Thalidomide-induced symptomatic third-degree atrioventricular block.
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Aged↗
Biomedical subjects
M Näbauer
Publications and source records attributed to M Näbauer.
Long QT syndrome. Why does sex matter?
There is increased awareness of the extent to which cardiac function is influenced by gender. One of the most dramatic and potentially lethal differences is that seen in cardiac repolarization reflected in the QT interval of the surface ECG. Gender differences in QT and QTc intervals have been observed to change during the lifetime in the general population. These differences can be explained to a large extent by sex hormone driven differences in gene expression of myocardial ion channels. Numerous studies have shown that women's risk to suffer arrhythmias in the context of QT prolonging drugs is doubled compared to men. For familial long QT syndrome there is no conclusive evidence for gender effects with respect to disease onset or mortality. Only subgroup analysis by genotype demonstrated a higher risk in female patients carrying mutations in the LQT2 locus. Special attention should be given to drug-induced QT prolongation in women.
Adolescent↗
Tuning repolarization in the heart: a multitude of potassium channels and regulatory pathways.
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Animals↗
Shu 508 A (Levovist)-enhanced Doppler echocardiography improves the assessment of valvular heart disease.
OBJECTIVE: To investigate whether intravenous injection of SHU 508 A improves the diagnostic accuracy of Doppler echocardiography in the assessment of valvular pathologies. METHODS AND RESULTS: One hundred and twenty-five consecutive patients with valvular pathology (aortic stenosis, n = 48; aortic regurgitation, n = 20; mitral stenosis, n = 21; and mitral regurgitation, n = 36) and diagnostically insufficient Doppler signal were enrolled in this multicenter study. The severity of valvular pathology was graded on a four-point scale using unenhanced and contrast-enhanced Doppler echocardiography as well as cardiac catheterization. Agreement with cardiac catheterization findings increased from 63% using the unenhanced examination to 73% using the contrast-enhanced Doppler examination. Grading was possible in all patients using SHU 508 A, whereas the unenhanced Doppler examination remained inconclusive in six patients. The weighted kappa coefficient between contrast-enhanced Doppler and cardiac catheterization for all diagnoses was 0.76 as compared to 0.68 between unenhanced Doppler and cardiac catheterization. Agreement was especially improved in aortic stenosis (kappa 0.69 unenhanced vs 0.81 contrast-enhanced) and in aortic regurgitation (kappa 0.45 unenhanced vs 0.75 contrast-enhanced). Patients with mitral stenosis and mitral regurgitation experienced less improvement. CONCLUSIONS: In case of an inconclusive unenhanced Doppler echo study, the administration of a left heart contrast agent should be considered. SHU 508 A is especially useful in improving the severity grading of aortic stenosis and aortic regurgitation, while grading of mitral stenosis and mitral regurgitation is less improved.
Adult↗
Na+-channel modulating effect of the inotropic compound S(-)BDF 9196 in human myocardium.
S(-)BDF 9196, the active enantiomer of racemic (+/-)BDF 9148, has been shown to increase force of contraction in myocardium from different species including humans. The present study aimed to investigate the mechanism of the positive inotropic action of the active enantiomer S(-)BDF 9196 in human myocardium. In electrically driven human left ventricular papillary muscle strips (dilated cardiomyopathy, NYHA IV, cardiac transplantation, n=9), S(-)BDF 9196 increased force of contraction concentration-dependently. The maximal positive inotropic effect remained unchanged after the addition of carbachol (1 mmol/l, indicating a cAMP-independent mode of action of S(-)BDF 9196. While [3H]ouabain binding in human myocardial membranes was not influenced by S(-)BDF 9196 up to 10 micromol/l, the inward Na(+)-current in isolated human left ventricular myocytes was increased significantly by S(-)BDF 9196 (1 micromol/l, n=5). These results provide evidence that S(-)BDF 9196 increases force of contraction in human myocardium primarily by enhancing Na(+)-influx, while cAMP-dependent or Na(+),K(+)-ATPase blocking effects do not seem to play a role.
Azetidines↗
Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density.
