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2.
Artigo em Inglês | MEDLINE | ID: mdl-33566628

RESUMO

Background - Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibro-fatty replacement of the right and/or left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants, in the non-desmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. Methods - A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was assessed. Results - Genetic screening of CDH2 led to the identification of 7 rare variants: five, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and/or sudden cardiac death occurred in 5/9 (56%). Conclusions - In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

3.
Int J Cardiol ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33581180

RESUMO

BACKGROUND: This sub-study of the Australian Genomics Cardiovascular Genetic Disorders Flagship sought to conduct the first nation-wide audit in Australia to establish the current practices across cardiac genetics clinics. METHOD: An audit of records of patients with a suspected genetic heart disease (cardiomyopathy, primary arrhythmia, autosomal dominant congenital heart disease) who had a cardiac genetics consultation between 1st January 2016 and 31 July 2018 and were offered a diagnostic genetic test. RESULTS: This audit included 536 records at multidisciplinary cardiac genetics clinics from 11 public tertiary hospitals across five Australian states. Most genetic consultations occurred in a clinic setting (90%), followed by inpatient (6%) and Telehealth (4%). Queensland had the highest proportion of Telehealth consultations (9% of state total). Sixty-six percent of patients had a clinical diagnosis of a cardiomyopathy, 28% a primary arrhythmia, and 0.7% congenital heart disease. The reason for diagnosis was most commonly as a result of investigations of symptoms (73%). Most patients were referred by a cardiologist (85%), followed by a general practitioner (9%) and most genetic tests were funded by the state Genetic Health Service (73%). Nationally, 29% of genetic tests identified a pathogenic or likely pathogenic gene variant; 32% of cardiomyopathies, 26% of primary arrhythmia syndromes, and 25% of congenital heart disease. CONCLUSION: We provide important information describing the current models of care for genetic heart diseases throughout Australia. These baseline data will inform the implementation and impact of whole genome sequencing in the Australian healthcare landscape.

4.
Forensic Sci Med Pathol ; 17(1): 10-18, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33464532

RESUMO

Conventional autopsy is the gold standard for identifying unexplained death but due to declines in referrals, there is an emerging role for post-mortem imaging. We evaluated whether post-mortem magnetic resonance (PMMR) and computed tomography (PMCT) are inferior to conventional autopsy. Deceased individuals ≥ 2 years old with unexplained death referred for coronial investigation between October 2014 to December 2016 underwent PMCT and PMMR prior to conventional autopsy. Images were reported separately and then compared to the autopsy findings by independent and blinded investigators. Outcomes included the accuracy of imaging modalities to identify an organ system cause of death and other significant abnormalities. Sixty-nine individuals underwent post-mortem scanning and autopsy (50 males; 73%) with a median age of 61 years (IQR 50-73) and median time from death to imaging of 2 days (IQR 2-3). With autopsy, 48 (70%) had an organ system cause of death and were included in assessing primary outcome while the remaining 21 (30%) were only included in assessing secondary outcome; 12 (17%) had a non-structural cause and 9 (13%) had no identifiable cause. PMMR and PMCT identified the cause of death in 58% (28/48) of cases; 50% (24/48) for PMMR and 35% (17/48) for PMCT. The sensitivity and specificity were 57% and 57% for PMMR and 38% and 73% for PMCT. Both PMMR and PMCT identified 61% (57/94) of other significant abnormalities. Post-mortem imaging is inferior to autopsy but when reported by experienced clinicians, PMMR provides important information for cardiac and neurological deaths while PMCT is beneficial for neurological, traumatic and gastrointestinal deaths.

5.
Int J Cardiol ; 328: 235-240, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309759

RESUMO

BACKGROUND: Left ventricular non-compaction (LVNC) is a complex clinical condition with several diagnostic criteria but no diagnostic gold standard. We aimed to evaluate our thresholding technique in a group of patients with LVNC and assess the risk of major adverse cardiovascular and cerebrovascular events (MACCE). METHODS: We retrospectively analyzed cardiac magnetic resonance (CMR) scans of patients with Petersen criteria LVNC and quantified noncompacted myocardial mass. We assessed the association of noncompacted myocardial mass, CMR derived LV volumetric parameters and late gadolinium enhancement (LGE) to MACCE including cardiac death, cardiac transplantation, sustained ventricular tachycardia/ventricular fibrillation (VT/VF) and ischemic stroke. Patients with known genetic mutations and cardiovascular disease were excluded. RESULTS: 98 patients with LVNC were included (55 males,56.7%); 17(17.3%) patients had impaired LV function and five (5.1%) had LGE. Patients with impaired LV function had more end-systolic noncompacted mass (61.9 g±22.4 vs. 38.1 g±15.8, p < 0.001) and larger end-systolic noncompacted to total myocardial mass (44%±9 vs. 36%±12, p = 0.003). At 78 months follow-up [interquartile range(IQR) 66-90], MACCE occurred in 11(11.3%) patients; nine(81.8%) had impaired LV function and two(18.2%) had LGE. Impaired LV function and LV LGE were predictors of MACCE (HR = 35.6, 95% CI = 7.65-165.21, p < 0.001 and HR = 16.2, 95% CI = 4.54-57.84, p < 0.001) whereas noncompacted mass were not. CONCLUSION: Noncompacted mass was not an independent predictor of major adverse events but in patients with impaired LV function and/or LV LGE, the risk of MACCE was high. These results highlight the importance of including LV volumetrics and scar in the assessment of patients with LV noncompaction.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33284039

