Insulin stimulates the L-type Ca2+ current in rat cardiac myocytes.

OBJECTIVE: The aim was to study the L-type calcium current (ICa,L) in cardiac myocytes as a possible target of insulin in the regulation of cardiac function. METHOD: Using the whole-cell configuration of the patch-clamp technique, we investigated the stimulation of ICa,L by insulin in isolated rat ventricular myocytes. RESULTS: The stimulation of ICa,L by insulin was dose-dependent (EC50 = 33 nM) and reversible. Maximum stimulation of ICa,L over basal ICa,L was 86 +/- 11% (n = 25) at 1 microM insulin. Insulin (1 microM) shifted the current-voltage relationship and potential-dependent availability of ICa,L to more negative potentials by about 3.5 and 1.5 mV, respectively. The maximum conductance of ICa,L was increased by 1 microM insulin, from 26 +/- 4 to 39 +/- 5 nS (n = 11). Isoproterenol (100 nM), which stimulated ICa,L by 156 +/- 23% (n = 10) over basal ICa,L, acted faster than insulin. The half-maximum stimulation of ICa,L by isoproterenol and insulin was reached after 44 +/- 5 and 80 +/- 9 s, respectively. Insulin and isoproterenol responses were not additive. Insulin (1 microM) and isoproterenol (100 nM) stimulation of ICa,L was inhibited by Rp-cAMPS (1 mM) to 12 +/- 3 and 32 +/- 4%, respectively. Insulin (1 microM) increased cAMP content in rat cardiomyocytes by about two-fold. Insulin-like growth factor-1 (IGF-1; 5 microM) increased ICa,L by only 5.9 +/- 0.9% (n = 6). CONCLUSIONS: Our data show that insulin stimulates the L-type calcium current in isolated rat ventricular myocytes in a dose-dependent and reversible manner and suggest that this effect is mediated by insulin receptors and the cAMP-dependent protein kinase.

Stimulation of L-type Ca2+ current in human atrial myocytes by insulin.

OBJECTIVE: The L-type calcium current (ICa,L) in isolated human atrial myocytes was investigated as a possible target of insulin in the regulation of cardiac function. METHODS: Atrial myocytes were obtained from patients undergoing cardiac surgery. Using the whole-cell configuration of the patch-clamp technique, we investigated the stimulation of ICa,L by insulin in single human atrial myocytes. RESULTS: We found a dose-dependent stimulation of ICa,L by insulin at concentrations of 100 nM, 1 microM and 10 microM. Maximum stimulation of ICa,L over basal ICa,L was 140 +/- 12% (n = 11) at 10 microM insulin. The maximum conductance of ICa,L was increased by 10 microM insulin from 4.0 +/- 0.3 nS to 8.3 +/- 1.0 nS (n = 6). The stimulation of ICa,L by insulin was dose-dependent and reversible. Isoproterenol (10 nM) that stimulates ICa,L by 271 +/- 48% (n = 10) over basal ICa,L acted faster than insulin. The half-maximum stimulation of ICa,L by isoproterenol and insulin (10 microM) was reached after 31 +/- 2 s and 52 +/- 5 s, respectively. The insulin effect shown was totally reversed by acetylcholine (3 microM) which is known to inhibit adenylyl cyclase activity/cAMP-production via Gi-proteins. Also, the selective insulin receptor tyrosine kinase inhibitor (hydroxy-2-naphthanelyl-methyl)phosphonic acid completely inhibited the insulin induced effect. CONCLUSION: Our data show that insulin stimulates the L-type calcium current in isolated human atrial myocytes in a dose-dependent and reversible manner which appears to involve the insulin receptor tyrosine kinase. Insulin regulation of ICa,L in human atrial myocytes may be an interesting system for the analysis of the metabolic syndrome in man.

Electrophysiological profile of the antiarrhythmic compound asocainol studied on perfused guinea-pig hearts and on isolated cardiac preparations.

