Martin A. Denvir

Implementation of a Sensitive Troponin I Assay and Risk of Recurrent Myocardial Infarction and Death in Patients With Suspected Acute Coronary Syndrome

CONTEXT Although troponin assays have become increasingly more sensitive, it is unclear whether further reductions in the threshold of detection for plasma troponin concentrations will improve clinical outcomes in patients with suspected acute coronary syndrome (ACS). OBJECTIVE To determine whether lowering the diagnostic threshold for myocardial infarction (MI) with a sensitive troponin assay could improve clinical outcomes. DESIGN, SETTING, AND PATIENTS All consecutive patients admitted with suspected ACS to the Royal Infirmary of Edinburgh, Edinburgh, Scotland, before (n = 1038; February 1-July 31, 2008, during the validation phase) and after (n = 1054; February 1-July 31, 2009, during the implementation phase) lowering the threshold of detection for myocardial necrosis from 0.20 to 0.05 ng/mL with a sensitive troponin I assay were stratified into 3 groups (<0.05 ng/mL, 0.05-0.19 ng/mL, and ≥0.20 ng/mL). During the validation phase, only concentrations above the original diagnostic threshold of 0.20 ng/mL were reported to clinicians. MAIN OUTCOME MEASURE Event-free survival (recurrent MI and death) at 1 year in patients grouped by plasma troponin concentrations. RESULTS Plasma troponin concentrations were less than 0.05 ng/mL in 1340 patients (64%), 0.05 to 0.19 ng/mL in 170 patients (8%), and 0.20 ng/mL or more in 582 patients (28%). During the validation phase, 39% of patients with plasma troponin concentrations of 0.05 to 0.19 ng/mL were dead or had recurrent MI at 1 year compared with 7% and 24% of those patients with troponin concentrations of less than 0.05 ng/mL (P < .001) or 0.20 ng/mL or more (P = .007), respectively. During the implementation phase, lowering the diagnostic threshold to 0.05 ng/mL was associated with a lower risk of death and recurrent MI (from 39% to 21%) in patients with troponin concentrations of 0.05 to 0.19 ng/mL (odds ratio, 0.42; 95% confidence interval, 0.24-0.84; P = .01). CONCLUSIONS In patients with suspected ACS, implementation of a sensitive troponin assay increased the diagnosis of MI and identified patients at high risk of recurrent MI and death. Lowering the diagnostic threshold of plasma troponin was associated with major reductions in morbidity and mortality.

Acute Cardiovascular Effects of Apelin in Humans Potential Role in Patients With Chronic Heart Failure

Background— Apelin, the endogenous ligand for the novel G protein–coupled receptor APJ, has major cardiovascular effects in preclinical models. The study objectives were to establish the effects of acute apelin administration on peripheral, cardiac, and systemic hemodynamic variables in healthy volunteers and patients with heart failure. Methods and Results— Eighteen patients with New York Heart Association class II to III chronic heart failure, 6 patients undergoing diagnostic coronary angiography, and 26 healthy volunteers participated in a series of randomized, double-blind, placebo-controlled studies. Measurements of forearm blood flow, coronary blood flow, left ventricular pressure, and cardiac output were made by venous occlusion plethysmography, Doppler flow wire and quantitative coronary angiography, pressure wire, and thoracic bioimpedance, respectively. Intrabrachial infusions of (Pyr1)apelin-13, acetylcholine, and sodium nitroprusside caused forearm vasodilatation in patients and control subjects (all P<0.0001). Vasodilatation to acetylcholine (P=0.01) but not apelin (P=0.3) or sodium nitroprusside (P=0.9) was attenuated in patients with heart failure. Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum rate of rise in left ventricular pressure and reduced peak and end-diastolic left ventricular pressures (all P<0.05). Systemic infusions of (Pyr1)apelin-13 (30 to 300 nmol/min) increased cardiac index and lowered mean arterial pressure and peripheral vascular resistance in patients and healthy control subjects (all P<0.01) but increased heart rate only in control subjects (P<0.01). Conclusions— Acute apelin administration in humans causes peripheral and coronary vasodilatation and increases cardiac output. APJ agonism represents a novel potential therapeutic target for patients with heart failure.

Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a randomised controlled trial

Objective To determine whether or not radiofrequency ablation (RFA) for persistent atrial fibrillation in patients with advanced heart failure leads to improvements in cardiac function. Setting Patients were recruited from heart failure outpatient clinics in Scotland. Design and intervention Patients with advanced heart failure and severe left ventricular dysfunction were randomised to RFA (rhythm control) or continued medical treatment (rate control). Patients were followed up for a minimum of 6 months. Main outcome measure Change in left ventricular ejection fraction (LVEF) measured by cardiovascular MRI. Results 22 patients were randomised to RFA and 19 to medical treatment. In the RFA group, 50% of patients were in sinus rhythm at the end of the study (compared with none in the medical treatment group). The increase in cardiovascular magnetic resonance (CMR) LVEF in the RFA group was 4.5±11.1% compared with 2.8±6.7% in the medical treatment group (p=0.6). The RFA group had a greater increase in radionuclide LVEF (a prespecified secondary end point) than patients in the medical treatment group (+8.2±12.0% vs +1.4±5.9%; p=0.032). RFA did not improve N-terminal pro-B-type natriuretic peptide, 6 min walk distance or quality of life. The rate of serious complications related to RFA was 15%. Conclusions RFA resulted in long-term restoration of sinus rhythm in only 50% of patients. RFA did not improve CMR LVEF compared with a strategy of rate control. RFA did improve radionuclide LVEF but did not improve other secondary outcomes and was associated with a significant rate of serious complications. Clinical trials registration number NCT00292162.

Quality of life in patients with chronic heart failure and their carers: a 3-year follow-up study assessing hospitalization and mortality

Chronic heart failure (CHF) due to left ventricular systolic dysfunction is associated with poor quality of life (QoL). This study aimed to assess factors affecting health‐related QoL in CHF patients and their carers and the impact of QoL on clinical outcomes.

A randomised study of home-based electrical stimulation of the legs and conventional bicycle exercise training for patients with chronic heart failure

AIMS Recent guidelines recommend regular exercise in the management of patients with chronic heart failure (CHF). This study was designed to compare the safety and efficacy of conventional bicycle exercise and functional electrical stimulation (FES) of the legs as forms of home-based exercise training for patients with stable CHF. METHODS AND RESULTS Forty-six patients (38 male) with stable NYHA Class II/III heart failure underwent a 6-week training programme using either a bicycle ergometer or electrical stimulation of the quadriceps and gastrocnemius muscles. In the bike group, significant increases were seen in 6-min walk (44.6m, 95% confidence interval (CI) 29.3-60.9 m), treadmill exercise time (110 s, 95% CI 72.2-148.0 s), maximum leg strength (5.32 kg, 95% CI 3.18-7.45 kg), and quadriceps fatigue index (0.08, 95% CI 0.04-0.12) following training. In the stimulator group, similar significant increases were seen following training for 6-min walk (40.6m, 95% CI 28.2-53.0m), treadmill exercise time (67 s, 95% CI 11.8-121.8s), maximum leg strength (5.35 kg, 95% CI 1.53-9.17 kg), and quadriceps fatigue index (0.10, 95% CI 0.04-0.17). Peak VO(2)did not change in either group following training, indicating a low-intensity regime. Quality of life scores improved following training when the bicycle and stimulator groups were considered together, but not when considered separately (-0.43, 95% CI -8.13 to -0.56). CONCLUSIONS FES produces beneficial changes in muscle performance and exercise capacity in patients with CHF. Within this study, the benefits were similar to those observed following bicycle training. FES could be offered to patients with heart failure as an alternative to bicycle training as part of a home-based rehabilitation programme.

