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Aims Controversy exists regarding the importance of glycaemic control in patients with type 2 diabetes mellitus (T2DM) and chronic heart failure (CHF) based on conflicting reports using single baseline glycosyated haemoglobin (HbA1c). Using the time-weighted mean of serial HbA1c measurements has been found to be a better predictor of diabetic complications as it reflects the glycaemic burden for that individual over time. We therefore sought to confirm this in a large cohort of patients with T2DM and incident CHF. Methods and results A time-weighted mean HbA1c was calculated using all HbA1c measurements following CHF diagnosis. Patients were grouped into five categories of HbA1c (≤6.0%, 6.1–7.0%, 7.1–8.0%, 8.1–9.0%, and >9.0%). The relationship between time-weighted mean HbA1c and all-cause death after CHF diagnosis was assessed. A total of 1447 patients with T2DM met the study criteria. During a median follow-up of 2.8 years, there were 826 (57.1%) deaths, with a crude death rate of 155 deaths per 1000 person-years [95% confidence interval (CI) 144–166]. A Cox regression model, adjusted for all significant predictors, with the middle HbA1c category (7.1–8.0%) as the reference, showed a U-shaped relationship between HbA1c and outcome [HbA1c 9.0%, HR 1.8, 95% CI 1.4–2.3]. Further analysis revealed a protective effect of insulin sensitizers (i.e. metformin) (HR 0.7, 95% CI 0.61–0.93) but not other drug classes. Conclusions In patients with T2DM and CHF, our study shows a U-shaped relationship between HbA1c and mortality, with the lowest risk in patients with modest glycaemic control (HbA1c 7.1–8.0%) and those treated with insulin sensitizers.

Plasma BNP and high-sensitivity cardiac troponin-T (hs-TnT) are elevated by both ischaemia and LV systolic dysfunction (LVSD). As a result, it is unknown whether BNP and/or hs-TnT could be useful biomarkers to identify ischaemia in the presence of LVSD.Three separate patient populations were studied. Study A (n = 500) involved consecutive patients undergoing clinically indicated myocardial perfusion scintigraphy, study B (n = 100) included patients with vascular disease but no known cardiac disease, and study C (n = 300) recruited primary prevention patients with controlled risk factors. Levels of BNP and hs-TnT were measured prior to the stress testing to detect myocardial ischaemia. The prevalence of myocardial ischaemia was 28.2, 28, and 6.3% in study A, B, and C, respectively. For BNP, area under curve (AUC) values to identify ischaemia in the presence and absence of coincidental LVSD were: 0.73 vs. 0.63 (study A), 0.90 vs. 0.81 (study B), and 0.83 vs. 0.80 (study C). Equivalent figures for hs-TnT were: 0.64 vs. 0.60 (study A), 0.75 vs. 0.68 (study B), and 0.53 vs. 0.68 (study C). BNP and hs-cTnT, when combined together, performed better with an AUC of 0.75 vs. 0.65 (study A), 0.91 vs. 0.92 (study B), and 0.84 vs. 0.83 (study C).In three separate populations a consistent finding is that BNP is increased further by myocardial ischaemia even in the presence of LVSD. A disproportionately high BNP for the degree of LVSD might be due to (unsuspected) ischaemia, and a disproportionately low BNP could be useful as a 'rule out' test for ischaemia even in the presence of LVSD.

Aims Chronic heart failure (CHF) is an insulin-resistant state. The degree of insulin resistance (IR) correlates with disease severity and is associated with reduced exercise capacity. In this proof of concept study, we have examined the effect of metformin on IR and exercise capacity in non-diabetic CHF patients identified to have IR. Methods and results In a double-blind, placebo-controlled study, 62 non-diabetic IR CHF patients (mean age, 65.2 ± 8.0 years; male, 90%; left ventricular ejection fraction, 32.6 ± 8.3%; New York Heart Association class I/II/III/IV, 11/45/6/0) were randomized to receive either 4 months of metformin (n = 39, 2 g/day) or matching placebo (n = 23). IR was defined by a fasting insulin resistance index (FIRI) ≥2.7. Cardiopulmonary exercise testing and FIRI were assessed at baseline and after 4 months of intervention. Compared with placebo, metformin decreased FIRI (from 5.8 ± 3.8 to 4.0 ± 2.5, P < 0.001) and resulted in a weight loss of 1.9 kg (P < 0.001). The primary endpoint of the study, peak oxygen uptake (VO2), did not differ between treatment groups. However, metformin improved the secondary endpoint of the slope of the ratio of minute ventilation to carbon dioxide production (VE/VCO2 slope), from 32.9 ± 15.9 to 28.1 ± 8.8 (P = 0.034). In the metformin-treated group, FIRI was significantly related to the reduction of the VE/VCO2 slope (R = 0.41, P = 0.036). Conclusion Metformin treatment significantly improved IR but had no effect on peak VO2, the primary endpoint of our study. However, metformin treatment did result in a significant improvement in VE/VCO2 slope. Trial registration: NCT00473876.