RESUMO

Background - The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts. Methods - Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed. Results - Of 5,873 patients (3,788 genotyped), 2,226 (37.9%) were women. At baseline, women were older (49.0±19.9 vs. 42.9±18.4 years, p<0.001) and more likely to have pathogenic/likely-pathogenic sarcomeric variants (SARC+; 51% vs 43%, p<0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (p<0.02) except for patients with MYH7 variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 vs 33.3±16.8 years, p=0.39). Over 7.7 median years of follow up, NYHA III-IV heart failure (HF) was more common in women (HR 1.87, CI 1.48-2.36, p<0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, SARC+, age and hypertension. All-cause mortality was increased in women (HR 1.50, CI 1.13-1.99, p<0.01), but neither ICD utilization nor ventricular arrhythmia varied by sex. Conclusions - In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe HF symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.

7.
Medicina (Kaunas) ; 56(12)2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33327510

RESUMO

Left ventricular non-compaction (LVNC) is a complex clinical condition with no diagnostic gold standard. At present, there is trepidation about the accuracy of the diagnosis, the correlation to clinical outcomes and the long-term medical management. This article reviews the current imaging criteria, the limitations of echocardiography and cardiac magnetic resonance and the consequences of LV hypertrabeculation in athletes.

8.
J Am Coll Cardiol ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33229115

RESUMO

AIM: This executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in adult and pediatric patients as well as supporting documentation to encourage their use. METHODS: A comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. STRUCTURE: Many recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.

11.
Heart Lung Circ ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33199184

RESUMO

In 2019, the first multi-source registry of sudden cardiac arrest and death for patients aged 1-50 years launched in Victoria, Australia. Sudden cardiac arrest (SCA) affects approximately fifteen hundred younger Victorians per year. The End Unexplained Cardiac Death (EndUCD) Registry enrols SCA/D cases aged 1-50 years, providing family screening, access to psychological support through clinical sites and creating a genetic biorepository for whole-genome sequencing. The registry will support clear pathways of cardiac assessment, epidemiological profiling and routine family screening and psychological support.

13.
Circulation ; : CIR0000000000000938, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33215938

RESUMO

Aim This executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in adult and pediatric patients as well as supporting documentation to encourage their use. Methods A comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Structure Many recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.

14.
Heart Rhythm ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33091602

RESUMO

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

15.
Hum Genome Var ; 7: 33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33082984

RESUMO

The genetic etiology and heritability of left ventricular noncompaction (LVNC) in adults is unclear. This study sought to assess the value of genetic testing in adults with LVNC. Adults diagnosed with LVNC while undergoing screening in the context of a family history of cardiomyopathy were excluded. Clinical data for 35 unrelated patients diagnosed with LVNC at ≥18 years of age were retrospectively analyzed. Left ventricular (LV) dysfunction, electrocardiogram (ECG) abnormalities, cardiac malformations or syndromic features were identified in 25 patients; 10 patients had isolated LVNC in the absence of cardiac dysfunction or syndromic features. Exome sequencing was performed, and analysis using commercial panels targeted 193 nuclear and mitochondrial genes. Nucleotide variants in coding regions or in intron-exon boundaries with predicted impacts on splicing were assessed. Fifty-four rare variants were identified in 35 nuclear genes. Across all 35 LVNC patients, the clinically meaningful genetic diagnostic yield was 9% (3/35), with heterozygous likely pathogenic or pathogenic variants identified in the NKX2-5 and TBX5 genes encoding cardiac transcription factors. No pathogenic variants were identified in patients with isolated LVNC in the absence of cardiac dysfunction or syndromic features. In conclusion, the diagnostic yield of genetic testing in adult index patients with LVNC is low. Genetic testing is most beneficial in LVNC associated with other cardiac and syndromic features, in which it can facilitate correct diagnoses, and least useful in adults with only isolated LVNC without a family history. Cardiac transcription factors are important in the development of LVNC and should be included in genetic testing panels.

