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Michael R Rosen

Publications and source records attributed to Michael R Rosen.

17 recordsLinked to original sources
PubMed2003

Heterogeneous ventricular repolarization provides a substrate for arrhythmias in a German shepherd model of spontaneous arrhythmic death.

BACKGROUND: German shepherd dogs with inherited arrhythmias and sudden death appear to be a model for catecholamine-dependent ventricular tachycardias in human subjects. We tested the hypothesis that heterogeneity of left ventricular repolarization creates an arrhythmogenic substrate for pause-dependent ventricular tachycardia in these animals. METHODS AND RESULTS: We used microelectrode techniques to record action potentials (AP) from midmyocardial sections of anteroseptal, anterobasal, and posterobasal left ventricular (LV) wall of unafflicted and afflicted dogs. There were no differences in AP duration to 90% repolarization (APD) among LV regions in unafflicted dogs. In contrast, in afflicted dogs, there was significant heterogeneity, with the longest APD in anterobasal and shortest in anteroseptal regions. Isoproterenol did not affect repolarization in unafflicted dogs, whereas in afflicted dogs, it shortened APD anterobasally and prolonged APD anteroseptally. We studied the repolarizing currents, IKr and IKs, in single anteroseptal and anterobasal LV myocytes with the use of a whole-cell voltage clamp. There were no differences in IKr and IKs between anteroseptal and anterobasal regions in unafflicted dogs, whereas in afflicted dogs, IKr was smaller anterobasally (P<0.05). Isoproterenol produced a more prominent leftward shift in IKs voltage-dependent activation in anterobasal regions of afflicted than unafflicted dogs. CONCLUSIONS: Spatial heterogeneity in expression and catecholamine responsiveness of IKr and IKs results in heterogeneous LV repolarization in afflicted German shepherd dogs, contributing importantly to the arrhythmogenic substrate.

Action Potentials↗
PubMed2003

Developmental changes in IKr and IKs contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia.

OBJECTIVE: Clinical and experimental studies suggest that immature hearts are as or more sensitive than adult hearts to adverse effects of I(Kr) blocking drugs. We hypothesized that age-dependent changes in I(Kr) and I(Ks) contribute to the different repolarization reserves and proarrhythmic effects of I(Kr) blockers in the young and adult heart. METHODS: Dogs aged 1-150 days and adults were used to study (1) proarrhythmic effects in situ of the I(Kr) blocker dofetilide; (2) dofetilide effects on action potential duration (APD) recorded with microelectrodes from left ventricular (LV) slabs; (3) I(Kr) and I(Ks) in single LV myocytes using whole-cell voltage clamp. RESULTS: In situ, dofetilide-induced proarrhythmia occurred in 40% of adults, 86% of young (20-150 day) dogs and 0% of neonatal (1-19 day) dogs (P<0.05). Isolated tissue experiments showed no transmural gradient for repolarization from neonate through 3 months of age, after which the gradient increased through adulthood. In the presence of dofetilide, the greatest APD prolongation occurred in neonates. Yet, transmural dispersion did not increase in neonates but significantly increased in young and adults. Dofetilide-induced early after depolarization (EAD) incidence was 23% in adults, 59% in young and 8% in neonates (P<0.05). I(Kr) but not I(Ks) was expressed at <30 days, whereas both currents were present in adult myocardium. CONCLUSIONS: Our data suggest that a lack of I(Ks) results in a greater dependence on I(Kr) for repolarization in neonates and is associated with exaggerated effects of I(Kr)-blockade on APD. However, APD prolongation alone is insufficient for expression of proarrhythmia, which also requires transmural dispersion of repolarization and EADs. The extent to which APD prolongation, transmural dispersion and EADs are manifested at various ages in the absence and presence of I(Kr) blocking drugs appears to be the ultimate determinant of proarrhythmia.

Action Potentials↗
PubMed2003

Cardiac memory is associated with decreased levels of the transcriptional factor CREB modulated by angiotensin II and calcium.

