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Journal of the American College of... Feb 2022Hypertrophic cardiomyopathy (HCM) is a relatively common often inherited global heart disease, with complex phenotypic and genetic expression and natural history,...
Hypertrophic cardiomyopathy (HCM) is a relatively common often inherited global heart disease, with complex phenotypic and genetic expression and natural history, affecting both genders and many races and cultures. Prevalence is 1:200-1:500, largely based on the disease phenotype with imaging, inferring that 750,000 Americans may be affected by HCM. However, cross-sectional data show that only a fraction are clinically diagnosed, suggesting under-recognition, with most clinicians exposed to small segments of the broad disease spectrum. Highly effective HCM management strategies have emerged, altering clinical course and substantially lowering mortality and morbidity rates. These advances underscore the importance of reliable HCM diagnosis with echocardiography and cardiac magnetic resonance. Family screening with noninvasive imaging will identify relatives with the HCM phenotype, while genetic analysis recognizes preclinical sarcomere gene carriers without left ventricular hypertrophy, but with the potential to transmit disease. Comprehensive initial patient evaluations are important for reliable diagnosis, accurate portrayal of HCM and family history, risk stratification, and distinguishing obstructive versus nonobstructive forms.
Topics: Cardiac Imaging Techniques; Cardiomyopathy, Hypertrophic; Humans
PubMed: 35086660
DOI: 10.1016/j.jacc.2021.12.002 -
Circulation Jan 2024Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted.
METHODS
A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up.
RESULTS
In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for (myosin light chain 3) to ≈55% for (myosin-binding protein C3), ≈60% for (troponin T2) and (troponin I3), and ≈65% for (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for and ≈23% for .
CONCLUSIONS
The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.
Topics: Humans; Adult; Penetrance; Mutation; Cross-Sectional Studies; Pedigree; Cardiomyopathy, Hypertrophic; Troponin T
PubMed: 37929589
DOI: 10.1161/CIRCULATIONAHA.123.065987 -
Journal of Biomechanics Dec 2021Understanding passive skeletal muscle mechanics is critical in defining structure-function relationships in skeletal muscle and ultimately understanding pathologically... (Review)
Review
Understanding passive skeletal muscle mechanics is critical in defining structure-function relationships in skeletal muscle and ultimately understanding pathologically impaired muscle. In this systematic review, we performed an exhaustive literature search using PRISMA guidelines to quantify passive muscle mechanical properties, summarized the methods used to create these data, and make recommendations to standardize future studies. We screened over 7500 papers and found 80 papers that met the inclusion criteria. These papers reported passive muscle mechanics from single muscle fiber to whole muscle across 16 species and 54 distinct muscles. We found a wide range of methodological differences in sample selection, preparation, testing, and analysis. The systematic review revealed that passive muscle mechanics is species and scale dependent-specifically within mammals, the passive mechanics increases non-linearly with scale. However, a detailed understanding of passive mechanics is still unclear because the varied methodologies impede comparisons across studies, scales, species, and muscles. Therefore, we recommend the following: smaller scales may be maintained within storage solution prior to testing, when samples are tested statically use 2-3 min of relaxation time, stress normalization at the whole muscle level be to physiologic cross-sectional area, strain normalization be to sarcomere length when possible, and an exponential equation be used to fit the data. Additional studies using these recommendations will allow exploration of the multiscale relationship of passive force within and across species to provide the fundamental knowledge needed to improve our understanding of passive muscle mechanics.
Topics: Animals; Muscle Fibers, Skeletal; Muscle, Skeletal; Sarcomeres
PubMed: 34736082
DOI: 10.1016/j.jbiomech.2021.110839 -
Journal of Cardiovascular Development... Apr 2022Traditional definitions of Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), two rare congenital heart defects (CHDs), confine disease to either the... (Review)
Review
Traditional definitions of Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), two rare congenital heart defects (CHDs), confine disease to either the right or left heart, respectively. Around 15-29% of patients with EA, which has a prevalence of 1 in 20,000 live births, commonly manifest with LVNC. While individual EA or LVNC literature is extensive, relatively little discussion is devoted to the joint appearance of EA and LVNC (EA/LVNC), which poses a higher risk of poor clinical outcomes. We queried PubMed, Medline, and Web of Science for all peer-reviewed publications from inception to February 2022 that discuss EA/LVNC and found 58 unique articles written in English. Here, we summarize and extrapolate commonalities in clinical and genetic understanding of EA/LVNC to date. We additionally postulate involvement of shared developmental pathways that may lead to this combined disease. Anatomical variation in EA/LVNC encompasses characteristics of both CHDs, including tricuspid valve displacement, right heart dilatation, and left ventricular trabeculation, and dictates clinical presentation in both age and severity. Disease treatment is non-specific, ranging from symptomatic management to invasive surgery. Apart from a few variant associations, mainly in sarcomeric genes and , the genetic etiology and pathogenesis of EA/LVNC remain largely unknown.
