Prognostic value of the 12-lead surface electrocardiogram in sarcomeric hypertrophic cardiomyopathy: data from the REMY French register.

AIMS: To identify independent electrocardiogram (ECG) predictors of long-term clinical outcome based on standardized analysis of the surface ECG in a large multicentre cohort of patients with sarcomeric hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Retrospective observational study from the REMY French HCM clinical research observatory. Primary endpoint was a composite of all-cause mortality, major non-fatal arrhythmic events, hospitalization for heart failure (HF), and stroke. Secondary endpoints were components of the primary endpoint. Uni- and multivariable Cox proportional hazard regression analysis was performed to identify independent predictors. Among 994 patients with HCM, only 1.8% had a strictly normal baseline ECG. The most prevalent abnormalities were inverted T waves (63.7%), P-wave abnormalities (30.4%), and abnormal Q waves (25.5%). During a mean follow-up of 4.0 ± 2.0 years, a total of 272 major cardiovascular events occurred in 217 patients (21.8%): death or heart transplant in 98 (9.8%), major arrhythmic events in 40 (4.0%), HF hospitalization in 115 (11.6%), and stroke in 23 (2.3%). At multivariable analysis using ECG covariates, prolonged QTc interval, low QRS voltage, and PVCs of right bundle branch block pattern predicted worse outcome, but none remained independently associated with the primary endpoint after adjustment on main demographic and clinical variables. For secondary endpoints, abnormal Q waves independently predicted all-cause death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.23-4.47; P = 0.009] and prolonged QTc the risk of HF hospitalization (HR 1.006, 95% CI 1.001-1.011; P = 0.024). CONCLUSION: The 12-lead surface ECG has no independent value to predict the primary outcome measure in patients with HCM. The 12-lead surface ECG has been widely used as a screening tool in HCM but its prognostic value remains poorly known. The value of baseline surface ECG to predict long-term clinical outcomes was studied in a cohort of 994 patients with sarcomeric HCM. The surface ECG has no significant additional value to predict outcome in this patient population.

FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations.

Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.

High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations.

AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations. METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations. CONCLUSION: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management.

Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance in Cardiac Amyloidosis.

BACKGROUND: The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced by cardiac involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown. METHODS AND RESULTS: Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P<0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1-13.7; P<0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E', and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3-13.1; P<0.05). CONCLUSIONS: There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after adjustment for known prognostic factors.

Abnormal septal convexity into the left ventricle occurs in subclinical hypertrophic cardiomyopathy.

BACKGROUND: Sarcomeric gene mutations cause hypertrophic cardiomyopathy (HCM). In gene mutation carriers without left ventricular (LV) hypertrophy (G + LVH-), subclinical imaging biomarkers are recognized as predictors of overt HCM, consisting of anterior mitral valve leaflet elongation, myocardial crypts, hyperdynamic LV ejection fraction, and abnormal apical trabeculation. Reverse curvature of the interventricular septum (into the LV) is characteristic of overt HCM. We aimed to assess LV septal convexity in subclinical HCM. METHODS: Cardiovascular magnetic resonance was performed on 36 G + LVH- individuals (31 ± 14 years, 33 % males) with a pathogenic sarcomere mutation, and 36 sex and age-matched healthy controls (33 ± 12 years, 33 % males). Septal convexity (SCx) was measured in the apical four chamber view perpendicular to a reference line connecting the mid-septal wall at tricuspid valve insertion level and the apical right ventricular insertion point. RESULTS: Septal convexity was increased in G + LVH- compared to controls (maximal distance of endocardium to reference line: 5.0 ± 2.5 mm vs. 1.6 ± 2.4 mm, p ≤ 0.0001). Expected findings occurred in G + LVH- individuals: longer anterior mitral valve leaflet (23.5 ± 3.0 mm vs. 19.9 ± 3.1 mm, p ≤ 0.0001), higher relative wall thickness (0.31 ± 0.05 vs. 0.29 ± 0.04, p ≤ 0.05), higher LV ejection fraction (70.8 ± 4.3 % vs. 68.3 ± 4.4 %, p ≤ 0.05), and smaller LV end-systolic volume index (21.4 ± 4.4 ml/m(2) vs. 23.7 ± 5.8 ml/m(2), p ≤ 0.05). Other morphologic measurements (LV angles, sphericity index, and eccentricity index) were not different between G + LVH- and controls. CONCLUSIONS: Septal convexity is an additional previously undescribed feature of subclinical HCM.

