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(1/2050) Investigation of the theory and mechanism of the origin of the second heart sound.

To investigate further the origin of the second heart sound we studied human subjects, dogs, and a model in vitro of the cardiovascular system. Intra-arterial sound, pressure, and, where possible, flow and high speed cine (2,000 frames/sec) were utilized. The closure sound of the semilunar valves was of higher amplitude in be ventricles than in their respective arterial cavities. The direction of inscription of the main components of intra-arterial sound were opposite in direction to the components of intraventricular sound. Notches, representative of pressure increments, were noted on the ventricular pressure tracings and were coincident with the components of sound. The amplitude of the closure sound varied with diastolic pressure, but remained unchanged with augmentation of forward and retrograde aortic flow. Cines showed second sound to begin after complete valvular closure, and average leaflet closure rate was constant regardless of pressure. Hence, the semilunar valves, when closed, act as an elastic membrane and, when set into motion, generate compression and expansion of the blood, producing transient pressure changes indicative of sound. The magnitude of the initial stretch is related to the differential pressure between the arterial and ventricular chambers. Sound transients which follow the major components of the second sound appear to be caused by the continuing stretch and recoil of the leaflets. Clinically unexplained findings such as the reduced or absent second sound in calcific aortic stenosis and its paradoxical presence in congenital aortic stenosis may be explained by those observations.  (+info)

(2/2050) Hierarchy of ventricular pacemakers.

To characterize the pattern of pacemaker dominance in the ventricular specialized conduction system (VSCS), escape ventricular pacemakers were localized and quantified in vivo and in virto, in normal hearts and in hearts 24 hours after myocardial infarction. Excape pacemaker foci were localized in vivo during vagally induced atrial arrest by means of electrograms recorded from the His bundle and proximal bundle branches and standard electrocardiographic limb leads. The VSCS was isolated using a modified Elizari preparation or preparations of each bundle branch. Peacemakers were located by extra- and intracellular recordings. Escape pacemaker foci in vivo were always in the proximal conduction system, usually the left bundle branch. The rate was 43+/-11 (mean+/-SD) beats/min. After beta-adrenergic blockade, the mean rate fell to 31+/-10 beats/min, but there were no shifts in pacemaker location. In the infarcted hearts, pacemakers were located in the peripheral left bundle branch. The mean rate was 146+/-20 beats/min. In isolated normal preparations, the dominant pacemakers usually were in the His bundle, firing at a mean rate of 43+/-10 beats/min. The rates of pacemakers diminished with distal progression. In infarcted hearts, the pacemakers invariably were in the infarct zone. The mean firing rates were not influenced by beta-adrenergic blockade. The results indicate that the dominant pacemakers are normally in the very proximal VSCS, but after myocardial infarction pacemaker dominance is shifted into the infarct. Distribution of pacemaker dominance is independent of sympathetic influence.  (+info)

(3/2050) Taurine modulates I(Kr) but I(Ks) in guinea-pig ventricular cardiomyocytes.

1. Effects of taurine on the delayed rectifier K+ current (I(K)) in isolated guinea-pig ventricular cardiomyocytes were examined at different intracellular Ca2+ concentration ([Ca2+]i), using whole-cell voltage and current clamp techniques. Experiments were performed at 36 degrees C. 2. Addition of taurine (10-20 mM) decreased the action potential duration (APD) at pCa 8, but increased the APD at pCa 6. Taurine (20 mM) enhanced I(K) at 70 mV by 22.4 +/- 3.1% (n = 6, P < 0.01) at pCa 8, whereas taurine inhibited the I(K) by 27.1 +/- 2.7% (n = 6, P < 0.01) at pCa 6. These responses behaved in a concentration-dependent manner. 3. The I(K) is composed of the rapid and slow components (I(Kr) and I(Ks)). When [Ca2+]i was pCa 6, taurine at 20 mM reduced the tail current of I(Kr) at 70 mV by 16.5 +/- 2.7% (n = 5, P < 0.05) and that of I(Ks) at 70 mV by 27.1 +/- 2.8% (n = 6, P < 0.01). In contrast, at pCa 8, the tail currents of I(Kr) and I(Ks) at 70 mV were enhanced by 13.4 +/- 3.2% (n = 7, P < 0.05) and by 22.4 +/- 3.1% (n = 7, P < 0.01), respectively. The voltages of half-maximum activation (V1/2) for I(Kr) and I(Ks) were not modified by taurine. 4. Addition of E-4031 (5 microM) to taurine had a complete blockade of the tail current of I(Kr), but not I(Ks). The remained tail current (I(Ks)) in the presence of E-4031 (5 microM) was not affected by taurine (20 mM), but was blocked by 293B (30 microM). 5. These results indicate that taurine modulates I(Kr) but not I(Ks), depending on [Ca2+]i, resulting in regulation of the APD.  (+info)

(4/2050) A comparison of an A1 adenosine receptor agonist (CVT-510) with diltiazem for slowing of AV nodal conduction in guinea-pig.

