Bradykinin receptor blockade restores the baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal failure rats.

AIM: This study investigated the effect of renal bradykinin B1 and B2 receptor blockade on the high- and low-pressure baroreceptor reflex regulation of renal sympathetic nerve activity (RSNA) in rats with cisplatin-induced renal failure. METHODS: Cisplatin (5 mg/kg) or saline was given intraperitoneally 4 days prior to study. Following chloralose/urethane anaesthesia, rats were prepared for measurement of mean arterial pressure (MAP), heart rate and RSNA and received intrarenal infusions of either Lys-[des-Arg9 , Leu8 ]-bradykinin (LBK), a bradykinin B1 receptor blocker, or bradyzide (BZ), a bradykinin B2 receptor blocker. RSNA baroreflex gain curves and renal sympatho-inhibitory responses to volume expansion (VE) were obtained. RESULTS: In the control and renal failure groups, basal MAP (89 ± 3 vs. 80 ± 8 mmHg) and RSNA (2.0 ± 0.3 vs. 1.7 ± 0.6 µV.s) were similar but HR was lower in the latter group (331 ± 8 vs. 396 ± 9 beats/min). The baroreflex gain for RSNA in the renal failure rats was 39% (P < 0.05) lower than the control but was restored to normal values following intrarenal infusion of BZ, but not LBK. VE had no effect on MAP or HR but reduced RSNA by some 40% (P < 0.05) in control but not renal failure rats. Intrarenal LBK infusion in the renal failure rats normalized the VE induced renal sympatho-inhibition whereas BZ only partially restored the response. CONCLUSION: These findings suggest that pro-inflammatory bradykinin acting at different receptors within the kidney generates afferent neural signals which impact differentially within the central nervous system on high- and low-pressure regulation of RSNA.

Human ventricular action potential duration during short and long cycles. Rapid modulation by ischemia.

BACKGROUND: Mechanisms underlying the initiation of ventricular arrhythmias in ischemia by a premature beat or after a pause remain unclear. The kinetics of electrical restitution, which is the modulation of action potential duration (APD) by an abrupt alteration in cycle length, may be important. METHODS AND RESULTS: We recorded one or two simultaneous monophasic action potentials (MAPs) from the right ventricular septum during balloon occlusion of the left anterior descending coronary artery (LAD) (14 patients), which is expected to induce ischemia at the recording site, and during occlusion of the right coronary artery (RCA) (7 patients), which is not expected to induce ischemia at the recording area. The latter acted as a control. A test pulse sequence was incorporated whereby during steady-state pacing, test beats of altered cycle length were interpose. During LAD occlusion, APD for basic beats shortened from 260 +/- 4 to 236 +/- 4 ms (P < .0001), whereas the control group (RCA occlusion) showed no significant change (251 +/- 7 to 249 +/- 9 ms; P = NS). LAD occlusion resulted in flattening of the slope relating APD of test beats to diastolic interval (P = .001), whereas in the control group (RCA occlusion) the slope remained unchanged. Similar results were obtained during a second occlusion. CONCLUSIONS: LAD occlusion in patients during balloon angioplasty shortened MAP duration of basic beats and minimized, abolished, or reversed the normal APD/diastolic-interval relation of test beats of altered cycle length at sites served by the occluded vessel. The results suggest that ischemia flattens the electrical restitution curve in the human endocardium. These findings may have important implications in arrhythmogenesis.

Aortic root replacement and extraanatomic bypass for interrupted aortic arch in an adult.

We describe an unusual case of interrupted aortic arch, aneurysmal ascending aorta, and aortic regurgitation in a 24-year-old man. He presented with general malaise, weakness of his legs, and hypertension. A single-stage operation was performed in which the aortic root was replaced with concomitant extraanatomic bypass of the interrupted segment of the aortic arch. He made a full recovery and has returned to work.

Combined rest thallium-201/stress technetium-99m-tetrofosmin SPECT: feasibility and diagnostic accuracy of a 90-minute protocol.