Frequency of drug-induced valvular heart disease in patients previously exposd to benfluorex: a multicentre prospective study.

AIMS: The epidemiologic link between benfluorex use and an increased global frequency of left heart valve regurgitation has been well documented. However, no data linking previous drug exposure to the frequency of diagnosis of drug-induced valvular heart disease (DI-VHD) are available. The present study was conducted to address this issue. METHODS AND RESULTS: This echocardiography reader-blinded, controlled study conducted in 10 centres between February 2010 and February 2012 prospectively included 835 subjects previously exposed to benfluorex referred by primary care physicians for echocardiography. Based on blinded off-line analysis, echocardiography findings were classified as: (i) DI-VHD⁺ for patients with an echocardiographic diagnosis of DI-VHD, (ii) inconclusive, and (iii) DI-VHD⁻ for patients without signs of DI-VHD. Fifty-seven (6.8%) patients exposed to benfluorex were classified as DI-VHD⁺, 733 (87.8%) patients were classified as DI-VHD⁻, and 45 (5.4%) were classified as inconclusive. Mitral and aortic DI-VHD were reported in 43 patients (5.1%) and 30 (3.6%) patients, respectively. Longer duration of exposure, female gender, smoking, and lower BMI were independently associated with a diagnosis of DI-VHD. Good inter-observer reproducibility was observed for the echocardiography classification (Kappa = 0.83, P < 0.00001). CONCLUSIONS: About 7% of patients without a history of heart valve disease previously exposed to benfluorex present echocardiography features of DI-VHD. Further studies are needed to study the natural history of DI-VHD and to identify risk factors for the development of drug-induced valve lesions.

Hypersynchrony in sarcomeric hypertrophic cardiomyopathy: description and mechanistic approach using multimodal electro-mechanical non-invasive cartography (HSYNC study).

Background: Little is known about left ventricular (LV) sequences of contraction and electrical activation in hypertrophic cardiomyopathy (HCM). A better understanding of the underlying relation between mechanical and electrical activation may allow the identification of predictive response criteria to right ventricular DDD pacing in obstructive patients. Objective: To describe LV mechanical and electrical activation sequences in HCM patients compared to controls. Materials and methods: We prospectively studied, in 40 HCM patients (20 obstructive and 20 non-obstructive) and 20 healthy controls: (1) mechanical activation using echocardiography at rest and cardiac magnetic resonance imaging, (2) electrical activation using 3-dimensional electrocardiographic mapping (ECM). Results: In echocardiography, healthy controls had a physiological apex-to-base delay (ABD) during contraction (23.8 ± 16.2 ms). Among the 40 HCM patients, 18 HCM patients presented a loss of this ABD (<10 ms, defining hypersynchrony) more frequently than controls (45% vs. 5%, p = 0.017). These patients had a lower LV end-diastolic volume (71.4 ± 9.7 ml/m2 vs. 82.4 ± 14.8 ml/m2, p = 0.01), lower native T1 values (988 ± 32 ms vs. 1,028 ± 39 ms, p = 0.001) and tended to have lower LV mass (80.7 ± 23.7 g/m2 vs. 94.5 ± 25.3 g/m2, p = 0.08) compared with HCM patients that had a physiological contraction sequence. There was no significant relation between ABD and LV outflow tract obstruction. While HCM patients with a physiological contraction sequence presented an ECM close to those encountered in controls, patients with a loss of ABD presented a particular pattern of ECM with the first potential more frequently occurring in the postero-basal region. Conclusion: The LV contraction sequence can be modified in HCM patients, with a loss of the physiological ABD, and is associated with smaller LV dimensions and a particular pattern of ECM. Further research is needed to determine whether this pattern is related to an electrical substrate or is the consequence of the hypertrophied heart's specific geometry. Clinical trial registration: ClinicalTrial.gov: NCT02559726.