BACKGROUND: Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world. A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic. Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K+ currents-prominently, the Ca2+-independent transient outward current (Ito). The mechanism for the reduction of Ito in heart failure is unknown. The K+ channel alpha-subunit Kv4.3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac Ito in humans. METHODS AND RESULTS: We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and Ito in human tissues and isolated ventricular myocytes, respectively. We found that the level of Kv4.3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak Ito density measured in ventricular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA studied (HERG, Kv1.4, Kir2.1, Kvss1.3, and the alpha1C subunit of the Ca2+ channel). mRNAs encoding Kv1.2, Kv1.5, and Kv2.1 were found in low abundance in human ventricle. CONCLUSIONS: These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac Ito in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.
Action Potentials↗
Potassium channel down-regulation in heart failure.
Prolongation of action potential duration is the most consistent electrophysiological abnormality in myocardium and myocytes from hypertrophied and failing hearts. Measurements of currents in myocytes from hypertrophied and failing hearts indicate that, in most cases, this is due to a decrease in outward potassium currents. If present, a calcium-independent transient outward current is usually substantially reduced, but delayed rectifier and inward rectifier currents have also been found to be diminished. There is increasing evidence that potassium current down-regulation contributes significantly to the enhanced lability of the repolarization process in heart failure, predisposing to early after-depolarizations, dispersion of repolarization and ventricular arrhythmias. The reduction of outward potassium currents may also be involved in the enhanced sensitivity of failing myocardium to triggering factors like hypokalemia, ischemia, and antiarrhythmic agents with Class III effects. A thorough understanding of the mechanisms of cardiac excitability and arrhythmogenesis at the cellular and molecular level under normal and pathological conditions will be essential for the development of new pharmacological strategies to prevent sudden cardiac death in heart failure.
Action Potentials↗
Electrical heterogeneity in the ventricular wall--and the M cell.
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Action Potentials↗
Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle.
BACKGROUND: Recordings of outward currents in human ventricular myocytes revealed the presence of a large calcium-insensitive transient outward current. This current has been suggested to contribute significantly to regional electrophysiological heterogeneity in myocardial cells and tissue of several animal species and to cause electrical gradients across the ventricular wall. METHODS AND RESULTS: The patch-clamp technique was used to record action potentials and outward currents in myocytes enzymatically isolated from thin subepicardial and subendocardial layers of human nonfailing and failing left ventricle. In all subepicardial cells studied, a calcium-insensitive transient outward current (Ito1) could be recorded with large density (10.6 +/- 1.08 pA/pF at 40 mV), whereas current density of Ito1 in subendocardial cells was fourfold smaller (2.63 +/- 0.31 pA/pF, P<.0001, nonfailing myocardium). In failing hearts, the density of Ito1 was significantly smaller in subepicardial cells (7.81 +/- 0.53 pA/pF, P=.012) but not different in subendocardial myocytes (2.01 +/- 0.23 pA/pF, P=.25). Rate-dependent reduction of peak Ito1 at a 2-Hz depolarization rate was minimal in subepicardial cells (to 92.3 +/- 1.9%), whereas peak Ito1 in subendothelial myocytes was almost suppressed at 2 Hz (reduction to 13.2 +/- 2.1%, P<.0001). The different rate-dependent reduction of the transient outward current was due to a much slower time course of recovery from inactivation in subendocardial cells. Kinetic data, including action potentials recorded at 35 degree C, allow assessment of the role of the transient outward current for electrical activity and transmural voltage gradients in human left ventricle. CONCLUSIONS: Marked regional differences in density and rate-dependent properties of the transient outward current exist in subendocardial and subepicardial layers in human left ventricular myocardium, causing transmural electrical gradients that are important for normal and pathological electrical behavior of the human heart. The difference in recovery rates of the transient outward current is a distinguishing feature between subepicardial and subendocardial myocytes.
Action Potentials↗
[Spontaneous hemothorax in dermatomyositis and long-term glucocorticoid treatment].
A 65-year-old woman with dermatomyositis for which she had been treated for ten years with prednisone (latterly 15 mg daily) suddenly experienced severe pain in the left thoracolumbar region. Cardiovascular, pulmonary and vertebral causes of the pain were excluded. But serological tests indicated inflammatory disease and the haemoglobin concentration was low (10.4 g/dl). Left pleural effusions were repeatedly aspirated and some haemorrhagic fluid obtained (haematocrit 0.31 in blood, 0.28 in the pleural effusion). Five days after admission her cardiovascular status became unstable and she developed respiratory failure (haemoglobin 7.6 g/dl). Chest radiograph showed increased pleural effusion. Subsequent thoracotomy revealed a left coagulothorax which was removed and flushed. During this procedure severe bleeding occurred from a covered perforation of the descending aorta, 1.5 x 1.5 cm in size. Although the aortic wall was thin, there was no aneurysm but arteriosclerotic changes and an external erosion near an abscessing mediastinitis, originating from a chronic purulent pleuritis and bronchopneumonia. The severe blood loss caused circulatory failure from which the patient could not be resuscitated.
