Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in ...one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates. Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death. On the basis of these findings, we conclude that mutations in the gene encoding the sarcomeric protein filamin C cause a new form of familial HMC.
Recent exome sequencing studies identified filamin C (
) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of
candidate variants in a large cohort of HCM ...patients who were also sequenced for the main sarcomere genes.
A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the
,
,
,
,
,
,
,
, and
genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20
candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (
=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign.
We provide a compelling evidence of the involvement of
in the development of HCM. Most of the
variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found
variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.
In human long-standing persistent atrial fibrillation, rotors potentially explain atrial fibrillation maintenance, but their ablation remains controversial. We aimed to explore original ...phase/frequency mapping methods to locate rotors and track changes induced by their ablation.
Thirteen patients with long-standing persistent atrial fibrillation (duration, 12-72 months) underwent phase/frequency mapping (Hilbert/Fourier transforms; CARTO-Finder) of the left and right atria (PentaRay catheter). A rotor domain was defined as an area displaying at least 3 consecutive rotations. Ablation was performed by circumferential pulmonary vein isolation plus linear ablation of extrapulmonary rotor domains. We identified 19 rotor domains in 10 patients (1.8±1.1 per patient; 7 in the right atrium versus 12 in the left atrium; 15 extrapulmonary). Overall, rotor domains (9.2±2.2 rotations) displayed higher frequency of activation (6.41 Hz; 95% confidence interval, 6.24-6.57) than nonrotor domains (6.17 Hz; 95% confidence interval, 6.1-6.23;
=0.021), with interatrial frequency gradients established by the spatial location of the rotor domain (
=0.016). Fibrillatory conduction was suggested as a decrease in the frequency of the slower atria after ablation close to main interatrial conduction fascicles (
=0.035). Ablation of rotor domains (ablation line, 3.5±0.9 cm) effectively decreased the frequency of activation in both ipsilateral and contralateral atria (
<0.05 for both), whereas ablation of nonrotor domains did not. Acute conversion to sinus rhythm was observed in 2 patients after ablation of rotor domains. At 1-year follow-up, 70% remained in sinus rhythm (85% out-of-antiarrhythmic drugs).
Rotor domains appropriately explain long-standing persistent atrial fibrillation physiology at its frequency content. Their ablation effectively modifies dynamics on restricted ablation.
To the Editor, This is the case of a 72-year-old male examined due to exertional angina, and severe inferior wall ischemia through a single-photon emission computed tomography with Tc-99. After ...obtaining the patient's written informed consent he was referred for a coronary angiography that confirmed the chronic total coronary occlusion (CTO) of the proximal right coronary artery (RCA) (figure 1A) with a J-CTO score of 3 (blunt entry shape, lesion > 20 mm, and calcification), and the presence of septal collaterals from the left anterior descending coronary artery (figure 1B, video 1 of the supplementary data). Initial antegrade approach was planned that quickly had to be changed for the retrograde approach due to the unfavorable characteristics of the lesion. Figure 1. A: total occlusion of proximal RCA. B: septal collaterals from the left anterior descending coronary artery. C: externalized retrograde wire from the septal collateral crossing the right coronary artery occlusion. D: antegrade wiring with the help of a microcatheter placed in the distal right coronary artery. E: angiographic result after occlusion predilatation and stenting with TIMI grade-1 flow. F: after drug-eluting balloon, TIMI grade-3 flow is achieved with a diseased distal vessel. After surfing across the septal collateral channels, the distal cap...
Introduction
The clinical impact of slow ventricular tachycardia (VT), occurring in patients carrying implantable cardiac defibrillators (ICD), is still under debate.
Methods and results
From the ...UMBRELLA registry (multicenter, observational, and prospective study on patients with ICD), 659 episodes of slow VT were observed in 97 patients. Untreated slow VT (
n
= 93) had longer duration (23.7 min, CI95%: 10–39), compared with episodes treated effectively by anti-tachycardia pacing (ATP;
n
= 527; 0.32 min, IC95%: 0.22–0, 48) or shock (
n
= 39; 1 min, CI95%: 0.8–1.2). Despite of longer duration, the time to the first contact with the medical services was similar to those episodes treated by ATP (50 days CI95%: 45–55 vs. 41 days CI95%: 39–44). However, both were significantly longer than the time observed in episodes treated with shock (10 days, CI95%: 6–15). This tendency was maintained with successive interrogations of the device (2nd and 3rd). There were no significant differences in mortality during follow-up (48 ± 16 months), neither other adverse outcomes, between patients who presented untreated slow TV and those who did not (log-rank
p
= 0.28). In a Cox regression analysis, the variable “presenting untreated episodes of slow VT” was not able to predict mortality. However, being in sinus rhythm (vs. atrial fibrillation, OR: 0.31,
p
= 0.009), narrower QRS (OR: 1.036,
p
= 0.037) and diabetes (OR 4.673,
p
= 0.049) appropriately predict survival.