UNLABELLED: Technetium-99m tetrofosmin is a recently developed compound that clears from background organs rapidly. Tetrofosmin has a good correlation with 201Tl. This study assesses the feasibility and diagnostic accuracy of a combined protocol involving rest 201Tl SPECT and stress imaging with 99mTc-tetrofosmin. METHODS: Twenty-five patients (23 men, 2 women; aged 36-73 yr) with known coronary artery disease underwent the combined protocol. Twenty minutes after the resting injection of 201Tl, resting SPECT data were acquired using low-energy, high-resolution collimators. A stress test using adenosine infusion combined with low-level dynamic exercise was performed. The stress data were collected 20 min later. The reconstructed vertical long-axis, horizontal long-axis and short-axis slices were analyzed qualitatively. Analysis was carried out using nine segments of the left ventricle. The segments were reported either as fixed or reversible. The results were compared to coronary angiography results. RESULTS: The sensitivity and specificity for the detection of diseased coronary vessels were 85% and 70% for the left anterior descending territory, respectively, 78% and 71% for the right coronary artery, and 69% and 70% for the left circumflex. Overall, the sensitivity was 80% and the specificity 70%. CONCLUSION: Combined rest 201Tl/stress 99mTc-tetrofosmin SPECT provides a protocol of short duration which displays similar diagnostic accuracy to a protocol using tetrofosmin as a single agent.

Repolarization gradients derived by subtraction of monophasic action potential recordings in the human heart. Studies incorporating altered mechanical loading and ischemia.

Information derived from the analysis of the electrocardiographic waveform remains one of the most valuable diagnostic aids in modern cardiology. Paradoxically, although changes in the ST-T segment probably have the widest clinical application, it is the analysis of this repolarization phase that has been surrounded by the greatest difficulties in interpretation.

Direct effect of dobutamine on action potential duration in ischemic compared with normal areas in the human ventricle.

BACKGROUND AND OBJECTIVES: The arrhythmogenic effect of beta-adrenoceptor stimulation is complex and may differ in ischemic and normal myocardium. In this study we examined the differential effect of beta-adrenergic stimulation on ventricular action potential duration and, hence, dispersion of repolarization in potentially ischemic versus nonischemic human ventricular myocardium. METHODS: Simultaneous biventricular monophasic action potentials were recorded in 14 patients (28 recording sites) during infusion of dobutamine in incremental doses (low dose 5 micrograms/kg per min, high dose 10 to 15 micrograms/kg per min) during atrial pacing. Perfusion at the action potential recording site was assessed by incorporating myocardial perfusion scintigraphy with injection of technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile during the recording at peak doses of dobutamine. Action potential duration during dobutamine infusion was compared with that during atrial pacing to identical rates in the absence of dobutamine. RESULTS: In 21 normal zone recordings, dobutamine produced a variable effect over that produced by atrial pacing to identical heart rates, either lengthening or shortening the action potential duration. The mean (+/- SEM) value for the additional effect of dobutamine was 0.9 +/- 2.5 ms with low doses and -4 +/- 2.6 ms with high doses (p = NS). In seven recordings from potentially ischemic zones, low dose dobutamine had a similar effect (mean change -3.4 +/- 6.5 ms; p = NS vs. normal zone values). However, the high dose dobutamine invariably shortened the action potential duration by a mean of -22.9 +/- 2.9 ms. (p less than 0.05 vs. low dose in ischemic areas, p less than 0.01 vs. normal zone recordings). Pacing alone or the addition of dobutamine had no significant effect on the normal dispersion of action potential duration between two nonischemic recording sites. In recordings in a normal and an abnormally perfused site, high dose dobutamine significantly altered the dispersion of action potential duration. CONCLUSIONS: These results suggest a different effect of beta adrenergic stimulation in potentially ischemic compared with nonischemic human ventricular myocardium. The abnormal dispersion of repolarization thus created may well be important in beta-receptor-mediated arrhythmogenesis during myocardial ischemia.

Vasodilator myocardial perfusion imaging: demonstration of local electrophysiological changes of ischaemia.

OBJECTIVE: To examine the incidence and severity of myocardial ischaemia provoked in the course of perfusion scintigraphy by coronary vasodilators using endocardial recordings of steady state monophasic action potentials as an independent marker of early localised myocardial ischaemia. PATIENTS: 31 men undergoing routine cardiac catheterisation for investigation of chest pain were studied. SETTING: A tertiary cardiac referral centre. DESIGN: Single site monophasic action potentials were recorded from the left or right ventricle or both (50 recording sites) during intravenous infusion of dipyridamole (0.015 mg/kg/min) for four minutes. Heart rate was held constant with atrial pacing at 20% above the patient's resting rate. Technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile (MIBI) was administered four minutes after dipyridamole, and single photon emission tomographic imaging was performed an hour later. Rest images were obtained the next day (two day, two dose protocol). Recordings were divided into three groups based on the scintigraphic perfusion characteristics and coronary anatomical data for the action potential recording site: group 1--recordings from areas with a normal perfusion pattern (n = 30), group 2--recordings from areas with a perfusion defect and subtended by significantly narrowed coronary arteries without obvious angiographic collateral supply (n = 10), and group 3--recordings from areas with a perfusion defect and subtended by occluded arteries with angiographically evident collaterals from adjacent vessels (n = 10). RESULTS: There were changes in the duration of the monophasic action potential indicative of ischaemia--that is, shortening of duration of steady state action potential--in 18 of the 20 recordings from areas of abnormal perfusion. Peak changes were apparent eight minutes from the start of the dipyridamole infusion. Mean (SEM) values for duration of the action potential between control and peak effect at eight minutes were 276.5 (5.3) ms v 276.6 (5.4) for group 1 (NS), 289.6 (4.7) ms v 278.4 (4.9) ms for group 2 (p less than 0.001), and 269.6 (5.7) ms v 242.0 (4.4) for group 3 (p less than 0.0001). These changes were significantly different between the three groups (p less than 0.01). ST segment changes on the surface electrocardiogram were seen in only eight patients, all with areas of viable myocardium supplied by collateral vessels. CONCLUSIONS: These data provide strong evidence for the presence of myocardial ischaemia in regions of reversible perfusion defects induced by dipyridamole. This study also shows that such ischaemia is more intense and more likely to be seen when myocardial viability is dependent on collateral circulation.

