BACKGROUND AND AIMS:Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) ≥15 mm. The condition is often hereditary, and family screening is recommended to reduce the risk of adverse disease complications and premature death among relatives. Correct diagnosis of index patients is important to ensure that only relatives at risk of disease development are invited for family screening. To investigate whether patients with International Classification of Disease, Tenth Revision (ICD-10) codes for HCM (DI421) or hypertrophic obstructive cardiomyopathy (HOCM) (DI422) fulfilled recognized diagnostic criteria. METHODS:All patients with ICD-10 codes for HCM or HOCM at a Department of Cardiology were identified and had their diagnosis validated by a cardiac investigation or a review of their medical records and previous investigations. RESULTS:A total of 240 patients had ICD-10 codes for HCM/HOCM, of whom 202 (84%, 202/240) underwent re-examination, while 38 (16%, 38/240) had their hospital notes reviewed. A total of 76 patients (32%, n = 76/240) did not fulfil diagnostic criteria, of whom 39 (51%, n = 39/76) had normal (10 mm) or modest LV wall thickness (11-14 mm). The remaining 37 patients (49%, n = 37/76) had LVH ≥15 mm, which was well explained by uncontrolled hypertension (32%, n = 24/76), aortic valve stenosis (19%, n = 7/76), or wild-type amyloidosis (16%, n = 6/76). CONCLUSION:One-third of patients with ICD-10 codes for HCM or HOCM did not fulfil recognized diagnostic criteria. Incorrect diagnosis of HCM may cause unnecessary family investigations, which may be associated with anxiety, and a waste of healthcare resources. This highlights the need for specialized cardiomyopathy services to ensure correct diagnosis and management of HCM.

BACKGROUND AND AIMS:Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. METHODS:An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. RESULTS:A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23). CONCLUSIONS:Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant ( TBX20tv ) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90–541.45; P <0.0001) and 99.76 (95% CI, 34.60–287.62; P <0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25–75:3.6–14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv -associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

BACKGROUND:Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS:Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS:Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS:RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

