OBJECTIVE:The bodily distress syndrome (BDS) checklist has proven to be useful diagnostic aid and as screening tool for functional somatic disorder (FSD). It has been hypotheses that the symptoms clusters of the checklist represent autonomic activity. This study aims to investigate associations between autonomic activity (Heart rate variability, HRV) and somatic symptoms profiles measured by the BDS checklist and diagnoses of FSD based on interviews. METHODS:This cross-sectional population-based study included 6891 men and women aged 18-72 years. Somatic symptom profiles were measured by the 25-item BDS checklist, and five short-term HRV measures (MeanRR, RMSSD, LF, HF, and LF/HF) were obtained. In a stratified subsample (n = 1590), diagnoses of FSD was established by diagnostic interviews, performed by trained family physicians. Associations were tested with regression models. Measures of associations were mean difference with 95 % confidence intervals (CIs) for Mean RR and median ratio and 95 % CI for RMSS, LF, HF, and LF/HF. RESULTS:Overall, higher BDS checklist scores were associated with lower HRV, particularly reduced mean RR intervals (-0.86, 95 % CI: -0,24;-0,49 for the total sum score). The strongest associations were seen for the cardiopulmonary symptom cluster (-3.58, 95 % CI: -0,05;-2.10). Clinically diagnosed FSD cases also showed lower mean RR compared to non-cases (-23.12, 95 % CI: -41.17;-5.07), especially the multi-organ type (-39.44, 95 % CI: -75.49;-3.39). CONCLUSIONS:The study indicate that the symptom clusters of the BDS checklist are associated with autonomic arousal as measured by HRV. Further that individuals with FSD, especially the multi-organ type, had an increased sympathetic neural and neurohormonal activity, suggesting this may be an important physiological mechanism in FSD.

Spontaneous coronary artery dissection (SCAD) is characterized by intramural hematoma in a coronary artery leading to partial or complete vessel obstruction. A 51-year-old female was hospitalized with acute myocardial infarction and cardiogenic shock. She was diagnosed with severe SCAD, affecting the proximal left coronary artery. A complex percutaneous coronary intervention, complicated by cardiac arrest and need for cardio pulmonary support, succeeded with stent insertion and revascularization. In the following days, the patient developed severe heart failure due to extensive cardiac reperfusion injury and subsequently experienced multiple organ failure, ultimately resulting in death. The patient had previously been acutely hospitalized twice with myocardial infarctions and both the times was also diagnosed with SCAD affecting the left coronary artery. This case highlights an unfortunate patient outcome due to recurrent SCAD and serves as an important reminder to consider SCAD differential diagnostically in younger female patients with myocardial infarction.

BACKGROUND:Hereditary transthyretin (ATTRv) amyloidosis is a rare but life-threatening multisystemic disease. Multiple disease-modifying treatments are now available and standardised instruments for early detection and disease monitoring are essential. Still, validated and easy-to-use tools for clinical follow-up are scarce. METHODS:The Kumamoto scale was first described in 1997 as a method for systematically evaluating patients with ATTRv amyloidosis and has been used in clinical trials since. A panel of amyloidosis experts from Sweden, Denmark, and Norway discussed the strengths and limitations of the Kumamoto scale at the Nordic Amyloidosis Day at Arlanda in 2023, and it was decided to revise and improve the scale that has been used in routine clinical monitoring of patients in Sweden since 2020. Our aim is to introduce the revised version of the Kumamoto scale as a useful clinical monitoring tool. RESULTS:Minor adjustments were applied to make the scale more sensitive and precise. Bedside instruments for sensory examination were defined as well as the sensory and motor levels. Constipation was added as a sign of autonomic dysfunction. The subtotal and total scores remain unchanged. CONCLUSIONS:We believe that the revised Kumamoto scale is a reliable and easy-to-use clinical tool for monitoring ATTRv amyloidosis.

