Julian O.M. Ormerod

The role of vascular myoglobin in nitrite-mediated blood vessel relaxation

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.

Short-Term Intravenous Sodium Nitrite Infusion Improves Cardiac and Pulmonary Hemodynamics in Heart Failure Patients

Background—Nitrite exhibits hypoxia-dependent vasodilator properties, selectively dilating capacitance vessels in healthy subjects. Unlike organic nitrates, it seems not to be subject to the development of tolerance. Currently, therapeutic options for decompensated heart failure (HF) are limited. We hypothesized that by preferentially dilating systemic capacitance and pulmonary resistance vessels although only marginally dilating resistance vessels, sodium nitrite (NaNO2) infusion would increase cardiac output but reduce systemic arterial blood pressure only modestly. We therefore undertook a first-in-human HF proof of concept/safety study, evaluating the hemodynamic effects of short-term NaNO2 infusion. Methods and Results—Twenty-five patients with severe chronic HF were recruited. Eight received short-term (5 minutes) intravenous NaNO2 at 10 &mgr;g/kg/min and 17 received 50 &mgr;g/kg/min with measurement of cardiac hemodynamics. During infusion of 50 &mgr;g/kg/min, left ventricular stroke volume increased (from 43.22±21.5 to 51.84±23.6 mL; P=0.003), with marked falls in pulmonary vascular resistance (by 29%; P=0.03) and right atrial pressure (by 40%; P=0.007), but with only modest falls in mean arterial blood pressure (by 4 mm Hg; P=0.004). The increase in stroke volume correlated with the increase in estimated trans-septal gradient (=pulmonary capillary wedge pressure–right atrial pressure; r=0.67; P=0.003), suggesting relief of diastolic ventricular interaction as a contributory mechanism. Directionally similar effects were observed for the above hemodynamic parameters with 10 &mgr;g/kg/min; this was significant only for stroke volume, not for other parameters. Conclusions—This first-in-human HF efficacy/safety study demonstrates an attractive profile during short-term systemic NaNO2 infusion that may be beneficial in decompensated HF and warrants further evaluation with longer infusion regimens.

Impaired energetics in heart failure — A new therapeutic target

Heart failure is a syndrome of huge and growing importance worldwide. It is widely accepted that the energy status of the myocardium in heart failure is impaired, irrespective of etiology. Agents which modify cardiac substrate utilisation have the potential to ameliorate this energy deficiency by increasing cardiac mechanical efficiency. This may represent a new therapeutic paradigm in heart failure. In this review we discuss existing and new agents that alter cardiac substrate use and summarise the data on clinical efficacy.

Cost-Effectiveness Analysis of Quadripolar Versus Bipolar Left Ventricular Leads for Cardiac Resynchronization Defibrillator Therapy in a Large, Multicenter UK Registry

Objectives The objective of this study was to evaluate the cost-effectiveness of quadripolar versus bipolar cardiac resynchronization defibrillator therapy systems. Background Quadripolar left ventricular (LV) leads for cardiac resynchronization therapy reduce phrenic nerve stimulation (PNS) and are associated with reduced mortality compared with bipolar leads. Methods A total of 606 patients received implants at 3 UK centers (319 Q, 287 B), between 2009 and 2014; mean follow-up was 879 days. Rehospitalization episodes were costed at National Health Service national tariff rates, and EQ-5D utility values were applied to heart failure admissions, acute coronary syndrome events, and mortality data, which were used to estimate quality-adjusted life-year differences over 5 years. Results Groups were matched with regard to age and sex. Patients with quadripolar implants had a lower rate of hospitalization than those with bipolar implants (42.6% vs. 55.4%; p = 0.002). This was primarily driven by fewer hospital readmissions for heart failure (51 [16%] vs. 75 [26.1%], respectively, for quadripolar vs. bipolar implants; p = 0.003) and generator replacements (9 [2.8%] vs. 19 [6.6%], respectively; p = 0.03). Hospitalization for suspected acute coronary syndrome, arrhythmia, device explantation, and lead revisions were similar. This lower health-care utilization cost translated into a cumulative 5-year cost saving for patients with quadripolar systems where the acquisition cost was <£932 (US

Human Second Window Pre-Conditioning and Post-Conditioning by Nitrite Is Influenced by a Common Polymorphism in Mitochondrial Aldehyde Dehydrogenase

1,398) compared with bipolar systems. Probabilistic sensitivity analysis results mirrored the deterministic calculations. For the average additional price of £1,200 (US

Massive vegetation in device-related endocarditis.

1,800) over a bipolar system, the incremental cost-effective ratio was £3,692 per quality-adjusted life-year gained (US

Implementation of NICE clinical guideline 95 on chest pain of recent onset: experience in a district general hospital

5,538), far below the usual willingness-to-pay threshold of £20,000 (US

89 Implementation of a Modified Version of Nice Clinical Guideline 95 On Chest Pain of Recent Onset: Experience in a District General Hospital

30,000). Conclusions In a UK health-care 5-year time horizon, the additional purchase price of quadripolar cardiac resynchronization defibrillator therapy systems is largely offset by lower subsequent event costs up to 5 years after implantation, which makes this technology highly cost-effective compared with bipolar systems.

Percutaneous Device Closure of Paravalvular LeakClinical Perspectives: Combined Experience From the United Kingdom and Ireland

Visual Abstract

Percutaneous Device Closure of Paravalvular LeakClinical Perspectives

A 71-year-old man was transferred to the extraction centre with Staphylococcus aureus endocarditis and a 3.5 × 1.7 cm vegetation adherent to the ventricular lead of his 7-year-old secondary-prevention dual chamber ICD (see Panel A and Supplementary material online, Videos S1–S3). He had been initially managed medically but the vegetation …