Long-term vagal stimulation for heart failure: Eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial.

BACKGROUND: The NECTAR-HF study evaluated safety and feasibility of vagal nerve stimulation (VNS) for the treatment of heart failure patients. The first six-month randomized phase of the study did not show improvement in left ventricular remodelling in response to VNS. This study reports the 18-month results and provides novel findings aiming to understand the lack of efficacy of VNS, including a new technique assessing the effects of VNS. METHODS: Ninety-six patients were randomized 2:1 to active or inactive VNS for 6months, thereafter VNS was activated for all patients. The primary safety endpoint was 18-month all-cause mortality. RESULTS: Ninety-one patients continued in the long-term evaluation with active VNS. The on-therapy survival estimate at 18months was 95% with a 95% one-sided lower confidence limit of 91%, (better than the predefined criterion). Left ventricular systolic volume decreased in the crossover group (VNS OFF→ON; 144±37 to 139±40, p<0.05) after VNS activation; LVESD (5.02±0.77 to 4.96±0.82, p>0.05) and LVEF (33.2±4.9 to 33.3±6.5, p>0.05) did not change. A new technique to detect subtle heart rate changes during Holter recordings, i.e. "heat maps", revealed that VNS evoked heart rate response in only 13/106 studies (12%) at 6 and 12months with active VNS. CONCLUSIONS: Although a favourable long-term safety profile was found, improvements in the efficacy endpoints were not seen with VNS. A new technique for detecting acute heart rate responses to VNS suggests that the recruitment of nerve fibres responsible for heart rate changes were substantially lower in NECTAR-HF than in pre-clinical models.

Rationale and study design of the REM-HF study: remote management of heart failure using implanted devices and formalized follow-up procedures.

AIMS: We wish to assess the clinical and cost-effectiveness of remote monitoring of heart failure patients with cardiac implanted electronic devices. METHODS: REM-HF is a multicentre, randomized, non-blinded, parallel trial designed to compare weekly remote monitoring-driven management with usual care for patients with cardiac implanted electronic devices (ICD, CRT-D, or CRT-P). The trial is event driven, and the final analysis will be performed when 546 events have been observed or the study is terminated at the interim analysis. We have randomized 1650 patients to be followed up for a minimum of 2 years. Patients will remain in the trial up to study termination. The first patient was randomized in September 2011 and the study is expected to complete in early 2016. The primary combined endpoint is time to first event of all-cause death or unplanned hospitalization for cardiovascular reasons. An economic evaluation will be performed, estimating the cost per quality-adjusted life year, with direct costs estimated from the National Health Service perspective and quality of life assessed by the EQ-5D, Short-Form 12, and Kansas City Cardiomyopathy Questionnaires. The study design has been informed by a feasibility study. CONCLUSION: REM-HF is a multicentre randomized study that will provide important data on the effect of remote monitoring-driven management of implanted cardiac devices on morbidity and mortality, as well as the cost-effectiveness of this approach.

Patient radiation dose during fluoroscopically guided biventricular device implantation.

OBJECTIVE: Implantation of biventricular devices (BiV) with a transvenous left ventricular lead is complex requiring a significant fluoroscopy time and radiation dose. In the United Kingdom, the Health Protection Agency (HPA) collects data regarding radiographic procedures and sets national diagnostic reference levels (DRL) at the 75th percentile of the distribution of doses for a wide range of procedures. Insufficient data were returned to the HPA to allow them to set DRL for BiV devices at the last publication in 2010. Due to the large variation in data available and small datasets for BiV procedures we aimed to collect a large dataset to guide standards for implantation. METHODS: We collected retrospective data (fluoroscopy time and radiation dose [DAP]) for new BiV devices for the three years 2009-2011 from three high volume tertiary centres in the North West of England. Databases were scrutinised to ensure the quality of the data. RESULTS: From a total of 1374 implants we identified data for 1319 patients for fluoroscopy time and 1316 for DAP. The mean fluoroscopy time for all three centres combined was 18.7±0.3 min. The 75th percentile fluoroscopy time for the combined data was 24.2 min. The mean DAP for the three centres combined was 25.1±1.3 Gy cm2. The 75th percentile DAP for the combined data was 27.7 Gy cm2. CONCLUSIONS: We present a large dataset of new biventricular device implants, based on the 75th percentile data we suggest a DRL of 24.2 min and 27.7 Gy cm2.

