No abstract

Although fast sodium current (INa) plays a major role in the generation and conduction of the cardiac impulse, the electrophysiological characteristics of INa in isolated human ventricular myocytes have not yet been fully described. We characterized the human ventricular INa of enzymatically isolated myocytes using whole cell voltage-clamp techniques. Sixty myocytes were isolated from ventricular specimens obtained from 22 patients undergoing open-heart surgery. A low temperature (17 degrees C) and Na+ concentration in the external solution (5 or 10 mM) allowed good voltage control and facilitated the measurement of INa. Cs+ was substituted for K+ in both internal and external solutions to block K+ currents, and F- was added to the internal solution to block Ca2+ current. INa was activated at a voltage threshold of approximately -70 mV, and maximal inward current was obtained at approximately -30 mV (holding potential = -140 mV). The voltage dependence of steady-state INa availability (h infinity) was sigmoidal with half inactivation occurring at -97.3 +/- 1.1 mV and a slope factor of 5.77 +/- 0.10 mV (n = 60). We did not detect any significant differences in these parameters in cells from patients with a variety of disease states, with or without congestive heart failure. The overlap in voltage dependence of h infinity and Na+ conductance suggested the presence of a Na+ "window" current. An inactivation time course was voltage dependent and was fitted best by the sum of two exponentials. The rate of recovery from inactivation also was voltage dependent and fitted by the sum of two exponentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Patch-clamp recording techniques have permitted measurement of the fast Na+ current (INa) [Na+]., and the current was completely blocked by 100 ,uM tetrodotoxin, findings typical of the fast cardiac Na+ current. The tetrodotoxin dose-response curve was best fitted by an equation describing binding to high-and low-affinity sites. INa was activated at a voltage threshold of -70 to -60 mV, and peak inward current was obtained at =-30 mV (holding potential, -140 mV). The inactivation time course was voltage dependent and was fitted best by the sum of two exponentials. The relation between voltage and steady-state availability (h.,) was sigmoidal with the half-inactivation at -95.8±0.9 mV and a slope factor of 5.3+0.1 mV (n=46), and we did not observe a significant difference with disease and age.

Atrial myocytes isolated from failing human hearts exhibited a lower resting membrane potential and reduced sensitivity to ACh compared with donor atria. Whole-cell and single-channel measurements suggest that these alterations are caused by reduced IK1 and IK(ACh) channel density and reduced IK(ACh) channel sensitivity to Gi-mediated channel activation in HF.

SUMMARY The mechanical properties of the normal left ventricular wall during diastole were studied in 15 chronically instrumented, conscious dogs. Left ventricular minor and major axis diameters and equatorial wall thickness were measured with implanted pulse-transit ultrasonic dimension transducers. Left ventricular and pleural pressures were measured with high fidelity micromanometers. Circumferential mural stress was calculated by using an ellipsoidal shell theory; circumferential strain was calculated by using a natural strain definition. The static elastic properties of the myocardium were estimated by fitting the stress-strain values at the points of diastasis during a vena caval occlusion to an exponential function. A modified creep test was used to evaluate the series viscous properties of the myocardium. Acute increases in systolic and diastolic loading were produced by inflating implanted aortic occluders for 15 minutes in five dogs. In these dogs, the static stress-strain curves were not altered significantly after this period of pressure loading, indicating tbat short-term series viscous properties are negligible. Parallel viscous properties were evaluated in 10 dogs by means of the variable rate stretch test of dynamic diastolic filling. A viscoelastic model incorporating a parallel viscous element fit the dynamic stress-strain data better and predicted the static elastic properties more accurately than a simple exponential model. Thus, the mechanical characteristics of the diastolic left ventricle can be represented most precisely by a viscoelastic model that includes a parallel viscous element.AN EXPONENTIAL relationship between ventricular pressure and volume during diastole was first demonstrated by Frank.1 Influenced by Blix, 2 Frank concluded that this observation represented a fundamental relationship between diastolic force and length within the ventricular wall. During the past two decades there has been a renewed interest in describing the mechanical properties of diastolic myocardium, and numerous investigators have confirmed Frank's observations in a variety of experimental preparations. "5 On the basis of these studies it generally has been accepted that, in both the isolated and the intact heart, an exponential relationship exists between left ventricular pressure and volume during diastole. 6 However, several authors recently have suggested that fitting pressure-volume or pressure-dimension data from a single diastolic filling period with a simple exponential function may be an oversimplification. "12 Indeed, previous experiments that demonstrated exponential pressure-dimension curves in the intact heart utilized static measurements during induced volume changes.13 So far as we are aware, there are no directly measured data in the literature which indicate that ventricular pressure and di- Received July 9,1976; accepted for publication December 10,1976. mensions are exponentially related during the dynamic filling of a single diastole. The diastolic mechanical properties of isolate...

Ventilation with positive end-expiratory pressure (PEEP) is associated with reduced cardiac output, but the mechanisms involved are controversial. Possible explanations include increased intrathoracic pressure, reflex changes in myocardial inotropism, pulmonary vascular obstruction and abnormal ventricular interaction. Three types of conscious canine preparations were developed to examine simultaneously each of these factors during ventilation with PEEP. In addition, similar measurements were obtained in patients after cardiac surgical procedures and compared with the results of animal experiments. The primary cause of reduced cardiac output during PEEP appeared to be a diminished end-diastolic volume of the left ventricle, and this appeared to be the result of elevated intrathoracic pressure and increased impedance to blood flow through the lungs. Abnormal interventricular septal shifting and reflex autonomic alterations did not appear to be significant in the normal cardiovascular system. These data provide insight into the cardiac effects of PEEP and emphasize the importance of simultaneous quantification of biventricular performance when assessing cardiopulmonary function.

The f8-adrenergic modulation of the inwardly-rectifying K+ channel (IK,) When fi-adrenergic modulation of IKi was compared between ventricular myocytes isolated from the failing and the nonfailing heart, channel response to ISO and PKA was significantly reduced in myocytes from the failing heart. Although ISO inhibited IKi in a concentration-dependent fashion in both groups, a half-maximal concentration was greater in failing (0.12 ,uM) than in nonfailing hearts (0.023 ,LM). These results suggest that IKi in human ventricular myocytes can be inhibited by a PKA-mediated phosphorylation and the modulation is significantly reduced in ventricular myocytes from the failing heart compared to the nonfailing heart. (J. Clin. Invest. 1995. 96:2870-2881

These results suggest that the electrophysiological characteristics of human atrial and ventricular IK1 channels were similar to those of other mammalian hearts, with the possible exception that the channel open probability in humans may be higher, that the whole-cell IK1 density is higher in human ventricle than in atrium, and that IK1 channels in patients with DCM exhibited electrophysiological properties distinct from IK1 channels found in patients with ICM and in donors.