The interrelation between the monophasic action potential duration, cycle length and ischaemia in the human left ventricle.

Steady state monophasic action potentials were recorded from a single site in the left ventricular endocardium during incremental atrial pacing to the point of angina in 25 patients. Ischaemic areas of the left ventricle were documented using a perfusion marker (99mTc-MIBI) simultaneously with the action potential recording procedure. Recordings were obtained from an ischaemic area in 13 patients and from a non-ischaemic area in 12. A linear correlation between action potential duration and cycle length changes was demonstrated for both ischaemic and non-ischaemic zone recordings between cycle length changes of 750 and 428 ms. Ischaemia induced a shortening of the action potential duration significantly greater than that produced by cycle length changes (P less than 0.0001). Mean action potential duration shortening corrected for 100 ms change in cycle length for ischaemic zone recordings was 31.4 +/- 4.2 (SD) compared to 23.3 +/- 3.1 ms for non-ischaemic zone recordings. A range of values of action potential duration shortening in unit time was analysed for sensitivity and specificity for the detection of ischaemia. A value of 26.5 ms per 100 ms change in cycle length provided the optimum compromise with 88% sensitivity and specificity. Our data provide a means of employing the monophasic action potential duration to quantify early localized ischaemia in the presence of an alteration in cycle length.

Monophasic action potential recordings during acute changes in ventricular loading induced by the Valsalva manoeuvre.

OBJECTIVE: The strong association between ventricular arrhythmia and ventricular dysfunction is unexplained. This study was designed to investigate a mechanism by which a change in ventricular loading could alter the time course of repolarisation and hence refractoriness. A possible mechanism may be a direct effect of an altered pattern of contraction on ventricular repolarisation and hence refractoriness. This relation has been termed contraction-excitation feedback or mechano-electric feedback. METHODS: Monophasic action potentials were recorded from the left ventricular endocardium as a measure of the time course of local repolarisation. The Valsalva manoeuvre was used to change ventricular loading by increasing the intrathoracic pressure and impeding venous return, and hence reducing ventricular pressure and volume (ventricular unloading). PATIENTS: 23 patients undergoing routine cardiac catheterisation procedures: seven with no angiographic evidence of abnormal wall motion or history of myocardial infarction (normal), five with a history of myocardial infarction but with normal wall motion, and 10 with angiographic evidence of abnormal wall motion--with or without previous infarction. One patient was a transplant recipient and was analysed separately. SETTING: Tertiary referral centre for cardiology. RESULTS: In patients with normal ventricles during the unloading phase of the Valsalva manoeuvre (mean (SD)) monophasic action potential duration shortened from 311 (47) ms to 295 (47) ms (p less than 0.001). After release of the forced expiration as venous return was restored the monophasic action potential duration lengthened from 285 (44) ms to 304 (44) ms (p less than 0.0001). In the group with evidence of abnormal wall motion the direction of change of action potential duration during the strain phase was normal in 7/21 observations, abnormal in 6/21, and showed no clear change in 8/21. During the release phase 11/20 observations were normal, five abnormal, and four showed no clear change. In those with myocardial infarction four out of five patients had changes that resembled those with normal ventricles but the changes were less pronounced. There were no differences in any of the three groups between the changes in monophasic action potential duration in patients taking beta blockers and those who were not. The changes in monophasic action potential duration in the transplanted heart resembled those in the group with normal ventricles. Inflections on the repolarisation phase of the monophasic action potential consistent with early afterdepolarisations were seen in three of the patients with abnormal wall motion and in none of those with normal wall motion. CONCLUSIONS: These results are further evidence that changes in ventricular loading influence repolarisation. When wall motion was abnormal the effects on regional endocardial repolarisation were often opposite in direction to those when it was normal. Thus regional differences in wall motion could generate local electrophysiological inhomogeneity which may be relevant to the association of arrhythmia with impaired left ventricular function.