Target population for a selective cardiac myosin inhibitor in hypertrophic obstructive cardiomyopathy: Real-life estimation from the French register of hypertrophic cardiomyopathy (REMY).

BACKGROUND: The efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a first-in-class treatment for symptomatic hypertrophic obstructive cardiomyopathy. AIMS: To assess the profile and burden of cardiac myosin inhibitor candidates in the hypertrophic cardiomyopathy prospective Register of hypertrophic cardiomyopathy (REMY) held by the French Society of Cardiology. METHODS: Data were collected at baseline and during follow-up from patients with hypertrophic cardiomyopathy enrolled in REMY by the three largest participating centres. RESULTS: Among 1059 adults with hypertrophic cardiomyopathy, 461 (43.5%) had obstruction; 325 (30.7%) of these were also symptomatic, forming the "cardiac myosin inhibitor candidates" group. Baseline features of this group were: age 58±15years; male sex (n=196; 60.3%); diagnosis-to-inclusion delay 5 (1-12)years; maximum wall thickness 20±6mm; left ventricular ejection fraction 69±6%; family history of hypertrophic cardiomyopathy or sudden cardiac death (n=133; 40.9%); presence of a pathogenic sarcomere gene mutation (n=101; 31.1%); beta-blocker or verapamil treatment (n=304; 93.8%), combined with disopyramide (n=28; 8.7%); and eligibility for septal reduction therapy (n=96; 29%). At the end of a median follow-up of 66 (34-106) months, 319 (98.2%) were treated for obstruction (n=43 [13.2%] received disopyramide), 46 (14.2%) underwent septal reduction therapy and the all-cause mortality rate was 1.9/100 person-years (95% confidence interval 1.4-2.6) (46 deaths). Moreover, 41 (8.9%) patients from the initial hypertrophic obstructive cardiomyopathy group became eligible for a cardiac myosin inhibitor. CONCLUSIONS: In this cohort of patients with hypertrophic cardiomyopathy selected from the REMY registry, one third were eligible for a cardiac myosin inhibitor.

Clinical outcomes for 2788 patients with transthyretin amyloidosis: Tafamidis meglumine early access program in France.

BACKGROUND: Early access experience in France with tafamidis meglumine, a selective transthyretin stabilizer for transthyretin-related amyloidosis cardiomyopathy (ATTR-CM), following transthyretin-related amyloidosis (ATTR) polyneuropathy approval and positive ATTR-ACT study results. AIM: To describe the characteristics and clinical outcomes for patients in the French ATTR-CM tafamidis meglumine early access programme (28 Nov 2018 to 01 Jun 2021). METHODS: Patients with confirmed ATTR-CM received tafamidis meglumine 20mg/day or 80mg/day. Demographic and clinical data were collected prospectively until patients discontinued treatment or died, or the programme ended. RESULTS: Overall, 222 physicians from 126 centres enrolled 2788 patients. The median age was 82years, 81.6% were male and New York Heart Association severity was class I for 12.8%, class II for 60.1% and class III for 27.0%. Overall, 1943 (74.6%) had genetic testing, and the results were available at tafamidis start for 1208 (62.2%) patients: 995 (82.4%) had wild-type ATTR and 213 (17.6%) had hereditary ATTR. Most patients started treatment≤12months after diagnosis (88.3%): 2268 (81.3%) at 20mg/day, with 401 (17.7%) increasing to 80mg/day. Median follow-up duration was 11.8months. New York Heart Association class improved or remained stable for 1299 (77.6%), whereas 376 (22.4%) worsened between inclusion and last follow-up. Among patients initiated at 80mg, 297 (81.1%) improved or remained stable and 69 (18.9%) worsened. New York Heart Association class progression did not vary with age. The 18-month survival rates were 89.8% (95% confidence interval: 87.0-92.0) among patients aged<80years, and 86.5% (95% confidence interval: 83.9-88.7) among those aged≥80years. CONCLUSIONS: Early tafamidis meglumine access was given to 2788 patients with ATTR-CM. New York Heart Association class progression and survival were consistent with previously published data.

