B. Silke

Accuracy and precision of blood pressure determination with the Finapres : an overview using re-sampling statistics

The Finapres non-invasive blood pressure (BP) monitor uses the method of Penaz to indirectly record the arterial waveform; studies on its accuracy have suggested little systematic bias vs intra-arterial pressure (IAP) but substantial variability. Inconsistency between studies, in respect of the magnitude, direction and variance of bias, was described in the validation studies against the direct IAP. We have employed a novel re-sampling statistical method to combine the data from 20 published studies; a robust overall estimate of the accuracy and precision of the Finapres was thereby obtained. Based on 449 patients and 4490 re-samples, the average Finapres systolic bias (IAP - Finapres) was 2.2 mm Hg (s.d. ±12.4) with limits of agreement (bias ±2 s.d.) of −22.6 and 26.9 mm Hg. The average precision was 12.1 mm Hg (s.d. ±8.4). The Finapres diastolic bias was −0.3 mm Hg (s.d. ±7.9) with the limits of agreement of −16.1 and 15.5 mm Hg. The average precision was 7.6 mm Hg (s.d. ±5.3). The average Finapres mean arterial pressure bias was 2.1 mm Hg (s.d. ±8.6) with precision of 7.6 mm Hg (s.d. ±5.3). The calculated percentage of Finapres systolic values expected to fall within ±5 or ±10 of the direct intra-arterial pressure was 35.9% and 73.1%, respectively. The calculated precision of the Finapres systolic pressure between 0–5 mm Hg was 1.6% and between 0–10 mm Hg 36.4%. The comparable values for Finapres diastolic BP for accuracy were 63.5% and 92.8% and for precision 23.1% and 79.2%. The Finapres device can provide an accurate estimate of diastolic and mean arterial pressure compared with the intra-arterial record; the apparent inaccuracy of the Finapres systolic pressure may have a physiological explanation. When the Finapres device is used in experimental or in clinical situations, then calibration against a reliable reference arterial pressure is desirable to obviate the possibility of an ‘offset’ error.

Time and frequency domain assessment of heart rate variability: A theoretical and clinical appreciation

Non-invasive techniques for assessing heart rate variability can be used either diagnostically, as in identification of autonomic neuropathy associated with diabetes mellitus or tissue rejection following cardiac transplantation, or as a prognostic indicator in coronary artery disease. The methodology is based upon calculation of successive R—R intervals from an electrocardiogram, which can then be plotted as a frequency histogram (time domain analysis), undergo power spectral analysis to yield information in the frequency domain or be applied to chaos theory. In this review, several parameters are discussed which can be derived to quantify heart rate variability in the time and frequency domains; the latter providing information on autonomic balance. In the frequency domain up to three peaks may be observed, with the peak below 0.15 Hz being mediated by sympathetic and parasympathetic activity and peaks above 0.15 Hz being of vagal origin. The effects of different physiological and pathophysiological conditions on various indices of heart rate variability, and the use of heart rate variability analysis as a pharmacological method to assess the impact of drug therapy on sympathovagal balance are discussed.

Reliability of blood pressure determination with the Finapres with altered physiological states or pharmacodynamic conditions

The blood pressure waveform is modified on distal propagation by phenomena such as dispersion, reflection and the state of the arterial compliance. The consequent effects are amplification and narrowing of the wave, with an increased systolic, reduced diastolic and essentially unaltered mean blood pressure. The Finapres measures the peripheral pressure using the volume clamp principle; it has not been validated under altered physiological conditions and during pharmacodynamic interventions. We studied simultaneous Finapres and brachial blood pressures (using a conventional oscillometric sphygmomanometer—Vitalmap) in ten normal volunteers at rest, and during dynamic exercise and a cold pressor test. The effects of pharmacodynamic intervention were examined following beta-adrenoceptor blockade with propranolol (160 mg) or beta-adrenoceptor modulation with the beta-adrenoceptor partial agonist celiprolol (400 mg). The Finapres systolic pressure was significantly higher than the brachial value during all three test states. The difference between the systolic pressures measured by the two devices was shown to increase significantly during the cold pressor test, but not during dynamic (supine bicycle) exercise. The Finapres diastolic pressure was significantly higher than the Vitalmap value during exercise and the cold pressor test. The differences between the two methods increased significantly over time. Beta-adrenergic blockade with propranolol or modulation with celiprolol had no significant interaction with the pressure differences between the Finapres and Vitalmap techniques. The results would support the view that the Finapres can provide blood pressure information which is robust under most circumstances. Although this pharmacodynamic intervention did not alter the relationship between the peripheral and central blood pressure, it is important to note that this dynamic relationship is sensitive to circulatory loading conditions and wave transmission characteristics; it is possible that the Finapres could be less reliable in clinical settings where potent vasoactive agents were being administered.