1. The purpose of this study was to compare the pharmacological properties (i.e. the AV nodal depressant, vasodilator, and inotropic effects) of two AV nodal blocking agents belonging to different drug classes; a novel A1 adenosine receptor (A1 receptor) agonist, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside (CVT-510), and the prototypical calcium channel blocker diltiazem. 2. In the atrial-paced isolated heart, CVT-510 was approximately 5 fold more potent to prolong the stimulus-to-His bundle (S-H interval), a measure of slowing AV nodal conduction (EC50 = 41 nM) than to increase coronary conductance (EC50 = 200 nM). At concentrations of CVT-510 (40 nM) and diltiazem (1 microM) that caused equal prolongation of S-H interval (approximately 10 ms), diltiazem, but not CVT-510, significantly reduced left ventricular developed pressure (LVP) and markedly increased coronary conductance. CVT-510 shortened atrial (EC50 = 73 nM) but not the ventricular monophasic action potentials (MAP). 3. In atrial-paced anaesthetized guinea-pigs, intravenous infusions of CVT-510 and diltiazem caused nearly equal prolongations of P-R interval. However, diltiazem, but not CVT-510, significantly reduced mean arterial blood pressure. 4. Both CVT-510 and diltiazem prolonged S-H interval, i.e., slowed AV nodal conduction. However, the A1 receptor-selective agonist CVT-510 did so without causing the negative inotropic, vasodilator, and hypotensive effects associated with diltiazem. Because CVT-510 did not affect the ventricular action potential, it is unlikely that this agonist will have a proarrythmic action in ventricular myocardium.  (+info)

(5/2050) Effects of tumour necrosis factor-alpha on left ventricular function in the rat isolated perfused heart: possible mechanisms for a decline in cardiac function.

1. The cardiac depressant actions of TNF were investigated in the isolated perfused rat heart under constant flow (10 ml min(-1)) and constant pressure (70 mmHg) conditions, using a recirculating (50 ml) mode of perfusion. 2. Under constant flow conditions TNF (20 ng ml(-1)) caused an early (< 25 min) decrease in left ventricular developed pressure (LVDP), which was maintained for 90 min (LVDP after 90 min: control vs TNF; 110 +/- 4 vs 82 +/- 10 mmHg, P < 0.01). 3. The depression in cardiac function seen with TNF under constant flow conditions, was blocked by the ceramidase inhibitor N-oleoylethanolamine (NOE), 1 microM, (LVDP after 90 min: TNF vs TNF with NOE; 82 +/- 10 vs 11 +/- 5 mmHg, P < 0.05). 4. In hearts perfused at constant pressure, TNF caused a decrease in coronary flow rate (change in flow 20 min after TNF: control vs TNF; -3.0 +/- 0.9 vs -8.7 +/- 1.2 ml min(-1), P < 0.01). This was paralleled by a negative inotropic effect (change in LVDP 20 min after TNF: control vs TNF; -17 +/- 7 vs -46 +/- 6 mmHg, P < 0.01). The decline in function was more rapid and more severe than that seen under conditions of constant flow. 5. These data indicate that cardiac function can be disrupted by TNF on two levels, firstly via a direct, ceramidase dependant negative inotropic effect, and secondly via an indirect coronary vasoconstriction.  (+info)

(6/2050) Heterogeneous cardiac sympathetic denervation and decreased myocardial nerve growth factor in streptozotocin-induced diabetic rats: implications for cardiac sympathetic dysinnervation complicating diabetes.

