Diagnosis and treatment of myocarditis and inflammatory cardiomyopathy. Consensus document of the SEC-Working Group on Myocarditis.

Myocarditis is defined as myocardial inflammation and its etiology is highly diverse, including infectious agents, drugs, and autoimmune diseases. The clinical presentation also varies widely, extending beyond the classic clinical picture of acute chest pain, and includes cases of cardiomyopathy of unknown cause whose etiology may be inflammatory. Because certain patients may benefit from targeted treatments, the search for the etiology should begin when myocarditis is first suspected. There remain several areas of uncertainty in the diagnosis and treatment of this disease. Consequently, this consensus document aims to provide clear recommendations for its diagnosis and treatment. Hence, a diagnostic algorithm is proposed, specifying when a noninvasive diagnosis with cardiac MR is appropriate vs an invasive approach with endomyocardial biopsy. In addition, more novel aspects are discussed, such as when to suspect an underlying genetic etiology. The recommendations cover the management of myocarditis and inflammatory cardiomyopathy, both for general complications and specific clinical entities.

Penetrance of Dilated Cardiomyopathy in Genotype-Positive Relatives.

BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.

Vaccine-carditis study: Spanish multicenter registry of inflammatory heart disease after COVID-19 vaccination.

INTRODUCTION AND OBJECTIVES: Vaccines against SARS-CoV-2 have been a major scientific and medical achievement in the control of the COVID-19 pandemic. However, very infrequent cases of inflammatory heart disease have been described as adverse events, leading to uncertainty in the scientific community and in the general population. METHODS: The Vaccine-Carditis Registry has included all cases of myocarditis and pericarditis diagnosed within 30 days after COVID-19 vaccination since August 1, 2021 in 29 centers throughout the Spanish territory. The definitions of myocarditis (probable or confirmed) and pericarditis followed the consensus of the Centers for Disease Control and the Clinical Practice Guidelines of the European Society of Cardiology. A comprehensive analysis of clinical characteristics and 3-month evolution is presented. RESULTS: From August 1, 2021, to March 10, 2022, 139 cases of myocarditis or pericarditis were recorded (81.3% male, median age 28 years). Most cases were detected in the 1st week after administration of an mRNA vaccine, the majority after the second dose. The most common presentation was mixed inflammatory disease (myocarditis and pericarditis). 11% had left ventricular systolic dysfunction, 4% had right ventricular systolic dysfunction, and 21% had pericardial effusion. In cardiac magnetic resonance studies, left ventricular inferolateral involvement was the most frequent pattern (58%). More than 90% of cases had a benign clinical course. After a 3-month follow-up, the incidence of adverse events was 12.78% (1.44% mortality). CONCLUSIONS: In our setting, inflammatory heart disease after vaccination against SARS-CoV-2 predominantly affects young men in the 1st week after the second dose of RNA-m vaccine and presents a favorable clinical course in most cases.

Impact of a wearable-based physical activity and sleep intervention in multimorbidity patients: protocol for a randomized controlled trial.

BACKGROUND: The benefits of physical activity (PA) and adequate sleep are well documented, and their importance strengthens with the increasing prevalence of chronic diseases and multimorbidity (MM). Interventions to promote physical activity and sleep that use commercial activity trackers may be useful non-pharmacological approaches to managing individual health; however, limited evidence exists on their use to improve physical activity in older adult patients with MM. METHODS: This study aims to measure the effects of behavioral change techniques (BCTs) delivered by a wearable device on physical activity and quality of sleep (QS) in older adult patients with MM. We designed an open-label randomized controlled trial with participants recruited through primary care and a specialist outpatient clinic. Participants must be more than 65 years old, have MM, and have access to smartphones. All eligible participants will receive PA promotion content and will be randomly assigned to wear a smartwatch. The primary outcome will be the participants' PA measurement at baseline and at six months using the International Physical Activity Questionnaire - Short Form (IPAQ-SF). Secondary outcomes will include changes in the participants' frailty status, biometric measurements, quality of life, and biopsychosocial assessments. A sample size of 40 participants per arm was calculated to detect group differences, with 50 participants planned to recruit and randomize into each arm. DISCUSSION: This study aims to contribute to a better understanding of PA patterns and the impact of wearable-based PA interventions in patients with MM. In addition, we aim to contribute to more knowledge about the relationship between PA patterns, Patient Reported Outcomes Measures (PROMs), and healthcare resource utilization in patients with MM. To achieve this, the study will leverage a locally developed PROMs registry and assess data from participants' medical records, in order to understand the added impact of wearable data and medical information data on predicting PROMs and unplanned hospital admissions. TRIAL REGISTRATION: NCT05777291.

