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The association between atrial fibrillation and thromboembolism is not as simple as portrayed.1 Labelling epiphenomena of heart ageing as illness is risky when causality in a complex confounded statistical association (stroke with chronic atrial fibrillation) is linked to defining the point at which anticoagulation reduces or defers recurrent injury and death. Stroke in chronic atrial fibrillation is not always thromboembolic, and anticoagulation reduces but does not eliminate stroke. Anticoagulation also causes death due to bleeding in a minority of cases, which are not reliably …

The sensitivity and specificity of structural assessment of the heart by echocardiography in black hypertensive patients presenting with symptoms of heart failure is often incomplete. Cardiovascular magnetic resonance, mainly by virtue of its ability to characterize myocardial tissue composition, may be of value in differentiating some of the common pathologies noninvasively. We present an illustrative case of hypertrophic cardiomyopathy in a British Afro Caribbean hypertensive patient where at least some features of familial amyloidosis were present on screening echocardiography. Cardiovascular magnetic resonance examination of this case established not only the usefulness of this technique, but also highlighted the importance of recognizing the variations and departure from the usual which one associates with hypertrophic cardiomyopathy, so as to arrive at the final diagnosis.

The aim of this paper is to review and discuss current methods of risk stratification for cardiovascular disease (CVD) prevention, emerging biomarkers, and imaging techniques, and their relative merits and limitations. This report is based on discussions that took place among experts in the area during a special CardioVascular Clinical Trialists workshop organized by the European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy in September 2009. Classical risk factors such as blood pressure and low-density lipoprotein cholesterol levels remain the cornerstone of risk estimation in primary prevention but their use as a guide to management is limited by several factors: (i) thresholds for drug treatment vary with the available evidence for cost-effectiveness and benefit-to-risk ratios; (ii) assessment may be imprecise; (iii) residual risk may remain, even with effective control of dyslipidemia and hypertension. Novel measures include C-reactive protein, lipoprotein-associated phospholipase A2, genetic markers, and markers of subclinical organ damage, for which there are varying levels of evidence. High-resolution ultrasound and magnetic resonance imaging to assess carotid atherosclerotic lesions have potential but require further validation, standardization, and proof of clinical usefulness in the general population. In conclusion, classical risk scoring systems are available and inexpensive but have a number of limitations. Novel risk markers and imaging techniques may have a place in drug development and clinical trial design. However, their additional value above and beyond classical risk factors has yet to be determined for risk-guided therapy in CVD prevention.

Optimizing responses to intravenous furosemide (ivF) in acute pulmonary edema is limited by current insensitive noninvasive means of volume assessment. We conducted a pilot study to assess the feasibility of performing repeated measures of echocardiographic and bioimpedance analysis (BIA) parameters and test their response as noninvasive markers of volume response to ivF. We also aimed to identify the most potentially sensitive markers of this response. Patients receiving ivF for a clinical diagnosis of acute cardiogenic pulmonary edema were studied. Echocardiographic and BIA parameters were measured at 0, 0.5, 1, 2, and 3 h after ivF. Intraobserver variability for each parameter was determined. Thirty-one patients were enrolled who were receiving 40–100 mg of ivF. Transmitral (MV) early peak velocity following Valsalva maneuver and transtricuspid (TV) early peak velocity reduced significantly (P= 0.012 and 0.010, respectively), whereas MV deceleration time increased significantly (P= 0.006) in response to ivF. Short-axis inferior vena cava diameter (SIVC) in expiration and inspiration and SIVC corrected for body surface area in expiration and inspiration reduced significantly following ivF (P= 0.039, 0.020, 0.032, and 0.016, respectively). BIA estimates of extracellular water decreased significantly (P= 0.001), whereas impedance (Z) at currents of 5, 50, 100, and 200 kHz increased following ivF; the changes were significant with all but the last parameter (P < 0.0001, 0.006, 0.010, and 0.051, respectively). Maximal change from baseline for each parameter was greater than its respective intraobserver variability. Performing repeated measures of echocardiographic and BIA parameters is feasible in this unstable group of patients. The above panel of parameters could potentially be used to track volume response to ivF and, thus, to optimize treatment in acute pulmonary edema.

“For this issue, Therapy has collated submissions from a range of experts from across the world to provide an up-to-date insight and ana lysis from differing perspectives, hopefully to further focus readers’ minds and clinical practice on this major clinical management issue.” Robert J MacFadyen† †Author for correspondence: University Department of Medicine and Department of Cardiology, University of Birmingham, City Hospital, Dudley Road, Birmingham, B18 7QH, England, UK Tel.: +44 121 507 4476/ 5080/5634 Fax: +44 121 554 4083 Robert.Macfadyen@ swbh.nhs.uk Looking backwards and moving forwards in the therapy of hypertension

In cardiovascular disease, soluble CD40 ligand (sCD40L) has been associated with an adverse prognosis. Angiogenesis has been implicated in the progression of coronary artery disease (CAD) and sCD40L has pro-angiogenic effects in vitro. Angiogenesis itself is regulated by many mediators, such as vascular endothelial growth factor (VEGF) and the angiopoietins (Ang). Ang-1 promotes vascular maturation whilst Ang-2 destabilises the blood vessel and permits vascular growth with VEGF. Hence, selective elevation of VEGF and Ang-2 suggest a state of vascular plasticity and increased angiogenesis. We hypothesised raised plasma levels of VEGF and Ang-2, but not Ang-1, and correlations with raised sCD40L levels and CAD severity/collateralisation in patients with CAD.We recruited 153 patients attending diagnostic angiography for CAD and 47 healthy controls. Patients with previous revascularisation or unequivocally normal angiograms were excluded. The coronary atheroma score (CAS) and coronary stenosis score (CSS), and the presence of collaterals, were assessed by 2 blinded observers. Plasma sCD40L, VEGF, Ang-1 and -2 levels were measured by ELISA.Plasma levels of sCD40L, VEGF and Ang-2, but not Ang-1, were higher in CAD patients compared to controls. Both plasma VEGF (r=0.526, p0.001) and Ang-2 (r=0.429, p0.001) were correlated with sCD40L, but not with CAS, CSS or collateralisation. On stepwise multivariate regression analysis, plasma sCD40L was an independent predictor of plasma VEGF (p=0.002), and Ang-2 (p0.001) levels.These data suggest abnormal indices of angiogenesis in CAD, which may be associated with increased CD40-CD40L interactions in patients with CAD. Plasma sCD40L, VEGF and Ang-2 levels were not correlated to angiographic CAD/collateralisation.

