Abstract Background The SARS-CoV-2 pandemic led to worldwide initiation of vaccination campaigns. The new mRNA vaccines were unexpectedly associated with vaccine-associated myocarditis (VAM). The incidence and severity of VAM has not been validated in a nation-wide and well-defined population. From December 2020 onwards the mRNA vaccines Comirnaty and Spikevax have been in widespread use in Norway. The National Patient Register (NPR) includes all hospital contacts with corresponding diagnostic codes (ICD-10), and all vaccinations are registered in the Norwegian Immunization Register (SYSVAK). Purpose We aimed to identify and validate all cases of suspected COVID-19 VAM in Norway during the national vaccination campaign between 2020-22. Methods We identified all cases of myocarditis acquired within 90 days of a COVID-19 vaccination through linkage of diagnostic codes for myocarditis in NPR and vaccination data in SYSVAK. Cases were included from December 2020 through April 2022. We assessed medical records, cardiac imaging, and biochemistry to retrospectively validate all myocarditis cases. The Brighton Criteria (international criteria for myocarditis diagnosis following immunization with defining levels of diagnostic certainty) were used to confirm the VAM diagnosis. Results From December 2020 to April 2022, 4 114 750 unique subjects (2 036 792 men and 2 077 958 women, median age first dose 47 years) above 16 years of age, received 10 915 098 unique doses of COVID-19 vaccines (8 651 703[79%] Comirnaty and 2 263 395[21%] Spikevax). Of 277 cases of myocarditis identified in NPR<90 days after receiving a COVID-19 vaccine, 176(64%) were validated as VAM (78 definite, 90 probable, and 8 possible VAM). Among the patients with VAM, 137(78%) were men with median age 30(IQR 24-47) years, and 39(22%) were women with median age 54(IQR 32-65) years. There were 4 cases of VAM per 100 000 vaccinated subjects: 7 per 100 000 men and 2 per 100 000 women. Sixty-three percent of VAM occurred after the second mRNA vaccine dose. There were 3.3 cases of VAM per 100 000 unique doses of Spikevax compared to 1.1 per 100 000 unique doses of Comirnaty. The most common time interval from vaccination to VAM was 3 days and occurred in 30 patients (17.3% of VAM, 93% men), and 34% of VAM (90% men) occurred during the first 5 days from vaccination(Figure). Median duration of hospital stay was 4(IQR 3-5) days, with only 7(4%) patients needing intensive care and 1 myocarditis related patient death during hospitalization. Conclusions In this unique nationwide study including all COVID-19 vaccinated subjects in Norway from 2020-22 we found 4 cases of VAM per 100 000 vaccinated subjects. The majority of VAM occurred in young men. Interestingly, women presented later than men with VAM and most frequently at middle to older age. The occurrence of this unexpected serious adverse event underscores the importance of large studies in broad populations in future vaccine programs.

The first heart transplantation in Norway was performed in 1983. Since then, over 1050 patients have received a heart transplant (HTx). About 400 patients had a diagnosis of non-ischemic cardiomyopathy (CM). Over the last 15 years, new genes have been found to be associated with an increased risk of developing CM and neuromuscular disease (NMD). This particularly applies to mutations in the LMNA, TTN and MYH7 genes. Well-known NMDs such as Myotonic dystrophy (MD) type 1 and 2, Duchenne`s and Beckers MD may be dominated by and diagnosed after, cardiac manifestations of the disorder. The aims of the study were to explore to what extent HTx recipients with non-ischemic CM have mutations in genes that may cause NMD. We identified patients using a national HTx registry. Family history, subtype of CM and results from genetic testing were recorded from medical records. Patients not previously tested were offered a genetic test, and previously tested patients with negative results were offered a new test with an updated panel (hereditary CM including genes for NMD). 279 living HTx recipients fulfilled the criteria and 181 patients (112 men) have so far given informed consent. Of these, 108 (60%) were previously genetically tested. An underlying mutation causing CM was identified in 65 (60 %). The mutations were identified in both genes associated with NMD (TTN, LMNA, MYBPC3, MYH7, DMD, BAG3, FKRP, DES) as well as in genes associated with CM only (TNNT2, DSP, PKP2, TNNI3, RBM20). Among the 73 patients (43%) who had not previously been tested, an underlying mutation causing CM was identified in 20 patients (27%) all in genes associated with NMD (TTN, LMNA, MYH7, BAG3, MYBPC3, TNNT2 and DES). 24 patients tested negative, and 29 test results are still pending. Further studies will include neurologic clinical examination and standardized functional tests as well as more elaborate genetic testing in patients with an obvious NMD.