Implications of lowering threshold of plasma troponin concentration in diagnosis of myocardial infarction: cohort study

Objective To assess the relation between troponin concentration, assay precision, and clinical outcomes in patients with suspected acute coronary syndrome. Design Cohort study. Setting Tertiary centre in Scotland. Participants 2092 consecutive patients admitted with suspected acute coronary syndrome were stratified with a sensitive troponin I assay into three groups (<0.012, 0.012-0.049, and ≥0.050 µg/L) based on the 99th centile for troponin concentration (0.012 µg/L; coefficient of variation 20.8%) and the diagnostic threshold (0.050 µg/L; 7.2%). Main outcome measure One year survival without events (recurrent myocardial infarction, death) in patients grouped by troponin concentration. Results Troponin I concentrations were <0.012 µg/L in 988 patients (47%), 0.012-0.049 µg/L in 352 patients (17%), and ≥0.050 µg/L in 752 patients (36%). Adoption of the 99th centile would increase the number of people receiving a diagnosis of myocardial infarction from 752 to 1104: a relative increase of 47%. At one year, patients with troponin concentrations of 0.012-0.049 µg/L were more likely to be dead or readmitted with recurrent myocardial infarction than those with troponin concentrations <0.012 µg/L (13% v 3%, P<0.001; odds ratio 4.7, 95% confidence interval 2.9 to 7.9). Compared with troponin ≥0.050 µg/L, patients with troponin 0.012-0.049 µg/L had a higher risk profile but were less likely to have a diagnosis of, or be investigated and treated for, acute coronary syndrome. Conclusion Lowering the diagnostic threshold to the 99th centile and accepting greater assay imprecision would identify more patients with acute coronary syndrome at risk of recurrent myocardial infarction and death but would increase the diagnosis of myocardial infarction by 47%. It remains to be established whether reclassification of these patients and treatment for myocardial infarction would improve outcome.

Identifying community based chronic heart failure patients in the last year of life: a comparison of the Gold Standards Framework Prognostic Indicator Guide and the Seattle Heart Failure Model

Objective To assess the clinical utility of the Gold Standards Framework Prognostic Indicator Guide (GSF) and the Seattle Heart Failure Model (SHF) to identify patients with chronic heart failure (CHF) in the last year of life. Design, setting and patients An observational cohort study of 138 community based ambulatory patients with New York Heart Association (NYHA) class III and IV CHF managed by a specialist heart failure nursing team. Main outcome measures 12 month mortality, and sensitivity and specificity of GSF and SHF. Results 138 CHF patients with NYHA class III and IV symptoms were identified from a population of 368 ambulatory CHF patients. 119 (86%) met GSF criteria for end of life care. The SHF model identified six (4.3%) patients with a predicted life expectancy of 1 year or less. At the 12 month follow-up, 43 (31%) patients had died. The sensitivity and specificity for GSF and SHF in predicting death were 83% and 22%, and 12% and 99%, respectively. Receiver operator characteristic analysis of SHF revealed a C index of 0.68±0.05 (95% CI 0.58 to 0.77). Chronic kidney disease (serum creatinine ≥140 μmol/l) was a strong univariate predictor of 12 month mortality, with a sensitivity of 56% and specificity of 72%. Conclusions Neither the GSF nor the SHF accurately predicted which patients were in the last year of life. The poor prognostic ability of these models highlights one of the barriers to providing timely palliative care in CHF.

Making sure services deliver for people with advanced heart failure: a longitudinal qualitative study of patients, family carers, and health professionals

The objective of this study was to evaluate the key components of services for people with advanced heart failure from multiple perspectives and recommend how care might be delivered in line with UK policies on long-term conditions, palliative and end-of-life care. Serial interviews were conducted over 2 years with patients, case-linked family carers and professionals (n =162); followed by four focus groups involving patients, carers and key professionals (n =32). There were 36 patients with advanced heart failure, 30 family carers and 62 professionals included in the study from a UK health region with various heart failure care models. Participants confirmed the value of a key health professional coordinating care, holistic assessment and regular monitoring. A lack of time and resources due to competing priorities in primary care, failure to respond to the fluctuations of a heart failure illness trajectory, concerns about the balance between direct care from specialist nurses or a more advisory role and difficulty in judging when to move towards palliative care hindered consistent access to proactive care. A heart failure care framework, with key stages and service responses, was developed. We conclude that patients with long-term conditions needing palliative care should be identified and managed using pragmatic criteria that include a proactive shift in care goals.

