Biomedical subjects

Guy Salama

Publications and source records attributed to Guy Salama.

25 records · Page 2Linked to original sources

PubMed2003

Fiber orientation and cell-cell coupling influence ventricular fibrillation dynamics.

UNLABELLED: Cell Coupling Influences VF Dynamics. INTRODUCTION: The structure of ventricular fibrillation (VF) is influenced by regional differences in action potential durations and perhaps restitution kinetics and fiber anisotropy. The spatial organization of VF was investigated by measuring the cross-correlation (CC) and mutual information (MI) of membrane potential (Vm) oscillations recorded from multiple sites. METHODS AND RESULTS: Rabbit hearts (n = 6) were retrogradely perfused and stained with di-4-ANEPPS, and VF was elicited by burst pacing. Vm oscillations were recorded optically from multiple locations on the epicardium using a 16 x 16 photodiode array or a 72 x 78 CCD camera. The spatial organization of VF was investigated by calculating the maximum CC (CCmax) and MI (MImax) that can be obtained between any two sites. CCmax and MImax were extended to all pixels and served as indices of the similarities between Vm transients at a reference pixel and all other pixels on the map. We found that maps of CCmax and MImax did not contain discrete regions with high CC or MI. However, CCmax and MImax decreased monotonically with increasing distance between any arbitrarily chosen reference pixel and all other pixels. In VF, maps of CCmax and MImax revealed elliptical gradients of CC and MI that were closely aligned with fiber orientation, with major axis at 127 degrees +/- 8 degrees on the left ventricles. CONCLUSION: CC and MI analysis in fibrillation provides new evidence that anisotropy of fiber orientation and cell-cell coupling have a direct influence on VF dynamics.

Action Potentials↗

PubMed2003

In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype.

Mutations in cardiac voltage-gated K+ channels cause long QT syndrome (LQTS) and sudden death. We created a transgenic mouse with a long QT phenotype (Kv1DN) by overexpression of a truncated K+ channel in the heart and investigated whether the dominant negative effect of the transgene would be overcome by the direct injection of adenoviral vectors expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. End points at 3-10 days included electrophysiology in isolated cardiomyocytes, surface ECG, programmed stimulation of the right ventricle, and in vivo optical mapping of action potentials and repolarization gradients in Langendorff-perfused hearts. Overexpression of Kv1.5 reconstituted a 4-aminopyridine-sensitive outward K+ current, shortened the action potential duration, eliminated early afterdepolarizations, shortened the QT interval, decreased dispersion of repolarization, and increased the heart rate. Each of these changes is consistent with a physiologically significant primary effect of adenoviral expression of Kv1.5 on ventricular repolarization of Kv1DN mice.

4-Aminopyridine↗

PubMed2002

Calcium-dependent arrhythmias in transgenic mice with heart failure.

Transgenic mice overexpressing the inflammatory cytokine tumor necrosis factor (TNF)-alpha (TNF-alpha mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias on ambulatory telemetry monitoring, and decreased survival compared with nontransgenic littermates. Programmed stimulation in vitro with single extra beats elicits reentrant ventricular arrhythmias in TNF-alpha (n = 12 of 13 hearts) but not in control hearts. We performed optical mapping of voltage and Ca(2+) in isolated perfused ventricles of TNF-alpha mice to study the mechanisms that lead to the initiation and maintenance of the arrhythmias. When compared with controls, hearts from TNF-alpha mice have prolonged of action potential durations (action potential duration at 90% repolarization: 23 +/- 2 ms, n = 7, vs. 18 +/- 1 ms, n = 5; P < 0.05), no increased dispersion of refractoriness between apex and base, elevated diastolic and depressed systolic [Ca(2+)], and prolonged Ca(2+) transients (72 +/- 6 ms, n = 10, vs. 54 +/- 5 ms, n = 8; P < 0.01). Premature beats have diminished action potential amplitudes and conduct in a slow, heterogeneous manner. Lowering extracellular [Ca(2+)] normalizes conduction and prevents inducible arrhythmias. Thus both action potential prolongation and abnormal Ca(2+) handling may contribute to the initiation of reentrant arrhythmias in this heart failure model by mechanisms distinct from enhanced dispersion of refractoriness or triggered activity.

Action Potentials↗

PubMed2002

Cytosolic Ca2+ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with type 2 long QT syndrome.