We appreciate the interest by Finsterer and Mehri in our recent report on Leber’s hereditary optic neuropathy (LHON).1Finsterer J. Stollberger C. Gatterer E. Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G > A.J Int Med Res. 2018; 46: 2054-2060Crossref PubMed Scopus (8) Google Scholar In mitochondrial disease, the heteroplasmy rate (HR) expresses the ratio of the number of abnormal mitochondria to the total number of mitochondria in a specific tissue. The ratio is often tissue-specific, which implies that the HR of myocardial tissue may differ significantly from the HRs of other tissues. Given that the severity of disease expression in mitochondrial disease is associated with the tissue-specific HR, establishing the HR is of little clinical significance. Furthermore, obtaining myocardial tissue may be harmful to the patient, due to the risk of myocardial perforation occurring during the sampling procedure. In our study, the genetic investigations included only part of the mitochondrial DNA harboring recognized pathogenic variants. However, as Finsterer and Mehri point out, information about copy number variants and haplotype may be of scientific interest to better understand the pathophysiology of LHON.1Finsterer J. Stollberger C. Gatterer E. Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G > A.J Int Med Res. 2018; 46: 2054-2060Crossref PubMed Scopus (8) Google Scholar As described in our report, the index patient had multiple organ involvement, including demyelination of the posterior portion of the optical nerves, consistent with LHON. He had an otherwise normal neurologic investigation and no signs or symptoms of Harding’s disease.2Hey T.M. Nielsen S.K. Eriksen U. Hansen F. Mogensen J. Leber's hereditary optic neuropathy and hypertrophic cardiomyopathy.CJC Open. 2022; 4: 813-815Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar,3Harding A.E. Sweeney M.G. Miller D.H. et al.Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation.Brain. 1992; 115: 979-989Crossref PubMed Scopus (342) Google Scholar Recently, Finsterer and Mehri suggested that left ventricular hypertrabeculation (LVHT) is a specific disease expression associated with LHON, based on the clinical findings in 2 patients carrying a m.3460G > A mutation.1Finsterer J. Stollberger C. Gatterer E. Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G > A.J Int Med Res. 2018; 46: 2054-2060Crossref PubMed Scopus (8) Google Scholar However, LVHT is well recognized to be potentially part of the normal left ventricular anatomy, as well as part of the disease expression in both dilated and hypertrophic cardiomyopathy (HCM).4Oechslin E. Jenni R. Left ventricular noncompaction: from physiologic remodeling to noncompaction cardiomyopathy.J Am Coll Cardiol. 2018; 71: 723-726Crossref PubMed Scopus (56) Google Scholar Therefore, LVHT is less likely to represent a specific disease entity with a well-defined prognosis. Finsterer and Mehri suggest that loop recorders be implanted in LHON patients with LVHT, due to the sudden cardiac death of one patient in their report.1Finsterer J. Stollberger C. Gatterer E. Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G > A.J Int Med Res. 2018; 46: 2054-2060Crossref PubMed Scopus (8) Google Scholar We appreciate these considerations, although our opinion is that management of patients should be individualized and based on their clinical disease expression, which was benign in the patients in our report. The patient had no family history of sudden cardiac death, did not experience syncopes, and had repeated Holter recordings without arrhythmias. Loop recorder implantation was therefore not indicated. Previous studies of LHON patients have also reported cardiac manifestations similar to those in HCM caused by pathogenic sarcomeric variants, which suggests that routine cardiac investigations should be offered to all LHON patients. In addition, a clear indication is that at least ND1 should be part of the genetic screening of HCM patients.1Finsterer J. Stollberger C. Gatterer E. Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G > A.J Int Med Res. 2018; 46: 2054-2060Crossref PubMed Scopus (8) Google Scholar,2Hey T.M. Nielsen S.K. Eriksen U. Hansen F. Mogensen J. Leber's hereditary optic neuropathy and hypertrophic cardiomyopathy.CJC Open. 2022; 4: 813-815Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar This letter was in accordance with the ethical guidelines. The authors have no funding sources to declare.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial condition that gradually affects the central vision. In the current case report, we present 2 relatives with LHON due to a pathogenic variant within ND1 with a clinical phenotype resembling hypertrophic cardiomyopathy, including a short PQ-interval and hypertrophy on electrocardiogram as well as severe hypertrophy of the left ventricle on echocardiography. These findings highlight the importance of offering routine cardiac investigation to patients with LHON and their relatives carrying the ND1 variant to hopefully improve correct diagnosis and clinical management of LHON patients.

BACKGROUND:It was the aim to investigate the frequency and genetic basis of dilated cardiomyopathy (DCM) among relatives of index patients with unexplained heart failure at a tertiary referral center.METHODS:Clinical investigations were performed in 109 DCM index patients and 445 of their relatives. All index patients underwent genetic investigations of 76 disease-associated DCM genes. A family history of DCM occurred in 11% (n=12) while clinical investigations identified familial DCM in a total of 32% (n=35). One-fifth of all relatives (n=95) had DCM of whom 60% (n=57) had symptoms of heart failure at diagnosis, whereas 40% (n=38) were asymptomatic. Symptomatic relatives had a shorter event-free survival than asymptomatic DCM relatives (P<0.001).RESULTS:Genetic investigations identified 43 pathogenic (n=27) or likely pathogenic (n=16) variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Forty-four percent (n=48/109) of index patients carried a pathogenic/likely pathogenic variant of whom 36% (n=27/74) had sporadic DCM, whereas 60% (21/35) were familial cases. Thirteen of the pathogenic/likely pathogenic variants were also present in ≥7 affected individuals and thereby considered to be of sufficient high confidence for use in predictive genetic testing.CONCLUSIONS:A family history of DCM identified only 34% (n=12/35) of hereditary DCM, whereas systematic clinical screening identified the remaining 66% (n=23) of DCM families. This emphasized the importance of clinical investigations to identify familial DCM. The high number of pathogenic/likely pathogenic variants identified in familial DCM provides a firm basis for offering genetic investigations in affected families. This should also be considered in sporadic cases since adequate family evaluation may not always be possible and the results of the genetic investigations may carry prognostic information with an impact on individual management.

Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). Results: Median follow-up was 49 (18–105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04–3.44]; P =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30–2.04]; P <0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis ( P =0.07). Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.

