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Tobias Opthof

Publications and source records attributed to Tobias Opthof.

At least 19 recordsLinked to original sources
PubMed2007

Embryological development of pacemaker hierarchy and membrane currents related to the function of the adult sinus node: implications for autonomic modulation of biopacemakers.

The sinus node is an inhomogeneous structure. In the embryonic heart all myocytes have sinus node type pacemaker channels (I (f)) in their sarcolemma. Shortly before birth, these channels disappear from the ventricular myocytes. The response of the adult sinus node to changes in the interstitium, in particular to (neuro)transmitters, results from the interplay between the responses of all of its constituent cells. The response of the whole sinus node cannot be simply deduced from these cellular responses, because all cells have different responses to specific agonists. A biological pacemaker will be more homogeneous. Therefore it can be anticipated that tuning of cycle length may be problematic. It is discussed that efforts to create a biological pacemaker responsive to vagal stimulation, may be counterproductive, because it may have the potential risk of 'standstill' of the biological pacemaker. A normal sinus node remains spontaneously active at high concentrations of acetylcholine, because it has areas that are unresponsive to acetylcholine. The same is pertinent to other substances with a negative chronotropic effect. Such functional inhomogeneity is lacking in biological pacemakers.

Adult↗
PubMed2006

Dietary n-3 fatty acids promote arrhythmias during acute regional myocardial ischemia in isolated pig hearts.

OBJECTIVE: Dietary supplementation with fish oil-derived n-3 fatty acids reduces mortality in patients with myocardial infarction, but may have adverse effects in angina patients. The underlying electrophysiologic mechanisms are poorly understood. We studied the arrhythmias and the electrophysiologic changes during regional ischemia in hearts from pigs fed a diet rich in fish oil. METHODS: Pigs received diets rich in fish oil, in sunflower oil, or a control diet for 8 weeks. Hearts were isolated and perfused. Ischemia was created by occluding the left anterior descending artery. Diastolic stimulation threshold, refractory period, conduction velocity, activation recovery intervals and the maximum downstroke velocity of 176 electrograms were measured in the ischemic zone. Spontaneous arrhythmias during 75 min of regional ischemia were counted. RESULTS: More episodes of spontaneous ischemia-induced sustained ventricular tachycardia and ventricular fibrillation occurred in the fish oil and sunflower oil group than in the control group. More inexcitable myocardium was present in the ischemic zone in the group fed fish oil or sunflower oil than in the control group after 20 min of ischemia. After 40 min of ischemia, more block occurred in the control group than in the other groups. The downstroke velocity of the electrograms in the ischemic border zone was lower in the fish oil group and sunflower oil group than in the control after 20 min. CONCLUSIONS: A diet rich in fish oil results in proarrhythmia compared to a control diet during regional ischemia in pigs. Myocardial excitability is reduced in the fish oil and sunflower oil group during the early phase of arrhythmogenesis. In the late phase of arrhythmogenesis, excitability is more reduced in the control group than in the fish oil and sunflower oil group.

Animals↗
PubMed2006

Pro- and antiarrhythmic properties of a diet rich in fish oil.

Increased consumption of fish rich in omega-3 polyunsaturated fatty acids (omega3-PUFAs) is associated with decreased incidence of sudden cardiac death in post-myocardial infarction patients, but is also related to increased incidence of sudden death and arrhythmias in patients with acute myocardial ischemia. This review discusses the possible pro- and antiarrhythmic mechanisms of omega3-PUFAs in relation to various cardiac pathologies. Differences between circulating and incorporated omega3-PUFAs with respect to electrophysiology are emphasized. We conclude that omega3-PUFAs alter cardiac electrophysiology and thereby may be pro- or antiarrhythmic, dependent on the mechanism of arrhythmia. As omega3-PUFAs may be antiarrhythmic under conditions that favour triggered activity, they may facilitate re-entrant arrhythmias. This may explain the contradictory outcomes of increased intake of fish oil on sudden death and arrhythmias in clinical trials. Advice to increase intake of omega3-PUFA supplements or fatty fish should be tailored to individual patients with respect to the arrhythmogenic mechanisms associated with the underlying pathology.

Action Potentials↗
PubMed2006

Monophasic action potentials and activation recovery intervals as measures of ventricular action potential duration: experimental evidence to resolve some controversies.

