Absence of atherosclerosis in human intramyocardial coronary arteries: a neglected phenomenon.

Atherosclerosis is absent in human intramyocardial (buried) coronary arteries but atherosclerosis may be severe in superficial segments of the same vessels. The development of atherosclerosis has three phases: a plasma phase, a transfer phase and an intramural phase. The transfer phase involves the transfer of low-density lipoproteins and macrophages from the plasma into the arterial wall. Efficiency of transfer is low where plasma flow near the wall is rapid. Eddy currents caused by arterial branches produce low flow near the arterial wall. Plasma recalculates and moves slowly in these eddy currents and thus prolongs contact of LDL and macrophages with the wall, increasing the occurrence of atherosclerosis. Absence of atherosclerosis in buried vessels appears due to the effects of myocardial contraction on the transfer phase. Contraction of the myocardium surrounding buried arterial vessel compresses these vessels and moves the plasma, LDL and macrophages away from the wall. This will decrease transfer into the wall and act to prevent the development of atherosclerosis. Similar but less striking effects occur where bridges of myocardium cross arterial vessels. Possible applications to human disease are discussed briefly.

Studies of the electrical activity of the ventricles and the origin of the QRS complex.

Historical events in the development of cardiac electrophysiology are described briefly. Observations before 1900 showed that electrical changes accompanied activity of muscle and nerve. Other studies showed that electrical activity of the heart produced voltage changes on the human torso. In 1903 Einthoven developed the string galvanometer which made measurement of electrocardiographic potentials much easier, more accurate and more common. The bases of understanding of arrhythmias were established by Lewis in the early 1900's. Soon thereafter Wilson devised practical and theoretical approaches to the human electrocardiogram which led to many further developments. Events before 1950 established the existence and mechanism of electrical activity in excitable cells. Studies of the origin of QRS began in about 1950, with studies of depolarization of the canine ventricle. Studies of the human ventricle followed. In the 70's it appeared possible to solve the electrocardiographic forward problem, prediction of electrocardiographic potentials from a knowledge of intracardiac events. That solution appeared possible because of new approaches to the associated physical and computational problems. Attempts to solve the forward problem at that time assumed that the cardiac generator (the boundary between resting and depolarized cells) was a uniform double layer generator. (The strength of the generator is constant everywhere along the boundary). Meanwhile physiologists and anatomists had worked out the mechanism of communication between cardiac cells. The cells are longer than they are wide, and each cell can depolarize contiguous cells. The connections between cells are predominantly at the ends of the cell and the longitudinal depolarization of a cardiac mass travels three times as fast as transverse depolarization. The generator is not uniform but is strongest parallel to the long axes of the cells. Many or most of those working in the field did not recognize the importance of the connections between cardiac cells in not only the pathway of excitation, but also the potentials produced as the cells depolarized. A number of experiments indicated that the uniform double layer assumption led to both qualitative and quantitative errors in prediction of fields generated by depolarization of cardiac muscle. These are reviewed. There are now alternatives to the uniform model which recognize the non-uniformity of the cardiac generators, particularly the axial model. The forward problem is unsolved but it appears possible that these newer models will make a solution possible.

Validity of the uniform double layer in the solution of the ECG forward problem.

This study attempted to solve the electrocardiographic forward problem (ie, to predict body surface potential fields from pathways of depolarization). A perfused heart was suspended in a cylinder and surrounded with fluid of the conductivity of the lung. Computation of potential fields included conductivity and boundary effects and assumed a uniform double-layer source. Three instants (early, late, and mid QRS) during normal depolarization and one instant during a stimulated beat were studied. There was good qualitative agreement between recorded and predicted fields early and late in the QRS and during the stimulated beat, but there were quantitative differences. The cardiac generator was far stronger late in the QRS. In mid QRS, the agreement between recorded and predicted fields was very poor. To resolve questions raised in this study, potentials around a small volume of stimulated tissue were recorded and predicted. Recorded potentials were compared with potentials calculated (1) on the assumption that the cardiac generator is a uniform double layer and (2) on the assumption that all current flows along the long axes of the cardiac fibers. The recorded potentials compared most favorably with the second of these. These studies led to the opinion that the uniform double-layer assumption is inadequate for prediction of body surface potential fields from depolarization pathways. Other studies of the forward and inverse problem that assume a uniform double-layer source are considered to be successful and therefore disagree with this study's conclusion. It appears that the question needs further experimental study.

