in women.
• Higher severity of the Covid-19 disease seems to play a critical role, more important than the hormonal influence, in the development of TE.
• The severity of inflammation related to TE and Covid-19 could also play a role as suggested by the higher levels of CRP and platelets and IL1β.