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.

Mapping the interplay of atrial fibrillation, brain structure, and cognitive dysfunction.

INTRODUCTION: Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. Understanding the cognitive sequelae and brain structural changes associated with AF is vital for addressing ensuing health care needs. METHODS AND RESULTS: We examined 1335 stroke-free individuals with AF and 2683 matched controls using neuropsychological assessments and multimodal neuroimaging. The analysis revealed that individuals with AF exhibited deficits in executive function, processing speed, and reasoning, accompanied by reduced cortical thickness, elevated extracellular free-water content, and widespread white matter abnormalities, indicative of small vessel pathology. Notably, brain structural differences statistically mediated the relationship between AF and cognitive performance. DISCUSSION: Integrating a comprehensive analysis approach with extensive clinical and magnetic resonance imaging data, our study highlights small vessel pathology as a possible unifying link among AF, cognitive decline, and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies. Highlights We investigated neuropsychological and multimodal neuroimaging data of 1335 individuals with atrial fibrillation (AF) and 2683 matched controls. Our analysis revealed AF-associated deficits in cognitive domains of attention, executive function, processing speed, and reasoning. Cognitive deficits in the AF group were accompanied by structural brain alterations including reduced cortical thickness and gray matter volume, alongside increased extracellular free-water content as well as widespread differences of white matter integrity. Structural brain changes statistically mediated the link between AF and cognitive performance, emphasizing the potential of structural imaging markers as a diagnostic tool in AF-related cognitive decline.

Differentiation of acute non-ST elevation myocardial infarction and acute infarct-like myocarditis by visual pattern analysis: a head-to-head comparison of different cardiac MR techniques.

OBJECTIVES: Parametric cardiac magnetic resonance (CMR) techniques have improved the diagnosis of pathologies. However, the primary tool for differentiating non-ST elevation myocardial infarction (NSTEMI) from myocarditis is still a visual assessment of conventional signal-intensity-based images. This study aimed at analyzing the ability of parametric compared to conventional techniques to visually differentiate ischemic from non-ischemic myocardial injury patterns. METHODS: Twenty NSTEMI patients, twenty infarct-like myocarditis patients, and twenty controls were examined using cine, T2-weighted CMR (T2w) and late gadolinium enhancement (LGE) imaging and T1/T2 mapping on a 1.5 T scanner. CMR images were presented in random order to two experienced fully blinded observers, who had to assign them to three categories by a visual analysis: NSTEMI, myocarditis, or healthy. RESULTS: The conventional approach (cine, T2w and LGE combined) had the best diagnostic accuracy with 92% (95%CI: 81-97) for NSTEMI and 86% (95%CI: 71-94) for myocarditis. The diagnostic accuracies using T1 maps were 88% (95%CI: 74-95) and 80% (95%CI: 62-91), 84% (95%CI: 67-93) and 74% (95%CI: 54-87) for LGE, and 83% (95%CI: 66-92) and 73% (95%CI: 53-87) for T2w. The accuracies for cine (72% (95%CI: 52-86) and 60% (95%CI: 38-78)) and T2 maps (62% (95%CI: 40-79) and 47% (95%CI: 28-68)) were significantly lower compared to the conventional approach (p < 0.001 and p < 0.0001). CONCLUSIONS: The conventional approach provided a reliable visual discrimination between NSTEMI, myocarditis, and controls. The diagnostic accuracy of a visual pattern analysis of T1 maps was not significantly inferior, whereas the diagnostic accuracy of T2 maps was not sufficient in this context. CLINICAL RELEVANCE STATEMENT: The ability of parametric compared to conventional CMR techniques to visually differentiate ischemic from non-ischemic myocardial injury patterns can avoid potentially unnecessary invasive coronary angiography and help to shorten CMR protocols and to reduce the need of gadolinium contrast agents. KEY POINTS: • A visual differentiation of ischemic from non-ischemic patterns of myocardial injury is reliably achieved by a combination of conventional CMR techniques (cine, T2-weighted and LGE imaging). • There is no significant difference in accuracies between visual pattern analysis on native T1 maps without providing quantitative values and a conventional combined approach for differentiating non-ST elevation myocardial infarction, infarct-like myocarditis, and controls. • T2 maps do not provide a sufficient diagnostic accuracy for visual pattern analysis for differentiating non-ST elevation myocardial infarction, infarct-like myocarditis, and controls.

CMR-Based Risk Stratification of Sudden Cardiac Death and Use of Implantable Cardioverter-Defibrillator in Non-Ischemic Cardiomyopathy.

Non-ischemic cardiomyopathy (NICM) is one of the most important entities for arrhythmias and sudden cardiac death (SCD). Previous studies suggest a lower benefit of implantable cardioverter-defibrillator (ICD) therapy in patients with NICM as compared to ischemic cardiomyopathy (ICM). Nevertheless, current guidelines do not differentiate between the two subgroups in recommending ICD implantation. Hence, risk stratification is required to determine the subgroup of patients with NICM who will likely benefit from ICD therapy. Various predictors have been proposed, among others genetic mutations, left-ventricular ejection fraction (LVEF), left-ventricular end-diastolic volume (LVEDD), and T-wave alternans (TWA). In addition to these parameters, cardiovascular magnetic resonance imaging (CMR) has the potential to further improve risk stratification. CMR allows the comprehensive analysis of cardiac function and myocardial tissue composition. A range of CMR parameters have been associated with SCD. Applicable examples include late gadolinium enhancement (LGE), T1 relaxation times, and myocardial strain. This review evaluates the epidemiological aspects of SCD in NICM, the role of CMR for risk stratification, and resulting indications for ICD implantation.