Cardiac memory (CM) has short- (STCM) and long-term (LTCM) components modulated by calcium and angiotensin II. LTCM is associated with reduced Ito and Kv4.3 mRNA levels. Because the cAMP response element binding protein, CREB, contributes to CNS memory transcription, we hypothesized that it might be a transcriptional factor in CM, influenced by calcium and angiotensin II. We studied STCM in dogs that were AV sequentially paced (AVP) for 2 hours or sham-operated. STCM was evaluated with ECG and vectorcardiogram (VCG), and subepicardial biopsies were taken at 5 to 120 minutes and investigated for CREB. LTCM was studied in dogs paced for 3 weeks and in sham controls. At 3 weeks the heart was excised, biopsies obtained, and CRE binding tested. STCM induction occurred in AVP dogs but not in sham or AVP dogs treated with saralasin or nifedipine. Nuclear CREB was significantly decreased at 2 hours in the AVP no-drug group only. LTCM dogs manifested reduced binding of nuclear proteins to CRE, and CRE binding activity in the promoter region of Kv4.3. In conclusion, there is an association between STCM induction and decreased nuclear CREB that is angiotensin-modulated and calcium-dependent. Moreover, the decreased CRE binding after 3 weeks of AVP combined with CRE binding activity in the Kv4.3 promoter can explain the Kv4.3 mRNA and Ito downregulation that characterize LTCM.

Angiotensin II↗
PubMed2003

Chronic atrial fibrillation does not further decrease outward currents. It increases them.

Rapid atrial pacing causes electrical remodeling that leads to atrial fibrillation (AF). AF can further remodel atrial electrophysiology to maintain AF. Our previous studies showed that there was a marked difference in the duration of AF in dogs that have been atrial paced at 400 beats/min for 6 wk. We hypothesized that this difference is based on the changes in the degree of electrical remodeling caused by rapid atrial pacing versus that by AF. Right atrial cells were isolated from control dogs (Con, N = 28), from dogs with chronic AF (cAF dogs, N = 13, episodes lasting at least 6 days), or from dogs with nonsustained or brief episodes of AF (nAF dogs, N = 10, episodes lasting minutes to hours). Both transient outward (Ito) and sustained outward K+ current (Isus) densities/functions were determined using whole cell voltage-clamp techniques. In nAF cells, Ito density was reduced by 69% at +40 mV: from 7.1 +/- 0.5 pA/pF (Con, n = 59) to 2.2 +/- 0.2 pA/pF (nAF, n = 24) (P < 0.05). The voltage dependence of inactivation of Ito was shifted positively and decay kinetics were changed; however, recovery from inactivation was not altered in nAF cells. In contrast, Ito density in cAF cells was both significantly different from Con cells and larger than that in nAF cells [at +40 mV, 3.5 +/- 0.3 pA/pF (cAF, n = 29), P < 0.05]. In cAF cells, recovery from inactivation and decay of Ito were both slow; yet, voltage dependence inactivation of Ito approached that of Con cells. Furthermore, "recovered" Ito of cAF cells was more sensitive to tetraethylammonium than currents of Con and nAF cells. Isus densities of nAF and cAF cells did not differ. Both nAF and cAF cells have reduced Ito versus Con cells, but Ito remodeling of nAF cells differed from that of cAF cells. Ito in cAF dogs was likely remodeled by AF per se, whereas that in nAF dogs was likely the consequence of the rapid rate in the absence of sustained AF.

Animals↗
PubMed2003

Calcium and potassium currents in cells from adult and aged canine right atria.

