Effect of Vitamin K on Vascular Health and Physical Function in Older People with Vascular Disease--A Randomised Controlled Trial.

BACKGROUND AND AIMS: Vitamin K insufficiency is common and linked to an increased risk of cardiovascular disease and osteoporotic fractures. The aim of this study was to examine whether daily supplementation with oral vitamin K could improve vascular health and physical function in older people with established vascular disease. METHODS AND RESULTS: A double blind, randomised, placebo-controlled trial. Participants aged ≤ 70 years with a history of vascular disease were randomised to receive 6 months of daily oral 100mcg vitamin K2 (MK7 subtype) or matching placebo with outcomes measured at 0, 3 and 6 months. The primary outcome was between-group difference in endothelial function assessed using flow-mediated dilatation of the brachial artery at 6 months. Secondary outcomes included carotid-radial pulse wave velocity, augmentation index, blood pressure, carotid intima-media thickness, C-reactive protein, B-type natriuretic peptide, cholesterol and desphospho-uncarboxylated matrix Gla protein levels. Handgrip strength and the Short Physical Performance Battery assessed physical function, while postural sway was measured using a 3-dimensional force platform. RESULTS: 80 participants were randomised, mean age 77 (SD 5) years; 44/80 were male. Vitamin K levels rose in the intervention arm compared to placebo (+48 pg/ml vs -6 pg/ml, p=0.03) at 6 months. Desphospho-uncarboxylated Matrix Gla protein levels fell in the intervention group compared to placebo at 6 months (-130 [SD 117] pmol/L vs +13 [SD 180] pmol/L, p<0.001). No change was seen in endothelial function (between group difference -0.3% [95%CI -1.3 to 0.8], p=0.62). A modest, non-significant improvement in pulse wave velocity was seen in the vitamin K group (-0.8m/s [95%CI -1.8 to 0.3], p=0.15) while all other vascular and physical function outcomes unchanged. CONCLUSIONS: Six months of vitamin K2 supplementation did not improve markers of vascular health or physical function in older patients with vascular disease.

Technical assessment of whole body angiography and cardiac function within a single MRI examination.

AIM: To evaluate a combined protocol for simultaneous cardiac MRI (CMR) and contrast-enhanced (CE) whole-body MR angiography (WB-MRA) techniques within a single examination. MATERIALS AND METHODS: Asymptomatic volunteers (n = 48) with low-moderate risk of cardiovascular disease (CVD) were recruited. The protocol was divided into four sections: (1) CMR of left ventricle (LV) structure and function; (2) CE-MRA of the head, neck, and thorax followed by the distal lower limbs; (3) CMR LV "late gadolinium enhancement" assessment; and (4) CE-MRA of the abdomen and pelvis followed by the proximal lower limbs. Multiple observers undertook the image analysis. RESULTS: For CMR, the mean ejection fraction (EF) was 67.3 ± 4.8% and mean left ventricular mass (LVM) was 100.3 ± 22.8 g. The intra-observer repeatability for EF ranged from 2.1-4.7% and from 9-12 g for LVM. Interobserver repeatability was 8.1% for EF and 19.1 g for LVM. No LV delayed myocardial enhancement was observed. For WB-MRA, some degree of luminal narrowing or stenosis was seen at 3.6% of the vessel segments (involving n = 29 of 48 volunteers) and interobserver radiological opinion was consistent in 96.7% of 1488 vessel segments assessed. CONCLUSION: Combined assessment of WB-MRA and CMR can be undertaken within a single examination on a clinical MRI system. The associated analysis techniques are repeatable and may be suitable for larger-scale cardiovascular MRI studies.

Modulation of the renin-angiotensin-aldosterone system in heart failure.

The renin-angiotensin-aldosterone system (RAAS) is well-established and continues to be pursued as a therapeutic target in the treatment of heart failure, predominantly due to the success of agents that block RAAS in clinical trials of systolic heart failure. The optimal treatment of heart failure patients with preserved ejection fraction (HFpEF), however, remains unclear. Early trials of direct renin inhibitors have suggested that these agents may play a role in HFpEF, but recent clinical trial results have not been encouraging. Preliminary trials of angiotensin-receptor/neprilysin inhibitors look promising. Whether results with these or other drugs will alter current recommendations remains to be seen. In this review, we assess the current understanding of the role of RAAS modulation in heart failure.

