German Centre for Cardiovascular Research

Phase singularities are a common problem in image reconstruction with auto-calibrated sensitivities due to an inherent ambiguity of the estimation problem. The purpose of this work is to develop a method for detecting and correcting phase poles in non-linear inverse (NLINV) reconstruction of MR images and coil sensitivity maps. Phase poles are detected in individual coil sensitivity maps by computing the curl in each pixel. A weighted average of the curl in each coil is computed to detect phase poles. Phase pole detection and correction is then integrated into the iteratively regularized Gauss-Newton method of the NLINV algorithm. In addition, we demonstrate the algorithm can also remove phase poles in ESPIRiT coil sensitivity maps. Phase pole correction is evaluated for reconstruction of accelerated Cartesian MPRAGE data of the brain and interactive radial real-time MRI of the human heart. For both applications, phase pole correction can be used for estimation of coil sensitivity profiles free from singularities. For NLINV, we demonstrate reliable and efficient estimation even from very small ( ) auto-calibration (AC) regions. With the proposed method, phase poles can be reliably removed in reconstructions and coil sensitivities.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) have gained interest as a pharmacological modelbut their immaturity leads to uncertainty regarding translation. We studied the key player in maintaining ionic homeostasis, the Na+/K+-ATPase (NKA), in hiPSC-CM. Atrial and ventricular engineered heart tissues (EHTs) were produced from hiPSC-CMs. For comparison, adult atrial and ventricular tissues were obtained from patients undergoing open heart surgery. We measured NKA gene expression, NKA pump currents (INKA) and ouabain effects on action potentials and contractility. Computational modelling was used to further investigate the direct and indirect impacts of NKA inhibition. The mRNA abundance of the major NKA isoforms was higher in ventricular than atrial cardiomyocytes (adult and hiPSC-CM). Consistently, INKA was also higher in ventricular than in atrial hiPSC-CM and higher in ventricular than in atrial adult cardiomyocytes. Ouabain potency to block INKA did not differ between hiPSC-derived and adult cardiomyocytes. Ouabain shortened plateau phase in EHT and adult tissue. However, lower ouabain concentrations depolarized diastolic potential and depressed force more in EHTs, demonstrating a higher integrated sensitivity to NKA inhibition. Computational modelling indicated that weaker IK1 increases the susceptibility to depolarisation by NKA block. HiPSC-EHTs express NKA with biophysical characteristics and ouabain-sensitivity that are not different from human tissue. Action potential duration responses in EHT reproduces chamber-specific response pattern as seen in human heart. The higher sensitivity of EHTs to depolarize under ouabain-induced block of NKA needs to be considered when employing hiPSC-CM in drug research.

The aim of this study was to identify biological processes associated with neuroaxonal degeneration in multiple sclerosis (MS) by analyzing protein patterns linked to neurofilament light (NfL) protein in CSF and serum samples. The highly sensitive proximity extension assay technology was used to quantify protein levels in paired CSF and serum samples from treatment-naïve, early-stage active MS patients (n = 114). The cohort was stratified into above and below median of CSF-NfL level. A discovery phase identified proteins upregulated in CSF, and a validation cohort (n = 128) confirmed findings in a more clinically diverse MS population, including patients receiving disease-modifying therapies. In the discovery cohort, 13 proteins were upregulated in CSF (leukocyte immunoglobulin like receptor B4, CXCL6, CXCL5, cluster of differentiation 38, CCL19, CXCL11, IMPA1, macrophage scavenger receptor 1 (MSR1), CXCL10, monocyte chemotactic protein 2, ITM2A, TNFRSF12A, and CCL23). It is important to note that associations with CCL19, CXCL11, MSR1, CXCL10, TNFRSF12A, and CCL23 were replicated in a validation MS cohort. By contrast, no consistent serum protein profiles associated with serum levels of NfL could be discerned in this group-based analysis. Furthermore, 75 CSF proteins showed a positive adjusted linear association with CSF-NfL, whereas no such significant association remained in the corresponding analysis in serum. The identified and replicated CSF protein profile indicates distinct inflammatory processes associated with ongoing neuroaxonal degeneration. All of these most robust 6 proinflammatory markers-CCL19, CXCL11, MSR1, CXCL10, TNFRSF12A, and CCL23-independently replicated and were individually observed to be relevant in the context of MS. These findings may further elucidate the immunologic pathways underlying disease processes leading to neuroaxonal degeneration.

