Andrew J.S. Coats

Ethical authorship and publishing.

Principles of Ethical Publishing in the International Journal of Cardiology: 1. That the corresponding author has the approval of all other listed authors for the submission and publication of all versions of the manuscript. 2. That all people who have a right to be recognised as authors have been included on the list of authors and everyone listed as an author has made an independent material contribution to the manuscript.3. That the work submitted in the manuscript is original and has not been published elsewhere and is not presently under consideration of publication by any other journal. The oral or poster presentation of parts of the work and its publishing as a single page abstract does not count as prior publication for this purpose. 4. That the material in the manuscript has been acquired according to modern ethical standards and does not contain material copied from anyone else without their written permission.5. That all material which derives from prior work, including from the same authors, is properly attributed to the prior publication by proper citation.6. That the manuscript will be maintained on the servers of the Journal and held to be a valid publication by the Journal only as long as all statements in these principles remain true.7. That if any of the statements above ceases to be true the authors have a duty to notify the journal as soon as possible so that the manuscript can be withdrawn.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure : The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC

Authors/Task Force Members: Piotr Ponikowski* (Chairperson) (Poland), Adriaan A. Voors* (Co-Chairperson) (The Netherlands), Stefan D. Anker (Germany), Héctor Bueno (Spain), John G. F. Cleland (UK), Andrew J. S. Coats (UK), Volkmar Falk (Germany), José Ramón González-Juanatey (Spain), Veli-Pekka Harjola (Finland), Ewa A. Jankowska (Poland), Mariell Jessup (USA), Cecilia Linde (Sweden), Petros Nihoyannopoulos (UK), John T. Parissis (Greece), Burkert Pieske (Germany), Jillian P. Riley (UK), Giuseppe M. C. Rosano (UK/Italy), Luis M. Ruilope (Spain), Frank Ruschitzka (Switzerland), Frans H. Rutten (The Netherlands), Peter van der Meer (The Netherlands)

Wasting as independent risk factor for mortality in chronic heart failure

BACKGROUND Wasting in chronic heart failure (CHF) has long been known but is little investigated. We sought to find out whether the cachectic state in CHF provides additional prognostic information about all-cause mortality. METHODS Between June, 1993, and May, 1995, we studied 171 consecutive patients with CHF (mean age 60 years [SD 11; range 27-86]; 17 female). We assessed exercise capacity (peak oxygen consumption; mean 17.5 mL kg-1 min-1 [6.7]), functional status (New York Heart Association [NYHA] class: 21 class I, 63 class II, 68 class III, 19 class IV), and left-ventricular ejection fraction (mean 30% [SD 15]; n = 115). The cachectic status was defined prospectively as a non-intentional documented weight loss of at least 7.5% of previous normal weight (28 patients; range 9-36% or 6-30 kg) during at least 6 months. The Cox proportional-hazards model was used to assess the association of variables with survival, and Kaplan-Meier cumulative survival plots were constructed to estimate the influence of risk factors. FINDINGS At the end of follow-up in November, 1996, 49 patients had died (after a mean 324 days [SD 283]). The mean follow-up of the survivors was 834 days (SD 186; range 549-1269). The cachectic state was predictive of 18-month mortality independent of age, NYHA class, left-ventricular ejection fraction, and peak oxygen consumption. Mortality in the cachectic patients (n = 28) was 18% at 3 months, 29% at 6 months, 39% at 12 months, and 50% at 18 months. Patients who had a peak oxygen consumption below 14 mL kg-1 min-1 (n = 53) had mortality at 3, 6, 12, and 18 months of 19%, 30%, 40%, and 51%. 18-month survival was 23% (95% CI 0-46) for the 13 patients with both of these risk factors (cachexia and low peak oxygen consumption) compared with 93% (88-98) in those (n = 103) with neither risk factor (p < 0.0001). INTERPRETATION The cachectic state is a strong independent risk factor for mortality in patients with CHF. Combined with a low peak oxygen consumption, it identifies a subset of patients at extremely high risk of death. Assessment of cachexia should be included in transplant programmes and studies that investigate the effect of interventions by survival analyses.

Differentiation of Heart Failure Related to Dilated Cardiomyopathy and Coronary Artery Disease Using Gadolinium-Enhanced Cardiovascular Magnetic Resonance