Myocardial fibrosis and QTc are reduced following treatment with spironolactone or amiloride in stroke survivors: a randomised placebo-controlled cross-over trial.

INTRODUCTION: Myocardial fibrosis is dysrhythmogenic and may contribute to the high incidence of cardiac death in stroke survivors, especially if they have long QTc. We tested the hypothesis that procollagen-1-carboxy terminal peptide (P1CP), a biomarker of myocardial fibrosis, might be improved following treatment with spironolactone or amiloride in stroke survivors. We also tested the hypothesis that both drugs would shorten QTc. STUDY DESIGN: randomised, double-blinded, placebo-controlled, cross-over trial (spironolactone vs. amiloride vs. placebo). Duration of Study: 3 months (1 month per drug). Primary endpoints: P1CP, QTc RESULTS: 11 stroke survivors (5 female), aged 71 ± 4, BP 139/81 mmHg ± 20/11 mmHg, completed the study. Both spironolactone and amiloride significantly reduced P1CP [Spironolactone-Placebo = -24 ug/L, 95% CI = -40 to -6.9; Amiloride-Placebo = -28 ug/L, 95% CI = -44 to -11]. Spironolactone and amiloride both shortened QTc [Spironolactone vs. Placebo=-18 ms(1/2), 95% CI = -36 to -0.55; Amiloride vs Placebo = -25 ms(1/2), 95% CI = -42 to -7.5]. CONCLUSIONS: Procollagen-1-carboxy terminal peptide was reduced following treatment with spironolactone within a month. Further, this is the first study demonstrating amiloride could also improve myocardial fibrosis. The beneficial effects of both drugs on myocardial fibrosis, coupled with their effects on raising potassium translated to a shortening of QTc. Future studies should test the hypothesis that these drugs might reduce the risk of sudden cardiac death in stroke survivors.

Renin-angiotensin-aldosterone system inhibitors in heart failure.

Heart failure (HF) is a very common condition that, despite advances in treatment, carries significant morbidity and mortality. Although there is good evidence for the treatment of HF with reduced ejection fraction (HFrEF), the treatment for HF with preserved ejection fraction (HFpEF) is not well defined. The renin-angiotensin-aldosterone system (RAAS) has been shown to be an effective target in the treatment of HFrEF using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone blockade, although the evidence in HFpEF is less clear. This review aims to look first at the evidence for these drugs, and second at the newer drugs that act on the RAAS, namely, direct renin inhibitors, neutral endopeptidase inhibitors, vasopeptidase inhibitors, and angiotensin receptor blockers.

The prognostic significance of early and late anaemia in acute coronary syndrome.

BACKGROUND AND AIM: Anaemia in acute coronary syndrome (ACS) is a common and strong independent risk factor but it is unknown whether early anaemia is transient or whether it persists over the subsequent weeks. We also sought to evaluate whether late anaemia carries the similar prognostic significance as baseline anaemia. Another unknown is whether haemoglobin improves risk stratification over and above the GRACE score. DESIGN AND METHODS: Haemoglobin levels were prospectively measured in 448 consecutive patients presenting with ACS and at 7-weeks follow-up. Cardiovascular endpoints were defined as death or acute myocardial infarction (AMI) over a median duration of 30 months (range 1-50). RESULTS: The prevalence of anaemia on admission was 20% and this increased to 40% at 7-weeks follow-up. New anaemia occurred in 31% of patients. Baseline anaemia predicted CV endpoints independent of the admission GRACE (Global Registry of Acute Coronary Events) score [adjusted RR 2.54 (95% CI 1.73-3.71)]. Anaemia at 7-weeks follow-up was also a strong predictor of adverse outcomes [adjusted RR 1.67 (95% CI 1.04-2.69)]. Patients with persistent anaemia at 7 weeks were at an increased risk of death or AMI compared to those with persistently normal haemoglobin [unadjusted RR 3.58 (95% CI 2.04-6.29)]. CONCLUSION: In ACS, the prevalence of anaemia doubles from admission to 7-weeks follow-up (40%). Not only did baseline anaemia predict long-term prognosis independent of the admission GRACE score, but haemoglobin at 7-weeks post-ACS was also a simple independent predictor of adverse prognosis.