Background Platelet activation and aggregation play a key role in coronary artery disease, with antiplatelet therapies leading to improved clinical outcomes. Limited data exist as to whether peripheral venous blood measurements of platelet physical indexes ( eg , platelet count, volume, and granularity) and soluble markers of platelet activation ( eg , P-selectin [sP-sel] and CD40 ligand [CD40L]) reflect the local (intracardiac) coronary environment. Furthermore, how percutaneous coronary interventions (PCIs) affect levels of peripheral/cardiac platelet indexes is unclear. Methods Blood samples were sequentially acquired from the coronary os, aortic root, coronary sinus, and the femoral vein, and where relevant, pre-PCI and post-PCI. Eighty-seven patients undergoing coronary angiography were recruited (mean [± SD] age, 59.8 ± 10.8 years; 54 men [62%]), of whom 36 proceeded to PCI. Platelet physical indexes and plasma sP-sel and CD40L levels were measured (by enzyme-linked immunosorbent assay). Results At baseline, no intracardiac vs peripheral differences were noted in sP sel levels, while CD40L levels were elevated in the aorta compared to the coronary sinus and femoral venous. The mean platelet count (MPC) was similar at all four sites, but within the coronary sinus blood, mean platelet volume (MPV) was significantly lower and mean platelet granularity (MPG) was higher when compared to arterial levels. Though aortic and femoral levels of sP-sel were raised following PCI, transcardiac gradients of plasma sP-sel levels were unaffected. PCI was associated with lower CD40L, MPC, and MPV levels but with a higher MPG level in all sampling sites. Conclusions sP-sel levels measured peripherally reflect the cardiac environment, unlike CD40L, MPC, MPV, and MPG. PCI leads to further platelet activation (raised sP-sel) despite aggressive antiplatelet therapy.

Several beta blocking drugs (BB) reduce mortality in systolic heart failure (LVSD). We have compared the initial response to introduction of carvedilol and bisoprolol during the standard dose titration protocols for each drug.Approximately 31 unselected patients with stable LVSD were randomised to either carvedilol or bisoprolol measuring blood pressure, heart rate responses and both time and frequency domain heart rate variability (HRV).One subject died; five withdrew due to intolerable BB related side effects. Carvedilol (n = 13) and bisoprolol (n = 12) attained similar maximal heart rate reduction and induced comparable falls in systolic and diastolic blood pressure. Higher carvedilol doses were associated with lower blood pressure compared to baseline. Individual time domain HRV indices remained unchanged over the initial titration period. Significant increases in triangular Index (TI) were seen with both BB. Carvedilol demonstrated greater (but non-significant) rises in TI compared to Bisoprolol.In this study we found similar degrees and rate of onset of HR, HRV and BP response to both carvedilol and bisoprolol in treated LVSD patients. Carvedilol appears to show superior HRV rises compared to bisoprolol during initial titration. Any significant increases in HRV attributable to carvedilol compared to bisoprolol may emerge over a longer treatment interval in LVSD.

We hypothesized that indices of angiogenesis (vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and -2), platelet activation (soluble P-selectin)) and endothelial damage/dysfunction (von Willebrand factor (vWf)) would be more deranged in South Asians than in white Europeans when measured within the coronary sinus or coronary artery per se (that is, intracardiac sampling of blood supplying and draining the heart), as compared to measurements from the peripheral venous system.To test this hypothesis, we performed a cross-sectional study of 87 subjects undergoing cardiac catheterization, where 43 were South Asian and 44 were white European.South Asian participants were younger (P = 0.01) but had a lower rate of self-reported smoking (P = 0.01). The extent of coronary atherosclerosis, assessed using presence of lesions50%, number of vessels diseased and Gensini score, was comparable between the two ethnic groups (all P = NS). When samples were analysed from the coronary circulation or the femoral vein in relation to South Asian and white European ethnicity, there were no significant differences in the levels of VEGF, angiopoietins 1 and 2, soluble P-selectin and vWf levels between the two ethnic groups.Indices of angiogenesis, platelet activation, and endothelial damage/dysfunction are comparable in South Asians and their white European counterparts. Our results suggest that their pathophysiological roles may be comparable in South Asians and white Europeans in the context of coronary artery disease.

Heart rate recovery following a Bruce exercise protocol provides prognostic information on survival. We investigated the impact of ethnicity on HRR in 271 consecutive patients being assessed for CAD in three main ethnic groups (Caucasian (C); South Asian (SA); Afro-Caribbean (AC)). Our sample contained greater referral of younger, male South Asian subjects than would be expected on the basis of census data. The AC group had a low frequency of typical ischaemic pain. The SA sub-group, despite greater prevalence of diabetes, had marginally better HRR and a more preserved response to exercise. Multiple regression analysis revealed that age and not ethnicity was the main independent predictor of HRR (p = 0.007) with all three ethnic sub-groups having a similar range of exercise time. There was no evidence of under referral of ethnic minorities. Ethnic effects in raw HRR data are most likely confounded by age.

Vascular growth factors are involved in the pathophysiology of human atherosclerotic vascular disease and plaque destabilization. We hypothesized that in stable patients with coronary artery disease (CAD), plasma levels of vascular endothelial growth factor (VEGF) and angiopoietins 1 and 2 (as indices of angiogenesis) would be no higher in coronary sinus blood when compared to the aortic root, coronary ostium, and peripheral femoral vein. Secondly, we hypothesized that percutaneous coronary intervention (PCI; angioplasty+/-stenting) would increase intracardiac levels of these indices, perhaps by destabilizing coronary plaques.Patients undergoing elective diagnostic coronary angiography (n = 70; mean age 58.8+/-11.2 years) of which 37 proceeded to PCI were recruited. Blood samples were obtained from the aortic root, coronary ostium, coronary sinus, and femoral vein. Plasma VEGF, angiopoietin-1 and angiopoietin-2 levels were measured by immunoassays.There were no significant differences in VEGF, angiopoietin-1 and angiopoietin-2 levels when aortic root, coronary ostium, coronary sinus, and femoral vein samples were compared (P = not significant (NS)). In patients undergoing PCI, peripheral angiopoietin-2 levels were increased significantly post PCI (P = 0.01). There was also a difference in intracardiac gradient (that is, aortic root-coronary sinus difference) in angiopoietin-1 (P = 0.02) following PCI. No significant changes in VEGF with PCI were noted.There were no differences in indices of angiogenesis when aortic root, coronary ostium, coronary sinus, and femoral vein levels of VEGF and angiopoietins are compared, suggesting that peripheral blood measurements of these indices are comparable to intracardiac levels. Although no immediate effects were observed in soluble VEGF levels, PCI affected intracardiac angiopoietin-1 with a systemic release of angiopoietin-2. Further investigations are necessary to determine the relative systemic and intracardiac effects of the angiopoietins in vascular remodelling post PCI.

To determine the effects of n3-PUFA supplementation, in the dose used in the GISSI-Prevenzione study, on indices of heart rate variability (HRV) in patients following myocardial infarction (AMI).Open label randomised single blind controlled trial. Thirty eight patients post AMI, stable on standard secondary prevention drug therapy were single blind randomised to receive either Omacor 1 g/day (n = 21) or usual care (n = 17). HRV indices (time and frequency-domain) were measured at baseline and following 3 months of treatment.At baseline there were no significant differences in clinical, biochemical or HRV indices between patient groups. After 3 months therapy there were no observed changes in measured HRV indices in either the Omacor supplemented or 'usual care' groups.Three month supplementation of omega 3 PUFA (Omacor) 1 g/day has no effect on HRV is patients post AMI.

