Neurological affection and serum neurofilament light chain in wild type transthyretin amyloidosis.

In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Clinical course and follow-up of pediatric patients with COVID-19 vaccine-associated myocarditis compared to non-vaccine-associated myocarditis within the prospective multicenter registry-"MYKKE".

BACKGROUND: Since the onset of widespread COVID-19 vaccination, increased incidence of COVID-19 vaccine-associated myocarditis (VA-myocarditis) has been noted, particularly in male adolescents. METHODS: Patients <18 years with suspected myocarditis following COVID-19 vaccination within 21 days were enrolled in the PedMYCVAC cohort, a substudy within the prospective multicenter registry for pediatric myocarditis "MYKKE." Clinical data at initial admission, 3- and 9-months follow-up were monitored and compared to pediatric patients with confirmed non-vaccine-associated myocarditis (NVA-myocarditis) adjusting for various baseline characteristics. RESULTS: From July 2021 to December 2022, 56 patients with VA-myocarditis across 15 centers were enrolled (median age 16.3 years, 91% male). Initially, 11 patients (20%) had mildly reduced left ventricular ejection fraction (LVEF; 45%-54%). No incidents of severe heart failure, transplantation or death were observed. Of 49 patients at 3-months follow-up (median (IQR) 94 (63-118) days), residual symptoms were registered in 14 patients (29%), most commonly atypical intermittent chest pain and fatigue. Diagnostic abnormalities remained in 23 patients (47%). Of 21 patients at 9-months follow-up (259 (218-319) days), all were free of symptoms and diagnostic abnormalities remained in 9 patients (43%). These residuals were mostly residual late gadolinium enhancement in magnetic resonance imaging. Patients with NVA-myocarditis (n=108) more often had symptoms of heart failure (P = .003), arrhythmias (P = .031), left ventricular dilatation (P = .045), lower LVEF (P < .001) and major cardiac adverse events (P = .102). CONCLUSIONS: Course of COVID-19 vaccine-associated myocarditis in pediatric patients seems to be mild and differs from non-vaccine-associated myocarditis. Due to a considerable number of residual symptoms and diagnostic abnormalities at follow-up, further studies are needed to define its long-term implications.

Myocarditis and sports in the young: data from a nationwide registry on myocarditis-"MYKKE-Sport".

Background: Myocarditis represents one of the most common causes of Sudden Cardiac Death in children. Myocardial involvement during a viral infection is believed to be higher as a consequence of intensive exertion. Recommendations for return to sports are based on cohort and case studies only. This study aims to investigate the relationship between physical activity and myocarditis in the young. Patient: Every patient in the MYKKE registry fulfilling criteria for suspicion of myocarditis was sent a questionnaire regarding the physical activity before, during and after the onset of myocarditis. Method: This study is a subproject within the MYKKE registry, a multicenter registry for children and adolescents with suspected myocarditis. The observation period for this analysis was 93 months (September 2013-June 2021). Anamnestic, cardiac magnetic resonance images, echocardiography, biopsy and laboratory records from every patient were retrieved from the MYKKE registry database. Results: 58 patients (mean age 14.6 years) were enrolled from 10 centers. Most patients participated in curricular physical activity and 36% in competitive sports before the onset of myocarditis. There was no significant difference of heart function at admission between the physically active and inactive subjects (ejection fraction of 51.8 ± 8.6% for the active group vs. 54.4 ± 7.7% for the inactive group). The recommendations regarding the return to sports varied widely and followed current guidelines in 45%. Most patients did not receive an exercise test before returning to sports. Conclusion: Sports before the onset of myocarditis was not associated with a more severe outcome. There is still a discrepancy between current literature and actual recommendations given by health care providers. The fact that most participants did not receive an exercise test before being cleared for sports represents a serious omission.

Sequencing and titrating approach of therapy in heart failure with reduced ejection fraction following the 2021 European Society of Cardiology guidelines: an international cardiology survey.