Systematic analysis of SCN5A variants associated with inherited cardiac diseases.

BACKGROUND: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes or pleiotropy, which have not been systematically described. In addition, the involvement of SCN5A in dilated cardiomyopathies (DCMs) remains controversial. OBJECTIVE: We aimed to evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and to determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers. METHODS: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced with a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped. RESULTS: The study included 170 P/LP variants found in 495 patients. Of them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, 6 with progressive cardiac conduction disease, 4 with multifocal ectopic Purkinje-related premature contractions, and 3 with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Of those, 8 were carried by 8 patients presenting with DCM with a debatable causative genotype/phenotype link. CONCLUSION: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960) if not questionable.

Increased risk of left heart valve regurgitation associated with benfluorex use in patients with diabetes mellitus: a multicenter study.

BACKGROUND: Benfluorex was withdrawn from European markets in June 2010 after reports of an association with heart valve lesions. The link between benfluorex and valve regurgitations was based on small observational studies and retrospective estimations. We therefore designed an echocardiography-based multicenter study to compare the frequency of left heart valve regurgitations in diabetic patients exposed to benfluorex for at least 3 months and in diabetic control subjects never exposed to the drug. METHODS AND RESULTS: This reader-blinded, controlled study conducted in 10 centers in France between February 2010 and September 2011 prospectively included 376 diabetic subjects previously exposed to benfluorex who were referred by primary care physicians for echocardiography and 376 diabetic control subjects. Through the use of propensity scores, 293 patients and 293 control subjects were matched for age, sex, body mass index, smoking, dyslipidemia, hypertension, and coronary artery disease. The main outcome measure was the frequency of mild or greater left heart valve regurgitations. In the matched sample, the frequency and relative risk (odds ratio) of mild or greater left heart valve regurgitations were significantly increased in benfluorex patients compared with control subjects: 31.0% versus 12.9% (odds ratio, 3.55; 95% confidence interval, 2.03-6.21) for aortic and/or mitral regurgitation, 19.8% versus 4.7% (odds ratio, 5.29; 95% confidence interval, 2.46-11.4) for aortic regurgitation, and 19.4% versus 9.6% (odds ratio, 2.38; 95% confidence interval, 1.27-4.45) for mitral regurgitation. CONCLUSIONS: Our results indicate that the use of benfluorex is associated with a significant increase in the frequency of left heart valve regurgitations in diabetic patients. The natural history of benfluorex-induced valve abnormalities needs further research.

Pre- and intra-procedural predictors of reverse remodeling after cardiac resynchronization therapy: an MRI study.