Abstract Background Recurrent non-epileptic episodes resembling paroxysmal sympathetic hyperactivity (PSH) have been observed in adolescents with Juvenile Ceroid Lipofuscinosis (CLN3-disease) and a possible association to an autonomic dysfunction has been suggested. The objective of the present study was to investigate the dynamics of the autonomic activity up to, during, and in the time after individual attacks. We include all seven suitable CLN3 patients in Denmark ≥ 15 years of age. HRV parameters were assessed from continuous heart rate monitoring during seven consecutive days and a particular focus of HRV parameters was obtained in close temporal context to clinically recurrent PSH-like episodes. In addition, the likelihood of PSH was assessed by caregiver’s description and by video documentation. Results Respectively eight and five episodes were recorded in two patients (18 and 20 years of age). The episodes were all safely superior to the cut off values of the clinical assessment score to be considered PSH-like episodes. During all 13 episodes, HRV revealed a statistically significant decrease in root mean square of successive differences (RMSSD) and standard deviation of the Poincaré-Plot interval (SD1) in the minutes prior to the clinical onset of the episodes, both indicating a sudden decrease in parasympathetic activity in advance of the onset. The reduced activity remained low during the episodes, and 15–30 min following the attack cessation, the parasympathetic activity had returned to pre-attacks levels. The sympathetic HRV parameters were unchanged resulting in a sympathetic overactivity during the episodes. In a third participant (32 years of age), in whom severity of PSH-like episodes had been gradually reduced during the last years, five episodes were registered. A similar temporally related reduction of the parasympathetic activity was found, but because the sympathetic activity decreased as well, no sympathetic dominance developed, which most reasonable is the reason to the clinically reduced expression of the episodes. Conclusion The documented transient withdrawal of parasympathetic activity leading to a paroxysmal unbalanced sympathetic hyperactivity most probably accounts for the PSH-like episodes occurring in post-adolescent CLN3 patients. The findings shed new light on both aetiology and possible preventative and therapeutic measures.

Phase 2 studies showed that focal seizures could be detected by algorithms using heart rate variability (HRV) in patients with marked autonomic ictal changes. However, wearable surface electrocardiographic (ECG) devices use electrode patches that need to be changed often and may cause skin irritation. We report the first study of automated seizure detection using a subcutaneously implantable cardiac monitor (ICM; Confirm Rx, Abbott). For this proof-of-concept (phase 1) study, we recruited six patients admitted to long-term video-electroencephalographic monitoring. Fifteen-minute epochs of ECG signals were saved for each seizure and for control (nonseizure) epochs in the epilepsy monitoring unit (EMU) and in the patients' home environment (1-8 months). We analyzed the ICM signals offline, using a previously developed HRV algorithm. Thirteen seizures were recorded in the EMU, and 41 seizures were recorded in the home-monitoring period. The algorithm accurately identified 50 of 54 focal seizures (sensitivity = 92.6%, 95% confidence interval [CI] = 85.6%-99.6%). Twelve of the 13 seizures in the EMU were detected (sensitivity = 92.3%, 95% CI = 77.2%-100%), and 38 of the 41 seizures in the out-of-hospital setting were detected (sensitivity = 92.7%, 95% CI = 84.7%-100%). Four false detections were found in the 141 control (nonseizure) epochs (false alarm rate = 2.7/24 h). Our results suggest that automated seizure detection using a long-term, subcutaneous ICM device is feasible and accurate in patients with focal seizures and autonomic ictal changes.

OBJECTIVES:Fetal heart rate variability (FHRV) has shown potential in fetal surveillance. Therefore, we aimed to evaluate the reliability of time domain and spectral domain parameters based on non-invasive fetal electrocardiography (NI-FECG). METHOD:NI-FECG, with a sampling frequency of 1 kHz, was obtained in 75 healthy, singleton pregnant women between gestational age (GA) 20+0 to 41+0. The recording was divided into a) heart rate pattern (HRP) and b) periods fulfilling certain criteria of stationarity of RR-intervals, termed stationary heart rate pattern (SHRP). Within each recording, the first and the last time series from each HRP with less than 5% artifact correction were analyzed and compared. Standard deviation of normal-to-normal RR-intervals (SDNN), root mean square of successive differences (RMSSD), high frequency power (HF-power), low frequency power (LF-power), and LF-power/HF-power were performed. A multivariate mixed model was used and acceptable reliability was defined as intraclass correlation coefficient (ICC) ≥ 0.80 and a coefficient of variation (CV) ≤ 15%. Based on these results, the CV and ICC were computed if the average of two to six time series was used. RESULTS:For GA 28+0 to 34+6, SDNN and RMSSD exhibited acceptable reliability (CV < 15%; ICC > 90%), whereas GA 35+0 to 41+0and 20+0 to 27+6 showed higher CVs. Spectral domain parameters also showed high CVs However, by using the mean value of two to six time series, acceptable reliability in SDNN, RMSSD and HF-power from GA 28+0 was achieved. Stationarity of RR-intervals showed high influence on reliability and SHRP was superior to HRP, whereas the length of the time series showed minor influence. CONCLUSION:Acceptable reliability seems achievable in SDNN, RMSSD and HF-power from gestational week 28. However, stationarity of RR-intervals should be considered when selecting time series for analyses.