While symptoms are common during the detection and treatment of hypertensive patients it is rarely the case that either uncomplicated essential hypertension (of whatever severity) or treatment presents insurmountable problems. Unfortunately they frequently result in changes in effective therapy or encourage clinicians and prescribers to settle with altered and inadequate treatment goals. This review considers the association of patients' symptoms in the management of hypertension. It considers the relationship of symptoms at the time of diagnosis and the impact of symptoms voiced during active drug treatment. The data relating antihypertensive therapy to adverse symptoms during chronic therapy and the consequences of this on treatment goals are summarised.

Platelet microparticles (PMPs), procoagulant membrane vesicles derived from activated platelets, are elevated in acute myocardial infarction and unstable angina but their relationship to inflammation and indices of coronary artery disease are unclear. We therefore hypothesised that PMPs are related to scores of coronary atheroma and/or coronary stenosis. Our study was completed by comparing PMP data with other platelet markers and with hs-CRP, marking inflammation. We recruited 54 patients attending for coronary angiography, comparing them to 35 age- and sex-matched controls. Peripheral blood was analysed for PMPs, percent platelets positive for CD62P and CD63 (all flow cytometry), soluble P selectin and hsCRP (both immunoassay). Patients exhibited higher PMPs, increased platelet %CD62P, %CD63 and soluble P selectin (all P < 0.01) and hs-CRP (P = 0.0167) than healthy controls. However, analysing only patients with an unequivocal classification, there were no significant (P

Since late summer 2004, regulatory and patient concerns over retrospective data on the overall safety of cyclooxygenase (COX)-2 inhibitors (coxibs), such as rofecoxib, valdecoxib and celecoxib, in patients with coronary disease have evolved in an ever-upward spiral of increasingly public rather than scientific debate. The episode was heralded to the wider world by the precautionary withdrawal of rofecoxib from the world market following discussions by the US Food and Drug Administration (FDA). A serious drop in the stock valuation of Merck Sharpe and Dohme Ltd (MSD) and a worldwide media frenzy followed. In particular, the US media reaction to this step was openly criticised by AJJ Wood (the Scottish clinical pharmacologist based at Vanderbilt who chaired the relevant FDA advisory panel on COX-2 inhibitors and is a potential new commissioner of the FDA). Regulatory concern over data on safety is not a new feature in the assessment of drugs following marketing. Paradoxically, adverse events involving a common disease such as coronary disease are harder to define than rare or idiosyncratic side effects. Unlike the latter, they tend to be below the limits of recognition of individual clinicians and most current systems of postmarketing surveillance. Specifically, recognition of an impact of concomitant drug treatment on coronary disease in patients with arthritides (where the background symptom burden is traditionally very high) is a good case study in the complexity of pharmacoepidemiology. These patients have a long-established excess incidence of coronary and vascular events recognized long before the era of COX-2 inhibitor use [1]. The safety and efficacy of any drug entity (new or old) is of course a product of the number and duration of patient exposures and the unpredictable impact of prescription to unselected patients (those not systematically studied during development). Clearly there were no data to suggest an adverse interaction with coronary disease or its treatment before marketing. In general, no drug therapy is anything other than relatively safe in this regard and, routinely, prescribers place a disproportionate amount of faith in the developmental and regulatory assessment process. What can be learnt from the regulatory process laid out in the postmarketing surveillance of COX-2 inhibition?

The autonomic nervous system marks beneficial drug responses in systolic heart failure management. The impact of statin therapy in this broad disease class is unclear and patient studies are extremely limited. Methods: We studied a group of 23 patients with stable systolic ventricular impairment and randomised them single (patient) blind to high dose Atorvastatin 40 mg daily or placebo in addition to standard therapies over a 12-week treatment interval. Impact on the autonomic nervous system was assessed by anonymised short-term (20 min) standardised supine heart rate variability analyses. Results: Two subjects withdrew one due to decompensation and one due to gastric intolerance. The remaining subjects completed both monitoring events without changes in standard medicines. Frequency domain but not time domain HRV indices improved with active statin therapy suggesting beneficial effects in attenuating sympathetic tone. Conclusions: In this small study we saw short-term high potency statin treatment had a beneficial impact on frequency domain HRV measures suggestive of an impact on sympatho-activation. We found no effect on time domain HRV indices. This may suggest a lesser or no effect on parasympathetic tone.

Matrix metalloproteinases (MMP) and their inhibitors (TIMP) are central factors in the control of extracellular matrix turnover. They are important in normal physiology and also during a range of pathological states. Only recently has their role in cardiovascular disease been explored and their analysis through measurements in blood been studied. We have systematically identified clinical articles relevant to coronary artery disease from the last 10 years using MEDLINE. In this review we outline the structure, function and regulation of metalloproteinases and their key roles in angiogenesis, stable and unstable coronary artery disease. Metalloproteinases and their inhibitors are fundamental mediators of change in aging and atherosclerosis, the cell membrane, and in myocardial and vascular tissue. Defining their overall importance and understanding their complex interrelationships with pressure, thrombosis and local neural and hormonal tone will require detailed clinical study. The modulation of MMP and TIMP activity using drugs that affect the expression and function of these proteins will provide us with new ways to treat these serious and disabling diseases, and we explore potential mechanisms and treatments.

Background Gestational hypertension (GH) is dangerous to both mother and child. Arterial invasiveness and growth are dependent on successful extracellular matrix (ECM) breakdown, which may be abnormal in GH. We hypothesized abnormalities in circulating matrix metalloproteinase–9 (MMP-9) and tissue inhibitors of metalloproteinases–1 and –2 (TIMP-1 and TIMP-2, respectively) in patients with GH, when compared with normotensive women with normal pregnancies and healthy nonpregnant control subjects. Methods Plasma MMP-9, TIMP-1, and TIMP-2 were measured by ELISA in 23 women with GH, 30 normotensive pregnant women, and 28 nonpregnant women who were matched for age, gestational age, and parity. Results Levels of circulating MMP-9, TIMP-1 and TIMP-2, and the MMP-9/TIMP-1 and MMP-9/TIMP-2 ratios were significantly different among the three groups ( P = .026, P = .006, P = .007, P = .001 and P = .008 respectively). Within the GH group, MMP-9 and the MMP-9/TIMP-1 ratio correlated negatively with age ( r = −0.581, P = .004 and r = −0.563, P = .005, respectively) and levels of diastolic blood pressure ( r = −0.432, P = .040 and r = −0.461, P = .027, respectively). With multiple regression analysis, only age independently correlated with circulating levels of MMP-9 ( P = .010); neither age nor levels of diastolic blood pressure had any effect on the MMP-9/TIMP-1 ratio. Conclusions We have demonstrated altered MMP/TIMP ratios in maternal blood during GH. These observations suggest pregnancy-related changes in ECM breakdown and turnover. Given the importance of changes in ECM composition to vascular and cardiac structure in hypertension, we suggest that these observations may be related to the pathophysiology of human GH.

Ambulatory blood pressure monitoring has established its use in the definition of white coat hypertension and monitoring of treatment of essential hypertension. Any role for ambulatory blood pressure monitoring in heart failure is not well defined. However, from the limited studies available, ambulatory blood pressure monitoring may be used to optimise heart failure therapy, and as a prognosis marker in this patient group. Most studies that have examined the circadian pressure profile have found blunting of decline of blood pressure during sleep in patients with heart failure. In advanced heart failure, this may be due to hypoperfusion of vital organs partly due to pump failure and partly due to multiple drug therapy associated with the treatment of heart failure. Ambulatory blood pressure monitoring may also clarify hypoperfusion effects on vital organs in individual patients and improve the risk/benefit ratio of treatments in advanced heart failure. Prospective controlled studies on the impact of treatments on circadian blood pressure profile in congestive heart failure patients are needed.

