Evaluation of biomarkers for cardiotoxicity of anthracyclin-based chemotherapy.

INTRODUCTION: The clinical assessment of the myocardial damage caused by anthracyclin (ANT)-therapy is difficult. Therefore a study was performed to evaluate non-invasive markers of anthracyclin-induced cardiac effects, with emphasis on course-to-course variation. METHODS: Eligible for study participation were patients, without known cardiologic abnormalities who did not use cardiotoxic medication (except for ANT-therapy), who had previously completed at least three cycles of anthracyclin-containing chemotherapy (n = 14) and patients who were ANT-naïve and who were scheduled to receive doxorubicin-containing chemotherapy (n = 12). Seven patients in this last group also completed at least three cycles and were available for follow-up assessments; thus a total population of 21 patients (12F/9M) completed at least three courses ANT-chemotherapy. In these patients blood samples and ECG-recordings were taken within 6 months after completion of ANT-therapy. In 12 patients (10F/2M) assessments were also done before, immediately afterwards and at 24 h after each course of ANT. RESULTS AND CONCLUSIONS: In the patients who completed chemotherapy, NT-proBNP was 277% (n = 21; 95% CI: 86-661%, P < 0.001) higher compared to healthy volunteers. During the first course NT-proBNP rose 269% (n = 12; 167-409%, P < 0.0001) at 24 h post-administration. The linear corrected QT (QTcL) directly after the first administration of ANT increased by 9.56 ms (n = 12; 3.85-15.27, P < 0.001) and this prolongation was still present at 24 h, 11.48 ms (n = 12; 5.61-17.34, P < 0.0001). Both NT-proBNP and QTcL returned to baseline before the start of the next course and a similar pattern was observed during each course. NT-proBNP and QTcL may be useful markers for course-to-course evaluation of anthracyclin-induced cardiotoxicity.

Fiducial segment averaging to improve cardiac time interval estimates.

To improve the accuracy of fiducial point estimates, a technique was developed and tested that uses the coherence of relatively small segments within the P-QRS-T complex from beat to beat. The methodology is applied to digitally stored electrocardiogram traces from various sources. It can be applied to single or multiple leads. First, the individual QRS complexes are identified with a matched filter technique. The trigger time points obtained are fine-adjusted by cross-correlating in turn each individual complex with the average of the remainder complexes and then shifting the complex till maximum correlation is achieved. The process is repeated till no improvement can be attained. Then the individual fiducial points are identified and a similar fine-adjustment is made to the individual points with a segment of approximately 60 ms around the fiducial point. This process is performed in turn for P-onset, QRS-onset and offset, peak of T wave and end of T wave. The values of PR-interval, QRS-duration and QT follow from these measurements. The validity of the result can be assessed by visual inspection and by examining the standard deviation of the measurements obtained. From the above intervals, it is generally accepted that QRS-duration is fairly constant over a short recording duration, whereas PR and QT are inherently heart-rate dependent. Often a linear regression of QT onto RR can be calculated with a significant correlation coefficient, indicating a physiological QT/RR relationship in these recordings of relative short duration. It would be impossible to show this last relationship if the individual QT changes had not been preserved by the technique described.

Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: does it exist and does it affect the antihypertensive response?

OBJECTIVE: To investigate whether the compensatory rise in renin and plasma angiotensin I in response to repeated angiotensin converting enzyme (ACE) inhibitor treatment results in a partial escape of ACE inhibition over a 24-h dosing interval. DESIGN: A single-blind placebo-controlled study in two parallel groups of eight hypertensive subjects receiving a once-daily dose of the ACE inhibitor, spirapril, of either 12.5 or 25 mg. Detailed 24-h studies were performed at the end of 2 weeks of placebo, and after the first dose and 2 weeks administration of spirapril. METHODS: Twenty-four-hour ambulatory blood pressure was measured invasively. True' angiotensins I and II were measured by radioimmunoassay after high-performance liquid chromatography separation. RESULTS: Both for the lower and higher doses of spirapril, the time-course of changes of spiraprilat, the active metabolite of spirapril, and ACE activity was similar but the maximal rise in angiotensin I was twofold higher after 2 weeks administration than after the first dose. Angiotensin II after the first dose of spirapril fell rapidly, with lowest values 2 to 4 h after dosing. At the end of dosing interval angiotensin II had returned to values seen under placebo with the 12.5-mg dose, but at the end of the 24-h period it was still suppressed with the 25-mg dose. Compared with these first-dose responses the initial maximal degree of angiotensin II suppression after 2 weeks administration of either dose was similar, but during the subsequent hours the degree of angiotensin II suppression tended to be less with the lower and was significantly less with the higher dose of spirapril. With the lower dose of spirapril responses of 24-h ambulatory blood pressure to the first dose and to 2 weeks of administration were almost superimposable, although blood pressures in the second half of the dosing interval tended to be higher during chronic treatment. With the higher dose the response of nocturnal blood pressure after 2 weeks administration was diminished by 8.8 mmHg systolic and 6.8 mmHg diastolic. CONCLUSIONS: Repeated ACE inhibitor treatment with once-daily spirapril leads to a partial escape of ACE inhibition, as reflected by a shorter duration of angiotensin II suppression. This escape also affects the antihypertensive response in the second half of the dosing interval.