BACKGROUND: Activation recovery intervals (ARIs) and monophasic action potential (MAP) duration are used as measures of action potential duration in beating hearts. However, controversies exist concerning the correct way to record MAPs or calculate ARIs. We have addressed these issues experimentally. OBJECTIVES: To experimentally address the controversies concerning the correct way to record MAPs or calculate ARIs. METHODS: Left ventricular local electrograms were recorded in isolated pig hearts with an exploring electrode grid, with a KCl reference electrode on the left ventricular myocardium, the aortic root, or the left atrium. Local activation was determined from calculated Laplacian electrograms. RESULTS: With the KCl electrode on the aortic root, local electrograms represented local activation. However, with the KCl electrode on the myocardium remote from the exploring electrode, a combined electrogram emerged consisting of local activation recorded from the grid and remote activation recorded from the reference electrode. The remote, inverted monophasic component did not show propagation and did not correlate with the Laplacian complex. When the KCl electrode was placed on the atrium during AV block, remote atrial monophasic components were completely dissociated from local, ventricular deflections. At left ventricular sites with a positive T wave, the Laplacian signal showed that the end of the T wave was caused by remote repolarization. During cooling-induced regional action potential prolongation, the T wave became negative, whereby the positive flank of the T wave remained correlated with repolarization (recorded with a MAP at the same site). CONCLUSIONS: MAPs are recorded from the depolarizing electrode. In both negative and positive T waves, the moment of maximum dV/dt corresponds to local repolarization.

Action Potentials↗
PubMed2006

Molecular aspects of adrenergic modulation of the transient outward current.

Transient outward channels have a different impact on action potential configuration in small mammals compared to large mammals. Small mammals depend primarily on Ito1 for repolarization, while in larger animals Ito1 only indirectly determines action potential duration by setting the level of the plateau. Transient outward channel expression and distribution also differ between animal species. Nevertheless, the primary protein sequence of the underlying Kv1.4, Kv4.2 and Kv4.3 alpha1-subunits displays remarkably high levels of amino acid identity. Transient outward channels are subject to alpha- and beta-adrenergic regulation, mainly decreasing Ito1. However, adrenergic stimulation is also an important determinant of transient outward channel downregulation in cardiac disease. Adrenergic stimulation of PKA as well as PKC leads to an inhibition of Ito1, which has been correlated with phosphorylation of the Kv1.4, Kv4.2 and Kv4.3 alpha1-subunits. Calmodulin-dependent kinase II, on the other hand, has been shown to be involved in an increase of Ito1. Comparison of Kv1.4, Kv4.2 and Kv4.3 primary amino acid sequences demonstrates a strong conservation of (potential) phosphorylation sites between different species, despite the fact that Ito1 has a different effect on action potential configuration in mammalian species.

Action Potentials↗
PubMed2006

Incorporated sarcolemmal fish oil fatty acids shorten pig ventricular action potentials.

BACKGROUND: Omega-3 polyunsaturated fatty acids (omega3-PUFAs) from fish oil reduce the risk of sudden death presumably by preventing life-threatening arrhythmias. Acutely administered omega3-PUFAs modulate the activity of several cardiac ion channels, but the chronic effects of a diet enriched with fish oil leading to omega3-PUFA-incorporation into the sarcolemma on membrane currents are unknown. METHODS: Pigs received a diet either rich in omega3-PUFAs or in omega9-fatty acids for 8 weeks. Ventricular myocytes (VMs) were isolated and used for patch-clamp studies. RESULTS: omega3-VMs contained higher amounts of omega3-PUFAs and had a shorter action potential (AP) with a more negative plateau than control VM. In omega3 VMs, L-type Ca(2+) current (I(Ca,L)) and Na(+)-Ca(2+) exchange current (I(NCX)) were reduced by approximately 20% and 60%, respectively, and inward rectifier K(+) current (I(K1)) and slow delayed rectifier K(+) current (I(Ks)) were increased by approximately 50% and 70%, respectively, compared to control. Densities of rapid delayed rectifier K(+) current, Ca(2+)-activated Cl(-) current, and Na(+) current (I(Na)) were unchanged, although voltage-dependence of I(Na) inactivation was more negative in omega3 VMs. CONCLUSIONS: A fish oil diet increases omega3-PUFA content in the ventricular sarcolemma, decreases I(Ca,L) and I(NCX), and increases I(K1) and I(Ks), resulting in AP shortening. Incorporation of omega3-PUFAs in the sarcolemma may have consequences for arrhythmias independent of circulating omega3-PUFAs.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2006

Larger cell size in rabbits with heart failure increases myocardial conduction velocity and QRS duration.

