A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers.

BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.

Imaging Features of Arrhythmogenic Cardiomyopathies.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by replacement of ventricular myocardium with fibrofatty tissue, predisposing the patient to ventricular arrhythmias and/or sudden cardiac death. Most cases of ACM are associated with pathogenic variants in genes that encode desmosomal proteins, an important cell-to-cell adhesion complex present in both the heart and skin tissue. Although ACM was first described as a disease predominantly of the right ventricle, it is now acknowledged that it can also primarily involve the left ventricle or both ventricles. The original right-dominant phenotype is traditionally diagnosed using the 2010 task force criteria, a multifactorial algorithm divided into major and minor criteria consisting of structural criteria based on two-dimensional echocardiographic, cardiac MRI, or right ventricular angiographic findings; tissue characterization based on endomyocardial biopsy results; repolarization and depolarization abnormalities based on electrocardiographic findings; arrhythmic features; and family history. Shortfalls in the task force criteria due to the modern understanding of the disease have led to development of the Padua criteria, which include updated criteria for diagnosis of the right-dominant phenotype and new criteria for diagnosis of the left-predominant and biventricular phenotypes. In addition to incorporating cardiac MRI findings of ventricular dilatation, systolic dysfunction, and regional wall motion abnormalities, the new Padua criteria emphasize late gadolinium enhancement at cardiac MRI as a key feature in diagnosis and imaging-based tissue characterization. Conditions to consider in the differential diagnosis of the right-dominant phenotype include various other causes of right ventricular dilatation such as left-to-right shunts and variants of normal right ventricular anatomy that can be misinterpreted as abnormalities. The left-dominant phenotype can mimic myocarditis at imaging and clinical examination. Additional considerations for the differential diagnosis of ACM, particularly for the left-dominant phenotype, include sarcoidosis and dilated cardiomyopathy. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Mutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series. METHODS: Clinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. RESULTS: DSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant). CONCLUSIONS: DSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.

Determining Which Prosthetic to Use During Aortic Valve Replacement in Patients Aged Younger than 70 Years: A Systematic Review of the Literature.

BACKGROUND: The choice of bioprosthesis versus mechanical prosthesis in patients aged less than 70 years undergoing aortic valve replacement (AVR) remains controversial, with guidelines disparate in their recommendations. The objective of this study was to explore outcomes after AVR for various age ranges based on type of prosthesis. METHODS: A systematic review was undertaken according to the Preferred Reporting Instructions for Systematic Reviews and Meta-Analyses (PRISMA) guidelines by using Medline (PubMed), Cochrane, Web of Science, Embase, and Scopus databases. Rates of long-term survival (primary outcome), reoperation, major bleeding, thromboembolism, stroke, structural valve deterioration, and endocarditis were compared between subjects receiving biologic and mechanical prostheses. Findings were grouped into patients aged <60 years, aged ≤65 years, and finally aged <70 years. RESULTS: A total of 19 studies met inclusion criteria. Seven evaluated patients aged <60 years, 4 of which found mechanical prosthesis patients to have higher long-term survival, whereas the remaining studies found no difference. Eight additional studies included patients aged 65 years or younger, and 9 studies included patients aged <70 years. The former found no difference in survival between prosthesis groups, whereas the latter favored mechanical prostheses in 3 studies. Bleeding, thromboembolism, and stroke were more prevalent in patients with a mechanical prosthesis, whereas reoperation was more common in those receiving a bioprosthesis. CONCLUSIONS: Published literature does not preclude the use of bioprostheses for AVR in younger patients. As new valves are developed, the use of bioprosthetic aortic valves in younger patients will likely continue to expand. Clinical trials are needed to provide surgeons with more accurate guidelines.

What Could You Really Learn on Your Own?: Understanding the Epistemic Limitations of Knowledge Acquisition.

Three studies explored the abilities of 205 children (5-11 years) and 74 adults (18-72 years) to distinguish directly versus indirectly acquired information in a scenario where an individual grew up in isolation from human culture. Directly acquired information is knowledge acquired through firsthand experience. Indirectly acquired information is knowledge that requires input from others. All children distinguished directly from indirectly acquired knowledge (Studies 1-3), even when the indirectly acquired knowledge was highly familiar (Study 2). All children also distinguished difficult-to-acquire direct knowledge from simple-to-acquire direct knowledge (Study 3). The major developmental change was the increasing ability to completely rule out indirect knowledge as possible for an isolated individual to acquire.