Aged↗
Altered diastolic [Ca2+]i handling in human ventricular myocytes from patients with terminal heart failure.
To investigate whether the slow diastolic decay of [Ca2+]i in myocardium of patients with heart failure is a result of alterations of the Ca2+ adenosine triphosphatase of the sarcoplasmic reticulum of the sarcolemma, [Ca2+]i transients were recorded in voltage-clamped ventricular cells isolated from hearts of patients with terminal heart failure or from undiseased donor hearts. To isolate the [Ca2+]i-reuptake function of the sarcoplasmic reticulum, myocytes were dialyzed via the patch pipette with Na(+)-free solution and incubated in Ca(2+)-free and Na(+)-free solution to inhibit Na+/Ca2+ exchange. After superfusion with Ca(2+)-containing, Na(+)-free medium, the sarcoplasmic reticulum was loaded with Ca2+ through repetitive voltage-clamp pulses to +10 mV. Under these conditions, [Ca2+]i decay was significantly slower in myocytes from patients with heart failure (538 +/- 66 msec) than in controls (305 +/- 16 msec; p < 0.05). After the addition of 10 mmol/L of caffeine, [Ca2+]i levels did not show appreciable decay between two voltage-clamp pulses in diseased and undiseased myocytes. We conclude that diastolic decay of [Ca2+]i in ventricular myocytes from patients with terminal heart failure is partially the result of a decreased rate of Ca2+ reuptake by the sarcoplasmic reticulum. Sarcolemmal Ca2+ adenosine triphosphatase does not contribute significantly to cytoplasmic [Ca2+]i removal during an individual heartbeat.
Calcium↗
Intracellular calcium handling in isolated ventricular myocytes from cardiomyopathic hamsters (strain BIO 14.6) with congestive heart failure.
Intracellular [Ca2+]i handling has been shown to be altered in isolated ventricular myocytes from patients with terminal heart failure. The aim of this study was to evaluate if alterations of intracellular [Ca2+]i handling and triggering Ca2+ currents in cardiomyopathic hamsters (strain BIO 14.6) with congestive heart failure might be similar to changes found in myocytes of patients with terminal heart failure and, therefore if the hamster might serve as a model for heart failure in man. Cells were isolated from hearts of hamsters developing hereditary cardiomyopathy (CMP) (strain BIO 14.6) at 12-14 months of age with overt signs of congestive heart failure. Results were compared with age-matched, undiseased control animals (CTRL). [Ca2+]i transients and Ca2+ currents were recorded simultaneously from isolated cells under voltage clamp perfused internally with the Ca2+ indicator, Fura-2. Ca2+ current densities in myocytes from CMP hamsters were -6.6 +/- 0.6 versus -8.3 +/- 0.5 microA/cm2 (P < 0.05) in CTRL. Resting [Ca2+]i levels were not significantly different. Peak [Ca2+]i transients were significantly decreased in CMP cells (450 +/- 52 nM versus 1031 +/- 98 nM in CTRL, P < 0.05). The rate of diastolic [Ca2+]i decay was slower in cells from CMP animals (t1/2: 167 +/- 19 versus 109 +/- 16 ms; P < 0.05). A moderate negative correlation was found between cell surface area and [Ca2+]i transients (r = 0.42; P < 0.05). It is concluded that changes of intracellular [Ca2+]i handling may play an important role in altered contractility of the myocardium of hamsters with hereditary cardiomyopathy in the late stage of congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure.
