Ian S Stone

Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms?

In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms ‘asthma’ and ‘COPD’ as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory.

Lung Deflation and Cardiovascular Structure and Function in Chronic Obstructive Pulmonary Disease. A Randomized Controlled Trial

RATIONALE Patients with chronic obstructive pulmonary disease develop increased cardiovascular morbidity with structural alterations. OBJECTIVES To investigate through a double-blind, placebo-controlled, crossover study the effect of lung deflation on cardiovascular structure and function using cardiac magnetic resonance. METHODS Forty-five hyperinflated patients with chronic obstructive pulmonary disease were randomized (1:1) to 7 (maximum 14) days inhaled corticosteroid/long-acting β2-agonist fluticasone furoate/vilanterol 100/25 μg or placebo (7-day minimum washout). Primary outcome was change from baseline in right ventricular end-diastolic volume index versus placebo. MEASUREMENTS AND MAIN RESULTS There was a 5.8 ml/m(2) (95% confidence interval, 2.74-8.91; P < 0.001) increase in change from baseline right ventricular end-diastolic volume index and a 429 ml (P < 0.001) reduction in residual volume with fluticasone furoate/vilanterol versus placebo. Left ventricular end-diastolic and left atrial end-systolic volumes increased by 3.63 ml/m(2) (P = 0.002) and 2.33 ml/m(2) (P = 0.002). In post hoc analysis, right ventricular stroke volume increased by 4.87 ml/m(2) (P = 0.003); right ventricular ejection fraction was unchanged. Left ventricular adaptation was similar; left atrial ejection fraction improved by +3.17% (P < 0.001). Intrinsic myocardial function was unchanged. Pulmonary artery pulsatility increased in two of three locations (main +2.9%, P = 0.001; left +2.67%, P = 0.030). Fluticasone furoate/vilanterol safety profile was similar to placebo. CONCLUSIONS Pharmacologic treatment of chronic obstructive pulmonary disease has consistent beneficial and plausible effects on cardiac function and pulmonary vasculature that may contribute to favorable effects of inhaled therapies. Future studies should investigate the effect of prolonged lung deflation on intrinsic myocardial function. Clinical trial registered with www.clinicaltrials.gov (NCT 01691885).

Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease?

Significant cardiac morbidity and mortality exists in patients with COPD. Shared risk factors include age, smoking history and exposure to air pollution and passive smoke. Although the inappropriate under-prescribing of β-blockers contributes, it is now appreciated that the observed cardiac risk is not only due to smoking and conventional cardiovascular risk factors, but also other independent factors. A number of hypotheses exist for the increased cardiovascular morbidity and mortality seen in COPD including inflammation, pulmonary hypertension, lung hyperinflation and shared genetics models. Mounting evidence from large randomised controlled trials suggests that COPD treatment may be cardio-protective. We review the current evidence supporting the aforementioned hypotheses and how their modulation may prevent cardiovascular morbidity and mortality in COPD. The persisting underdiagnosis of COPD may have significant consequences. Further mechanistic studies identifying the onset and impact of individual interventions will develop our understanding of this emerging and highly relevant clinical field.

Raised troponin in COPD: clinical implications and possible mechanisms

Chronic obstructive pulmonary disease (COPD) is predicted to become the sixth leading cause of disability and the third most common cause of death by 2020. Reduced forced expiratory volume in 1s, a hallmark of COPD, is ranked second to smoking and above blood pressure and cholesterol as a predictor of all-cause and cardiovascular mortality. Even in mild to moderate COPD patients succumb to cardiovascular disease rather than respiratory failure although the causative mechanism is unknown.1 Over the past decade it has become apparent that during an exacerbation of COPD, classically defined by the combination of worsening dyspnoea with increased sputum volume and/or purulence, there is subclinical myocardial damage typified by an increase in troponin level and other biomarkers which predict mortality.2–4 The key question relates to the mechanisms behind this rise, since without an understanding of the mechanisms the ability to identify an appropriate intervention that will improve outcome is hindered. Soyseth and colleagues5 seek to further the understanding of this relationship. Specifically they addressed the important issue as to whether the raised levels of troponin found at exacerbation are chronically raised or are a phenomenon related to the exacerbation itself, and found that the troponin levels were significantly higher in the exacerbator group compared with stable patients. The study compared those patients admitted to hospital for an exacerbation with those from a pulmonary rehabilitation clinic. It is however questionable whether these groups really represent similar populations in …

