Heart rate—QT relationships during baroreceptor stimulation with diminished autonomic influence on the ventricles

The shortening of the QT interval of the electrocardiogram coincident with acceleration of heart rate and vice versa has been accepted for many years as evidence that the action potential duration and hence QT are necessarily dependant on heart rate. Exceptions to this rule have been attributed to the intervention of counteracting autonomic effects. In order to test this assumption, 26 conscious dogs divided into three groups were tested during baroreceptor stimulation by a bolus injection of phenylephrine. Seventeen dogs had been used in earlier studies in which they had undergone an experimental anterior myocardial infarction with apparent full recovery. A group of those dogs underwent beta-adrenergic blockade by intravenous atenolol 30 min prior to the baroreceptor activation. To test the intactness of the baroreceptor responses in the previously infarcted dogs, a third group of nine dogs that had had no prior myocardial infarction was included. All dogs were adapted to the laboratory environment and were not sedated during experiments. Simultaneous recordings of RR, QT interval, and phasic arterial pressure were made in all dogs before and during baroreceptor stimulation. In the normal group, and the previously infarcted group that received no atenolol, baroreceptor stimulation elicited a small (8/msec), but significant prolongation of the QT associated with a nearly 50% reduction in heart rate. The QT interval of the atenolol-treated dogs, although significantly more prolonged before stimulation, remained unchanged during the reflex. The data indicate that withdrawal of ventricular sympathetic tone may prolong the QT interval, thereby confirming the role of sympathetic innervation in the control of QT. This inference was strengthened by the complete absence of change of QT after atenolol block and the absence of any detectable influence of vagal activity on ventricular repolarization during the reflex. Therefore, in what appeared to be the absence of evidence of autonomic influence, no inverse relationship between heart rate and QT was observed.     

Shortening of the QT interval of the EKG is associated primarily with increased ventricular contractility rather than heart rate

The objective of this study was to gather direct evidence on whether the duration of the QT interval relates primarily to heart rate or to ventricular contractility. The electrocardiographic and cardiodynamic consequences of electrical stimulation (15 V, 5 ms, 10Hz) of various intrathoracic sympathetic efferent neuronal structures were studied in 10 anesthetized mongrel dogs. Stimulation of efferent sympathetic axons in the right intraganglionic nerve, which innervates the sinoatrial node, induced tachycardia (110±5 - 133±6 bpm; p<0.01) without significantly altering right or left ventricular intramyocardial ventricular chamber pressures. The QT interval, as determined by leads I, II and III of the EKG and a transthoracic lead, was not affected by this intervention (310±8 - 302±ms). Increasing heart rate to a similar degree (111±3 - 131±3 bpm) by right atrial pacing did not induce changes in the QT interval. When right (23±3 - 49±8 mm Hg; p<0.01) and left (81±10 - 127±19 mm Hg; p<0.01) ventricular forces were augmented without concomitant increases in heart rate by stimulating efferent sympathetic axons in the left caudal pole cardiopulmonary nerve the QT interval shortened (322±11 - 290±12 ms; p<0.01). Only when an efferent sympathetic nerve, that contains fibers destined for both the sinoatrial node and the ventricles was stimulated did both heart rate and ventricular contractility augment and QT shorten (318±10 - 290±11 ms; p<0.01). These results indicate that QT interval shortening induced by efferent sympathetic neurons is primarily associated with augmentation of ventricular contractility rather than heart rate.     

Mental stress enhances the sympathetic fraction of QT variability in an RR-independent way

In 10 healthy male volunteers aged 19–20, spectral power of the beat-by-beat QT interval was measured at the Traube-Herring-Mayer (THM) band (0.05 to 0.15 Hz) when the subject was at rest and during atrial pacing. After resting in dorsal decubitus for 10 minutes, right atrial pacing was performed at a slight elevation above sinus rhythm as well as at 100 or at 110 beats per minute for 7 minutes each. In addition, during pacing at 100 or 110 bpm, the subject was required to perform a Kraepelin Arithmetic test. There was a statistically significant increase in QT spectral power at the THM band, while heart rate was maintained unchanged during the periods of mental stress versus rest. This experiment confirms the potential independence of the QT interval from heart rate and suggests that THM fraction of QT spectral power has a double subordination: during relaxed rest it follows mostly RR-fluctuation; during stress an RR-independent contribution is added, which presumably reflects the supra-normal sympathetic drive on the ventricles.     