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

OBJECTIVE: To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN: Exploratory study in which active treatment was preceded by placebo. SETTING: Inpatient unit of teaching hospital. PATIENTS: Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS: Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS: With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS: The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.

Comparison of the acute and chronic antihypertensive effect of two once-daily doses of spirapril by invasive twenty-four-hour ambulatory blood pressure monitoring.

Spirapril is a new non-sulphydryl angiotensin converting enzyme (ACE) inhibitor which is eliminated mainly through the liver. In a placebo-controlled study the acute and chronic (2 weeks) antihypertensive effects of two doses of spirapril (12.5 and 25 mg) were assessed by invasive 24-h ambulatory blood pressure monitoring in two groups of eight hypertensive subjects. After the first doses of 12.5 and 25 mg, blood pressure rapidly decreased, with a nadir after 4-6 h. At this time, mean arterial pressure was decreased by 24 +/- 2% with the 12.5 and 19 +/- 1% with the 25-mg dose. The antihypertensive response was sustained for almost the whole 24-h period with the 25-mg dose, but it was attenuated during the second half of the 24-h blood pressure monitoring with the 12.5-mg dose, leaving a residual antihypertensive effect of 6 +/- 2% 24 h after dosing. Compared with the response to the first dose, the antihypertensive response after 2 weeks of treatment was similar to that following the 12.5-mg dose, but with the 25-mg dose the response during the second half of the 24-h monitoring period, especially during the night, was attenuated. The reason for this attenuated antihypertensive response during prolonged ACE inhibition remains to be established.

Comparison of Finapres non-invasive beat-to-beat finger blood pressure with intrabrachial artery pressure during and after bicycle ergometry.

To evaluate the accuracy of continuous non-invasive blood pressure measurements in the finger during exercise, Finapres blood pressures of six normotensive healthy males were measured during increasing levels of bicycle exercise, using simultaneously registered ipsilateral intrabrachial artery pressures as a reference. At rest, finger systolic blood pressure was higher and finger diastolic and mean arterial pressures were lower than the corresponding intrabrachial pressures in five of the six subjects. During exercise, average finger diastolic and mean arterial pressures did not differ further from these intrabrachial pressures, but finger systolic pressure increased considerably more than the direct systolic pressure, exceeding it by 26 +/- 20 mmHg (mean +/- s.d.) at maximal exercise. This latter finding potentially limits the use of finger blood pressure measurements during exercise.

Support for adrenaline-hypertension hypothesis: 18 hour pressor effect after 6 hours adrenaline infusion.

In a double blind, crossover study 6 h infusions of adrenaline (15 ng/kg/min; 1 ng = 5.458 pmol), noradrenaline (30 ng/kg/min; 1 ng = 5.911 pmol), and a 5% dextrose solution (5.4 ml/h), were given to ten healthy volunteers in random order 2 weeks apart. By means of intra-arterial ambulatory monitoring the haemodynamic effects were followed for 18 h after the infusions were stopped. Adrenaline, but not noradrenaline, caused a delayed and protracted pressor effect. Over the total postinfusion period systolic and diastolic arterial pressure were 6 (SEM 2)% and 7 (2)%, respectively, higher than after dextrose infusion (ANOVA, p less than 0.001). Thus, "stress" levels of adrenaline (230 pg/ml) for 6 h cause a delayed and protracted pressor effect. These findings are strong support for the adrenaline-hypertension hypothesis in man.

Systemic and renal vasodilation after beta-adrenoceptor blockade with pindolol: a hemodynamic study on the onset and maintenance of its antihypertensive effect.