Fetal heart rate variability (FHRV) reflects autonomic cardiac regulation. The autonomic nervous system constantly adjusts the heart rate to maintain homeostasis. By providing insight into the fetal autonomic state, FHRV has the potential to become an investigational and clinical instrument. However, the method needs standardization and the influence of fetal movements, including fetal respiratory movements, is not well explored. Therefore, in a highly standardized setting, the aim was to evaluate the association between fetal movements and fetal heart rate variability (FHRV) including their impact on reliability. Fetal heart rate was obtained by noninvasive fetal electrocardiography (NI-FECG) and fetal movements by simultaneous ultrasound scanning in 30 healthy singleton pregnant women on two occasions with a maximum interval of 7 days. The standard deviation of normal-to-normal RR-intervals (SDNN), root mean square of successive RR-interval differences (RMDDS), high-frequency power (HF-power), low-frequency power (LF-power), and LF/HF were measured. A multivariate mixed model was used and reliability was defined as acceptable by a coefficient of variance (CV) <= 15% and an intraclass correlation coefficient (ICC) >= 0.80. During time periods with fetal respiratory movements, the highest reliability was achieved. Intra- and inter-observer reliability measurements were very high (CV: 0-9%; ICC >= 0.86). Within the same recording, SDNN and RMSSD achieved acceptable reliability (CV: 14-15%; ICC >= 0.80). However, day-to-day reliability displayed high CV's. In time periods with fetal respiratory movements, as compared to periods with quiescence RMSSD and HF-power were higher (Ratio: 1.33-2.03) and LF/HF power lower (Ratio: 0.54). In periods with fetal body movements SDNN, RMSSD and HF-power were higher (Ratio: 1.27-1.65). In conclusion, time periods with fetal respiratory movements were associated with high reliability of FHRV analyses and the highest values of parameters supposed to represent vagal activity.

Genotyping divides transthyretin cardiac amyloidosis (ATTR-CA) in hereditary (ATTRv) and wild type (ATTRwt) forms. This study investigated the prevalence and clinical presentation of ATTRv in a contemporary cohort of consecutive ATTR-CA patients diagnosed at a tertiary Danish amyloidosis center. Age at diagnosis, clinical- and echocardiographic data, and transthyretin (TTR) genotype were recorded. Relatives of ATTRv patients underwent clinical phenotyping and predictive gene testing. Genetic testing in 102 patients identified four TTR variant carriers: p.Pro63Ser, p.Ala65Ser (n = 2) and p.Val142Ile. The mean age of ATTRv index patients was significantly lower compared to ATTRwt patients: 70.2 ± 1.2 versus 80.0 ± 6.2, p-value: 0.005. Evaluation of ATTRv families identified seven TTR variant carriers with a median age of 65 years (range 48–76) and three were diagnosed with ATTR-CA by DPD-scintigraphy. Family members with ATTR-CA were all asymptomatic and had normal levels of cardiac biomarkers. In conclusion, the prevalence of ATTRv in a contemporary Danish ATTR-CA cohort is 4%. ATTRv index patients were significantly younger age at diagnosis than ATTRwt patients. Non-p.Leu131Met TTR variants have reduced penetrance at the age of 65 years in which approximately half of variant carriers have asymptomatic ATTR-CA with normal LV systolic function and cardiac biomarker analyses.

It is well documented that deteriorating heart function due to deposition of ceroid lipopigment is a significant co-morbidity in Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease) although the exact disease mechanisms remain unknown in any NCL form. An increasing frequency of cardiac conduction disorders including severe bradycardia and sinus arrest is seen in the late teens, as is a left ventricular hypertrophy in the early 20s. Only a few case reports of pacemaker implantation have been published, and so far, no long-term follow-up study exists. As new treatment options emerge, more patients will live longer and the need for pacemaker will likely increase, why knowledge of long-term outcome is needed. In the present study, we present the course of six patients from the original Danish CLN3-heart population study (n = 29) published in 2011 in whom pacemaker implantation was indicated from a cardiac point of view. In two cases, the families deselected pacemaker implantation. In four males, aged 19-29 years, all having a good general condition, a dual-chamber pacemaker (St. Jude Medical™ Accent/Assurity MRI™) was implanted in general anesthesia without any complications. At follow-up 9 years later, three were still alive. According to the parents' opinion they still have a good quality of life, now 26, 30, and 36 years old. Pacemaker treatment is safe and may have great impact on quality of life. However, the medical indication for pacemaker treatment is relative and it is important that various aspects, including the patient's general condition and family preferences, are thoroughly discussed before making the final decision.