Background Heart failure treatment depends partly on the underlying cause of the disease. We evaluated cardiovascular magnetic resonance (CMR) for the problem of differentiating dilated cardiomyopathy (DCM) from left ventricular (LV) dysfunction caused by coronary artery disease (CAD). Methods and Results Late gadolinium enhancement with CMR was performed in 90 patients with heart failure and LV systolic dysfunction (63 patients with DCM and unobstructed coronary arteries and 27 with significant CAD at angiography). We also studied 15 control subjects with no coronary risk factors and/or unobstructed coronary arteries. None (0%) of the control subjects had myocardial gadolinium enhancement; however, all patients (100%) with LV dysfunction and CAD had enhancement, which was subendocardial or transmural. In patients with DCM, there were 3 findings: no enhancement (59%); myocardial enhancement indistinguishable from the patients with CAD (13%); and patchy or longitudinal striae of midwall enhancement clearly different from the distribution in patients with CAD (28%). Conclusions Gadolinium CMR is a powerful technique to distinguish DCM from LV dysfunction related to CAD and yields new insights in DCM. These data suggest that using the coronary angiogram as the arbiter for the presence of LV dysfunction caused by CAD could have lead to an incorrect assignment of DCM cause in 13% of patients, possibly because of coronary recanalization after infarction. The midwall myocardial enhancement in patients with DCM is similar to the fibrosis found at autopsy; it has not previously been visualized in vivo and warrants further investigation. CMR may become a useful alternative to routine coronary angiography in the diagnostic workup of DCM. (Circulation. 2003;108:54‐59.)

Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study

Background—&bgr;-Blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure. Methods and Results—We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months. Carvedilol reduced the combined risk of death or hospitalization for a cardiovascular reason by 27% (P =0.00002) and the combined risk of death or hospitalization for heart failure by 31% (P =0.000004). Patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (P =0.0005) and 40% fewer days in the hospital for heart failure (P <0.0001). These differences were as a result of both a decrease in the number of hospitalizations and a shorter duration of each admission. More patients felt improved and fewer patients felt worse in the carvedilol group than in the placebo group after 6 months of maintenance therapy (P =0.0009). Carvedilol-treated patients were also less likely than placebo-treated patients to experience a serious adverse event (P =0.002), especially worsening heart failure, sudden death, cardiogenic shock, or ventricular tachycardia. Conclusion—In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.

Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation, and autonomic function.

BackgroundMany secondary abnormalities in chronic heart failure (CHF) may reflect physical deconditioning. There has been no prospective, controlled study of the effects of physical training on hemodynamics and autonomic function in CHIF. Methods and ResultsIn a controlled crossover trial of 8 weeks of exercise training, 17 men with stable moderate to severe CHF (age, 61.8±1.5 years; left ventricular ejection fraction, 19.6±2.3%), increased exercise tolerance (13.9±1.0 to 16.5±1.0 minutes, p<0.001), and peak oxygen uptake (13.2±0.9 to 15.6±1.0 mI/kg/min, p<0.01) significantly compared with controls. Training increased cardiac output at submaximal (5.9-6.7 1/min, p<0.05) and peak exercise (6.3-7.1 /min, p<0.05), with a significant reduction in systemic vascular resistance. Training reduced minute ventilation and the slope relating minute ventilation to carbon dioxide production (−10.5%, p<0.05). Sympathovagal balance was altered by physical training when assessed by three methods: 1) RR variability (+19.2%, p<0.05); 2) autoregressive power spectral analysis of the resting ECG divided into low-frequency (−21.2%, p<0.01) and high-frequency (+51.3%, p<0.05) components; and 3) whole-body radiolabeled norepinephrine spillover (−16%, p<0.05). These measurements all showed a significant shift away from sympathetic toward enhanced vagal activity after training. ConclusionsCarefully selected patients with moderate to severe CHF can achieve significant, worthwhile improvements with exercise training. Physical deconditioning may be partly responsible for some of the associated abnormalities and exercise limitation of CHF, including abnormalities in autonomic balance.

Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care

BACKGROUND The reliability of a clinical diagnosis of heart failure in primary care is poor. Concentrations of natriuretic peptides are high in heart failure. This population-based study examined the predictive value of natriuretic peptides in patients with a new primary-care diagnosis of heart failure. METHODS Concentrations of plasma atrial (ANP and N-terminal ANP) and B-type (BNP) natriuretic peptides were measured by radioimmunoassay in 122 consecutive patients referred to a rapid-access heart-failure clinic with a new primary-care diagnosis of heart failure. On the basis of clinical assessment, chest radiography, and transthoracic echocardiography, a panel of three cardiologists decided that 35 (29%) patients met the case definition for new heart failure. ANP and NT-ANP results were available for 117 patients (34 with heart failure) and BNP results for 106 (29 with heart failure). FINDINGS Geometric mean concentrations of natriuretic peptides were much higher in patients with heart failure than in those with other diagnoses (29.2 vs 12.4 pmol/L for ANP; 63.9 vs 13.9 pmol/L for BNP; 1187 vs 410.6 pmol/L for NT-ANP; all p < 0.001). At cut-off values chosen to give negative predictive values for heart failure of 98% (ANP > or = 18.1 pmol/L, NT-ANP > or = 537.6 pmol/L, BNP > or = 22.2 pmol/L), the sensitivity, specificity, and positive predictive value for ANP were 97%, 72%, and 55%; for NT-ANP 97%, 66%, and 54%; and for BNP 97%, 84%, and 70%. Addition of ANP or NT-ANP concentration or both did not improve the predictive power of a logistic regression model containing BNP concentration alone. INTERPRETATION In patients with symptoms suspected by a general practitioner to be due to heart failure, plasma BNP concentration seems to be a useful indicator of which patients are likely to have heart failure and require further clinical assessment.

Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH)

Abstract Objective To determine the effect of exercise training on survival in patients with heart failure due to left ventricular systolic dysfunction. Design Collaborative meta-analysis. Inclusion criteria Randomised parallel group controlled trials of exercise training for at least eight weeks with individual patient data on survival for at least three months. Studies reviewed Nine datasets, totalling 801 patients: 395 received exercise training and 406 were controls. Main outcome measure Death from all causes. Results During a mean (SD) follow up of 705 (729) days there were 88 (22%) deaths in the exercise arm and 105 (26%) in the control arm. Exercise training significantly reduced mortality (hazard ratio 0.65, 95% confidence interval, 0.46 to 0.92; log rank χ2 = 5.9; P = 0.015). The secondary end point of death or admission to hospital was also reduced (0.72, 0.56 to 0.93; log rank χ2 = 6.4; P = 0.011). No statistically significant subgroup specific treatment effect was observed. Conclusion Meta-analysis of randomised trials to date gives no evidence that properly supervised medical training programmes for patients with heart failure might be dangerous, and indeed there is clear evidence of an overall reduction in mortality. Further research should focus on optimising exercise programmes and identifying appropriate patient groups to target.

Hormonal Changes and Catabolic/Anabolic Imbalance in Chronic Heart Failure and Their Importance for Cardiac Cachexia

BACKGROUND The role of hormonal and cytokine abnormalities in the development of cardiac cachexia remains obscure. METHODS AND RESULTS Healthy control subjects (n=16) and patients with chronic heart failure (CHF), classified clinically as cachectic (8% to 35% weight loss over > or = 6 months before study, n=16) or noncachectic (n=37), were assessed for markers of disease severity (maximal oxygen consumption, left ventricular ejection fraction, NYHA functional class). These markers were compared with plasma concentrations of potentially important anabolic and catabolic factors. The degree of neurohormonal activation and catabolic/anabolic imbalance was closely related to wasting but not to conventional measures of the severity of heart failure. Compared with control subjects and noncachectic patients, cachectic patients had reduced plasma sodium and increased norepinephrine, epinephrine (all P<.0001), cortisol, tumor necrosis factor (TNF)-alpha (both P<.002), and human growth hormone (P<.05). Insulin-like growth factor-1, testosterone, and estrogen were similar in all groups. Insulin was increased only in the noncachectic patients (P<.005 versus control subjects). Dehydroepiandrosterone was reduced in the cachectic patients (P<.02 versus control subjects). Insulin, cortisol, TNF-alpha, and norepinephrine correlated independently with wasting in CHF (P<.05; multiple regression of these four factors versus percent ideal weight, R2=.50, P<.0001). CONCLUSIONS Cachexia is more closely associated with hormonal changes in CHF than conventional measures of the severity of CHF. This study suggests that the syndrome of heart failure progresses to cardiac cachexia if the normal metabolic balance between catabolism and anabolism is altered.

Endotoxin and immune activation in chronic heart failure: a prospective cohort study.

BACKGROUND Immune activation in patients with chronic heart failure may be secondary to endotoxin (lipopolysaccharide) action. We investigated the hypothesis that altered gut permeability with bacterial translocation and endotoxaemia would be increased in patients with oedema secondary to congestive heart failure. METHODS We compared 20 patients who had chronic heart failure with recent-onset peripheral oedema (mean age 64 years [SD 10], New York Heart Association [NYHA] class 3.3 [0.7]), 20 stable non-oedematous patients with chronic heart failure (mean age 63 years [19], NYHA class 2.6 [0.7]), and 14 healthy volunteers (mean age 55 years [16]). Biochemical markers of endotoxaemia, inflammation, and immune activation were measured. Ten patients were studied within 1 week of complete resolution of oedema. Five patients survived longer than 6 months and were restudied again after remaining free of oedema for more than 3 months. FINDINGS Mean endotoxin concentrations were higher in oedematous patients with chronic heart failure than in stable patients with chronic heart failure (0.74 [SD 0.45] vs 0.37 EU/mL [0.23], p=0.0009) and controls (0.46 EU/mL [0.21], p=0.02). Oedematous patients had the highest concentrations of several cytokines. After short-term diuretic treatment, endotoxin concentrations decreased from 0.84 EU/mL [0.49] to 0.45 EU/mL [0.21], p<0.05) but cytokines remained raised. After freedom of oedema for more than 3 months after oedema resolved, endotoxin concentrations remained unchanged from the previous visit (0.49 EU/mL [0.06], p=0.45). INTERPRETATION Raised concentrations of endotoxin and cytokines are found in patients with chronic heart failure during acute oedematous exacerbation. Intensified diuretic treatment can normalise endotoxin concentrations. Our preliminary findings suggest that endotoxin may trigger immune activation in patients with chronic heart failure during oedematous episodes.