The role of intracellular Ca2+ (Ca2+i) in triggering early afterdepolarizations (EADs), the origins of EADs and the mechanisms underlying Torsade de Pointes (TdP) were investigated in a model of long QT syndrome (Type 2). Perfused rabbit hearts were stained with RH327 and Rhod-2/AM to simultaneously map membrane potential (V(m)) and Ca2+i with two photodiode arrays. The I(Kr) blocker E4031 (0.5 microM) together with 50 % reduction of [K+]o and [Mg2+]o elicited long action potentials (APs), V(m) oscillations on AP plateaux (EADs) then ventricular tachycardia (VT). Cryoablation of both ventricular chambers eliminated Purkinje fibres as sources of EADs. E4031 prolonged APs (0.28 to 2.3 s), reversed repolarization sequences (baseapex) and enhanced repolarization gradients (30 to 230 ms, n = 12) indicating a heterogeneous distribution of I(Kr). At low [K+]o and [Mg2+]o, E4031 elicited spontaneous Ca2+iand V(m) spikes or EADs (3.5 +/- 1.9 Hz) during the AP plateau (n = 6). EADs fired 'out-of-phase' from several sites, propagated, collided then evolved to TdP. Phase maps (Ca2+ivs. V(m)) had counterclockwise trajectories shaped like a 'boomerang' during an AP and like ellipses during EADs, with V(m) preceding Ca2+iby 9.2 +/- 1.4 (n = 6) and 7.2 +/- 0.6 ms (n = 5/6), respectively. After cryoablation, EADs from surviving epicardium (~1 mm) fired at the same frequency (3.4 +/- 0.35 Hz, n = 6) as controls. At the origins of EADs, Ca2+ipreceded V(m) and phase maps traced clockwise ellipses. Away from EAD origins, V(m) coincided with or preceded Ca2+i. In conclusion, overload elicits EADs originating from either ventricular or Purkinje fibres and 'out-of-phase' EAD activity from multiple sites generates TdP, evident in pseudo-ECGs.

Animals↗

PubMed2002

Life span of ventricular fibrillation frequencies.

The nature and organization of electrical activity during ventricular fibrillation (VF) are important and controversial subjects dominated by 2 competing theories: the wavebreak and the dominant mother rotor hypothesis. To investigate spatiotemporal characteristics of ventricular fibrillation (VF), transmembrane potentials (V(m)) were recorded from multiple sites of perfused rabbit hearts using a voltage-sensitive dye and a photodiode array or a CCD camera, and the time-frequency characteristics of V(m) were analyzed by short-time fast Fourier transform (FFT) or generalized time-frequency representation with a cone-shaped kernel. The analysis was applied to all pixels to track VF frequencies in time and space. VF consisted of blobs, which are groups of contiguous pixels with a common frequency and an ill-defined shape. At any time t, several VF frequency blobs coexisted in the field of view, and the number of coexisting blobs was on average 5.9+/-2.1 (n=8 hearts) as they appeared and disappeared discontinuously with time and were not fixed in space. The life span of frequency blobs from birth to either annihilation or breakup to another frequency had a half-life of 0.39+/-0.13 second (n=4 hearts). The Ca2+ channel blocker nifedipine increased the stability of VF frequencies and reduced the number of frequency blobs progressing to a single frequency. In conclusion, VF consists of dynamically changing frequency blobs, which have a short life span and can be modified by pharmacological interventions, suggesting that VF is maintained by dynamically changing multiple wavelets.

Action Potentials↗

PubMed2002

Mice display sex differences in halothane-induced polymorphic ventricular tachycardia.

BACKGROUND: Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little is known about sex differences in the electrophysiology of mouse hearts. METHODS AND RESULTS: This study investigated the influence of sex on drug-induced polymorphic ventricular tachycardia (PVT) in Langendorff-perfused male and female mice hearts (n=54) by injecting a bolus of halothane (1.75 mmol/L) in the perfusate while recording ECGs or optical action potentials (APs). There were no statistically significant differences between male and female hearts (n=54) with respect to mean RR (193+/-5 ms), PR (47+/-1 ms), QT intervals (101+/-3 ms), optical AP durations (APD(75)=23.11+/-4.2 ms), dispersion of refractory periods, and conduction velocities (n=5 male and 5 female). Halothane induced PVTs lasting a mean duration of 90 seconds; in female hearts, 55% of PVTs lasted longer than the median, whereas in male hearts 17% exceeded the mean (P<0.05). The total duration of PVTs exposed a marked sex difference, 378+/-144 seconds in female versus 27+/-10 seconds in male hearts (P<0.05). In optically mapped male hearts, halothane reduced APD(75) (17.61+/-1.6 ms) and then elicited VTs (n=6 of 6), but in female hearts, halothane elicited PVTs (n=1 of 6) or arrested the hearts (n=5 of 6). Except for KCNE1, Northern blots (KCNQ1, MERG, Kv1.5, connexins 40 and 43, TREK1, and TASK1) did not detect sex differences. CONCLUSIONS: This mouse model reveals sex difference in response to a pharmacological challenge yet does not display sex differences in standard electrophysiological parameters. Differences in KCNE1 may contribute to sex differences uncovered by halothane.

Action Potentials↗

PubMed2000

Images of Action Potential Propagation in Heart.

Activation and repolarization across mammalian hearts follow complex three-dimensional pathways that are governed by fiber structure, intercellular coupling, and action potentials (APs) with spatially heterogeneous properties. Voltage-sensitive dyes and imaging techniques offer new insights on how spatiotemporal heterogeneities of APs govern propagation, repolarization, and AV node conduction and help us visualize arrhythmias with previously unattainable details.

Journal Article↗