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Background High adherence to remote monitoring (RM) in pacemaker (PM) patients improves outcomes; however, adherence remains suboptimal. Bluetooth low-energy (BLE) technology in newer-generation PMs enables communication directly with patient-owned smart devices using an app without a bedside console. Objective To evaluate the success rate of scheduled RM transmissions using the app compared to other RM methods. Methods The BlueSync Field Evaluation was a prospective, international cohort evaluation, measuring the success rate of scheduled RM transmissions using a BLE PM or cardiac resynchronization therapy PM coupled with the MyCareLink Heart app. App transmission success was compared to 3 historical “control” groups from the Medtronic de-identified CareLink database: (1) PM patients with manual communication using a wand with a bedside console (PM manual transmission), (2) PM patients with wireless automatic communication with the bedside console (PM wireless); (3) defibrillator patients with similar automatic communication (defibrillator wireless). Results Among 245 patients enrolled (age 64.8±15.6 years, 58.4% men), 953 transmissions were scheduled through 12 months, of which 902 (94.6%) were successfully completed. In comparison, transmission success rates were 56.3% for PM manual transmission patients, 77.0% for PM wireless patients, and 87.1% for defibrillator wireless patients. Transmission success with the app was superior across matched cohorts based on age, sex, and device type (single vs dual vs triple chamber). Conclusion The success rate of scheduled RM transmissions was higher among patients using the smart device app compared to patients using traditional RM using bedside consoles. This novel technology may improve patient engagement and adherence to RM., Graphical abstract

Background and Purpose Nitrite (NO2−) has recently been shown to represent a potential source of NO, in particular under hypoxic conditions. The aim of the current study was to compare the haemodynamic effects of NO2− in healthy volunteers and patients with stable congestive heart failure (CHF). Experimental Approach The acute haemodynamic effects of brachial artery infusion of NO2− (0.31 to 7.8 μmol·min−1) was assessed in normal subjects (n = 20) and CHF patients (n = 21). Key Results NO2− infusion was well tolerated in all subjects. Forearm blood flow (FBF) increased markedly in CHF patients at NO2− infusion rates which induced no changes in normal subjects (anova: F = 5.5; P = 0.02). Unstressed venous volume (UVV) increased even with the lowest NO2− infusion rate in all subjects (indicating venodilation), with CHF patients being relatively hyporesponsive compared with normal subjects (anova: F = 6.2; P = 0.01). There were no differences in venous blood pH or oxygen concentration between groups or during NO2− infusion. Venous plasma NO2− concentrations were lower in CHF patients at baseline, and rose substantially less with NO2− infusion, without incremental oxidative generation of nitrate, consistent with accelerated clearance in these patients. Plasma protein-bound NO concentrations were lower in CHF patients than normal subjects at baseline. This difference was attenuated during NO2− infusion. Prolonged NO2− exposure in vivo did not induce oxidative stress, nor did it induce tolerance in vitro. Conclusions and Implications The findings of arterial hyper-responsiveness to infused NO2− in CHF patients, with evidence of accelerated transvascular NO2− clearance (presumably with concomitant NO release) suggests that NO2− effects may be accentuated in such patients. These findings provide a stimulus for the clinical exploration of NO2− as a therapeutic modality in CHF.

Background— It has been proposed that under hypoxic conditions, nitrite may release nitric oxide, which causes potent vasodilation. We hypothesized that nitrite would have a greater dilator effect in capacitance than in resistance vessels because of lower oxygen tension and that resistance-vessel dilation should become more pronounced during hypoxemia. The effect of intra-arterial infusion of nitrite on forearm blood flow and forearm venous volumes was assessed during normoxia and hypoxia. Methods and Results— Forty healthy volunteers were studied. After baseline infusion of 0.9% saline, sodium nitrite was infused at incremental doses from 40 nmol/min to 7.84 μmol/min. At each stage, forearm blood flow was measured by strain-gauge plethysmography. Forearm venous volume was assessed by radionuclide plethysmography. Changes in forearm blood flow and forearm venous volume in the infused arm were corrected for those in the control arm. The peak percentage of venodilation during normoxia was 35.8±3.4% (mean±SEM) at 7.84 μmol/min ( P P P Conclusions— Nitrite is a potent venodilator in normoxia and hypoxia. Arteries are modestly affected in normoxia but potently dilated in hypoxia, which suggests the important phenomenon of hypoxic augmentation of nitrite-mediated vasodilation in vivo. The use of nitrite as a selective arterial vasodilator in ischemic territories and as a potent venodilator in heart failure has therapeutic implications.