The studies deal with electrophysiological effects of asocainol [(+/-)-6,7,8,9-tetrahydro-2,12-dimethoxy-7-methyl-6-phenetyl-5 H-dibenz(d,f)azonine-1-ol] on isolated perfused guinea-pig hearts (Langendorff-preparation), on right ventricular papillary muscles, on Purkinje fibres from the guinea pig, and on isolated sinus nodes from the rabbit. In the perfused heart (n = 5) the lowest effective concentration of asocainol is about 0.2 mumol/l. At a concentration of 2 mumol/l the cardiac electrogram shows in spontaneously beating hearts a mean decrease in frequency of 15%, in electrically driven hearts (150/min at 32 degrees C) prolongation of PQ (+31%), of QRS (+24%) and of QT (+5%). In papillary muscles (32 degrees C; K+e 5.9 mmol/l; stimulation rate 0.5 Hz) asocainol (3-30 mumol/l) exerts the following effects: no change of the resting potential, concentration-dependent reduction of the maximum rate of rise (Vmax) of the action potential (AP) (-16 to -67%) as well as of the AP-amplitude (-4 to -16%), and shortening of the AP-duration at 50% repolarisation (-18 to -43%). The steady-state dependence of Vmax on the resting potential (RP) determined by variation of K+e (5.9-15 mmol/l) is shifted by asocainol to more negative potentials. The percentage deviation from controls of the Vmax-RP relationship is more pronounced at lower membrane potentials. The influence of asocainol on the recovery from inactivation of Vmax shows marked time-dependence. Slow response (Ca2+-mediated) APs elicited by strong stimuli in a K+e-rich solution (K+e 20-24 mmol/l) respond to asocainol (3-10 mumol/l) with a marked reduction in amplitude, Vmax and duration.(ABSTRACT TRUNCATED AT 250 WORDS)

[PROWESS, ENHANCE and ADDRESS: clinical implications for the treatment with drotrecogin alfa (activated)]. / PROWESS, ENHANCE und ADDRESS: klinische konsequenzen für die behandlung mit drotrecogin alfa (aktiviert).

Drotrecogin alfa (activated) (DrotAA) represents a therapeutic advance in the treatment of severe sepsis. In the pivotal PROWESS trial DrotAA had demonstrated a significant decrease in 28-day mortality, most evident in the subgroup of patients at higher risk of death. Thus, DrotAA was licensed throughout Europe for treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The ADDRESS trial was mandated by the FDA to investigate prospectively the treatment effect of DrotAA in patients at low risk of death, e.g. single organ failure. The trial was prematurely stopped due to futility, because no reduction in mortality was observed in this non-indicated patient population. The ENHANCE open-label trial enrolled similar patients to the PROWESS trial and the observed 28-day mortality was consistent with the results seen in the PROWESS trial. Survival rates for patients receiving DrotAA early within 24 h from the first sepsis-induced organ dysfunction were significantly higher than in patients treated later. In this overview we will discuss the results of the ENHANCE and ADDRESS trials in the context of the PROWESS study and clinical implications for the treatment with DrotAA.

Rate adaptive pacing--clinical experience with three different pacing systems.

Physiological stimulation can be achieved by either bifocal or rate responsive pacing. The latter pacemakers adapt the heart rate to physical activity by biological signals. Out of many possible approaches only three pacemaker systems for rate responsive pacing are available: the QT-pacemaker (Tx or Quintech), the respiratory biorate pacemaker, and the activity detecting Activitrax. Our own experiences (8 QT, 6 Biorate, 8 Activitrax pacemakers) and a survey of 95 QT- and 37 Biorate pacemakers from 11 centers are reported. The Biorate pacemaker functions without any problems; its present disadvantage is limited programmability. With the Tx pacemaker failing, frequency adaptation (26%) was found more often in the early series, mostly due to voltage polarization at the tip of the electrode. The Activitrax pacemaker gives satisfactory frequency adaptation, largely depending on the activity of the muscles of the shoulder and pectoral region.

[Clinical experiences with 3 different rate-adaptive pacemaker systems]. / Klinische Erfahrung mit drei verschiedenen frequenzadaptiven Schrittmachersystemen.