BACKGROUND: Patients with heart failure (HF) have an increased QRS duration, usually attributed to decreased conduction velocity (CV) due to ionic remodeling but which may alternatively result from increased heart size or cellular uncoupling. We investigated the relationship between QRS width, heart size, intercellular coupling, and CV in a rabbit model of moderate HF and in computer simulations. METHODS AND RESULTS: HF was induced by pressure-volume overload. Heart weight (21.1+/-0.5 versus 10.2+/-0.4 g, mean+/-SEM; P<0.01) and QRS duration (58+/-1 versus 50+/-1 ms; P<0.01) were increased in HF versus control. Longitudinal CV (thetaL; 79+/-2 versus 67+/-4 cm/s; P<0.01) and transversal subepicardial CV (thetaT; 43+/-2 versus 37+/-2 cm/s; P<0.05) were higher in HF than in controls. Transmural CV (thetaTM) was unchanged (25+/-2 versus 24+/-1 cm/s; P=NS). Patch-clamp experiments demonstrated that sodium current was unchanged in HF versus control. Immunohistochemical experiments revealed that connexin43 content was reduced in midmyocardium but unchanged in subepicardium. Myocyte dimensions were increased in HF by approximately 30%. Simulated strands of mammalian ventricular cells (Luo-Rudy dynamic model) revealed increased thetaL and thetaT with increased myocyte size; however, increased CV could not compensate for increased strand size of longitudinally coupled cells, and consequently, total activation time was longer. CONCLUSIONS: Increased myocyte size combined with the observed expression pattern of connexin43 yields increased thetaL and thetaT and unchanged thetaTM in our nonischemic model of HF. A hypertrophied left ventricle together with insufficiently increased thetaL and unaltered thetaTM results in a prolonged QRS duration.

Animals↗
PubMed2005

Pathophysiological significance of T-type Ca2+ channels: expression of T-type Ca2+ channels in fetal and diseased heart.

Re-expression of fetal genes has been considered to underlie ionic remodeling in diseased heart. T-type Ca(2+) channels have been reported to be functionally expressed in embryonic hearts. In this review, we summarize developmental changes of T-type Ca(2+) channels in mouse ventricles from 9.5 days postcoitum (dpc) to adulthood, using patch clamp and quantitative PCR. In addition, we introduced T-type Ca(2+) channel expression in hypertrophied ventricles caused by myocardial infarction (MI) and aortic banding (AOB). Substantial T-type Ca(2+) channel current was recorded at both 9.5 and 18 dpc. The currents were inhibited by Ni(2+) at low concentrations. The current was not detectable in the adult stage. Ca(v)3.2 (alpha(1H)) mRNA is expressed dominantly at both 9.5 and 18 dpc. Ca(v)3.1 (alpha(1G)) increases from 9.5 to 18 dpc, but remains at low level compared with Ca(v)3.2. In contrast, Ca(v)3.1 is greater than Ca(v)3.2 at the adult stage. In MI, Ca(v)3.1 mRNA correlates negatively with brain natriuretic peptide (BNP) mRNA, whereas Ca(v)3.2 mRNA correlates positively with BNP mRNA. In AOB, these correlations are weak. We also analyzed the neuron-restrictive silencer factor (NRSF) in these hearts because it is the suppressor of transcription of the fetal cardiac gene program. The negative correlation between NRSF and BNP was stronger in MI than in AOB. Our findings show that Ca(v)3.2 underlies the functional T-type Ca(2+) channel in embryonic heart and suggest that NRSF may regulate Ca(v)3.2 expression in diseased hearts.

Animals↗
PubMed2005

Discontinuous conduction in mouse bundle branches is caused by bundle-branch architecture.

