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Aim We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. Methods and results We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference −1.37 (95% confidence interval: −2.63 to −0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. Conclusion Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.

Aim We tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with type 2 diabetes (T2D). Methods and results We randomly assigned 66 people (mean age 67 ± 7 years, 38 males) with T2D, LVH, and controlled blood pressure (BP) to receive dapagliflozin 10 mg once daily or placebo for 12 months. Primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging. In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo with an absolute mean change of −2.82g [95% confidence interval (CI): −5.13 to −0.51, P = 0.018]. Additional sensitivity analysis adjusting for baseline LVM, baseline BP, weight, and systolic BP change showed the LVM change to remain statistically significant (mean change −2.92g; 95% CI: −5.45 to −0.38, P = 0.025). Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h systolic BP (P = 0.012), nocturnal systolic BP (P = 0.017), body weight (P < 0.001), visceral adipose tissue (VAT) (P < 0.001), subcutaneous adipose tissue (SCAT) (P = 0.001), insulin resistance, Homeostatic Model Assessment of Insulin Resistance (P = 0.017), and high-sensitivity C-reactive protein (hsCRP) (P = 0.049). Conclusion Dapagliflozin treatment significantly reduced LVM in people with T2D and LVH. This reduction in LVM was accompanied by reductions in systolic BP, body weight, visceral and SCAT, insulin resistance, and hsCRP. The regression of LVM suggests dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to the cardio-protective effects of dapagliflozin. ClinicalTrials.gov Identifier NCT02956811

Aims Our aim was to test the prediction and clinical applicability of high-sensitivity assayed troponin I for incident cardiovascular events in a general middle-aged European population. Methods and results High-sensitivity assayed troponin I was measured in the Scottish Heart Health Extended Cohort ( n = 15 340) with 2171 cardiovascular events (including acute coronary heart disease and probable ischaemic strokes), 714 coronary deaths (25% of all deaths), 1980 myocardial infarctions, and 797 strokes of all kinds during an average of 20 years follow-up. Detection rate above the limit of detection (LoD) was 74.8% in the overall population and 82.6% in men and 67.0% in women. Troponin I assayed by the high-sensitivity method was associated with future cardiovascular risk after full adjustment such as that individuals in the fourth category had 2.5 times the risk compared with those without detectable troponin I ( P < 0.0001). These associations remained significant even for those individuals in whom levels of contemporary-sensitivity troponin I measures were not detectable. Addition of troponin I levels to clinical variables led to significant increases in risk prediction with significant improvement of the c-statistic ( P < 0.0001) and net reclassification ( P < 0.0001). A threshold of 4.7 pg/mL in women and 7.0 pg/mL in men is suggested to detect individuals at high risk for future cardiovascular events. Conclusion Troponin I, measured with a high-sensitivity assay, is an independent predictor of cardiovascular events and might support selection of at risk individuals.

This Editorial refers to ‘Efficacy of the long acting nitro vasodilator pentaerithrityltetranitrate in patients with chronic stable angina pectoris receiving antianginal background therapy with betablockers: a 12-weeks, randomized, double-blind, placebo controlled trial’, by Munzel et al . doi:10.1093/eurheartj/eht384 Today, patients with coronary artery disease can expect to live longer and with less symptom burden than their counterparts of 30 years ago. This is because of better medical therapies and better revascularization strategies. However, the stalwarts of medical anti-anginal therapy—the β-blockers, calcium channel blockers, and nitrates—are not without their problems. Nitrates, although effective at relieving acute anginal pain and well established as a mainstay of chronic angina therapy, may have particular problems.1,2 One problem with nitrates is that traditional nitrate use can increase oxidative stress and so induce endothelial dysfunction.1 In addition to endothelial dysfunction, another major practical problem with nitrate is nitrate tolerance.2 Furthermore, a review of 52 693 patients from the Global Registry of Acute Coronary Evidence shows that longer-term use of nitrates is associated with fewer ST elevation myocardial infarctions but more non-ST elevation acute coronary syndromes.3 One hypothesis is that nitrates might pre-condition the heart more towards ischaemic episodes. Newer medical therapies—or new applications of existing therapies—are therefore needed to reduce the symptom burden in chronic stable angina and, if possible, to improve prognosis. This need is particularly relevant to those who have run out of revascularization options. This is the approach …

Aims To test the hypothesis that urate predicts cardiac death after stroke independent of conventional risk factors of atherosclerosis, creatinine and diuretic use. Methods and Results Serum urate concentration was measured in an unselected cohort of 354 stroke survivors who were followed-up for a median of 2·8 years. Cardiac death was the primary end-point. Urate was associated with a statistically significant threefold increase in relative risk of cardiac death even after adjustment for other conventional risk factors. In the subgroup of patients who were not on diuretics, raised urate was associated with a 12-fold significant increase in relative risk of cardiac death after adjusting for renal function and other conventional risk factors. A urate concentration of greater than 0·31mmol.l−1 was 78% sensitive at predicting cardiac death within 5 years after stroke, but was only 54% specific. If urate exceeded 0·38mmol.l−1, specificity of predicting cardiac death within 5 years after stroke was 88%. Conclusions Elevated serum urate concentration may be used to stratify risk of future cardiac death after stroke. This appeared to be true even in stroke survivors who were not on diuretic therapy.