Central hemodynamic effects of diuretic therapy in chronic heart failure

SummaryIn chronic heart failure diuretic drugs improve central hemodynamic variables and cardiac pumping secondary to altered plasma and extracellular volumes; humoral markers of these changes include increased plasma renin and aldosterone levels. The latter increases are maximal over the first week but decline with chronic therapy. The plasma alpha-ANP levels show a reciprocal effect; these data are compatible with a rapid contraction of the plasma volume which is sustained during chronic therapy.The acute hemodynamic actions of diuretic agents reflect both immediate and direct vascular actions and also effects secondary to diuresis (volume redistribution). At rest substantial reductions in pulmonary “wedge” pressure (−29%), with a consequent fall in cardiac output (−10%), are described. Total systemic vascular resistance initially increases but “reverse autoregulation” over subsequent weeks returns this elevation gradually towards control values. Tolerance to these initial hemodynamic effects does not occur with maintained therapy; moreover, echocardiographic markers of contractility and exercise capacity may increase. The early venodilator effects of diuretic drugs can be attributed to prostaglandin release and the initial pressor actions to activation of the renin angiotensin system; these vascular actions may have limited relevance to long-term beneficial effects on hemodynamics. Direct pulmonary vasodilation and improved pulmonary compliance remain an interesting finding. Although most patients are both symptomatically and hemodynamically improved at rest, the actions during exercise are more varied. Some individuals with severely impaired left ventricular function show little hemodynamic improvement, whereas those with milder dysfunction usually benefit; in the main this is probably related to the latter being on a steeper cardiac function curve. The impact of diuretic therapy on the underlying disease process is unclear; however, there is little convincing evidence of remodelling or improvement in intrinsic performance (as distinct from that induced by altered loading conditions).

Evaluation of non-invasive blood pressure measurement by the Finapres method at rest and during dynamic exercise in subjects with cardiovascular insufficiency.

The accuracy and precision of the Finapres in recording rest and exercise blood pressure compared with the intra-arterial (aortic and brachial) and random-zero sphygmomanometer methods was assessed in 84 ischaemic patients in three different studies. Firstly, comparison at rest with the aortic intraarterial pressure in 50 ischaemic patients demonstrated that the Finapres systolic (136.5 ± 21.1 vs. 129.3 ± 19.0 mmHg;p < 0.001) and mean (92.4 ± 13.4 vs. 90.7 ± 11.4 mmHg;p < 0.001) arterial pressures were higher and diastolic pressures lower (70.4 ± 11.5 vs. 71.5 ± 9.8 mmHg;p < 0.001). The reproducibility of the Finapres and invasive method was similar for systolic (4.6% vs. 4.0%), diastolic (2.8% vs. 2.7%) and mean (3.3% vs. 3.0%) blood pressures. Second, in seven subjects studied twice at rest and during 4 min supine bicycle exercise, the exercise increase in blood pressure was greater on the Finapres compared with the brachial intra-arterial pressure (systolic +10.2 ± 6.3 vs. +3.6 ± 9.8 mmHg; diastolic +9.6 ± 11.1 vs. +0.2 ± 2.1 mmHg;p = 0.02 for each); however, at steady-state the peak/trough differences in pressure between the methods were similar. Thirdly, compared under rest conditions, to random zero sphygmomanometer (RZO), the Finapres systolic pressure was higher (6.8 ± 3.5 mmHg) and diastolic pressure lower (−6.0 ± 1.9 mmHg). During upright bicycle exercise, the difference between the Finapres and RZO in systolic blood pressure increased at each level of exercise (+14.3 ± 4.2, +17.9 ± 4.0 and +22.2 ± 4.1 mmHg respectively at each exercise stage:p < 0.01). For RZO, diastolic blood pressure fell as exercise workload increased whereas Finapres diastolic blood pressure increased on exercise (3.1 ± 2.6, 7.0 ± 2.1 and 8.1 ± 2.0 mmHg respectively:p < 0.01). Thus there were systematic differences between the values recorded by the Finapres and proximal blood pressure methods and limited agreement in the rest to exercise increments related to light exercise. Calibration of the Finapres values in terms of the other methods is limited by the variable relationship to these related changes in arterial distensibility.