Cardiovascular responses to avoidance conditioning in the dog: Effects of alpha adrenergic blockade

Laboratory dogs were trained to press a response panel to postpone shocks during daily one-hour avoidance conditioning periods. Each dog was also confined in the experimental environment for 5 hours prior to the avoidance periods. Blood pressure and heart rate were monitored continuously during these experiments from chronically indwelling arterial catheters. Extended training resulted in the emergence of a cardiovascular response pattern during the pre-avoidance interval characterized by gradual increases in blood pressure together with decreases in heart rate. Elevations in both blood pressure and heart rate were sustained during the avoidance periods. During sessions in which alpha adrenergic activity was suppressed by phenoxybenzamine, absolute levels of blond pressure were found to be lower than during control (non-drug) sessions, but a progressive rise in blood pressure continued to be observed during pre-avoidance. These results suggest that sustained cardiovascular responses during avoidance periods are associated with activation of the sympathetic nervous system, but that the gradual rise in blood pressure during pre-avoidance is due to other factors.     

Heart rate-Qt interval relationship during postural change and exercise. A possible connection to cardiac contractility

The QT interval of the electrocardiogram, although often coordinated in an inverse relationship to heart rate, appears from the existing evidence to be regulated by mechanisms separate from those that govern heart rate. The purpose of this inquiry was to explore further the relationship of the two and to test other factors that may contribute to the regulation of QT. Heart rate and QT duration were measured in healthy human subjects during postural change and exercise. The data showed that, while coordinated in an inverse relationship under some circumstances, under others heart rate and QT were discordant, leading to the inference that there is no fixed linkage between the two. Previous work by the authors and other published studies have suggested that ventricular contractility may have more predictable association with QT shortening than do increases in heart rate. Observations of force of ventricular contraction (HI and IJ velocity) as reflected in ballisto-cardiographic tracings were made using each of 12 human subjects as the authors' own control. The data revealed a highly significant correlation between the velocity measures and QT duration (p less than 0.01) but not heart rate. These findings led to the conclusion that there is clearly not a fixed relationship between heart rate and QT interval and to the hypothesis that QT may more closely reflect the degree of cardiac contractility.     

Enhanced involvement of brain vasopressin V1 receptors in cardiovascular responses to stress in rats with myocardial infarction

Stress is one of the factors provoking cardiovascular complications. The purpose of the study was to explore the role of vasopressin (VP) in central control of arterial blood pressure and heart rate under resting conditions and during stimulation by an alarming stress (air jet stress) in myocardial infarct-induced cardiac failure. Six groups of male Sprague Dawley (SD) rats were subjected either to sham surgery (sham rats) or to ligation of a left coronary artery (infarcted rats). After 5 weeks both infarcted and sham rats were subjected either to intracerebroventricular infusion of artificial cerebrospinal fluid (aCSF) (sham aCSF and infarcted aCSF), [Arg8]-VP (sham VP and infarcted VP) or VP V1a receptor antagonist (d(CH2)5[Tyr(Me)2Ala-]VP, sham V1ANT and infarcted V1ANT). Air jet stress elicited significantly greater increases in mean arterial blood pressure (MABP) and heart rate in the infarcted aCSF than in the sham aCSF rats. Intracerebroventricular infusion of V1ANT significantly reduced resting MABP and MABP and heart rate increases in response to stress in the infarcted but not in the sham rats. Intracerebroventricular infusion of VP elicited a significant increase in resting MABP in the infarcted VP but not in the sham VP rats. The results provide evidence for enhanced engagement of the brain V1 VP receptors in regulation of resting MABP and in generation of exaggerated cardiovascular responses to air jet stress during the post-infarct state.     

