👤 Luigi Tavazzi

Ivabradine has been approved in heart failure with reduced ejection fraction (HFrEF) and elevated heart rate despite guideline-directed medical therapy (GDMT) to reduce cardiovascular (CV) death and hospitalization for worsening HF. The median value of 77 b.p.m. is the lower bound selected for the regulatory approval in Canada, South Africa, and Australia. Patient-reported outcomes (PROs) including symptoms, quality of life, and global assessment are considered of major interest in the global plan of care of patients with HF. However, the specific impact of GDMT, and specifically ivabradine, on PRO remains poorly studied. In the subgroup of patients from the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) who had heart rate above the median of 77 b.p.m. (pre-specified analysis) and for whom the potential for improvement was expected to be larger, we aimed (i) to evaluate the effects of ivabradine on PRO (symptoms, quality of life, and global assessment); (ii) to consolidate the effects of ivabradine on the primary composite endpoint of CV death and hospitalization for HF; and (iii) to reassess the effects of ivabradine on left ventricular (LV) remodelling. Comparisons were made according to therapy, and proportional hazards models (adjusted for baseline beta-blocker therapy) were used to estimate the association between ivabradine and various outcomes. In SHIFT, n = 3357 (51.6%) patients had a baseline heart rate > 77 b.p.m. After a median follow-up of 22.9 months (inter-quartile range 18-28 months), ivabradine on top of GDMT improved symptoms (28% vs. 23% improvement in New York Heart Association functional class, P = 0.0003), quality of life (5.3 vs. 2.2 improvement in Kansas City Cardiomyopathy Questionnaire overall summary score, P = 0.005), and global assessment [from both patient (improved in 72.3%) and physician (improved in 61.0%) perspectives] significantly more than did placebo (both P < 0.0001). Ivabradine induced a 25% reduction in the combined endpoint of CV death and hospitalization for HF (hazard ratio 0.75; P < 0.0001), which translates into a number of patients needed to be treated for 1 year of 17. Patients under ivabradine treatment demonstrated a significant reduction in LV dimensions when reassessed at 8 months (P < 0.05). In patients with chronic HFrEF, sinus rhythm, and a heart rate > 77 b.p.m. while on GDMT, the present analysis brings novel insights into the role of ivabradine in improving the management of HFrEF, particularly with regard to PRO (ISRCTN70429960). Show less

The lack of early diagnosis, progression markers and effective pharmacological treatment has dramatic unfavourable effects on clinical outcomes in patients with peripheral artery disease (PAD). Addressing these issues will require dissecting the molecular mechanisms underlying this disease. We sought to characterize the Notch signaling and atherosclerosis relevant markers in lesions from femoral arteries of symptomatic PAD patients. Plaque material from the common femoral, superficial femoral or popliteal arteries of 20 patients was removed by directional atherectomy. RNA was obtained from 9 out of 20 samples and analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). We detected expression of Notch ligands Delta-like 4 (Dll4) and Jagged1 (Jag1), of Notch target genes Hes1, Hey1, Hey2, HeyL and of markers of plaque inflammation and stability such as vascular cell adhesion molecule 1 (VCAM1), smooth muscle 22 (SM22), cyclooxygenase 2 (COX2), Bcl2, CD68 and miRNAs 21-5p, 125a-5p, 126-5p,146-5p, 155-5p, 424-5p. We found an "inflamed plaque" gene expression profile characterized by high Dll4 associated to medium/high CD68, COX2, VCAM1, Hes1, miR126-5p, miR146a-5p, miR155-5p, miR424-5p and low Jag1, SM22, Bcl2, Hey2, HeyL, miR125a-5p (2/9 patients) and a "stable plaque" profile characterized by high Jag1 associated to medium/high Hey2, HeyL, SM22, Bcl2, miR125a and low Dll4, CD68, COX2, VCAM1, miR126-5p, miR146a-5p, miR155-5p, miR424-5p (3/9 patients). The remaining patients (4/9) showed a plaque profile with intermediate characteristics. This study reveals the existence of a gene signature associated to Notch activation by specific ligands that could be predictive of PAD progression. Show less