Systolic and diastolic ventricular function in zebrafish embryos: Influence of norepenephrine, MS-222 and temperature

BackgroundZebrafish are increasingly used to study the influences of gene mutation and manipulation on cardiac development, structure and function. In this study, a video edge detection system was used to characterise, continuously, cardiac ventricle function in 2–5 days old zebrafish embryos embedded in 0.6% agar and examined under light microscopy at room temperature (22°C). Using video edge detection software (IonOptix Inc), the motion of a small region of the cardiac ventricle wall was converted to a continuous chart trace allowing analysis of wall motion amplitude (WMA) and myocardial wall velocity during systole (MWVs) and diastole (MWVd).ResultsCardiac wall motion characteristics changed progressively from day 2 to 5 (WMA, 2-days, 17.6 ± 4.4 μm vs 5-days, 24.6 ± 4.7 μm, p < 0.01). MWVd was more rapid than MWVs at all developmental time points. Embryonic hearts were also assessed after increasing concentrations of norepenephrine (NE) and the anaesthetic agent MS222 (tricaine) were added to the bathing water. In response to NE, WMA increased significantly more in 4 day embryos compared with 2 day embryos (change in WMA,13.6 ± 8.2 μm vs 4.0 ± 8.8 μm, p = 0.01, respectively) while the decrease in WMA in response to MS222 was similar in both 2 and 4-day embryos. Heart rate, MWVs and MWVd were significantly higher at 28°C compared with 22°C. No differences in cardiac function were observed between AB and Golden strains.ConclusionVideo edge detection appears sufficiently sensitive to detect subtle changes in diastolic and systolic cardiac function during development and changes resulting from pharmacological and environmental interventions. Such measurements could be valuable in assessment of altered cardiac function after genetic manipulation.

Impaired Pulmonary Diffusion During Exercise in Patients With Chronic Heart Failure

BACKGROUND Pulmonary diffusion is impaired at rest in patients with chronic heart failure (CHF) and has been implicated in the generation of symptoms and exercise intolerance. The aim of this study was to determine whether pulmonary diffusion is impaired during exercise in CHF, to examine its relationship to pulmonary blood flow, and to consider its functional significance in relation to metabolic gas exchange. METHODS AND RESULTS Carbon monoxide transfer factor (TLCO) and pulmonary blood flow (Q(C)) were measured by a rebreathe technique at rest and during steady-state cycling at 30 W in 24 CHF patients and 10 control subjects. Both patients and control subjects were able to raise TLCO and Q(C) during exercise. However, the patient group had a lower diffusion for a given blood flow (TLCO/Q(C)) both at rest (3.6+/-0.16 and 4.8+/-0.23 mL x L(-1) x mm Hg(-1); P<0.001) and during exercise (2.8+/-0.16 and 3.4+/-0.13 mL x L(-1) x mm Hg(-1) for CHF patients and control subjects, respectively; P<0.05). TLCO/Q(C) was related to the ventilatory equivalent for carbon dioxide (VEVCO(2)) production at 30 W (TLCO/Q(c) versus VEVCO(2), r = -0.58, P<0.01) and to peak exercise oxygen consumption measured during a progressive test (TLCO/Qc versus VO(2peak), r = 0.57, P<0.01) in these patients. CONCLUSIONS Patients with CHF are able to recruit reserves of TLCO and Q(C) during exercise. However, the TLCO/Q(C) ratio is consistently impaired in these patients and relates to both exercise hyperpnea and peak exercise oxygen consumption. Whether this impairment in alveolar gas exchange is reversible in CHF and therefore is a potential target for therapy has yet to be determined.