Arthur Mark Richards

Beneficial Hemodynamic and Renal Effects of Adrenomedullin in an Ovine Model of Heart Failure

BACKGROUND Adrenomedullin is a recently discovered endogenous peptide with hypotensive and natriuretic actions in normal animals. Circulating and ventricular adrenomedullin are elevated in congestive heart failure, suggesting a possible role in the pathophysiology of this disease. No studies have previously examined the effects of adrenomedullin in heart failure. METHODS AND RESULTS Eight sheep with pacing-induced heart failure received human adrenomedullin(1-52) at 10 and 100 ng x kg(-1) x min(-1) I.V. for 90 minutes each. Compared with vehicle control data, adrenomedullin increased plasma cAMP (high dose, P<.05) in association with dose-dependent falls in calculated peripheral resistance (13 mm Hg x L(-1) x min(-1), P<.001), mean arterial pressure (9 mm Hg, P<.001), and left atrial pressure (5 mm Hg, P<.001) and increases in cardiac output (0.5 L/min, P<.001). Adrenomedullin increased urine sodium (threefold, P<.05), creatinine (P<.05) and cAMP excretion (P<.01), creatinine clearance (P<.05), and renal production of cAMP (P<.05), whereas urine output was maintained during infusion and raised after infusion (P<.05). Adrenomedullin reduced plasma aldosterone levels (P<.05), whereas plasma atrial and brain natriuretic peptide concentrations were unchanged during infusion and rose after infusion (P<.01 and P<.05, respectively). Plasma catecholamine, cortisol, renin, calcium, and glucose concentrations were not significantly altered. CONCLUSIONS Adrenomedullin reduced ventricular preload and afterload and improved cardiac output in sheep with congestive heart failure. Despite the clear fall in arterial pressure, adrenomedullin increased creatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomedullin in the regulation of pressure and volume in heart failure and raise the possibility of a new therapeutic approach to this disease.

Chronic inhibition of endopeptidase 24.11 in essential hypertension : evidence for enhanced atrial natriuretic peptide and angiotensin II

Aim: To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in essential hypertension Methods: Two groups of 12 white male patients with essential hypertension were treated with candoxatril at 25 mg every 12 h (group 1) or at 200 mg every 12 h (group 2) for 5 days in double-blind, placebo-controlled, crossover studies Results: Candoxatril enhanced natriuresis over the initial 48 h of treatment. Twenty-fourhour diurnal hormone profiles (day 4) showed modest elevations in plasma atrial natriuretic factor (ANF) concentrations and more clear-cut increases in plasma and urinary cyclic CMP. Plasma angiotensin II and aldosterone concentrations were also significantly increased. Plasma catecholamine concentrations were significantly increased by the higher dose of candoxatril. Blood pressure (day 4, 24-h intra-arterial recordings) fell significantly with both doses. The infusions of exogenous ANF and angiotensin II on day 5 showed that candoxatril impaired the metabolic clearance of both ANF and angiotensin II with consequent enhancement of the biological effects of both effector peptides Conclusions: Candoxatril augments the effects of ANF and lowers blood pressure in patients with hypertension. However, the antihypertensive effects may be offset by increased angiotensin-aldosterone and sympathetic nervous system activity. The blood pressure response to endopeptidase inhibition in hypertensive patients may depend on the relative effects on humoral vasodilator (including ANF) and vasoconstrictor (including the angiotensin-aldosterone and sympathetic) systems

Growth differentiation factor 15, ST2, high‐sensitivity troponin T, and N‐terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction

Growth differentiation factor 15 (GDF15), ST2, high‐sensitivity troponin T (hsTnT), and N‐terminal pro brain natriuretic peptide (NT‐proBNP) are biomarkers of distinct mechanisms that may contribute to the pathophysiology of heart failure (HF) [inflammation (GDF15); ventricular remodelling (ST2); myonecrosis (hsTnT); and wall stress (NT‐proBNP)].

Effect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human volunteers.