Background: Circulating metalloproteinases (MMP) and their inhibitors (TIMP) are indices of vascular and cardiac tissue matrix turnover. However, the temporal changes and relationship of these parameters to age, gender, ethnicity and exercise have been poorly defined. We therefore studied these aspects on plasma levels of MMP-2 and -9 and TIMP-1 and -2, as the major metalloproteinases (and their inhibitors) implicated in pathophysiology of vascular disease. Methods: Venous citrated blood was collected from 93 normal healthy volunteers from four ethnic groups (Afro-Caribbean, South Asian, Caucasian and Far Eastern) for a cross-sectional study. In addition, 20 separate healthy volunteers were studied during supine rest, before and immediately following peak treadmill stress using a Bruce protocol. MMP-2 and -9 and TIMP-1 and -2 were all measured by ELISA. Results: There was a categorical distribution of MMP-2 concentration with individual subjects showing high levels, yet others being undetectable, although these changes were unrelated to age, gender or ethnicity. TIMP-1 and -2 showed a modest negative correlation with age (r=−0.251, p=0.015; r=−0.254, p=0.014). There was a positive correlation between MMP-2 and TIMP-2 (r=0.399, p

In acute coronary syndromes (ACS), the difference between myocardial (reversible) ischaemia and (irreversible) infarction can often be due to either a delay in presentation from the onset of symptoms and the timing and efficacy of any administered treatment. Whilst current guidelines promote aggressive coronary revascularisation for troponin positive unstable angina (UA) or Non-ST elevation MI (NSTEMI), most patients who fall into this category are identified by their recurrent or worsening chest pain symptoms [1]. What is often forgotten is that myocardial ischaemia can also be identified by the development of classical heart failure-type symptoms, including breathlessness at rest or signs of left ventricular systolic dysfunction (S3 gallop, radiographic pulmonary oedema, or rarely, new or worsening mitral regurgitation (MR)). Where the signs or symptoms of heart failure predominate with little or no complaints of chest pain, some cases of potentially reversible ischaemia will be labelled nonspecifically as ‘acute heart failure’. While some expert cardiologists suggest that this is ‘common knowledge’, there are no reliable estimates of how many acute heart failure patients have symptoms mainly due to reversible ischaemia rather than irreversible infarction or an acute presentation of chronic heart failure. This distinction is important in the first 24 h following presentation, as it is likely that many such patients are not

Background Hypertension, hypertensive heart disease, and left ventricular (LV) hypertrophy are integral to symptomatic diastolic heart failure. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is linked to extracellular matrix fibrosis and is elevated in hypertension. We hypothesized a link between circulating TIMP-1, matrix metalloproteinase-9 (MMP-9), and resting echocardiographic LV filling parameters using tissue Doppler parameters of diastolic (dys)function. Methods Circulating MMP-9 and TIMP-1 levels were measured in citrated plasma by ELISA in 74 patients with hypertension (58 men, mean age 58 ± 11 years) and 34 controls (23 men, mean age 53 ± 13 years). All had confirmed normal short axis systolic contractility, with no significant wall motion abnormalities; the LV mass and standard resting tissue Doppler echocardiographic indices of diastolic function were also recorded. Results Both MMP-9 and TIMP-1 levels were higher in the hypertensive group ( P = .0039 and P = .0054, respectively). When compared to controls, hypertensive patients had a greater LV mass ( P = .0054), and differences in many of the parameters reflecting diastolic dysfunction (controls versus hypertensives: E: 0.71 ± 0.15 v 0.81 ± 0.15 m/sec, P = .004; A: 0.66 ± 0.12 v 0.81 ± 0.16 m/sec, P v 0.09 (0.07–0.10) m/sec, P = .0017; e′/a′: 1.20 (1.00–1.80) v 0.88 (0.71–1.05), P v 8.89 (7.55–10.75), P r = 0.271, P = .024), LV mass index ( r = 0.323, P = .007), and tissue Doppler parameters of diastolic dysfunction, including e′ ( r = −0.338, P = .005), a′ ( r = −0.350, P = .005), and E/e′ ( r = 0.334, P = .005). Conclusions TIMP-1 is thought to increase tissue concentrations of collagen type I by preventing its breakdown by MMPs. Our findings therefore add weight to a hypothesis suggesting that TIMP-1 may be a key mediator of LV diastolic dysfunction through definition of ventricular matrix composition.

Sudden death is one of the most common modes of death in those who survive a myocardial infarction. A recent study of 11,324 patients showed a marked decrease in risk of sudden cardiac death as well as a reduction in all-cause mortality in the post-myocardial infarction group taking a highly purified form of omega-3 fatty acids, added to the use of other secondary prevention drugs, including b-blockers and lipid-lowering therapy. There is now amounting evidence indicating that the clinical benefits of highly purified omega-3 fatty acids may be attributed to their anti-arrhythmogenic properties. Evidence for this mechanism of benefit is reviewed here.

Background Hypertension results in structural changes to the cardiac and vascular extracellular matrix (ECM). Matrix metalloproteinases (MMP) and their inhibitors (TIMP) may play a central role in the modulation of this matrix. We hypothesized that both MMP-9 and TIMP-1 would be abnormal in hypertension, reflecting alterations in ECM turnover, and that their circulating levels should be linked to cardiovascular (CHD) and stroke (CVA) risk scores using the Framingham equation. Second, we hypothesized that treatment would result in changes in ECM indices. Methods Plasma MMP-9 and TIMP-1 were measured before and after treatment (median 3 years) from 96 patients with uncontrolled hypertension participating in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Pretreatment values were compared to circulating MMP-9 and TIMP-1 levels in 45 age- and sex-matched healthy controls. Results Circulating pretreatment MMP-9 and TIMP-1 levels were significantly higher in patients with hypertension than in the normotensive controls (P = .0041 and P = .0166, respectively). Plasma MMP-9 levels decreased, and TIMP-1 levels increased after treatment (P = .035 and P = .005, respectively). Levels of MMP-9 correlated with CHD risk (r = 0.317, P = .007) and HDL cholesterol (r = −0.237, P = .022), but not CVA risk. There were no significant correlations between TIMP-1 and CVA or CHD scores. Conclusions Increased circulating MMP-9 and TIMP-1 at baseline in patients with hypertension could reflect an increased deposition and retention of type I collagen at the expense of other components of ECM within the cardiac and vascular ECM. After cardiovascular risk management, MMP-9 levels decreased and TIMP-1 levels increased. Elevated levels of MMP-9 also appeared to be associated with higher Framingham cardiovascular risk scores. Our observations suggest a possible role for these surrogate markers of tissue ECM composition and the prognosis of cardiovascular events in hypertension.