Physiological stimulation can be achieved by either bifocal or rate responsive pacing. The latter pacemakers adapt the heart rate to physical activity by biological signals. Of many possible approaches only three pacemaker systems for rate responsive pacing are available: the QT pacemaker (Tx or Quintech), the respiratory Biorate pacemaker and the activity detecting Activitrax. First our own experiences (8 QT, 6 Biorate, 8 Activitrax pacemakers) and a survey of 95 QT- and 37 Biorate pacemakers from 11 centers are reported. The Biorate pacemaker functions without any problems, its present disadvantage is limited programmability. With the Tx pacemaker failing frequency adaptation (26%) was found more often in the early series, mostly due to voltage polarisation at the tip of the electrode. The Activitrax pacemaker gives satisfactory frequency adaptation, largely depending on the activity of the muscles of the shoulder and pectoral region.

[Congenital aneurysm of the membranous interventricular septum]. / Angeborenes Aneurysma des membranösen interventrikulären Septums.

In a 50-year-old patient with complex ventricular arrhythmia (monotopic ventricular extrasystoles in bigeminy and triplet form), coronary angiography with ventriculography revealed an aneurysm of about 2-3 cm diameter that bulged visibly into the right ventricle during the systole. Electrophysiology was able to localise the earliest excitation during the ventricular extrasystoles at the septal border of the aneurysm. Hence, the congenital aneurysm was definitely identified as the source of the arrhythmia. Surgery or drug therapy were not indicated since there was no haemodynamically effective ventricular tachycardia in the patient who was largely free from complaints.

[Radiation-induced pacemaker malfunction]. / Schrittmacherschaden durch Bestrahlung.

As the number of implanted pacemakers and the incidence of malignant tumors increases, the probability of radiation-mediated pacemaker dysfunction increases. Radiation can substantially damage pacemaker electronics. We report here a case, with loss of communication after radiation therapy.

Symptoms, cardiovascular risk profile and spontaneous ECG in paced patients: a five-year follow-up study.

UNLABELLED: Only few data are available about the course of symptoms, cardiac diseases, and spontaneous rhythm in pacemaker patients. Therefore, we followed the course of 308 paced patients (age 72 +/- 11 years) with a mean implantation time of 63 +/- 45 months. RESULTS: The symptom triad of syncope, dizziness, and dyspnea improved remarkably in 93% of patients. Thirty-nine percent suffered from coronary heart disease. The risk factors of hypertension (47%), nicotine (37%), and diabetes mellitus (25%) were found significantly more often than in a normal population with the same age and sex profile. In VVI paced patients with sick sinus syndrome (SSS, n = 67) atrial fibrillation (AF) occurred significantly more often (42%) than in patients with AV block (n = 80, 23%, P less than 0.05). Only one out of 41 DDD paced patients showed AF at follow-up. VVI stimulation seems to favor AF due to retrograde conduction in SSS. Only 3% of patients with SSS developed second- or third-degree AV block. Therefore, atrial pacing is preferable in most patients with SSS.

Electrophysiological interactions between carbachol and class I antiarrhythmic drugs (lidocaine, quinidine)--experimental studies in rabbit atrial myocardium.

UNLABELLED: Cholinergic agents exert no direct effect on the fast Na+ inward current but may influence the binding characteristic of class I antiarrhythmic drugs in atrial myocardium by shortening the action potential (AP) duration or by increasing the resting potential (RP). In order to examine such possible interactions we performed experiments using conventional intracellular microelectrodes on isolated preparations of rabbit atrial myocardium (Ke 2.7 mM, temperature 32 degrees C). At first the influence of the cholinergic agent carbachol (1 mg/l = 6.7 x 10(-6) M) on the RP and AP was examined at different stimulation rates (1.0, 2.5, and 3.3 Hz). Thereafter measurements were repeated under the influence of lidocaine (10 mg/l = 2.2 x 10(-5) M) or quinidine (5 mg/l = 2.2 x 10(-5) M) alone and in combination with carbachol (1 mg/l). RESULTS: (statistically significant differences, p less than 0.05): Carbachol increased the RP by about 10 mV and shortened the AP by about 60%. The maximal upstroke velocity of the AP (Vmax) was not significantly altered at 1.0 and 2.5 Hz, but increased under carbachol at 3.3 Hz. After addition of carbachol to the lidocaine-containing solution, Vmax increased to its control level at all stimulation rates. In experiments with quinidine, Vmax also increased after addition of carbachol but remained significantly below the control values. CONCLUSIONS: Carbachol effects on Vmax are most likely attributable to earlier recovery (caused by the shortening of the AP) and to faster recovery kinetics (due to hyperpolarization). The attenuation of the class I effect of lidocaine by carbachol can thus be considered mainly a consequence of the shortening of the inactivated state which results in a reduced affinity of lidocaine to its receptor and allows earlier dissociation of the drug. Minor binding of the drug due to hyperpolarization may play the major role in interactions between carbachol and quinidine.