Pulsatile sinus pressure changes evoke sustained baroreflex responses in awake dogs.

A modified Stephenson-Donald preparation was used to control pressure in an isolated carotid sinus in conscious dogs with all other arterial baroreceptors denervated. Sinus pressure was changed from preisolation control levels to either an elevated static or an elevated pulsatile pressure for 5 min. These sinus pressure changes evoked similar initial decreases in arterial pressure. The elevated static sinus pressure (150 or 175 mmHg) caused an initial depressor response of -32.7 +/- 5.5 mmHg, which then decayed rapidly. Five minutes after the change in sinus pressure, the depressor response was abolished, as arterial pressure returned to control pressure. This decay of the response would be expected if resetting occurred. In contrast, when the sinus was exposed to elevated pulsatile pressures (125 or 150 mmHg mean, 50 mmHg pulse pressure) depressor responses were sustained throughout the sinus pressure change (-23.2 +/- 5.3 mmHg initial, -29.0 +/- 4.8 mmHg at 5 min; P greater than 0.4). These results demonstrate that while the reflex responses rapidly reset to elevated static sinus pressures, elevated pulsatile pressures elicit sustained reflex responses.

Recovery of arterial pressure control after partial baroreceptor denervation in awake rabbits.

We examined recovery of control of heart rate (HR) and total peripheral resistance (TPR) by arterial baroreceptors after bilateral carotid sinus and aortic denervation or unilateral carotid sinus and aortic denervation in conscious rabbits. In one group of animals, HR responses to changes in mean arterial pressure (MAP) after injection of nitroglycerin or phenylephrine were measured in control studies and at 2, 5, 10, and 15 days after partial baroreceptor denervation. All denervation procedures increased MAP and HR at 2 and 5 days after denervation. Reflex sensitivity decreased to 57-67% of control on day 2 after denervation. HR responses recovered by day 10 after bilateral aortic or carotid sinus denervation; however, recovery following unilateral denervation was less complete. In a second group of animals, studied after implantation of aortic flowmeters, TPR changes following reduction in cardiac output by inferior vena caval occlusion were 49% of control responses on day 2 after denervation and returned close to control level on day 5. Controls of HR and TPR recovered substantially and were not significantly different from control 10 days after partial denervation. Recovery apparently occurred through the remaining arterial baroreceptors, possibly due to central reorganization of reflex pathways.

Hypertension following denervation of aortic baroreceptors in unanesthetized dogs.

After cervical aortic nerve section, mean arterial pressure in the unanesthetized dog increased by an average of 7.4 mm Hg. Following a more extensive denervation of aortic arch receptors by section of intrathoracic vagal branches, arterial pressure increased by 16.7 mm Hg. The above changes were seen in the stable state after the effects of surgery had disappeared. In both cases carotid baroreceptors were functional. After administration of nitroglycerin and phenylephrine subsequent to either denervation procedure, blood pressure changes were larger and heart rate responses were smaller than in the control state. The unanesthetized dog regulates mean arterial pressure at a higher-than-normal pressure after aortic baroreceptor denervation. Reflexes from the aortic baroreceptors continuously participate in the normal control of mean arterial pressure. Section of the cervical aortic nerves only partially denervates aortic baroreceptors. Our findings may be relevant to human essential hypertension.

The canine heart as an electrocardiographic generator. Dependence on cardiac cell orientation.