Association of NT-proBNP and hs-cTnT with Imaging Markers of Diastolic Dysfunction and Focal Myocardial Fibrosis in Hypertrophic Cardiomyopathy.

Serum biomarkers such as N-terminal prohormone of the brain natriuretic peptide (NT-proBNP) and cardiac troponins are elevated in patients with hypertrophic cardiomyopathy (HCM). At present, it is not clear if these markers are associated with distinct clinical alterations in HCM, such as left ventricular hypertrophy, outflow tract obstruction, myocardial fibrosis and/or diastolic dysfunction (DD), which are associated with adverse cardiovascular outcome. Here we evaluate the association of NT-proBNP and high sensitivity cardiac troponin T (hs-cTnT) to a variety of cardiac imaging parameters in HCM patients in a multivariable regression analysis. This retrospective cross-sectional study included 366 HCM patients who underwent transthoracic echocardiography (TTE), 218 of whom also obtained cardiovascular magnetic resonance (CMR) to assess focal myocardial fibrosis by LGE. Multivariable regression analyses revealed the strongest association of the DD parameters E/E' mean and E/E' septal with NT-proBNP (b = 0.06, 95%-CI [0.05−0.07], p < 0.001, R2 = 0.28; b = 0.08, 95%-CI [0.06−0.1], p < 0.001, R2 = 0.25) and LGE size showed the strongest association with hs-cTnT (b = 0.20, 95%-CI [0.15−0.24], p < 0.001, R2 = 0.28). This study indicates that NT-proBNP and hs-cTnT are associated with structural and functional alterations in HCM. NT-proBNP is a stronger predictor for DD, while hs-cTnT is associated with the extent of focal myocardial fibrosis. Both biomarkers might be useful in the diagnostic procedure in addition to imaging parameters.

CMR feature tracking in patients with dilated cardiomyopathy: patterns of myocardial strain and focal fibrosis.

BACKGROUND: There is a paucity of data on cardiovascular magnetic resonance feature tracking (CMR-FT) in patients with dilated cardiomyopathy (DCM). We aimed at describing global and segmental myocardial strain patterns and a potential association with the presence of focal myocardial scarring in DCM patients by CMR-FT. METHODS: Thirty-nine patients with DCM and reduced left ventricular (LV) ejection fraction (mean 21±8%) underwent CMR including standard cine steady-state free precession (SSFP) sequences and late gadolinium enhancement (LGE). We measured global LV longitudinal as well as global and segmental circumferential and radial strain. The presence of focal myocardial fibrosis was assessed on LGE images. RESULTS: Nineteen patients had focal myocardial fibrosis on LGE images with the highest prevalence in the basal septal segments II and III, which were affected in 12 (63%) and 13 (68%) patients. Furthermore, there was a significantly lower average short-axis LV radial strain (LVSAX-RS) in these segments (4.89 (-1.55 to 11.34) %) compared with the average of the other myocardial segments (21.20 (17.36 to 25.05)%; p<0.001) after adjusting for LGE and left-bundle branch block (LBBB). In general, LV segments with LGE had lower model-based mean LVSAX-RS values (17.65 (10.37 to 24.93) %) compared with those without LGE (19.40 (15.43 to 23.37) %), but this effect was not significant after adjusting for the presence of LBBB (p=0.630). CONCLUSION: Our findings revealed a coincidence of impaired radial strain and focal myocardial fibrosis in the basal septal LV myocardial segments of patients with DCM. Regardless of this pattern, we did not find a general, significant effect of myocardial fibrosis on strain in our cohort. Future studies are required to assess the potential prognostic implications of myocardial strain patterns in addition to the assessment of myocardial fibrosis in patients with DCM.

Impact of Sex and Cardiovascular Risk Factors on Myocardial T1, Extracellular Volume Fraction, and T2 at 3 Tesla: Results From the Population-Based, Hamburg City Health Study.