Comparative analysis of the action of class I antiarrhythmic drugs (lidocaine, quinidine, and prajmaline) in rabbit atrial and ventricular myocardium.

Effects of three class I antiarrhythmic drugs (quinidine, lidocaine, and prajmaline) on transmembrane resting (RMP) and action potentials (AP) of isolated rabbit atrial and ventricular myocardium were studied at different stimulation rates. The frequency-dependent depression of the maximal upstroke velocity (Vmax) of the AP (sodium channel block) was analyzed according to the "guarded receptor" hypothesis. The resting block (Vmax depression after a resting period) induced by prajmaline (10(-6) M), quinidine (2.2 x 10(-5) M), and lidocaine (4.3 x 10(-5) M) was more expressed in the atrium (44, 28, and 19%, respectively) than in the ventricle (32, 9, and 0%, respectively). There were also significant (p less than 0.05) atrioventricular differences in the frequency-dependent extra block (Vmax reduction on stimulation at 3.3 Hz) for quinidine (39 vs. 26%) and lidocaine (4 vs. 25%). From the analysis, according to the guarded receptor hypothesis, it follows that the three compounds bind preferentially to inactivated sodium channels with about the same affinity to the atrium and ventricle, except for quinidine which shows a significantly smaller dissociation constant in the atrium (5 x 10(-6) M vs. 2.7 x 10(-5) M; p less than 0.001). We conclude that the atrioventricular differences in the resting block are mainly due to atrioventricular differences in the RMP, whereas the differences in the frequency-dependent extra block are based on the shorter atrial AP duration (lidocaine) or are due to higher affinity to atrial sodium channels (quinidine).

Atrial fibrillation and embolic complications in paced patients.

UNLABELLED: Atrial fibrillation (AF) and thromboembolism are discussed to be complications of the VVI mode. We reinvestigated the spontaneous ECG and the anamnesis of 246 pacemaker patients with the indications second and third degree atrioventricular block (AV block, n = lll), sick sinus syndrome (SSS, n = 101) and other indications (n = 34), all had shown sinus rhythm at implantation. The mean implantation time was 63 +/- 45 months (203 VVI and 43 dual chamber pacemakers). THE RESULTS: (1) Atrial fibrillation was found in 63 patients (26%). Only one of them had a DDD pacemaker inserted, the implantation time of dual chamber devices being shorter, however, (2) The incidence of AF in patients with SSS (37%) was significantly higher (P less than 0.01) than in patients with AV block (19%). (3) Three patients suffered from strokes or transitory ischemic attacks in the follow-up, only one of them had AF at control. CONCLUSIONS: Our results confirm that VVI stimulation favors AF long-term which is most likely due to irritation of the atrial rhythm by retrograde conduction. In our patients the incidence of thromboembolic complications was not higher in the group of patients with AF. However, from this study in surviving patients, we cannot exclude that we lost some patients due to severe stroke.

Course of symptoms and spontaneous ECG in pacemaker patients: a 5-year follow-up study.