P21 The applicability of current cardiovascular risk scores and cardiovascular surrogates in chronic obstructive pulmonary disease: A case-control study

Background COPD is a complex multi-morbid disorder with significant cardiac mortality. Despite this, current cardiovascular scoring systems do not include COPD in their risk prediction models. The aims of this study were to assess whether differences in cardiovascular surrogate markers exist in COPD and to further our understanding of the relationship of COPD to cardiovascular structure and function. Methods This post-hoc cross-sectional analysis utilised baseline data from two randomised controlled trials (n = 36 and 54). 26 COPD patients were matched for global cardiovascular risk with 26 controls with normal lung function using QRISK2, a validated scoring system for predicting the 10-year risk of cardiovascular disease in a United Kingdom population. Patients underwent cardiac magnetic resonance imaging, arterial stiffness and lung function measurements. Results Pulse wave velocity (PWV) (mean difference +1.0 m/s, 95% CI 0.02–1.92; p = 0.045) and total arterial compliance (TAC) (mean difference -0.27 mL/m2/mmHg, 95% CI -0.39, -0.15; p < 0.001) were adversely affected in COPD compared to the control group matched for cardiovascular risk. In the whole cohort (n = 90) QRISK2 (β = 0.046, p = 0.017) and FEV1 (β = -0.013, p = 0.022) were associated with PWV in multivariate analysis. The relationship between QRISK2 and PWV appeared to be modified by COPD, where the interaction term reached borderline significance (p = 0.060). FEV1 (β = 0.005, p = 0.004) was also associated with TAC in multivariate analysis. Cardiac chamber size and stroke volume was decreased in COPD compared to controls. The mean difference in left ventricle stroke volume index (LVSVI) and left and right end diastolic volume index was -10.3 ml/m2 (95% CI -15.1, -5.5, p < 0.001), -14.1 ml/m2 (95% CI -21.9,-6.3 p < 0.001) and -13.0 ml/m2 (95% CI -23.3, -2.6 P < 0.015) respectively, which were shown to be associated with airflow limitation in multivariate models. In the COPD group associations were found with lung hyperinflation (LVSVI: β = -0.075, p = 0.032; Left atrial size: β = -0.129, p = 0.047) and fibrinogen (TAC: β = 0.716, p = 0.030). Conclusion Surrogates for cardiovascular outcomes are adversely affected in COPD compared to a group matched for global cardiovascular risk, suggesting that current scoring systems may be suboptimal for cardiovascular risk prediction in COPD.Abstract P21 Figure 1

Cardiac magnetic resonance myocardial feature tracking: feasibility for use in left ventricular non-compaction

Background Cardiac magnetic resonance (CMR) myocardial feature tracking (FT) is emerging as a sensitive and reproducible method for measuring myocardial strain parameters without the need to acquire additional images. Up until now adult CMRFT studies have primarily focussed on the reproducibility of the software,with very few studies addressing disease states beyond ischaemic cardiomyopathy. The aim of this pilot study was to assess the feasibility of cine-images derived quantitative CMR FT strain parameters to differentiate between normal individuals and patients with Left ventricular non-compaction (LVNC). Methods Patients were identified retrospectively from an established clinical CMR database. 8 LVNC patients with negative invasive angiography or stress CMR myocardial perfusion imaging were compared to 21 normal controls. LVNC was defined according to the Petersen criteria,with an end-diastolic ratio of non-compacted to compacted layer (NC/C) >2.3. LV morphological and functional parameters were performed off-line on a dedicated workstation. CMR 4chamber(4CH) and mid-ventricular short axis(SAX) cineimages were analysed in systole(S) and diastole(D) using dedicated FT software(Diogenes MRI,TomTec Imaging Systems,Munich Germany).