Early vascular abnormalities and de novo nitrate tolerance in diabetes mellitus.

Objective: The haemodynamic consequence of altered mechanical wall properties in diabetes can impair the compliance characteristics or pulsatile function of arteries before changes in calibre or peripheral resistance become evident. We studied the sensitivity of pulsatile and steady‐state haemodynamic variables in identifying vascular abnormalities and assessing arterial responsiveness to glyceryl trinitrate (GTN) in patients with diabetes, free from clinical complications of the disease.

Actions of the novel vasodilator, flosequinan, in isolated ventricular cardiomyocytes

Summary Although the potent vasodilating effect of flosequinan is well characterised, the positive inotropic action reported is more varied and less well understood. We examined the contractile and electrophysiologic effects of flosequinan and its metabolite. BTS 53554, in cardiomyocytes from either adult male Sprague-Dawley rats (200–250 g) or New-Zealand White rabbits (2–2.5 kg) and compared the effects with those of sulmazole and enoximone [selective phosphodiesterase (PDE) III inhibitors], Ro 20–1724 and rolipram (selective PDE IV inhibitors) and 3-isobutyl-l-methylxanthine (IBMX, nonselective PDE inhibitor). Flosequinan and BTS 53554 had positive contractile effects (p < 0.05) in both rat and rabbit ventricular cardiomyocytes only at the maximum concentration (10-3 M). Differences were noted between species, however. Flosequinan 10-3 M had a greater contractile effect than BTS 53554 (10-3 M) in rabbit cardiomyocytes, but not in rat cardiomyocytes. We studied the interaction of flosequinan or the metabolite with other PDE inhibitors in rat cardiomyocytes. Contractile amplitudes were not significantly different with equimolar concentrations (3 × 10 4 M) of Ro 20–1724, flosequinan, or BTS 53554 alone (15 ± 6. 18 ± 4. and 32 ± 10%, respectively, greater than the mean basal dL value of 7.38 ± 0.12%, mean ± SE error). However, the combinations of Ro 20–1724 with flosequinan and Ro 20–1724 with BTS 53554 produced synergistic responses: 71 ± 10 and 72 ± 14%, respectively, greater than the mean basal dL value (p < 0.05). In contrast, the combinations of either flosequinan or BTS 53554 with IBMX or sulmazole produced no further increase in contractile amplitude. Neither flosequinan nor BTS 53554 produced any detectable increase in cyclic AMP, whereas significant increases were noted with Ro 20–1724, IBMX, and sulmazole (p < 0.05) in rat cardiomyocytes. Flosequinan increased beating frequency in rat isolated right auricles concentration dependently and was significant over the concentration range of 10-5-3 × 10-4 M; flosequinan 3 × 10 4 M maximally increased the mean frequency of beating by 35% of the predrug value (255 ± 15 beats/min). Flosequinan had no effect on resting membrane potential, amplitude, or maximum upstroke velocity in rat isolated left ventricular (LV) papillary muscle, but at the maximum concentration (10 3 M), flosequinan decreased action potential duration (APD) at 10, 50, and 75% of repolarization (p < 0.05). BTS 53554 produced no changes in AP characteristics over the concentration range of 10 5-10-3 M. The positive contractile and electrophysiologic effects of flosequinan and its major metabolite. BTS 53554, result from selective inhibition of the PDE III isoenzyme. However, these effects were observed only at increased concentrations and probably have no clinical value. Flosequinan had a more pronounced effect on chronotropy (10-5-3 × 10 4 M) than on contractile function, which was influenced significantly only at an increased concentration (10-3 M). Potentiation of the response to rolipram, in terms of APD prolongation, may be caused by a novel mechanism of action such as enhanced intracellular release of Ca2+ by flosequinan.