Abstract Introduction Cardiac laminopathy is a malignant and highly arrhythmogenic form of dilated cardiomyopathy caused by variants in the lamin A/C (LMNA) gene. Atrial fibrillation (AF) is common during disease progression and often occurs at a young age, before evident structural cardiac changes and therefore, decision making on anticoagulation for AF is challenging. Whether atrial cardiomyopathy is present at this early stage of LMNA disease has not yet been explored. Purpose We aimed to evaluate for atrial cardiomyopathy in LMNA genotype positive subjects without prior atrial arrhythmias and assess whether atrial cardiomyopathy would be associated with the occurrence of AF during follow-up. Methods We prospectively recruited LMNA genotype-positive patients in a cohort study. Patients without prior documented atrial arrhythmias were evaluated for atrial cardiomyopathy by echocardiography. Atrial cardiomyopathy was evaluated by left atrial (LA) volume index (LAVI) and LA strain (peak reservoir strain and peak conduit strain). LA strain was assessed by 2D speckle-tracking echocardiography, averaged from apical four- and two-chamber views using a LA strain dedicated software with R-wave at end diastole as zero-reference point. Results We evaluated 129 LMNA genotype positive patients (51% women, age 40±15 years), of whom 57 patients (44%) had previous AF. Hence, we included 72 patients (32±14 years old, 49% female, left ventricular ejection fraction 53±11%) for assessment of atrial cardiomyopathy. The mean LA reservoir strain was 35±14%, conduit strain 25±13% and LAVI 38±23 ml/m2. During 7.7±5.0 years of follow-up, 28 (39%) patients developed AF after a median of 2.2 years. Patients with AF during follow-up had larger LAVI (47±30 vs. 32±10ml/m2, p=0.01) and worse LA reservoir strain (29±12% vs. 38±14%, p=0.02) at baseline than those who did not develop AF. LA reservoir strain and LAVI at baseline were both predictors of AF during short-term follow-up (HR 0.95 [CI 0.90-0.99], p=0.025 and HR 1.02 [CI 1.01-1.03], p=0.009, respectively), whereas LA conduit strain was not (HR 0.98 [CI 0.94-1.03], p=0.45). ROC analysis identified LA reservoir strain better than 32.5% as the best discriminating value for survival free of AF (log rank p=0.05) (Figure). Conclusion Atrial cardiomyopathy was common in LMNA genotype positive patients without previous atrial arrhythmias. LA volume and and LA reservoir strain predicted new onset AF during follow-up and may be used as markers for detecting short term risk of AF and potentially guide anticoagulation treatment in LMNA disease.LA reservoir strain and AF in LaminA/C

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Oslo University Hospital, Procardio Center for Innovation Introduction Arrhythmogenic cardiomyopathy (AC) is an inheritable heart disease caused by mutations in genes encoding the cardiac desmosomes, while exercise-induced AC (EiAC) has been proposed as an acquired similar phenotype in athletes. Little is known about the progression of EiAC compared to AC. Purpose To assess functional and structural disease progression in EiAC compared to desmosomal AC during long-term follow-up. Methods We consecutively included probands with definite AC diagnosis according to the 2010 Task Force Criteria and patients with EiAC in a longitudinal cohort study. EiAC was diagnosed in competitive endurance athletes (>24 MET-hours/week for >6 consecutive