D. P. Nicholls

Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are known to be elevated in patients with chronic heart failure at rest. While it is known that during exercise the circulating level of ANP increases in patients with heart failure, the response of BNP to exercise in these patients relative to control subjects is unclear. Ten patients with stable chronic heart failure and 10 normal control subjects performed symptom‐limited exercise with respired gas analysis. All patients had depressed left ventricular ejection fractions (LVEF). Patients had lower peak oxygen consumption PV˙O2) than the control group [median (range) 1.18 (0.98–1.76) vs. 1.94 (1.53–2.31) L min−1; P < 0.001]. Circulating plasma levels of ANP and BNP were higher at rest in patients than in control subjects [ANP 335 (140–700) vs. 90 (25–500) pg mL−1; BNP 42 (25–50) vs. 20 (10–20) pg mL−1], and at peak exercise [ANP 400 (200–1000) vs. 130 (10–590); BNP 46 (40–51) vs. 20 (10–30)]. The rise in ANP at peak exercise was significant in patients compared with the resting level, but not in control subjects. For BNP, there was a significant rise in patients but no change in control subjects. The circulating plasma levels of both peptides showed a strong negative correlation with LVEF (ANP, P < 0.005; BNP, P < 0.0001) and, to a less extent, with RVEF. It is possible that BNP may give a better indication of cardiac function.

Abnormal vascular responses in human chronic cardiac failure are both endothelium dependent and endothelium independent

Objective To study underlying vascular responses in chronic heart failure in patients without ACE inhibitor treatment, and to compare them with age matched controls. Design Forearm blood flow was studied using venous occlusion plethysmography in patients with chronic heart failure (n = 12) and matched controls (n = 13), after infusion of L-NMMA (a nitric oxide synthase inhibitor), glyceryl trinitrate (an endothelium independent vasodilator), and serotonin (an endothelium dependent vasodilator). Results L-NMMA produced significant vasoconstriction in normal subjects (forearm blood flow reduced by 24%), but not in patients (6%; difference between groups p < 0.03). The vasodilator responses to glyceryl trinitrate were impaired in patients (p < 0.02). In normal controls, serotonin produced initial dilatation, followed by vasoconstriction at high doses. In patients, no vasodilator responses were observed, only late vasoconstriction (p < 0.03). Conclusions The vascular responses of patients are confirmed as being abnormal. The lack of response to L-NMMA suggests that nitric oxide does not contribute to basal vascular tone in patients with chronic heart failure. The responses to glyceryl trinitrate and to serotonin suggest that there is both smooth muscle and endothelial dysfunction in patients with chronic heart failure.

Cytokine profile in chronic cardiac failure

Elevated tumour necrosis factor α (TNF‐α) has been demonstrated in chronic cardiac failure (CCF) and may relate to severity of CCF and development of cachexia. We measured TNF receptor p55 in addition to TNF‐α in an attempt to improve the detection rate of TNF‐α activation, and simultaneously measured interleukin 6 (IL‐6), interleukin 8 (IL‐8) and C‐reactive protein. Thirty‐four patients with CCF and 24 control subjects were studied. Only TNF receptor p55 [6.95 (0.77−42.3) vs. 5.52 (1.50−13.36) ngmL−1 (median (range)] and IL‐6 [0.335 (0−9.79) vs. 0 (0−14.71) pgmL−1) were significantly elevated in patients compared with control subjects (both P<0.05). All inflammatory markers were more frequently elevated in patients, but none correlated with any of the clinical parameters studied. Reasons for inflammatory marker elevation in CCF are uncertain, but future studies should measure the p55 TNF receptor and IL‐6 in addition to TNF‐α, to improve detection of cytokine activity.

Gas exchange responses to constant work rate exercise in chronic cardiac failure.

OBJECTIVE--To examine the time course of changes in minute oxygen consumption and other gas exchange variables and heart rate during constant work rate exercise in patients with chronic cardiac failure. DESIGN--Treadmill exercise with on line measurement of gas exchange and a target duration of 10 minutes. SUBJECTS--Seven men in New York Heart Association class II, six in class III, and seven controls. MAIN OUTCOME MEASURES--Gas exchange variables and heart rate were averaged for the final two minutes of exercise. Time constants were calculated for the increase in all variables. RESULTS--Consumption of oxygen at the end of exercise (VO2) was similar in class II patients (mean (95% confidence interval (95% CI) 14.9 (13.6 to 16.1) ml kg-1 min-1), class III patients (13.2 (11.2 to 15.1) ml kg-1 min-1), and controls (13.3 (12.5 to 14.2) ml kg-1 min-1). The patients reached this VO2 more slowly with longer exponential time constants of 0.82 (0.59 to 1.04) min in class II and 1.19 (0.86 to 1.51) min in class III, than the 0.49 (0.35 to 0.64) min in the controls. Time constants of other gas exchange variables and heart rate were also longer in patients. By analysis of covariance, peak VO2 accounted for the between group difference in the time constant for VO2, suggesting that circulatory factors may be an important cause of the delayed kinetics. CONCLUSIONS--A delayed rise in VO2 in response to exercise may be responsible for subnormal values of VO2 early in exercise in patients with chronic cardiac failure.