BACKGROUND: Action potential (AP) contours vary considerably between normal adult and aged right atrial fibers. The ionic bases for these differences remain unknown. Therefore we studied Ca(2+) and K(+) currents in cells from adult and aged canine right atria (RA). METHODS AND RESULTS: We used whole cell patch clamp recording techniques to measure L-type Ca(2+) currents (I(CaL)) with either Ca(2+) or Ba(2+) (3 mM) as the charge carrier, and both the transient outward (I(to)) and sustained potassium currents (I(sus)) in cells dispersed from normal adult (Adult, 2-5 years) and older dogs (Aged, >8 years). There is a significant reduction in peak I(CaL) (47%) and I(BaL) (43%) in Aged cells, yet differences in I(BaL) disappear with maximal beta adrenergic stimulation (isoproterenol, 1 microM). Composite I(to) and I(sus) densities were significantly increased in the Aged versus Adult cell group (by 31 and 27% at +50 mV, respectively). I(to) decay during a maintained depolarization was slowed in Aged cells. Furthermore, I(to) steady-state inactivation curve was shifted positively in Aged cells. Finally, composite I(to) and I(sus) currents of Aged cells were more sensitive to tetraethylammonium chloride (TEA), a specific inhibitor of some types of K(+) currents. In the presence of TEA (5 mM), I(to) in Aged cells was significantly greater than that in Adult cells. CONCLUSIONS: Ionic currents differ in Aged versus Adult right atrial cells, such that a reduced Ca(2+) current and augmented outward currents could contribute significantly to the altered AP contour of the Aged RA cell. Adrenergic stimulation appears to restore Ba(2+) currents in Aged cells. Finally, an augmented TEA sensitive current plays a role in changes of I(sus) in Aged right atrial cells.

Action Potentials↗
PubMed2003

Role of L-type calcium channels in pacing-induced short-term and long-term cardiac memory in canine heart.

BACKGROUND: We tested the hypothesis that ICa,L is important to the development of cardiac memory. METHODS AND RESULTS: The effects of L-type Ca2+ channel blockade and beta-blockade were tested on acutely anesthetized and on chronically instrumented, conscious dogs. Short-term memory (STM) was induced by 2 hours of ventricular pacing and long-term memory (LTM) by ventricular pacing for 21 days. STM dogs received placebo, nifedipine, or propranolol, and LTM dogs received placebo, atenolol, or amlodipine. AT1 receptor blockade (candesartan) and ACE inhibition (trandolapril) were also tested in LTM. Microelectrodes were used to record transmembrane potentials from isolated epicardial and endocardial slabs using a protocol simulating STM in intact animals. Left ventricular epicardial myocytes from LTM or sham control dogs were dissociated, and ICa,L was recorded (whole-cell patch-clamp technique). Evolution of STM and LTM was attenuated by ICa,L blockers but not beta-blockers. Neither AT1 receptor blockade nor ACE inhibition suppressed LTM. In microelectrode experiments, pacing induced an epicardial-endocardial gradient change mimicking STM that was suppressed by nifedipine. In patch-clamp experiments, peak ICa,L density in LTM and control were equivalent, but activation was more positive and time constants of inactivation longer in LTM (P<0.05). CONCLUSIONS: ICa,L blockade but not beta-adrenergic blockade suppresses cardiac memory. LTM evolution is unaffected by angiotensin II blockade and is associated with altered ICa,L kinetics.

Action Potentials↗
PubMed2003

Expression and function of a biological pacemaker in canine heart.

BACKGROUND: We hypothesized that localized overexpression of the hyperpolarization-activated, cyclic nucleotide-gated (HCN2) pacemaker current isoform in canine left atrium (LA) would constitute a novel biological pacemaker. METHODS AND RESULTS: Adenoviral constructs of mouse HCN2 and green fluorescent protein (GFP) or GFP alone were injected into LA, terminal studies performed 3 to 4 days later, hearts removed, and myocytes examined for native and expressed pacemaker current (I(f)). Spontaneous LA rhythms occurred after vagal stimulation-induced sinus arrest in 4 of 4 HCN2+GFP dogs and 0 of 3 GFP dogs (P<0.05). Native I(f) in nonexpressed atrial myocytes was 7+/-4 pA at -130 mV (n=5), whereas HCN2+GFP LA had expressed pacemaker current (I(HCN2)) of 3823+/-713 pA at -125 mV (n=10) and 768+/-365 pA at -85 mV. CONCLUSIONS: HCN2 overexpression provides an I(f)-based pacemaker sufficient to drive the heart when injected into a localized region of atrium, offering a promising gene therapy for pacemaker disease.

Adenoviridae↗
PubMed2003

Analysis of a municipal wastewater treatment plant using a neural network-based pattern analysis.