AIMS: In symptomatic patients with heart failure and reduced ejection fraction (HFrEF), recent international guidelines recommend initiating four major therapeutic classes rather than sequential initiation. It remains unclear how this change in guidelines is perceived by practicing cardiologists versus heart failure (HF) specialists. METHODS AND RESULTS: An independent academic web-based survey was designed by a group of HF specialists and posted by email and through various social networks to a broad community of cardiologists worldwide 1 year after the publication of the latest European HF guidelines. Overall, 615 cardiologists (38 [32-47] years old, 63% male) completed the survey, of which 58% were working in a university hospital and 26% were HF specialists. The threshold to define HFrEF was ≤40% for 61% of the physicians. Preferred drug prescription for the sequential approach was angiotensin-converting enzyme inhibitors or angiotensin receptor-neprilysin inhibitors first (74%), beta-blockers second (55%), mineralocorticoid receptor antagonists third (52%), and sodium-glucose cotransporter 2 inhibitors (53%) fourth. Eighty-four percent of participants felt that starting all four classes was feasible within the initial hospitalization, and 58% felt that titration is less important than introducing a new class. Age, status in training, and specialization in HF field were the principal characteristics that significantly impacted the answers. CONCLUSION: In a broad international cardiology community, the 'historical approach' to HFrEF therapies remains the preferred sequencing approach. However, accelerated introduction and uptitration are also major treatment goals. Strategy trials in treatment guidance are needed to further change practices.

Incremental value of mineralocorticoid receptor antagonists in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan.

AIMS: We investigated the incremental advantage in terms of N-terminal pro-B-type natriuretic peptide (NT-proBNP) reduction in patients affected by heart failure with reduced ejection fraction (HFrEF) treated with sacubitril/valsartan (S/V) and mineralocorticoid receptor antagonists (MRA) versus patients treated with S/V only. METHODS: Consecutive adult patients with a left ventricular ejection fraction (LVEF) of ≤40% who were followed in our outpatient clinic from January 2016 to December 2019 and treated with S/V were analysed. RESULTS: Out of eligible 147 patients, 99 were treated with S/V+MRA at baseline and 48 patients were treated with S/V. Patients treated with S/V+MRA were significantly younger (61.5 vs 67.8 years, p=0.006), had better basal renal function (serum creatinine 1.2 vs 1.4 mg/dL, p=0.006) and lower LVEF (30.9% vs 33.1%, p=0.039). At follow-up at 8-16 months, 84 out of 99 patients continued to be on S/V+MRA, and 39 out of 48 patients continued to be on S/V. Between these two groups, at follow-up, LVEF did not vary significantly, ΔNT-proBNP was not significantly different (-215.7 vs -165.9 pg/mL, p=0.93) and neither was the rate of hospitalisation for heart failure (9.5% vs 12.8%, p=0.58). Using general linear models, both age and basal NT-proBNP influenced significantly ΔNT-proBNP (respectively, p=0.002; p=0.005), while treatment with S/V+MRA versus S/V only did not significantly influence ΔNT-proBNP (p=0.462). CONCLUSION: Even with the limitations of a small retrospective study, our results generate the hypothesis that MRA might not provide any additional value in patients with HFrEF treated with S/V. Larger studies are needed to test if MRA should remain a standard treatment in patients with HFrEF treated with S/V.

Myocardial extracellular volume is a non-invasive tissue marker of heart failure in patients with transposition of the great arteries and systemic right ventricle.

Background: Focal myocardial fibrosis in the systemic right ventricle (RV) is related to ventricular dysfunction and adverse outcome in patients with d-transposition of the great arteries (dTGA) post atrial redirection and those with congenitally corrected TGA (ccTGA). The role of diffuse fibrotic lesions in these conditions remains poorly understood. Our study aimed to investigate diffuse myocardial fibrosis by measuring extracellular volume (ECV) with cardiovascular magnetic resonance (CMR) and to explore correlations between ECV and clinical as well as functional markers of heart failure in patients with TGA and systemic RV. Methods: We prospectively included dTGA and ccTGA patients aged ≥14 years and compared them to healthy controls. Standardized CMR included modified Look-Locker Inversion recovery T1 mapping to quantify diffuse myocardial fibrosis in the systemic RV and the subpulmonary left ventricle (LV). The centerline of RV and LV myocardium was marked with a line of interest tool to determine native and post-contrast T1 for quantification of ECV. Results: In total, 13 patients (dTGA: n = 8, ccTGA: n = 5) with a median age of 30.3 years were enrolled. LV ECV was higher in patients than in controls [34% (30%-41%) vs. 26% (23%-27%), p < 0.001], with values increased above the upper limit of normal in 10/13 patients (77%). RV ECV tended to be higher in patients than in controls, albeit without statistical significance [29% (27%-32%) vs. 28% (26%-29%), p = 0.316]. Patients with elevated LV ECV had lower LV ejection fraction than those with normal ECV (52 ± 5% vs. 65 ± 4%, p = 0.007). Correlations with clinical parameters were not observed. LV ECV was significantly higher than RV ECV (p = 0.016) in the patient group. Conclusions: In this study, LV ECV was significantly increased in TGA patients compared to controls, and was associated with LV dysfunction. Our data suggest that ECV may serve as a non-invasive tissue marker of heart failure in TGA with systemic RV. Further research is necessary to evaluate the prognostic implications and the potential role of ECV in monitoring disease progression and guiding therapy, aiming to maintain LV function or train the LV for subaortic location in TGA patients from infancy to adulthood.