years) referred with symptomatic ventricular arrhythmias who had no family history, no genetic mutations associated with heart disease, and no other identified etiology after through clinical work-up. All patients in both groups were recommended to avoid high intensity exercise. Progression of the structural phenotype was assessed by regular repeated echocardiographic examinations during long-term follow-up. Right ventricular (RV) function and size were assessed by RV fractional area change (FAC), RV basal diameter (RVD) and RV outflow tract (RVOT) diameter. Disease progression was evaluated and compared using linear mixed model regression. Results Forty-one EiAC patients (15% women, age 45±13 years) and 84 AC probands (51% mutation positive, 35% women, age 43±15) were followed for 6.6 (IQR 3.7-10.5) and 7.9 (IQR 5.2-10.8) years, respectively. Key parameters from 570 echocardiographic examinations (184 EiAC and 386 AC) were assessed. There was no deterioration of RV function during follow-up in EiAC patients, in contrast to AC patients (FAC yearly progression rate: EiAC +0.02% [95% CI -0.27 to 0.31] vs AC -0.60% [95% CI -0.71 to -0.50] per year, p=0.001, Figure left panel). RV size did not increase in EiAC patients in contrast to AC patients (RVD: EiAC +0.01 mm [95% CI -0.00 to 0.03] vs AC +0.78 mm [95% CI 0.68 to 0.89] per year, p<0.001, Figure mid panel, and RVOT: EiAC +0.01 mm [95% CI -0.01 to 0.02] vs AC +0.47 mm [95% CI 0.38 to 0.56] per year, p<0.001, Figure right panel). Conclusion Patients with exercise-induced AC had no evidence of disease progression during long-term follow-up. These patients had a more benign disease trajectory than patients with desmosomal AC. Despite the limited sample size, these results seem reassuring for patients diagnosed with exercise-induced AC.

Abstract Background & aims Echocardiography has a central role in diagnosis and follow-up of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). It is however not included in the risk calculator for ventricular arrhythmia (VA) which was recently developed and validate, since traditional echo parameters were outperformed by RV ejection fraction (RVEF) measured by CMR. CMR is however not as widely available as echocardiography. We aimed to investigate whether echocardiographic RV deformation imaging could be used as a substitute for RVEF by CMR in arrhythmic risk prediction in ARVC. Methods & results From two referral centres, 150 consecutive patients with a definite ARVC diagnosis, no prior sustained VA and an echocardiogram suitable for deformation analysis were included (aged 41 ± 17 years, 50% female). During a median follow-up of 6.3 (IQR 3.1-9.8) years, 37 (25%) experienced a first-time sustained VA. The current ARVC risk calculator, including RVEF by CMR performed well in this cohort, with an optimism corrected C-statistic of 0.77 (95% CI 0.71 – 0.84). When RVEF was replaced by RV free wall longitudinal strain, the latter was an independent predictor (p = 0.005) and C-statistic changed to 0.80 (95% CI 0.74 – 0.86). The model including RV deformation imaging reduced the Akaike information criterion by >2. Conclusions This study showed that echocardiographic RV deformation imaging is able to replace RVEF by CMR in ARVC risk prediction without losing discriminative power. In clinical use, repeated yearly risk assessment using echocardiography could be alternated with a CMR every few years.