High sensitivity troponin T provides useful prognostic information in non-acute chest pain.

OBJECTIVE: To evaluate the prognostic value of high-sensitivity troponin T (hs-cTnT) in patients who present to General Practitioners (GPs) with non-acute chest pain. DESIGN, SETTING AND PATIENTS: A total of 625 patients who were referred by their GPs to a regional Rapid Access Chest Pain Clinic in Tayside, Scotland were consented and recruited. Diamond-Forrester pretest probability of coronary artery disease (CAD) was used to select patients with intermediate and high-pretest probability. Hs-cTnT and B-type Natriuretic Peptide (BNP) were measured and final diagnosis recorded. Twelve-month follow-up for cardiac events and hospital admission data was collected. Sensitivity, specificity, positive predictive value and negative predictive value (NPV), for both prognosis and diagnosis, were produced using various pre-specified cut-off values for hs-cTnT and BNP. RESULTS: A total of 579 patients were included in the final analysis. Of these, 477 had intermediate/high-pretest probability of CAD. A total of 431 (90.4%) of patients had a hs-cTnT ≤14 ng/l. In this study, hs-cTnT of 14 ng/l was the best cut-off for ruling out if a patient would have an admission for cardiac chest pain in the following 12 months (specificity 90%, NPV 91.4%). It performed well as a predictor of a subsequent negative diagnosis of cardiac chest pain with a specificity of 92.4% and NPV of 83.5%. CONCLUSIONS: Hs-cTnT, at the same level currently used in clinical practice as a diagnostic cut-off for myocardial infarction and acute coronary syndromes, is also a clinically-meaningful indicator for further 12-month cardiac chest pain hospital admissions in patients with non-acute chest pain referred to chest pain clinics by GPs.

The effect of vitamin D replacement on markers of vascular health in stroke patients - a randomised controlled trial.

BACKGROUND AND AIMS: Low vitamin D levels are associated with increased incidence of future cardiovascular events and are common in stroke patients. We tested whether vitamin D supplementation could reduce blood pressure and improve markers of vascular health in patients who had previously suffered a stroke. METHODS AND RESULTS: Randomised, placebo-controlled, double-blind trial. Community-dwelling patients with a history of stroke and baseline 25-hydroxyvitamin D levels <75 nmol/L received 100,000 units of oral vitamin D2 or placebo at baseline. Office and 24 h blood pressure, endothelial function measured by flow-mediated dilatation of the brachial artery, cholesterol, oxidised low density lipoprotein, B-type natriuretic peptide and heart rate turbulence were measured at baseline, 8 weeks and 16 weeks. 58 patients were randomised. Mean age was 67 years, mean baseline blood pressure 128/72 mmHg, mean baseline 25-hydroxyvitamin D level was 38 nmol/L. Serum 25-hydroxyvitamin D levels were higher in the intervention group at 8 weeks compared to placebo (54 vs 42 nmol/L, P = 0.002) and remained higher at 16 weeks. Office systolic and diastolic blood pressure showed no significant change between groups at 8 weeks (systolic 126.1 vs 131.3 mmHg; adjusted P = 0.97); (diastolic 73.1 vs 74.9 mmHg, adjusted P = 0.15). Flow mediated dilatation was significantly higher in the intervention group at 8 weeks (6.9% vs 3.7%, adjusted P = 0.007) but was not significantly different at 16 weeks. CONCLUSIONS: High dose oral vitamin D supplementation did not improve blood pressure but produced short-term improvement in endothelial function in stroke patients with well-controlled baseline blood pressure. CLINICAL TRIALS REGISTRATION: ISRCTN28737567.

Effects of aldosterone and related steroids on LPS-induced increased expression of inducible NOS in rat aortic smooth muscle cells.