A variety of community-based epidemiological studies have suggested that 30-50% of patients with heart failure symptoms appear to have preserved left ventricular (LV) systolic function when assessed by echocardiography or similar techniques suggesting 'diastolic heart failure' (DHF) as its cause. The prognosis of these patients is characterised by morbidity and mortality similar to, but less overt than, patients with systolic dysfunction. However, rates of readmission for symptom control are broadly similar in patients with DHF or in those with systolic impairment. Thus, there are many similarities in the portrayal of both systolic and DHF but equally; there are also many key differences. Certainly, while there are several successful therapies for patients with systolic heart failure, the management of patients with DHF is poorly defined. In this review, the gaps in current knowledge and practice, which is creating this therapeutic void will be addressed.

Aims Allopurinol improves endothelial function in chronic heart failure by reducing oxidative stress. We wished to explore if such an effect would attenuate autonomic dysfunction in CHF in line with many other effective therapies in CHF. Methods We performed a prospective, randomized, double-blind cross-over study in 16 patients with NYHA Class II-IV chronic heart failure (mean age 67 ± 10 years, 13 male, comparing allopurinol (2 months) at a daily dose of 300 mg (if creatinine 150 µmol l−1) with matched placebo. Mean heart rate and dysrhythmia counts were recorded from 24 h Holter tapes at monthly intervals for 6 months. We assessed autonomic function using standard time domain heart rate variability parameters (HRV): SDNN, SDANN, SDNN index, rMSSD and TI. Results Allopurinol had no significant effect on heart rate variability compared with placebo; the results are expressed as a difference in means ± s.d. with 95% confidence interval (CI) between allopurinol and placebo: SDNN mean=6.5 ± 4.8 ms, P = 0.18 and 95% CI (−3.7, 17); TI mean=−2.1 ± 1.4, P = 0.16 and 95% CI (−5.2, 0.8); SDANN mean=−2.8 ± 7 ms, P = 0.68 and 95% CI (−18, 12); SDNNi mean=2 ± 6.6, P = 0.7 and 95% CI (−12, 16); RMSSD mean=−0.9 ± 2, P = 0.68 and 95% CI (−5.6, 3.7). For mean heart rate the corresponding results were 0.9 ± 1.4, P = 0.5 and 95% CI (−2, 3.8). Log 24 h ventricular ectopic counts (VEC) were 0.032 ± 0.37, P = 0.7 and 95% CI (−0.1, 0.2). Patient compliance with study medication was good since allopurinol showed its expected effect of reducing plasma uric acid (P

BACKGROUND—It remains uncertain whether angiotensin converting enzyme (ACE) inhibitors benefit all heart failure patients or just those with renin-angiotensin-aldosterone system (RAAS) activation. OBJECTIVE—To determine whether the response to an ACE inhibitor, assessed by urine sodium excretion, was different in patients with low renin versus those with high renin. DESIGN—Plasma renin activity (PRA) was measured in 38 patients with stable chronic heart failure (21 male, 17 female; mean (SD) age 71 (6) years, range 59-82 years) on chronic diuretic treatment alone. They were divided into three groups: low (PRA ⩽ 1.5 ng/ml/h, n = 11); normal (1.5 5, n = 13). The effect of ACE inhibition was then assessed on diuretic induced natriuresis with respect to renin status. RESULTS—There were no significant differences in age and sex distribution between the groups. Plasma angiotensin II and aldosterone increased serially from low to high renin groups, while 24 h urinary sodium concentrations fell from low to high renin groups (low PRA, 96.7 (39.5); normal PRA, 90.4 (26.7); high PRA, 66.3 (18.9) mmol/l; p = 0.033), despite a higher diuretic dose in the high renin group. This blunted natriuretic effect of loop diuretics was caused by RAAS activation, which could partly be reversed by ACE inhibition. ACE inhibitors increased natriuresis by 22% in the high renin group (p = 0.029), but had no effect in the normal and low renin groups. Within the low renin group, five of the 11 patients had persistently low renin levels despite ACE inhibition. There was a non-significant reduction in natriuresis (−9.6%, p = 0.335) following ACE inhibition in this subgroup of patients. CONCLUSIONS—About one third of heart failure patients in our study had low renin status and a non-activated RAAS, despite diuretic treatment. ACE inhibitors did not alter natriuresis significantly in this subgroup of patients, and enhanced natriuresis only in patients with high renin. There is thus tentative support for renin profiling in targeting ACE inhibitors to the most deserving, by showing that short term sodium retention does not occur in low renin patients if ACE inhibitors are withdrawn. Keywords: chronic heart failure; renin profiling; ACE inhibition; urinary sodium excretion

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.

OBJECTIVES This study was designed to compare different proposed methods of assessing adherence with angiotensin-converting enzyme (ACE) inhibitor (ACEI) therapy in chronic heart failure. BACKGROUND The use of ACEIs in chronic heart failure gives us a unique opportunity to assess a patient’s adherence by measuring whether the expected biochemical effect of an ACEI is present in the patient’s bloodstream. In fact, there are several different ways of assessing ACE in vivo: these are serum ACE activity itself, plasma N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), urine AcSDKP, plasma angiotensin I (AI), plasma angiotensin II (AII), or the AII/AI ratio. METHODS Patients with chronic heart failure (n = 39) were randomized to regimens of ACEI nonadherence for one week, ACEI adherence for one week or two versions of partial adherence for one week, after which the above six tests were performed. RESULTS All six tests significantly distinguished between full nonadherence for one week and full or partial adherence. Only plasma AcSDKP produced a significantly different result between partial adherence and either full adherence or full nonadherence for one week. In terms of their ability to distinguish full nonadherence from full adherence, plasma AcSDKP was 89% sensitive and 100% specific with an area under its ROC of 0.95. Corresponding figures for urine AcSDKP were 92%, 97% and 0.95 and for serum ACE they were 86%, 95% and 0.90. CONCLUSIONS All six tests distinguished full nonadherence from all other forms of adherence. The rank order of performance was plasma AcSDKP, urine AcSDKP, serum ACE, AII/AI ratio and plasma AII followed by plasma AI.

OBJECTIVE—To assess whether serum angiotensin converting enzyme (ACE) activity during routine clinical practice accurately reflects patient adherence to ACE inhibitor treatment for chronic heart failure (CHF). DESIGN—Retrospective assessment of ACE inhibitor adherence and serum ACE activity measurements. SETTING—Teaching hospital outpatient department PATIENTS AND INTERVENTIONS—During 1994-95, serum ACE was measured in 73 CHF patients who were routinely attending the heart failure clinic at Ninewells Hospital. At the same time, the medicines monitoring unit collected data on whether and when prescriptions for ACE inhibitors were redeemed at community pharmacies, which enabled each patient's adherence over a prolonged period to be assessed. MAIN OUTCOME MEASURES—Routine collected serum ACE measurements were correlated with measured adherence with ACE inhibitor treatment. RESULTS—In total, 18% of CHF patients appeared to exhibit 12 u/l gave 91% positive predictive accuracy that the patient was 85% adherent with ACE inhibitor treatment. CONCLUSIONS—Non-adherence with ACE inhibitor treatment was found to be common in patients with CHF. The simple, inexpensive test of serum ACE activity can be used in CHF patients to identify many, although not all, non-adherent patients so that adherence enhancing strategies can be targeted towards them. Further work is clearly required to explore the precise clinical use of this promising test. Keywords: angiotensin converting enzyme inhibitors; heart failure; compliance

The European Society of Cardiology (ESC) in Munich represents the second of the three major annual international cardiovascular meetings. The East European involvement in this meeting (in terms of numbers of delegates, if not presentations) continues to emerge, while the representation from North America, Australasia and the Far East represents an increasing proportion. Of note, the cardiovascular nursing representation is much greater than that of 10 years ago, while the basic science presentations may be less noticeable. The format of the meeting has shifted significantly towards plenary clinical commentaries with limited discussion rather than presentations by individuals or groups. In my opinion, the quality of some debate is marginal. Occasionally, a small number of internationally known speakers appear to move effortlessly between multiple presentations in plenary sessions to industry stands all in 1 day!

