Unrecognized myocardial scar by late-gadolinium-enhancement cardiovascular magnetic resonance: Insights from the population-based Hamburg City Health Study.

BACKGROUND: The presence of myocardial scar is associated with poor prognosis in several underlying diseases. Late-gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging reveals clinically silent "unrecognized myocardial scar" (UMS), but the etiology of UMS often remains unclear. This population-based CMR study evaluated prevalence, localization, patterns, and risk factors of UMS. METHODS: The study population consisted of 1064 consecutive Hamburg City Health Study participants without a history of coronary heart disease or myocarditis. UMS was assessed by standard-phase-sensitive-inversion-recovery LGE CMR. RESULTS: Median age was 66 [quartiles 59, 71] years and 37% (388/1064) were females. UMS was detected in 244 (23%) participants. Twenty-five participants (10%) had ischemic, and 217 participants (89%) had non-ischemic scar patterns, predominantly involving the basal inferolateral left-ventricular (LV) myocardium (75%). Two participants (1%) had coincident ischemic and non-ischemic scar. The presence of any UMS was independently associated with LV ejection fraction (odds ratios (OR) per standard deviation (SD) 0.77 (confidence interval (CI) 0.65-0.90), p = 0.002) and LV mass (OR per SD 1.54 (CI 1.31-1.82), p < 0.001). Ischemic UMS was independently associated with LV ejection fraction (OR per SD 0.58 (CI 0.39-0.86), p = 0.007), LV mass (OR per SD 1.74 (CI 1.25-2.45), p = 0.001), and diabetes (OR 4.91 (CI 1.66-13.03), p = 0.002). Non-ischemic UMS was only independently associated with LV mass (OR per SD 1.44 (CI 1.24-1.69), p < 0.001). CONCLUSION: UMS, in particular with a non-ischemic pattern, is frequent in individuals without known cardiac disease and predominantly involves the basal inferolateral LV myocardium. Presence of UMS is independently associated with a lower LVEF, a higher LV mass, and a history of diabetes.

Retinal Layer Thinning After Optic Neuritis Is Associated With Future Relapse Remission in Relapsing Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Remission of relapses is an important contributor to both short- and long-term prognosis in relapsing multiple sclerosis (RMS). In MS-associated acute optic neuritis (MS-ON), retinal layer thinning measured by optical coherence tomography (OCT) is a reliable biomarker of both functional recovery and the degree of neuroaxonal damage. However, prediction of non-ON relapse remission is challenging. We aimed to investigate whether retinal thinning after ON is associated with relapse remission after subsequent non-ON relapses. METHODS: For this longitudinal observational study from the Vienna MS database, we included patients with MS with (1) an episode of acute ON, (2) available spectral domain OCT scans within 12 months before ON onset (OCTbaseline), within 1 week after ON onset (OCTacute), and 3-6 months after ON (OCTfollow-up), and (3) at least 1 non-ON relapse after the ON episode. Subsequent non-ON relapses were classified as displaying either complete or incomplete remission based on change in the Expanded Disability Status Scale score assessed 6 months after relapse. Association of retinal thinning in the peripapillary retinal nerve fiber layer (ΔpRNFL) and macular ganglion cell and inner plexiform layer (ΔGCIPL) with incomplete remission was tested by multivariate logistic regression models adjusting for age, sex, disease duration, relapse severity, time to steroid treatment, and disease-modifying treatment status. RESULTS: We analyzed 167 patients with MS (mean age 36.5 years [SD 12.3], 71.3% women, mean disease duration 3.1 years [SD 4.5]) during a mean observation period of 3.4 years (SD 2.8) after the ON episode. In 61 patients (36.5%), at least 1 relapse showed incomplete remission. In the multivariable analyses, incomplete remission of non-ON relapse was associated with ΔGCIPL thinning both from OCTbaseline to OCTfollow-up and from OCTacute to OCTfollow-up (OR 2.4 per 5 µm, p < 0.001, respectively), independently explaining 29% and 27% of variance, respectively. ΔpRNFL was also associated with incomplete relapse remission when measured from OCTbaseline to OCTfollow-up (OR 1.9 per 10 µm, p < 0.001), independently accounting for 22% of variance, but not when measured from OCTacute to OCTfollow-up. DISCUSSION: Retinal layer thinning after optic neuritis may be useful as a marker of future relapse remission in RMS.

Humoral immune response to SARS-CoV-2 third vaccination in patients with multiple sclerosis and healthy controls: A prospective multicenter study.