Low-flow mediated constriction is endothelium-dependent: effects of exercise training after radial artery catheterization.

BACKGROUND: Radial artery catheterization is associated with endothelial denudation and impaired vasodilator function, while postcatheterization exercise training may enhance artery function. The impact of catheterization and subsequent exercise training on low-flow mediated vasoconstriction (L-FMC) has not previously been studied. The aim of this study was to examine whether radial artery L-FMC is impaired by catheterization and consequent endothelial denudation. A further aim was to examine the effect of local handgrip exercise training on radial artery L-FMC and flow-mediated dilation (FMD) after transradial catheterization. METHODS AND RESULTS: Thirty-two subjects undergoing transradial catheterization underwent assessment of L-FMC and FMD in the catheterized and contralateral radial artery before, and the day after, catheterization. A further 18 patients were recruited and randomly assigned to either a 6-week handgrip exercise training program (N=9) or a nonexercise control period (N=9). L-FMC was attenuated 1 day postcatheterization in the catheterized arm (-2.07±0.84 to 0.35±0.83), but unchanged in the noncatheterized arm (-0.93±0.86 to -0.90±0.92; P<0.05). In the training study, both FMD and L-FMC of the catheterized arm were preserved in the exercise group 7 weeks after catheterization (FMD-pre, 6.84±0.79; FMD-post, 6.85±1.16; L-FMC-pre, -2.14±1.42; L-FMC-post, -3.58±1.04%), but reduced in the control group (FMD-pre, 8.27±1.52; FMD-post, 4.66±0.70; P=0.06; L-FMC-pre, -3.26±1.19; L-FMC-post, -1.34±1.27%; P<0.05). CONCLUSIONS: Catheterization, and associated endothelial denudation, decreases L-FMC in the radial artery, suggesting that it is endothelium-dependent. Moreover, we demonstrate for the first time that exercise training has beneficial impacts on radial artery vasodilator and constrictor function.

Arterial prehabilitation: can exercise induce changes in artery size and function that decrease complications of catheterization?

Coronary angiography and angioplasty are common invasive procedures in cardiovascular medicine, which involve placement of a sheath inside peripheral conduit arteries. Sheath placement and catheterization can be associated with arterial thrombosis, spasm and occlusion. In this paper we review the literature pertaining to the possible benefits of arterial 'prehabilitation'--the concept that interventions aimed at enhancing arterial function and size (i.e. remodelling) should be undertaken prior to cardiac catheterization or artery harvest during bypass graft surgery. The incidence of artery spasm, occlusion and damage is lower in larger arteries with preserved endothelial function. We conclude that the beneficial effects of exercise training on both artery size and function, which are particularly evident in individuals who possess cardiovascular diseases or risk factors, infer that exercise training may reduce complication rates following catheterization and enhance the success of arteries harvested as bypass grafts. Future research efforts should focus directly on examination of the 'prehabilitation' hypothesis and the efficacy of different interventions aimed at reducing clinical complications of common interventional procedures.

Impact of introducer sheath coating on endothelial function in humans after transradial coronary procedures.

BACKGROUND: The aim of this study was to compare the impact of transradial catheterization with hydrophilic-coated catheter sheaths versus uncoated sheaths on NO-mediated endothelial-dependent and -independent vasodilator function. METHODS AND RESULTS: Thirty-five subjects undergoing transradial catheterization were recruited and assessed before and the day after catheterization. A subgroup was also assessed 3 to 4 months after catheterization. Subjects received hydrophilic-coated sheaths (n=15) or uncoated sheaths (n=20). Radial artery flow-mediated dilatation and endothelium- and NO-dependent arterial dilatation were assessed within the region of sheath placement. Glyceryl trinitrate endothelium-independent NO-mediated function was also assessed. The noncatheterized arm provided an internal control. Flow-mediated dilatation in the catheterized arm decreased from 10.3+/-3.8% to 5.3+/-3.3% and 8.1+/-2.4% to 5.2+/-3.7% in the coated and uncoated groups, respectively (P<0.01). These values returned toward baseline levels approximately 3 months later (coated, 6.4+/-1.4%; uncoated, 9.4+/-4.1%; P<0.05) versus postprocedure. Glyceryl trinitrate decreased from 14.8+/-7.2% to 9.5+/-4.1% (P<0.05) in the coated group and from 12.2+/-4.6% to 7.5+/-4.2% (P<0.01) in the uncoated group. Values returned to baseline at approximately 3 months (coated, 16.6+/-5.6%; uncoated, 12.1+/-3.9%; P<0.05). There was no difference in the magnitude of decrease in flow-mediated dilatation or glyceryl trinitrate between coated and uncoated groups. No changes in function occurred in the noncatheterized arm. CONCLUSIONS: Placement of a catheter sheath inside the radial artery disrupts vasodilator function, which recovers after 3 months. No differences were evident between hydrophilic-coated and uncoated sheaths.