The protein titin determines cardiomyocyte contraction and truncating variants in the titin gene ( TTN ) are the most common cause of dilated cardiomyopathy (DCM). Different to truncations, missense variants in TTN are currently classified as variants of uncertain significance due to their high frequency in the population and the absence of functional annotation. Here, we report the regulatory role of conserved, mechanically active titin cysteines, which, contrary to current views, we uncover to be reversibly oxidized in basal conditions leading to isoform- and force-dependent modulation of titin stiffness and dynamics. Building on our functional studies, we demonstrate that missense mutations targeting a conserved titin cysteine alter myocyte contractile function and cause DCM in humans. Our findings have a direct impact on genetic counselling in clinical practice.One sentence summary Mutations targeting cysteines key to the mechanoredox control of titin cause human dilated cardiomyopathy### Competing Interest StatementThe authors have declared no competing interest.

Background As pathogenic variants in the gene for RBM20 appear with a frequency of 6% among Danish patients with dilated cardiomyopathy (DCM), it was the aim to investigate the associated disease expression in affected families. Methods and Results Clinical investigations were routinely performed in DCM index-patients and their relatives. In addition, ≥76 recognized and likely DCM-genes were investigated. DNA-sequence-variants within RBM20 were considered suitable for genetic testing when they fulfilled the criteria of (1) being pathogenic according to the American College of Medical Genetics and Genomics-classification, (2) appeared with an allele frequency of <1:10.000, and (3) segregated with DCM in ≥7 affected individuals. A total of 80 individuals from 15 families carried 5 different pathogenic RBM20 -variants considered suitable for genetic testing. The penetrance was 66% (53/80) and age-dependent. Males were both significantly younger and had lower ejection fraction at diagnosis than females (age, 29±11 versus 48±12 years; P <0.01; ejection fraction, 29±13% versus 38±9%; P <0.01). Furthermore, 11 of 31 affected males needed a cardiac transplant while none of 22 affected females required this treatment ( P <0.001). Thirty percent of RBM20 -carriers with DCM died suddenly or experienced severe ventricular arrhythmias although no adverse events were identified among healthy RBM20 -carriers with a normal cardiac investigation. The event-free survival of male RBM20 -carriers was significantly shorter compared with female carriers ( P <0.001). Conclusions The disease expression associated with pathogenic RBM20 -variants was severe especially in males. The findings of the current study suggested that close clinical follow-up of RBM20 -carriers is important which may ensure early detection of disease development and thereby improve management.

This study aimed to investigate different echocardiographic parameters for predicting atrial fibrillation (AF) in patients with transient ischemic attack (TIA). Echocardiography was performed in 110 patients (median age 65.8 years, 53% males) with TIA and no history of stroke or AF. All patients underwent monitoring with ECG and 72 h Holter-monitoring, and if no AF was found, an insertable cardiac monitor (ICM) was implanted and patients were followed for a median of 2.2 years. AF was found in 14 patients: five with Holter-monitoring and nine with ICM. AF patients had significantly larger left atrial (LA) volumes indexes compared to patients without AF (26.7 vs. 33.7 ml/m2, P = 0.03 for 2D images and 26.5 vs. 33.5 ml/m2, P = 0.0008 for 3D images). Patients with AF also had depressed LA function assessed with LA emptying fraction measured with 2D echocardiography (46.3 vs. 57.3%, P = 0.005 for patients with and without AF, respectively). Patients with AF also had depressed left ventricular (LV) function compared to patients without AF. LV ejection fraction was 55 versus 61%, P = 0.04 in patients with and without AF, respectively. LV global longitudinal strain (absolute value) was 16.7 in patients with AF compared to 21.2 in patients without AF (P = 0.001). Echocardiographic measurements of LA and LV size and function can noninvasively predict AF in patients with TIA and could potentially be used to guide AF monitoring strategy.

BACKGROUND:The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood. OBJECTIVES:This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort. METHODS:The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 ± 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry. RESULTS:At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 ± 13.2 years vs. 40.7 ± 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Male sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc. CONCLUSIONS:DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations.