PubMed: 35448091
DOI: 10.3390/jcdd9040115 -
Journal of Child Neurology Jun 2022Nemaline myopathy is a skeletal muscle disease that affects 1 in 50 000 live births. The objective of this study was to develop a narrative synthesis of the findings of...
Nemaline myopathy is a skeletal muscle disease that affects 1 in 50 000 live births. The objective of this study was to develop a narrative synthesis of the findings of a systematic review of the latest case descriptions of patients with NM. A systematic search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using the keywords , , , , and . Case studies focused on pediatric NM and published in English between January 1, 2010, and December 31, 2020, in order to represent the most recent findings. Information was collected about the age of first signs, earliest presenting neuromuscular signs and symptoms, systems affected, progression, death, pathologic description, and genetic changes. Of a total of 385 records, 55 case reports or series were reviewed, covering 101 pediatric patients from 23 countries. We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with NM. This review synthesizes genetic, histopathologic, and disease presentation findings from pediatric NM case reports. These data strengthen our understanding of the wide spectrum of disease seen in NM. Future studies are needed to identify the underlying molecular mechanism of pathology, to improve diagnostics, and to develop better methods to improve the quality of life for these patients.
Topics: Child; Humans; Myopathies, Nemaline; Muscle, Skeletal; Quality of Life; Muscular Diseases; Mutation
PubMed: 36960434
DOI: 10.1177/08830738221096316 -
Open Heart Apr 2022This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives.
METHODS
A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool.
RESULTS
A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), versus cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003).
CONCLUSIONS
This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study.
Topics: Cardiomyopathy, Hypertrophic; Child; Genetic Association Studies; Genetic Testing; Genotype; Humans; Penetrance
PubMed: 35387861
DOI: 10.1136/openhrt-2021-001815 -
Journal of the American Heart... Dec 2019Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to... (Comparative Study)
Comparative Study
Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to heart failure with major adverse cardiac events (MACE). Methods and Results To investigate genotype-phenotype correlations, the genotypes and clinical features of genetic NCCM patients were collected from the literature. We compared age at diagnosis, cardiac features and risk for MACE according to mode of inheritance and molecular effects for defects in the most common sarcomere genes and NCCM subtypes. Geno- and phenotypes of 561 NCCM patients from 172 studies showed increased risk in children for congenital heart defects (<0.001) and MACE (<0.001). In adult NCCM patients the main causes were single missense mutations in sarcomere genes. Children more frequently had an X-linked or mitochondrial inherited defect (=0.001) or chromosomal anomalies (<0.001). was involved in 48% of the sarcomere gene mutations. and mutations had lower risk for MACE than and (=0.001). The NCCM/dilated cardiomyopathy cardiac phenotype was the most frequent subtype (56%; =0.022) and was associated with an increased risk for MACE and high risk for left ventricular systolic dysfunction (<0.001). In multivariate binary logistic regression analysis , arrhythmia -, non-sarcomere non-arrhythmia cardiomyopathy-and X-linked genes were genetic predictors for MACE. Conclusions Sarcomere gene mutations were the most common cause in adult patients with lower risk of MACE. Children had multi-systemic disorders with severe outcome, suggesting that the diagnostic and clinical approaches should be adjusted to age at presentation. The observed genotype-phenotype correlations endorsed that DNA diagnostics for NCCM is important for clinical management and counseling of patients.
Topics: Adolescent; Adult; Age Factors; Cardiomyopathies; Child; Child, Preschool; Female; Genetic Association Studies; Heart Diseases; Humans; Infant; Male; Risk Assessment; Sarcomeres; Young Adult
PubMed: 31771441
DOI: 10.1161/JAHA.119.012993 -
Frontiers in Cardiovascular Medicine 2022The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic...
The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic dysfunction led to new concepts regarding how levels of oxidative stress affect the heartbeat. Major sarcomere proteins for which there is evidence of S-glutathionylation include cardiac myosin binding protein C (cMyBP-C), actin, cardiac troponin I (cTnI) and titin. Our hypothesis is that these S-glutathionylated proteins are significant factors in acquired and familial disorders of the heart; and, when released into the serum, provide novel biomarkers. We consider the molecular mechanisms for these effects in the context of recent revelations of how these proteins control cardiac dynamics in close collaboration with Ca fluxes. These revelations were made using powerful approaches and technologies that were focused on thin filaments, thick filaments, and titin filaments. Here we integrate their regulatory processes in the sarcomere as modulated mainly by neuro-humoral control of phosphorylation inasmuch evidence indicates that S-glutathionylation and protein phosphorylation, promoting increased dynamics and modifying the Frank-Starling relation, may be mutually exclusive. Earlier studies demonstrated that in addition to cTnI as a well-established biomarker for cardiac disorders, serum levels of cMyBP-C are also a biomarker for cardiac disorders. We describe recent studies approaching the question of whether serum levels of S-glutathionylated-cMyBP-C could be employed as an important clinical tool in patient stratification, early diagnosis in at risk patients before HFpEF, determination of progression, effectiveness of therapeutic approaches, and as a guide in developing future therapies.