FICD deficiency protects mice from hypertrophy-induced heart failure via BiP-mediated activation of the UPR ER and ER-phagy.

Cardiomyocytes require the HSP70 chaperone BiP to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase (AMPylase) FICD is increasingly recognized to regulate BiP activity through the post-translational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown. Here, we find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis, and that FICD knockout mice maintain normal cardiac function after cardiac pressure overload. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response (UPR ER ) and impairs BiP interaction with FAM134B, an ER-phagy receptor, thus limiting ER-phagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent UPR ER induction and ER-phagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue. Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.

Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy.

Mutations in cardiac myosin binding protein C (MyBP-C, encoded by MYBPC3) are the most common cause of hypertrophic cardiomyopathy (HCM). Most MYBPC3 mutations result in premature termination codons (PTCs) that cause RNA degradation and a reduction of MyBP-C in HCM patient hearts. However, a reduction in MyBP-C has not been consistently observed in MYBPC3-mutant induced pluripotent stem cell cardiomyocytes (iPSCMs). To determine early MYBPC3 mutation effects, we used patient and genome-engineered iPSCMs. iPSCMs with frameshift mutations were compared with iPSCMs with MYBPC3 promoter and translational start site deletions, revealing that allelic loss of function is the primary inciting consequence of mutations causing PTCs. Despite a reduction in wild-type mRNA in all heterozygous iPSCMs, no reduction in MyBP-C protein was observed, indicating protein-level compensation through what we believe is a previously uncharacterized mechanism. Although homozygous mutant iPSCMs exhibited contractile dysregulation, heterozygous mutant iPSCMs had normal contractile function in the context of compensated MyBP-C levels. Agnostic RNA-Seq analysis revealed differential expression in genes involved in protein folding as the only dysregulated gene set. To determine how MYBPC3-mutant iPSCMs achieve compensated MyBP-C levels, sarcomeric protein synthesis and degradation were measured with stable isotope labeling. Heterozygous mutant iPSCMs showed reduced MyBP-C synthesis rates but a slower rate of MyBP-C degradation. These findings indicate that cardiomyocytes have an innate capacity to attain normal MyBP-C stoichiometry despite MYBPC3 allelic loss of function due to truncating mutations. Modulating MyBP-C degradation to maintain MyBP-C protein levels may be a novel treatment approach upstream of contractile dysfunction for HCM.

Improved electrospray ionization efficiency compensates for diminished chromatographic resolution and enables proteomics analysis of tyrosine signaling in embryonic stem cells.

Characterization of signaling pathways in embryonic stem cells is a prerequisite for future application of these cells to treat human disease and other disorders. Identification of tyrosine signaling cascades is of particular interest but is complicated by the relatively low levels of tyrosine phosphorylation in embryonic stem cells. These hurdles correlate with the primary limitations of mass spectrometry-based proteomics; namely, poor detection limit and dynamic range. To overcome these obstacles, we fabricated miniaturized LC-electrospray assemblies that provided approximately 15-fold improvement in LC-MS performance. Significantly, our characterization data demonstrate that electrospray ionization efficiency compensates for diminished chromatographic performance at effluent flow rates below Van Deemter minima. Use of these assemblies facilitated quantitative proteomics-based analysis of tyrosine signaling cascades in embryonic stem cells. Our results suggest that a renewed focus on miniaturized LC coupled to ultralow flow electrospray will provide a viable path for proteomic analysis of primary cells and rare post-translational modifications.

Exercise hemodynamics in hypertrophic cardiomyopathy identify risk of incident heart failure but not ventricular arrhythmias or sudden cardiac death.

