Dissecting the genetic overlap between severe mental disorders and markers of cellular aging: Identification of pleiotropic genes and druggable targets.

Patients with severe mental disorders such as bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) show a substantial reduction in life expectancy, increased incidence of comorbid medical conditions commonly observed with advanced age and alterations of aging hallmarks. While severe mental disorders are heritable, the extent to which genetic predisposition might contribute to accelerated cellular aging is not known. We used bivariate causal mixture models to quantify the trait-specific and shared architecture of mental disorders and 2 aging hallmarks (leukocyte telomere length [LTL] and mitochondrial DNA copy number), and the conjunctional false discovery rate method to detect shared genetic loci. We integrated gene expression data from brain regions from GTEx and used different tools to functionally annotate identified loci and investigate their druggability. Aging hallmarks showed low polygenicity compared with severe mental disorders. We observed a significant negative global genetic correlation between MDD and LTL (rg = -0.14, p = 6.5E-10), and no significant results for other severe mental disorders or for mtDNA-cn. However, conditional QQ plots and bivariate causal mixture models pointed to significant pleiotropy among all severe mental disorders and aging hallmarks. We identified genetic variants significantly shared between LTL and BD (n = 17), SCZ (n = 55) or MDD (n = 19), or mtDNA-cn and BD (n = 4), SCZ (n = 12) or MDD (n = 1), with mixed direction of effects. The exonic rs7909129 variant in the SORCS3 gene, encoding a member of the retromer complex involved in protein trafficking and intracellular/intercellular signaling, was associated with shorter LTL and increased predisposition to all severe mental disorders. Genetic variants underlying risk of SCZ or MDD and shorter LTL modulate expression of several druggable genes in different brain regions. Genistein, a phytoestrogen with anti-inflammatory and antioxidant effects, was an upstream regulator of 2 genes modulated by variants associated with risk of MDD and shorter LTL. While our results suggest that shared heritability might play a limited role in contributing to accelerated cellular aging in severe mental disorders, we identified shared genetic determinants and prioritized different druggable targets and compounds.

Symptomatic remission and recovery in major psychosis: Is there a role for BDNF? A secondary analysis of the LABSP cohort data.

Remission, relapse prevention, and clinical recovery are crucial areas of interest in schizophrenia (SCZ) research. Although SCZ is a chronic disorder with poor overall outcomes, years of research demonstrated that recovery is possible. There are considerable data linking brain-derived neurotrophic factor (BDNF) to SCZ, however, evidence on the role of BDNF in remission in SCZ is scarce. This secondary analysis of the Longitudinal Assessment of BDNF in Sardinian patients (LABSP) data aimed to investigate the relationship between serum BDNF levels and symptomatic remission, simultaneous clinical and functional remission, and recovery in patients with SCZ. A total of 105 patients with SCZ or schizoaffective disorder were recruited for a longitudinal assessment of BDNF levels over 24 months. Longitudinal data were analyzed using mixed-effects linear regression models. The study found significant associations between use of long acting injectables (χ2 = 7.075, df = 1, p = 0.008), baseline serum BDNF levels (U = 701, z = -2.543, p = 0.011), and "childhood" (U = 475, z = -2.124, p = 0.034) and "general" (U = 55, z = -2.014, p = 0.044) subscales of the Premorbid Adjustment Scale (PAS) with patients maintaining remission and recovery. The diagnosis of SCZ was significantly associated with lower BDNF levels for patients with simultaneous clinical and functional remission (Z = 2.035, p = 0.0419) and recovery (Z = 2.009, p = 0.0445) compared to those without. There were no significant associations between remission in the entire sample and longitudinal serum BDNF levels or genetic variants within the BDNF gene. These findings provide further insight into the complex relationship between BDNF and SCZ.

Probing the Association between Cognition, Suicidal Behavior and Tryptophan Metabolism in a Sample of Individuals Living with Bipolar Disorder: A Secondary Analysis.