BACKGROUND: Recordings of the electrical activity of mouse bundle branches (BBs) suggest reduced conduction velocity (CV) in the midseptal compared with the proximal part of the BB. The present study was performed to elucidate the mechanism responsible for this slowing of conduction. METHODS AND RESULTS: Hearts of 16 mice were isolated and Langendorff perfused. After the right and left ventricular free walls were removed, the extracellular activity of the BB was mapped with a 247-point electrode. Premature stimulation was used to estimate CV restitution in the BBs. Expression/distribution of connexin40 (Cx40), Cx43, and Cx45 was determined. Morphology of the conduction system was assessed by whole-mount acetylcholine esterase staining and in Cx40(+/KI-GFP) hearts. Effective CV in the midseptal part of the left and right BBs was reduced by 50% compared with the proximal BB. CV restitution in the proximal and midseptal parts of the BBs was similar. Myocytes labeled positive for Cx40 and Cx45 in the entire BB. Cx43 colocalized with Cx40 and Cx45 only in the very distal BB. Subcellular distribution of gap junctions differed between proximal and distal BBs. Geometry of the midseptal and distal BBs revealed on both sides a profuse network of interlacing fibers, whereas the proximal BB consisted of a single (right BB) or multiple (left BB) parallel fibers. CONCLUSIONS: Comparison of connexin expression/distribution, geometry of the BBs, and CV characteristics suggests that increased path length for activation resulting from BB geometry is responsible for the apparently reduced CV in the midseptal BB of the mouse heart.

Animals↗
PubMed2005

Repolarization gradients in the canine left ventricle before and after induction of short-term cardiac memory.

BACKGROUND: Questions remain about the contributions of transmural versus apicobasal repolarization gradients to the configuration of the T wave in control settings and after the induction of short-term cardiac memory. METHODS AND RESULTS: Short-term cardiac memory is seen as T-wave changes induced by altered ventricular activation that persists after restoration of sinus rhythm. We studied cardiac memory in anesthetized, open-chest dogs paced from the ventricle for 2 hours. Unipolar electrograms were recorded from as many as 98 epicardial and 144 intramural sites, and activation times and activation-recovery intervals (ARIs) were measured. In separate experiments, epicardial monophasic action potentials were recorded. We found no appreciable left ventricular intramural gradients in repolarization times (activation time+ARI) in either control conditions or after the induction of memory. In controls, there was a left ventricular apicobasal gradient, with the shortest repolarization times in anterobasal regions and longest repolarization times posteroapically. After induction of memory, repolarization times shortened uniformly throughout the ventricular wall. Monophasic action potential duration at 90% repolarization decreased by approximately 10 ms after induction of memory. CONCLUSIONS: In the intact canine left ventricle at physiological rates, there is no transmural gradient in repolarization. Apicobasal gradients in repolarization time, with shortest repolarization times in anterobasal areas and longest repolarization times in posteroapical regions, are important in the genesis of the T wave. Repolarization times and monophasic action potentials at the 90% repolarization level shorten after the induction of memory. The deeper T wave in the ECG after induction of memory may be explained by the more rapid phase 3 of the action potential.

Action Potentials↗
PubMed2005

The patient U wave.

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Computer Simulation↗
PubMed2005

Ventricular repolarization: an overview of (patho)physiology, sympathetic effects and genetic aspects.

Most textbook knowledge on ventricular repolarization is based on animal data rather than on data from the in vivo human heart. Yet, these data have been extrapolated to the human heart, often without an appropriate caveat. Here, we review multiple aspects of repolarization, from basic membrane currents to cellular aspects including extrinsic factors such as the effects of the sympathetic nervous system. We critically discuss some mechanistic aspects of the genesis of the T-wave of the ECG in the human heart. Obviously, the T-wave results from the summation of repolarization all over the heart. The T-wave in a local electrogram ideally reflects local repolarization. The repolarization moment is composed of the moment of local activation plus local action potential duration (APD) at 90% repolarization (APD90). The duration of the latter largely depends on the balance between L-type Ca2+ current and the delayed rectifier currents. Generally speaking, there is an inverse relationship between local activation time and local APD90, leading to less dispersion in repolarization moments than in activation moments or in APD90. In transmural direction, the time needed for activation from endocardium toward epicardium has been considered to be overcompensated by shorter APD90 at the epicardium, leading to the earliest repolarization at the subepicardium. In addition, mid-myocardial cells would display the latest repolarization moments. The sparse human data available, however, do not show any transmural dispersion in repolarization moment. Also, the effect of adrenergic stimulation on APD90 has been studied mainly in animals. Again, sparse human data suggest that the effect of adrenergic stimulation is different in the human heart compared to many other mammalian hearts. Finally, aspects of the long QT syndrome are discussed, because this intrinsic genetic disease results from repolarization disorders with extrinsic aspects.