BACKGROUND: Third vaccination against SARS-CoV-2 is recommended for patients with multiple sclerosis (pwMS), usually six months after the last vaccination. METHODS: In this prospective multicenter study on 292 pwMS and 46 healthy controls (HC), who had all received two vaccinations prior to study enrollment, SARS-CoV-2 IgG response was measured in the month before and 2-4 months after third vaccination. PwMS were categorized as follows: untreated (N-DMT, n = 32), receiving disease-modifying therapy (DMT) with expected humoral response (er-DMT: interferon-beta preparations, glatiramer acetate, dimethyl fumarate, teriflunomide, natalizumab, cladribine, alemtuzumab; n = 120) or no expected humoral response (nr-DMT: S1PMs, CD20mAb; n = 140). RESULTS: PwMS on nr-DMT had significantly lower median antibody levels before (12.1 U/ml [0.4-2500]) and after third vaccination (305 U/ml [0.4-2500]) in comparison to other groups (p<0.001). We did not find differences in antibody levels after homologous (n = 281; 2500 [0.4-2500]) and heterologous (n = 57; 2500 [0.4-2500]) vaccination regime regardless of the DMT group. The DMT group (ß= -0.60; 95% CI -1195.73, -799.10; p<0.001) was associated with antibody levels after third vaccination, while time to revaccination (6 months [1-13]) was not. After third vaccination, seropositivity was reached in 75.8% and 82.2% of pwMS on anti-CD20 mAbs and S1PMs, respectively. Complete B-cell depletion significantly decreased the probability of seroconversion even after the third vaccination (OR 0.14; p = 0.021), whereas time interval to last DMT intake and time to revaccination did not. Twenty-two patients reported a SARS-CoV-2 infection (3 N-DMT, 9 er-DMT, 10 nr-DMT), one being asymptomatic and the rest having a mild course. CONCLUSION: Humoral response to SARS-CoV-2 third vaccination in pwMS is excellent. While reduced by S1PMs and CD20mAb, protective response is still expected in the majority of patients.

Retinal layer thinning as a biomarker of long-term disability progression in multiple sclerosis.

BACKGROUND: Peripapillary retinal nerve fibre layer and macular ganglion cell plus inner plexiform layer thinning are markers of neuroaxonal degeneration in multiple sclerosis. OBJECTIVE: We aimed to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning for prediction of long-term disability. METHODS: This is a 6-year prospective longitudinal study on 93 multiple sclerosis patients. Optical coherence tomography scans were performed at baseline, after 1, 2 and 6 years. Primary endpoint was disability progression after 6 years, defined as expanded disability status scale worsening and/or cognitive deterioration. Univariate and multivariate analysis was used to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer to predict the primary endpoint. RESULTS: A total of 57 (61.3%) patients had disability worsening, 40 (43.0%) expanded disability status scale worsening and 34 (36.6%) cognitive deterioration. Mean peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness were 93.0 and 75.2 µm, and mean annualised peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning rates over 6 years were 1.3 and 1.6 µm, respectively. Univariate and multivariate analysis revealed lower peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness and higher annualised thinning rates in patients with disability progression after 6 years. Effects were more pronounced for ganglion cell plus inner plexiform layer and expanded disability status scale worsening than for peripapillary retinal nerve fibre layer models and cognitive deterioration. CONCLUSION: Ganglion cell plus inner plexiform layer and peripapillary retinal nerve fibre layer measurements depict neurodegeneration and predict disability progression in multiple sclerosis.

Has the pandemic changed treatment strategy in multiple sclerosis?

BACKGROUND: Social distancing measures during the Covid-19 pandemic reduced access to health care and concerns were raised over the safety of immunosuppressive disease modifying treatments (DMT) for multiple sclerosis (MS). OBJECTIVE: To investigate changes in DMT prescription before and during the pandemic in a large and well-characterized real-world cohort of MS patients. METHODS: From the Vienna MS database (VMSD) we extracted MS patients who were initiated on a new DMT (both treatment-naïve and switching) between January 1st 2017 and December 31st 2021. Two time periods were defined: 1) the preCovid-19 era (January 1st 2017 to March 15th 2020, i.e. the day of the first lockdown in Austria) and the Covid-19 era (March 16th 2020 to December 31st 2021). Average annualized DMT prescription rates were descriptively compared between the two periods. RESULTS: The average annualized number of prescriptions in the preCovid-19 era was 90.3/year and dropped to 74.8/year (-17.2%) in the Covid-19 era, driven by a marked reduction to 41.7/year (-54%) in the first nine months of the Covid-19 era, partly offset by a rise to 101 in 2021. Use of alemtuzumab (-64%), antiCD20 (-49%), cladribine (-46%), and S1PM (-38%) was reduced, while natalizumab increased by 24%. Lower efficacy treatments remained stable. CONCLUSIONS: The pandemic coincides with a drop in DMT prescription, most markedly for immunosuppressive high-efficacy treatments, strongly suggesting the pandemic as the causal factor. If and how much this affects long-term outcome is yet to be determined.

