[Show abstract][Hide abstract] ABSTRACT: Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality.
Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (<75 or ≥75 years), and left ventricular ejection fraction (LVEF, ≤45 or >45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45-0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45-0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75-1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67-0.94); P = 0.009] or cardiovascular disease [0.82 (0.67-0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF.
Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalization.
European Heart Journal 03/2014; · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The B-type natriuretic peptides (BNP and N-terminal pro-BNP) are secreted by the heart and, in the case of BNP, serve to maintain circulatory homeostasis through renal and vascular actions and oppose many effects of the renin-angiotensin system. Recent evidence suggests that in patients with severe heart failure, circulating immunoreactive BNP is made up mainly of metabolites that may have reduced bioactivity. We hypothesized that BNP may be degraded before it even leaves the heart.METHODS: Peripheral venous plasma plus atrial and ventricular tissue, obtained from explanted hearts at the time of transplantation, were collected from 3 subjects with end-stage heart failure. In a separate study, plasma was collected from the coronary sinus and femoral artery of 3 separate subjects undergoing cardiac catheterization. Plasma C18 reverse-phase extracts were separated on reverse-phase HPLC, and the collected fractions were subjected to RIAs with highly specific antisera directed to the amino- and carboxy-terminal ends of BNP(1-32).RESULTS: ProBNP, BNP(1-32), and 2 major BNP metabolites were present in atrial and ventricular tissue, where BNP(1-32) represented 45% and 70% of total processed BNP, respectively. Neither BNP(1-32) nor the 2 metabolites were detected in peripheral venous plasma. Nor was BNP(1-32) detected in matching coronary sinus and femoral artery plasma from the 3 subjects undergoing cardiac catheterization.CONCLUSIONS: BNP(1-32) is partly degraded within the hearts of subjects with end-stage heart failure, and even in patients with relatively well-preserved left ventricular systolic function, only BNP metabolites enter the systemic circulation.
[Show abstract][Hide abstract] ABSTRACT: Major restructuring of the health sector has been undertaken in many countries, including New Zealand and England, yet objective assessment of the outcomes has rarely been recorded. In the absence of comprehensive objective data, the success or otherwise of health reforms has been inferred from narrowly-focussed data or anecdotal accounts. A recent example relates to a buoyant King's Fund report on the quest for integrated health and social care in Canterbury, New Zealand which prompted an equally supportive editorial article in the British Medical Journal (BMJ) suggesting it may contain lessons for England's National Health Service. At the same time, a report published in the New Zealand Medical Journal expressed concerns at the level of unmet healthcare needs in Canterbury. Neither report provided objective information about changes over time in the level of unmet healthcare needs in Canterbury. We propose that the performance of healthcare systems should be measured regularly, objectively and comprehensively through documentation of unmet healthcare needs as perceived by representative segments of the population at formal interview. Thereby the success or otherwise of organisational changes to a health system and its adequacy as demographics of the population evolve, even in the absence of major restructuring of the health sector, can be better documented.
The New Zealand medical journal. 01/2014; 127(1404):63-6.
[Show abstract][Hide abstract] ABSTRACT: A history of pre-eclampsia increases the risk of cardiovascular morbidity by mechanisms yet unknown. The aim of the present study was to assess whether plasma norepinephrine (NE) levels are increased 5-6 years after pre-eclamptic pregnancy and to investigate associations with pathophysiological mechanisms of cardiovascular disease: insulin sensitivity, vascular function and arterial pressure. A total of 28 women with previous pre-eclampsia and 20 controls were examined. Blood pressure (BP) and plasma levels of NE and endothelin-1 (ET-1) were measured at rest and after standing for 5 min. Insulin sensitivity was assessed with minimal model analysis and vascular function was assessed using venous occlusion plethysmography and pulse wave analysis. Twenty-four-hour BP measurements were carried out. Women with previous pre-eclampsia had higher levels of NE at rest (P=0.02), which did not associate significantly with insulin sensitivity or overall vasodilatory capacity. The 24-h mean of systolic and diastolic blood pressures (BPs) and heart rate did not differ between the groups (P=0.30, P=0.10 and P=0.46, respectively), and there was no significant association with NE levels. ET-1 levels were similar between the groups, but a positive correlation with systolic (P=0.04) and diastolic (P=0.03) BPs in the upright position was shown in the patient group. Increased levels of plasma NE are sustained in women with previous pre-eclampsia and may contribute to the increased risk for cardiovascular disease in these women.Journal of Human Hypertension advance online publication, 19 September 2013; doi:10.1038/jhh.2013.84.