The Heart-Musc Study is a combined retrospective and cross-sectional study on heart transplant (HTx) recipients. Our main hypothesis is that patients with a non-ischemic cause of cardiomyopathy (CMP) may have a genotype that can cause both cardiomyopathy and a neuromuscular disorder (NMD). In Norway, 1057 subjects have received an HTx since the first procedure performed in 1983. In this retrospective study based on medical records, we studied deceased adult HTx patients that received a transplant in the 20-year period between 2002 and 2022. During these years, genetic tests became more available than previously. We aimed to assess the prevalence of probable genetic cause of CMP with or without NMD. We have until now investigated the phenotypic CMP and NMD, i.e symptoms and findings prior to HTx, family history and genetic test results if reported. From 2002 to 2022, 597 adult subjects received an HTx. Among these, 163 were deceased. Sixty-nine (42%) of these deceased patients had a non-ischemic CMP, while ninety-four (58%) had an ischemic heart disease or other acquired causes of heart failure. The mean age at HTx in the non-ischemic group was 53 years versus 54 years in the other group, and the majority were men in both groups. Genetic testing had been performed in only fourteen (20%) of the 69 HTx recipients with non-ischemic CMP. Eight patients were found to have a pathogenic variant in a known CMP gene, and for six of these patients the mutations were in genes that may also give rise to a NMD phenotype. Biopsies and other supplementary tests indicated NMD in additional three patients. Twenty-one (30 %) of the patients in the non-ischemic group had a positive family history of cardiomyopathy, arrhythmia, or suspected sudden cardiac death but were not tested In addition, 26 /69 subjects (38 %) had a possible clinical NMD phenotype based on journal records. Genetic and clinical investigations of the living HTx cohort is needed, to get a true number of genetic CMP with or without NMD in HTx recipients. The Heart-Musc Study is a combined retrospective and cross-sectional study on heart transplant (HTx) recipients. Our main hypothesis is that patients with a non-ischemic cause of cardiomyopathy (CMP) may have a genotype that can cause both cardiomyopathy and a neuromuscular disorder (NMD). In Norway, 1057 subjects have received an HTx since the first procedure performed in 1983. In this retrospective study based on medical records, we studied deceased adult HTx patients that received a transplant in the 20-year period between 2002 and 2022. During these years, genetic tests became more available than previously. We aimed to assess the prevalence of probable genetic cause of CMP with or without NMD. We have until now investigated the phenotypic CMP and NMD, i.e symptoms and findings prior to HTx, family history and genetic test results if reported. From 2002 to 2022, 597 adult subjects received an HTx. Among these, 163 were deceased. Sixty-nine (42%) of these deceased patients had a non-ischemic CMP, while ninety-four (58%) had an ischemic heart disease or other acquired causes of heart failure. The mean age at HTx in the non-ischemic group was 53 years versus 54 years in the other group, and the majority were men in both groups. Genetic testing had been performed in only fourteen (20%) of the 69 HTx recipients with non-ischemic CMP. Eight patients were found to have a pathogenic variant in a known CMP gene, and for six of these patients the mutations were in genes that may also give rise to a NMD phenotype. Biopsies and other supplementary tests indicated NMD in additional three patients. Twenty-one (30 %) of the patients in the non-ischemic group had a positive family history of cardiomyopathy, arrhythmia, or suspected sudden cardiac death but were not tested In addition, 26 /69 subjects (38 %) had a possible clinical NMD phenotype based on journal records. Genetic and clinical investigations of the living HTx cohort is needed, to get a true number of genetic CMP with or without NMD in HTx recipients.