Heart rate—QT interval relationship during postural change and exercise

The QT interval of the electrocardiogram, although often coordinated in an inverse relationship to heart rate, appears from the existing evidence to be regulated by mechanisms separate from those that govern heart rate. The purpose of this inquiry was to explore further the relationship of the two and to test other factors that may contribute to the regulation of QT. Heart rate and QT duration were measured in healthy human subjects during postural change and exercise. The data showed that, while coordinated in an inverse relationship under some circumstances, under others heart rate and QT were discordant, leading to the inference that there is no fixed linkage between the two. Previous work by the authors and other published studies have suggested that ventricular contractility may have more predictable association with QT shortening than do increases in heart rate. Observations of force of ventricular contraction (HI and IJ velocity) as reflected in ballisto-cardiographic tracings were made using each of 12 human subjects as the authors’ own control. The data revealed a highly significant correlation between the velocity measures and QT duration (p<0.01) but not heart rate. These findings led to the conclusion that there is clearly not a fixed relationship between heart rate and QT interval and to the hypothesis that QT may more closely reflect the degree of cardiac contractility.     

Differential sensitisation to central cardiovascular effects of angiotensin II in rats with a myocardial infarct: relevance to stress and interaction with vasopressin

The purpose of the present study was to elucidate if rats with myocardial infarction manifest altered responsiveness to central cardiovascular effects of low doses of angiotensin II (ANG II), and if ANG II and vasopressin (VP) cooperate in the central regulation of cardiovascular functions at rest and during stress. Conscious Sprague-Dawley rats with myocardial infarction induced by left coronary artery ligation, or sham-ligated (SL) controls were infused intracerebroventricularly with artificial cerebrospinal fluid (aCSF), ANG II, ANG II + VP or ANG II + V1a receptor antagonist (V1ANT) 4 weeks after cardiac surgery. In the infarcted but not in the SL rats, the resting mean arterial blood pressure (MABP) was significantly elevated by infusions of ANG II and ANG II + VP, while infusion of ANG II + V1ANT was not effective. During administration of aCSF, the pressor, and tachycardic responses to an air-jet stressor were significantly greater in the infarcted than in the SL rats. In the SL rats, the pressor responses to the stressor were significantly greater during infusions of ANG II, ANG II + VP and ANG II + V1ANT than during infusion of aCSF. The tachycardic response in the SL rats was enhanced only by the combined infusion of ANG II + VP. In the infarcted rats, the pressor and the tachycardic responses to the stressor were similar in all groups. It is concluded that: (1) under resting conditions the infarcted rats manifest sensitisation to the central pressor effect of ANG II and that this effect depends on concomitant stimulation of V1a VP receptors, (2) central ANG II may enhance the pressor response to an alarming stressor in the SL rats through an action which does not depend on the concomitant stimulation of V1a receptors, (3) the cooperative action of ANG II and VP is required for intensification of the tachycardic response to the alarming stressor in the SL rats and (4) exaggeration of the cardiovascular responses to the alarming stressor in the infarcted rats cannot be further augmented by an additional stimulation of central ANG II receptors or combined stimulation of ANG II and VP receptors.     

Selective autonomic blockade of conditioned and unconditioned cardiovascular changes in rhesus monkeys (Macaca mulatta).

Changes in heart rate and in systolic and diastolic blood pressures were examined in eight rhesus monkeys during six sessions of differential classical conditioning. The conditioned stimuli consisted of tones differing in frequency and the unconditioned stimuli consisted of tail shock. Both the conditioned responses (CRS) and unconditioned responses (UCRs) consisted of increases in heart rate and in systolic and diastolic pressures, but blood pressure CRs sometimes occurred in the absence of heart rate CRs. Graded doses of the selective blocking agents propranolol, phentolamine, and atropine methylnitrate were systemically administered to four of the monkeys prior to additional conditioning sessions. The results suggested that the CRs and UCRs were mediated by both sympathetic and parasympathetic influences.     