Traditionally it is assumed that during cardiac depolarization the macroscopic current generators that produce electrocardiographic voltages can be represented as a uniform double-layer source, coincident with the macroscopic boundary between resting and depolarized cardiac fibers as measured with extracellular electrodes ("uniform" hypothesis). A segment of this boundary is thus considered as a current dipole oriented perpendicular to the boundary. We present evidence that, contrary to the above, the effective dipoles largely parallel the long axes of cardiac fibers ("axial" hypothesis). Calculated potentials in volume conductors differ markedly in the two cases. The magnitudes of rapid local "intrinsic" deflections also differ markedly. In our experiments, potential fields prodlced by stimulation at several cardiac sites and measured magnitudes of intrinsic deflections during normal depolarization and that caused by stimulation support the axial hypothesis and are incompatible with the uniform hypothesis. Our results suggest that axial orientation of sources is sufficiently strong so that predictions assuming the uniform hypothesis would be seriously in error, although the axial theory alone does not exactly describe all the measured potentials. Axial orientation of current generators must be considered in quantitative prediction of electrocardiographic potentials. tfurther study of the geometry of the intracellular depolarization boundary and its relation to fiber direction and to the frequency of lateral intercellular junctions is required to describe the generators exactly.

Effect of tissue anisotropy on extracellular potential fields in canine myocardium in situ.

The extracellular epicardial potential fields produced by simple depolarization waves in the in situ canine left ventricular myocardium were analyzed. A mathematical model that included tissue anisotrophy was developed to explain the observed fields. Values of intracellular (i), extracellular (o), longitudinal (l), and transverse (t) resistivity which gave the best fit between the model and experimental data were (in ohm-cm, mean +/- SD): rol = 852 +/- 232, rot = 1247 +/- 210, ril = 291 +/- 38, rit = 1677 +/- 331. The potential fields around simple stimulated waves on the epicardium can best be explained if the extracellular wavefront voltage is (mean +/- SD) 74 +/- 7 mV for a wave propagating parallel to the local muscle fibers, and 43 +/- 6 mV for a wave propagating perpendicular to these fibers. We conclude that the anisotrophy of the electrical conductivity of cardiac muscle has important effects on he propagation of waves of depolarization and on the potential fields produced by depolarization in the intact heart.

Hypertension following arterial baroreceptor denervation in the unanesthetized dog.

Studies were conducted on unanesthetized dogs (1) in the control state, (2) after carotid sinus denervation plus section of the cervical aortic nerves (SCAD), and (3) after carotid sinus denervation plus section of intrathoracic vegal branches which innervate arterial and cardiopulmonary baroreceptors, the heart, lungs, and other structures (STD). Mean values and standard deviations of blood pressure and heart rate were measured during many 75-minute recording sessions. The control mean arterial pressure was 94.8 +/- 8.9 mm Hg. The mean pressure after SCAD was 105.5 +/- 9.5 mm Hg, 10.0 mm Hg higher (P less than 0.05) than in the control state, whereas after STD, the mean pressure was 119.5 +/- 16.8 mm Hg, 25.3 mm Hg higher (P less than 0.001) than in the control state. The standard deviation of pressure was increased (P less than 0.01) by either denervation procedure. The mean pressure after STD was higher than after SCAD (P less than 0.05). Ten of 12 animals with SCAD showed residual baroreceptor reflexes (seven from intrathoracic receptors) whereas, after STD, six of 11 animals showed reflexes (one from intrathoracic receptors). SCAD only occasionally produces denervation as complete as that produced by STD. A larger increase in arterial pressure follows a more complete denervation of vagally innervated baroreceptors. We believe that our procedures do not denervate all arterial baroreceptors. Chronic denervation of arterial baroreceptors leads to a widely varying, elevated arterial pressure. The increase in pressure has persisted more than 1 1/2 years.

Pulsatile pressure can prevent rapid baroreflex resetting.