Heterogeneous myocardial sympathetic denervation complicating diabetes has been invoked as a factor contributing to sudden unexplained cardiac death. In subjects with diabetic autonomic neuropathy (DAN), distal left ventricular (LV) denervation contrasts with preservation of islands of proximal innervation, which exhibit impaired vascular responsiveness. The aims of this study were to determine whether this heterogeneous pattern of myocardial sympathetic denervation occurs in a rat model of diabetes and to explore a potential association with regional fluctuations in myocardial nerve growth factor (NGF) protein. Myocardial sympathetic denervation was characterized scintigraphically using the sympathetic neurotransmitter analog C-11 hydroxyephedrine ([11C]HED) and compared with regional changes in myocardial NGF protein abundance and norepinephrine content after 6 and 9 months in nondiabetic (ND) and streptozotocin-induced diabetic (STZ-D) rats. In ND rats, no difference in [11C]HED retention or norepinephrine content was detected in the proximal versus distal myocardium. After 6 months, compared with ND rats, myocardial [11C]HED retention had declined in the proximal segments of STZ-D rats by only 9% (NS) compared with a 33% decrease in the distal myocardium (P < 0.05). Myocardial norepinephrine content was similar in both ND and STZ-D rats. At 6 months, LV myocardial NGF protein content in STZ-D rats decreased by 52% in the proximal myocardial segments (P < 0.01 vs. ND rats) and by 82% distally (P < 0.01 vs. ND rats, P < 0.05 vs. proximal segments). By 9 months, [11C]HED retention had declined in both the proximal and distal myocardial segments of the STZ-D rats by 42% (P < 0.01 vs. ND rats), and LV norepinephrine content and NGF protein were decreased in parallel. Therefore, 6 months of STZ-induced diabetes results in heterogeneous cardiac sympathetic denervation in the rat, with maximal denervation occurring distally, and is associated with a proximal-to-distal gradient of LV NGF protein depletion. It is tempting to speculate that regional fluctuations of NGF protein in the diabetic myocardium contribute to heterogeneous cardiac sympathetic denervation complicating diabetes.  (+info)

(7/2050) Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes.

The high incidence of sudden death in heart failure may reflect abnormalities of repolarization and heightened susceptibility to arrhythmogenic early afterdepolarizations (EADs). We hypothesized that overexpression of the human K+ channel HERG (human ether-a-go-go-related gene) could enhance repolarization and suppress EADs. Adult rabbit ventricular myocytes were maintained in primary culture, which suffices to prolong action potentials and predisposes to EADs. To achieve efficient gene transfer, we created AdHERG, a recombinant adenovirus containing the HERG gene driven by a Rous sarcoma virus (RSV) promoter. The virally expressed HERG current exhibited pharmacologic and kinetic properties like those of native IKr. Transient outward currents in AdHERG-infected myocytes were similar in magnitude to those in control cells, while stimulated action potentials (0.2 Hz, 37 degrees C) were abbreviated compared with controls. The occurrence of EADs during a train of action potentials was reduced by more than fourfold, and the relative refractory period was increased in AdHERG-infected myocytes compared with control cells. Gene transfer of delayed rectifier potassium channels represents a novel and effective strategy to suppress arrhythmias caused by unstable repolarization.  (+info)

(8/2050) Ventricular excitation maps using tissue Doppler acceleration imaging: potential clinical application.

OBJECTIVES: The purpose of this study is to validate the use of tissue Doppler acceleration imaging (TDAI) for evaluation of the onset of ventricular contraction in humans. BACKGROUND: Tissue Doppler acceleration imaging can display the distribution, direction and value of ventricular acceleration responses to myocardial contraction and electrical excitation. METHODS: Twenty normal volunteers underwent TDAI testing to determine the normal onset of ventricular acceleration. Two patients with paroxysmal supraventricular tachycardia and 30 patients with permanent pacemakers underwent introduction of esophageal and right ventricular pacing electrodes, respectively, and were studied to visualize the onset of pacer-induced ventricular acceleration. Eight patients with dual atrioventricular (AV) node and 20 patients with Wolff-Parkinson-White (WPW) syndrome underwent TDAI testing to localize the abnormal onset of ventricular acceleration, and the results were compared with those of intracardiac electrophysiology (ICEP) tests. RESULTS: The normal onset and the onset of dual AV node were localized at the upper interventricular septum (IVS) under the right coronary cusp within 25 ms before the beginning of the R wave in the electrocardiogram (ECG). In all patients in the pacing group, the location and timing of the onset conformed to the positions and timing of electrodes (100%). In patients with WPW syndrome, abnormal onset was localized to portions of the ventricular wall other than the upper IVS at the delta wave or within 25 ms after the delta wave in the ECG. The agreement was 90% (18 of 20) between the abnormal onset and the position of the accessory pathways determined by ICEP testing. CONCLUSIONS: These results suggest that TDAI is a useful noninvasive method that frequently is successful in visualizing the intramural site of origin of ventricular mechanical contraction.  (+info)