BACKGROUND AND PURPOSE: Expression of inducible NOS (iNOS) is important in certain inflammatory diseases. We determined if the hormone aldosterone, a mineralocorticoid receptor (MR) agonist, affects LPS activation of iNOS expression in rat aortic smooth muscle cells (RASMC). EXPERIMENTAL APPROACH: Cultured RASMC were treated with LPS, with or without agonists/antagonists of steroid receptors. iNOS expression was determined by nitrite assays on culture medium removed from treated cells and by immunoblotting of cell protein extracts. KEY RESULTS: LPS (1 µg·mL(-1) ) increased nitrite and iNOS protein above that in control (untreated) cells. These effects of LPS were reduced by aldosterone (0.1-10 µM). The MR antagonists, eplerenone (10 µM) and spironolactone (10 or 50 µM), did not inhibit these actions of 1 µM aldosterone, but the latter were prevented by 10 µM mifepristone, a glucocorticoid (GR) and progestogen receptor (PR) antagonist. Mifepristone also prevented the reduction of LPS-induced nitrite increase produced by 1 µM dexamethasone (GR agonist) and 10 µM progesterone (PR agonist). Spironolactone (10-50 µM) by itself decreased LPS-induced increases in nitrite and iNOS protein. Mifepristone (10 µM) partially reversed these effects of 10 µM spironolactone, but not those of 50 µM; the effects of 50 µM spironolactone were also unchanged when mifepristone was increased to 50 µM. CONCLUSIONS AND IMPLICATIONS: This pharmacological profile suggests that aldosterone, and possibly 10 µM spironolactone, use mechanisms that are dependent on PR and/or GR, but not MR, to inhibit iNOS induction in RASMC. With 50 µM spironolactone, other inhibitory mechanisms requiring further investigation may become predominant.

The effect of different doses of vitamin D(3) on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Low 25-hydroxyvitamin D levels predict future cardiovascular events and are common in patients with type 2 diabetes. We compared the effect of 100,000 and 200,000 IU doses of vitamin D(3) on endothelial function, blood pressure and markers of glycaemic control in patients with type 2 diabetes. METHODS: This was a randomised, parallel group, placebo-controlled trial. Patients with type 2 diabetes and baseline 25-hydroxyvitamin D levels <100 nmol/l were enrolled from community and hospital-based diabetes clinics. Participants were assessed in a university department of clinical pharmacology and received a single oral dose of placebo or vitamin D(3) (100,000 IU or 200,000 IU) at baseline, randomly allocated via numbered bottles prepared offsite; participants and investigators were both blinded to treatment allocation. Endothelial function, office blood pressure, B-type natriuretic peptide, insulin resistance and glycosylated haemoglobin were measured at baseline, and at 8 and 16 weeks. RESULTS: We randomised 61 participants to the three groups (placebo 22, 100,000 IU vitamin D(3) 19, 200,000 IU vitamin D(3) 20). There was no significant difference in the primary outcome of endothelial function at 8 weeks (placebo 5.2%, n = 22; 100,000 IU 4.3%, n = 19; 200,000 IU 4.9%, n = 17) or at 16 weeks. Insulin resistance and glycosylated haemoglobin did not improve with either dose of vitamin D(3). On covariate analysis, systolic blood pressure was significantly lower in both treatment arms than in the placebo group at 8 weeks (placebo 146.4 mmHg, 100,000 IU 141.4 mmHg [p = 0.04 vs placebo], 200,000 IU 136.8 mmHg [p = 0.03 vs placebo]). B-type natriuretic peptide levels were significantly lower in the 200,000 IU group by 16 weeks (placebo 34 pg/ml, 200,000 IU 21 pg/ml, p = 0.02). No significant excess of adverse effects was noted in the treatment arms. CONCLUSIONS/INTERPRETATION: High-dose vitamin D(3) improved systolic blood pressure and B-type natriuretic peptide levels, but not endothelial function, insulin resistance or glycosylated haemoglobin in patients with type 2 diabetes.

Oxidative stress in renal dysfunction: mechanisms, clinical sequelae and therapeutic options.