SCMR expert consensus statement for cardiovascular magnetic resonance of acquired and non-structural pediatric heart disease.

Cardiovascular magnetic resonance (CMR) is widely used for diagnostic imaging in the pediatric population. In addition to structural congenital heart disease (CHD), for which published guidelines are available, CMR is also performed for non-structural pediatric heart disease, for which guidelines are not available. This article provides guidelines for the performance and reporting of CMR in the pediatric population for non-structural ("non-congenital") heart disease, including cardiomyopathies, myocarditis, Kawasaki disease and systemic vasculitides, cardiac tumors, pericardial disease, pulmonary hypertension, heart transplant, and aortopathies. Given important differences in disease pathophysiology and clinical manifestations as well as unique technical challenges related to body size, heart rate, and sedation needs, these guidelines focus on optimization of the CMR examination in infants and children compared to adults. Disease states are discussed, including the goals of CMR examination, disease-specific protocols, and limitations and pitfalls, as well as newer techniques that remain under development.

Quantitative Ultrasound Assessment of Early Osteoarthritis in Human Articular Cartilage Using a High-Frequency Linear Array Transducer.

Quantitative ultrasound (QUS) assessment of osteoarthritis (OA) using high-frequency, research-grade single-element ultrasound systems has been reported. The objective of this ex vivo study was to assess the performance of QUS in detecting early OA using a high-frequency linear array transducer. Osteochondral plugs (n = 26) of human articular cartilage were scanned with ExactVu Micro-Ultrasound using an EV29L side-fire transducer. For comparison, the samples were also imaged with SAM200Ex, a custom 40-MHz scanning acoustic microscope with a single-element, focused transducer. Thirteen QUS parameters were derived from the ultrasound data. Magnetic resonance imaging (MRI) data, with T1 and T2 extracted as the quantitative parameters, were also acquired for comparison. Cartilage degeneration was graded from histology and correlated to all quantitative parameters. A maximum Spearman rank correlation coefficient (ρ) of 0.75 was achieved using a combination of ExactVu QUS parameters, while a maximum ρ of 0.62 was achieved using a combination of parameters from SAM200Ex. A maximum ρ of 0.75 was achieved using the T1 and T2 MRI parameters. This study illustrates the potential of a high-frequency linear array transducer to provide a convenient method for early OA screening with results comparable to those of research-grade single-element ultrasound and MRI.

Compensatory Upregulation of Anti-Beta-Adrenergic Receptor Antibody Levels Might Prevent Heart Failure Presentation in Pediatric Myocarditis.