Heart-rate variability effects of β-adrenoceptor agonists (xamoterol, prenalterol, and salbutamol) assessed nonlinearly with scatterplots and sequence methods

Full antagonists of the cardiac beta-adrenoceptor improve heart-rate variability (HRV) in humans; however, partial agonism at the beta2-adrenoceptor has been suggested to decrease HRV. We therefore studied the HRV effects of some partial agonists of the beta1- and beta2-adrenoceptors in normal volunteers. Under double-blind and randomised conditions (Latin square design), eight healthy volunteers received placebo; xamoterol, 200 mg (beta1-adrenoceptor partial agonist); prenalterol, 50 mg (beta1- and beta2-adrenoceptor partial agonist); salbutamol, 8 mg (beta2-adrenoceptor partial agonist); ICI 118,551, 25 mg (selective beta2-adrenoceptor antagonist); and combinations of each partial agonist with ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22:30 h with HRV assessed from the overnight sleeping heart rates. HRV was determined by using standard time-domain summary statistics and two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence analysis. On placebo, the sleeping heart rate decreased significantly, between 2 and 8 h after dosing. The heart rate with ICI 118,551 was unaltered. Xamoterol, prenalterol, and salbutamol increased the sleeping heart rate. ICI 118,551 blocked the heart-rate effects of salbutamol, attenuated those of prenalterol, but did not influence the xamoterol heart rate. The scatterplot (Poincaré) area was reduced by beta1-adrenoceptor (xamoterol), beta2-adrenoceptor (salbutamol), and combined beta1- and beta2-adrenoceptor (prenalterol) agonism. A reduction in scatterplot length followed salbutamol, prenalterol alone, and prenalterol in combination with ICI 118,551. The geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At higher heart rates (i.e., 25 and 50% of RR scatterplot length), dispersion was decreased after xamoterol, prenalterol, and prenalterol/ICI 118,551. Cardiac sequence analysis (differences between three adjacent beats; deltaRR vs. deltaRRn+1) assessed the short-term patterns of cardiac acceleration and deceleration; four patterns were identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). Cardiac acceleration or deceleration episodes (i.e., number of times deltaRR and deltaRRn+1 were altered in the same direction) were increased after salbutamol and prenalterol. In conclusion, partial agonism at either the cardiac beta1-adrenoceptor (xamoterol), beta2-adrenoceptor (salbutamol), and beta1- plus beta2-adrenoceptors (prenalterol) altered the autonomic balance toward sympathetic dominance in healthy volunteers; blockade of the beta2-adrenoceptor with the highly selective beta2-antagonist ICI 118,551 prevented the effects of salbutamol on HRV, attenuated the HRV effects of prenalterol, but had no effect on the actions of xamoterol. Agonism at both the beta1- and beta2-adrenoceptor reduced HRV in healthy subjects; the implications for the preventive use of the beta-adrenoceptor compounds in cardiovascular disease warrant further investigation.

Sources of inaccuracy in the use of the Hawksley random-zero sphygmomanometer.