The aim was to assess the association between fetal growth restriction (FGR) and fetal heart rate variability (FHRV) in relation to fetal movements. A prospective observational cohort study was performed. Non-invasive fetal electrocardiography (NI-FECG) allowed beat-to-beat assessments with <5% corrections of RR intervals. FHRV analyses included: Root mean square of successive RR interval differences (RMSSD), high frequency power (HF power), and low frequency power (LF power). Fetal movements were categorized by continuous ultrasound scanning. We enrolled 36 singleton pregnant women expecting a small fetus (< the 2.3 percentile of mean weight for gestational age) diagnosed by ultrasound, of whom 25 presented with a birthweight < the 2.3 percentile. Among these, 11 were excluded due to low quality NI-FECG recordings, leaving 14 women with 28 recordings eligible for inclusion in the analyses. The control group consisted of 22 healthy fetuses with birthweights between the 10th and the 90th percentile (average for gestational age [AGA]). In FGR fetuses the HRV response to respiratory activity was comparable to that of AGA fetuses. RMSSD (Ratio 1.54 [95% CI: 1.33; 1.79]) and HF power (Ratio 2.88 [95% CI: 2.12; 3.91]) increased, whereas LF/HF power (Ratio: 0.44 [95% CI: 0.31;0.63]) decreased. However, during fetal quiescence, FGR fetuses differed significantly from AGA fetuses. Compared to AGA fetuses, FGR fetuses displayed lower RMSSD (Ratio 0.77 (95% CI: 0.58; 1.02)) and HF power (Ratio 0.56 (95% CI:0.32; 0.98)). This reduction was associated with the severity of the FGR. In conclusion, FGR fetuses displayed a respiratory sinus arrhythmia (RSA) comparable to AGA fetuses; however, more important, parameters representing cardiac vagal activity were impaired in FGR fetuses during quiescence. RSA may constitute an intrinsic function of the cardiovascular system, which is unaffected by fetal compromise. However, the basic cardiac outflow assessed during fetal quiescence indicates a suppressed cardiac vagal activity in the FGR fetuses.

Abstract Background The incidence of sudden cardiac death (SCD) following heart transplantation (HTx) accounts for approximately 10% of post-HTx deaths. Ischemia, brady- and tachy-arrhythmias caused by rejection and cardiac allograft vasculopathy (CAV) seem related to SCD. Hence, we aimed to investigate the relation between CAV, arrhythmias and silent ischemia in long-term HTx patients. Methods. 49 HTx patients were included. Patients were CAV classified in accordance with guidelines from the International Society of Heart and Lung Transplantation. Patients were divided into predefined CAV groups (CAV 0, CAV 1, CAV 2 + 3). Incidences of arrhythmia and silent ischemia were detected by 48-h electrocardiogram monitoring and analyzed blinded to CAV-status. Results. Median time since transplantation was 9 years [IQR 4–14]. We observed a higher incidence of non-sustained ventricular tachycardia (NSVT) in CAV 2 + 3 patients than CAV 0 and 1 patients (p = .01). Likewise, isolated premature ventricular complexes (PVC) (p = .01) and PQ-interval prolongation (p = .01) were more frequent in CAV 2 + 3 patients than CAV 0 and 1 patients. Silent ischemia was only observed among CAV 3 patients (p = .04). We saw no significant difference in the incidence of supraventricular tachycardia among CAV groups (p = .21). Likewise, no difference in the right bundle branch block was observed (p = .68). Conclusion. NSVT was associated with CAV status in long-term HTx patients. Patients with moderate to severe CAV showed higher incidences of PVCs and PQ-interval prolongation than patients with mild or no CAV. Silent ischemia was only seen in patients with severe CAV.

Veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) is commonly used to provide haemodynamic support for patients with severe cardiac failure. However, timing ECMO weaning remains challenging. We aimed to examine if an integrative weaning approach based on predefined haemodynamic, respiratory and echocardiographic criteria is associated with successful weaning.

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.