Alemtuzumab induced hemodynamic change in relapsing multiple sclerosis occurs independent of corticosteroid premedication - a retrospective multicentre study.

Background Alemtuzumab (ATZ), a highly effective disease modifying treatment for relapsing multiple sclerosis (MS), is associated with the rare risk of intracerebral hemorrhage. Increase of blood pressure (BP) was hypothesized to be causative, but prior administration of high-dose methylprednisolone (HDMP) is a potential confounder. Objective To analyze BP change in MS patients treated with ATZ and prior HDMP treatment compared to patients receiving HDMP only for acute relapse. Methods In this retrospective study, 30 patients treated with ATZ/HDMP and 60 age-, sex- and disability-matched controls treated with HDMP were included. Primary endpoint was the change of systolic BP (SBP) between before ATZ cycle and the maximum value measured during the treatment cycle; secondary endpoints were change in diastolic BP (DBP) and heart rate (HR). Results Change of SBP observed in ATZ/HDMP treated patients was significantly higher than in HDMP controls (mean maximal change of 12.8 vs. 8.1 mmHg, p = 0.033). An increase of SBP exceeding 20% from baseline was observed in 5 (16.7%) patients on ATZ/HDMP compared to 3 (5.0%) on HDMP (p = 0.078). The day after the 1st ATZ infusion, mean HR was higher in the ATZ/HDMP group compared to HDMP controls (82.5 vs. 73.2 bpm, p = 0.005), although there was no significant group difference over time. Conclusions ATZ treatment induced a slight, but significant increase in SBP independent of HDMP. Although hemodynamic alterations alone seem unlikely as putative mechanism for cerebral bleedings, strict cardiovascular monitoring is recommended to reduce rare, but severe cardiovascular side effects.

Cascaded learning in intravascular ultrasound: coronary stent delineation in manual pullbacks.

Purpose: Implanting stents to re-open stenotic lesions during percutaneous coronary interventions is considered a standard treatment for acute or chronic coronary syndrome. Intravascular ultrasound (IVUS) can be used to guide and assess the technical success of these interventions. Automatically segmenting stent struts in IVUS sequences improves workflow efficiency but is non-trivial due to a challenging image appearance entailing manifold ambiguities with other structures. Manual, ungated IVUS pullbacks constitute a challenge in this context. We propose a fully data-driven strategy to first longitudinally detect and subsequently segment stent struts in IVUS frames. Approach: A cascaded deep learning approach is presented. It first trains an encoder model to classify frames as "stent," "no stent," or "no use." A segmentation model then delineates stent struts on a pixel level only in frames with a stent label. The first stage of the cascade acts as a gateway to reduce the risk for false positives in the second stage, the segmentation, which is trained on a smaller and difficult-to-annotate dataset. Training of the classification and segmentation model was based on 49,888 and 1826 frames of 74 sequences from 35 patients, respectively. Results: The longitudinal classification yielded Dice scores of 92.96%, 82.35%, and 94.03% for the classes stent, no stent, and no use, respectively. The segmentation achieved a Dice score of 65.1% on the stent ground truth (intra-observer performance: 75.5%) and 43.5% on all frames (including frames without stent, with guidewires, calcium, or without clinical use). The latter improved to 49.5% when gating the frames by the classification decision and further increased to 57.4% with a heuristic on the plausible stent strut area. Conclusions: A data-driven strategy for segmenting stents in ungated, manual pullbacks was presented-the most common and practical scenario in the time-critical clinical workflow. We demonstrated a mitigated risk for ambiguities and false positive predictions.

Association of Cerebrospinal Fluid Parameters and Neurofilament Light Chain With Retinal Nerve Fiber Layer Thickness in Multiple Sclerosis.