In a previous study [Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H673-H678, 1988] we demonstrated that baroreflex responses decay (reset) to increased static sinus pressures, but with increased pulsatile pressure, responses are maintained. To determine more conclusively whether pulsatile pressure prevents rapid baroreflex resetting in this study we examined resetting as shifts of the baroreflex (sinus pressure-arterial pressure) curve. In seven anesthesized rabbits the left sinus was vascularly isolated and conditioned for 5 min to static or pulsatile pressures of 60, 100, or 140 mmHg mean pressure, 0 or 35-40 mmHg pulse pressure. The baroreflex curve was then determined by stepwise changing sinus pressure from 40 to 160 mmHg in 20-mmHg increments. Threshold, midpoint, and saturation sinus pressures shifted 25-39% with static conditioning pressures but did not shift significantly with pulsatile pressures. Also, the baroreflex responses to step increases in static sinus pressure decayed, as resetting occurred, but did not decay with pulsatile sinus pressure increases. Thus the baroreflex rapidly resets with static pressures, but there is minimal, if any, resetting with pulsatile pressures.

The control of atrial contraction by ventriculo-atrial pacing in the dog with AV block.

Atrial contraction in dogs with atrioventricular (AV) block was controlled by multiple atrial stimuli delivered during ventricular diastole. Acute hemodynamic changes were assessed. At a ventricular rate of 60 bpm, the spontaneous atrial rate averaged 83, and atrial cannon waves were frequent. When the atria were given two stimuli at an interval of 500 ms during ventricular diastole, the cannon waves were eliminated completely, and a fall in mean central venous pressure and a rise in systemic blood pressure were found. At a pacing rate of 90 bpm, similar changes in the cannon waves, mean central venous pressure, and systemic blood pressure were found when two atrial stimuli followed ventricular stimulation. Ventriculo-atrial multiple pacing may be useful in both clinical and experimental AV block.

Is rapid rise in vascular conductance at onset of dynamic exercise due to muscle pump?

We tested the hypothesis that rapid increases in muscle blood flow and vascular conductance (C) at onset of dynamic exercise are caused by the muscle pump. We measured arterial (AP) and central venous pressure (CVP) in nine awake dogs, eight with atrioventricular block, pacemakers, and ascending aortic flow probes for control of cardiac output (CO) (2 also had terminal aortic flow probes). One dog had only an iliac artery probe. At exercise onset (0 and 10% grade, 4 mph) C and CVP rose to early plateaus, and AP reached a nadir, all in 2-5 s. At 20% grade and 4 mph, C increased continuously after its initial sudden rise. Timing and magnitude of initial change in conductance (delta C) were independent of CO, AP, work rate (change in grade at constant speed), or autonomic function (blocked by hexamethonium). Speed of initial delta C and its independence from work rate and blood flow ruled out metabolic vasodilation as its cause; insensitivity to AP and autonomic blockade ruled out myogenic relaxation and sympathetic vasodilation as causes of sudden delta C. Sensitivity to contraction frequency (not work per se) implicates the muscle pump. When reflexes were blocked, a large secondary rise in C, presumably caused by metabolic vasodilation, began after 10 s of mild exercise. When reflexes were intact in mild exercise, C was lowered below its initial plateau by sympathetic vasoconstriction, which partially raised AP from its nadir toward its preexercise level. Our conclusion is that dynamic exercise has a large rapid effect on C that is not explained by known neural, metabolic, myogenic, or hydrostatic influences.(ABSTRACT TRUNCATED AT 250 WORDS)

Arterial pressure control after chronic carotid sinus denervation.

This study examines the control of arterial blood pressure in conscious, instrumented dogs with atrioventricular block before and greater than or equal to 9 days after carotid sinus baroreceptor denervation. Strength of reflex control of blood pressure was quantitated by measuring the changes in peripheral resistance and atrial rate after square wave changes in cardiac output. Surprisingly, nine or more days after carotid denervation, the strength of baroreflex control of peripheral resistance and atrial rate were not different (P greater than 0.05) from the values before denervation. This was not due to a change in the base-line levels of arterial pressure, atrial rate, cardiac output, or peripheral resistance. Bilateral vagal block after carotid denervation removed reflex effects from remaining baroreceptors and virtually eliminated changes in peripheral resistance in response to changes in arterial pressure. Therefore, the compensatory responses observed after carotid denervation were mediated by the remaining baroreceptors. Thus, after chronic carotid sinus denervation, there is no decrease in the strength of baroreflex control of peripheral resistance or heart rate.

