Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADH-associated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identified 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identified, were studied by minigene reporter assay confirming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identified in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identified APOE sequence changes were predicted to impact protein function.

Effect of ivabradine on left ventricular remodelling after reperfused myocardial infarction: A pilot study.

BACKGROUND: Heart rate is a major determinant of myocardial oxygen demand; in ST-segment elevation myocardial infarction (STEMI), patients treated with primary percutaneous intervention (PPCI), heart rate at discharge correlates with mortality. Ivabradine is a pure heart rate-reducing agent that has no effect on blood pressure and contractility, and can reverse left ventricular (LV) remodelling in patients with heart failure. AIMS: To evaluate whether ivabradine, when added to current guideline-based therapy, improves LV remodelling in STEMI patients treated with PPCI. METHODS: This paired-cohort study included 124 patients between June 2011 and July 2012. Ivabradine (5mg twice daily) was given promptly after PPCI, along with beta-blockers, to obtain a heart rate<60 beats per minute (ivabradine group). This group was matched with STEMI patients treated in line with current guidelines, including beta-blockers (bisoprolol), according to age, sex, infarct-related coronary artery, ischaemia time and infarct size determined by initial cardiac magnetic resonance imaging (CMR) (control group). Statistical analyses were performed according to an intention-to-continue treatment principle. CMR data at 3 months were available for 122 patients. RESULTS: Heart rate was lower in the ivabradine group than in the control group during the initial CMR (P=0.02) and the follow-up CMR (P=0.006). At the follow-up CMR, there was a smaller increase in LV end-diastolic volume index in the ivabradine group than in the control group (P=0.04). LV end-systolic volume index remained unchanged in the ivabradine group, but increased in the control group (P=0.01). There was a significant improvement in LV ejection fraction in the ivabradine group compared with in the control group (P=0.04). CONCLUSIONS: In successfully reperfused STEMI patients, ivabradine may improve LV remodelling when added to current guideline-based therapy.

First report of a subacute stent thrombosis in a prasugrel resistant patient successfully managed with ticagrelor.

Prasugrel is a widely used antiplatelet agent in the setting of percutaneous coronary intervention. In case of resistance to this third-generation thienopyridine, choices of alternative drugs remain limited. Here, we describe a case of a 49-year-old man with stent thrombosis occurring 5 days after drug-eluting stent implantation despite a well-conducted antiplatelet therapy with aspirin and prasugrel. Evaluation of platelet functions by different tests revealed prasugrel resistance. Genotyping for various CYP single-nucleotide polymorphisms showed that the patient carried mutant alleles encoding enzymes CYP2B6 and CYP2C9 involved in prasugrel metabolic pathway. Strikingly, an adequate platelet response was rapidly obtained after switching from prasugrel to ticagrelor.

The role of echocardiography in the assessment of right ventricular systolic function in patients with transposition of the great arteries and atrial redirection.

BACKGROUND: Although dysfunction of the systemic right ventricle (RV) in patients with complete transposition of the great arteries (TGA) after atrial redirection by Mustard or Senning procedures is well recognized, there are few data on systemic RV geometry and function. Echocardiography is a widely available imaging technique that is particularly suitable for clinical follow-up because of its non-invasive nature, low cost and lack of ionizing radiation. AIM: To examine the feasibility and variability of transthoracic echocardiography variables in the assessment of the systemic RV. METHODS: Multivariable transthoracic echocardiographic analysis, including assessment of global function variables (RV ejection fraction [RVEF; Simpson's method], RV fractional shortening [RVFS] and dP/dt), longitudinal function variables (tricuspid annular plane systolic excursion [TAPSE], peak systolic velocity at the junction of the RV free wall and the tricuspid annulus, assessed with pulsed tissue Doppler imaging [S' TDI]), tricuspid regurgitation and asynchrony, was performed in 35 consecutive patients with TGA after atrial redirection. Functional variables were compared with magnetic resonance imaging (MRI). Inter- and intraobserver echocardiographic analysis variability was assessed in ten randomly selected cases. RESULTS: Global and longitudinal function variables were not correlated with RVEF calculated by MRI, except for S' TDI, which was weakly correlated (P = 0.02, r = 0.37). Asynchrony assessment was feasible in all patients. Inter- and intraobserver echocardiographic analysis variability was high for RVEF, RVFS and dP/dt (> 10%), and low for TAPSE and S' TDI (5%). CONCLUSION: Owing to geometric changes, presumed contractility pattern shift and retrosternal position, conventional echocardiographic variables are not relevant for RV function assessment. Assessment of asynchrony and tricuspid regurgitation is easily feasible in routine practice and highly reproducible. Echocardiography does not permit complete assessment of the systemic RV after atrial redirection but is fully complementary with MRI and should not be abandoned. Future improvements in transducers and dedicated software should permit major improvements in the near future.

Large right ventricular fibroma in a 6-month-old infant.

This report describes the case of a 6-month-old girl with a large cardiac fibroma in the right ventricle. Ventricular tachycardia associated with the fibroma was successfully treated with amiodarone. At the age of 3 years, surgical resection was indicated because of right ventricular outflow tract obstruction caused by progression of the tumor. The fibroma was successfully resected, and further follow-up evaluation was uneventful.

Effects of nonsystemic ventricular pacing in patients with transposition of the great arteries and atrial redirection.

INTRODUCTION: Ventricular pacing may add additional risk for right ventricular (RV) dysfunction in patients with transposition of the great arteries (TGA) and atrial redirection. The aim of our study was to evaluate the effects of long-term nonsystemic ventricular pacing on cardiac function, dyssynchrony, and clinical performance in patients with systemic RV. METHODS AND RESULTS: Forty-six adults with TGA and atrial redirection, of whom 11 were permanently paced at the nonsystemic ventricle, underwent assessment of clinical status and exercise stress testing, as well as echocardiography to assess parameters of RV function and dyssynchrony. In paced patients, median NYHA functional class was II, which was significantly higher than in nonpaced patients (median class I; P = 0.002). Maximum performance and peak oxygen consumption on exercise testing were significantly lower in paced patients when compared with nonpaced patients (100 ± 30 vs 120 ± 32 W and 22 ± 6 vs 27 ± 7 mLO(2)/kg/min, respectively; P < 0.05 for both). On echocardiography, RV shortening fraction (27 ± 11 vs 33 ± 10%), RV ejection fraction (39 ± 7 vs 44 ± 10%) and RV dP/dt(max) (891 ± 470 vs 1,024 ± 318 mmHg/s) were significantly lower (P < 0.05 for all) in paced versus nonpaced patients. Inter- and intraventricular dyssynchrony was most pronounced in the paced group (99 ± 10 vs 25 ± 9 ms and 70 ± 29 vs 21 ± 15 ms, respectively; P < 0.001 for both). CONCLUSIONS: Long-term pacing of the nonsystemic ventricle in patients with atrial switch for TGA was associated with significantly impaired functional status, exercise capacity, and systemic ventricular function.