Introduction: Fetal heart rate variability (FHRV) evaluates the fetal neurological state, which is poorly assessed by conventional prenatal surveillance including cardiotocography (CTG). Accurate FHRV on a beat-to-beat basis, assessed by time domain and spectral domain analyses, has shown promising results in the scope of fetal surveillance. However, accepted standards for these techniques are lacking, and the influence of fetal breathing movements and gross movements may be especially challenging. Thus, current standards for equivalent assessments in adults prescribe rest and controlled respiration. The aim of this review is to clarify the importance of fetal movements on FHRV. Methods: A systematic review in accordance with the PRISMA guidelines based on publications in the EMBASE, the MEDLINE, and the Cochrane Library databases was performed. Studies describing the impact of fetal movements on time domain, spectral domain and entropy analyses in healthy human fetuses were reviewed. Only studies based on fetal electrocardiography or fetal magnetocardiography were included. PROSPERO registration number: CRD42018068806. Results: In total, 14 observational studies were included. Fetal movement detection, signal processing, length, and selection of appropriate time series varied across studies. Despite these divergences, all studies showed an increase in overall FHRV in the moving fetus compared to the resting fetus. Especially short-term, vagal mediated indexes showed an increase during fetal breathing movements including an increase in Root Mean Square of the Successive Differences (RMSSD) and High Frequency power (HF) and a decrease in Low Frequency power/High Frequency power (LF/HF). These findings were present even in analyses restricted to one specific fetal behavioral state defined by Nijhuis. On the other hand, fetal body movements seemed to increase parameters supposed to represent the sympathetic response [LF and Standard Deviation of RR-intervals from normal sinus beats (SDNN)] proportionally more than parameters representing the parasympathetic response (RMSSD, HF). Results regarding entropy analyses were inconclusive. Conclusion: Time domain analyses as well as spectral domain analyses are affected by fetal movements. Fetal movements and especially breathing movements should be considered in these analyses of FHRV.

Abstract Purpose To investigate the prevalence of mATTR in a cohort of consecutive ATTR patients in a tertiary Danish Amyloidosis Center. Methods Consecutive patients in the period from 2001 to 2019 with a definite diagnosis of ATTR-CA or ATTR-FAP based on either 99-Tc-DPD-scintigraphy, or transthyretin deposition in the myocardium or fatty tissue proved by immunohistology or protein mass spectrometry underwent testing for exonic genetic TTR variants. The distributions of age at time of diagnosis of mATTR and wildtype ATTR (wtATTR) are described by mean age, standard deviations, and range. Results Seventy-four caucasian patients of Danish ancestry except one (Swedish) with ATTR were included (72 ATTR-CA, 2 ATTR-FAP). TTR missense variants were present in 13.5% (10/74) of ATTR patients concluded to have mATTR: c.148G>A/p.Val50Met, n=1; c.187C>T/p.Pro63Ser, n=1; c.193G>T/p.Ala65Ser, n=2; c.218G>C; p.Gly73Ala, n=1; c.391C>A/p.Leu131Met, n=3; c.424G>A/p.Val142Ile, n=2. The mean age of mATTR patients was 57.6 years ±13.0, range 37.1–71.3 years, and was significantly lower than mean age for wtATTR patients: 79.4 years ±5.5, range 65.7–90.2 years, p=0.0004 (Welch's two-sample t-test with unequal variances). All patients with mATTR had familial disease proven by clinical phenotyping of family members or had a positive family history with heart failure and pacemaker use. Conclusion A minority of Danish patients (10–15%) with ATTR have mATTR. These mATTR patients are characterised by a significantly younger age at time of diagnosis than wtATTR patients. This observation indicates that TTR gene test may not be necessary in ATTR in patients older than 75 years. For the first time, the p.Val142Ile TTR variant, associated with mATTR and prevalent in 4% of African-Americans, was identified in a Danish family with mATTR-CA – a finding that may be explained by a common founder effect. Funding Acknowledgement Type of funding source: None

Background. Liraglutide, a glucagon-like peptide-1 agonist, is used for treatment of type 2 diabetes and has beneficial cardiovascular properties. However, treatment increases heart rate (HR) and possibly the risk of cardiovascular events in chronic heart failure (CHF) patients. We investigated potential associations between HR changes and clinical, laboratory and echocardiographic parameters and clinical events in liraglutide treated CHF patients.Methods. This was a sub-study of the LIVE study. CHF patients (N = 241) with a left ventricular ejection fraction <= 45% were randomised to 1.8 mg liraglutide daily or placebo for 24 weeks. Electrocardiograms (N = 117) and readouts from cardiac implanted electronic devices (N = 20) were analysed for HR and arrhythmias.Results. In patients with sinus rhythm (SR), liraglutide increased HR by 8 +/- 9 bpm (pulse measurements), 9 +/- 9 bpm (ECG measurements) and 9 +/- 6 bpm (device readouts) versus placebo (allp<.005). Increases in HR correlated with liraglutide dose (p=.01). HR remained unchanged in patients without SR. Serious cardiac adverse events were not associated with HR changes.Conclusions. During 6 months of treatment, HR increased substantially in CHF patients with SR treated with liraglutide but was not associated with adverse events. The long-term clinical significance of increased HR in liraglutide treated CHF patients needs to be determined.

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.