West et al. 1 report a small, well designed post hoc nested case–control sample from the LIPID trial of pravastatin.2 This was completed in low risk subjects with documented coronary disease in the form of a previous confirmed acute coronary syndrome (ACS). This additional report examines biomarker linkage over a relatively short time frame of 2–3 years and highlights two measurements perhaps not intuitively linked to the biology of coronary disease progression. The conditional logistic regression analysis shows a significant linkage association following point analysis for N-terminal brain natriuretic peptide (NT-BNP) and tissue metalloproteinase-1 (TIMP-1). TIMP-1 has been linked to cardiovascular events in low risk patients previously, in patients with less well confirmed coronary disease.3 Its re-affirmation here as a population predictor of events in this group of patients is of value. Similarly for NT-BNP, which is frequently presumed to be linked to cardiac events largely via the presence of association with ventricular dilatation, remodelling, or ventricular ‘dysfunction’ (not factors intuitively present even in patients with a confirmed yet uncomplicated ACS), this is not the first report to link it to coronary outcomes even in the absence of overt ventricular impairment.4 More interestingly, in this report there was a significant linkage expressed by both markers to subsequent emergent stroke disease.5 Both NT-BNP (indirectly) and TIMP-1 (directly) can be linked, at least theoretically, to structural change within the heart, be it myocytic, functional (i.e. linked to dynamic contractile changes), geometric (fixed changes in cardiac shape or wall thickness), or within the connective tissue support structure.6,7 Both are of course linked in the biology of hypertension and/or hypertensive heart disease and vascular atherosclerosis,8.9 but this … *Corresponding author. Tel: +44 121 507 4476/5080, Fax: +44 121 554 4083, Email: Robert.macfadyen{at}swbh.nhs.uk

The anaemia of chronic left ventricular systolic dysfunction (LVSD) or systolic heart failure is common, increases over time,1 and is linked with a bad clinical outcome. It is often considered an expression of the chronic vascular inflammation of endstage disease similar to that seen in conjunction with many other chronic disease states. Failure of haematinic function, particularly renal erythropoietin (Epo) synthesis and release, is also seen as a key mechanism and is cited as a major justification for considering exogenous Epo therapy in this disease. Westenbrink et al .2 from Groningen contribute a simple but critical clinical paper highlighting that variable mechanisms contribute to this clinical setting. By defining these carefully, Westenbrink shows that notwithstanding the impact of altered Epo kinetics and dynamics, many of these patients might also have ‘simple’ dilutional anaemia related to poorly perceived and asymptomatic fluid imbalance. This simple finding has important implications for management. The anaemia of LVSD is readily identified by simple measurement; its haematological severity begets a poor outcome. Its prevalence is poorly defined due to the application of variable diagnostic cut-offs. Haematinic deficiencies secondary to poor nutrition, poor micronutrient absorption, and/or chronic gastrointestinal bleeding are common in LVSD and might contribute to a third of cases.3 In the absence of haematinic deficiency, reduced Epo production, (controlling proliferation and differentiation of erythroid cells) may also be involved. As the primary stimulus for Epo release is renal hypoxia, it is understandable that this might be implicated given that reduced renal perfusion is common in LVSD. Anaemia would result if Epo release was insufficient to meet the demands of normal erythropoiesis. Opasich et al .4 have already reported that 76% of their sample of anaemic chronic heart failure patients showed impaired … *Corresponding author. Tel: +44 121 507 4476 5080; fax: +44 121 554 4854. E-mail address : robert.macfadyen{at}swbh.nhs.uk

Abnormal circulating neutrophil linked matrix metalloproteinase - 9 in stable coronary artery disease

Previous studies in heart failure (CHF) after temporary diuretic withdrawal have suggested that perindopril is associated with no first dose hypotension in comparison with other ACE inhibitors (ACEI) or placebo. The aim of this study was to explore further the profile of perindopril during chronic dosing.We report the effects of acute and chronic (8 weeks) treatment with the ACE inhibitor perindopril (Per, 2--4 mg daily) or placebo (P) in a double-blind parallel group study of 24 diuretic treated patients (17M; 67 +/- 8 years, 80 +/- 17 kg) with ischaemic cardiomyopathy (fractional shortening, 19 +/- 5%; radionuclide ejection fraction, 31 +/- 3%). Baseline biochemical, hormonal (ACE, Ang I, Ang II), isotopic renal function (GFR, ERPF, ECFV), pretreatment diuretic dose and heart failure scores were similar between groups. Concomitant cardiac treatments remained unchanged and diuretic withdrawal was not used to introduce treatment.There were no significant effects on electrolytes, liver function tests, serum or erythrocyte magnesium. There was no significant first dose fall in SBP over 6 h) (P, baseline 137 +/- 18; min 115 +/- 16 mmHg; Per, baseline 137 +/- 15; min 118 +/- 17 mmHg). Neither supine nor erect BP was significantly affected by chronic treatment (P, erect baseline 134 +/- 23/76 +/- 10 to 124 +/- 41/74 +/- 10 mmHg; Per, baseline 135 +/- 21/76 +/- 14 to 128 +/- 22/70 +/- 12 mmHg, P=NS). Active treatment was associated with significant ACE inhibition (P, baseline 47 +/- 17 to 43 +/- 17; Per baseline 49 +/- 15 to 14 +/- 7); aldosterone (P, baseline 337 +/- 179 to 375 +/- 306; Per, baseline 335 +/- 357 to 293 +/- 155 pg ml(-1)) and Ang II suppression (P, baseline 9 +/- 9 to 20 +/- 39; Per baseline 10 +/- 9 to 3 +/- 3 pM). Isotopic renal function was unaffected by either treatment.At this dose (2-4 mg orally) chronic perindopril therapy has no significant effect on blood pressure or renal function. Sustained neurohormonal suppression of ACE and AII occurred without evidence of AII reactivation. A lack of effect on BP at these doses may make perindopril suitable for study in unstable patients with acute HF or useful in those patients where there are concerns over ACEI induced hypotension.