Aim: We used Near Infrared Spectrophotometry (NIRS) during arterial occlusion to measure resting skeletal muscle oxygen consumption in chronic heart failure (CHF) patients and in age-matched healthy volunteers (HVs). Methods: Fifteen CHF patients (ten males) and eleven HVs (six males) had echocardiographic evaluation followed by measurement of the oxygen consumption of the brachioradialis muscle using NIRS. This involved continuous measurement of the oxygenated haemoglobin concentration ([Oxy-Hb]) and deoxy-haemoglobin concentration ([Deoxy-Hb]) with an Oxiplex TS NIRS probe first under basal overnight fasted resting conditions followed by 1 min of forearm arterial occlusion. A linear decline was observed in [Oxy-Hb–Deoxy-Hb] during the arterial occlusion and the oxygen consumption rate was calculated from the initial slope observed. Results: CHF patients were 59±2.8 years old with Left Ventricular Ejection Fraction (LVEF) 31%±2.2 and the HVs were 52±4.8 years old with LVEF 62%±2.5. The resting muscle oxygen consumption rate was significantly reduced in CHF patients versus HVs (0.04±0.01 mlO2/min/100 g versus 0.07±0.01 mlO2/min/100 g) p

Summary New researchers may find starting and conducting clinical studies in the UK complicated and time-consuming. In this article, we describe our collective experiences and provide some pointers on how to navigate through the various committees and regulatory bodies. The article is intended to aid junior researchers in understanding the study process and to provide them with some insight on how to get through this complex system successfully.

AIMS: This work investigates the role of myoglobin in mediating the vascular relaxation induced by nitrite. Nitrite, previously considered an inert by-product of nitric oxide metabolism, is now believed to play an important role in several areas of pharmacology and physiology. Myoglobin can act as a nitrite reductase in the heart, where it is plentiful, but it is present at a far lower level in vascular smooth muscle-indeed, its existence in the vessel wall is controversial. Haem proteins have been postulated to be important in nitrite-induced vasodilation, but the specific role of myoglobin is unknown. The current study was designed to confirm the presence of myoglobin in murine aortic tissue and to test the hypothesis that vascular wall myoglobin is important for nitrite-induced vasodilation. METHODS AND RESULTS: Aortic rings from wild-type and myoglobin knockout mice were challenged with nitrite, before and after exposure to the haem-protein inhibitor carbon monoxide (CO). CO inhibited vasodilation in wild-type rings but not in myoglobin-deficient rings. Restitution of myoglobin using a genetically modified adenovirus both increased vasodilation to nitrite and reinstated the wild-type pattern of response to CO. CONCLUSION: Myoglobin is present in the murine vasculature and contributes significantly to nitrite-induced vasodilation.

Background— Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Methods and Results— Forty-six consecutive patients with symptomatic exercise limitation (peak V̇ o 2 31 P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak V̇o 2 , symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P =0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to −0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P =0.03). These changes were accompanied by an improvement in primary end point (peak V̇ o 2 ) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL · kg −1 · min −1 ; P =0.003) and New York Heart Association class ( P P values ANCOVA, perhexiline versus placebo). Conclusions— In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00500552.

Heart failure continues to have a significant morbidity and mortality rate despite several recent advances in treatment such as additional neurohumoral blockades and cardiac resynchronisation therapy. There is emerging evidence that, irrespective of etiology, heart failure is associated with an energetic disorder and that this may contribute to the pathogenesis of the syndrome. Recently, a number of studies have suggested that some metabolic agents may have potential as adjunctive therapy in patients with heart failure. These agents cause a shift of myocardial-substrate utilization away from free fatty acids toward glucose. Free fatty acid utilization consumes more oxygen to generate an equivalent amount of energy compared with glucose. Some of these agents are also effective antianginals, presumably by reducing the myocardial oxygen requirement. In this review we will discuss some of the current issues and progresses relating to metabolic manipulation in heart failure.