Journal of human hypertension 09/2013; · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: -Mineralocorticoid receptor antagonists (MRAs) have become established therapy in heart failure (HF). Urocortin 2 (Ucn2) is a novel peptide with potential in the treatment of this disease. The present study investigated the interactions of acute administration of Ucn2 and an MRA in experimental HF. METHODS AND RESULTS: -Ucn2 and an MRA (canrenoic acid (CA)) were infused for 4hours, both singly and together, in eight sheep with pacing-induced HF. Ucn2, when administered as an adjunct to CA, further improved hemodynamic indices relative to that achieved by CA alone, producing additional increases in cardiac output and decreases in left atrial pressure and peripheral resistance, but without eliciting a supplementary reduction in arterial pressure. Ucn2 co-treatment reversed CA-induced rises in circulating aldosterone levels, and also significantly reduced plasma renin activity, angiotensin II and vasopressin concentrations. While both CA and Ucn2 infusion produced a diuresis and natriuresis, responses with Ucn2 and Ucn+CA were 2-3-fold greater than that elicited by separate CA. Ucn2 co-therapy additionally increased urine potassium and creatinine excretion. In contrast to the rise in plasma potassium induced by CA, Ucn2 co-treatment reduced potassium concentrations. CONCLUSIONS: -Ucn2 co-treatment with an MRA in HF further improved hemodynamics relative to that achieved by CA alone, whilst also reducing plasma renin activity, angiotensin II, aldosterone and vasopressin levels, and enhancing renal function. Importantly, Ucn2 prevented CA-induced rises in plasma potassium. These data demonstrate a favorable profile of effects with short-term adjunct Ucn2 therapy and an MRA in HF.
[Show abstract][Hide abstract] ABSTRACT: We propose that conflict between paternally and maternally derived genes in the fetus explains three apparently unrelated observations in epidemiological studies of type 2 diabetes mellitus (DM2): (i) low birth weight is a risk factor for the development of DM2, (ii) there is a high prevalence of low birth weight among babies of fathers who develop DM2, and (iii) an exceptionally high prevalence of DM2 exists in modern day Arabs. Genetic conflict is caused by a particular relationship between the parents, their genes and their offspring: (i) mothers are sometimes polyandrous i.e. have children with more than one man, (ii) mothers provide more biological resources to the fetus than fathers, and (iii) the genes that regulate fetal growth come from both parents and both sets of genes determine the use of resources which are only those of the mother. There is a tendency for maternally derived genes (that promote fetal growth) to be suppressed, in order to spare use of mother's resources, while the same paternally derived genes tend to be expressed (to enhance use of the mother's resources). These same genes are pleiotropic: they affect not only fetal growth (birth weight) but also insulin resistance and hence the development of DM2. Polyandry increases differences in the expression between two parental alleles in the fetus i.e. increases genetic conflict and results in the production of bigger babies whereas monandry has the opposite effect. Consequently, parent-of-origin-biased expression of pleiotropic developmental genes could explain why smaller babies are more common when the fathers have DM2. Similarly less genetic conflict in Arabs (resulting from the tradition of strict monandry, the practice of levirate, and preference for a paternal cousin as spouse) could explain, at least in part, their exceptionally high prevalence of DM2. This hypothesis links human mate selection with the risk of developing DM2.
[Show abstract][Hide abstract] ABSTRACT: To update activities of the Canterbury Charity Hospital (CCH) and its Trust over the 3 years 2010-2012, during which the devastating Christchurch earthquakes occurred.
Patients' treatments, establishment of new services, expansion of the CCH, staffing and finances were reviewed.
Previously established services including general surgery continued as before, some services such as ophthalmology declined, and new services were established including colonoscopy, dentistry and some gynaecological procedures; counselling was provided following the earthquakes. Teaching and research endeavours increased. An adjacent property was purchased and renovated to accommodate the expansion. The Trust became financially self-sustaining in 2010; annual running costs of $340,000/year were maintained but were anticipated to increase soon. Of the money generously donated by the community to the Trust, 82% went directly to patient care. Although not formally recorded, hundreds of appointment request were rejected because of service unavailability or unmet referral criteria.
This 3-year review highlights substantial, undocumented unmet healthcare needs in the region, which were exacerbated by the 2010/2011 earthquakes. We contend that the level of unmet healthcare in Canterbury and throughout the country should be regularly documented to inform planning of public healthcare services.
The New Zealand medical journal 01/2013; 126(1386):31-42.
[Show abstract][Hide abstract] ABSTRACT: The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.