Background: Myocarditis can be associated with severe heart failure and is caused by different inflammatory and autoimmune responses. The aim of this study was to describe the immunological response in children with myocarditis by analyzing anti-beta-adrenergic receptor antibodies (anti-ß-AR Abs). Methods: Sera of children who were hospitalized with biopsy-proven myocarditis were prospectively collected between April 2017 and March 2019. Anti-ß1-AR Ab, anti-ß2-AR Ab, and anti-ß3-AR Ab were quantified by a CE-certified ELISA kit. According to normal values for immunoglobulin G (IgG), three age groups, <1, 1-5, and >5-17 years, were defined. Children without inflammatory cardiac pathology and no heart failure signs were served as a control group. Results: We compared 22 patients with biopsy-proven myocarditis and 28 controls. The median age (interquartile range) of the myocarditis group (MYC) was 12.1 (2.7-16.4) years, 13 men, left ventricular ejection fraction (LVEF) 51% and for control group, the median age was 5.0 (3.0-6.8) years, nine men, LVEF 64%. Myocarditis patients in the age group >5-17 years showed significantly higher anti-ß3-AR Ab levels as compared to controls (p = 0.014). Lower anti-ß2-AR Ab and anti-ß3-AR Ab levels were significantly correlated with higher left ventricular diameters in myocarditis patients. The event-free survival using a combined endpoint (mechanical circulatory support [MCS], transplantation, and/or death) was significantly lower in myocarditis patients with antibody levels below the median as compared to myocarditis patients with antibody levels ≥ the median. Conclusion: Anti-ß-AR Ab levels are increased in children with myocarditis and >5 years of age. These antibodies might be upregulated compensatory to prevent further cardiac deterioration. A worse event-free survival in patients with lower anti-ß-AR Ab levels might be a therapeutic target for immunoglobulin substitution.

Hemodynamic Changes During Physiological and Pharmacological Stress Testing in Patients With Heart Failure: A Systematic Review and Meta-Analysis.

Although disease etiologies differ, heart failure patients with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively) both present with clinical symptoms when under stress and impaired exercise capacity. The extent to which the adaptation of heart rate (HR), stroke volume (SV), and cardiac output (CO) under stress conditions is altered can be quantified by stress testing in conjunction with imaging methods and may help to detect the diminishment in a patient's condition early. The aim of this meta-analysis was to quantify hemodynamic changes during physiological and pharmacological stress testing in patients with HF. A systematic literature search (PROSPERO 2020:CRD42020161212) in MEDLINE was conducted to assess hemodynamic changes under dynamic and pharmacological stress testing at different stress intensities in HFpEF and HFrEF patients. Pooled mean changes were estimated using a random effects model. Altogether, 140 study arms with 7,248 exercise tests were analyzed. High-intensity dynamic stress testing represented 73% of these data (70 study arms with 5,318 exercise tests), where: HR increased by 45.69 bpm (95% CI 44.51-46.88; I 2 = 98.4%), SV by 13.49 ml (95% CI 6.87-20.10; I 2 = 68.5%), and CO by 3.41 L/min (95% CI 2.86-3.95; I 2 = 86.3%). No significant differences between HFrEF and HFpEF groups were found. Despite the limited availability of comparative studies, these reference values can help to estimate the expected hemodynamic responses in patients with HF. No differences in chronotropic reactions, changes in SV, or CO were found between HFrEF and HFpEF. When compared to healthy individuals, exercise tolerance, as well as associated HR and CO changes under moderate-high dynamic stress, was substantially impaired in both HF groups. This may contribute to a better disease understanding, future study planning, and patient-specific predictive models. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020161212].

Clinical characteristics and outcome of biopsy-proven myocarditis in children - Results of the German prospective multicentre registry "MYKKE".

BACKGROUND: Heart failure (HF) due to myocarditis might not respond in the same way to standard therapy as HF due to other aetiologies. The aim of this study was to investigate the value of endomyocardial biopsies (EMB) for clinical decision-making and its relation to the outcome of paediatric patients with myocarditis. METHODS: Clinical and EMB data of children with myocarditis collected for the MYKKE-registry between 2013 and 2020 from 23 centres were analysed. EMB studies included histology, immunohistology, and molecular pathology. The occurrence of major adverse cardiac events (MACE) including mechanical circulatory support (MCS), heart transplantation, and/or death was defined as a combined endpoint. RESULTS: Myocarditis was diagnosed in 209/260 patients: 64% healing/chronic lymphocytic myocarditis, 23% acute lymphocytic myocarditis (AM), 14% healed myocarditis, no giant cell myocarditis. The median age was 12.8 (1.4-15.9) years. Time from symptom-onset to EMB was 11.0 (4.0-29.0) days. Children with AM and high amounts of mononuclear cell infiltrates were significantly younger with signs of HF compared to those with healing/chronic or healed myocarditis. Myocardial viral DNA/RNA detection had no significant effect on outcome. The worst event-free survival was seen in patients with healing/chronic myocarditis (24%), followed by acute (31%) and healed myocarditis (58%, p = 0.294). A weaning rate of 64% from MCS was found in AM. CONCLUSIONS: EMB provides important information on the type and stage of myocardial inflammation and supports further decision-making. Children with fulminant clinical presentation, high amounts of mononuclear cell infiltrates or healing/chronic inflammation and young age have the highest risk for MACE.