Action Potentials↗
PubMed2005

A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families.

BACKGROUND: Mutations in the gene encoding the human cardiac sodium channel (SCN5A) have been associated with three distinct cardiac arrhythmia disorders: the long QT syndrome, the Brugada syndrome and cardiac conduction disease. Here we report the biophysical features of a novel sodium channel mutation, E161K, which we identified in individuals of two non-related families with symptoms of bradycardia, sinus node dysfunction, generalized conduction disease and Brugada syndrome, or combinations thereof. METHODS AND RESULTS: Wild-type (WT) or E161K sodium channel alpha-subunit and beta-subunit were cotransfected into tsA201 cells to study the functional consequences of mutant sodium channels. Characterization of whole-cell sodium current (I(Na)) using the whole cell patch-clamp technique revealed that the E161K mutation caused an almost threefold reduction in current density (P < 0.001), and an 11.9 mV positive shift of the voltage-dependence of activation (P < 0.0001). The inactivation properties of mutant and WT sodium channels were similar. These results suggest an overall reduction of E161K I(Na). Incorporation of the experimental findings into computational models demonstrate atrial and ventricular conduction slowing as well as a reduction in sinus rate by slowing of the diastolic depolarization rate and upstroke velocity of the sinus node action potential. This reduction in sinus rate was aggravated by application of acetylcholine, simulating the dominant vagal tone during night. CONCLUSION: Our experimental and computational analysis of the E161K mutation suggests that a loss of sodium channel function is not only associated with Brugada syndrome and conduction disease, but may also cause sinus node dysfunction in carriers of this mutation.

Acetylcholine↗
PubMed2005

Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure.

OBJECTIVE: In patients with heart disease, the transition from compensatory hypertrophy to heart failure (HF) is associated with altered calcium handling. Up-regulated Na(+)/H(+)-exchanger (NHE-1) activity underlies increased [Na(+)](i) and disturbance of cellular calcium handling in HF. We hypothesize that chronic inhibition of NHE-1 activity prevents the hypertrophic response, cellular remodeling, and development of HF. METHODS: Rabbits received a control or cariporide (inhibitor of NHE-1) diet for 3 months, starting after induction of combined volume and pressure overload. Age-matched animals served as control. Development of HF was examined echocardiographically and electrocardiographically after 3 months. [Na(+)](i), [Ca(2+)](i), pH(i), and action potentials were measured in left ventricular midmural myocytes with SBFI, indo-1, SNARF, and di-4-anepps. Sarcoplasmic reticulum calcium content was calculated from the response of [Ca(2+)](i) to rapid cooling. Calcium after-transients were elicited by cessation of rapid stimulation (3 Hz) in the presence of 100 nmol/l noradrenalin. RESULTS: Chronic treatment of rabbits with the specific Na(+)/H(+)-exchanger activity inhibitor cariporide greatly attenuated development of hypertrophy and entirely abolished development of HF; the heart/body weight ratio increased only little, no change in lung weight occurred, left ventricular dimensions and fractional shortening changed mildly, ascites was not present, QT duration did not increase, and sudden death did not occur. Chronic cariporide treatment also prevented cellular electrical and ionic remodeling. Myocyte dimensions were unaltered, action potentials were not prolonged, cytoplasmic sodium and NHE-1 activity did not increase, cytoplasmic and SR calcium handling remained undisturbed, and no increase of the incidence of calcium after-transient dependent delayed after depolarizations (DADs) occurred. CONCLUSION: We conclude that enhanced activity of NHE-1 underlies cardiac cellular electrical and ionic remodeling in experimental heart failure, and that chronic dietary treatment with cariporide attenuates hypertrophy, development of HF, and cellular remodeling.

Action Potentials↗