Abstract Background Lamin A/C gene (LMNA) variants cause familial dilated cardiomyopathy (DCM) with a malignant cardiac phenotype characterized by atrioventricular (AV) block and supraventricular and ventricular arrhythmias, often preceding cardiac dilatation and dysfunction. Current guidelines recommend genetic and clinical screening of family members, starting at 10-12 years of age. However, children with LMNA variants are underrepresented in research publications and data are lacking on both the onset of a cardiac phenotype and the prevalence of cardiac events in this population. Purpose The study aimed to investigate the prevalence of cardiac events in LMNA genotype positive children and penetrance of LMNA cardiac phenotype in genotype positive paediatric relatives. Methods We conducted a longitudinal cohort study including consecutive genotype-positive LMNA patients and genotype positive relatives, all ≤18 years of age, followed between 2009 and 2022. The patients were examined by electrocardiography, Holter monitoring, and echocardiography. A cardiac phenotype was defined as the presence of either atrioventricular (AV) block, prolonged sinus arrest, atrial fibrillation/ flutter (AF), ventricular tachycardia (VT), or echocardiographic DCM. Cardiac events were defined as AF, VT, cardiac syncope, sudden cardiac arrest (SCA) or heart transplantation (Htx). Childhood-onset disease was defined as the presence of a cardiac phenotype ≤12 years of age. Results Among 44 LMNA genotype-positive children (age 10.4 [IQR 6.5-12.9] years, 34 relatives), 12 (27 %) became phenotype-positive at a median age of 12.8 [IQR 7.9-14.1] years, of which 7 (58 %) had childhood-onset disease (Figure 1). Nine (18 %) of the children experienced a cardiac event and 44 % of these were ≤12 years of age (Figure 2). Three children had AF, 5 had VT, and one had cardiac syncope. Htx was performed in two unrelated children, at 6 and 8 years of age, respectively. Among the 34 genotype-positive paediatric relatives, 21 % (n=7) became phenotype-positive at a median age of 10.9 [IQR 7.5-15.1] years, of which 57 % (n=4) had childhood-onset disease. Conclusions In a cohort of LMNA genotype children, there was a high prevalence of cardiac events and 44 % of these occurred in children ≤12 years of age. The penetrance of LMNA cardiac phenotype in genotype positive paediatric relatives was 21 %, highlighting the importance of early family screening and cardiological follow-up.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): 1) Precision Health Care Center for optimized cardiac care (ProCardio) supported by the Norwegian Research Council 2) European Research Area Network on Cardiovascular Diseases (ERA-CVD) Background/Introduction Cardiac laminopathies are malignant and pro-arrhythmic variants of familial dilated cardiomyopathy caused by mutations in the LMNA gene. Correct timing of implantable cardioverter defibrillator (ICD) implantation is crucial in these patients, but optimal timing of primary preventive ICD remains a great challenge in clinical practice. Purpose We aimed to explore threshold values by electrocardiogram and echocardiography to identify transition to a more arrhythmic phenotype in LMNA disease. Methods We prospectively included consecutively recruited LMNA genotype positive patients in a primary prevention cohort study. Patients underwent repeated clinical-, electrocardiogram- and echocardiographic examinations during long-term follow-up. Ventricular arrhythmia was defined as sustained ventricular tachycardia, appropriate therapy by a primary preventive ICD or aborted cardiac arrest. We explored electrocardiographic and echocardiographic cut-off values for increased odds of experiencing first-time ventricular arrhythmia during follow-up by threshold regression analyses. The cardiac phenotype at time of ventricular arrhythmia was assessed from electrocardiogram recording and echocardiographic examinations acquired ±12 months of the arrhythmic event. Results We included 94 LMNA genotype positive patients with no history of ventricular arrhythmia at baseline (age 38±15 years, 32% probands, 53% female). Incidence of VA was 20% (19 patients) during 4.6 (inter quartile range [IQR] 2.1-7.3) years follow-up, at mean age 50±11 years. We analysed 261 electrocardiogram recordings and 536 echocardiographic examinations. At time of first ventricular arrhythmia, most patients had pronounced conduction delay (PR interval 312 [IQR 204-430] ms) and evident left ventricular pathology (left ventricular ejection fraction [LVEF] 40±12 %, left ventricular end diastolic volume indexed [LVEDVi] 83±22 ml/m2). Electrocardiographic threshold values for increased arrhythmic risk were PR interval 280 ms (OR 1.9, 95% CI 1.5-2.5, per 5 ms increase after threshold, p<0.001), and QRS width 108 ms (OR 2.6, 95% CI 1.9-3.7, per 5 ms increase after threshold, p<0.001). Echocardiographic threshold values were LVEF 44 % (OR 1.6, 95% CI 1.4-2.0, per 5 % decrease after threshold, p<0.001), and LVEDVi threshold 77 ml/m2 (OR 1.5, 95% CI 1.3-1.8, per 5 ml/m2 increase after threshold, p<0.001) (Figure). Conclusions Incidence of first time ventricular arrhythmic event was 20% in LMNA genotype positive patients during 4.6 years of follow up. PR interval >280ms, LVEF <44% or LVEDVi >77 ml/m2 should alert the clinician of transition to a more arrhythmic phenotype in cardiac laminopathies and implantation of a primary preventive ICD should be considered.