AIMS:Lamin A/C mutations are generally believed to be associated with a severe prognosis. The aim of this study was to investigate disease expression in three affected families carrying different LMNA missense mutations. Furthermore, the potential molecular disease mechanisms of the mutations were investigated in fibroblasts obtained from mutation carriers.METHODS AND RESULTS:A LMNA-p.Arg216Cys missense mutation was identified in a large family with 36 mutation carriers. Disease expression was unusual with a late onset and a favourable prognosis. Two smaller families with severe disease expression were shown to carry a LMNA-p.Arg471Cys and LMNA-p.Arg471His mutation, respectively. LMNA gene and protein expression was investigated in eight different mutation carriers by quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry, and protein mass spectrometry. The results showed that all mutation carriers incorporated mutated lamin protein into the nuclear envelope. Interestingly, the ratio of mutated to wild-type protein was only 30:70 in LMNA-p.Arg216Cys carriers with a favourable prognosis while LMNA-p.Arg471Cys and LMNA-p.Arg471His carriers with a more severe outcome expressed significantly more of the mutated protein by a ratio of 50:50.CONCLUSION:The clinical findings indicated that some LMNA mutations may be associated with a favourable prognosis and a low risk of sudden death. Protein expression studies suggested that a severe outcome was associated with the expression of high amounts of mutated protein. These findings may prove to be helpful in counselling and risk assessment of LMNA families.

Background: Dilated cardiomyopathy (DCM) is a cardiac condition characterized by unexplained heart failure. More than 100 DCM genes have been reported of which only one gene (RBM20) has regulatory properties. Purpose: To investigate the frequency of RBM20 mutations in Danish DCM patients and compare the sex specific disease expression. Methods: The cohort consisted of 112 consecutive DCM index-patients who underwent genetic investigations of 67 DCM genes. All relatives at risk of disease development were invited for clinical investigations including ECG-recording and echocardiography. When a disease-associated mutation was identified in a indexpatient, relatives were offered genetic cascade screening. Statistical analyses were made by use of T-, χ2or Fishers exacttest. Results (see table 1): Nine families were identified with 4 different recognized RBM20 mutations. The frequency of RBM20 mutations was 8% (9/112). Cascade screening identified a total of 69 mutation carriers. Males were diagnosed at an earlier age (p<0.001) with a significantly larger left ventricular end diastolic diameter (LVEDd) (p=0.001) and a lower left ventricular ejection fraction (LVEF) (p=0.016) than female carriers. Eight males and no females underwent heart transplantation (HTx) (p=0.037).

Background: Due to a number of common proteins expressed both in cardiac and skeletal muscles, all types of cardiomyopathies are associated with neuromuscular phenotype.Thus, mutations in LMNA, DES or FLNC, and TTN genes could be found in dilated, restrictive, or hypertrophic cardiomyopathy often in combination with conduction disorders, myopathy, or myodystrophy.The genetic spectrum of cardiomyopathies associated with neuromuscular disorders is increasing, therefore giving an additional knowledge of molecular pathogenesis of cardiomyopathies.In the present study, we applied an exome sequencing strategy to identify a new genetic causes of cventricardiomyopathies and myopathies. Materials and methods:The study was approved by the Institute Ethical Review Board.Written informed consent was obtained from all subjects and their representatives prior to investigation.The genotyping was performed using Halo-Plex target enrichment panel followed by Sure Select Exome sequencing in genotype-negative patients.The identified genetic variants were classified according to ACMG guidelines.Satellite cells were isolated enzymatically from m. soleus biopsy.Immunocytochemistry and Western blot analysis were performed according to standard protocols.Results: 17 patients with cardiomyopathy and neuromuscular phenotype were included into the study.In all patients, cardiac manifestation of the disorder (dilated, restrictive, hypertrophic, or arrhythmogenic cardiomyopathy) preceded the diagnosis of neuromuscular disorder.In 16 patients, the mutation in earlier described cardiomyopathy and myopathy-associated genes such as DYS, DES, LMNA, FLNC, and SYNE1 were identified.In one patient, a mutation in a newly described MYOF (2615delG:p.G872fs) was identified by exome sequencing.The patient presented with recurrent ventricular tachycardia (8 000 per day), frequent ventricular extrasystoles, and moderate left ventricular dilation with preserved systolic and diastolic function at 43 years old.Routine clinical testing revealed marked CK elevation (2 500 U/L) and detailed neurological examination showed limb girdle muscle weakness more prominent in the low extremities.Myopathic pattern was confirmed by electromyography and morphological examination of muscle biopsy confirmed myodystrophic features.Staining of patient's muscle satellite cells with anti-MYOF antibody showed weakened and moderately disorganized pattern compared to control cells.Western blot analysis performed on patient's satellite cells demonstrated 50% reduction of MYOF content compared to donor cells.According to ACMG guidelines, the variant was classified as pathogenic (PVS1, PS1, PM1). Conclusion:In the present study, we demonstrated for the first time the association of MYOF gene with the development of cardiac and skeletal muscle disorders.More detailed functional and morphological studies are needed to evolve the role of MYOF in cardiac myocyte function.