Prolongation of the action potential has been postulated to be a major reason for the altered diastolic relaxation of the heart in patients with severe heart failure. To investigate the electrophysiological basis for this action potential prolongation in terminal heart failure, K+ currents were recorded in single ventricular myocytes isolated from 16 explanted hearts of patients undergoing transplantation. Results from diseased hearts were compared with ventricular cells isolated from six undiseased donor hearts. Action potential duration was significantly prolonged in cells from patients with heart failure. A delayed rectifier K+ current was hardly detectable in most cells, and if it could be recorded, it was very small in both diseased and undiseased cells. When currents were normalized for cell surface area, the average current density of the inward rectifier K+ current was significantly reduced in diseased cells when compared with normal control cells (hyperpolarization at -100 mV, -15.9 +/- 2.2 vs -9.0 +/- 1.2 microA/cm2; P < .01). In addition, a large transient outward K+ current could be recorded in human myocytes. The average current density of the time-dependent component of this transient outward K+ current was significantly reduced in heart failure (depolarization at +40 mV, 9.1 +/- 1.0 vs 5.8 +/- 0.64 microA/cm2; P < .01). Action potential prolongation in severe heart failure may partially be explained by a reduction in current densities of the inward rectifier K+ current and of the transient outward K+ current. These alterations may thereby have a significant effect on cardiac relaxation.
Action Potentials↗
Characteristics of transient outward current in human ventricular myocytes from patients with terminal heart failure.
A variety of outward currents exists in ventricular myocardium of different species influencing action potential duration and electrical activity. Transient outward currents have been reported in ventricular tissue of some animals but are small or absent in others. This study was conducted to investigate whether a transient outward current exists in human ventricular myocardium and to characterize its basic electrophysiological properties. Currents were recorded from enzymatically isolated human ventricular myocytes obtained from explanted hearts of 22 patients with terminal heart failure. In almost all cells studied, a transient outward current could be recorded on depolarization to between -20 and +80 mV. The size of the transient outward current was usually large enough to mask the Ca2+ current. It could be recorded under conditions in which Ca2+ influx and intracellular Ca2+ transients were suppressed. Basic current characteristics were similar to transient outward currents observed in other species. Inactivation of the transient outward current was monoexponential, with a time constant of 54.8 +/- 3.7 milliseconds at +40 mV. Half-maximal activation occurred at 16.7 +/- 1.6 mV; half-maximal steady-state inactivation occurred at -34.5 +/- 2.3 mV. Frequency-dependent reduction of peak transient outward current was 29.8 +/- 1.4% at 2 Hz compared with resting conditions. Recovery from inactivation was voltage dependent and had a biexponential time course; the faster time constant (41.0 +/- 6.5 milliseconds at -80 mV) accounted for 86.0 +/- 5.2% of total current. The transient outward current was sensitive to 4-aminopyridine (IC50, 1.15 mM). These results indicate that a large Ca(2+)-independent transient outward K+ current is present in human ventricular myocytes that might be regulated by physiological or pathological events and is a potential site for pharmacological intervention.
4-Aminopyridine↗
Modulation of contraction by intracellular Na+ via Na(+)-Ca2+ exchange in single shark (Squalus acanthias) ventricular myocytes.
1. The effect of direct alteration of intracellular Na+ concentration on contractile properties of whole-cell clamped shark ventricular myocytes was studied using an array of 256 photodiodes to monitor the length of the isolated myocytes. 2. In myocytes dialysed with Na(+)-free solution, the voltage dependence of Ca2+ current (ICa) and contraction were similar and bell shaped. Contractions activated at all voltages were completely suppressed by nifedipine (5 microM), and failed to show significant tonic components, suggesting dependence of the contraction on Ca2+ influx through the L-type Ca2+ channel. 3. In myocytes dialysed with 60 mM Na+, a ICa-dependent and a ICa-independent component of contraction could be identified. The Ca2+ current-dependent component was prominent in voltages between -30 to +10 mV. The ICa-independent contractions were maintained for the duration of depolarization, increased with increasing depolarization between +10 to +100 mV, and were insensitive to nifedipine. 4. In such myocytes, repolarization produced slowly decaying inward tail currents closely related to the time course of relaxation and the degree of shortening prior to repolarization. 5. With 60 mM Na+ in the pipette solution, positive clamp potentials activated decaying outward currents which correlated to the size of contraction. These outward currents appeared to be generated by the Na(+)-Ca(2+)-exchanger since they depended on the presence of intracellular Na+, and were neither suppressed by nifedipine nor by K+ channel blockers. 6. The results suggest that in shark (Squalus acanthias) ventricular myocytes, which lack functionally relevant Ca2+ release pools, both Ca2+ channel and the Na(+)-Ca2+ exchanger deliver sufficient Ca2+ to activate contraction, though the effectiveness of the latter mechanism was highly dependent on the [Na+]i.
Animals↗
Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure.