INTRODUCTION: Response rate after cardiac resynchronization therapy (CRT) remains suboptimal. We sought to identify pre- and intraprocedural predictors of response using MRI. METHODS AND RESULTS: Sixty patients underwent MRI before CRT. Left ventricular (LV) volumes and ejection fraction were assessed on cine images. Intra-LV dyssynchrony was defined as the maximal delay between first peaks of radial wall motion over 20 segments. Myocardial scar extent was quantified using delayed-enhanced MRI. After CRT, the paced LV segment was characterized on preprocedural MRI with respect to presence of scar and mechanical delay, the latter being quantified using time to first peak of wall motion, expressed in percentage of the total LV activation. Echocardiography was performed before and 6 months after CRT to quantify reverse remodeling (RR). Mean RR at 6 months was 30 ± 29% of baseline LV end-systolic volume. At univariate analysis, RR related to baseline LV end-diastolic and end-systolic volumes (R(2) = 0.101, P = 0.01; R(2) = 0.072, P = 0.04), intra-LV mechanical dyssynchrony (R(2) = 0.351, P < 0.0001), scar extent (R(2) = 0.273, P < 0.0001), and presence of scar at pacing site (R(2) = 0.100, P = 0.01). QRS duration and mechanical delay at pacing site were not found related to RR (R(2) = 0.041, P = 0.12 and R(2) = 0.012, P = 0.4, respectively). At multivariate analysis intra-LV mechanical dyssynchrony, scar extent, and LV end-diastolic volume were independent predictors of RR (R(2) = 0.307, P = 0.001; R(2) = 0.096, P = 0.002, R(2) = 0.078, P = 0.005, respectively). CONCLUSION: Intra-LV dyssynchrony and scar extent are independent predictors of RR after CRT. Scar at pacing site is associated to a lesser response to CRT. Mechanical delay at this site has no impact on the response.

Venous dysfunction in obstructive hypertrophic cardiomyopathies: Results from the "HCM-Vein" pilot study.

Background: Hypertrophic cardiomyopathies (HCM) can be complicated by left ventricular outflow-tract obstruction (LVOTO) responsible for disabling exercise symptoms, a phenomenon influenced by hemodynamic factors including venous return. Methods: We aimed to evaluate venous dysfunction in obstructive HCM patients compared to healthy controls, and to investigate the relationship between venous dysfunction parameters and LVOTO in HCM. This is a clinical, monocentric, prospective, pilot study, in a tertiary care center. We investigated venous function using venous air plethysmography, and endothelial function. Results: Among the 30 symptomatic obstructive HCM patients, 30% (n = 9) presented abnormal venous residual volume fraction (RVFv) which translates in elevated ambulatory venous pressure vs. 0% in the 10 healthy controls (p < 0.05). Comparing obstructive HCM patients with abnormal RVFv (n = 9) to other obstructive HCM patients with normal RVFv (n = 21), there were no significant differences in terms of age, sex (67% male), and classical echocardiographic parameters both at rest and during exercise, except for left ventricular end-diastolic volume index which was significantly lower in the group with abnormal RVFv compared to the other HCM patients (40.1 ± 9.0 ml/m2 vs. 50.2 ± 10.6 ml/m2, p = 0.01). Fifty six percent of obstructive HCM patients with abnormal RVFv had an absolute increase in Willebrand factor (vs. 26% of other obstructive HCM patients, p < 0.05). Conclusions: In this pilot monocentric study, venous insufficiency was observed in about 30% of symptomatic obstructive HCM patients. Patients with venous insufficiency had more frequently a smaller LV cavity volume. Due to the small sample size, this study is only hypothesis-generating, and further investigations are needed.

Abnormal Cellular Phenotypes Induced by Three TMPO/LAP2 Variants Identified in Men with Cardiomyopathies.