OBJECTIVE: To determine whether abnormal blood pressure response (ABPR), with or without left ventricular outflow tract obstruction (LVOTO), is associated with adverse heart failure and arrhythmia outcomes in hypertrophic cardiomyopathy (HCM). METHODS: A retrospective, single-center analysis was performed for adult HCM patients who underwent exercise stress testing. RESULTS: Of 589 patients included in the study, 192 (33%) demonstrated ABPR. A similar proportion of patients with ABPR had LVOTO compared to those without ABPR (56% vs 63%, p = 0.11). Patients with ABPR demonstrated lower percent predicted VO2 and METs achieved than those with LVOTO (16.9 ±â€¯6.8 vs 21.6 ±â€¯7.9, p = 0.002 and 5.3 ±â€¯2.4 vs 7.4 ±â€¯3.1, p < 0.001). In a subgroup of 17 patients with LVOTO and ABPR who subsequently underwent successful myectomy, 5 (30%) demonstrated persistent ABPR. 23 patients (3.8%) experienced sudden cardiac death or ventricular arrhythmias, which were not associated with ABPR, regardless of age group. In multivariable analysis, syncope (p = 0.04), left ventricular hypertrophy (p = 0.02) and left atrial diameter (p = 0.006) were significantly associated with the composite outcome of sudden death or severe ventricular arrhythmia, whereas ABPR was not (p = 0.38). In contrast, ABPR was associated with subsequent heart failure hospitalization (p = 0.002), regardless of presence or absence of LVOTO (p = 0.04, p = 0.02). CONCLUSIONS: ABPR is associated with reduced functional capacity in HCM regardless of the presence of LVOTO but is not associated with adverse arrhythmia outcomes. Patients with ABPR have a higher incidence of subsequent heart failure hospitalization.

Detecting regular sound changes in linguistics as events of concerted evolution.

BACKGROUND: Concerted evolution is normally used to describe parallel changes at different sites in a genome, but it is also observed in languages where a specific phoneme changes to the same other phoneme in many words in the lexicon­a phenomenon known as regular sound change. We develop a general statistical model that can detect concerted changes in aligned sequence data and apply it to study regular sound changes in the Turkic language family. RESULTS: Linguistic evolution, unlike the genetic substitutional process, is dominated by events of concerted evolutionary change. Our model identified more than 70 historical events of regular sound change that occurred throughout the evolution of the Turkic language family, while simultaneously inferring a dated phylogenetic tree. Including regular sound changes yielded an approximately 4-fold improvement in the characterization of linguistic change over a simpler model of sporadic change, improved phylogenetic inference, and returned more reliable and plausible dates for events on the phylogenies. The historical timings of the concerted changes closely follow a Poisson process model, and the sound transition networks derived from our model mirror linguistic expectations. CONCLUSIONS: We demonstrate that a model with no prior knowledge of complex concerted or regular changes can nevertheless infer the historical timings and genealogical placements of events of concerted change from the signals left in contemporary data. Our model can be applied wherever discrete elements­such as genes, words, cultural trends, technologies, or morphological traits­can change in parallel within an organism or other evolving group.

Further examination of the immediate impact of television on children's executive function.

Three studies examined the short-term impact of television (TV) on children's executive function (EF). Study 1 (N = 160) showed that 4- and 6-year-olds' EF is impaired after watching 2 different fast and fantastical shows, relative to that of children who watched a slow, realistic show or played. In Study 2 (N = 60), 4-year-olds' EF was as depleted after watching a fast and fantastical educational show as it was after a fast and fantastical entertainment 1, relative to that of children who read a book based on the educational show. Study 3 (N = 80) examined whether show pacing or fantasy was more influential, and found that only fantastical shows, regardless of their pacing, disrupted 4-year-olds' EF. Taken together, these studies show that 10-20 min watching televised fantastical events, relative to other experiences, results in lower EF in young children.

Deletions of the PRKAR1A locus at 17q24.2-q24.3 in Carney complex: genotype-phenotype correlations and implications for genetic testing.

BACKGROUND: Carney complex (CNC) is a multiple neoplasia syndrome caused by PRKAR1A-inactivating mutations. One-third of the patients, however, have no detectable PRKAR1A coding sequence defects. Small deletions of the gene were previously reported in few patients, but large deletions of the chromosomal PRKAR1A locus have not been studied systematically in a large cohort of patients with CNC. SETTING: A tertiary care referral center was the setting for analysis of an international cohort of patients with CNC. METHODS: Methods included genome-wide array analysis followed by fluorescent in situ hybridization, mRNA, and other studies as well as a retrospective analysis of clinical information and phenotype-genotype correlation. RESULTS: We detected 17q24.2-q24.3 deletions of varying size that included the PRKAR1A gene in 11 CNC patients (of 51 tested). Quantitative PCR showed that these patients had significantly lower PRKAR1A mRNA levels. Phenotype varied but was generally severe and included manifestations that are not commonly associated with CNC, presumably due to haploinsufficiency of other genes in addition to PRKAR1A. CONCLUSIONS: A significant number (21.6%) of patients with CNC that are negative in currently available testing may have PRKAR1A haploinsufficiency due to genomic defects that are not detected by Sanger sequencing. Array-based studies are necessary for diagnostic confirmation of these defects and should be done in patients with unusual and severe phenotypes who are PRKAR1A mutation-negative.