Background and Objectives: Alterations in hot cognition and in the tryptophan metabolism through serotonin (5-HT) and kynurenine (KYN) pathways have been associated with an increased risk of suicidal behavior. Here, we aim at probing the association between Stroop test performances and tryptophan pathway components in a sample of individuals with bipolar disorder (BD). Materials and Methods: We explored the association between the Emotion Inhibition Subtask (EIS) performances of the Brief Assessment of Cognition for Affective Disorders (BAC-A) and plasmatic levels of 5-hydroxytriptophan (5-HTP), 5-HT, KYN, 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KYNA) among subjects reporting lifetime suicide ideation (LSI) vs. non-LSI and subjects reporting lifetime suicide attempts (LSA) vs. non-LSA. Results: In a sample of 45 subjects with BD, we found a statistically significant different performance for LSA vs. non-LSA in the color naming (CN) and neutral words (NW) EIS subtasks. There was a significant association between CN performances and plasma 5-HTP levels among LSI and LSA subjects but not among non-LSI or non-LSA. Conclusions: In our sample, patients with LSA and LSI presented lower performances on some EIS subtasks compared to non-LSA and non-LSI. Moreover, we found an inverse correlation between plasma 5-HTP concentration and some EIS performances in LSA and LSI but not among non-LSA or non-LSI. This may represent an interesting avenue for future studies probing this complex association.

A genome-wide association study of antidepressant-induced mania.

Antidepressant-induced mania (AIM) is a side effect of antidepressant treatment that is characterized by mania or hypomania after the start of medication. It is likely polygenic, but its genetic component remains largely unexplored. We aim to conduct the first genome-wide association study of AIM in 814 bipolar disorder patients of European ancestry. We report no significant findings from our single-marker or gene-based analyses. Our polygenic risk score analyses also did not yield significant results with bipolar disorder, antidepressant response, or lithium response. Our suggestive findings on the hypothalamic-pituitary-adrenal axis and the opioid system in AIM require independent replications.

Converging Evidence Points to BDNF as Biomarker of Depressive Symptoms in Schizophrenia-Spectrum Disorders.

Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses.

Investigation of Genetic Variants Associated with Tryptophan Metabolite Levels via Serotonin and Kynurenine Pathways in Patients with Bipolar Disorder.

The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine (KYN) pathways in 44 patients with BD and 45 healthy controls. We assessed whether variants that were differentially associated with metabolite levels based on the diagnostic status improved the prediction accuracy of BD using penalized regression approaches. We identified several genetic variants that were significantly associated with metabolites (5-HT, 5-hydroxytryptophan (5-HTP), TRP, and quinolinic acid (QA) or metabolite ratios (5-HTP/TRP and KYN/TRP) and for which the diagnostic status exerted a significant effect. The inclusion of genetic variants led to increased accuracy in the prediction of the BD diagnostic status. Specifically, we obtained an accuracy of 0.77 using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictors retained as informative in this model included body mass index (BMI), the levels of TRP, QA, and 5-HT, the 5-HTP/TRP ratio, and genetic variants associated with the levels of QA (rs6827515, rs715692, rs425094, rs4645874, and rs77048355) and TRP (rs292212) or the 5-HTP/TRP ratio (rs7902231). In conclusion, our study identified statistically significant associations between metabolites of TRP via the 5-HT and KYN pathways and genetic variants at the genome-wide level. The discriminative performance of penalized regression models incorporating clinical, genetic, and metabolic predictors warrants a follow-up analysis of this panel of determinants.

Exploring the association between brain-derived neurotrophic factor levels and longitudinal psychopathological and cognitive changes in Sardinian psychotic patients.

BACKGROUND AND HYPOTHESIS: Schizophrenia spectrum disorders are among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Furthermore, we examined whether genetic variation within the BDNF gene could moderate these relationships. STUDY DESIGN: Every 6 months, 105 patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and social measures. We performed a targeted analysis of four tag single nucleotide polymorphisms within the BDNF gene that were selected and analyzed using polymerase chain reaction. Longitudinal data were analyzed using mixed-effects linear regression models. STUDY RESULTS: We observed a declining longitudinal trajectory of BDNF levels in psychotic patients in general, and in relation to the severity of depressive and negative symptoms. BDNF serum levels also declined in patients scoring lower in cognitive measures such as attention and speed of information processing and verbal fluency. The rs7934165 polymorphism moderated the significant association between verbal fluency and BDNF levels. CONCLUSIONS: These findings in patients from real-world settings suggest a plausible role of peripheral BDNF levels as a marker of illness burden in schizophrenia spectrum disorders.

Analysis on in vitro effect of lithium on telomere length in lymphoblastoid cell lines from bipolar disorder patients with different clinical response to long-term lithium treatment.