Cardiovascular magnetic resonance in children with suspected myocarditis: current practice and applicability of adult protocols.

BACKGROUND: Cardiovascular magnetic resonance serves as a useful tool in diagnosing myocarditis. Current adult protocols are yet to be validated for children; thus, it remains unclear if the methods used can be applied with sufficient image quality in children. This study assesses the use of cardiovascular magnetic resonance in children with suspected myocarditis. METHODS: Image data from clinical cardiovascular magnetic resonance studies performed in children enrolled in Mykke between June 2014 and April 2019 were collected and analysed. The quality of the data sets was evaluated using a four-point quality scale (4: excellent, 3: good, 2: moderate, 1: non-diagnostic). RESULTS: A total of 102 patients from 9 centres were included with a median age (interquartile range) of 15.4(10.7-16.6) years, 137 cardiovascular magnetic resonance studies were analysed. Diagnostic image quality was found in 95%. Examination protocols were consistent with the original Lake Louise criteria in 58% and with the revised criteria in 35%. Older patients presented with better image quality, with the best picture quality in the oldest age group (13-18 years). Sedation showed a negative impact on image quality in late gadolinium enhancement and oedema sequences. No such correlation was seen in cardiac function assessment sequences. In contrast to initial scans, in follow-up examinations, the use of parametric mapping increased while late gadolinium enhancement and oedema sequences decreased. CONCLUSION: Cardiovascular magnetic resonance protocols for the assessment of adult myocarditis can be applied to children without significant constraints in image quality. Given the lack of specific recommendations for children, cardiovascular magnetic resonance protocols should follow recent recommendations for adult cardiovascular magnetic resonance.

Same same, but different? The neurological presentation of wildtype transthyretin (ATTRwt) amyloidosis.

BACKGROUND: Both hereditary transthyretin (ATTRv) amyloidosis and wildtype transthyretin (ATTRwt) amyloidosis can be associated with neurological diseases such as carpal tunnel syndrome and polyneuropathy. While ATTRv amyloidosis has been extensively studied, to date little is known about neurological complications of ATTRwt amyloidosis. In particular, the prevalence, pattern and extent of polyneuropathy and autonomic dysfunction has not been adequately investigated in the context of ATTRwt amyloidosis. To tackle this issue, we aimed to characterise the neurological presentation of ATTRwt amyloidosis and to compare between the presentations of ATTRv and ATTRwt amyloidoses. PATIENTS AND METHODS: Between November 2019 and September 2020, we included 50 patients with ATTRwt amyloidosis in this cohort study. All patients presented to the amyloidosis centre in Berlin, Germany and underwent neurological, cardiological and radiological work-up including neurological examination, laboratory testing, nerve conduction studies (NCS), echocardiography and scintigraphy. Patients were screened for symptoms of autonomic dysregulation and a subgroup of patients underwent tilt-table testing for orthostatic dysregulation. RESULTS: The cohort included 46 men and 4 women; the mean age of the study participants was 80.6 (standard deviation [SD] ± 5.0) years. All patients showed signs of cardiomyopathy on echocardiography. Neurological examination revealed peripheral, symmetric and length-depended predominately sensory polyneuropathy in 74% (n = 37) of patients. Neuropathy impairment scores (NIS) ranged from 0 to 50 with an average score of 8.4 (SD ± 10.1) indicating mild to moderate impairment. 90% and 92% of patients were classified as FAP stage I and PND stage I, respectively. Unilateral or bilateral carpal tunnel syndrome (CTS) was present in 70% (n = 35) and spinal stenosis was seen in 11% (n = 5) of patients. We detected a low rate of autonomic symptoms with a median COMPASS-31 total score of 18.4 points (IQR 32.4 points). Additional tilt-table testing of a subgroup of 8 patients yielded negative results for orthostatic intolerance. CONCLUSION: Distal-symmetric, predominantly sensory polyneuropathy is a common neurological complication in ATTRwt amyloidosis besides carpal tunnel syndrome and spinal stenosis, further substantiating the systemic character of the disease. Compared to ATTRv amyloidosis, the severity of polyneuropathy in ATTRwt amyloidosis is milder and without relevant motor involvement. Symptoms of autonomic dysfunction were not common in this cohort. Nevertheless, ATTRwt amyloidosis is a treatable disease and should be included in the differential diagnosis of sensory polyneuropathy in the elderly.