Mastering emotion regulation is crucial for social skills and mental health. Hormonal fluctuations, particularly in estradiol (E2) levels across the menstrual cycle, significantly impact emotion processing. E2 is known to influence emotion regulation, mental health, and the plasticity of limbic and striatal regions, which are involved in emotion processing and are rich in E2 receptors. Although research indicates that E2 levels may impact gray matter volume (GMV) of limbic and striatal areas, sufficient causal evidence is missing so far. Furthermore, because of the additional fluctuations of progesterone across the menstrual cycle, the sole impact of E2 on brain volume has been difficult to disentangle. To isolate the effects of E2 from other fluctuating sex hormones, we used a randomized, placebo-controlled, double-blind, crossover design and administered oral E2 to 27 naturally cycling females during their early follicular phase (low endogenous sex hormone levels). We analyzed emotion regulation strategies and E2 levels to assess their impact on regional GMV. Our data showed that a rapid increase of E2 was negatively associated with right striatal GMV. Moreover, greater use of reappraisal was associated with reduced GMV of the right striatum. Rapidly increased E2 did not influence GMV of other limbic regions. These results highlight that rapid increases in E2 and individual differences in emotion regulation dynamically modulate GMV. This offers important implications for female mental and brain health associated with hormonal fluctuations. Considering female endocrine profiles improves hormone-informed health care and therefore supports individualized medicine.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality globally. Low-density lipoprotein cholesterol is a causal risk factor for atherosclerotic cardiovascular disease, with multiple classes of cholesterol-lowering therapies effective at reducing atherosclerotic cardiovascular disease risk. Despite robust efficacy data from randomized trials, real-world implementation of guideline-recommended lipid-lowering therapies is suboptimal. Barriers to the implementation of guideline lipid-lowering therapy recommendations exist at the healthcare systems level, the medical therapy level, and the patient level. A combination of strategies, including the incorporation of quality improvement and cost-effectiveness analysis among payers, pharmacist-based educational initiatives, digital health tools directed towards patients, the simplification of drug regimens via polypill, and emerging novel therapies, including PCSK9 gene silencing and editing technologies, may bridge these implementation gaps. This review highlights challenges and solutions to alleviating barriers to optimal implementation of guideline-recommended lipid-lowering therapies.

Cerebral small vessel disease (CSVD) is a common incidental MRI finding in patients with transient ischemic attack (TIA) and stroke and has been linked to cognitive decline. This study investigated the prevalence of CSVD imaging biomarkers in TIA patients and their association with cognitive performance over 3 years. We included 246 TIA patients from the INSPiRE-TMS study (ClinicalTrials.gov: NCT01586702). CSVD was assessed on baseline 3 T MRI using a composite score (0-4) including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVS). Cognitive performance was evaluated using the Montreal Cognitive Assessment (MoCA) at baseline and annually for 3 years. At least one CSVD imaging biomarker was present in 58.5% of patients. Lacunes (36.6%) were the most common, followed by PVS (28.1%), WMH (19.5%), and CMBs (17.9%). Higher CSVD-score was independently associated with greater cognitive decline over 3 years (β = -0.52, 95% CI -0.95- -0.08, p = 0.020), along with older age (β = -0.08, 95% CI -0.13 to -0.03, p = 0.001). CMB burden was the strongest predictive component of the CSVD-score (β = 0.42, 95% CI -0.63 to -0.22, p < 0.001). CSVD-score was particularly associated with decline in the memory domain (adjusted β of -0.18, 95% CI -0.32 to -0.04, p = 0.015). CSVD imaging markers are present in over half of TIA patients and are independently associated with cognitive decline up to 3 years, with the strongest effect on memory. Whether the presence of CMBs is the strongest predictive imaging biomarker of cognitive decline in TIA patients requires confirmation in further studies.