Giant ascending aortic aneurysm with impending rupture as presentation of cutis laxa 1B: a case report.

Background: Thoracic aortic aneurysms are rarely symptomatic but can result in acute aortic syndromes, associated with a high mortality rate. While most cases may be acquired, a genetic basis is evident in approximately 20-25% of the cases, especially among patients under 50 years of age, and those exhibiting syndromic features or family history. Although autosomal dominant inheritance is predominant in familial aortopathies, exceptions exist, such as cutis laxa 1B (CL1B)-related aortic disease, caused by variants in EFEMP2 gene, that follows an autosomal recessive inheritance pattern. Case summary: We present the case of a 26-year-old male with a giant ascending aorta aneurysm and massive pericardial effusion, which was ultimately diagnosed of CL1B due to the p.Ser137Cys variant in the EFEMP2 gene in homozygosis. The patient underwent successful ascending aorta replacement (Bentall´s procedure). There were not complications or further events after 2 years of follow-up. Discussion: This case underscores the importance of genetic testing in young patients presenting with aortopathies, syndromic features, or atypical presentations, irrespective of family history.

Late gadolinium enhancement distribution patterns in non-ischaemic dilated cardiomyopathy: genotype-phenotype correlation.

AIMS: Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. METHODS AND RESULTS: Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. CONCLUSION: LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.

Comparison of MRI Features of Fat Fraction and ADC for Early Treatment Response Assessment in Participants with Multiple Myeloma.

Background An imaging-based predictor of response could provide prognostic information early during treatment course in patients with multiple myeloma (MM). Purpose To investigate if very early changes in bone marrow relative fat fraction (rFF) and apparent diffusion coefficient (ADC) histogram metrics, occurring after one cycle of induction therapy in participants with newly diagnosed MM, could help predict overall best response status. Materials and Methods This prospective study included participants with MM who were enrolled between August 2014 and December 2017. Histogram metrics were extracted from ADC and rFF maps from MRI examinations performed before treatment and after the first treatment cycle. Participants were categorized into the very good partial response (VGPR) or better group and the less than VGPR group per the International Myeloma Working Group response criteria. ADC and rFF map metrics for predicting treatment response were compared using the Wilcoxon rank test, and the false discovery rate (FDR) was used to correct for multiple comparisons. Results A total of 23 participants (mean age, 65 years ± 11 [SD]; 13 men) were evaluated. There was no evidence of a difference in ADC metrics between the two responder groups after correcting for multiple comparisons. The rFF histogram changes between pretreatment MRI and MRI after the first treatment cycle (ΔrFF) that provided significant differences between the VGPR or better and less than VGPR groups were as follows: ΔrFF_10th Percentile (median, 0.5 [95% CI: 0, 1] vs -2.5 [95% CI: -5.1, 0.1], respectively), ΔrFF_90th Percentile (median, 2 [95% CI: 1, 6.8] vs -0.5 [95% CI: -1, 0]), ΔrFF_Mean (median, 3.4 [95% CI: 0.3, 7.6] vs -1.1 [95% CI: -1.8, -0.7]), and ΔrFF_Root Mean Squared (median, 3.2 [95% CI: 0.3, 6.1] vs -0.7 [95% CI: -1.3, -0.4]) (FDR-adjusted P = .03 for all), and the latter two also presented mean group increases in the VGPR or better group that were above the upper 95% CI limit for repeatability. Conclusion Very early changes in bone marrow relative fat fraction histogram metrics, calculated from MRI examination at baseline and after only one cycle of induction therapy, may help to predict very good partial response or better in participants with newly diagnosed multiple myeloma. © RSNA, 2022 Online supplemental material is available for this article.

Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant.

INTRODUCTION AND OBJECTIVES: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. METHODS: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. RESULTS: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. CONCLUSIONS: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

Diagnostic and prognostic value of cardiac imaging in amyloidosis.

Amyloidosis is an infiltrative disease caused by extracellular protein deposition that has accumulated a lot of scientific production in recent years. Different types of amyloidosis can affect the heart. Transthyretin amyloidosis and light chain amyloidosis are the two most common types of cardiac amyloidosis. These entities have a poor prognosis, so accurate diagnostic techniques are imperative for determining an early therapeutic approach. Recent advances in cardiac imaging and diagnostic strategies show that these tools are safe and can avoid the use of invasive diagnostic techniques to histological confirmation, such as endomyocardial biopsy. We performed a review on the diagnostic and prognostic implications of different cardiac imaging techniques in cardiac amyloidosis. We mainly focus on reviewing echocardiography, cardiac magnetic resonance, computed tomography and nuclear imaging techniques and the different safety measurements that can be done with each of them.

optoPAD, a closed-loop optogenetics system to study the circuit basis of feeding behaviors.