BACKGROUND: It has been suggested that bipolar disorder (BD) is associated with clinical and biological features of accelerated aging. In our previous studies, we showed that long-term lithium treatment was correlated with longer leukocyte telomere length (LTL) in BD patients. A recent study explored the role of TL in BD using patients-derived lymphoblastoid cell lines (LCLs), showing that baseline TL was shorter in BD compared to controls and that lithium in vitro increased TL but only in BD. Here, we used the same cell system (LCLs) to explore if a 7-day treatment protocol with lithium chloride (LiCl) 1 mM was able to highlight differences in TL between BD patients clinically responders (Li-R; n = 15) or non-responders (Li-NR; n = 15) to lithium, and if BD differed from non-psychiatric controls (HC; n = 15). RESULTS: There was no difference in TL between BD patients and HC. Moreover, LiCl did not influence TL in the overall sample, and there was no difference between diagnostic or clinical response groups. Likewise, LiCl did not affect TL in neural precursor cells from healthy donors. CONCLUSIONS: Our findings suggest that a 7-day lithium treatment protocol and the use of LCLs might not represent a suitable approach to deepen our understanding on the role of altered telomere dynamics in BD as previously suggested by studies in vivo.

Cost-Utility Analysis of Pharmacogenetic Testing Based on CYP2C19 or CYP2D6 in Major Depressive Disorder: Assessing the Drivers of Different Cost-Effectiveness Levels from an Italian Societal Perspective.

BACKGROUND AND OBJECTIVES: Major depressive disorder (MDD) is a common and severe psychiatric disorder that has enormous economical and societal costs. As pharmacogenetics is one of the key tools of precision psychiatry, we analyze the cost-utility of test screening of CYP2C19 and CYP2D6 for patients suffering from major depressive disorder (MDD) and try to understand the main drivers that influence the cost-utility. METHODS: We developed two pharmacoeconomic nonhomogeneous Markov models to test the cost-utility, from an Italian societal perspective, of pharmacogenetic testing genetic to characterize the metabolizing profiles of cytochrome P450 (CYP) 2C19 and CYP2D6 in a hypothetical case study of patients suffering from major depressive disorder (MDD). The model considers different scenarios of adjustment of antidepressant treatment according to the patient's metabolizing profile or treatment over a period of 18 weeks. The uncertainty of model parameters is tested through both a probabilistic sensitivity analysis and a one-way deterministic sensitivity analysis, and these results are used in a post-hoc analysis to understand the main drivers of three alternative cost-effectiveness levels ("poor," "standard," and "high"). These drivers are first evaluated from an exploratory multidimensional perspective and next from a predictive perspective as the probability that a patient belongs to a specific cost-effectiveness level is estimated on the basis of a restricted set of parameters used in the original pharmacoeconomic model. RESULTS: The models for CYP2C19 and CYP2D6 indicate that screening has an incremental cost-effectiveness ratio of 60,000€ and 47,000€ per quality-adjusted life year (QALY), respectively. The probabilistic sensitivity analysis shows that the treatments are cost-effective for a 75,000€ willingness to pay (WTP) threshold in 58% and 63% of the Monte Carlo replications, respectively. The post-hoc analysis highlights the factors that allow us to clearly discriminates poor cost-effectiveness from high cost-effectiveness scenarios and demonstrates that it is possible to predict with reasonable accuracy the cost-effectiveness of a genetic test and the associated therapeutic pattern. CONCLUSIONS: Our findings suggest that screenings for both CYP2C19 and CYP2D6 enzymes for patients with MDD are cost-effective for a WTP threshold of 75,000€ per QALY, and provide relevant suggestions about the most important aspects to be further explored in clinical studies aimed at addressing the cost-effectiveness of genetic testing for patients diagnosed with MDD.

Genetic and Epigenetic Markers of Lithium Response.

The mood stabilizer lithium represents a cornerstone in the long term treatment of bipolar disorder (BD), although with substantial interindividual variability in clinical response. This variability appears to be modulated by genetics, which has been significantly investigated in the last two decades with some promising findings. In addition, recently, the interest in the role of epigenetics has grown significantly, since the exploration of these mechanisms might allow the elucidation of the gene-environment interactions and explanation of missing heritability. In this article, we provide an overview of the most relevant findings regarding the pharmacogenomics and pharmacoepigenomics of lithium response in BD. We describe the most replicated findings among candidate gene studies, results from genome-wide association studies (GWAS) as well as post-GWAS approaches supporting an association between high genetic load for schizophrenia, major depressive disorder or attention deficit/hyperactivity disorder and poor lithium response. Next, we describe results from studies investigating epigenetic mechanisms, such as changes in methylation or noncoding RNA levels, which play a relevant role as regulators of gene expression. Finally, we discuss challenges related to the search for the molecular determinants of lithium response and potential future research directions to pave the path towards a biomarker guided approach in lithium treatment.