Atrial fibrillation (AF) is a well-known risk factor for ischaemic stroke. Emerging evidence suggests that atrial cardiomyopathy (AtCM), independent of AF, may be a key contributor to stroke risk. We aimed to evaluate whether non-invasive AtCM markers assessed by electrocardiography (ECG), transthoracic echocardiography (TTE), and blood-based biomarkers provide incremental diagnostic value beyond established clinical risk factors for identifying cerebral stroke lesions on magnetic resonance imaging (MRI). We analysed 1794 Hamburg City Health Study participants who underwent cerebral MRI with available baseline 12-lead ECG and TTE in sinus rhythm. Logistic regression analyses were performed to identify associations between non-invasive AtCM markers and stroke lesions. The incremental discriminatory performance of these markers beyond clinical risk factors was assessed. Stroke lesions were present in 152 participants (8.5%). Male sex, history of prior AF, and higher CHA2DS2-VA score were significantly associated with stroke lesions. Among AtCM markers, amplified P-wave duration (APWD), P-wave area in lead II, PR interval, left atrial volume index, left atrial ejection fraction, and NT-proBNP were also significant. Combining both clinical and AtCM markers, only CHA2DS2-VA score (OR: 1.95 per point, 95% CI: 1.49-2.55, P < 0.001) and P-wave area in lead II (OR: 0.99 per 100 µV·ms, 95% CI: 0.98-1.00, P = 0.031) remained independent predictors. However, this resulted in only marginal improvement in discrimination (ΔAUC: 0.03, 95% CI: 0.0001-0.0594) compared with the clinical risk factor model alone. The incremental diagnostic value of AtCM markers beyond clinical risk factors for MRI-defined cerebral lesions is limited, likely reflecting the heterogeneous aetiology of stroke lesions in a general population cohort.

Cardiac patients face a higher risk of developing depression or anxiety, displaying a bidirectional risk-relationship. While previous studies have focused on specific cardiac subgroups, such as heart failure (HF) populations, our study investigates a broad cardiac population to explore cofactors most strongly correlating with depressive or anxious symptoms. A total of n = 511 patients (mean age 63.57 ± 15.86 years, 41.9% female, 58.1% male) with heterogenous admission diagnoses admitted to the “Siebeck” ward of the Centre of Internal Medicine at the University Hospital Heidelberg were retrospectively analyzed. Psychiatric symptoms were quantified using the Patient Health Questionnaire-9-item depression module (PHQ-9), the 7-item Generalized Anxiety Disorder scale (GAD-7) and the Short Form-36 (SF-36) to evaluate health-related quality of life (HRQoL). Regression analyses included the variables sex, age, HF (mild, moderate and severe), the presence of an implanted cardioverter defibrillator (ICD), former or current cardiac decompensation (CD), cardiomyopathy (CM), and diabetes mellitus (DM) as predictors. A p < 0.05 was considered statistically significant. Younger age (PHQ-9: β = -0.117, p = 0.012; GAD-7: β = -0.205, p < 0.001) and female sex (PHQ-9: β = 0.118, p = 0.01; GAD-7: β = 0.164, p < 0.001) were significantly associated with elevated PHQ-9 and GAD-7 scores. CD (β = 0.149, p = 0.001), an ICD (β = 0.15, p = 0.002), and comorbid DM (β = 0.095, p = 0.036) were significantly associated with higher depression scores, while an ICD additionally correlated with more anxiety (β = 0.112, p = 0.024). Lower physical HRQoL was present in patients with DM (β = -0.163, p = 0.001) and CD (β = -0.147, p = 0.004). Relatively low adjusted R² values in the regression models reflect that only a small proportion of the variance in PHQ-9 (R² = 0.094) and GAD-7 (R² = 0.079) can be explained. Although severe HF was associated with higher PHQ-9 scores, the multivariate regression analyses did not confirm a significant association. Depressive and anxious symptoms, as well as physical HRQoL, are more strongly linked to specific clinical characteristics than to HF severity itself. Instead, younger age, female sex, CD, an ICD, and comorbid DM showed stronger associations with significantly increased depressive symptoms and lower HRQoL, while those with an ICD additionally described higher levels of anxiety. These findings support targeted psychosocial screening in these high-risk cardiac subgroups.