Impact of catheter insertion using the radial approach on vasodilatation in humans.

The aim of this study was to determine the impact of catheter sheath insertion, a model of endothelium disruption in humans, on the conventional FMD (flow-mediated dilatation) response in vivo. Seventeen subjects undergoing transradial catheterization were recruited and assessed prior to, the day after, and 3-4 months postcatheterization. The catheter sheath's external diameter was 2.7 mm, and the average preprocedure internal radial artery diameter was 2.8 mm, indicating a high likelihood of endothelial denudation as a consequence of sheath placement. Radial artery flow-mediated and endothelium-derived NO (nitric oxide)-dependent function (FMD) was assessed within the region of sheath placement (sheath site) and also above the sheath (catheter site). GTN (glyceryl trinitrate) endothelium-independent NO-mediated function was also assessed distally. Measurements were made in both arms at all time points; the non-catheterized arm provided an internal control. Neither sheath (4.5+/-0.9%) nor catheter (4.4+/-0.9%) insertion abolished FMD, although both significantly decreased FMD from preintervention levels (9.0+/-0.8% sheath segment; 8.4+/-0.8% catheter segment; P<0.05). The impact of sheath and catheter placement on FMD was no longer evident after approximately 3 months recovery (8.0+/-1.5 and 8.1+/-1.7%, sheath and catheter, respectively). GTN responses also decreased from 14.8+/-1.7 to 7.9+/-1.0% (P<0.05) as a result of sheath placement, but values returned to baseline at approximately 3 months (13.0+/-1.8%). These results suggest that the presence of an intact, functional endothelial layer and consequent NO release may not be obligatory for some component of the FMD response. This raises the possibility of an endothelium-independent contribution to the flow-induced vasodilatation in humans.

Is plasma N-BNP a good indicator of the functional reserve of failing hearts? The FRESH-BNP study.

AIMS: Whether plasma N-terminal brain natriuretic peptide (N-BNP) is useful in the diagnosis of heart failure (HF) depends traditionally on whether it is as good as the putative 'gold-standard', left ventricular ejection fraction (LVEF), in indicating cardiac dysfunction. However, since HF is primarily an impairment of function of the cardiac pump, we explored the relationship between N-BNP and direct and indirect indicators of cardiac pump dysfunction. METHODS AND RESULTS: Eighty-six HF patients (mean age 56 years) with a range of LVEF's (mean 36.9+/-15.2%, range 15-66%) and 10 age-matched healthy controls were recruited into the study and had resting N-BNP measured. Cardiopulmonary exercise testing was performed to assess peak oxygen consumption (Vo(2)). A subgroup of 23 subjects underwent further exercise haemodynamic assessment to evaluate peak cardiac power output (CPO). The CHF group had significantly higher N-BNP (median [interquartile range]) levels (299 [705] fmol/ml) than the control group (7 [51] fmol/ml, P<0.005). Significant correlations between N-BNP and peak Vo(2), and N-BNP and peak CPO were observed (R> or =0.5, P<0.005). Although significant correlation was observed between N-BNP and LVEF (R=0.34, P=0.01), the correlations between LVEF and peak Vo(2) or peak CPO (all R<0.3, P>0.3) were not significant. Multivariate analysis identified plasma N-BNP and NYHA class, but not LVEF, as independent predictors of peak Vo(2). CONCLUSIONS: We have found that N-BNP was surprisingly good as a simple indicator of cardiac pump dysfunction. Since heart failure is an inadequacy of function, these results strongly support the notion that N-BNP is a useful blood test in estimating the extent of cardiac pump dysfunction and helpful in establishing positive diagnosis of heart failure.