Introduction: Multiple sclerosis (MS) pathophysiology comprises both inflammatory and neurodegenerative characteristics. Cerebrospinal fluid (CSF) analysis allows for assessment of inflammation while neurofilament light chain can indicate neuroaxonal damage. Retinal thinning is a robust prognostic biomarker for neurodegeneration in MS. To date, an association between CSF parameters upon MS diagnosis and retinal thinning has not been investigated. Aims and Objectives: We aimed to determine whether CSF parameters are associated with the evolution of retinal layer thinning in people with MS (pwMS). Methods: For this longitudinal observational study, we investigated pwMS from the Vienna MS database (VMSD), who had undergone (1) a diagnostic lumbar puncture (LP) between 2015 and 2020, and (2) simultaneous optical coherence tomography (OCT) and/or (3) a follow-up OCT scan. Linear stepwise regression models were calculated with OCT parameters (peripapillary retinal nerve fiber layer [pRNFL] thickness at LP and at follow-up, annualized loss of pRNFL thickness [aLpRNFL]) as a dependent variable, and CSF parameters (white blood cell [WBC] count, total protein [CSFTP], CSF/serum albumin ratio [Qalb], intrathecal synthesis of immunoglobulins, neurofilament light chain [NfL] in both CSF and serum [CSFNfL/sNfL]) as independent variables adjusted for age, sex, and disease duration. Results: We analyzed 61 pwMS (median age 30.0 years [interquartile range 25.5-35.0], 57.4% female, median disease duration 1.0 month [IQR 0-2.0] before LP, median follow-up 1.9 years [IQR 1.1-3.5]). CSFNfL and sNfL measurements were available in 26 and 31 pwMS, respectively. pRNFL thickness at LP was inversely associated with the CSF WBC count (ß = -0.36; 95% CI -0.51, -0.08; p = 0.008). We did not find any association between other CSF parameters, including CSFNfL, sNfL, and aLpRNFL. Conclusions: Increased WBC count as an indicator of acute inflammation and blood-brain-barrier breakdown seems to be associated with the amount of retinal thickness already lost at the time of LP. However, neither routine CSF parameters nor a singular NfL measurement allows the prediction of future retinal thinning.

Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme.

AIMS: Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population. METHODS AND RESULTS: Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient -3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography -0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P < 0.001). Glomerular filtration rate (regression coefficient -2.35, adjusted P = 0.019) was lower in post-SARS-CoV-2 cases. Relative brain volume, prevalence of cerebral microbleeds, and infarct residuals were similar, while the mean cortical thickness was higher in post-SARS-CoV-2 cases. Cognitive function was not impaired. Similarly, patient-related outcomes did not differ. CONCLUSION: Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management.

Coronary CT angiography derived FFR in patients with left main disease.

The presence of left main coronary artery disease (LMCAD) is associated with an unfavorable clinical outcome. The clinical utility of FFRCT testing for non-invasive physiological assessment in LMCAD remains largely unknown. In this single center observational study LMCAD patients were retrospectively identified between November 2015 and December 2017. We evaluated the relationship between LMCAD diameter stenosis and downstream FFRCT values, and the clinical consequences following FFRCT testing in patients with LMCAD. The composite endpoint (all-cause death, myocardial infarction, unplanned revascularization) was determined over a median follow-up of 1.1 years. LMCAD was registered in 432 of 3202 (13%) patients having coronary CTA. FFRCT was prescribed in 213 (49%), while 59 (14%) patients were referred directly to invasive angiography or myocardial perfusion imaging. FFRCT was performed in 195 (45%) patients. LM stenosis severity was inversely related to downstream FFRCT values. In patients with simple LMCAD with stenosis ≥ 50%, > 80% had FFRCT > 0.80 in non-diseased proximal and downstream segments (n = 7). No patients with simple LMCAD and FFRCT > 0.80 (n = 20) suffered an adverse clinical outcome. FFRCT testing in patients with LMCAD is feasible. LM stenosis severity is inversely related to FFRCT value. Patients with LMCAD and FFRCT > 0.80 have favorable clinical outcomes at short-term follow-up. Large-scale studies assessing the clinical utility and safety of deferring invasive catheterization following FFRCT testing in patients with LMCAD are warranted.

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score.

BACKGROUND AND PURPOSE: There is a lack of evidence guiding discontinuation of disease-modifying therapy (DMT) in relapsing multiple sclerosis (RMS). Thus, the objective of this study was to generate and validate a risk score for disease reactivation after DMT discontinuation in RMS. METHODS: We drew a generation and validation dataset from two separate prospectively collected observational databases including RMS patients who received interferon-ß or glatiramer acetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n = 168), regression analysis was performed to identify clinical or magnetic resonance imaging (MRI) variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model and applied to the validation sample (n = 98). RESULTS: The variables included in the final model as independent predictors of disease reactivation were age at discontinuation, MRI activity at discontinuation, and duration of clinical stability (all p < 0.001). The resulting score was able to robustly identify patients at high (83%-85%), moderate (36%-38%), and low risk (7%) of disease reactivation within 5 years after DMT discontinuation in both cohorts. CONCLUSIONS: The composite VIAADISC score is a valuable tool to inform and support patients and neurologists in the process of decision making to discontinue injectable DMTs.