Oxidative stress has been increasingly linked to the high incidence of cardiovascular events in patients with chronic kidney disease (CKD), especially as traditional cardiovascular risk factors seem to not be able to account for the huge cardiovascular morbidity and mortality in this population group. Oxidative stress is increased in patients with renal impairment as a result of increased oxidant activity and reduced antioxidant capacity, and this is increased in a graded manner with increasing renal dysfunction. Inflammation, which is also present in CKD, further amplifies the oxidant generation process. The two clinical sequelae of oxidative stress are endothelial dysfunction and left ventricular hypertrophy, which have adverse cardiovascular consequences. With our new understanding of oxidative stress, it is now important to assess treatment options that reduce it in the hope that they reverse endothelial dysfunction and left ventricular hypertrophy and the clinical sequelae of these abnormalities.

Left ventricular hypertrophy: reduction of blood pressure already in the normal range further regresses left ventricular mass.

OBJECTIVE: Left ventricular hypertrophy (LVH) confers high cardiovascular risk. Regression of LVH reduces risk. Patients with blood pressure in the normal range and LVH are common. We investigated whether further reduction in blood pressure would further regress LVH. METHODS: 51 subjects with blood pressure in the normal range and echocardiographic left ventricular hypertrophy were randomly assigned to active treatment (antihypertensive medication) or placebo in a ratio of 2:1. The aim was to maintain office systolic blood pressure at 10 mm Hg less than baseline in the active arm and at baseline level in the placebo arm. Cardiac magnetic resonance imaging was used to measure change in left ventricular mass index over 12 months. RESULTS: 35 subjects completed the study (active 23: placebo 12). Average mean baseline office systolic blood pressure was 122 (SD 9) mm Hg in the active group and 124 (9) mm Hg in the placebo group (p = 0.646). The mean baseline left ventricular mass index was 65.88 (11.87) g/m(2) in the active group and 59.16 (11.13) g/m(2) in the placebo group (p = 0.114). The mean difference between baseline and end of study office systolic blood pressure was -9.33 (8.56) mm Hg in the active group and -0.08 (9.27) mm Hg in the placebo group (p = 0.007). The mean change in left ventricular mass index was -4.68 (7.31) g/m(2) in the active group and +1.97 (6.68) g/m(2) in the placebo group (p = 0.014). CONCLUSIONS: Reduction in office systolic blood pressure, already in the normal range, of approximately 9 mm Hg, leads to a reduction in left ventricular mass. Further work is required to see if this also leads to a reduction in cardiovascular events. TRIAL REGISTRATION NUMBER: ISRCTN48331653.

Association between allopurinol and mortality in heart failure patients: a long-term follow-up study.

AIMS: The aim of the study was to explore the long-term effect of allopurinol on mortality and cardiovascular hospitalisations in heart failure (HF) patients. METHODS: This is a population-based cohort study using a record-linkage database in Tayside, Scotland. A total of 4785 HF patients (4260 non-users, 267 incident users and 258 prevalent users) were studied between 1993 and 2002. RESULTS: Compared with non-users, low-dose users in the incident group had a significant increased risk of all-cause mortality, cardiovascular mortality and cardiovascular recurrence (adjusted HR, 1.60, 95%CI 1.26-2.03; 1.70, 1.29-2.23 and 1.44, 1.01-2.07). For the prevalent users, the adjusted HR were 1.27, 0.98-1.64; 1.43, 1.07-1.90 and 1.27, 0.91-1.76 respectively. There was no increased risk of outcome for high-dose users when compared with non-users (adjusted HR, 1.18, 0.84-1.66; 1.14, 0.76-1.71 and 1.36, 0.88-2.10 for the incident users, and 0.86, 0.64-1.15; 0.90, 0.64-1.26; and 1.27, 0.93-1.74 for the prevalent users respectively). High-dose allopurinol was associated with reduced risk of all-course mortality for prevalent users when compared with low-dose (adjusted HR 0.65, 95%CI 0.42-0.99). CONCLUSIONS: The prevalent high-dose allopurinol use had a lower risk of mortality than the prevalent low-dose use suggesting that allopurinol may be of benefit in HF patients.

More than skin deep: atherosclerosis as a systemic manifestation of psoriasis.