Angiotensin causes vasoconstriction during hemorrhage in baroreceptor-denervated dogs.

The participation of angiotensin II (ANG II) in the maintenance of arterial blood pressure during hypotensive hemorrhage was examined in unanesthetized, baroreceptor-denervated dogs. When mean aortic blood pressure was reduced to 69.0 +/- 2.2 mmHg, plasma renin activity increased from 0.6 +/- 0.3 ng ANG I X ml-1 X h-1 during the prehemorrhage control period to 4.5 +/- 1.6. Twenty minutes after the hemorrhage, mean aortic blood pressure rose to 78.9 +/- 3.1 mmHg. Subsequent infusion of the angiotensin II antagonist saralasin (5.2-14.0 micrograms X kg-1 X min-1) decreased mean aortic pressure to 59.6 +/- 3.3 mmHg. When 5% dextrose was infused in place of saralasin, mean aortic pressure was 79.3 +/- 4.3 mmHg. The lower aortic blood pressure caused by saralasin infusion was the result of a significant decrease in total peripheral resistance. Resistance was 10.3 +/- 3.2 mmHg X l-1 X min lower during saralasin infusion than during dextrose infusion. We conclude that baroreceptor reflexes are not essential for the elevation of plasma renin activity during hemorrhage. In baroreceptor-denervated dogs subjected to hypotensive hemorrhage, the increased formation of ANG II has a vasoconstrictor action that contributes to the maintenance of arterial blood pressure.

Influence of cardiac fiber orientation on wavefront voltage, conduction velocity, and tissue resistivity in the dog.

When the canine epicardium is stimulated, the spread of epicardial excitation is 2.4 times faster parallel to the long axes of the cardiac fibers than perpendicular to them. Likewise, gross tissue resistivity is lower parallel to fibers by a factor of 3.2, and the voltage across the depolarization wave is approximately three times as great in the longitudinal direction. Equations are presented which relate these variables. Theoretical considerations confirm the experimental finding that the potentials around a wave of depolarization cannot be accounted for by the conventional hypothesis that the wavefront is a uniform double-layer current source.

Heart rate response to sympathetic stimulation before and after sodium pentobarbital.

Heart rate response to electrical stimulation of the right stellate ganglion of vagotomized cats was studied before and after the administration of sodium pentobarbital. The increase and decrease of heart rate with the initiation and cessation of sympathetic stimulation could be accurately described by separate exponential time functions. The time constants of rise and decline, the maximum steady-state heart rate, and the time between cessation of stimulation and initial decrease of heart rate (lag) were functions of the frequency and voltage of stimulation. The main effects of sodium pentobarbital were: 1) to prolong the rise of heart rate by 20-30 percent (P smaller than 0.0001),2) to prolong the decay of heart rate by 36-56 percent (P smaller than 0.005), and 3) to decrease the resting heart rate. The effects were observed 10 min after administration of the drug and lasted at least 4 h.

Long-term responses of atrial rate and peripheral resistance to changes in ventricular pacing rate in awake dogs with atrioventricular block.

We wished to see if a maintained change in pressure at the baroreceptors leads to a maintained or a transient change in heart rate and total peripheral resistance, and if long-term changes in rate and resistance paralleled one another. In awake dogs with intact baroreceptors and complete atrioventricular block, ventricular rate was held alternately at high (90 beats/min) and low (50 beats/min) levels, each for 2 days. This cycle was repeated several times. Data were recorded for 1.5 hours each day. With this change in ventricular rate, there was a maintained change over 2 days in arterial (14.4 +/- 1.0 mm Hg) and central venous (3.0 +/- 1.2 mm Hg) pressures. These changes in pressure were accompanied by a maintained change in atrial rate of 41.1 +/- 9.4 beats/min; peripheral resistance, however, changed only transiently. In three animals, the half-cycle length was 1 week. Changes in heart rate also persisted for this period. It appears from these studies that there is long-term control of heart rate, but not of peripheral resistance. Hypotheses to explain these results are presented.