A single missense variant of the TMPO/LAP2α gene, encoding LAP2 proteins, has been associated with cardiomyopathy in two brothers. To further evaluate its role in cardiac muscle, we included TMPO in our cardiomyopathy diagnostic gene panel. A screening of ~5000 patients revealed three novel rare TMPO heterozygous variants in six males diagnosed with hypertrophic or dilated cardiomypathy. We identified in different cellular models that (1) the frameshift variant LAP2α p.(Gly395Glufs*11) induced haploinsufficiency, impeding cell proliferation and/or producing a truncated protein mislocalized in the cytoplasm; (2) the C-ter missense variant LAP2α p.(Ala240Thr) led to a reduced proximity events between LAP2α and the nucleosome binding protein HMGN5; and (3) the LEM-domain missense variant p.(Leu124Phe) decreased both associations of LAP2α/ß with the chromatin-associated protein BAF and inhibition of the E2F1 transcription factor activity which is known to be dependent on Rb, partner of LAP2α. Additionally, the LAP2α expression was lower in the left ventricles of male mice compared to females. In conclusion, our study reveals distinct altered properties of LAP2 induced by these TMPO/LAP2 variants, leading to altered cell proliferation, chromatin structure or gene expression-regulation pathways, and suggests a potential sex-dependent role of LAP2 in myocardial function and disease.

Early detection of left ventricular systolic dysfunction using two-dimensional speckle tracking strain evaluation in healthy subjects after acute alcohol intoxication.

OBJECTIVES: We evaluated the ability of two-dimensional speckle tracking strain echocardiography to detect left ventricular (LV) systolic dysfunction as compared with LV ejection fraction (EF) in healthy subjects following acute alcohol intoxication. METHODS AND RESULTS: In total, 25 healthy subjects were investigated using echocardiography 4-6 hours after the onset of alcohol intoxication at a regional festive gathering, and then compared to 23 healthy control subjects without alcohol consumption. Heart rate, blood pressure, blood alcohol level, LV volumes, EF, shortening fraction, E/A ratio, as well as global longitudinal strain (LS) were recorded. Mean blood alcohol level was 1.3 ± 0.3 g.L(-1) . Mean systolic blood pressure and heart rate were slightly increased in the alcohol group compared to controls (147.5 ± 21.8 mmHg vs 127.0 ± 9.9 mmHg, P = 0.003, and 79.7 ± 10.7 bpm vs 70.6 ± 7.6 bpm, P < 0.001, respectively). While there was no significant difference in terms of LVEF (62.9 ± 4.4% vs 64.8 ± 5.9%, P = 0.18) or shortening fraction (34.7 ± 5.9% vs 36.0 ± 4.3%, P = 0.54), global LS was significantly impaired (-17.8 ± 2.0% vs -21.2 ± 1.8%, P < 0.001). In addition, subjects who consumed alcohol had increased LV end-diastolic (108.3 ± 20.1 mL vs 95.5 ± 14.6 mL, P = 0.037) and end-systolic volumes (41.6 ± 11.4 mL vs 33.7 ± 6.9 mL, P = 0.024), along with depressed aortic time-velocity integral (19.9 ± 3.2 mL vs 21.9 ± 2.5 mL, P = 0.034). According to multivariate linear regression analyses, blood alcohol level was the only factor significantly associated with global LS (ß=-3.6 ± 1.0, P = 0.005). CONCLUSION: Alcohol intoxication around festive days induces acute LV contraction abnormalities, which may be detected using global LS by speckle tracking at an earlier stage and more accurately than LVEF decreases.

Fast track echo of abdominal aortic aneurysm using a real pocket-ultrasound device at bedside.