The applicability of current global cardiovascular risk scores and cardiovascular surrogates in chronic obstructive pulmonary disease

Background Chronic obstructive pulmonary disease (COPD) is a complex disorder associated with significant cardiovascular morbidity and mortality. Despite this, current cardiovascular scoring systems do not include COPD in their risk prediction models. The aims of this casecontrol study were to assess whether differences in cardiovascular surrogate markers exist in COPD to further understand the relationship of COPD to cardiovascular structure and function.

Splenic switch-off, a potential novel marker of lack of adenosine response: prevalence and measurement reproducibility

Background The sensitivity of adenosine stress perfusion CMR scans is reduced by inadequate response to adenosine. This can be due to a variety of environmental and pharmacological factors, including recent caffeine intake. Manisty et al (2014) observed that splenic blood flow is attenuated by adenosine, as the splanchnic circulation contains vasoconstrictor adenosine receptors, and may provide a simple visual marker of adequate pharmacological stress. The aim of this study was to validate measurement of splenic switch-off (SSO) in both a quantitative and qualitative manner and examine its prevalence in an East London tertiary cardiac centre.

The impact of chronic obstructive pulmonary disease (COPD) and its associated lung hyperinflation on cardiac structure and function

Background Significant cardiovascular morbidity and mortality exists in COPD, independent of traditional risk factors, although the mechanisms are poorly understood. Lung hyperinflation, the presence of supra-normal residual volumes (RVol) at the end of expiration, is one postulated mechanism. We sought to investigate the impact of COPD on cardiac structure and function compared to a control group with equivalent cardiovascular risk and look at the relative contributions of lung hyperinflation, defined as RVol per cent predicted value >120 %, as well as traditional spirometric measures. Methods 45 consecutive COPD patients with lung hyperinflation randomised to the DEFLATA study underwent cardiac magnetic resonance at 1.5 T, spirometric and body plethysmographic assessment at baseline. 9 were excluded from this analysis due to a history of known cardiovascular disease and/or atrial fibrillation and the remaining 36 were compared to 44 consecutive patients with increased cardiovascular risk and normal spirometry who underwent CMR as part of the HAPPY London Study. Results There was no difference in age, gender, renal function or cardiovascular risk (QRisk) scores between the groups. Decreased Right ventricular (RV) and Left ventricular (LV) indexed end diastolic volumes (EDVI) were found in the COPD group (RVEDVI 77±18 vs 88±19 ml p=0.009; LVEDVI 63±14 vs 77±15 ml p<0.0001) with decreased but preserved LV systolic function (LV Ejection fraction (EF) 60±7 vs 64±7 % p=0.005). RVEF was increased (63±7 vs 55±7 ml P<0.0001) as a consequence of preserved stroke volume (RVSVI 48±12 vs 47±9 ml, p=0.71). In the COPD group a 10% increase in RVol per cent predicted resulted in a 1.97 ml, 1.66 ml and 1.36 ml reduction in RVEDVI, LVEDVI and Left Atrial (LA) ESVI respectively (RVEDVI b=-0.197, p=0.017; LVEDVI b=-0.166, p=0.018; LAESVI b=-0.136, p=0.008) independent of age, sex, oxygen saturations, and Qrisk score. Furthermore a relationship between Rvol and LAEF (b=-0.197, p=0.024) was found although not between LVEF or RVEF. Similar relationships were found for the expiratory flow limitation measure per cent-predicted Forced expiratory volume in 1 second (FEV1), although no relationship was found with regard to airflow obstruction (FEV1/Forced vital capacity). Conclusions

Splenic switch-off, a potential novel marker of lack of adenosine response: relationship to heart rate response and demographic factors

Background Haemodynamic response is currently used as a marker of adenosine response during cardiovascular magnetic resonance (CMR) adenosine stress perfusion. However, the sensitivity of these scans is reduced by false negatives, some of which are due to inadequate response to adenosine. Blunted adenosine response can be due to a variety of environmental and pharmacological factors, including recent caffeine intake. Splenic blood flow falls in response to adenosine, splenic switch-off (SSO), and may provide a simple visual marker of adequate stress. The aim of this study was to compare the prevalence SSO to haemodynamic response, and assess its relationship to demographic factors.