Michael Gary Nicholls

Brain natriuretic factor: regional plasma concentrations and correlations with haemodynamic state in cardiac disease.

OBJECTIVE--To document regional plasma concentrations of brain natriuretic factor (BNF) and their relations to concurrent concentrations of atrial natriuretic factor, cyclic guanosine monophosphate, and haemodynamic state. DESIGN--Regional blood sampling from a systemic artery and vein, renal vein, and coronary sinus together with concurrent haemodynamic indices in patients coming forward for left and right cardiac catheterisation. SETTING--Tertiary referral centre. PATIENTS--22 consecutive unselected patients coming forward for left and right cardiac catheterisation or electrophysiological studies in the course of standard diagnosis for a range of cardiac disorders. MAIN OUTCOME MEASURES--Significant arteriovenous gradients for plasma BNF concentration were found across the lower limb, the kidney, and the heart. These were less than concurrent arteriovenous gradients in plasma atrial natriuretic factor (ANF). Arterial concentrations of plasma BNF were positively related to concurrent concentrations of ANF (r = 0.72, p < 0.01) and cyclic guanosine monophosphate (r = 0.52, p < 0.05). Arterial plasma concentrations of BNF showed a significant positive correlation with right atrial pressure and pulmonary artery wedge pressure and an inverse relation to cardiac output. CONCLUSIONS--Regional plasma concentrations of BNF indicate cardiac secretion of this peptide and clearance in a number of tissues. Renal clearance is proportionally greater than that found across the limb. Absolute and proportional arteriovenous gradients of this peptide are considerably less than for concomitant concentrations of ANF suggesting slower metabolic clearance of BNF. Plasma BNF concentrations rise with increasing cardiac impairment and are related to indices of cardiac function. These findings are consistent with a role for BNF in the neurohumoral response to cardiac impairment.

Arrhythmogenic potential of diuretic induced hypokalaemia in patients with mild hypertension and ischaemic heart disease.

In view of evidence suggesting an association of mild hypokalaemia with cardiac arrhythmia, the arrhythmogenic potentials of potassium losing and potassium sparing diuretic treatments were compared in a controlled prospective crossover study of 10 patients with mild hypertension and ischaemic heart disease. Mean (SEM) plasma potassium was 4.3(0.06) mmol/l and 3.3(0.07) mmol/l after potassium sparing and potassium losing treatments respectively. Blood pressure and volume depletion as assessed by weight change, plasma renin activity, and noradrenaline concentrations did not differ significantly in the two treatment periods. The potassium losing treatment phase was associated with an increased frequency of ventricular extrasystoles, a higher Lown grading during ambulatory electrocardiographic monitoring, prolonged duration and decreased phase 0 velocity of the monophasic action potential, a prolonged ventricular effective refractory period, and increased myocardial electrical instability as assessed by programmed ventricular stimulation. It is concluded that minor changes in plasma potassium concentration are associated with increased ventricular electrical instability in patients with ischaemic heart disease. Mild hypokalaemia in such patients may predispose to life threatening arrhythmias and should be avoided.

Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model

The time course of cardiac sympathetic nerve activity (CSNA) following acute myocardial infarction (MI) is unknown. We therefore undertook serial direct recordings of CSNA, arterial blood pressure (MAP) and heart rate (HR) in 11 conscious sheep before and after MI, and compared them with 10 controls. Conscious CSNA recordings were taken daily from electrodes glued into the thoracic cardiac nerves. Infarction was induced under pethidine and diazepam analgesia by applying tension to a coronary suture. MI size was assessed by left ventricular planimetry (%) at postmortem, peak troponin T and brain natriuretic peptide levels (BNP). Baroreflex slopes were assessed daily using phenylephrine‐nitroprusside ramps. The mean infarcted area was 14.4 ± 2.9%, troponin T 1.88 ± 0.39 μg l−1 and BNP 8.4 ± 1.3 pmol l−1. There were no differences in haemodynamic parameters or CSNA between groups at baseline. MAP and HR remained constant following MI. CSNA burst frequency increased from baseline levels of 55.8 ± 7.1 bursts min−1 to levels of 77.5 ± 8.7 bursts min−1 at 2 h post‐MI, and remained elevated for 2 days (P < 0.001). CSNA burst area also increased and was sustained for 7 days following MI (P= 0.016). Baroreflex slopes for pulse interval and CSNA did not change. CSNA increases within 1 h of the onset of MI and is sustained for at least 7 days. The duration of this response may be longer because the recording fields decrease with time. This result is consistent with a sustained cardiac excitatory sympathetic reflex.

