No abstract

Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that has been recommended in clinical practice guidelines to reduce morbidity and mortality in patients with chronic, symptomatic heart failure (HF) with reduced ejection fraction (HFrEF). This review provides an overview of ARNI therapy, proposes strategies to improve the implementation of sacubitril/valsartan in clinical practice, and provides clinicians with evidence-based, practical guidance on the use of sacubitril/valsartan in patients with HFrEF. Despite evidence demonstrating the benefits of ARNI therapy over standard of care, only a fraction of eligible patients takes sacubitril/valsartan. Barriers preventing the prescription of sacubitril/valsartan in eligible patients may include practitioners’ unfamiliarity with ARNIs, safety concerns, and payer reimbursement issues. The optimal implementation of sacubitril/valsartan in clinical practice has the potential to reduce the overall burden of HF. Throughout this review, we describe our experience with sacubitril/valsartan, including strategies for the management of adverse events and common patient concerns. In addition, a strategy for the gradual introduction of sacubitril/valsartan using a treatment sequence scheme is proposed.

No abstract

Most forms of congenital heart disease (CHD) result from aberrations in cardiac morphogenesis including errors in septation, valve formation, and proper patterning of the great vessels. Transcription factors are key proteins that dictate mRNA synthesis rate and subsequent protein production in most eukaryotes. NFATC1 belongs to the Rel family of transcription factors. In mice, it is expressed in the embryonic heart and is restricted to the endocardium where it plays a major role in valve formation. To establish a role for NFATC1 in CHD, we started screening for mutations in the exons encoding the DNA-binding domain of NFATC1 in patients enrolled in our study on CHD in Lebanon. DNA was extracted from patients with pulmonary stenosis (PS), tricuspid atresia (TA) and ventricular septal defect (VSD). PCR amplification and DNA sequencing were done on the patients and their parents and (or) siblings. PCR amplification of the exon 7 region showed that 2 bands are obtained in 57% of patients with CHD (32/56) and in 45% of their healthy parents and (or) siblings. Sequencing of the 2 bands revealed that both are amplicons of the exon 7 region, and that the additional band harbors an additional 44 nucleotides segment in the intronic region. The homozygous form of this allele was only present in patients with VSD (2/21). A screen of a pool of 81 healthy, unrelated individuals showed no presence for the homozygous form of this allele, suggesting that NFATC1 is a potential VSD-susceptibility gene.

Tricuspid Atresia (TA) is a rare form of congenital heart disease (CHD) with usually poor prognosis in humans. It presents as a complete absence of the right atrio-ventricular connection secured normally by the tricuspid valve. Defects in the tricuspid valve are so far not associated with any genetic locus, although mutations in numerous genes were linked to multiple forms of congenital heart disease. In the last decade, Knock-out mice have offered models for cardiologists and geneticists to study the causes of congenital disease. One such model was the Nfatc1 −/− mice embryos which die at mid-gestation stage due to a complete absence of the valves. NFATC1 belongs to the Rel family of transcription factors members of which were shown to be implicated in gene activation, cell differentiation, and organogenesis. We have previously shown that a tandem repeat in the intronic region of NFATC1 is associated with ventricular septal defects. In this report, we unravel for the first time a potential link between a mutation in NFATC1 and TA. Two heterozygous missense mutations were found in the NFATC1 gene in one indexed-case out of 19 patients with TA. The two amino-acids changes were not found neither in other patients with CHDs, nor in the control healthy population. Moreover, we showed that these mutations alter dramatically the normal function of the protein at the cellular localization, DNA binding and transcriptional levels suggesting they are disease-causing.