Background: Heart failure (HF) is difficult to diagnose and treat in older patients. Symptoms may be non-specific and the presence of co-morbidities and polypharmacy complicate treatment strategies. There are, however, few data to quantify the extent of these problems in the very elderly. Methods: A retrospective study of 116 patients (median age 86; range 65–98) with an established diagnosis of HF during their hospital admission. Main outcome measures: the accuracy of diagnosis of heart failure according to the European Society of Cardiology (ESC) definition. The aetiology and frequency of associated co-morbidities and the nature of drug treatment. Results: The specificities of clinical signs, chest X-rays and abnormal ECGs for heart failure (ESC definition) were 50%, 20% and 9%, respectively. Only 28% of patients were admitted for worsening symptoms which could be attributed to HF. None of the patients had HF as their only medical problem. Co-morbidities included chest disease (30%), incontinence (29%), cerebrovascular disease (26%), musculoskeletal problems (41%). Barthel (activities of daily living) score was ≤16/20 in 35%. Mental state questionnaire (MSQ) score was ≤7/10 in 38%. Ninety percent were taking four or more different medications. Thirty-nine percent were on psychotropic drugs. On discharge, a total of 88% of patients returned home to live independently and 35% were monitored by regular day hospital attendance. Conclusion: Heart failure in frail elderly patients is often compounded by other major illnesses and polypharmacy which have a profound impact on their functional status. This has implications for the most effective targeting of evidence based treatment.

Controversy exists regarding the importance of glycaemic control in patients with type 2 diabetes mellitus (T2DM) and chronic heart failure (CHF) based on conflicting reports using single baseline glycosyated haemoglobin (HbA1c ). Using the time-weighted mean of serial HbA1c measurements has been found to be a better predictor of diabetic complications as it reflects the glycaemic burden for that individual over time. We therefore sought to confirm this in a large cohort of patients with T2DM and incident CHF.A time-weighted mean HbA1c was calculated using all HbA1c measurements following CHF diagnosis. Patients were grouped into five categories of HbA1c (≤6.0%, 6.1-7.0%, 7.1-8.0%, 8.1-9.0%, and9.0%). The relationship between time-weighted mean HbA1c and all-cause death after CHF diagnosis was assessed. A total of 1447 patients with T2DM met the study criteria. During a median follow-up of 2.8 years, there were 826 (57.1%) deaths, with a crude death rate of 155 deaths per 1000 person-years [95% confidence interval (CI) 144-166]. A Cox regression model, adjusted for all significant predictors, with the middle HbA1c category (7.1-8.0%) as the reference, showed a U-shaped relationship between HbA1c and outcome [HbA1c6.0%, hazard ratio (HR) 2.5, 95% CI 1.8-3.4; HbA1c 6.1-7.0%, HR 1.4, 95% 1.1-1.7; HbA1c 8.1-9.0%, HR 1.3, 95% CI 1.0-1.6; and HbA1c9.0%, HR 1.8, 95% CI 1.4-2.3]. Further analysis revealed a protective effect of insulin sensitizers (i.e. metformin) (HR 0.7, 95% CI 0.61-0.93) but not other drug classes.In patients with T2DM and CHF, our study shows a U-shaped relationship between HbA1c and mortality, with the lowest risk in patients with modest glycaemic control (HbA1c 7.1-8.0%) and those treated with insulin sensitizers.