BACKGROUND: Reliable reference intervals are crucial for clinical application of myocardial T1 and T2 mapping cardiovascular magnetic resonance imaging. This study evaluated the impact of sex and cardiovascular risk factors on myocardial T1, extracellular volume fraction (ECV), and T2 at 3T in the population-based HCHS (Hamburg City Health Study). METHODS: The final study sample consisted of 1576 consecutive HCHS participants between 46 and 78 years without prevalent heart disease, including 1020 (67.3%) participants with hypertension and 110 (7.5%) with diabetes. T1 and T2 mapping were performed on a 3T scanner using 5b(3b)3b modified Look-Locker inversion recovery and T2 prepared, fast-low-angle shot sequence, respectively. Stepwise regression analyses were performed to identify variables with an independent impact on T1, ECV, and T2. Reference intervals were defined as the interval between the 2.5% and 97.5% quantiles. RESULTS: Sex was the major independent influencing factor of myocardial native T1, ECV, and T2. Female patients had significantly higher upper limits of reference intervals for native T1 (1112-1261 versus 1079-1241 ms), ECV (23%-33% versus 22%-32%), and T2 (36-46 versus 35-45 ms) compared with male patients (all P<0.001). Cardiovascular risk factors, such as diabetes and hypertension, did not systematically affect native T1. There was an independent association of T2 by hypertension and, to a lesser degree, by left ventricular mass, heart rate (all P<0.001), and body mass index (P=0.001). CONCLUSIONS: Sex needs to be considered as the major, independent influencing factor for clinical application of myocardial T1, ECV, and T2 measurements. Consequently, sex-specific reference intervals should be used in clinical routine. Our findings suggest that there is no need for specific reference intervals for myocardial T1 and ECV measurements in individuals with cardiovascular risk factors. However, hypertension should be considered as an additional factor for clinical application of T2 measurements. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03934957.

CMR feature tracking strain patterns and their association with circulating cardiac biomarkers in patients with hypertrophic cardiomyopathy.

AIMS: CMR feature tracking strain (CMR-FT) provides prognostic information. However, there is a paucity of data in hypertrophic cardiomyopathy (HCM). We sought to analyze global CMR-FT parameters in all four cardiac chambers and to assess associations with NT-proBNP and cardiac troponin T (hsTnT) in patients with HCM. METHODS: This retrospective study included 144 HCM patients and 16 healthy controls with CMR at 1.5 T. Analyses were performed on standard steady-state free precession cine (SSFP) CMR data using a commercially available software. Global left ventricular (LV) strain was assessed as longitudinal (LVLAX-GLS), circumferential (LVLAX-GCS) and radial strain (LVLAX-GRS) on long -axis (LAX) and as LVSAX-GCS and LVSAX-GRS on short- axis (SAX). Right ventricular (RV-GLS), left atrial (LA-GLS) and right atrial (RA-GLS) strain were assessed on LAX. RESULTS: We found LVLAX-GLS [- 18.9 (- 22.0, - 16.0), - 23.5 (- 25.5, - 22.0) %, p = 0.0001), LVSAX-GRS [86.8 (65.9-115.5), 119.6 (91.3-143.7) %, p = 0.001] and LALAX-GLS [LA2CH-GLS 29.2 (19.1-37.7), LA2CH-GLS 38.2 (34.3-47.1) %, p = 0.0036; LA4CH-GLS 22.4 (14.6-30.7) vs. LA4CH-GLS 33.4 (28.4-37.3) %, p = 0.0033] to be impaired in HCM compared to healthy controls despite normal LVEF. Furthermore, LV and LA strain parameters were impaired in HCM with elevated NT-proBNP and/or hsTnT, despite preserved LVEF compared to HCM with normal biomarker levels. There was a moderate correlation of LV and LA CMR-FT with levels of NT-proBNP and hsTnT. CONCLUSION: CMR-FT reveals LV and LA dysfunction in HCM despite normal LVEF. The association between impaired LV strain and elevated NT-proBNP and hsTnT indicates a link between unapparent functional abnormalities and disease severity in HCM. Typical CMR-FT findings in patients with hypertrophic cardiomyopathy.

MMP9 mRNA is a potential diagnostic and treatment monitoring marker for PTSD: Evidence from mice and humans.

Although matrix metalloproteinase 9 (MMP9) has been found associated with various psychiatric disorders and with threat memories in humans, its role in post-traumatic stress disorder (PTSD) and related animal models is understudied. Thus, we analyzed MMP9 mRNA expression kinetics during two different stress experiments, i.e., the Trier Social Stress Test and the dexamethasone suppression test (DST), in whole blood of two independent cohorts of PTSD patients vs. non-traumatized healthy controls (HC) and, moreover, in a mouse model of PTSD and in dexamethasone-treated mice. Besides MMP9, we quantified mRNA levels of four of its regulators, i.e., interleukin (IL)-1 receptor 1 and 2 (IL1R1, IL1R2), IL-6 receptor and tumor necrosis factor receptor 1 (TNFR1) in 10 patients exposed to the DST before vs. after successful PTSD psychotherapy vs. 13 HC and, except from Il6r, also in different brain regions of the PTSD mouse model. We are the first to show that blood MMP9 mRNA concentrations were elevated after acute dexamethasone in PTSD patients, improved upon partial remission of PTSD and were, furthermore, also elevated, together with its regulator Tnfr1, in the prefrontal cortex of PTSD-like mice. In contrast, blood TNFR1 and IL1R2 were markedly underexpressed in PTSD patients. In conclusion, we found translational evidence supporting that, I, TNFR1 and MMP9 mRNA expression might be involved in PTSD pathobiology, II, might constitute potential diagnostic blood biomarkers for PTSD and, importantly, III, post-dexamethasone blood MMP9 hyperexpression, which speculatively results from post-dexamethasone underexpression of IL1R2, might serve also as potential treatment monitoring biomarker for PTSD.