Implantable cardioverter defibrillator therapy for primary prevention of sudden cardiac death in the real world: Main findings from the French multicentre DAI-PP programme (pilot phase)

This review summarizes the main findings of the French multicentre DAI-PP pilot programme, and discusses the related clinical and research perspectives. This project included retrospectively (2002–2012 period) more than 5000 subjects with structural heart disease who received an implantable cardioverter defibrillator (ICD) for primary prevention of sudden cardiac death, and were followed for a mean period of 3 years. The pilot phase of the DAI-PP programme has provided valuable information on several practical and clinically relevant aspects of primary prevention ICD implantation in the real-world population, which are summarized in this review. This pilot has led to a prospective evaluation that started in May 2018, assessing ICD therapy in primary and secondary prevention in patients with structural and electrical heart diseases, with remote monitoring follow-up using a dedicated platform. This should further enhance our understanding of sudden cardiac death, to eventually optimize the field of preventative actions

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies.

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU. We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov. Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease

Early detection of hTTR cardiac amyloidosis with bone DPD scintigraphy in a patient with a rare transthyretin mutation

International audienc

Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detected by Diphosphonates scintigraphy in patients with aTTR-familial amyloidosis

ESC Congress 2016 - Congress of the European-Society-of-Cardiology, Rome, ITALY, AUG 27-31, 2016International audiencePoste

Early detection of skin and cardiac amyloid deposits among asymptomatic carriers of hereditary pathogenic transthyretin mutation with normal electroneuromyography

International audienc

Comparison of MIBG and Diphosphonate scintigraphy in patients with aTTR-FAP

Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Barcelona, SPAIN, OCT 15-19, 2016International audienc

Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients.

KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations (type-1 LQTS) are common. Homozygous KCNQ1 mutations cause type-1 Jervell and Lange-Nielsen syndrome (JLNS) with deafness and higher sudden cardiac death risk. KCNQ1 variants causing JLNS or type-1 LQTS might have distinct phenotypic expressions in heterozygous patients. The aim of this study is to evaluate QTc duration and incidence of LQTS-related cardiac events according to genetic presentation. We enrolled LQT1 or JLNS patients with class IV/V KCNQ1 variants from our inherited arrhythmia clinic (September 1993 to January 2023). Medical history, ECG, follow-up were collected. Additionally, we conducted a thorough literature review for JLNS variants. Survival curves were compared between groups, and multivariate Cox regression models identified genetic and clinical risk factors. Among 789 KCNQ1 variants carriers, 3 groups were identified; 30 JLNS (JLNS), 161 heterozygous carriers of JLNS variants (HTZ-JLNS), 550 LQT1 heterozygous carriers of non-JLNS variants (HTZ-Non-JLNS).At diagnosis, mean age was, 3.4±4.7 years (JLNS), 26.7±21 years (HTZ-JLNS), and 26±21 years (HTZ-non-JLNS), 55.3% were female, and the mean QTc was 551±54ms (JLNS), 441±32ms (HTZ-JLNS), 467±36ms (HTZ-Non-JLNS).Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of heterozygous KCNQ1 variants carriers and had a lower risk of cardiac events than heterozygous non-JLNS variants carriers (HTZ-Non-JLNS) (HR 0.34 [0.22-0.54]; p<0.01).After multivariate analysis, 4 genetic parameters were independently associated with events: haploinsufficiency (HR=0.60 [0.37-0.97]; p=0.04), pore localization (HR=1.61 [1.14-1.2.26]; p<0.01), C-terminal localization (HR=0.67 [0.46-0.98]; p=0.04), and group (HR=0.43 [0.27-0.69]; p<0.01). Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other type 1 LQTS patients

Upper limb onset of hereditary transthyretin amyloidosis is common in non-endemic areas.

The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset. The French TTR Familial Amyloid Polyneuropathy database was used for a retrospective evaluation of 32 consecutive patients with upper limb onset of the neuropathy (study group) and they were compared to 31 Portuguese early-onset patients and 99 late-onset patients without upper limb onset. Initial upper limb symptoms were mostly sensory. Lower limb symptoms began 2.3 ± 3 years after upper limb symptoms. Twenty-four (75%) patients were initially misdiagnosed, with 15 different diagnoses. More patients in the study group had a Neuropathy Impairment Score upper limb/lower limb ratio > 1 compared to the late-onset patient group. The study group had significantly more pronounced axonal loss in the median and ulnar motor nerves and the ulnar sensory and sural nerves. On radial nerve biopsies (n = 11), epineurial vessels were abnormal in six cases, including amyloid deposits in vessel walls (3/11), with vessel occlusion in two cases. Upper limb onset of hereditary ATTR neuropathy is not rare in non-endemic areas. It is important to propose early TTR sequencing of patients with idiopathic upper limb neuropathies, as specific management and treatment are required