PLoS ONE 01/2013; 8(3):e57806. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background- The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. Methods and Results- Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administration produced a dose-dependent decrease in plasma renin activity (P=0.004), with similar trends observed for plasma angiotensin II and aldosterone (P=0.093 and P=0.088, respectively). Circulating natriuretic peptides, endothelin-1, and catecholamine levels were unchanged. HRP also induced a reduction in plasma sodium concentrations relative to control (P=0.024), a natriuresis (P=0.046), and a tendency for creatinine excretion and clearance to improve. Conclusions- (P)RR antagonism in experimental HF resulted in cardiovascular and renal benefits in association with inhibition of the renin-angiotensin-aldosterone system. These findings suggest that (P)RR contributes to pressure/volume regulation in HF and identifies the receptor as a potential therapeutic target in this disease.
[Show abstract][Hide abstract] ABSTRACT: To determine whether there are differences in stickiness to hydrophobic surfaces among peptides and proteins under immunoassay conditions, peptides and proteins were radio-labeled with (125)I and competitive adsorption with human serum albumin (HSA) in polystyrene or polypropylene tubes was used to determine the IC (50), the concentration of HSA required to reduce the adsorption of the labeled polypeptides to 50% of maximal. Stickiness was defined as log(10)(10(9) IC (50)). Stickiness varied significantly between the labeled polypeptides (p < 0.00001) and ranged (±sem) from 0.99 ± 0.07 for angiotensin II to 5.30 ± 0.07 for tyr(0)-urocortin II. The stickiness of HSA and γ globulin was 1.62 ± 0.09 and 1.92 ± 0.05, respectively. No significant difference in stickiness between polystyrene and polypropylene was found. We conclude that some peptides are sufficiently sticky to risk adsorptive loss during sampling and analysis, and there may exist peptides so sticky that they remain uncharacterized.
Journal of Immunoassay and Immunochemistry 07/2012; 33(3):302-13. · 0.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the ratio of enzyme inhibitor volume to blood volume in angiotensin II (Ang II) blood collection tubes.
Whole blood was mixed with known volumes of inhibitor prior to angiotensin II analysis.
Imunoreactive Ang II levels increased at low blood volume to high inhibitor volume ratios, due to interference by o-phenanthroline.
To prevent falsely elevated Ang II levels in low volume blood samples an appropriate volume of inhibitor solution must be used.
[Show abstract][Hide abstract] ABSTRACT: Our aim was to examine the effects of adjunctive coenzyme Q(10) therapy on 24-h ambulatory blood pressure (BP) in subjects with the metabolic syndrome and inadequate BP control.
In a randomized, double-blind, placebo-controlled 12-week crossover trial, coenzyme Q(10) (100 mg twice daily) or placebo was administrated to 30 subjects with the metabolic syndrome, and inadequate BP control (an average clinic BP of ≥140 systolic mm Hg or ≥130 mm Hg for patients with type 2 diabetes) while taking an unchanged, conventional antihypertensive regimen. Clinic and 24-h ambulatory BP were assessed pre- and post-treatment phases. The primary outcomes were the changes in 24-h systolic and diastolic BP during adjunctive therapy with coenzyme Q(10) vs. placebo and prespecified secondary outcomes included changes in BP loads.
Compared with placebo, treatment with coenzyme Q(10) was not associated with statistically significant reductions in systolic (P = 0.60) or diastolic 24-h ambulatory BP (P = 0.12) or heart rate (P = 0.10), although daytime diastolic BP loads, were significantly lower during coenzyme Q(10) administration with thresholds set at >90 mm Hg (P = 0.007) and ≥85 mm Hg (P = 0.03). Coenzyme Q(10) was well tolerated and was not associated with any clinically relevant changes in safety parameters.
Although it is possible that coenzyme Q(10) may improve BP control under some circumstances, any effects are likely to be smaller than reported in previous meta-analyses. Furthermore, our data suggest that coenzyme Q(10) is not currently indicated as adjunctive antihypertensive treatment for patients with the metabolic syndrome whose BP control is inadequate, despite regular antihypertensive therapy.