This paper addresses the problem of how to capture the complex relationships that exist between process variables and to diagnose the dynamic behaviour of a municipal wastewater treatment plant (WTP). Due to the complex biological reaction mechanisms, the highly time-varying, and multivariable aspects of the real WTP, the diagnosis of the WTP are still difficult in practice. The application of intelligent techniques, which can analyse the multi-dimensional process data using a sophisticated visualisation technique, can be useful for analysing and diagnosing the activated-sludge WTP. In this paper, the Kohonen Self-Organising Feature Maps (KSOFM) neural network is applied to analyse the multi-dimensional process data, and to diagnose the inter-relationship of the process variables in a real activated-sludge WTP. By using component planes, some detailed local relationships between the process variables, e.g., responses of the process variables under different operating conditions, as well as the global information is discovered. The operating condition and the inter-relationship among the process variables in the WTP have been diagnosed and extracted by the information obtained from the clustering analysis of the maps. It is concluded that the KSOFM technique provides an effective analysing and diagnosing tool to understand the system behaviour and to extract knowledge contained in multi-dimensional data of a large-scale WTP.

Data Collection↗
PubMed2002

Testosterone diminishes the proarrhythmic effects of dofetilide in normal female rabbits.

BACKGROUND: Recent clinical and experimental data suggest that testosterone may protect males against the deleterious effects of repolarization-prolonging drugs. This study tests the hypothesis that 5alpha-dihydrotestosterone (DHT) protects normal females against drug-induced excessive prolongation of repolarization. METHODS AND RESULTS: We used microelectrode techniques to study isolated preparations of rabbit ventricular endocardium from age-matched normal control female rabbits and female rabbits treated with DHT for 4 weeks. Serum 17beta-estradiol levels were identical in the control and DHT-treated animals, whereas DHT levels were high (equaling those in normal males) only in the DHT-treated animals. Basal action potential duration to 90% repolarization (APD90) was significantly shorter in DHT-treated (155+/-7.4 ms, n=32) than control females (178+/-6.7 ms, n=29; P<0.05) at cycle length=1000 ms. The increase in APD90 induced by 10(-8) mol/L dofetilide at cycle length=1000 ms was significantly less in DHT-treated females than normal females (DeltaAPD90=8+/-7 and 29+/-5 ms, respectively, P<0.05). At 10(-6) mol/L dofetilide, the incidence of early afterdepolarizations was 28% in DHT-treated and 55% in normal female rabbits (P<0.05). CONCLUSIONS: Elevating DHT levels diminishes the effects of dofetilide to increase APD and induce early afterdepolarizations in females. Moreover, treatment of females with DHT results in prolongation of APD and an incidence of early afterdepolarization equal to values previously reported by us for dofetilide-treated normal males. That serum levels of 17beta-estradiol were the same in DHT-treated and untreated females suggests that estradiol is not involved in the response to dofetilide. Thus, these data suggest that DHT and perhaps other androgenic hormones may protect normal females against the risk of dofetilide-induced arrhythmia.

Action Potentials↗
PubMed2002

Sex, hormones, and repolarization.

There is increased awareness of the impact of gender and gonadal steroids on human cardiac rhythm and arrhythmias; e.g., drugs that prolong repolarization induce torsades de pointes (TdP) more frequently in women than men; female gender is an independent risk factor for syncope and sudden death in the congenital long QT syndrome; and the higher propensity toward arrhythmia in normal females is associated with fundamental differences in repolarization such that rate-corrected QT intervals are longer in females than males. Mechanisms underlying these differences are incompletely defined but are believed to involve gonadal steroids. This review discusses recent advances and prospects for further elucidation of the influence of gender and gonadal steroids on ventricular repolarization and arrhythmias.

Aging↗
PubMed2002

Effects of gonadal steroids on gender-related differences in transmural dispersion of L-type calcium current.