Estimating Risk of Multiple Sclerosis Disease Reactivation in Pregnancy and Postpartum: The VIPRiMS Score.

BACKGROUND: Evidence guiding personalized decision-making with respect to disease-modifying therapy (DMT) around pregnancy in relapsing multiple sclerosis (RMS) is lacking. OBJECTIVE: To generate and validate a risk score for disease reactivation intrapartum and postpartum in RMS. METHODS: From the Vienna Innsbruck MS database (VIMSD), we included 343 pregnancies in patients with RMS. Primary endpoint was disease reactivation. Patients were randomly assigned 2:1 in a generation and validation dataset. A predictive score was calculated using the Cox regression and validated. RESULTS: In the generation dataset, occurrence of relapse and type of DMT in the year before conception, DMT washout duration, the Expanded Disability Status Scale (EDSS) at conception, and time until DMT restart postpartum were identified as independent predictors of disease reactivation (p < 0.001). The resulting 10-point risk score robustly predicted reactivation (explaining 75% of variance, p < 0.001) identifying patients at high [≥6 points; mean risk 65%; range 50-100%; hazard ratio (HR) 14.5], intermediate (3-5 points; mean risk 24%; range 15-35%; HR 4.3), and low risk (≤2 points; mean risk 6%; range 0-8%) of disease reactivation in pregnancy and up to 6 months postpartum. CONCLUSION: The composite Vienna Innsbruck Pregnancy Risk in Multiple Sclerosis (VIPRiMS) score is a valuable clinical tool to support patients and neurologists in anticipating risk and, thus, individualizing treatment decision-making around pregnancy.

Clinical outcomes following real-world computed tomography angiography-derived fractional flow reserve testing in chronic coronary syndrome patients with calcification.

AIMS: This study sought to investigate outcomes following a normal CT-derived fractional flow reserve (FFRCT) result in patients with moderate stenosis and coronary artery calcification, and to describe the relationship between the extent of calcification, stenosis, and FFRCT. METHODS AND RESULTS: Data from 975 consecutive patients suspected of chronic coronary syndrome with stenosis (30-70%) determined by computed CT angiography and FFRCT to guide downstream management decisions were reviewed. Median (range) follow-up time was 2.2 (0.5-4.2) years. Coronary artery calcium (CAC) scores were ≥400 in 25%, stenosis ≥50% in 83%, and FFRCT >0.80 in 51% of the patients. There was a lower incidence of the composite endpoint (death, myocardial infarction, hospitalization for unstable angina, and unplanned coronary revascularization) at 4.2 years in patients with any CAC and FFRCT > 0.80 vs. FFRCT ≤ 0.80 (3.9% and 8.7%, P = 0.04), however, in patients with CAC scores ≥400 the risk difference between groups did not reach statistical significance, 4.2% vs. 9.7% (P = 0.24). A negative relationship between CAC scores and FFRCT irrespective of stenosis severity was demonstrated. CONCLUSION: FFRCT shows promise in identifying patients with stenosis and calcification who can be managed without further downstream testing. Moreover, an inverse relationship between CAC levels and FFRCT was demonstrated. Studies are needed to further assess the clinical utility of FFRCT in patients with extensive coronary calcification.

Wall shear stress analysis using 17.6 Tesla MRI: A longitudinal study in ApoE-/- mice with histological analysis.

This longitudinal study was performed to evaluate the feasibility of detecting the interaction between wall shear stress (WSS) and plaque development. 20 ApoE-/- mice were separated in 12 mice with Western Diet and 8 mice with Chow Diet. Magnetic resonance (MR) scans at 17.6 Tesla and histological analysis were performed after one week, eight and twelve weeks. All in vivo MR measurements were acquired using a flow sensitive phase contrast method for determining vectorial flow. Histological sections were stained with Hematoxylin and Eosin, Elastica van Gieson and CD68 staining. Data analysis was performed using Ensight and a Matlab-based "Flow Tool". The body weight of ApoE-/- mice increased significantly over 12 weeks. WSS values increased in the Western Diet group over the time period; in contrast, in the Chow Diet group the values decreased from the first to the second measurement point. Western Diet mice showed small plaque formations with elastin fragmentations after 8 weeks and big plaque formations after 12 weeks; Chow Diet mice showed a few elastin fragmentations after 8 weeks and small plaque formations after 12 weeks. Favored by high-fat diet, plaque formation results in higher values of WSS. With wall shear stress being a known predictor for atherosclerotic plaque development, ultra highfield MRI can serve as a tool for studying the causes and beginnings of atherosclerosis.