17.
Front Neurol ; 11: 925, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013630

RESUMO

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of premature mortality in individuals with epilepsy. Acute and adaptive changes in heart rhythm in epilepsy implicate cardiac dysfunction as a potential pathogenic mechanism in SUDEP. Furthermore, variants in genes associated with Long QT syndrome (LQTS) have been identified in patients with SUDEP. LQTS is a cardiac arrhythmia condition that causes sudden cardiac death with strong similarities to SUDEP. Here, we discuss the possibility of an additive risk of death due to the functional consequences of a pathogenic variant in an LQTS gene interacting with seizure-mediated changes in cardiac function. Extending this general concept, we propose a hypothesis that common variants in LQTS genes, which cause a subtle impact on channel function and would not normally be considered risk factors for cardiac disease, may increase the risk of sudden death when combined with epilepsy. A greater understanding of the interaction between epilepsy, cardiac arrhythmia, and SUDEP will inform our understanding of SUDEP risk and subsequent potential prophylactic treatment.

19.
Clin Res Cardiol ; 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32880676

RESUMO

BACKGROUND: Atrial fibrillation (AF) is an important arrhythmia in hypertrophic cardiomyopathy (HCM). OBJECTIVES: To conduct a systematic review of published literature to: (a) assess the incidence of AF in HCM and (b) examine the impact of AF on risk of thromboembolism, heart failure, sudden death and mortality in HCM. METHODS: Search of all major databases (Pubmed, MEDLINE, Embase, Cochrane, Scopus, Web of Science) was performed to April 2020 using the search terms "atrial fibrillation" AND/OR "hypertrophic cardiomyopathy" in the title or abstract. 51 of the 1,565 citations met the inclusion criteria. RESULTS: Using random-effects modelling, the estimated pooled prevalence of AF amongst 21,887 HCM patients (36 studies) was 22.3% (95%, 19.9-24.8) and the pooled incidence of AF was 2.5 cases per person-years (95% CI 1.9-3.0). 15,444 patients from 28 studies were included in analysis of outcome data (mean age was 49.9 years; 32.7% female; mean LVEF 69%). Over a median follow up duration of 6.9 years (range 2.8-11.7 years), AF, compared to sinus rhythm (SR), was associated with significantly increased risk of thromboembolism [relative risk (RR) 7.0; 95% CI 4.6-10.7; I2 = 57%], heart failure (RR 2.8; 95% CI 1.6-4.6; I2 = 82%), sudden death (RR 1.7; 95% CI 1.3-2.3; I2 = 0%), and all-cause mortality (RR 2.5; 95% CI 1.8-3.4; I2 = 69%). CONCLUSIONS: AF is highly prevalent in patients with HCM. The presence of AF is associated with major adverse clinical outcomes. These findings suggest that both, aggressive screening and treatment of AF, are likely to have major prognostic impact on outcomes in HCM. Incidence, prevalence and prognostic impact of AF in HCM. In this systematic review, AF incidence was 2.5 cases per-person years, prevalence was 22.3%. AF in HCM was associated with a seven-fold increased risk of thromboembolism, 2.8-fold increased risk of heart failure, 1.7-fold increased risk of sudden death and 2.5-fold increased risk of all-cause mortality.

20.
Circ Genom Precis Med ; 13(5): 453-459, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32894683

RESUMO

BACKGROUND: Missense variants in the MYH7-encoded MYH7 (beta myosin heavy chain 7) represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7-specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently but have yet to be assessed independently. We set out to assess the performance of the MYH7-specific ACMG guidelines and determine if the addition of phenotype-enhanced criteria (PE-ACMG) using the HCM Genotype Predictor Score can further reduce the burden of variants of uncertain significance (VUS). METHODS: Re-assessment was performed on 70 MYH7-variants in 121 unique patients from Mayo Clinic, and an independent cohort of 54 variants in 70 patients from Royal Prince Alfred Hospital (Australia). Qualifying variants were re-adjudicated using both standard ACMG and MYH7-ACMG guidelines, and HCM Genotype Predictor Score was used to provide a validated measure of strength of clinical phenotype to be incorporated into the MYH7-ACMG framework. RESULTS: Among Mayo Clinic identified variants, 11/70 (16%) were classified as pathogenic (P), 10/70 (14%) as likely pathogenic, and 49/70 (70%) as a VUS. A similar distribution was seen in the Australian patients (12/54 [22%] P, 12/54 [22%] likely pathogenic, and 30/54 [56%] VUS; P=not significant). Application of the MYH7-ACMG resulted in a nonsignificant reduction of the VUS burden in both cohorts from 49/70 to 39/70 (56%; P=0.1; Mayo Clinic) and from 30/54 to 20/54 (37%; P=0.1; Australia). Using the combined PE-MYH7-ACMG framework, the VUS decreased significantly from 49 to 27 (P<0.001, Mayo Clinic) and from 30 to 16 (P<0.001; Australia). CONCLUSIONS: Use of the MYH7-specific guidelines alone failed to significantly decrease VUS burden in 2 independent cohorts. However, a significant reduction in VUS burden was observed after the addition of phenotypic criteria. Using a patient's strength of sarcomeric HCM phenotype for variant adjudication can increase significantly the clinical utility of genetic testing for patients with HCM.

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