Atrial natriuretic peptide in spontaneous tachycardias.

Because anecdotal reports suggest that concentrations of atrial natriuretic peptide are raised during tachycardias, plasma immunoreactive atrial natriuretic peptide concentrations were measured in 34 consecutive patients when tachycardia was diagnosed and again five and 15 minutes after conversion to sinus rhythm. Plasma atrial natriuretic peptide concentrations were raised in all but four patients, and were higher in patients with known heart disease than in those without. The concentrations were higher with ventricular tachycardia than with atrial fibrillation or supraventricular tachycardia, and in acute versus chronic tachycardia. There was only a weak positive relation between ventricular rate and atrial natriuretic peptide (r = 0.31); but there was a closer inverse correlation between atrial natriuretic peptide and systolic arterial pressure (r = -0.60). Conversion to sinus rhythm was associated with a definite fall in plasma atrial natriuretic peptide concentrations. Despite very high baseline concentrations of atrial natriuretic peptide only two patients reported polyuria. It is likely that atrial pressure rather than ventricular rate determines atrial natriuretic peptide release during tachycardia. Despite the absence of polyuria in all but two patients in this study atrial peptides could still contribute to, or cause, the polyuria of tachycardias.

Hormone, calcium and blood pressure relationships in primary hyperparathyroidism.

The cause of hypertension in primary hyperparathyroidism and its response to corrective surgery remains a matter of controversy. We therefore studied blood pressure, vasoactive hormones and plasma calcium responses to parathyroidectomy in six hypertensive and two normotensive patients with primary hyperparathyroidism. Twenty-four-hour intra-arterial pressure recordings, together with hourly blood sampling for plasma renin activity (PRA), aldosterone, cortisol, catecholamines and calcium levels, were undertaken in each patient before surgery and were repeated under identical conditions 3-6 months after parathyroidectomy. Mean plasma calcium was 3.03 +/- 0.1 before, and 2.35 +/- 0.02 mmol/l after, parathyroidectomy. Changes in arterial pressure were small and variable in individual patients. Group mean arterial pressures before and after surgery were identical. Plasma cortisol and PRA were significantly higher in the hypercalcaemic state (P less than 0.01 and P less than 0.05, respectively) but there was no significant difference in plasma aldosterone or catecholamine levels. No correlations between changes in plasma calcium or parathyroid hormone levels and concomitant changes in plasma concentration of other hormones were observed. Our findings show that correction of primary hyperparathyroidism has no systematic effect on arterial pressure in a heterogeneous group, including some patients with probable background essential hypertension, when evaluated 3-6 months after surgery. Compared with values after corrective surgery, mean levels of PRA and cortisol-but not aldosterone or catecholamines--are elevated in patients with primary hyperparathyroidism. These findings are consistent with an inhibitory effect of raised ionic calcium concentration on the response of the adrenal glomerulosa to angiotensin and adrenocorticotrophic hormone.

Ambulatory pulmonary arterial pressure in primary pulmonary hypertension: variability, relation to systemic arterial pressure, and plasma catecholamines.

The variability of pulmonary arterial pressure, the relation of pulmonary pressure to systemic pressure, pulmonary pressure responses to stimuli (exercise, hypoxia, smoking, free ambulation), and plasma catecholamine responses were assessed in five patients with primary pulmonary hypertension. Ambulatory monitoring techniques provided data for the computerised analysis of continuous, beat-to-beat, direct recordings of both pulmonary and systemic arterial pressures for 8 to 10 hours. The absolute variability of pulmonary arterial pressure and the magnitude of absolute changes in this variable in response to stimuli were increased in primary pulmonary hypertension. The variability of systemic pressure was similar to that in healthy volunteers. Basal and stimulated plasma catecholamine values were normal, suggesting preservation of normal sympathetic nervous system activity in primary pulmonary hypertension.