Integration of imaging and circulating biomarkers in heart failure: a consensus document by the Biomarkers and Imaging Study Groups of the Heart Failure Association of the European Society of Cardiology.

Circulating biomarkers and imaging techniques provide independent and complementary information to guide management of heart failure (HF). This consensus document by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) presents current evidence-based indications relevant to integration of imaging techniques and biomarkers in HF. The document first focuses on application of circulating biomarkers together with imaging findings, in the broad domains of screening, diagnosis, risk stratification, guidance of treatment and monitoring, and then discusses specific challenging settings. In each section we crystallize clinically relevant recommendations and identify directions for future research. The target readership of this document includes cardiologists, internal medicine specialists and other clinicians dealing with HF patients.

Heart failure in COVID-19: the multicentre, multinational PCHF-COVICAV registry.

AIMS: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations. METHODS AND RESULTS: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P < 0.001). After adjusting, HF remained associated with in-hospital mortality (OR 1.45 [95% confidence interval: 1.01-2.06], P = 0.041). Importantly, 186 of 1282 [15%] patients had an acute HF event during hospitalization (76 [40%] with de novo HF), which was associated with higher in-hospital mortality (89 [48%] vs. 220 [23%]) than in patients without HF event (OR 3.10 [2.24-4.29], P < 0.001). CONCLUSIONS: Hospitalized COVID-19 patients with HF are at increased risk for in-hospital death. In-hospital worsening of HF or acute HF de novo are common and associated with a further increase in in-hospital mortality.

Radionuclide, magnetic resonance and computed tomography imaging in European round back slugs (Arionidae) and leopard slugs (Limacidae).

Other than in animal models of human disease, little functional imaging has been performed in most of the animal world. The aim of this study was to explore the functional anatomy of the European round back slug (Arionidae) and leopard slug (Limacidae) and to establish an imaging protocol for comparative species study. Radionuclide images with single photon emission computed tomography (SPECT) and positron emission tomography (PET) were obtained after injections of standard clinical radiopharmaceuticals 99mtechnetium dicarboxypropane diphosphonate (bone scintigraphy), 99mtechnetium mercaptoacetyltriglycine (kidney function), 99mtechnetium diethylenetriaminepentaacetic acid (kidney function), 99mtechnetium pertechnetate (mediated by the sodium-iodide symporter), 99mtechnetium sestamibi (cardiac scintigraphy) or 18F-fluoro-deoxyglucose (glucose metabolism) in combination with magnetic resonance imaging (MRI) and computed tomography (CT) for uptake anatomic definition. Images were compared with anatomic drawings for the Arionidae species. Additionally, organ uptake data was determined for a description of slug functional anatomy in comparison to human tracer biodistribution patterns identifying the heart, the open circulatory anatomy, calcified shell remnant, renal structure (nephridium), liver (digestive gland) and intestine. The results show the detailed functional anatomy of Arionidae and Limacidae, and describe an in vivo whole-body imaging procedure for invertebrate species.

Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis.