Conclusions
Untreated slow VT does not significantly worsen patient prognosis. Our results support the limitation of therapies to ATP only, thus avoiding therapies that have been associated with increased risk of morbidity and mortality.
This study sought to assess the influence of baseline right bundle branch block (RBBB) on all-cause and cardiovascular mortality as well as sudden cardiac death (SCD) among patients undergoing ...transcatheter aortic valve replacement (TAVR).
Few data exist regarding the late clinical impact of pre-existing RBBB in TAVR recipients.
A total of 3,527 patients (mean age 82 ± 8 years, 50.1% men) were evaluated according to the presence of RBBB on baseline electrocardiography. Intraventricular conduction abnormalities were classified according to the American Heart Association, American College of Cardiology Foundation, and Heart Rhythm Society recommendations for standardization and interpretation of the electrocardiogram. TAVR complications and causes of death were defined according to Valve Academic Research Consortium 2 definitions.
RBBB was present on baseline electrocardiography in 362 patients (10.3%) and associated with higher 30-day rates of permanent pacemaker implantation (PPI) (40.1% vs. 13.5%; p < 0.001) and death (10.2% vs. 6.9%; p = 0.024). At a mean follow-up of 20 ± 18 months, pre-existing RBBB was independently associated with all-cause mortality (hazard ratio HR: 1.31; 95% confidence interval CI: 1.06 to 1.63; p = 0.014) and cardiovascular mortality (HR: 1.45; 95% CI: 1.11 to 1.89; p = 0.006) but not with SCD (HR: 0.71; 95% CI: 0.22 to 2.32; p = 0.57). Patients with pre-existing RBBB and without PPI at discharge from the index hospitalization had the highest 2-year risk for cardiovascular death (27.8%; 95% CI: 20.9% to 36.1%; log-rank p = 0.007). In a subanalysis of 1,245 patients without PPI at discharge from the index hospitalization and with complete follow-up regarding the need for PPI, pre-existing RBBB was independently associated with the composite of SCD and PPI (HR: 2.68; 95% CI: 1.16 to 6.17; p = 0.023).
Pre-existing RBBB was found in 10% of TAVR recipients and was associated with poorer clinical outcomes. Patients with baseline RBBB without permanent pacemakers at hospital discharge may be at especially high risk for high-degree atrioventricular block and/or SCD during follow-up. Future studies should evaluate strategies aimed at the early detection of patients at risk for late development of high-degree atrioventricular block.
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The optimal chronic antithrombotic regimen for patients with atrial fibrillation undergoing transcatheter aortic valve implantation (TAVI) remains uncertain. Our aim was to compare the incidence of ...late bleeding events between patients on direct oral anticoagulants (DOACs) and those on vitamin-K antagonists (VKA).
This single-center observational study included TAVI patients requiring oral anticoagulation at discharge between 2015 and 2021. The primary endpoint was any clinically significant bleeding event. Secondary endpoints were stroke, heart failure, and all-cause mortality.
A total of 702 TAVI procedures were performed, with 297 patients requiring oral anticoagulation at discharge. Among them, 206 (69.4%) received VKA and 91 (30.6%) received DOAC. Baseline clinical, procedural and in-hospital characteristics did not significantly differ between groups, except for better renal function among DOAC patients. The median length of follow-up was 2.8 years. The risk of bleeding events was higher in patients receiving DOACs than in those receiving VKA (HR, 2.27; 95%CI, 1.21-4.26; incidence of 9.7 and 4.2 events per 100 patient-years of follow-up for DOAC and VKA patients, respectively). There were no statistically significant differences in the rates of stroke (HR, 1.28; 95%CI, 0.4-4.3), heart failure hospitalization (HR, 0.92; 95%CI, 0.46-1.86), or all-cause mortality (HR, 1.02; 95%CI, 0.68-1.55).
In older patients undergoing TAVI and receiving anticoagulant therapy for atrial fibrillation, the use of DOAC was associated with a higher risk of late bleeding events than VKA.
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