Background: Dilated cardiomyopathy (DCM) is a hereditary cardiac condition characterized by unexplained heart failure with reduced ejection fraction. So far more than 100 DCM genes have been report...

INTRODUCTION:Reducing hands-off time during cardiopulmonary resuscitation (CPR) is believed to increase survival after cardiac arrests because of the sustaining of organ perfusion. The aim of our study was to investigate whether charging the defibrillator before rhythm analyses and shock delivery significantly reduced hands-off time compared with the European Resuscitation Council (ERC) 2010 CPR guideline algorithm in full-scale cardiac arrest scenarios.METHODS:The study was designed as a full-scale cardiac arrest simulation study including administration of drugs. Participants were randomized into using the Stop-Only-While-Shocking (SOWS) algorithm or the ERC2010 algorithm. In SOWS, chest compressions were only interrupted for a post-charging rhythm analysis and immediate shock delivery. A Resusci Anne HLR-D manikin and a LIFEPACK 20 defibrillator were used. The manikin recorded time and chest compressions.RESULTS:Sample size was calculated with an α of 0.05 and 80% power showed that we should test four scenarios with each algorithm. Twenty-nine physicians participated in 11 scenarios. Hands-off time was significantly reduced 17% using the SOWS algorithm compared with ERC2010 [22.1% (SD 2.3) hands-off time vs. 26.6% (SD 4.8); P<0.05].CONCLUSION:In full-scale cardiac arrest simulations, a minor change consisting of charging the defibrillator before rhythm check reduces hands-off time by 17% compared with ERC2010 guidelines.

Pheochromocytoma is a catecholamine-secreting tumour associated with varying symptoms ranging from episodic headache, sweating, paroxysmal hypertension and tachycardia to intractable cardiogenic shock. Cardiogenic shock is rare but well-described and the timing of correct management is crucial since mortality is high. Fifty per cent of pheochromocytomas are diagnosed on autopsy. We report on a case of embolisation of the adrenal artery during ongoing extracorporeal life support (ECLS) in order to stabilise and wean the patient from ECLS as a bridge to final surgery.

Background Genetic investigations have established that mutations in proteins of the contractile unit of the myocardium, known as the sarcomere, may be associated with hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). It has become clinical practice to offer genetic testing in affected individuals to identify causative mutations, which provides the basis for presymptomatic testing of relatives who are at risk of disease development. This ensures adequate clinical follow-up of mutation carriers, whereas noncarriers can be discharged. However, before genetic testing can be used for individual risk assessment and prediction of prognosis, it is important to investigate if there is a relation between the clinical disease expression (phenotype) of the condition and mutations in specific disease genes (genotype). Methods We reviewed the literature in relation to phenotypic features reported to be associated with mutations in cardiac troponin I (cTnI; TNNI3), which is a recognized sarcomeric disease gene in all 3 cardiomyopathies. Results The results of this review did not identify specific genotype-phenotype relations in HCM or DCM, and cTnI appeared to be the most frequent disease gene in RCM. Conclusions To further explore if there is a genotype-phenotype relation, long-term follow-up studies are needed. It is essential to investigate the natural history of the condition among affected individuals and to provide clinical follow-up on disease development among healthy mutation carriers. Such information is required to provide evidence-based counselling for affected families and to elucidate if knowledge about specific genotypes can be used in future risk prediction models.