262 research outputs found
Social determinants of health in the setting of hypertrophic cardiomyopathy.
Social determinants of health play an important role in explaining poor health outcomes across many chronic disease states. The impact of the social gradient in the setting of an inherited heart disease, hypertrophic cardiomyopathy (HCM), has not been investigated. This study sought to profile the socioeconomic status of patients attending a specialized multidisciplinary clinic and to determine the impact on clinical factors, psychosocial wellbeing and adherence to medical advice
Opposing actions of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) in regulating microtubule stabilization during cardiac hypertrophy
Excessive proliferation and stabilization of the microtubule (MT) array in cardiac myocytes can accompany pathological cardiac hypertrophy, but the molecular control of these changes remains poorly characterized. In this study, we examined MT stabilization in two independent murine models of heart failure and revealed increases in the levels of post-translationally modified stable MTs, which were closely associated with STAT3 activation. To explore the molecular signaling events contributing to control of the cardiac MT network, we stimulated cardiac myocytes with an a-adrenergic agonist phenylephrine (PE), and observed increased tubulin content without changes in detyrosinated (glutubulin) stable MT’s. In contrast, the hypertrophic interleukin-6 (IL6) family cytokines increased both the glu-tubulin content and glu-MT density. When we examined a role for ERK in regulating cardiac MTs, we showed that the MEK/ERK-inhibitor U0126 increased glu-MT density in either control cardiac myocytes or following exposure to hypertrophic agents. Conversely, expression of an activated MEK1 mutant reduced glu-tubulin levels. Thus, ERK signaling antagonizes stabilization of the cardiac MT array. In contrast, inhibiting either JAK2 with AG490, or STAT3 signaling with Stattic or siRNA knockdown, blocked cytokine-stimulated increases in glu-MT density. Furthermore, the expression of a constitutively active STAT3 mutant triggered increased glu-MT density in the absence of hypertrophic stimulation. Thus, STAT3 activation contributes substantially to cytokine-stimulated glu-MT changes. Taken together, our results highlight the opposing actions of STAT3 and ERK pathways in the regulation of MT changes associated with cardiac myocyte hypertrophy
Participation in thrill-seeking activities by patients with hypertrophic cardiomyopathy: Individual preferences, adverse events and physician attitude
Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population
Background:
Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in TRDN-encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown.
Methods:
Exome sequencing was performed on 599 sudden infant death syndrome and 258 sudden unexplained death in the young cases. Allele frequencies of all TRDN null variants identified in the cardiac-specific isoform of TRDN in the Genome Aggregation Database were used to determine the estimated prevalence and ethnic distribution of TKOS.
Results:
No triadin null individuals were identified in 599 sudden infant death syndrome and 258 sudden unexplained death in the young exomes. Using the Genome Aggregation Database, we estimate the overall prevalence of TKOS to be ≈1:22.7 million individuals. However, TKOS prevalence is 5.5-fold higher in those of African descent (≈1:4.1 million).
Conclusions:
TKOS is an exceedingly rare clinical entity that does not contribute meaningfully to either sudden infant death syndrome or sudden unexplained death in the young. However, despite its rarity and absence in large sudden death cohorts, TKOS remains a malignant and potentially lethal disorder which requires further research to better care for these patients
Gene variant effects across sodium channelopathies predict function and guide precision therapy
Pathogenic variants in the voltage-gated sodium channel gene family (SCNs) lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function, but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterised in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. 35 out of 38 of those pairs resulted in similar functional consequences indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% CI = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non conserved domains (odds ratio = 18.6; 95% CI = 10.9 to 34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function (LoF) variants, whereas inactivation sites were associated with gain-of-function (GoF; odds ratio = 42.1, 95% CI = 14.5 to 122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first GoF versus LoF topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org)
Clinical Course and Significance of Hypertrophic Cardiomyopathy Without Left Ventricular Hypertrophy
Recommended from our members
Autopsy of all young sudden death cases is important to increase survival in family members left behind.
Sudden cardiac death (SCD) is an important public health problem worldwide, accounting for an estimated 6 to 20% of total mortality. A significant proportion of SCD is caused by inherited heart disease, especially among the young. An autopsy is crucial to establish a diagnosis of inherited heart disease, allowing for subsequent identification of family members who require cardiac evaluation. Autopsy of cases of unexplained sudden death in the young is recommended by both the European Society of Cardiology and the American Heart Association. Overall autopsy rates, however, have been declining in many countries across the globe and there is a lack of skilled trained pathologists able to carry out full autopsies. Recent studies show that not all cases of sudden death in the young are autopsied, likely due to financial, administrative, and organizational limitations as well as awareness among police, legal authorities, and physicians. Consequently, diagnoses of inherited heart disease are likely missed, along with the opportunity for treatment and prevention among surviving relatives. This article reviews the evidence for the role of autopsy in sudden death, how the cardiologist should interpret the autopsy-record and how this can be integrated and implemented in clinical practice. Finally, we identify areas for future research along with potential for healthcare reform aimed at increasing autopsy awareness and ultimately reducing mortality from SCD
Authors’ Response to Peer Reviews of “The Psychological Impact of Hypertension During COVID-19 Restrictions: Retrospective Case-Control Study”
<jats:p /
International Criteria for Reporting Study Quality for Sudden Cardiac Arrest/Death Tool
Background
Studies reporting on the incidence of sudden cardiac arrest and/or death (SCA/D) in athletes commonly lack methodological and reporting rigor, which has implications for screening and preventative policy in sport. To date, there are no tools designed for assessing study quality in studies investigating the incidence of SCA/D in athletes.
Methods and Results
The International Criteria for Reporting Study Quality for Sudden Cardiac Arrest/Death tool (IQ‐SCA/D) was developed following a Delphi process. Sixteen international experts in sports cardiology were identified and invited. Experts voted on each domain with subsequent moderated discussion for successive rounds until consensus was reached for a final tool. Interobserver agreement between a novice, intermediate, and expert observer was then assessed from the scoring of 22 relevant studies using weighted and unweighted κ analyses. The final IQ‐SCA/D tool comprises 8 domains with a summated score of a possible 22. Studies are categorized as low, intermediate, and high quality with summated IQ‐SCA/D scores of ≤11, 12 to 16, and ≥17, respectively. Interrater agreement was “substantial” between all 3 observers for summated IQ‐SCA/D scores and study categorization.
Conclusions
The IQ‐SCA/D is an expert consensus tool for assessing the study quality of research reporting the incidence of SCA/D in athletes. This tool may be used to assist researchers, reviewers, journal editors, and readers in contextualizing the methodological quality of different studies with varying athlete SCA/D incidence estimates. Importantly, the IQ‐SCA/D also provides an expert‐informed framework to support and guide appropriate design and reporting practices in future SCA/D incidence trials
- …