We investigated the course of symptoms and the spontaneous ECG retrospectively in 308 patients who had received a pacemaker because of atrioventricular (AV) block (n = 115), sick sinus syndrome (SSS, n = 107), bradyarrhythmic atrial fibrillation (bradyarrhythmia, n = 51), carotid sinus syndrome (CSS, n = 16), complete bifascicular block associated with 1st degree AV block (n = 13) and with other indications (n = 6). The mean implantation time was 63 months. The clinical state of 93% of all patients improved after pacemaker implantation; their symptoms decreased markedly. Persisting syncopy in some patients with SSS, however, supports a restricted implantation policy. We rarely saw improved AV conduction in patients with AV block (11%). Furthermore, in patients with SSS, atrial fibrillation occurred significantly more often (35%) than in those with AV block (17%; P less than 0.01). Only 3% of patients with SSS developed 2nd and 3rd degree AV block within the observation period. In all patients with initial bifascicular block and additional 1st degree AV block, pacing prevented further syncopal attacks; four of them showed 3rd degree AV block at control, indicating that pacemaker implantation is mandatory in symptomatic patients with bifascicular disease and 1st degree AV block.

New concept in activity-controlled pacemakers: clinical results with an accelerometer-based rate adaptive pacing system.

An accelerometer-based rate adaptive generator (EXCEL VR) has been introduced. A preclinical group of 22 subjects with strap-on devices was observed and reported. A clinical protocol including observation of rate adaptive response to typical daily activities and incremental exercise on a treadmill was administered in seven implanted patients. Indications for implantation in these patients was either second- or third-degree atrioventricular block (five patients, VVIR pacing mode) and sick sinus syndrome (two patients, AAIR pacing mode). Mean pacing rates were 50 ppm (supine), 56 ppm (standing), 77 ppm (descending the stairs), 81 ppm (slow walk), 83 ppm (slow stair climb), 91 ppm (fast walk), and 92 ppm (fast stair climb). When the arm proximal to the pulse generator was exercised, the rate rose to 92 ppm. When the distal arm was strained, the rate was 63 ppm. During treadmill testing, rates between 82 ppm (2 km/hour) and 104 ppm (5 km/hour) were observed. This accelerometer-based rate adaptive pulse generator provided a proportional response to graded activities of treadmill exercise and daily living in these groups of preclinical and clinical subjects.

[Elective coronary implantation of a newly developed stent without conventional anticoagulation]. / Elektive koronare Implantation eines neu entwickelten Stents ohne klassische Antikoagulation.

OBJECTIVE: To assess in an open prospective study the angiographic and clinical results of the elective implantation of the recently developed AVE micro-stent (Applied Vascular Engineering, Santa Rosa, CA, USA), in combination with dual antiaggregation treatment. PATIENTS AND METHODS: Between January and December 1995 AVE micro-stents were implanted into 128 vessels in 121 patients (20 women, 101 men; mean age 60.7 +/- 9.5 [34-84] years) with symptomatic coronary heart disease (CHD). Indication for the primary implantation of the stent type was a complex morphology of the stenosis with unfavourable short- and long-term prognosis. The stent consists of a 4 mm long tubular highly flexible segment made of 0.008 inch wire and can be advanced even into tortuous vessels. After balloon dilatation of the stenosis the stent was advanced into the vessel wall at a pressure of 10-12 bar, followed by further dilatation at 16-18 bar. Conventional long-term anticoagulation was dispensed with, patients only receiving antiaggregation medication: 500 mg ticlopidine and 100 mg aspirin daily for 6 weeks. RESULTS: The primary success rate of stent implantation was 99% (121 of 122). Neither acute nor subacute thromboses were revealed during hospital stay nor was there any emergency bypass operation or early repeat balloon angioplasty. There were no abnormal bleedings. CONCLUSION: Stenoses which are unsuitable for conventional balloon angioplasty can be reliably treated with the AVE microstent. Optimal high-pressure dilatation in combination with dual antiaggregation treatment will prevent stent thrombosis and bleeding complications.

Dose-dependent alteration of rat cardiac sodium current by isoproterenol: results from direct measurements on multicellular preparations.