BACKGROUND: Myocarditis is one of the most common causes leading to heart failure in children and a possible genetic background has been postulated. We sought to characterize the clinical and genetic characteristics in patients with myocarditis ≤18 years of age to predict outcome. METHODS: A cohort of 42 patients (Genetics in Pediatric Myocarditis) with biopsy-proven myocarditis underwent genetic testing with targeted panel sequencing of cardiomyopathy-associated genes. Genetics in Pediatric Myocarditis patients were divided into subgroups according to the phenotype of dilated cardiomyopathy (DCM) at presentation, resulting in 22 patients without DCM (myocarditis without phenotype of DCM) and 20 patients with DCM (myocarditis with phenotype of DCM). RESULTS: Myocarditis with phenotype of DCM patients (median age 1.4 years) were younger than myocarditis without phenotype of DCM patients (median age 16.1 years; P<0.001) and were corresponding to heart failure-like and coronary syndrome-like phenotypes, respectively. At least one likely pathogenic/pathogenic variant was identified in 9 out of 42 patients (22%), 8 of them were heterozygous, and 7 out of 9 were in myocarditis with phenotype of DCM. Likely pathogenic/pathogenic variants were found in genes validated for primary DCM (BAG3, DSP, LMNA, MYH7, TNNI3, TNNT2, and TTN). Rare variant enrichment analysis revealed significant accumulation of high-impact disease variants in myocarditis with phenotype of DCM versus healthy individuals (P=0.0003). Event-free survival was lower (P=0.008) in myocarditis with phenotype of DCM patients compared with myocarditis without phenotype of DCM and primary DCM. CONCLUSIONS: We report heterozygous likely pathogenic/pathogenic variants in biopsy-proven pediatric myocarditis. Myocarditis patients with DCM phenotype were characterized by early-onset heart failure, significant enrichment of likely pathogenic/pathogenic variants, and poor outcome. These phenotype-specific and age group-specific findings will be useful for personalized management of these patients. Genetic evaluation in children newly diagnosed with myocarditis and DCM phenotype is warranted.

An optimized imaging protocol for [99mTc]Tc-DPD scintigraphy and SPECT/CT quantification in cardiac transthyretin (ATTR) amyloidosis.

BACKGROUND: In [99mTc]Tc-DPD scintigraphy for myocardial ATTR amyloidosis, planar images 3 hour p.i. and SPECT/CT acquisition in L-mode are recommended. This study investigated if earlier planar images (1 hour p.i.) are beneficial and if SPECT/CT acquisition should be preferred in H-mode (180° detector angle) or L-mode (90°). METHODS: In SPECT/CT phantom measurements (NaI cameras, N = 2; CZT, N = 1), peak contrast recovery (CRpeak) was derived from sphere inserts or myocardial insert (cardiac phantom; signal-to-background ratio [SBR], 10:1 or 5:1). In 25 positive and 38 negative patients (reference: endomyocardial biopsy or clinical diagnosis), Perugini scores and heart-to-contralateral (H/CL) count ratios were derived from planar images 1 hour and 3 hour p.i. RESULTS: In phantom measurements, accuracy of myocardial CRpeak at SBR 10:1 (H-mode, 0.95-0.99) and reproducibility at 5:1 (H-mode, 1.02-1.14) was comparable for H-mode and L-mode. However, L-mode showed higher variability of background counts and sphere CRpeak throughout the field of view than H-mode. In patients, sensitivity/specificity were ≥ 95% for H/CL ratios at both time points and visual scoring 3 hour. At 1 hour, visual scores showed specificity of 89% and reduced reader's confidence. CONCLUSIONS: Early DPD images provided no additional value for visual scoring or H/CL ratios. In SPECT/CT, H-mode is preferred over L-mode, especially if quantification is applied apart from the myocardium.

Sex-Specific Differences of the Inflammatory State in Experimental Autoimmune Myocarditis.

Increasing evidence suggests male sex as a potential risk factor for a higher incidence of cardiac fibrosis, stronger cardiac inflammation, and dilated cardiomyopathy (DCM) in human myocarditis. Chronic activation of the immune response in myocarditis may trigger autoimmunity. The experimental autoimmune myocarditis (EAM) model has been well established for the study of autoimmune myocarditis, however the role of sex in this pathology has not been fully explored. In this study, we investigated sex differences in the inflammatory response in the EAM model. We analyzed the cardiac function, as well as the inflammatory stage and fibrosis formation in the heart of EAM male and female rats. 21 days after induction of EAM, male EAM rats showed a decreased ejection fraction, stroke volume and cardiac output, while females did not. A significantly elevated number of infiltrates was detected in myocardium in both sexes, indicating the activation of macrophages following EAM induction. The level of anti-inflammatory macrophages (CD68+ ArgI+) was only significantly increased in female hearts. The expression of Col3A1 and fibrosis formation were more prominent in males. Furthermore, prominent pro-inflammatory factors were increased only in male rats. These findings indicate sex-specific alterations in the inflammatory stage of EAM, with a pro-inflammatory phenotype appearing in males and an anti-inflammatory phenotype in females, which both significantly affect cardiac function in autoimmune myocarditis.