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T Opthof

Publications and source records attributed to T Opthof.

At least 19 recordsLinked to original sources
PubMed2003

Right atrial modification of maze surgery does not affect refractoriness and conduction patterns of human lone atrial fibrillation.

BACKGROUND: Tissue mass and structure are relevant for initiation and persistence of fibrillation. Modification of the right atrium during maze surgery may change the arrhythmogenic substrate of atrial fibrillation (AF). METHODS AND RESULTS: Epicardial mapping was performed in 9 patients undergoing unmodified maze III surgery for lone paroxysmal AF. Simultaneous recording of AF on the right and left atrium was carried out with two spoon-electrodes each harbouring 64 terminals. Activation maps of AF were made to study AF wavelet organization. The recording position on right and left atria was outside the surgical field and remained unchanged before and after surgery. Before surgery, mean right and left fibrillatory intervals were 174+/-23 ms, and 175+/-26 ms, respectively, and did not differ. After completed right atrial surgery, these fibrillary intervals remained unchanged. Mean right and left atrial dispersion of refractoriness (expressed as the coefficient of variation) were 4.2+/-0.8 and 5.2+/-3.8 ms. Only right atrial dispersion of refractoriness increased significantly after right-sided surgery. Prior to surgery, activation patterns of the left atrium were more complex than that of the right atrium. The left activation patterns became less complex afterwards; the right atrial activation patterns did not change. CONCLUSION: The right atrial modification of maze III surgery neither affects atrial refractoriness during human lone AF nor changes AF wavelet organization. Thus, right atrial surgery does not modify the arrhythmogenic substrate of AF. These findings may imply that maze surgery can be restricted to the left atrium.

Atrial Fibrillation↗
PubMed2002

Cardiomyocyte differentiation of mouse and human embryonic stem cells.

Ischaemic heart disease is the leading cause of morbidity and mortality in the western world. Cardiac ischaemia caused by oxygen deprivation and subsequent oxygen reperfusion initiates irreversible cell damage, eventually leading to widespread cell death and loss of function. Strategies to regenerate damaged cardiac tissue by cardiomyocyte transplantation may prevent or limit post-infarction cardiac failure. We are searching for methods for inducing pluripotent stem cells to differentiate into transplantable cardiomyocytes. We have already shown that an endoderm-like cell line induced the differentiation of embryonal carcinoma cells into immature cardiomyocytes. Preliminary results show that human and mouse embryonic stem cells respond in a similar manner. This study presents initial characterization of these cardiomyocytes and the mouse myocardial infarction model in which we will test their ability to restore cardiac function.

Adult↗
PubMed2001

Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit: implications for arrhythmogenesis in humans.

BACKGROUND: Class III antiarrhythmic agents commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). This is undesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of blockade of separate components of delayed rectifier K(+) current (I(K)) may help to develop agents effective at high heart rate. METHODS AND RESULTS: We assessed the density and kinetics of the 2 components of the delayed rectifier K(+) current, I(Kr) and I(Ks), in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for I(Ks) and E-4031 for I(Kr)) on the action potential was studied at different heart rates by use of whole-cell patch-clamp techniques. In guinea pig ventricular myocytes only, blockade of I(Ks) causes APD prolongation in a frequency-independent manner, whereas blockade of I(Ks) in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of I(Kr) in both species. This result can be explained primarily by the higher density of I(Ks) in guinea pig ventricle and by its slow deactivation kinetics, which allows I(Ks) to accumulate at high heart rate because little time is available for complete deactivation of it during diastole. CONCLUSIONS: Density and kinetics of components of I(K) explain why blockade of I(Ks) is more effective at high heart rate in the guinea pig ventricle than in the rabbit ventricle, without adverse effects at low heart rate.

Action Potentials↗
PubMed2001

Cardiac gap junction channels: modulation of expression and channel properties.

In the heart, intercellular gap junction channels constructed from connexin molecules are crucial for conduction of the electric impulse. Cardiomyocytes can be interconnected by channels composed of three types of connexin proteins: Cx40, Cx43 or Cx45. In mammalian hearts, these three isoforms are regionally differently expressed and even between the species differences exist. Each of these channel-types possesses specific properties and are susceptible to modulation by various mechanisms. In this paper we compare the differences in properties of these channels as deduced from studies on transfected cells and isolated cardiomyocytes and discuss the factors involved in modulation of channel properties. Next, we evaluate the consequences of alterations in expression and modulation of channel properties for cardiac function. Therefore, we have compared reports on genetically engineered animals and discuss this information in relation to various pathophysiological disorders.

Animals↗
PubMed2001

Impaired conduction in the bundle branches of mouse hearts lacking the gap junction protein connexin40.