Investigating the Role of Leukocyte Telomere Length in Treatment-Resistant Depression and in Response to Electroconvulsive Therapy.

Psychiatric disorders seem to be characterized by premature cell senescence. However, controversial results have also been reported. In addition, the relationship between accelerated aging and treatment-resistance has scarcely been investigated. In the current study, we measured leukocyte telomere length (LTL) in 148 patients with treatment-resistant depression (TRD, 125 with major depressive disorder, MDD, and 23 with bipolar disorder, BD) treated with electroconvulsive therapy (ECT) and analyzed whether LTL was associated with different response profiles. We also compared LTL between patients with TRD and 335 non-psychiatric controls. For 107 patients for which genome-wide association data were available, we evaluated whether a significant overlap among genetic variants or genes associated with LTL and with response to ECT could be observed. LTL was negatively correlated with age (Spearman's correlation coefficient = -0.25, p < 0.0001) and significantly shorter in patients with treatment-resistant MDD (Quade's F = 35.18, p < 0.0001) or BD (Quade's F = 20.84, p < 0.0001) compared to controls. Conversely, baseline LTL was not associated with response to ECT or remission. We did not detect any significant overlap between genetic variants or genes associated with LTL and response to ECT. Our results support previous findings suggesting premature cell senescence in patients with severe psychiatric disorders and suggest that LTL could not be a predictive biomarker of response to ECT.

Protocol for a pharmacogenetic study of antidepressants: characterization of drug-metabolizing profiles of cytochromes CYP2D6 and CYP2C19 in a Sardinian population of patients with major depressive disorder.

The effectiveness of antidepressants shows high interindividual variability ranging from full symptomatologic remission to treatment-resistant depression. Many factors can determine the variation in the clinical response, but a fundamental role is played by genetic variation within the genes encoding for the enzymes most involved in the metabolism of antidepressant drugs: the CYP2D6 and CYP2C19 isoforms of the cytochrome P450 system. This study is poised to clarify whether the different metabolizing phenotypes related to CYP2D6 and CYP2C19 could have an impact on the clinical efficacy of antidepressants and whether the frequency of these phenotypes of metabolization shows differences in the population of Sardinian patients compared to other Caucasian populations. The sample is being recruited from patients followed-up and treated at the Psychiatric Unit of the Department of Medical Science and Public Health, University of Cagliari and the University Hospital Agency of Cagliari (Italy). The study design includes three approaches: (1) a pharmacogenetic analysis of 80 patients diagnosed with MDD resistant to antidepressant treatment compared to 80 clinically responsive or remitted patients; (2) a prospective arm (N = 30) of the study where we will test the impact of genetic variation within the CYP2D6 and CYP2C19 genes on clinical response to antidepressants and on their serum levels and (3) the assessment of the socio-economic impact of antidepressant therapies, and estimation of the cost-effectiveness of the pharmacogenetic test based on CYP genes.

Telomere attrition and inflammatory load in severe psychiatric disorders and in response to psychotropic medications.

Individuals with severe psychiatric disorders have a reduced life expectancy compared to the general population. At the biological level, patients with these disorders present features that suggest the involvement of accelerated aging, such as increased circulating inflammatory markers and shorter telomere length (TL). To date, the role of the interplay between inflammation and telomere dynamics in the pathophysiology of severe psychiatric disorders has been scarcely investigated. In this study we measured T-lymphocytes TL with quantitative fluorescent in situ hybridization (Q-FISH) and plasma levels of inflammatory markers in a cohort comprised of 40 patients with bipolar disorder (BD), 41 with schizophrenia (SZ), 37 with major depressive disorder (MDD), and 36 non-psychiatric controls (NPC). TL was shorter in SZ and in MDD compared to NPC, while it was longer in BD (model F6, 137 = 20.128, p = 8.73 × 10-17, effect of diagnosis, F3 = 31.870; p = 1.08 × 10-15). There was no effect of the different classes of psychotropic medications, while duration of treatment with mood stabilizers was associated with longer TL (Partial correlation controlled for age and BMI: correlation coefficient = 0.451; p = 0.001). Levels of high-sensitivity C-Reactive Protein (hsCRP) were higher in SZ compared to NPC (adjusted p = 0.027), and inversely correlated with TL in the whole sample (r = -0.180; p = 0.042). Compared to NPC, patients with treatment resistant (TR) SZ had shorter TL (p = 0.001), while patients with TR MDD had higher levels of tumor necrosis factor-α (TNFα) compared to NPC (p = 0.028) and to non-TR (p = 0.039). Comorbidity with cardio-metabolic disorders did not influence the observed differences in TL, hsCRP, and TNFα among the diagnostic groups. Our study suggests that patients with severe psychiatric disorders present reduced TL and increased inflammation.

Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment.

Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

A multidisciplinary approach to mental illness: do inflammation, telomere length and microbiota form a loop? A protocol for a cross-sectional study on the complex relationship between inflammation, telomere length, gut microbiota and psychiatric disorders.

INTRODUCTION: Severe psychiatric disorders are typically associated with a significant reduction in life expectancy compared with the general population. Among the different hypotheses formulated to explain this observation, accelerated ageing has been increasingly recognised as the main culprit. At the same time, telomere shortening is becoming widely accepted as a proxy molecular marker of ageing. The present study aims to fill a gap in the literature by better defining the complex interaction/s between inflammation, age-related comorbidities, telomere shortening and gut microbiota in psychiatric disorders. METHODS AND ANALYSIS: A cross-sectional study is proposed, recruiting 40 patients for each of three different diagnostic categories (bipolar disorder, schizophrenia and major depressive disorder) treated at the Section of Psychiatry and at the Unit of Clinical Pharmacology of the University Hospital Agency of Cagliari (Italy), compared with 40 age-matched and sex-matched non-psychiatric controls. Each group includes individuals suffering, or not, from age-related comorbidities, to account for the impact of these medical conditions on the biological make-up of recruited patients. The inflammatory state, microbiota composition and telomere length (TL) are assessed. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the University Hospital Agency of Cagliari (PG/2018/11693, 5 September 2018). The study is conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki, and in compliance with the relevant Italian national legislation. Written, informed consent is obtained from all participants. Participation in the study is on a voluntary basis only. Patients will be part of the dissemination phase of the study results, during which a local conference will be organised and families of patients will also be involved. Moreover, findings will be published in one or more research papers and presented at national and international conferences, in posters or oral communications.

Leukocyte telomere length is reduced in patients with major depressive disorder.

Major depressive disorder (MDD) is a chronic, severe psychiatric illness with an incidence of 3% worldwide. MDD patients have a significantly impaired quality of life and reduced life expectancy compared to unaffected individuals, the latter being largely accounted for by an increased incidence of suicide and cardiovascular disorders. The premature mortality observed in MDD has been considered a signature of accelerated aging, a hypothesis supported by data showing altered functioning and morphology of several brain regions that are typically present in the aging population. Telomere shortening is a hallmark of cellular aging, and as such several studies explored the involvement of disrupted telomere dynamics in MDD, reporting contrasting findings. In the current study, we measured leukocyte telomere length (LTL) in a sample of 54 MDD patients and 47 non-psychiatric controls characterized for response to antidepressant treatment. After correcting for age, sex, and body mass index, we showed significantly reduced LTL in affected individuals compared to controls (beta = -.22, p = .02). There was no difference in LTL between treatment resistant or responsive MDD patients. Moreover, we observed no correlation between lifetime exposure to antidepressants and LTL. Our study showed that MDD patients have shorter telomeres compared to controls, supporting the hypothesis of accelerated aging in this disorder. However, LTL seemed not to be influenced by antidepressant treatment or to correlate with clinical response to these antidepressants. Further investigations in larger samples and possibly with longitudinal design are warranted to elucidate the role of altered telomere dynamics in MDD.

Zinc finger proteins in psychiatric disorders and response to psychotropic medications.

Zinc finger proteins are a large family of abundantly expressed small motifs that play a crucial role in a wide range of physiological and pathophysiological mechanisms. Findings published so far support an involvement of zinc fingers in psychiatric disorders. Most of the evidence has been provided for the zinc finger protein 804A (ZNF804A) gene, which has been suggested to be implicated in schizophrenia and bipolar disorder. This evidence has been corroborated by a wide range of functional studies showing that ZNF804A regulates the expression of genes involved in cell adhesion and plays a crucial role in neurite formation and maintenance of dendritic spines. On the other hand, far less is known on other zinc finger proteins and their involvement in psychiatric disorders. In this review, we discussed studies exploring the role of zinc finger proteins in schizophrenia, bipolar disorder, and major depressive disorder as well as in pharmacogenetics of psychotropic drugs.