The regulation of feeding plays a key role in determining the fitness of animals through its impact on nutrition. Elucidating the circuit basis of feeding and related behaviors is an important goal in neuroscience. We recently used a system for closed-loop optogenetic manipulation of neurons contingent on the feeding behavior of Drosophila to dissect the impact of a specific subset of taste neurons on yeast feeding. Here, we describe the development and validation of this system, which we term the optoPAD. We use the optoPAD to induce appetitive and aversive effects on feeding by activating or inhibiting gustatory neurons in closed-loop - effectively creating virtual taste realities. The use of optogenetics allowed us to vary the dynamics and probability of stimulation in single flies and assess the impact on feeding behavior quantitatively and with high throughput. These data demonstrate that the optoPAD is a powerful tool to dissect the circuit basis of feeding behavior, allowing the efficient implementation of sophisticated behavioral paradigms to study the mechanistic basis of animals' adaptation to dynamic environments.

Internal amino acid state modulates yeast taste neurons to support protein homeostasis in Drosophila.

To optimize fitness, animals must dynamically match food choices to their current needs. For drosophilids, yeast fulfills most dietary protein and micronutrient requirements. While several yeast metabolites activate known gustatory receptor neurons (GRNs) in Drosophila melanogaster, the chemosensory channels mediating yeast feeding remain unknown. Here we identify a class of proboscis GRNs required for yeast intake. Within this class, taste peg GRNs are specifically required to sustain yeast feeding. Sensillar GRNs, however, mediate feeding initiation. Furthermore, the response of yeast GRNs, but not sweet GRNs, is enhanced following deprivation from amino acids, providing a potential basis for protein-specific appetite. Although nutritional and reproductive states synergistically increase yeast appetite, reproductive state acts independently of nutritional state, modulating processing downstream of GRNs. Together, these results suggest that different internal states act at distinct levels of a dedicated gustatory circuit to elicit nutrient-specific appetites towards a complex, ecologically relevant protein source.

Trends in referral patterns, invasive management, and mortality in elderly patients referred for exercise stress testing.

INTRODUCTION: Scarce data are available on the temporal patterns in clinical characteristics and outcomes of elderly patients referred for exercise stress testing. We aimed to assess the trends in baseline characteristics, tests results, referrals for invasive management, and mortality in these patients. METHODS: We evaluated 11,192 patients aged ≥65years who were referred for exercise stress testing between January 1998 and December 2013. Calendar years were grouped into four quadrennia (1998-2001, 2002-2005, 2006-2009, and 2010-2013), and trends in clinical characteristics of the patients, type and results of the tests, referrals for invasive management, and mortality across the different periods were assessed. RESULTS: Despite a progressive decrease in the proportion of patients with non-interpretable baseline electrocardiograms or prior history of coronary artery disease, there was a gradual and marked increase in the use of cardiac imaging from 32.8% in 1998-2001 to 67.6% in 2010-2013 (p<0.001). In addition, despite a gradual decline in the probability of positive exercise stress testing both without imaging (from 18.9 to 13.6%, p<0.001) and with imaging assessment (from 40.2 to 29.7%, p<0.001), the cumulative rate of coronary revascularization at 1year increased (from 10.8 to 13.7%, p<0.001). One-year mortality also decreased progressively from 3% to 1.6% (p<0.001). CONCLUSIONS: Among older adults referred for exercise stress testing, we observed a decline over time in the probability of inducible myocardial ischemia, an increase in the use of cardiac imaging and in the rate of coronary revascularization, and an improvement in the survival rate at 1year.

Automated monitoring and quantitative analysis of feeding behaviour in Drosophila.

Food ingestion is one of the defining behaviours of all animals, but its quantification and analysis remain challenging. This is especially the case for feeding behaviour in small, genetically tractable animals such as Drosophila melanogaster. Here, we present a method based on capacitive measurements, which allows the detailed, automated and high-throughput quantification of feeding behaviour. Using this method, we were able to measure the volume ingested in single sips of an individual, and monitor the absorption of food with high temporal resolution. We demonstrate that flies ingest food by rhythmically extending their proboscis with a frequency that is not modulated by the internal state of the animal. Instead, hunger and satiety homeostatically modulate the microstructure of feeding. These results highlight similarities of food intake regulation between insects, rodents, and humans, pointing to a common strategy in how the nervous systems of different animals control food intake.