BACKGROUND: Connexin (Cx)40 and Cx45 are the major protein subunits of gap junction channels in the conduction system of mammals. To determine the role of Cx40, we correlated cardiac activation with Connexin distribution in normal and Cx40-deficient mice hearts. METHODS AND RESULTS: Epicardial and septal activation was recorded in Langendorff-perfused adult mice hearts with a 247-point compound electrode (interelectrode distance, 0.3 mm). After electrophysiological measurements, hearts were prepared for immunohistochemistry and histology to determine Connexin distribution and fibrosis. In both wild-type and Cx40-deficient animals, epicardial activation patterns were similar. The right and left ventricular septum was invariably activated from base to apex. Histology revealed a continuity of myocytes from the common bundle to the septal myocardium. Within this continuity, colocalization was found of Cx43 and Cx45 but not of Cx40 and Cx43. Both animals showed similar His-bundle activation. In Cx40-deficient mice, the proximal bundle branches expressed Cx45 only. The absence of Cx40 in the proximal bundles correlated with right bundle-branch block. Conduction in the left bundle branch was impaired as compared with wild-type animals. CONCLUSIONS: Our data show that (1) in mice, a continuity exists between the common bundle and the septum, and (2) Cx40 deficiency results in right bundle-branch block and impaired left bundle-branch conduction.

Animals↗
PubMed2001

I(f) current and spontaneous activity in mouse embryonic ventricular myocytes.

Knowledge of the initiation of electrical and contractile activity in the embryonic heart relies to a large extent on data obtained in chicken. In recent years, molecular biological techniques have raised an interest in mouse physiology, including early embryonic development. We studied action potentials and the occurrence of one of the pacemaker currents, I(f), by the whole-cell voltage and current-clamp technique at the earliest stage at which a regular heartbeat is established (9.5 days postcoitum) and at 1 day before birth. We show, first, that at the early stage there is a prominent I(f) in mouse embryonic ventricles, which decreases by 82% before birth in concert with the loss of regular spontaneous activity of ventricular cells. Second, the decrease in I(f) current is associated with a slight change in channel gating kinetics and a decrease in total mRNA expression of the genes encoding for I(f) current. Third, the most prevalent mRNA subtype is switched from HCN4 to HCN2 during the second half of embryonic development. Fourth, the I(f) current may be modulated by the beta-adrenergic cascade, although the coupling to the beta-adrenoceptor in the sarcolemma itself is not yet mature. We conclude that I(f) current of the sinus node type is present in early embryonic mouse ventricular cells. In association with a loss of I(f) current, the ventricle tends to lose pacemaker potency during the second half of embryonic development.

Action Potentials↗
PubMed2001

Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling.

OBJECTIVE: Acute ischemia comes with two phases of life-threatening arrhythmias, early (within 10 minutes, 1A) and late (after about 15 minutes, 1B). The mechanism of the latter is unknown and in this paper, we test the hypothesis that a phase of intermediate coupling between surviving epicardium and inexcitable midmyocardium underlies 1B arrhythmias. METHODS: Pig hearts (n=26) were retrogradely perfused with a blood Tyrode's mixture. The left anterior descending artery was occluded. We investigated (1) inducibility of ventricular fibrillation (VF) with programmed stimulation, (2) tissue impedance (Rt) heterogeneity within the ischemic zone, (3) multiple subepicardial and midmyocardial electrograms, (4) subepicardial lactate dehydrogenase (LDH) and glycogen content. RESULTS: In nine of ten hearts, one--three premature stimuli caused VF between 14 and 53 min of ischemia. This typically happened when the Rt of the ischemic zone had increased up to 40% of its final value. More uncoupling terminated the period of VF inducibility. The excitability of the surviving subepicardial layer was depressed during the same period with partial uncoupling, but recovered when the uncoupling from the midmyocardium had progressed further. CONCLUSIONS: We show that 1B-VF can be induced within a distinct time window and coincides with a distinct range of Rt rise. Subepicardium is electrically depressed, presumably through coupling with midmyocardium, complete uncoupling causes subepicardial recovery and terminates the substrate for 1B-VF. Hence, we suggest that the substrate for 1B-VF consists of intermediate coupling of subepicardium and midmyocardium.

Animals↗
PubMed2001

Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia.

BACKGROUND: Studies in isolated tissues and myocytes show different repolarisation properties in subepicardium, midmyocardium and subendocardium. Whether these differences are present in vivo and are relevant to humans has been the subject of controversy. Our objectives were (1) to ascertain whether transmural repolarisation gradients are present in humans, (2) to determine whether the greater sensitivity of subepicardial cells to ischaemia in vitro is manifest during early ischaemia in humans in vivo. METHODS AND RESULTS: We studied 21 patients during routine coronary artery surgery. Unipolar activation recovery intervals (ARI) were recorded from five transmural locations between subepicardium and subendocardium in the left ventricular wall. A pacing protocol spanned a range of cycle lengths from a cycle length of 300 ms to the maximum permitted by the intrinsic atrial activity. Following the onset of cardiopulmonary bypass recordings were obtained before (control) and during a 3-min period of global ischaemia. During control transmural ARIs were homogeneous between 300 and 1500 ms (ventricular pacing) and 750 and 1500 ms (atrial spontaneous beats). During ischaemia, ARIs shortened similarly at all transmural electrode sites and transmural homogeneity was maintained. CONCLUSIONS: Transmural repolarisation differences within the ventricular wall of the human heart were absent at cycle lengths within the physiological range but also during prolonged cycles. During early (global) ischaemia repolarisation changed equally in subepicardial and subendocardial regions and transmural homogeneity of repolarisation was preserved.