Abstract Background Arrhythmogenic cardiomyopathy (AC) is an inheritable and progressive cardiomyopathy characterized by high risk of ventricular tachyarrhythmias and sudden cardiac death. Pediatric patients are underrepresented in AC publications, and the AC penetrance and incidence of cardiac events in children have yet to be determined. Current guidelines recommend initiating family screening in first-degree relatives after age 10–12 years, but the clinical value of this approach has not been systematically evaluated. Purpose We aimed to explore the incidence of severe cardiac events in pediatric patients with AC and to describe the phenotype in early-onset AC. Furthermore, we wanted to estimate the penetrance of AC disease in genotype positive pediatric family members. Methods In a single-center follow-up study, we included consecutive AC pediatric patients and genotype positive family members ≤18 years of age. The patients were followed regularly with electrocardiographic, structural and arrhythmic characteristics according to the AC 2010 Task Force Criteria (TFC). Penetrance of AC disease was defined as fulfilling definite AC diagnosis by the 2010 TFC. We defined severe cardiac events as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias (VAs) (sustained ventricular tachycardia or aborted cardiac arrest). Results We included 62 individuals (11 probands, 51 family members). Fourteen events (5 HTx, 9 VAs) occurred during 6±4 years of follow-up, giving a cumulative incidence of 23% and a yearly incidence rate of 4%. Seven (50%) events occurred in patients ≤12 years of age (Figure 1). All children who underwent heart transplantation were ≤12 years. At inclusion, 13 patients (21%) fulfilled definite AC diagnosis (10 probands, 3 family members). At end of follow-up, AC diagnosis were fulfilled in 20 (32%) patients (11 probands, 9 family members), indicating progression of disease in 7 patients. Mean age at definite AC diagnosis was 13±4 years and 8 patients (40%) were ≤12 years old (Figure 1). All patients diagnosed with AC <12 years of age had biventricular disease with mean LVEF 30±9% and right ventricular fractional area change 21±5% at end of follow-up. Among the family members, 5 (10%) had signs of AC disease at the time of genetic diagnosis. At end of follow-up, AC penetrance was 18% and 3 (6%) experienced severe cardiac events at a mean age of 13±6 years. Conclusion In a pediatric AC cohort of probands and genotype positive family members, we found a high incidence of VA and HTx. Half of the events occurred in children ≤12 years of age, supporting a markedly severe phenotype in early-onset AC. AC penetrance among pediatric family members identified by screening was high, with a significant incident of events. Our findings emphasize the high risk features of early-onset AC disease and indicate a need to start AC family screening in children at an younger age than recommended by current guidelines. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Norwegian Research Council

Abstract Background A subset of patients with mitral valve prolapse experience ventricular arrhythmias (VA) and even sudden cardiac death, defined as arrhythmic mitral valve prolapse (AMVP). Risk stratification of VA is challenging in this relatively young population. The predictive role of exercise testing has not been investigated. Purpose We aimed to explore if VA burden on exercise ECG can predict severe ventricular arrhythmic events in AMVP patients. Methods We included consecutive AMVP patients without prior severe VA referred to our tertiary center. Exercise bicycle ECG test by standard protocol was performed at inclusion. Non-sustained VT (nsVT) during exercise testing was defined as ≥3 consecutive ventricular beats with a rate ≥100/min lasting <30 seconds. Our endpoint of severe VA during follow-up was defined as aborted cardiac arrest, sustained ventricular tachycardia, nsVT with syncope or appropriate ICD shock therapy detected by either ECG, Holter monitoring, implantable loop recorder or primary preventive ICD. Results We included 91 AMVP patients without prior severe VA (51±16 years of age, 63% women) with exercise test at baseline. NsVT occurred in 5 patients during exercise testing. During 67±7 months of follow-up, 5 (5.5%) patients experienced severe VA. In all, 3 of the 5 (60%) with nsVT at exercise test experienced severe VA during follow-up, compared to only 2 of 86 (2%) without nsVT at exercise testing (age adjusted hazard ratio [HR] 35 [95% CI 5–249], p<0.001). Survival free from severe VA was worse in those with nsVT at exercise test (log rank p<0.001) (Figure 1). Conclusions Non-sustained VT occurring during exercise ECG testing was a strong marker of subsequent severe VA in AMVP patients without previous severe VA. These novel findings indicate that exercise testing may improve risk stratification in AMVP patients. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The Research Council of Norway.