Cortical mechanisms of pretense observation.

Pretend play emerges in children the world over around 18 months and continues into adolescence and even adulthood. Observing and engaging in pretense are thought to rely on similar neural mechanisms, but little is known about them. Here we examined neural activation patterns associated with observing pretense acts, including high-likelihood, low-likelihood, and imaginary substitute objects, as compared with activation patterns when observing parallel real acts. The association between fantasy predisposition and cortical representations of pretense was also explored. Supporting prior research that used more limited types of pretense, observed pretense acts, when contrasted with real acts, elicited activity in regions associated with mentalizing. A novel contribution here is that substitute object pretense (high- and low-likelihood) elicited significantly more activity than imaginary (pantomime) acts not only in theory of mind regions but also in the superior parietal lobule, a region thought to aid in the prediction and error-monitoring of motor actions. Finally, when high-likelihood pretense acts were contrasted with real acts, participants with elevated fantasy predispositions evidenced significantly different activation patterns than their more reality-prone peers. Future research will explore the intersection of fantasy predisposition and experience with the neural representation of pretense.

Concepts and theories, methods and reasons: Why do the children (pretend) play? Reply to Weisberg, Hirsh-Pasek, and Golinkoff (2013); Bergen (2013); and Walker and Gopnik (2013).

We greatly appreciate the astute comments on Lillard et al. (2013) and the opportunity to reply. Here we point out the importance of keeping conceptual distinctions clear regarding play, pretend play, and exploration. We also discuss methodological issues with play research. We end with speculation that if pretend play did not emerge because it was naturally selected (due to helping causal reasoning or some other developmentally important skill), perhaps it emerged as a by-product of 2 other selected behaviors: play fighting and language.

The impact of pretend play on children's development: a review of the evidence.

Pretend play has been claimed to be crucial to children's healthy development. Here we examine evidence for this position versus 2 alternatives: Pretend play is 1 of many routes to positive developments (equifinality), and pretend play is an epiphenomenon of other factors that drive development. Evidence from several domains is considered. For language, narrative, and emotion regulation, the research conducted to date is consistent with all 3 positions but insufficient to draw conclusions. For executive function and social skills, existing research leans against the crucial causal position but is insufficient to differentiate the other 2. For reasoning, equifinality is definitely supported, ruling out a crucially causal position but still leaving open the possibility that pretend play is epiphenomenal. For problem solving, there is no compelling evidence that pretend play helps or is even a correlate. For creativity, intelligence, conservation, and theory of mind, inconsistent correlational results from sound studies and nonreplication with masked experimenters are problematic for a causal position, and some good studies favor an epiphenomenon position in which child, adult, and environment characteristics that go along with play are the true causal agents. We end by considering epiphenomenalism more deeply and discussing implications for preschool settings and further research in this domain. Our take-away message is that existing evidence does not support strong causal claims about the unique importance of pretend play for development and that much more and better research is essential for clarifying its possible role.

Shoulder imaging in athletes.

Shoulder pain and injuries are common in athletes. Overhead athletes, in particular, place great demands on the shoulder and supporting structures. Magnetic resonance (MR) imaging is well suited to evaluation of the osseous structures and soft tissues of the shoulder and plays an important role in evaluation of shoulder pain in athletes. Primary extrinsic impingement is well evaluated on MR imaging as are the less common posterior superior glenoid impingement and subcoracoid impingement. Rotator cuff tendinosis as well as partial- and full-thickness tears are frequently encountered in the athletic shoulder. The biceps tendon and rotator interval capsular structures are important sources of shoulder pain. Glenohumeral instability that results from a traumatic event or atraumatic multidirectional recurrent instability is assessed. The biceps labral complex is a source of considerable anatomic variability and pathology.