It is 10 years since the CONSENSUS I study showed that ACE inhibitors improved mortality in heart failure. This finding has been confirmed in numerous trials, for example SOLVD, SAVE. Indeed, in the intervening 10 years, many other potential therapies have been examined in mortality trials, but so far no other therapy has had as good effect on mortality as ACE inhibitors. The other therapies which have been examined are digoxin, amlodipine, beta-blockers, amiodarone, etc. Despite ACE inhibitors being a very effective therapy for heart failure, there is still remarkable under-use of them in clinical practice. The reason for this needs to be explained further, but fear of hypothermia and renal dysfunction appear to be major factors.

Aims Resting plasma levels of atrial natriuretic peptide and B-type natriuretic peptide rise with left ventricular dysfunction, but little is known about effects of cardiac ischaemia on atrial natriuretic peptide and B-type natriuretic peptide levels during exercise. We investigated exercise levels of atrial natriuretic peptide and B-type natriuretic peptide in patients with suspected angina to determine whether these measurements could improve non-invasive assessment of coronary disease severity. Methods and results One hundred patients performed an exercise test (Bruce protocol) within 2 weeks of coronary angiography. Plasma levels of atrial natriuretic peptide and B-type natriuretic peptide were measured at rest and at peak exercise. Multivariate regression analysis was used to assess effects of age, sex, coronary anatomy, exercise time and ventricular function on atrial natriuretic peptide and B-type natriuretic peptide levels. Increasing age and female sex were significantly associated with higher resting atrial natriuretic peptide levels; age alone was associated with higher exercise atrial natriuretic peptide levels. As expected, left ventricular end-diastolic pressure and disease of left anterior descending and circumflex coronary arteries were associated with increased resting B-type natriuretic peptide levels. However, the usual rise in B-type natriuretic peptide levels during exercise was independently reduced by disease of the right coronary artery. Conclusion This paradoxical effect of right coronary artery disease limits the value of natriuretic peptide measurements as predictors of coronary disease severity. Impaired release of B-type natriuretic peptide may reduce exercise tolerance in patients with right coronary artery disease.

In the setting of chronic heart failure (CHF), therapy with angiotensin converting enzyme (ACE) inhibitors generally reduces serum aldosterone levels acutely. However, long-term ACE inhibition is associated with aldosterone suppression that is weak, variable, and unsustained, i.e. aldosterone 'escape'. Magnesium loss caused by aldosterone and by diuretics can contribute to coronary artery spasm and arrhythmias. Aldosterone can block noradrenaline uptake by the myocardium; extracellular catecholamines may lead to arrhythmias and ischaemia. Aldosterone has been shown to have an acute arrhythmogenic effect as well as a potential detrimental effect on baroreflex function, a marker of prognosis in CHF. Both angiotensin II and aldosterone may stimulate myocardial fibrosis, which is associated with a higher incidence of malignant ventricular arrhythmias. ACE inhibition initiated early in the progression of CHF may prevent development of patchy myocardial fibrosis and its inherent arrhythmias and thus reduce the incidence of sudden death. Spironolactone therapy added to the regimen of an ACE inhibitor and diuretic can induce natriuresis and magnesium retention, increase myocardial noradrenaline uptake, and reduce the incidence of arrhythmias.

Methods of effective renal plasma flow measurement by 125I-orthoiodohippurate elimination and para-aminohippurate clearance were compared with and without captopril pretreatment in 10 chronic heart failure patients and in 20 patients after transmural myocardial infarction. In the chronic heart failure group measurements of effective renal plasma flow by the two techniques were strongly correlated (r = 0.92, P < 0.00001), as was the captopril-mediated change in effective renal plasma flow by the two methods (r = 0.85, P = 0.002). However, in absolute terms para-aminohippurate clearance significantly exceeded 125I-orthoiodohippurate clearance by a mean (+/- SD) of 24.8 +/- 43.7 ml.min-1 (P < 0.05) so that only using the former technique was a significant increment in renal perfusion observed in response to converting enzyme inhibition. In the post-myocardial infarction group, correlations between the two methods were variable and much poorer than in the chronic heart failure group (r = 0.54, P = 0.01 and r = 0.74, P = 0.002 on consecutive days). Furthermore, captopril-mediated increments in effective renal plasma flow by the two techniques were unrelated (r = -0.19, P = 0.59). In this group 125I-orthoiodohippurate elimination significantly exceeded para-aminohippurate clearance (P < 0.05). This reversed association and the weaker relationships between methods in post-infarction as compared to chronic heart failure patients may be related to interference by thrombolytic or aspirin treatments.