In the present study, we investigated the effects of basal and intra-arterial infusion of bradykinin on unstressed forearm vascular volume (a measure of venous tone) and blood flow in healthy volunteers (n=20) and in chronic heart failure patients treated with ACEIs [ACE (angiotensin-converting enzyme) inhibitors] (n=16) and ARBs (angiotensin receptor blockers) (n=14). We used radionuclide plethysmography to examine the effects of bradykinin and of the bradykinin antagonists B9340 [B1 (type 1)/B2 (type 2) receptor antagonist] and HOE140 (B2 antagonist). Bradykinin infusion increased unstressed forearm vascular volume in a similar dose-dependent manner in healthy volunteers and ARB-treated CHF patients (healthy volunteers maximum 12.3±2.1%, P

Background Patients with hypertrophic cardiomyopathy (HCM) exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathogenesis of HCM remains unproven. We hypothesised that the metabolic modulator, perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Methods Forty-six consecutive patients with symptomatic exercise limitation (peak oxygen consumption – peak VO2 Results Perhexiline improved myocardial PCr/ATP ratios (from 1.27±0.02 to 1.73±0.02; p=0.003) and normalised the abnormal prolongation of nTTPF between rest and exercise (δ nTTPF: +0.11±0.008 s vs −0.01±0.005; p=0.03). These changes were accompanied by improvement in peak VO2 (22.2±0.2 to 24.29±0.2 ml/kg/min; p=0.003) and symptoms (NYHA class by 0.8 units p Conclusion In symptomatic HCM, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathogenesis and provides a rationale for further consideration of metabolic therapies in HCM.

Background Nitric oxide (NO) is an important endogenous paracrine vasodilator. The nitrite anion represents an alternate humoural source of NO under hypoxic and/or acidotic conditions. During hypoxia and ischaemia, the usual production of NO by NO synthase enzymes, is markedly reduced. Recently it has emerged that nitrite serves as a biological reservoir for NO under hypoxic conditions. Animal studies have shown that exogenous treatment with nitrite has important hypoxia-specific vasodilator and cytoprotective effects. Our group demonstrated that when administered intra-arterially under normoxic conditions, nitrite substantially vasodilated the venous capacitance bed, but only modestly dilated resistance human forearm vessels. In contrast during hypoxia, potent vasodilation was also observed in resistance vessels. Therefore, in this study we assessed the effects of nitrite on cardiac and peripheral haemodynamics in humans. We hypothesised that an intravenous infusion of sodium nitrite would cause a significant reduction in blood pressure during hypoxia compared to normoxia. Methods Thirty-three healthy subjects (mean age 32±10 years) were recruited. An intravenous infusion of sodium nitrite was administered at incremental doses (3, 8, 30 and 60 μmol/min) during normoxic or hypoxic conditions in random order. Hypoxia was administered by asking subjects to inspire 12% oxygen via a facemask until oxygen saturations of 83–88% were achieved. Haemodynamic measurements were determined non-invasively through the use of impedance cardiography (Taskforce ® ). Aplanation tonometry (SphygmoCor) was used to delineate central (aortic) blood pressure (CBP). Results To allow for the time-dependent effect of hypoxia all measurements in this group were placebo-corrected. During hypoxia, systolic blood pressure (SBP) fell by a mean of 11 mmHg (123±19 mmHg to 112±15 mmHg, p≤0.05) from baseline during peak nitrite dose. There was a non-significant reduction in SBP during normoxia of 6 mmHg (120±13 mmHg to 114±22 mmHg, p=NS). No significant changes were observed in stroke volume or cardiac output in either group. In the hypoxia group, total peripheral resistance mirrored changes in SBP. CBP fell in both groups (9 vs13 mmHg, normoxia vs hypoxia, p=NS) from baseline. No significant changes were observed in parameters between the normoxia and hypoxia group. Conclusion An acute intravenous infusion of nitrite was safe and well tolerated in healthy volunteers. A significant decrease in blood pressure was observed during hypoxia, but not during normoxia, thus supporting the role of nitrite as a hypoxia-specific vasodilator.