Background: Angiotensin Converting Enzyme inhibitors reduce mortality in heart failure. One therapeutic mechanism is believed to be the reduction of circulating angiotensin II and aldosterone. However, the Renin–Angiotensin–Aldosterone axis (RAAS) is not uniformly suppressed during therapy for heart failure. This effect has been referred to as ‘angiotensin II reactivation’ and ‘aldosterone escape’ and their reactivation may herald clinical deterioration. In the CONSENSUS I trial, correlations were seen between mortality, and angiotensin II and aldosterone. Furthermore, mortality was lower in those with good angiotensin II suppression. Therefore, neurohormonal elevation despite adequate treatment may associate with a poorer prognosis. Aims: To follow chronic heart failure patients on ACE inhibitors for 18 months to assess whether or not angiotensin II and aldosterone reactivation are progressive with time, whether reactivation of both occurs simultaneously, and whether different ACE inhibitors have different neurohormonal profiles. Methods and results: We studied 22 patients (M/F 19:3, 72.5 ± 7 years) on stable ACE inhibitors. Five times, in 18 months, samples were taken for neurohormones and ACE activity. Mean levels of neurohormones were remarkably stable over time, although captopril takers had generally higher angiotensin II, but lower aldosterone and renin. Aldosterone ‘escape’ (> 80 pg/ml) occurred in 13/97 samples (13.5%), in 5/22 (23%) individuals. Angiotensin II was elevated ≥10 pg/ml in 8/102 samples (8%), in 6/22 (27%) individuals. Four subjects had isolated angiotensin II reactivation, and three had aldosterone escape alone. On regression analyses between neurohormones in captopril takers there were significant correlations between; renin and angiotensin II (r = 0.62; P < 0.02); angiotensin II and aldosterone (r = 0.6; P < 0.02); and renin and aldosterone (r = 0.92; P < 0.00001). Conclusion: In stable heart failure patients un-suppressed levels of angiotensin II and aldosterone occur despite therapy, but they are not necessarily progressive, nor simultaneous. Furthermore, contemporaneous serum ACE activity makes it unlikely the data presented reflects poor compliance. The results suggest that captopril takers may have different neurohormonal profiles, i.e. higher angiotensin II, and also better correlations between RAAS components, compared to longer acting preparations, although the numbers are small. Our data supports that of Swedberg et al. who showed reductions in both aldosterone and angiotensin II due to ACE inhibitor therapy, but no correlation between ACE activity and angiotensin II and only a limited correlation (r = 0.37) between angiotensin II and aldosterone. This suggests that the interaction between the components of the renin–angiotensin system is not simple and linear. The fact that each phenomenon appears to occur in isolation means that neurohormonal monitoring of individual could provide useful information to direct additional therapy. The RALES study has demonstrated reduced mortality from the addition of spironolactone to an ACE inhibitor emphasising the benefit of enhanced suppression of aldosterone in heart failure. Captopril may be less effective at suppressing the RAAS due to its short duration of action which would logically be associated with a more fluctuating pattern of ACE inhibition. In the presence of high levels of renin and angiotensin I even small differences in ACE activity will produce large variations in angiotensin II levels. Further studies should be directed at understanding the different mechanisms behind angiotensin II and aldosterone generation during ACE inhibition.

Aims The presence of pulmonary hypertension (PH) in left ventricular systolic dysfunction (LVSD) and symptomatic heart failure is an ominous sign. There are insufficient data regarding the risk conferred by increasing severity of PH in patients with heart failure. Methods and results We performed a record linkage study in Tayside, Scotland (population ∼400 000) utilizing the Tayside echocardiogram database (>50 000 echocardiograms) maintained by the Health Informatics Centre (HIC). Data sets from the HIC include mortality data, cardiovascular medications, and other healthcare activities linked anonymously by the community health index (CHI) number. Patients were included in the analysis if they had LVSD, had a valid right ventricular systolic pressure (RVSP) measurement, and had a loop diuretic prescription (provided not more than 1 year prior to echocardiogram). A Cox proportional hazard model was used to examine the effects of RVSP on all-cause mortality. A total of 1612 patients [mean age, 75.2 ± 10.9 (SD) years; 57.4% male] met the entry criteria. Mean RVSP for the cohort was 44.9 ± 13.1 mmHg and mean follow-up was 2.8 ± 2.5 years. For each 5 mmHg stepwise increase in RVSP, after adjustment for confounding factors including the degree of LVSD and the presence of chronic obstructive pulmonary disease, the hazard ratio (HR) for all-cause mortality was 1.06 (1.03–1.08, P < 0.001). Conclusions Pulmonary hypertension predicted all-cause mortality in a heterogeneous group of patients with heart failure. Each 5 mmHg rise in RVSP was associated with a 6% increased risk of death.