BNP: not just for heart failure

Measurement of circulating natriuretic peptides has found a secure place in the diagnosis and management of patients with heart failure. In this issue of Heart , Khan and colleagues report that plasma levels of immunoreactive N-terminal pro-B-type natriuretic peptide (NTproBNP) provide prognostic information better than that given by the TIMI risk score in patients with ST-segment elevation myocardial infarction (STEMI) ( see article on page 40 ).1 The paper adds significantly to an already impressive literature describing the response of circulating natriuretic peptides, especially the B-type peptides, to acute coronary syndromes (ACS) and their potential use as prognostic indicators. Circulating levels of the natriuretic peptides (BNP, NTproBNP and atrial natriuretic peptide (ANP)) exhibit a substantial and sustained increase after ACS, although the magnitude and pattern of change differs between the peptides.2 What accounts for this response? Enhanced cardiac secretion of the peptides results probably from increased mechanical stretch of the infarct and peri-infarct regions of the heart together with stimulatory effects from neurohormonal systems which are activated at the time of ACS. These include the sympathetic nervous system, the corticotrophin/ACTH/cortisol axis, renin–angiotensin systems (both systemic and cardiac) and endothelin, together with local tissue hypoxia and acidosis. Teleologically, this response can be viewed as protective through the actions of bioactive BNP and ANP, via cGMP, within cardiac tissue, to oppose the profibrotic and inflammatory effects of transforming growth factor β (TGFβ) and open KATP channels,3 for example, thereby …

Effect of central naloxone on hormone and blood pressure responses to hemorrhage in conscious sheep

The role of the brain opioid system in the control of hypothalamic-pituitary-adrenal activity was studied in 10 conscious sheep with an indwelling cannula in a cerebral lateral ventricle. On separate days, sheep received infusions of artificial CSF (control) and the opiate antagonist, naloxone (100 micrograms/hr) before and during acute moderate hemorrhage (15 ml/kg over 10 min). Infusion of naloxone before hemorrhage raised plasma ACTH and resulted in a significant increase in cortisol compared to the control infusion. In contrast, ACTH and cortisol responses to hemorrhage tended to be blunted by central naloxone infusion. The responses of vasopressin, aldosterone and the catecholamines remained unaffected by naloxone. The fall in blood pressure and the rise in heart rate accompanying hemorrhage were likewise unaltered. These results suggest that brain opioid peptides have an inhibitory effect on basal ACTH secretion but do not play a major role in modulating the hemodynamic or pituitary-adrenal responses to acute moderate hemorrhage in conscious sheep.

NITRIC OXIDE INHIBITION IN AN OVINE MODEL OF HEART FAILURE

1. The role of nitric oxide (NO) in congestive heart failure was investigated by studying the acute haemodynamic, hormonal and renal effects of NG‐monomethyl‐l‐arginine (l‐NMMA), a nitric oxide inhibitor, given as incremental bolus doses in six sheep before (normal) and after induction of heart failure (HF) by rapid left ventricular pacing (LVP).

Adrenomedullin in heart failure: potential therapeutic implications

Adrenomedullin (AM) may play a role in the pathophysiology of heart failure. Plasma levels of AM are raised in cardiovascular disease in proportion to severity of cardiac dysfunction, and plasma AM levels measured in acute myocardial infarction and heart failure are a useful prognostic indicator of outcome. AM administration in both experimental and human heart failure induces a beneficial spectrum of biological action including reduced arterial and atrial pressures, improved cardiac output, inhibition of plasma aldosterone and preservation or augmentation of urinary sodium excretion. Combining AM administration with either angiotensin-converting enzyme inhibition or neutral endopeptidase inhibition results in augmentation of the hemodynamic and renal effects of the individual treatments. Manipulating the AM system may prove beneficial as an adjunctive therapeutic strategy in cardiac disease.