OBJECTIVES: Repolarization-prolonging drugs induce torsades de pointes (TdP) in females more than males. The action potential plateau and the early afterdepolarizations that induce TdP are determined, in part, by L-type calcium current (I(Ca,L)). Therefore, we studied gender- and hormone-related differences in I(Ca,L) in age-, and weight-matched normal male, female and hormonally-treated, castrated rabbits. METHODS: Oophorectomized (OVX) or orchiectomized (ORCH) 50- to 60-day-old rabbits were subcutaneously implanted with pellets impregnated with placebo (PLA), 5 alpha-dihydroxytestosterone (DHT), or 17 beta-estradiol (EST). Four to five weeks later, epicardial and endocardial myocytes were isolated from the left ventricle. Patch clamp technique was performed to assess I(Ca,L). RESULTS: I(Ca,L) density (measured as peak current density [pA/pF] at +15 mV, V(h)= -40 mV), was greater in female epicardium (-7.4 +/- 0.9) than endocardium (-5.6 +/- 0.7, P<0.05), while male epicardial I(Ca,L) density (-6.5 +/- 0.7) did not differ from endocardial (-5.9 +/- 1.0, P>0.05). OVX-female, DHT and EST-treated groups had epicardial I(Ca,L) density (-5.6 +/- 0.6, and -5.9 +/- 0.7, respectively) greater than endocardial (-4.3 +/- 0.3, and -3.6 +/- 0.4, P<0.05). However, OVX-females had hormone levels not significantly different from female controls and EST-treated females had non-physiological levels of estradiol. There were no differences between endocardial and epicardial I(Ca,L) activation and inactivation. In contrast, epicardial-endocardial differences in I(Ca,L) density in EST-treated OVX-females were associated with epicardial-endocardial differences in I(Ca,L) activation and conductance; in DHT-treated OVX-females only epicardial-endocardial activation differed. The other groups, showed no I(Ca,L) transmural gradient, or differences in activation, inactivation or conductance. CONCLUSIONS: The greater dispersion in I(Ca,L) density of OVX-DHT and OVX-EST than OVX-PLA suggests both hormones can modulate I(Ca,L) density in females. That gonadal steroids had no effect on I(Ca,L) dispersion in males suggests gender differences in mechanism of action of both hormones. The greater I(Ca,L) dispersion in females may contribute to gender differences in repolarization.

Analysis of Variance↗
PubMed2002

Cellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis.

OBJECTIVE: The incidence of atrial fibrillation increases with age. We hypothesized that aging-associated changes in the atrial action potential (AP) and conduction velocity provide a substrate for abnormal conduction and arrhythmogenesis. METHODS: We used microelectrode techniques to record AP from the endocardium of the right atrial wall of dogs aged 1-5 (adult) and >8 years (old). Conduction velocity was measured between two microelectrodes 3-10 mm apart. Histological study was carried out to assess fibrosis. RESULTS: Whereas resting potential, AP amplitude and V(max) did not differ with age, the plateau was more negative and AP duration was longer in old tissue. The L-type calcium current (I(Ca,L)) agonist Bay K8644 (10(-8)-10(-6) mol/l) elevated the plateau and shortened APD more in old than in adult, such that AP contour in old atria approached that of adult. In contrast, the I(Ca,L) blocker nisoldipine (10(-8)-10(-5) mol/l) depressed the plateau in adult and had no effect in old. There was no difference between the two groups in conduction velocity of normal beats, whereas for early premature impulses, reduced conduction velocity and a wider time window manifesting slow conduction were detected in old in comparison to adult tissue. A twofold increase in the amount of fibrous tissue was detected in old atria. CONCLUSIONS: Our data show significant differences in contour of AP in adult and old atria. The responses to Bay K8644 and nisoldipine suggest a decreased I(Ca,L) in old atrial tissue. The alterations in AP contour and increased fibrosis may be responsible for slower conduction of early premature beats in old atria. The age-related changes in conduction of premature beats are consistent with those observed in patients with paroxysmal atrial fibrillation and may contribute to the greater propensity to atrial fibrillation in the aged.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

Density and function of inward currents in right atrial cells from chronically fibrillating canine atria.