Aims To determine whether valsartan improves treadmill exercise time, in patients with symptomatic heart failure with a preserved ejection fraction (HFPEF), compared with placebo. Methods and results In this multicentred, double-blind, 14-week study, patients were randomized to receive valsartan (V) 80 mg or placebo (P) once daily on top of background medications. The dose of valsartan was force-titrated up to 320 mg. A total of 152 patients were randomized (V = 70, P = 82). Most patients had well-controlled hypertension (V = 91.2%, P = 89.0%) (mean baseline systolic BP ~130 mmHg) and >50% were receiving an angiotensin-converting enzyme inhibitor and/or beta-blocker (V = 57.4%, P = 54.9%). The mean ejection fraction at baseline was 70.48% in the placebo group (n = 64) and 71.52% in the valsartan group (n = 79). Valsartan had no significant effect on exercise time (primary variable), gas exchange variables, 6 min walk test distance, exertion-related symptoms, brain natriuretic peptide levels, echocardiographic parameters, or quality-of-life scores. Valsartan significantly lowered peak exercise systolic BP (−13.1 mmHg vs. placebo; P < 0.001) and improved ratings of perceived exertion (Borg score) (−0.69 vs. placebo; P = 0.008). Conclusion In this population, which predominantly included patients with well-controlled hypertension and symptomatic HFPEF, addition of valsartan did not increase exercise time within 14 weeks. However, valsartan 320 mg reduced blood pressure and improved symptoms of perceived exertion (Borg score) during exercise and was generally well-tolerated.

Aims Patient beliefs about heart failure (HF) may be important determinants of adherence. This study assessed levels of adherence to angiotensin-converting-enzyme inhibitors (ACEI) and examined whether beliefs about HF were associated with adherence to ACEI. Methods and results Fifty-eight patients with chronic stable HF (mean age 80.2 years SD ± 4.6, 43% female) were recruited from two outpatient clinics in Dundee, UK. The Illness Perception Questionnaire-Revised was used to assess beliefs about HF. Adherence to ACEI was assessed by measuring serum levels of angiotensin-converting enzyme (sACE). Adherence to ACEI (defined as sACE

Background: ECG and BNP have been assessed as screening tests for LVSD and heart failure. However, echocardiography also provides information about valvular disease and LVH. We assessed how good these screening tests are in identifying whether the subsequent echocardiogram will have any significant abnormality. Aims: To re-appraise the ECG and BNP as screening tests for echocardiography since there are important practical deficiencies in our current knowledge in this area. Methods: General practitioners referred suspected heart failure patients for clinical assessment, echocardiography, electrocardiography, and BNP measurement. The accuracy of each screening test and combinations of screening tests were calculated for LVSD, heart failure, valvular disease, and LVH. Results: The sensitivities of the ECG for LVSD, heart failure, LVH and valvular disease were 97%, 95%, 76%, and 69%, respectively. The corresponding figures for BNP were 86%, 82%, 59%, and 48%, respectively. When patients with atrial fibrillation and murmurs were excluded, the values for ECG were 94%, 87%, 53%, and 55%, while for BNP they were 83%, 73%, 50%, and 32%. Conclusions: ECG interpretation and BNP are adequate screening tests to detect LVSD or heart failure but fail to screen for other echocardiographic abnormalities, like valvular disease and LVH. This remains the case even if patients with atrial fibrillation or heart murmurs are excluded on the basis that they require echocardiography anyway.

Background: Exercise capacity and daily activity are key outcomes for older, frail heart failure patients. Little is known about the determinants of these outcomes in this patient group. Aims: To explore predictors of exercise capacity and daily activity in older, frail heart failure patients. Methods: Analysis of prospectively collected data from a cohort of 82 patients aged 70 years and over, enrolled in a randomised controlled trial of exercise in heart failure patients. Pathophysiological, demographic, psychological and social factors were analysed by multivariate regression to determine predictors of exercise capacity (6-min walk distance) and daily activity (daily accelerometer counts). Results: Between 49% and 55% of the variance in 6-min walk distance was explained by variables including New York Heart Association class, depression score, attitude to ageing and use of walking aids. Only 11% to 26% of the variance in accelerometer scores was explained by the model; 6-min walk distance was the only consistent predictor of daily activity. Conclusions: Physical, psychological and attitudinal variables contribute to variance of the 6-min walk. Six-minute walk distance predicts a small amount of the variance in daily activity, but the majority of variance in daily activity remains unexplained and requires further investigation.