Pindolol, a beta blocker with considerable partial agonist activity (PAA), was studied in 10 hypertensive subjects. The maximal fall in mean arterial pressure (MAP) was seen 3 to 4 hours after oral dosing with 10 mg of pindolol (-15 +/- 3%, mean +/- SEM). This was caused by a reduction in total peripheral resistance (TPR), which amounted to 25 +/- 4% after 24 hours. Cardiac output increased by 16 +/- 5%. Cardiac filling pressures and pulmonary artery pressure did not change. Increasing the dose of pindolol, from 5 mg twice a day to 15 mg twice a day over a 3-week period, caused no further change in MAP. After 3 weeks, the fall in MAP (-11 +/- 2%) was maintained by reduced TPR (-26 +/- 6%), whereas cardiac output and stroke volume were increased by 16 +/- 6% and 26 +/- 6%. Renal blood flow and glomerular filtration rate did not change. Beta blockers devoid of PAA lower cardiac output, whereas the elevated TPR in hypertension is unchanged. The hemodynamic profile of pindolol essentially differs from that of beta blockers devoid of PAA.

Chronic effect of ketanserin in mild to moderate essential hypertension.

Ketanserin, an antagonist highly selective for 5-hydroxytryptamine (serotonin) type 2 (S2) receptors, was given as monotherapy in a dose of 40 mg b.i.d. to 24 subjects with mild to moderate essential hypertension. Its effects were evaluated in a placebo-controlled double-blind crossover study. The effect on blood pressure in 18 subjects was monitored by 24-hour ambulatory intra-arterial measurements. Systolic and diastolic intra-arterial pressures were significantly lowered by ketanserin both during the day and at night, whereas heart rate was unchanged. Cuff pressure readings (triplicate measurements) with the London School of Hygiene sphygmomanometer and an automatic device (12 measurements in 1 hour) in the outpatient clinic also showed a significant effect on both supine and standing pressures. No postural hypotension was noted. Ketanserin had no effect on endogenous creatinine clearance, serum cholesterol levels, and the plasma levels of norepinephrine, renin, and aldosterone. The only side effect that was significantly more common with ketanserin than with placebo treatment was an increase in body weight. Ketanserin may have a place in the treatment of mild to moderate essential hypertension.

Mechanism of generation of body surface electrocardiographic P-waves in normal, middle, and lower sinus rhythms.

We used comprehensive electrophysiological/anatomical digital computer models of atrial excitation and the human torso to study the mechanisms of generation of body surface P-waves in normal sinus rhythm, and in middle and lower sinus rhythm. Simulated atrial surface isochrone maps for normal sinus rhythm support the validity of the atrial excitation model. The results suggest that the presence of specialized internodal tracts containing fast-conducting fibers is not essential to account for propagation of excitation in apparent preferential directions from the sinoatrial (SA) node to the atrioventricular node. However, in the absence of fast conducting fibers, a slowly conducting segment in the intercaval region is necessary to achieve proper excitation of the interatrial septum. P-wave notches occur in the absence of specialized fast conducting atrial tracts and anisotropies due to fiber orientation. These notches are due to the atrial geometry and the separate contributions of the right atrium, left atrium, and interatrial septum to the P-waves, and become more pronounced as the pacemaker site shifts downward in the SA node. Thus, slight changes in the origin of excitation, which result in subtle changes in the atrial excitation isochrones, produce significant and complex changes in the simulated body surface P-waves.

Model studies on activation of the heart.

Multiple dipole models of activation of the heart, in combination with a model of the thorax as an electrical conductor relate the action of individual cells to features of the electrocardiogram. The models can be used to develop diagnostic electrocardiographic criteria for ventricular hypertrophy, myocardial infarction or conduction disorders. Criteria derived with the use of Holt, Barnard and Lynn's model proved to be superior to well-established empirical rules. Their approach restricts position, direction and polarity of the current dipole vectors in the model. In the Selvester model, and later in the Ritsema van Eck model, in addition to these restrictions time-constraints are imposed on the dipole activity. In a validation study of the Ritsema van Eck model activation of a beating dog heart is compared in detail with simulated activation in a computer replica of the same heart. Myocardial spread of activation is found to be stimulated correctly. Simulated spread of activation along the Purkinje fiber network however, differs considerably from reality. In apical regions excitation spreads in reality much faster than in the model, in basal regions much slower. The model can be improved by slowing endocardial excitation from apex to base with the time-course of activation. Further improvement is obtained by the use of a more detailed pattern of endocardial excitation, based on studies of endocardial excitation in opened ventricles. The model can predict the time-course of activation with an accuracy of 5% of total ventricular activation time.