Conflicting results have been reported in literature about the influence of beta-adrenergic stimulation on the fast cardiac sodium current (INa+). To elucidate these mechanisms in multicellular preparations we used the loose-patch-clamp technique to evaluate the effect of the beta-adrenergic agonist isoproterenol 1-1000 nmol/l. Isoproterenol enhanced INa+ at all membrane potentials by elevation of the maximal available INa+ . Only at the high concentration of 1 micromol/l was INa+ slightly depressed after depolarizing conditioning clamps. The most marked increase of the maximal available INa+ was 30+/-9% after application of 100 nmol/l isoproterenol. To learn about the mechanisms in view of sodium channel modulation we combined isoproterenol with the sodium channel blocker lidocaine (47 micromol/l). Under these circumstances the effects of both drugs were completely independent. This investigation shows clearly that low concentrations of isoproterenol increase INa+ in multicellular preparations by a gating-independent mechanism.

Peak endocardial acceleration-based clinical testing of the "BEST" DDDR pacemaker. European PEA Clinical Investigation Group.

The peak endocardial acceleration (PEA, unit g) shows a near correlation with myocardial contractility during the isometric systolic contraction of the heart (dP/dtmax), with sympathetic activity and, thus, with physiological heart rate modulation. The (Biomechanical Endocardial Sorin Transducer (BEST) sensor is incorporated in the tip of a pacing lead and measures PEA directly near the myocardium. In an international study, the lead was implanted with the dual chamber pacemaker Living-1 (Sorin) in 105 patients. The behavior of the PEA signal was tested under conditions of physical and mental stress and during daily life activities by 24-hour recordings of PEA (PEA Holter) at 1 to 2 months and approximately 1 year after implantation. Implantation of the BEST lead was performed without complications in all patients. The sensor functioned properly in the short- and long-term in 98% of patients. Although PEA values differed from patient to patient, the values closely reflected the variations in sympathetic activity due to physical and mental stress in each patient. During exercise and during daily life activities a close correlation between PEA and heart rate was observed among patients with normal sinus rhythm. Peak endocardial acceleration allows a nearly physiological control of the pacing rate.

Dissimilar action of two cyclic adenosine-monophosphate analogues on the sodium current in intact rat papillary muscle.

In intact papillary muscles from rat we have found with the loose-patch-clamp technique an increase of the fast cardiac sodium current (INa+) by isoproterenol (ISO). In this study we have tested two membrane permeable analogues of the intracellular second messenger cyclic adenosine-monophosphate (cAMP) to investigate the intracellular pathway: 8-Br-cAMP (50 microM) and the newer developed Sp-5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole- 3',5'-cyclic-monophosphorothioate (5,6-DCl-cBiMPS, 20 microM). The availability of INa+ was determined with test pulses to +/- 0 mV every 3.5 seconds after 2.5-second conditioning between -130 mV and -50 mV and a holding potential at the resting potential of the cell under examination, and after wash-in of either compound. The peak currents were fit to a Boltzmann equation, and expressed by the maximal attainable current INa+,max, the mid-point potential V1/2, and a steepness parameter alpha. Values are given by mean +/- SEM. 8-Br-cAMP showed a significant shift of the availability curve in the hyperpolarized direction (V1/2 = -82 +/- 2 mV vs -86 +/- 2 mV, n = 5, P < 0.05) with only minor changes of INa+,max and alpha. In contrast, 5,6-DCl-cBiMPS had no significant effect on V1/2 but increased INa+,max by 8% +/- 2% versus control (n = 5, P < 0.05). In an intact muscle preparation we have found that 5,6-DCl-cBiMPS has a similar effect as that observed with the beta-adrenergic agonist ISO (100 nM), whereas 8-Br-cAMP exhibited a dissimilar action.(ABSTRACT TRUNCATED AT 250 WORDS)

[Myocardial infarction after influenza vaccination]. / Myokardinfarkt nach Influenza-Schutzimpfung.

Influenza is a common disease in the population. Influenza vaccination is performed routinely and is usually well tolerated. Minor local or systemic side effects like fever and myalgia are described. Rarely there are more severe adverse events. Systemic vasculitis has been reported in some cases. In this case we report on a female patient with secondary vasculitis and myocardial infarction after influenza vaccination. The patient received cortisol and recovered. The literature about influenza vaccination, its side effects and recommendations about vaccination in patients with coronary artery disease is reviewed.