Background: Experimental data suggest that aldosterone has harmful effects promoting myocardial fibrosis and disturbing autonomic balance. There has been no evidence of these potential effects in intact man. Methods and Results: We report the findings in 31 patients with stable chronic heart failure (CHF) who were treated with spironolactone (50–100 mg/day) or placebo in addition to diuretics and angiotensin converting enzyme (ACE) inhibition. In a controlled randomised double-blind study, we found that spironolactone treatment reduced circulating levels of procollagen type III N-terminal amino peptide, a marker of vascular collagen turnover, and in addition increased time-domain parameters of heart rate variability ( n = 24). These latter parameters suggest a parasympathomimetic effect for additional spironolactone. Spironolactone significantly reduced heart rate (prolonged RR interval) particularly during the dawn hours (06.00–09.00 h). In this unbalanced study it was not possible to provide a detailed diurnal assessment of the impact of spironolactone on heart rate variability, but the preliminary data suggest that there may be an interaction with the autonomic nervous system which varies in time. Conclusions: These are the first human data to show that use of the aldosterone antagonist, spironolactone, can positively improve time-domain heart rate variability and reduce myocardial collagen turnover, as reflected by further reductions in serum procollagen peptide, despite concurrent ACE inhibitor treatment. Residual aldosterone after ACE inhibitor treatment may therefore have a role promoting arrhythmia and cardiac death by two mechanisms. Effects of additional spironolactone on slowing heart rate (and potentially the detrimental effect of aldosterone) were most prominent between 6 a.m. and 10 a.m. when cardiac death is also known to be most prominent.

Poor compliance may be responsible for symptomatic decompensation or neurohormonal "escape" in patients with heart failure treated over the long term with angiotensin-converting enzyme-1 (ACEI) drugs. Serum ACE activity is a poor index of neurohormonal suppression or haemodynamic effect after ACE-inhibitor treatment. Serum ACE activity may, however, be a useful index of compliance with treatment, as serum ACE is sensitive to the presence of an ACE inhibitor in the blood. Sixteen normotensive male volunteers of known ACE genotype received 7 days of randomised, double-blind therapy on four occasions 2 weeks apart with lisinopril 20 mg (L) or matched placebo (P) to simulate (A) noncompliance (all P), (B) full compliance (all L), (C) partial compliance (L days, 1, 3, 6; P days, 2, 4, 5, 7), or (D) single dose (L day 7; P, 1-6). Supine (30 min) blood pressure (BP)/heart rate (HR), ACE, and angiotensins were measured on d7 before dose and 4-6 h after dose. Results are mean +/- 1 SD. BP showed the expected small decrease with active treatment on d7 (B or D) but not with placebo (A) or partial compliance (C). Prestudy serum ACE, despite a wide range (16-124 U/L), was reproducible within subjects [coefficient of variation (CV), 1.7%]. Serum ACE activity, before (41.9 +/- 30) and after (41 +/- 30) angiotensin (A) I or II, were unaffected by treatment (placebo A). Active treatment (B) resulted in very low serum ACE activity and d7 and a small further suppression after dosing (before, 3.9 +/- 4; after, 1.8 +/- 4). AI was elevated in this group with further elevation after dosing (before, 234 +/- 116; after, 551 +/- 250). AII was only modestly reduced from baseline and showed little further suppression after dosing (before, 7.8 +/- 4; after, 6.3 +/- 5). Partial compliance (C) showed low ACE but no reduction after treatment (before, 7 +/- 3; after, 7 +/- 4), an elevated AI but no dosing effect (before, 187 +/- 198; after, 200 +/- 151) and reduced AII but with no further dose suppression (before, 6.4 +/- 3.4; after, 7 +/- 4) induced increase in peptide (compared with B). Single-dose treatment (D) showed ACE inhibition as expected (before, 47 +/- 30; after, 2.2 +/- 3). There was a dosing-related increase of AI but to a lesser extent than seen with chronic active dosing (B) (before, 39 +/- 10; after, 240 +/- 200). In contrast to long-term dosing, there was marked ANG II suppression (before, 8.8 +/- 4; after, 2.9 +/- 3). With this long-acting ACEI in a dose relevant to congestive heart failure management, we suggest that 4-6 h after-dosing serum ACE (5 EU/L) and elevated ANG I (300 pg/ml) can be used to confirm compliance with treatment. These absolute values may be altered in patients treated concomitant with loop diuretics. In principle, however, this may be a useful tool in clinical trials or in clinical practice after further work has been done to assess the limits in patients across the doses and across the range of available drugs used.

Background Experimental models suggest that brain natriuretic peptide (BNP) can modify left ventricular diastolic performance. The aim of this study was to evaluate the effects of BNP on resting and exercise hemodynamics and neurohormones in patients with isolated diastolic heart failure. Methods and Results Six patients with isolated diastolic heart failure were studied. After baseline hemodynamic measurements were obtained with use of thermistor-tipped pulmonary artery catheters, patients were randomized to receive infusion of BNP or placebo in a single-blind, crossover study. Hemodynamic and neurohormonal parameters were measured at rest after 30 minutes of infusion and during incremental supine bicycle exercise. BNP did not significantly affect resting hemodynamics but attenuated the rise in both pulmonary capillary wedge pressure (placebo, 23±2 mm Hg; BNP, 16±2 mm Hg; P P P Conclusions BNP infusion causes beneficial hemodynamic and neurohormonal effects during exercise in patients with isolated diastolic heart failure.

Cardiovascular risk reduction therapy in diabetic patients reduces vascular events (1) by retarding atherosclerosis and improving vascular reactivity. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are integral to the vascular changes of atheroma, and MMP-9 and TIMP-1 are raised in diabetes (2). We hypothesized that global risk reduction of intensified diabetes and cardiovascular risk management in type 2 diabetes would be associated with reductions in circulating markers of extracellular matrix turnover, namely MMP-9, TIMP-1, and TIMP-2. ### Cross-sectional study Eighty-six patients with type 2 diabetes (3) and treated hypertension with serum creatinine 7.0% despite …

We examined the haemodynamic and renal response to oral losartan potassium (100 mg) during activation of the renin system in humans. Eight healthy volunteers followed a low-salt (40 mmol sodium) diet for 4 days on four occasions 2 weeks apart. Double-blind salt depletion was achieved by 3-day administration of frusemide (40 mg twice daily, b.i,d.) with placebo salt replacement, salt repletion by placebo frusemide (b.i.d.), and active salt replacement (100 mmol/day). On day 4, subjects received randomised double-blind placebo or losartan. Prestudy salt depletion was associated with nonsignificant decreases in serum sodium (138±2 mM), potassium (3.5±0.2 mM) and increased urea (6.5±1.1 mM), and creatinine (91±6 μM) as compared with screening. Prestudy (day 3) 24-h urinary volume was similar during deplete preparation (placebo 1.707±0.81 L, losartan 1.509±0.626 L) or deplete preparation (placebo 1.726± 0.5 L, losartan 1.764±0.52 L), but sodium excretion was greater during replete preparation. Salt replete supine blood pressure (BP) profiles showed little effect of losartan (mean maximal supine BP-9±6 mm Hg) as compared with placebo (-1±4 mm Hg), with a similar relative result for erect BP. After salt depletion, losartan caused a greater response in both supine (-24±9) and erect (-33±15) BP than did placebo (supine -12±5, erect -14±9). In this protocol after salt depletion, losartan caused a transient increase in urea and creatinine (143±40 μML) 8 h after dosing as compared with placebo (105±13 μM). Creatinine clearance (6-8 h) was similar after placebo (161±37 ml/min) and losartan (147 ±32 ml/min) in salt repletion but was significantly less after losartan (47±54) than placebo after salt depletion (140±24). Pretreatment renin (salt replete) was similar (placebo 2.0±1.4, losartan 1.2±0.6 ngAI/ml/h) to screening (1.64±1.47 ngAI/ml/h). Salt deplete preparation increased baseline plasma renin activity (PRA) (placebo 7.7±4.5, losartan 11.5±8.7), with losartan producing a greater increase in PRA after salt depletion. In a controlled setting, losartan had little or no haemodynamic effect in salt-replete normal volunteers. Activation of the renin-angiotensin system (RAS) low salt by diet and loop-acting diuretics produces powerful BP-lowering activity associated with significant decreases in creatinine clearance. Care should be taken in susceptible patients in whom such combination therapy is deemed appropriate