American Journal of Hypertension 11/2011; 25(2):261-70. · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AM5 (adrenomedullin 5), a newly described member of the CGRP (calcitonin gene-related peptide) family, is reported to play a role in normal cardiovascular physiology. The effects of AM5 in HF (heart failure), however, have not been investigated. In the present study, we intravenously infused two incremental doses of AM5 (10 and 100 ng/min per kg of body weight each for 90 min) into eight sheep with pacing-induced HF. Compared with time-matched vehicle control infusions, AM5 produced progressive and dose-dependent increases in left ventricular dP/dt(max) [LD (low dose), +56 mmHg/s and HD (high dose), +152 mmHg/s] and cardiac output (+0.83 l/min and +1.81 l/min), together with decrements in calculated total peripheral resistance (-9.4 mmHg/min per litre and -14.7 mmHg/min per litre), mean arterial pressure (-2.8 mmHg and -8.4 mmHg) and LAP (left atrial pressure; -2.6 mmHg and -5.6 mmHg) (all P<0.001). HD AM5 significantly raised PRA (plasma renin activity) (3.5-fold increment, P<0.001), whereas plasma aldosterone levels were unchanged over the intra-infusion period and actually fell in the post-infusion period (70% decrement, P<0.01), resulting in a marked decrease in the aldosterone/PRA ratio (P<0.01). Despite falls in LAP, plasma atrial natriuretic peptide and B-type natriuretic peptide concentrations were maintained relative to controls. AM5 infusion also induced significant increases in urine volume (HD 2-fold increment, P<0.05) and urine sodium (2.7-fold increment, P<0.01), potassium (1.7-fold increment, P<0.05) and creatinine (1.4-fold increment, P<0.05) excretion and creatinine clearance (60% increment, P<0.05). In conclusion, AM5 has significant haemodynamic, endocrine and renal actions in experimental HF likely to be protective and compensatory in this setting. These results suggest that AM5 may have potential as a therapeutic agent in human HF.
[Show abstract][Hide abstract] ABSTRACT: "What I tell you three times is true"-Lewis Carroll. How many times have we been told that reducing dietary sodium intake will improve the health of whole populations? But is there adequate evidence to support this idea? Some recent studies have indicated that caution is needed. Targeting those most likely to benefit should prevent inadvertent harm and free the rest of the population from yet another nagging plea to alter their lifestyle.
Current Hypertension Reports 06/2011; 13(5):325-7. · 3.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although acute administration of urocortin 2 has beneficial actions in heart failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n=6) or urocortin 2 (0.75 μg/kg per hour; n=6) to sheep with pacing-induced heart failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905±73 versus urocortin 2 1424±158 mm Hg/s; P<0.001) and output (2.6±0.1 versus 3.8±0.3 L/min; P<0.001), together with reductions in left atrial pressure (28±1 versus 12±1 mm Hg; P<0.001) and peripheral resistance (30±2 versus 20±2 mm Hg/L per min; P<0.001). In contrast, urocortin 2-induced falls in mean arterial pressure were not established until the second day (day 4: 74±2 versus 72±2 mm Hg; P<0.05). Prolonged urocortin 2 administration was associated with sustained (days 0 to 4) declines in plasma renin activity (day 4: 1.33±0.27 versus 0.73±0.20 nmol/L per hour; P<0.001), aldosterone (970±383 versus 396±96 pmol/L; P<0.05), vasopressin (2.4±0.8 versus 1.3±0.1 pmol/L; P<0.05), endothelin 1 (7.2±0.7 versus 4.5±0.4 pmol/L; P<0.01), and atrial (269±27 versus 150±19 pmol/L; P<0.001) and B-type (65±9 versus 29±6 pmol/L; P<0.001) natriuretic peptides, as well as an acute transient rise in plasma cortisol (day 1: P<0.001). Chronic urocortin 2 also persistently augmented urinary sodium (day 4: 4-fold increase; P<0.001) and creatinine (1.4-fold; P<0.001) excretion and creatinine clearance (1.5-fold; P<0.01) compared with control. Food consumption was temporarily suppressed (P<0.05). In conclusion, 4-day urocortin 2 administration induces sustained improvements in hemodynamics and renal function, in association with inhibition of multiple vasoconstrictor/volume-retaining systems. These findings support the therapeutic potential for urocortin 2 in heart failure.
[Show abstract][Hide abstract] ABSTRACT: There is little recent information regarding outcome and its determinants following cardioversion (CV) for atrial fibrillation (AF) or flutter. This study aims to help improve prediction of cardiac rhythm outcome following CV for AF.
Cardiac rhythm at 6 weeks and 12 months was documented following elective (EC; n=496) or immediate (IC; n=52) cardioversion for AF or atrial flutter in a single referral centre.
65 and 58% of IC patients remained in sinus rhythm (SR) 6 weeks and 1 year after CV (respectively) compared with 43% and 30% in EC patients (P<0.001). Independent positive predictors of SR 6 weeks after cardioversion included amiodarone therapy (OR 2.04 [1.28-3.33], P<0.01) and atrial flutter (OR 1.85 [1.09-3.13], P<0.05). Negative predictors included the need for >1 shock to achieve SR (OR 1.61 [1.12-2.37], P=0.011) and arrhythmia duration, (OR 0.96 [0.95-0.97], P<0.001). At 1 year, amiodarone, duration of arrhythmia and the need for >1 shock remained independent predictors of rhythm.
The number of shocks required to achieve SR is a newly demonstrated independent predictor of rhythm outcome after elective CV.
The New Zealand medical journal 01/2011; 124(1343):48-56.