The effects of endopeptidase 24.11 inhibition on angiotensin-induced changes in plasma angiotensin II, aldosterone, and atrial natriuretic factor concentrations and blood pressure were assessed in normal volunteers. Two groups, each consisting of eight normal volunteers, received stepwise infusions of angiotensin II (2, 4, and 8 ng/kg per minute) on day 5 of dose administration with 25 mg every 12 hours (group 1) or 100 mg every 12 hours (group 2) of an oral inhibitor of endopeptidase 24.11 (UK 79300, candoxatril) or placebo in balanced randomized, double-blind, placebo-controlled crossover studies. Both doses of candoxatril significantly enhanced achieved plasma angiotensin II concentrations during infusions (group 1, p < 0.001; group 2, p < 0.01; overall treatment effect for combined data, p < 0.001). This effect was most pronounced at the highest dose of angiotensin II (treatment-time interaction, p < 0.0001 for combined data) and tended to be more marked with the higher dose of candoxatril (treatment-group interaction, p = 0.08). The pressor response to angiotensin II was clearly enhanced by the lower dose of candoxatril; peak systolic and diastolic pressures exceeded placebo values by approximately 10 mm Hg (p < 0.001 and p < 0.05 for systolic and diastolic pressures, respectively). This effect of candoxatril was absent in group 2, which (unlike group 1) had exhibited a modest natriuretic response (sustained cumulative negative sodium balance, -70 +/- 21 mmol; p < 0.01) to the higher dose of inhibitor. Baseline plasma aldosterone concentrations and the incremental aldosterone response to angiotensin II infusions were not significantly altered by low-dose (group 1) candoxatril.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterisation of proghrelin peptides in mammalian tissue and plasma

Ghrelin is a 28 amino acid stomach peptide, derived from proghrelin(1-94), that stimulates GH release, appetite and adipose deposition. Recently, a peptide derived from proghrelin(53-75) -- also known as obestatin -- has been reported to be a physiological antagonist of ghrelin in the rat. Using four specific RIAs, we provide the first characterisation of proghrelin(1-94) peptides in human plasma, their modulation by metabolic manipulation and their distribution in mammalian tissues. ghrelin(1-28) immunoreactivity (IR) in human plasma and rat plasma/stomach consisted of major des-octanoyl and minor octanoylated forms, as determined by HPLC/RIA. Human plasma ghrelin(1-28) IR was significantly suppressed by food intake, oral glucose and 1 mg s.c. glucagon administration. ghrelin(1-28) IR and proghrelin(29-94) IR peptide distributions in the rat indicated that the stomach and gastrointestinal tract contain the highest amounts of the peptides. Human and rat plasma and rat stomach extracts contained a major IR peak of proghrelin(29-94)-like peptide as determined by HPLC/RIA, whereas no obestatin IR was observed. Human plasma proghrelin(29-94)-like IR positively correlated with ghrelin(1-28) IR, was significantly suppressed by food intake and oral glucose and shared with ghrelin(1-28) IR a negative correlation with body mass index. We found no evidence for the existence of obestatin as a unique, endogenous peptide. Rather, our data suggest that circulating and stored peptides derived from the carboxyl terminal of proghrelin (C-ghrelin) are consistent in length with proghrelin(29-94) and respond to metabolic manipulation, at least in man, in similar fashion to ghrelin(1-28).

Obstructive Sleep Apnea and Cardiovascular Events After Percutaneous Coronary Intervention

Background— There is a paucity of data from large cohort studies examining the prognostic significance of obstructive sleep apnea (OSA) in patients with coronary artery disease. We hypothesized that OSA predicts subsequent major adverse cardiac and cerebrovascular events (MACCEs) in patients undergoing percutaneous coronary intervention. Methods and Results— The Sleep and Stent Study was a prospective, multicenter registry of patients successfully treated with percutaneous coronary intervention in 5 countries. Between December 2011 and April 2014, 1748 eligible patients were prospectively enrolled. The 1311 patients who completed a sleep study within 7 days of percutaneous coronary intervention formed the cohort for this analysis. Drug-eluting stents were used in 80.1% and bioresorbable vascular scaffolds in 6.3% of the patients, and OSA, defined as an apnea-hypopnea index of ≥15 events per hour, was found in 45.3%. MACCEs, a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned revascularization, occurred in 141 patients during the median follow-up of 1.9 years (interquartile range, 0.8 years). The crude incidence of an MACCEs was higher in the OSA than the non-OSA group (3-year estimate, 18.9% versus 14.0%; p=0.001). Multivariate Cox regression analysis indicated that OSA was a predictor of MACCEs, with an adjusted hazard ratio of 1.57 (95% confidence interval, 1.10–2.24; P=0.013), independently of age, sex, ethnicity, body mass index, diabetes mellitus, and hypertension. Conclusions— OSA is independently associated with subsequent MACCEs in patients undergoing percutaneous coronary intervention. Evaluation of therapeutic approaches to mitigate OSA-associated risk is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01306526.

Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction.

Growth differentiation factor 15 (GDF15) is a cytokine highly expressed in states of inflammatory stress. We aimed to study the clinical correlates and prognostic significance of plasma GDF15 in heart failure with preserved ejection fraction (HFpEF) vs. reduced ejection fraction(HFrEF), compared with N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), an indicator of haemodynamic wall stress.

B-type natriuretic peptide infusions in acute myocardial infarction

Background: Natriuretic peptides have actions likely to ameliorate cardiac dysfunction. B-type natriuretic peptide (BNP) is indicated as treatment for decompensated cardiac failure. Objective: To determine the utility of BNP in acute myocardial infarction (MI). Design: Double-blind randomised placebo-controlled trial. Setting: Tertiary hospital coronary care unit. Patients: 28 patients with acute MI with delayed or failed reperfusion and moderate left ventricular dysfunction. Interventions: Infusion of BNP or placebo for 60 hours after MI. Main outcome measures: Neurohormonal activation and renal function in response to BNP infusion, secondary end points of echocardiographic measures of left ventricular function and dimension. Results: BNP infusion resulted in a significant rise in BNP (276 pg/l vs 86 pg/l, p = 0.001). NT-proBNP levels were suppressed by BNP infusion (p = 0.002). Atrial natriuretic peptide (ANP) and NT-proANP levels fell with a significant difference in the pattern between BNP infusion and placebo during the first 5 days (p<0.005). C-type natriuretic peptide (CNP) and NT-proCNP levels rose during the infusion with higher levels than placebo at all measurements during the first 3 days (p<0.01). Cyclic guanosine monophosphate (cGMP) was raised during the infusion period showing a peak of 23 pmol/l on day 2 (placebo 8.9 pmol/l, p = 0.002), with a correlation between BNP and cGMP levels (p<0.001). Glomerular filtration rate (GFR) fell with BNP infusion but was not significantly lower than with placebo (71.0 (5.6) vs 75.8 (5.4) ml/min/1.73 m2, p = 0.62). Patients receiving nesiritide exhibited favourable trends in left ventricular remodelling. Conclusions: Nesiritide, given soon after MI, induced increments in plasma cGMP and CNP and decrements in other endogenous cardiac peptides with a neutral effect on renal function and a trend towards favourable ventricular remodelling.

Urocortins: putative role in cardiovascular disease.

Co-localization of urocortin (Ucn) and its putative receptor (CRF-R2beta) in peripheral tissues, including the heart and vasculature, suggests an important role for the peptide as a regulator of cardiovascular function. Indeed, Ucn gene expression and/or immunoreactivity are increased in the ventricles of patients with failing hearts. Hemodynamic effects of Ucn include vasodilation and increases in cardiac contractility, coronary blood flow and conductance, cardiac output and heart rate. Due to the likely benefit of such actions in states of cardiac compromise, our laboratory has recently reported the first study examining the effects of Ucn in ovine experimental heart failure. We observed profound and sustained cardiovascular (reduced cardiac preload and afterload and increased cardiac output), hormonal (inhibition of vasopressin, endothelin and renin-angiotensin-aldosterone axis) and renal effects (natriuresis, diuresis and augmented creatinine clearance). Such effects incorporate many of the therapeutic goals of heart failure management. Recently, two further members of the CRF peptide family have been identified. In contrast to Ucn, Ucn II and III are reported to be highly selective for the CRF-R2beta, displaying negligible affinity for CRF-R1. As such, one could speculate that these new peptides might produce the salutary effects in heart failure as seen with Ucn, without concomitant activation of the stress-related hormone ACTH (mediated via CRF-R1). Clearly, further study is essential to confirm whether manipulation of this new family of peptides (especially Ucn II and Ucn III) offers benefit to the syndrome of heart failure with potential clinical applications in humans.

Right ventricular dysfunction in left-sided heart failure with preserved versus reduced ejection fraction

Right ventricular (RV) dysfunction is recognized as a major prognostic factor in left‐sided heart failure (HF). However, the relative contribution of RV dysfunction in HF with preserved (HFpEF) vs. reduced ejection fraction (HFrEF) is unclear.