Adult↗
PubMed2001

Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I: Phenotypic characterisation.

OBJECTIVES: The KCNQ1 gene encodes the KvLQT1 potassium channel, which generates in the human heart the slow component of the cardiac delayed rectifier current, I(Ks). Mutations in KCNQ1 are the most frequent cause of the congenital long QT syndrome. We have previously cloned a cardiac KCNQ1 human isoform, which exerts a strong dominant-negative effect on KvLQT1 channels. We took advantage of this dominant-negative isoform to engineer an in vivo model of KvLQT1 disruption, obtained by overexpressing the dominant-negative subunit under the control of the alpha-myosin heavy chain promoter. RESULTS: Three different transgenic lines demonstrated a phenotype with increasing severity. Functional suppression of KvLQT1 in transgenic mice led to a markedly prolonged QT interval associated with sinus node dysfunction. Transgenic mice also demonstrated atrio-ventricular block leading to occasional Wenckebach phenomenon. The atrio-ventricular block was associated with prolonged AH but normal HV interval in His recordings. Prolonged QT interval correlated with prolonged action potential duration and with reduced K(+) current density in patch-clamp experiments. RNase protection assay revealed remodeling of K(+) channel expression in transgenic mice. CONCLUSIONS: Our transgenic mouse model suggests a role for KvLQT1 channels not only in the mouse cardiac repolarisation but also in the sinus node automaticity and in the propagation of the impulse through the AV node.

Action Potentials↗
PubMed2001

Arrhythmogenesis in heart failure.

In a rabbit model of heart failure produced by combined pressure and volume overload, nonsustained ventricular tachycardias developed in 15 of 23 failing rabbits. Sinus rate was increased in rabbits dying suddenly, but was decreased in survivors. This also was true in isolated preparations. Microelectrode recordings from ventricular trabeculae both from patients with end-stage failure and from failing rabbits showed that in half of the preparations, delayed afterdepolarizations and triggered activity occurred, but only in the presence of norepinephrine and a lowered extracellular K+ concentration of 3 mM. This was due to spontaneous release of Ca2+ from the sarcoplasmic reticulum.

Animals↗
PubMed2001

Norepinephrine induces action potential prolongation and early afterdepolarizations in ventricular myocytes isolated from human end-stage failing hearts.

AIMS: Congestive heart failure is characterized by high levels of norepinephrine which is considered to be arrhythmogenic. It is unclear whether increased norepinephrine is only a marker of the severity of heart failure or whether it directly triggers ventricular arrhythmias. METHODS AND RESULTS: Ventricular myocytes were isolated from eight explanted hearts of patients with end-stage heart failure (ischaemic or dilated cardiomyopathy). With the whole-cell configuration of the patch-clamp technique the effect of 1 micromol x l(-1)norepinephrine on action potentials and membrane currents was studied. The cells had a membrane capacitance of 256 +/- 25 pF (n = 26) and action potential duration (APD90) during control conditions was 620 +/- 45 ms at 1 Hz (n = 14). Norepinephrine induced action potential prolongation in all cells and early afterdepolarizations in 50% of them. Norepinephrine significantly increased the calcium current but had no effect on the delayed rectifier current, the inward rectifier current or the transient outward current. Norepinephrine also significantly increased the steady-state calcium window-current measured between -40 and 0 mV. CONCLUSIONS: In contrast to many animal species, norepinephrine induces action potential prolongation in ventricular myocytes from human failing hearts, as well as early afterdepolarization, by an increase in both the calcium peak current and window current. Thus norepinephrine seems to be an important arrhythmogenic factor in congestive heart failure.

Action Potentials↗
PubMed2000

Changes in sinus node function in a rabbit model of heart failure with ventricular arrhythmias and sudden death.

BACKGROUND: Heart failure is associated with profound changes in the balance of the autonomic nervous system, such as vagal withdrawal and increased catecholamine levels. It is not known whether the intrinsic sinus node function changes during the progression of heart failure. METHODS AND RESULTS: We implanted transmitters for Holter recording in an established rabbit model of heart failure (n=9) and observed changes in sinus cycle length and the occurrence of arrhythmias during the progression of heart failure. The in vitro sinus cycle length and the responses to acetylcholine and norepinephrine in the isolated right atria were analyzed in 12 rabbits with heart failure and in 6 control rabbits. In vivo cycle length increased in some animals and decreased in others. Sudden death occurred in 3 of 9 rabbits. These rabbits had developed a shorter cycle length than the surviving rabbits. Ventricular tachycardias developed in all but 1 rabbit. The in vitro sinus cycle length increased in heart failure. The response to acetylcholine also increased in heart failure, whereas the response to norepinephrine was unchanged. CONCLUSIONS: Changes in intrinsic sinus node function during the progression of heart failure cannot explain the observed decreases in heart rate variability and/or baroreflex sensitivity in this disease, because increased responsiveness to acetylcholine would be expected to cause the opposite.

Animals↗