BACKGROUND: Ultraminiaturization of echographic systems extraordinarily provides the image "within" the clinical examination. Abdominal aorta aneurysm (AAA) diagnosis based on conventional evaluation with a dedicated operator and ultrasound machine is still controversial due to the lack of evidence of the proposed management and guidelines' cost-effectiveness. We hypothesized that less expensive ultraportable devices could identify AAA with the same level of accuracy as conventional approaches. METHODS: A first step of this study was to validate the VSCAN's image capabilities in patients referred to the vascular Doppler laboratory. Abdominal aorta measurements were performed by an experienced physician using conventional equipment followed by a second blinded physician using the ultraportable device VSCAN. Then, 204 patients hospitalized in our cardiology institute were prospectively included for a systematic screening of AAA at bedside using the VSCAN in order to determine the feasibility and impact of fast track evaluation compared to clinical examination. RESULTS: A strong correlation was obtained between measurements of abdominal aorta diameters using the two ultrasound systems (r = 0.98, CI: 0.97-0.99, P < 0.001) with 100% of agreement for AAA diagnosis. In the second part of the study, visualization and measurement of the transverse diameter of the abdominal aorta was obtained in 199 patients, resulting in a feasibility of 97.5%. Among these patients, 18 AAAs were detected, which corresponds to a prevalence of 9%, whereas clinical evaluation did not detect any of them. Patients with AAA were more likely men (77.77% vs. 57.45%, P < 0.05) and hypertensive (88.8% vs. 56.9%, P < 0.05) as compared to those without AAA. Two patients with large AAA were quickly referred to the surgery department. CONCLUSION: Considering its low cost, diagnostic accuracy, and widespread availability, screening for AAA using an ultraportable ultrasound device such as VSCAN by an experienced physician is promising and should be used as an extension of routine physical examination in vascular patients.

Comparison of Surgical Ventricular Septal Reduction to Alcohol Septal Ablation Therapy in Patients with Hypertrophic Cardiomyopathy.

Ventricular septal myectomy (SM) and alcohol septal ablation (ASA), 2 septal reduction therapies (SRTs), are recommended in symptomatic obstructive hypertrophic cardiomyopathy (HCM) despite maximum tolerated medical therapy. Contradictory results between the outcomes of these 2 types of therapies persist to this day. The objective of this study was to compare in-hospital and mid-term outcomes of SM versus ASA, at a nationwide level in France. We collected information on patients who underwent SRT for HCM using the French nationwide Programme de Médicalisation des Systèmes d'Information database between 2010 and 2019. A total of 1,574 patients were identified in the database, including 340 patients in the SM arm and 1,234 patients in the ASA arm. No difference during the median follow-up of 1.3 years between the 2 groups was noted in terms of mortality (adjusted incidence rate ratio 0.687, 95% confidence interval 0.361 to 1.309, p = 0.25). However, there was a significantly lower risk of all-cause stroke (adjusted incidence rate ratio 0.180, 95% confidence interval 0.058 to 0.554, p = 0.003) in the ASA group. In conclusion, in our "real-life" data from France, mortality after SRT in patients with HCM was similar after ASA or SM. Moreover, ASA was more widely used than SM despite European Society of Cardiology guidelines recommendations.

Hypertrophic cardiomyopathies requiring more monitoring for less atrial fibrillation-related complications: a clustering analysis based on the French registry on hypertrophic cardiomyopathy (REMY).

AIMS: Defining the risk of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) patients is an important clinical and prognostic challenge. The aim of this study is to determine HCM phenogroups with different risk of AF occurrence at 5 years. METHODS AND RESULTS: We applied retrospectively the Bayesian method, which can analyze a large number of variables, to differentiate phenogroups of patients with different risks of AF and prognoses across a French prospective on-going hospital-based registry of adult HCM patients (REMY). Clinical and imaging data were prospectively recorded, and patients were followed for 5 years. A total of 1431 HCM patients were recruited, including 1275 analyzed in the present study after exclusion criteria. The population included 412 women, 369 patients with obstructive HCM, and 252 implanted with an ICD. AF occurred in 167 (11.6%) patients during the 5 year follow-up. Three phenogroups were defined according to their common clinical and echocardiographic characteristics. Patients at the highest risk were oldest, more often female, with more frequent comorbidities, anteroposterior diameter of the left atrium was significantly greater, with diastolic dysfunction, outflow-tract obstruction, and mitral valve abnormality, and presented higher pulmonary artery pressure and/or right-ventricular dysfunction. These also had a higher risk of all-cause hospitalizations and death. CONCLUSION: Based on a clustering analysis, three phenogroups of HCM according to the risk of AF occurrence can be identified. It can indicate which patients should be more monitored and/or treated, particular to prevent the risk of stroke.