PubMed: 36762302
DOI: 10.3389/fcvm.2022.1060716 -
Journal of B.U.ON. : Official Journal... 2018The purpose of this study was to systematically review the literature of esophageal carcinosarcomas (ECS) and report epidemiologic and clinicopathologic data for this...
PURPOSE
The purpose of this study was to systematically review the literature of esophageal carcinosarcomas (ECS) and report epidemiologic and clinicopathologic data for this rare entity. We also attempted to shed light to the biologic behavior of ECSs with special reference to factors that may affect disease-free (DES) and overall survival (OS).
METHODS
A systematic literature review was performed using MEDLINE, EMBASE and the Cochrane Library databases (Search date: 12 May 2017). The search strategy referred to carcinosarcoma OR pseudosarcoma OR polypoid carcinoma OR sarcomatoid carcinoma OR spindle-cell squamous cell carcinoma OR metaplastic carcinoma OR pseudosarcomatous carcinoma AND esophagus. A total number of 103 ECS patients was identified. Results: ECs most frequently occur in middle-aged as well as elderly men with a history of smoking or drinking. Middle and/or lower esophagus remains the most common location. Imaging plays a pivotal role in the management of ECS by delineating the anatomic extent of the tumor and thereby determining the appropriate therapeutic strategy. Nevertheless, immunohistochemistry is the gold standard for the diagnosis of carcinosarcomas, since it has been demonstrated that CEA, EMA, pancreatin, chromogranin A, CD56 and synaptophysin staining are highly specific markers for the carcinomatous components, while desmin, vimentin and smooth muscle/sarcomeric actin show affinity for the sarcomatous elements. Esophagectomy has been traditionally considered the treatment modality of choice. Endoscopic procedures, including mucosal resection and submucosal dissection have also been proposed. Alternative therapies, such as radio- and chemotherapy proved insufficient.
CONCLUSION
ECS is a rare tumor. Immunohistochemistry is the gold standard for the diagnosis of this disease. Esophagectomy has been traditionally considered the treatment modality of choice. Endoscopic procedures have also been proposed while potential benefit of alternative therapies, such as radiotherapy and chemotherapy remains controversial.
Topics: Carcinosarcoma; Esophageal Neoplasms; Female; Humans; Immunohistochemistry; Male
PubMed: 30570870
DOI: No ID Found -
Pflugers Archiv : European Journal of... May 2019Human-induced pluripotent stem cells (hiPSC) can be differentiated to cardiomyocytes at high efficiency and are increasingly used to study cardiac disease in a human...
Human-induced pluripotent stem cells (hiPSC) can be differentiated to cardiomyocytes at high efficiency and are increasingly used to study cardiac disease in a human context. This review evaluated 38 studies on hypertrophic (HCM) and dilated cardiomyopathy (DCM) of different genetic causes asking to which extent published data allow the definition of an in vitro HCM/DCM hiPSC-CM phenotype. The data are put in context with the prevailing hypotheses on HCM/DCM dysfunction and pathophysiology. Relatively consistent findings in HCM not reported in DCM were larger cell size (156 ± 85%, n = 15), more nuclear localization of nuclear factor of activated T cells (NFAT; 175 ± 65%, n = 3), and higher β-myosin heavy chain gene expression levels (500 ± 547%, n = 8) than respective controls. Conversely, DCM lines showed consistently less force development than controls (47 ± 23%, n = 9), while HCM forces scattered without clear trend. Both HCM and DCM lines often showed sarcomere disorganization, higher NPPA/NPPB expression levels, and arrhythmic beating behaviour. The data have to be taken with the caveat that reporting frequencies of the various parameters (e.g. cell size, NFAT expression) differ widely between HCM and DCM lines, in which data scatter is large and that only 9/38 studies used isogenic controls. Taken together, the current data provide interesting suggestions for disease-specific phenotypes in HCM/DCM hiPSC-CM but indicate that the field is still in its early days. Systematic, quantitative comparisons and robust, high content assays are warranted to advance the field.
Topics: Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Cell Differentiation; Humans; Induced Pluripotent Stem Cells; Mutation; Myocardial Contraction; Myocytes, Cardiac; Phenotype
PubMed: 30324321
DOI: 10.1007/s00424-018-2214-0