Clinical application of magnetocardiography.

Magnetocardiography is a noninvasive contactless method to measure the magnetic field generated by the same ionic currents that create the electrocardiogram. The time course of magnetocardiographic and electrocardiographic signals are similar. However, compared with surface potential recordings, multichannel magnetocardiographic mapping (MMCG) is a faster and contactless method for 3D imaging and localization of cardiac electrophysiologic phenomena with higher spatial and temporal resolution. For more than a decade, MMCG has been mostly confined to magnetically shielded rooms and considered to be at most an interesting matter for research activity. Nevertheless, an increasing number of papers have documented that magnetocardiography can also be useful to improve diagnostic accuracy. Most recently, the development of standardized instrumentations for unshielded MMCG, and its ease of use and reliability even in emergency rooms has triggered a new interest from clinicians for magnetocardiography, leading to several new installations of unshielded systems worldwide. In this review, clinical applications of magnetocardiography are summarized, focusing on major milestones, recent results of multicenter clinical trials and indicators of future developments.

Multichannel mapping of fetal magnetocardiogram in an unshielded hospital setting.

OBJECTIVES: To evaluate the feasibility of unshielded in-hospital multichannel mapping of fetal magnetocardiogram (FMCG), with a 36-channel system for standard adult magnetocardiographic (MCG) recordings, and its reliability according to the recommended standards for FMCG. METHODS: FMCG was ambulatory mapped with a 36-channel MCG system, in six normal pregnancies at different gestational ages. MCG analysis included adaptive digital filtering of 50 Hz, signal averaging, reconstruction of magnetic field distribution (MFD) and source localization. Fixed Point Independent Component Analysis algorithm (FastICA) was used to reconstruct the FMCG, separating them from maternal contamination and noise. RESULTS: The quality of FMCG recorded after the 32nd gestational week and reconstructed with FastICA was close to FMCG obtained in shielded rooms, and good enough to measure cardiac intervals and heart rate variability parameters. In two cases, reconstruction of the MFD during the QRS allowed three-dimensional localization of ventricular sources. CONCLUSIONS: A first demonstration has been given that multichannel mapping of FMCG can be performed in unshielded clinical environments, with resolution good enough for contactless assessment of fetal cardiac electrophysiology. FastICA processing on unshielded FMCG, recorded after the 32nd week, provided beat-to-beat analysis and heart rate variability assessment. Further work is needed to improve signal reconstruction in early pregnancy.

Contactless magnetocardiographic study of ventricular repolarization in intact Wistar rats: evidence of gender-related differences.

INTRODUCTION: Magnetocardiographic (MCG) mapping is increasingly used for the non-invasive study of coronary artery disease (CAD), cardiomyopathy (CMP) and arrhythmias. MCG study of small animals with ischemia or CMP would provide useful experimental models for the interpretation of abnormal human patterns. The aim of this study was to assess the range of normality of MCG ventricular repolarization parameters, in intact adult rats. METHODS AND RESULTS: 10 adult Wistar rats (weight 250 - 350 grams) were investigated with a 36-channel MCG mapping instrumentation (sensitivity is 20 fT/ radical Hz, at 1 Hz), designed for clinical recordings in unshielded hospital laboratories. To assess ventricular repolarization, MCG Q-T(peak), Q-T(end), J-T(peak), J-T(end), T(peak)-T(end) intervals were measured. MCG imaging was obtained by automatic calculation of isofield contour maps, and with inverse source localization based on the Equivalent Current Dipole and Effective Magnetic Dipole models, in a semi-infinite space with homogeneous conductance. Magnetic field (MF) orientation, dynamics and stability during the J-T(end) segment were also calculated. After averaging 300 s of continuous MCG recording, the S/N ratio was good enough for reproducible reconstruction of both atrial and ventricular magnetic maps and for three-dimensional localization of the underlying cardiac generators. Clear gender-related differences in ventricular repolarization duration were found, evidenced by significantly longer Q-T(end), J-T(end) and T(peak)-T(end) intervals in females. The differences in MF orientation, and stability during the J-T(end) segment were not significant. For J-T(peak) MF dynamics, only the ratio between the strengths of the positive and negative poles was significantly lower in the female group ( p < 0.05). CONCLUSIONS: Contactless MCG recording is a novel approach, which simplifies non-invasive mapping in small animals. In normal rats, gender-related differences of ventricular repolarization parameters equivalent to those reported in previous ECG studies were demonstrated.