Abstract Background Lamin A/C dilated cardiomyopathy is a highly penetrant inheritable cardiomyopathy with some patients developing muscluar dystrophy. Studies have indicated higher morbidity and mortality in men compared to women with lamin A/C. Purpose To explore sex differences in cardiac function, arrhythmias and muscular dystrophy in lamin A/C genotype positive family members of lamin A/C probands. Methods We included consecutive lamin A/C genotype positive family members recruited for cardiological evalutation based on the identification of lamin A/C genotype by cascade genetic screening. Cardiac function was assessed by echocardiography. Impaired cardiac function was defined according to guidelines as left ventricular ejection fraction (LVEF) <52% in men, <54% in women. Presence of AV-block, atrial fibrillation and ventricular arrhythmias were evaluated by12-lead ECG, Holter monitoring, and interrogation of cardiac implantable electronic devices. Presence of muscular dystrophy was assessed retrospectively from medical records, and defined as present or not based on description of typical symptoms and/or findings on neurological exam. Results We included 55 lamin A/C genotype positive family members (age 35±15 years, 49% female). Men were younger at time of evaluation (31±15 years vs. 40±14 years, p=0.047). Despite lower age, men had significantly lower LVEF (48±12% vs. 55±9%, p=0.016) (Figure left panel), and showed worse survival free from impaired cardiac function compared to women (log rank p=0.019) (Figure, mid panel). Male sex was a marker for impaired cardiac function when adjusted for age (adjusted OR 5.3 [95% CI; 1.5–18.8]). Women had higher prevalence of muscular dystrophy compared to men (35% vs. 0%, p=0.004) (Figure right panel). We observed no sex related differences for AV-block, atrial fibrillation, nor ventricular arrhythmias. Conclusions Male lamin A/C genotype family members had earlier penetrance and more frequently impaired cardiac function compared to women. AV-block and arrhythmic disease did not differ. Muscular dystrophy was more frequent in women. These findings indicate sex differences in the phenotypical expression of lamin A/C disease.

Purpose.We previously re-validated noninvasive estimation of pulmonary wedge pressure (PWP) measuring the CW pulmonary valve regurgitation end-diastolic pressure gradient (PWPecho).Using the latter as surrogate of PWP, we sought to test accuracy of left ventricular (LV) filling pressures estimation by the EAE guidelines algorithm (EAEalg) in a large non-selected population.Methods.We studied 1019 patients in sinus rhythm with GE Vivid7/9 systems (age: 10-93 y.; EF%: 13-83%, normal, n= 827 and reduced ,50%, n= 192), in whom PWPecho could be measured (feasibility 75%), with normal pulmonary vascular resistances (WU, 2).The EAEalg combined E/e' (average), left atrial volume (LAV), E/A, Edec, pulmonary venous systolic fraction (SF), and echo-derived pulmonary systolic pressure (PSPe) to obtain 3 groups: normal, high PWP and not classifiable.These were compared to the PWPecho estimate.Results: Feasibility was high for all variables (E/E' 90%, LAV 93%, E/A 95%, Edec 90%, SF 91%, PSPe 92%), and for the EAEAlg (94%).Using the EAEAlg, 17% (n=137) of patients with normal in contrast to 10% (n=19) of patients with EF,50% were not classifiable, in the former secondary to the combination of a E/E'= 9-13 range, and LAV≥ 34ml/m2.In the remaining (classified, 84%) patients, utility of EAEalg even when limited to patients with EF,50% was still hampered by a low positive predictive value (PPV) (Table ).Further, when only E/e' was tested in the same patients at ROC analysis (cutoff= 15; AUC=0.72,CI:0.6-0.8),accuracy was still impaired by a low PPV (53%), albeit a fair negative predictive value (NPV) (79%).Correlation between PWPecho and E/e' was modest even in patients with EF,50% (r=0.4,p,0.001), and at multiple regression analysis, E/ e' was independently determined by age and mitral regurgitation in all patients, and by LV end-diastolic volume in EF,50% (r= 0.7, p,0.001) and by LV mass index in EF.50% (r= 0.64, p,.001).Conclusions.Noninvasive estimation of PWP by EAE guidelines is limited by a low PPV in both patients with and without reduced LV EF.In this setting, utility of the E/e' is limited, it being influenced by patient age, preload and LV mass.