Endocardial monophasic action potential recordings for the detection of myocardial ischemia in man: a study using atrial pacing stress and myocardial perfusion scintigraphy.

In a study designed to appraise the use of monophasic action potentials (MAPs) to detect myocardial ischemia in endocardial recordings, changes in steady-state MAP duration were compared in recordings between normal and ischemic areas of myocardium identified by the use of a radionuclide tracer simultaneously with the MAP recording procedure. Single-site recordings were made from the left or right ventricular endocardium or both in 26 patients (32 recording sites) during atrial pacing up to angina threshold. Pacing was maintained for 2 minutes at each increment in heart rate and MAPs were recorded at the end of each 2-minute period. Perfusion defects produced by atrial pacing stress were detected using technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile injected at peak pacing stress. In 18 recordings from normally perfused areas of endocardium, MAP duration at 70% and 90% repolarization shortened by a mean (+/- SD) of 20.9 (3.7) msec and 22.0 (4.8 msec, respectively, for every 100 msec change in cycle length. This is in keeping with the effect of cycle length changes on the action potential duration. The extent of shortening was significantly greater (p less than 0.01) for 14 recordings from ischemic areas, being 32.0 (8.6) and 33.8 (9.7) msec, respectively, indicating the additional effect of localized myocardial ischemia. These results validate the applicability of the endocardially recorded MAPs for the detection of ischemia. Such methodology may provide a means of assessing therapeutic interventions aimed at the early phase of ischemia.

25 years of cardiology.

I have tried to highlight some of the extraordinary advances in cardiology over the last 25 years. Many conditions, however, such as primary pulmonary hypertension or cardiogenic shock remain as refractory to treatment now as then. There is no room for complacency. In addition the increasing cost of technology and the increasing demand for interventional cardiology are not being met. We are far behind our European colleagues in being able to provide this service.

The epicardial electrogram: a quantitative assessment during balloon angioplasty incorporating monophasic action potential recordings.

An electrogram was recorded from the angioplasty catheter guide wire when coronary blood flow was interrupted in 20 patients undergoing percutaneous transluminal coronary angioplasty. Monophasic action potentials were recorded from the right ventricular septum together with the routine electrocardiogram. The patients were studied during angioplasty for lesions in the left anterior descending (12), circumflex (3), and right coronary arteries (6). ST elevation in the electrogram recorded in the left anterior descending and circumflex systems was usually more obvious than that in the electrocardiogram. Signals obtained from the right coronary artery were of very low amplitude and registered only minimal ST changes. The ST elevation developed in the electrogram during insertion of the catheter before inflation of the balloon in 11 of the 15 patients undergoing angioplasty of the left system. In eight of the patients showing pre-inflation ST elevation the ST shift lessened after successive inflations. Monophasic action potential recordings were obtained during 45 balloon inflations in 19 patients. In those patients undergoing angioplasty for lesions of the circumflex coronary artery the monophasic action potential showed no change during balloon inflation. In patients undergoing angioplasty for the right coronary artery the mean normalised duration at 60 seconds' occlusion was 99.6 (1.5)% of control. Of a total of 25 occlusions in the patients undergoing angioplasty for the left anterior descending coronary artery 19 showed shortening of less than 5%, five showed shortening between 5 and 10%, and one showed a shortening of 16.4% in the monophasic action potential. The QT interval was satisfactorily measured in the electrogram during 36 balloon inflations, and in 24 of these it was also measured in the electrocardiogram. QT changes in the electrogram tended to be the opposite of those in the electrocardiogram. When changes in RR interval were minimal (less than 20 ms) during the balloon inflation 14 of 17 electrograms showed QT prolongation but only one of 12 electrocardiograms showed prolongation. Conversely one of 17 electrograms showed shortening compared with eight of 12 electrocardiograms. There was angiographic evidence of the development of collaterals in six of 15 patients undergoing angioplasty of the left system. ST segment elevation in both the electrogram and electrocardiogram was less pronounced in these patients than in those without evidence of the development of collaterals. ST segment changes recorded from the angioplasty guide wire provide a more sensitive index of ischaemia than the surface 12 lead electrocardiogram, and fall in ST segments on balloon deflation is a prognostic index of a good angiographic result in the left anterior descending and circumflex arteries, but not in the right coronary artery.