To assess the feasibility of introducing captopril in patients with chronic heart failure on an outpatient rather than an inpatient basis a double-blind placebo-controlled study was carried out to compare either 6·25 mg or 25·0 mg of captopril as a starting dose; followed by either incremental doses of 6·25, 12·5, and 25·0 mg (low dose group), or 25·0 mg 8 hourly (high dose group) respectively. Forty-one patients in a general medical ward within a large teaching hospital with moderate to severe, stable, diuretic-controlled chronic heart failure, who were not hyponatraemic, hypokalaemic or on a dose of diuretic greater than 120 mg of frusemide took part. No patient experienced symptomatic hypotension. Both doses of captopril produced a significant drop in blood pressure (BP), the magnitude of which was similar in both groups. The first dose-induced fall correlated significantly with subsequent dose-related reductions in BP. Therefore if a patient did not have a hypotensive response to the first dose of captopril he/she would be unlikely to have one with subsequent doses. In the group as a whole, the magnitude of the fall in BP after the first dose correlated significantly with starting plasma levels of angiotensin II, atrial natriuretic peptide (ANP), aldosterone, andrenin. However, on an individual basis, the two patients with the greatest fall in blood pressure did not have the most activated renin-angiotensin-aldosterone (RAA) system. This serves to emphasise the unpredictability of this response and the need to initiate therapy under clinical observation. The size of the starting dose, therefore, does not significantly affect the magnitude of the BP fall, and there is a correlation between BP fall to the first and fourth doses. Thus, if there is no hypotensive response to the first dose, it should be safe to discharge patients from hospital observation. Therefore captopril can be initiated on an outpatient rather than as an inpatient basis, provided that patients are observed for at least 1·5 h following their first dose.

0195-668X/01/120997+11 $35.00/0 conventional drug therapy, in order to reduce plasma aminoterminal BNP levels, resulted in reduced total cardiovascular events when compared to therapy directed by clinical acumen. Much less is known about C-type natriuretic peptide (CNP) which was first isolated from porcine brain in 1990. It is now known that CNP has a much wider distribution and of particular note both it and its receptor are located in peripheral blood vessels. In vitro and in vivo studies have shown CNP to be a powerful vasorelaxant. This together with its location would theoretically enable CNP to play an important role in local vascular regulation. In this review we examine the current literature relating to CNP, in particular its cardiovascular role. Wherever possible we will compare and contrast CNP with both ANP and BNP.

Clearly at present, the one perfect surrogate marker for mortality remains elusive. Chronic heart failure is a complex syndrome: as such it may perhaps be too simplistic to expect any single parameter to be universally predictive of drug effects on mortality, especially when each drug works by different mechanisms. Nevertheless, neurohormonal antagonists, such as ACE inhibitors and beta-blockers, seem to benefit both mortality and all surrogate markers of mortality. Equally, inotropic drugs and Class I antiarrhythmics appear to worsen both mortality and many surrogates. This is encouraging. However, significant discrepancies exist, particularly for digoxin, ibopamine and hydralazine-nitrates, although it is only with the latter two that diametrically opposite effects occurred, whereby favourable surrogate effects turned into unfavourable mortality effects (or vice versa). It appears appropriate to have guarded optimism about the potential use of these surrogates to predict drug effects in chronic heart failure. Given our current understanding, none of the parameters discussed above is perfect when used alone. Perhaps a battery of surrogates would be more appropriate rather than there being any single surrogate. The most promising surrogates are heart rate variability, QT dispersion and plasma neurohormones, the first two for sudden death and the last one for death from progressive disease.

Activation of the sympathetic nervous system may contribute to the renal vasoconstriction and sodium retention seen in congestive heart failure. Previous studies in congestive heart failure patients employing large doses of prazosin that lowered systemic blood pressure have been generally disappointing. The renal haemodynamic and segmental tubular effects of low non-depressor doses of prazosin (0.25 mg and 0.50 mg) were examined in eight female patients with mild to moderate congestive heart failure. Segmental tubular function was assessed by the lithium clearance method. Compared to placebo, prazosin caused a significant increase in urinary sodium excretion (from 56 +/- 7 to 92 +/- 7 mumol.min-1, P0.01), paralleled by significant increases in fractional excretion of sodium and lithium. Glomerular filtration rate and effective renal plasma flow were not altered by prazosin. Prazosin pre-treatment did not alter any of the renal responses to frusemide treatment (mean dose 85 +/- 14 mg). This study demonstrates that low non-depressor doses of prazosin have a clear natriuretic effect in congestive heart failure patients, which is predominantly established by interference with tubular reabsorption.