There is now growing evidence that psoriasis, like other inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus, is a systemic disorder that is associated with enhanced atherosclerosis and risk of coronary artery disease. Here we summarize the available epidemiological evidence for this association and analyse pathogenic features that are common to psoriasis and atherosclerosis. Further prospective studies are urgently needed to extend knowledge of the risk of cardiovascular morbidity and mortality in patients with psoriasis and to confirm the degree to which treatment of psoriasis reduces this risk. Nevertheless, existing data are sufficient to indicate that severe psoriasis should be more widely recognized as a potential risk factor for cardiovascular disease and should be considered with the established factors when formulating strategies for the management of cardiovascular risk.

A comparison between B-type natriuretic peptide, global registry of acute coronary events (GRACE) score and their combination in ACS risk stratification.

BACKGROUND: In acute coronary syndrome (ACS), both the Global Registry of Acute Coronary Events (GRACE) score and B-type natriuretic peptide (BNP) predict cardiovascular events. However, it is unknown how BNP compares with GRACE and how their combination performs in ACS. METHODS: The authors recruited 449 consecutive ACS patients and measured admission GRACE score and bedside BNP levels. The main outcome measure was all-cause mortality, readmission with ACS or congestive heart failure (defined as a cardiovascular event) at 10 months from presentation. RESULTS: Of the 449 patients, 120 patients presented with ST-elevation myocardial infarction (MI) (27%). There were 90 cardiovascular events at 10 months. Both higher GRACE terciles and higher BNP terciles predicted cardiovascular events. There was a significant but only partial correlation between the GRACE score and log BNP (R = 0.552, p<0.001). On multivariate analyses, after adjusting for the GRACE score itself, increasing BNP terciles independently predicted cardiovascular events (second BNP tercile adjusted RR 2.28 (95% CI 1.15 to 4.51) and third BNP tercile adjusted RR 4.91 (95% CI 2.62 to 9.22)). Patients with high GRACE score-high BNP were more likely to experience cardiovascular events at 10 months (RR 6.00 (95% CI 2.40 to 14.83)) compared to those with high GRACE score-low BNP (RR 2.40 (95% CI 0.76 to 7.56)). CONCLUSION: In ACS, most but not all of our analyses suggest that BNP can predict cardiovascular events over and above the GRACE score. The combined use of both the GRACE score and BNP can identify a subset of ACS patients at particularly high risk. This implies that both the GRACE score and BNP reflect somewhat different risk attributes when predicting adverse prognosis in ACS and their synergistic use can enhance risk stratification in ACS to a small but potentially useful extent.

A randomised, controlled, double-blind, cross-over pilot study assessing the effects of spironolactone, losartan and their combination on heart rate variability and QT dispersion in patients with chronic heart failure.

BACKGROUND AND OBJECTIVE: The blocking of aldosterone or angiotensin II receptors improves mortality in patients with chronic heart failure. We explored whether combining losartan and spironolactone would have any added benefit on the known surrogate of mortality by using heart rate variability (HRV) and QT dispersion as our endpoints. METHODS: We designed a three-phase, consecutive, randomised, controlled, double-blind, cross-over pilot study to assess the effects of losartan alone (50 mg/day), spironolactone (25 mg/day) with angiotensin converting enzyme (ACE) inhibitor and, finally, losartan with spironolactone, on HRV and QT dispersion. We enrolled eight patients (aged 47 to 72 years, mean = 63.7 years), with New York Heart Association (NYHA) class II-III heart failure and ejection fraction (EF) < 35%, in the study at a university-affiliated hospital in Dundee, Scotland. Digital 24-hour Holter recordings were analysed for time-domain HRV and the 12-lead ECG was optically scanned and digitised for analysis of QT dispersion. Evaluations were done at baseline, and at six, 12 and 18 weeks from baseline. RESULTS: Losartan and spironolactone showed statistically significant, favourable effects on HRV, QT dispersion and mean heart rate (p < 0.05). CONCLUSION: The data showed that in these patients with heart failure, the addition of spironolactone to an ACE inhibitor, or the use of losartan on its own, or the combination of losartan plus spironolactone induced a favourable sympathovagal balance. The drugs significantly improved HRV indices and QT dispersion further, and the combination appeared to be safe. However, no significant differences were seen between the effects of each of these regimes on HRV and QT dispersion.