We present the case of a 43 year-old female with an isolated episode of atypical chest pain and an ill-defined cardiac murmur who was coincidentally found to possess a large serpiginious residual embryonic structure in right atrium. Multiple modality imaging was required to confirm this to be a rare giant eustachian valve remnant. The eustachian valve in the fetus directs oxygenated blood towards the foramen ovale. While absent or very small in adult life it rarely persists to any significant degree and must be distinguished from other right atrial shelf anomalies. The true potential of these structures to cause pathological interference with cardiac function or symptoms is unknown due to their rarity.

The aim of this paper is to review and discuss current methods of risk stratification for cardiovascular disease (CVD) prevention, emerging biomarkers, and imaging techniques, and their relative merits and limitations. This report is based on discussions that took place among experts in the area during a special CardioVascular Clinical Trialists workshop organized by the European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy in September 2009. Classical risk factors such as blood pressure and low-density lipoprotein cholesterol levels remain the cornerstone of risk estimation in primary prevention but their use as a guide to management is limited by several factors: (i) thresholds for drug treatment vary with the available evidence for cost-effectiveness and benefit-to-risk ratios; (ii) assessment may be imprecise; (iii) residual risk may remain, even with effective control of dyslipidemia and hypertension. Novel measures include C-reactive protein, lipoprotein-associated phospholipase A(2) , genetic markers, and markers of subclinical organ damage, for which there are varying levels of evidence. High-resolution ultrasound and magnetic resonance imaging to assess carotid atherosclerotic lesions have potential but require further validation, standardization, and proof of clinical usefulness in the general population. In conclusion, classical risk scoring systems are available and inexpensive but have a number of limitations. Novel risk markers and imaging techniques may have a place in drug development and clinical trial design. However, their additional value above and beyond classical risk factors has yet to be determined for risk-guided therapy in CVD prevention.

Angiotensin-converting enzyme (ACE) inhibitors improve survival in heart failure and delay progression to clinical heart failure in patients with left ventricular dysfunction after myocardial infarction. Increasing numbers of older patients are being considered for such treatment. However, there are reports of excessive and prolonged decreases in blood pressure (BP) after the first dose of some ACE inhibitors. We have studied the hemodynamics, pharmacokinetics, and neurohumoral responses to the first dose of oral captopril 6.25 mg, enalapril 2.5 mg, perindopril 2.0 mg, intravenous enalaprilat 1.5 mg, and perindoprilat 1.0 mg, compared with oral or intravenous placebo in 6 parallel groups of 12 elderly patients each with moderate-to-severe (New York Heart Association classes II-IV) heart failure. Oral dosing with active drugs led to different temporal responses. After captopril, there was an early short-lived decrease in BP. Enalapril led to a later long-lasting decrease, but perindopril was not different from placebo. Intravenous enalaprilat and intravenous perindoprilat each lowered BP to a similar extent. The doses of drugs used appeared to be comparable because plasma ACE inhibition was similar following perindopril or enalapril and also comparing perindoprilat and enalaprilat. These studies indicate that oral ACE inhibitors have different profiles of acute BP changes after the first dose. The explanation is not clear, but could include physicochemical differences in the interaction between prodrug ester and diacid metabolites leading to differences in tissue distribution and local enzyme inhibition.

In a dose-ranging study, the angiotensin type I receptor antagonist losartan (DuP753/MK954) was administered orally to normal volunteers in whom the renin-angiotensin system (RAS) had been activated by a low sodium diet (40 mmol) and frusemide (40 mg twice daily) for 3 days before study. On the fourth day, subjects (n = 12) received placebo and three active doses (5, 10, 25, 50, or 100 mg) in a randomized, double-blind, three-panel, dose-ranging design. On the study day, 24-h urinary sodium excretion was approximately 10-20 mmol Na, with an increase in renin and aldosterone levels at baseline. Dose-dependent decreases in supine and erect blood pressures (BP) were statistically significant for 50 and 100 mg and were associated with a modest increase in supine heart rate (HR) at the higher dose. The peak BP decreases observed suggested that the highest dose studied (100 mg) was not necessarily the maximal response. Active treatments caused no increase in the sodium loss on the study day. Renin was significantly increased by doses > 10 mg in a dose-dependent fashion but there was little change in plasma aldosterone profile. Increase in renin was evident at doses (10 mg) below those significantly affecting overall BP (50 mg). Adverse symptoms were uncommon and limited to postural lightheadedness which was largely dose related. Our results indicate a BP and plasma renin dose-response relation for the orally active angiotensin II (AII) receptor blocker losartan in normotensive subjects with an activated RAS.

OBJECTIVE--Comparison of the first dose responses to low dose constant rate infusions of diacid angiotensin converting enzyme (ACE) inhibitors. DESIGN--Double blind, randomised, placebo controlled, parallel group prospective study. SETTING--General hospital inpatient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of ACE inhibitor treatment. PATIENTS--36 unselected elderly (aged 60-87 years) patients with symptomatic but stable chronic cardiac failure (New York Heart Association grades II-IV). ACE inhibitor started under double blind conditions with blood pressure monitoring. INTERVENTION--Patients were randomly allocated to receive intravenous placebo (saline), enalaprilat (1.5 mg over six hours) or perindoprilat (1 mg over six hours) by constant rate intravenous infusion (5 ml/hour). The protocol allowed for discontinuation of infusion if mean arterial blood pressure fell by 30% from the value before treatment. MAIN OUTCOME MEASURES--Blood pressure and heart rate responses, drug concentration, plasma renin, and ACE activities. RESULTS--The three groups had similar age, severity of heart failure, diuretic dose before treatment, plasma renin activity, and serum electrolyte state. All patients remained symptom free throughout the study. Infusions were only ended early with active treatment: 5/12 perindoprilat cases, (mean (SD) dose 0.88 (0.18) mg, and 5/12 enalaprilat cases (mean (SD) dose 1.2 (0.4) mg. Both active treatments lowered mean arterial pressure until discontinuation of infusion. Heart rate was not altered. Two patients (one perindoprilat, one enalaprilat) showed transient and symptom free renal impairment. CONCLUSIONS--Slow intravenous infusion of diacid ACE inhibitors may allow safe initiation of treatment in patients with heart failure and with activated renin angiotensin systems. The similar effects of intravenous perindoprilat and enalaprilat on blood pressure contrast with previously reported differences when perindopril and enalapril were given orally.