Neuroendocrine changes in chronic cardiac failure

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.

Variable patterns of atrial natriuretic peptide secretion in man

Abstract Peripheral circulating levels of atrial natriuretic peptide may exhibit short‐term variation compatible with a pulsatile pattern of secretion. We obtained samples every 2 min for 90 min from the antecubital vein of 16 patients with chronic cardiac failure and 13 controls. Overall levels were higher in the patients (median and quartiles 230 (125,325) vs. 26 (16,48) ng l‐1; P<0·001). In both groups there was considerable variability, with 10 (2–12) peaks, 9 (7–15) troughs (both defined as >2 SD from the mean) and 16 (13–18) pulses (defined by computer) during the sampling period in controls, and a similar number in patients. We then carried out simultaneous sampling in the pulmonary artery, femoral artery and peripheral vein in eight subjects with normal cardiac function and six patients with impaired function due to valvular heart disease. The pattern of variability was preserved in all three sites in both groups, suggesting intermittent secretion rather than variable breakdown of the peptide in the lung. No changes in right atrial pressure or heart rate were observed to coincide with the variations, but levels of the peptide in the pulmonary artery correlated with right atrial pressure in patients (r = 0·87; P<0·05). The mechanism of such periodicity and its pathophysiological importance remain unknown.

The natriuretic peptide family.

For several decades there has been a search for an endogenous natriuretic-diuretic hormone. As early as 1935, Peters proposed that the ‘fullness’ of the bloodstream may provide a diuretic response on part of the kidney. Experiments by De Wardener et al. [l] provided evidence in support of a hormonal mechanism influencing sodium excretion. If blood from a dog, in which volume expansion with normal saline had been performed, was used to perfuse the kidney of another dog, natriuresis occurred which was independent of the effect of aldosterone or renal perfusion pressure. Other experiments [2] showed that distension of the left atrium with a balloon in an anaesthetized dog led to an increase in urine output, suggesting a specific link between the heart and kidney. The concept that the heart might secrete a hormone which might play a role in the control of sodium and water excretion, and thereby blood volume, was reinforced by the observation of endocrine-like granules in atrial muscle cells [3] and by a change in the degree of granulation with the alteration of sodium and water balance [4]. These experiments led DeBold and co-workers to carry out the key experiments in which they injected rats with extracts prepared from rat atria and ventricles [5]. The natriuretic peptide family currently consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). Each peptide exhibits natriuretic-diuretic, vasorelaxant and other functions designed to lower blood pressure and to control electrolyte homeostasis. The natriuretic peptides exert their physiological actions via a series of cellular receptors. Ligand occupancy of the extracellular domain results in the activation of an intracellular guanylate cyclase with an associated rise in cGMP, which is thought to act as the second messenger for the peptides.

Chrome congestive heart failure

Cardiac output was measured in 11 patients undergoing routine cardiac catheterization using a carbon dioxide rebreathing technique and compared with cardiac output measured by direct Fick and thermodilution. The carbon dioxide rebreathing technique gave consistently lower values for cardiac output than the other two methods (mean difference −0·73, 95% CI −0·95 to−0·511. min−1 with the direct Fick and −0·72. 95% CI −1·19 to −0·261. min−1 with thermodilution). The direct Fick and thermodilution methods gave similar results (mean dtfference −0·08, 95% CI −0·32 to 0·16a. min−1). Cardiac output was also measured in 10 healthy subjects at rest and during two steady-state levels of exercise using the carbon dioxide rebreathing technique. Measurements were made in triplicate on 3 separate days. The technique gave reproducible results between replicates at rest (coefficient of variation 91%) and became more reproducible on exercise (coefficients of variation 56% and 54% respectively at each exercise level). There was a good correlation between cardiac output and oxygen consumption (r=0·98 The carbon dioxide rebreathing technique is a feasible non-invasive way of measuring cardiac output. It tends to underestimate cardiac output at rest but is reproducible and becomes more so on exercise which is where it should be of most value.

Exhaled nitric oxide during incremental and constant workload exercise in chronic cardiac failure

Nitric oxide (NO) is present in exhaled breath and produced by the pulmonary vascular endothelium as a potent vasodilator. Exercise is normally associated with pulmonary vasodilatation and a decrease in pulmonary vascular resistance to accommodate the increase in cardiac output. If production of NO is impaired in patients with chronic congestive cardiac failure (CCF), this might contribute to their exercise intolerance.

Oxygen consumption is increased relative to work rate in patients with McArdle's disease.

Background  Patients with McArdles disease suffer exercise incapacity as a result of myophosphorylase deficiency, and for a given work rate have excessive circulatory and ventilatory responses. We hypothesized that the rate of increase of oxygen consumption with work rate (ΔVO2‐ΔWR slope) would also be elevated in such patients as a result of these excessive responses.