Objective To identify possible causes of inaccuracy in the use of the Hawksley random-zero sphygmomanometer and methods that could reduce this. Methods Four Hawksley random-zero sphygmomanometers were compared with a standard sphygmomanometer under static conditions. Two methods (standard and rapid) were used to release pressure from the inflated cuff with pressures recorded by independent blinded observers. The rate at which the hand valve released pressure was analysed. The effects of varying filling times and pressures on the size of the final zero correction were investigated. Results The Hawksley devices all under-recorded pressure compared with that measured by using a standard machine. A rapid means of pressure release approximately halved this error in each case. Pressure release through the hand valve was shown to have a characteristic and prolonged exponential decay. Using low filling times and pressures reduced the observed range of zeros seen, with the production of a correlation between the size of the zero and the inflation pressure used. Conclusion These findings suggest that overestimation of the final zero correction is a common and major source of error in the use of the Hawksley sphygmomanometer. A simple change in the design of the final pressure release would improve the machines reliability in clinical usage. The machines zero mechanism is susceptible to unintentional misuse. Such misuse could occur when the machine is used in accordance with current sphygmomanometry guidelines.

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes.

1 The contractile effects of the novel cardiotonic agent HN‐10200 (2‐[3‐methoxy‐5‐methylsulphinyl‐2‐thienyl]‐1H‐imidazo‐[4,5‐c]‐pyridine hydrochloride), were examined and comparisons made with the responses obtained to a structurally similar compound, sulmazole, and to a number of other compounds which are known to inhibit phosphodiesterase (PDE) isoenzymes with differing selectivities; namely, enoximone (PDE III inhibitor), Ro 20–1724 (PDE IV inhibitor) and 3‐isobutyl‐1‐methylxanthine (non‐selective PDE inhibitor). 2 Contractile function, as measured by mechanical shortening, and biochemical systems involving cyclic AMP were investigated in ventricular cardiomyocytes isolated from adult Sprague‐Dawley rats (200–250 g). 3 HN‐10200 exerted a concentration‐dependent (10−8 m − 10−4 m) positive contractile effect, which was independent of α‐ or β‐adrenoceptor, or histamine receptor stimulation. 4 The efficacies of the contractile responses to the PDE inhibitors were of the order: HN‐10200 > IBMX > sulmazole > enoximone and maximum stimulations, which were obtained at concentrations of 10−4 m, were 54 ± 4%, 41 ± 7%, 38 ± 7% and 26 ± 5% (mean ± s.e.) greater than basal levels, respectively (n = 6); the basal value of contractile amplitude (dL), in the absence of PDE inhibitors was 7.39 ± 0.18% (mean ± s.e.). Ro 20–1724 did not have any effect on contractile activity. 5 Due to low basal levels of cyclic nucleotides in isolated cells, accumulation of cyclic AMP due to the presence of the PDE inhibitors was detected only when the levels of cyclic nucleotide were enhanced with forskolin (10 μm). 6 The PDE inhibitors increased levels of cyclic AMP only at concentrations > 10−4 m. HN‐10200 and sulmazole had similar concentration‐dependent profiles for the accumulation of cyclic AMP; their potencies were lower than that of IBMX (concentrations of forskolin required to increase cyclic AMP by 4 pmol mg−1 protein, in the presence of maximum concentrations of the PDE inhibitors, were 13 ± 3 μm, 14 ± 3 μm and 3 ± 0.6 μm [mean ± s.e.], respectively). 7 These results indicate that a similar mechanism, probably through a weak inhibition of the cyclic AMP‐specific PDE isoenzymes, is responsible for the increase in levels of cyclic AMP by HN‐10200 and sulmazole. However, cyclic AMP is only partially responsible for the positive contractile effect of HN‐10200 and, similarly, sulmazole and IBMX. The lack of apparent increase in levels of cyclic AMP by enoximone, highlights its degree of selectivity for the PDE III isoenzyme, such that the PDE IV isoform is still present in sufficient quantity to degrade cyclic AMP within the cell. On the other hand, the potent action of Ro 20–1724 on accumulation of cyclic AMP, in addition to the lack of effect on contractile function, is in agreement with the selectivity of this compound for the PDE IV isoenzyme and compartmentalization of cyclic AMP in rat isolated ventricular cardiomyocytes.