OBJECTIVE: To determine whether I(Na) and I(CaL) are altered in function/density in right atrial (RA) cells from dogs with chronic atrial fibrillation (cAF dogs, episodes lasting at least 6 days) and whether the changes that occur differ from those in dogs with nonsustained or brief episodes of fibrillation (nAF dogs). METHODS: Using whole cell voltage clamp, sodium and calcium current density and function were determined in disaggregated RA cells from nAF, cAF and control atria (Con). Ca(2+) currents were studied with either Ca(2+) or Ba(2+) as charge carrier, as well as with either EGTA or BAPTA as the internal solution Ca(2+) chelator. RESULTS: After rapid atrial pacing, dogs can either fibrillate for short periods of time (nAF) or longer, more sustained periods (cAF). Both the Na(+) and Ca(2+) current decrease in cells of the nAF atria. Na(+) current density remains reduced in cAF cells with some slowing of recovery kinetics. Ca(2+) current density does not further decrease with persistent atrial fibrillation (cAF cells) remaining significantly different from Con cells. However, the difference in density of Ca(2+) currents between nAF and Con cells is negligible when Ba(2+) is charge carrier and when Ca(i) is quickly and effectively chelated with BAPTA. On the contrary, cAF I(BaL) densities remain significantly reduced compared to Con and nAF values when Ba(2+)/BAPTA conditions are used. CONCLUSIONS: Na(+) current density/function does not recover to Con values in cAF. Further these enhanced Ca(2+)-dependent inactivation processes contribute significantly to the reduction of I(CaL) density observed in nAF cells while reduction of Ca(2+) currents in cAF atria is probably by another mechanism

Analysis of Variance↗
PubMed2002

Adrenergic-cholinergic interaction that modulates repolarization in the atrium is altered with aging.

INTRODUCTION: Aging is associated with involution of both limbs of the autonomic nervous system, and the prejunctional and postjunctional effects of adrenergic and cholinergic stimulation are altered with senescence. Hence, postjunctional age-related changes in adrenergic-cholinergic interaction are a likely occurrence and may contribute to an altered substrate for arrhythmias. METHODS AND RESULTS: Microelectrode techniques were used to record action potentials from epicardial slices of Bachmann's bundles of dogs aged 3 to 5 years (adult) and 8 to 12 years (old) in the absence or presence of acetylcholine and isoproterenol (separately and in combination). In control, action potential duration to 90% repolarization (APD) was longer in old atria. Acetylcholine (10(-8) to 10(-5) mol/L) in a concentration-dependent manner hyperpolarized and shortened APD in both tissues, with more prominent effects in the old. The effects of isoproterenol (10(-9) to 10(-6) mol/L) to elevate the plateau and shorten APD were about the same in both adult and old tissues. In adults, low concentrations of isoproterenol (10(-9) and 10(-8) mol/L) significantly prolonged APD, which had been first shortened by acetylcholine. This effect of isoproterenol was decreased in old atrial tissue, resulting in shorter APD in old than adult atria in the combined presence of beta-adrenergic and muscarinic agonists. CONCLUSION: In adult Bachmann's bundle, beta-adrenergic stimulation effectively operates as a "brake" to decrease the extent of cholinergic-induced APD shortening. The action of beta-adrenergic stimulation to antagonize acetylcholine-induced acceleration of repolarization declines with age, which may contribute to an altered arrhythmogenic substrate.

Acetylcholine↗
PubMed2002

beta(1)-Receptors increase cAMP and induce abnormal Ca(i) cycling in the German shepherd sudden death model.

We studied the role of beta-adrenergic receptor subtype signaling to cAMP and calcium in the genesis of catecholamine-dependent arrhythmias in German shepherd dogs that develop lethal arrhythmias at ~5 mo of age. There were three major findings in this study: 1) isoproterenol induces similar increases in cAMP in afflicted and control dogs exclusively through beta(1)-receptors (not beta(2)), 2) cells from afflicted dogs display prolonged relaxation kinetics at long cycle lengths and large frequent spontaneous calcium oscillations (and aftercontractions) with little increase in calcium transient amplitude in response to beta(1)-receptor agonists, and 3) beta(2)-receptor agonists induce a similar marked increases in calcium transient and twitch amplitude, with only rare spontaneous calcium oscillations in afflicted and control cells. These results indicate that catecholamines provide inotropic support to canine cardiomyocytes through distinct beta(1)- and beta(2)-receptor pathways with differing requirements for cAMP. The propensity to develop arrhythmias is not induced by beta(2)-receptors (or a rise in calcium alone), but rather occurs in the context of beta(1)-receptor activation of the cAMP-dependent pathway.

Adrenergic beta-Agonists↗