BACKGROUND: Experiments were performed in human ventricular myocytes to investigate properties of excitation-contraction coupling in patients with terminal heart failure. Myocytes were isolated from left ventricular myocardium of patients with cardiac failure caused by dilated or ischemic cardiomyopathy undergoing transplantation. These results were compared with those obtained from cells of healthy donor hearts that for technical reasons were not suitable for transplantation. METHODS AND RESULTS: [Ca2+]i transients and Ca2+ currents were recorded from isolated cells under voltage clamp perfused internally with the Ca2+ indicator fura 2. In cells that were stimulated externally, the cell-permeant form of the indicator, fura 2-AM, was used. When action potentials were to be recorded, cells were stimulated in current clamp mode. Unstimulated Ca2+ current densities were not significantly different in myopathic and control cells. In diseased myocytes, resting [Ca2+]i levels were 165 +/- 61 nmol/l, compared with 95 +/- 47 nmol/l in normal cells. With 5 mmol/l Na+ in the pipette, peak [Ca2+]i transients were 367 +/- 109 and 746 +/- 249 nmol/l, respectively. The decline of [Ca2+]i during diastole was significantly slower in myopathic cells than in control cells. This was a result of a prolongation of the action potential and of a reduced Ca2+ sequestration by the sarcoplasmic reticulum. CONCLUSIONS: These results may partly explain the alterations of contractility in vivo in patients with heart failure.
Action Potentials↗
Characteristics of calcium-current in isolated human ventricular myocytes from patients with terminal heart failure.
The Ca(2+)-current plays a prominent role in triggering excitation-contraction coupling in the mammalian heart. It is also a target of clinically important drugs such as catecholamines or Ca(2+)-channel blockers. Until now studies of Ca(2+)-channels in human ventricular myocardium have been hampered by the fact that adequate voltage control cannot be obtained in multicellular preparations. To characterize the properties of human myocardial Ca(2+)-currents, ventricular myocytes were isolated from explanted hearts of patients with end-stage heart failure undergoing cardiac transplantation. The current-voltage relation and voltage-dependent inactivation of L-type currents were similar to those in non-diseased guinea-pig myocardium. Currents could be stimulated with isoprenaline in a dose-dependent manner. When cells were superfused with a Na(+)-free solution in the presence of Tetrodotoxin, Cs+ and Tetraethylammonium to block interfering Na+ and K(+)-currents, depolarization from a holding potential of -90 mV to -80-(-)50 mV did not elicit any time-dependent inward-current. Changing the holding potential from -90 to -45 mV did not alter the current-voltage relation. We conclude that T-type Ca(2+)-currents do not seem to make a detectable contribution to the transmembrane Ca(2+)-influx and that L-type currents in human ventricular myocytes of patients with severe heart failure have characteristics that are similar to those in other mammalian species.
Action Potentials↗
Ca2(+)-induced Ca2+ release as examined by photolysis of caged Ca2+ in single ventricular myocytes.
In cardiac muscle, entry of Ca2+ through the voltage-gated Ca2+ channel and its interaction with an intracellular site are thought to trigger the release of the intracellular Ca2+ pools and to activate contraction. The availability of a novel "caged calcium" compound, and its effective use in neuronal and heart cells to modulate Ca2+ channel and contraction, made it possible to examine directly the Ca2(+)-induced Ca2+ release hypothesis in intact mammalian cardiac myocytes. We used the caged Ca2+ compound DM-nitrophen, which on photolysis, rapidly (less than 200 microseconds) changes its Ca2(+)-binding affinity from 3 X 10(-9) to 2 X 10(-3) M at pH 7.0. In isolated whole cell clamped guinea pig ventricular myocytes dialyzed with unphotolyzed DM-nitrophen (Ca2+ buffered to values less than 10(-7) M), we found that a 160-microseconds light pulse photoreleased sufficient Ca2+ to activate contraction. Photorelease of Ca2+ failed to activate significant contraction in myocytes pretreated with caffeine, supporting the idea that the release of Ca2+ from intracellular pools was necessary to generate tension. However, photorelease of Ca2+ after the depolarization-induced Ca2+ release failed to suppress contraction, as predicted from the Ca2(+)-induced inactivation hypothesis. The failure to suppress contraction was not sufficient to definitively reject the Ca2(+)-induced inactivation hypothesis, since the intracellular Ca2+ concentration may not have risen sufficiently to inactivate the release channel.
Acetates↗