Early maternal separation has mild effects on cardiac autonomic balance and heart structure in adult male rats

Early life adverse experiences have long-term physiologic and behavioral effects and enhance stress sensitivity. This study examined the effects of maternal separation (MS) on cardiac stress responsivity and structure in adulthood. Male Wistar rats were separated from the dams for 3?h per day from postnatal days 2 through 15. When exposed to 5-day intermittent restraint stress (IRS) as adults, MS, and control rats showed similar acute modifications of cardiac sympathovagal balance, quantified via heart rate variability analysis. In addition, MS had no effect on cardiac pacemaker intrinsic activity (as revealed by autonomic blockade with scopolamine and atenolol) and did not affect the circadian rhythmicity of heart rate, neither before nor after IRS. However, MS differed from control rats in cardiac parasympathetic drive following IRS, which was heightened in the latter but remained unchanged in the former, both during the light and dark phases of the daily rhythm. The evaluation of adult cardiac structure indicated that stress experienced during a crucial developmental period induced only modest changes, involving cardiomyocyte hypertrophy, increased density of vascular structures, and myocardial fibrosis. The mildness of these functional-structural effects questions the validity of MS as a model for early stress-induced cardiac disease in humans.     

Conditioned nausea after cancer chemotherapy and autonomic nervous system conditionability

There are marked individual differences in conditioned nausea after cancer chemotherapy. To examine if part of this variation is associated with individual differences in autonomic nervous system conditionability, the present study addressed whether patients with conditioned nausea acquired conditioned heart rate and electrodermal responses at a different rate than patients without conditioned nausea. Of 28 relapse-free patients who had completed cisplatinum treatment for testicular cancer between 1981 and 1986, 10 reported persistent conditioned nausea, 8 extinguished conditioned nausea and 10 no conditioned nausea. These three groups were subjected to a differential conditioning paradigm with 8 sec pictorial stimuli (circles and triangles) serving as conditioned stimuli for an unconditioned electric shock while heart rate and electrodermal activity was monitored. There were 4 habituation, 8 acquisition and 8 extinction trials with each of the two cues. Analyses of variance using nausea status as the independent variable and physiological responses as the dependent lended some support to the notion that conditioned heart rate deceleration developed in response to the reinforced compared to the nonreinforced cue during acquisition in the two groups with persistent or extinguished conditioned nausea but not in the group with no conditioned nausea. In addition, patients that displayed good, as compared to poor heart rate conditionability during acquisition, were more likely to have persistent conditioned nausea, whereas those who showed poor heart rate conditioning mostly were those without conditioned nausea. Electrodermal variables revealed no systematic differences between groups. This tentatively supports that individual differences in parasympathetic but not sympathetic nervous system conditionability may be associated with individual differences in conditioned nausea resulting from cancer chemotherapy.     

Total peripheral resistance changes in dogs during aversive classical conditioning

The arterial pressure, heart rate, stroke volume, cardiac output and total peripheral resistance of laboratory dogs were monitored continuously before and during a 30 min period in which aversive classical conditioning procedures were applied. The experimental stimulation generated inhibition of behavioral activity (“freezing”) together with sustained increases in arterial pressure averaging 30%, and increases in heart rate and cardiac output of 60–70%. The calculated total peripheral resistance decreased by an average of 20%. The behavioral and cardiovascular responses were sustained during the aversive conditioning period. The results suggest that significant peripheral vasodilation occurred under these conditions which was probably not due to metabolic byproducts of behavioral activity, but probably reflected sympathetic cholinergic effects upon blood vessels in the skeletal muscles. These data document the significance of the skeletal muscle circulation in the total peripheral resistance to blood flow in unanesthetized animals.     

Cardiovascular responses to acetylcholine: Effects of pentobarbital and autonomic blocking agents

The effect of acetylcholine chloride (ACh) on heart rate (HR) and blood pressure (BP) was studied in four dogs, awake and under anesthesia by means of pentobarbital sodium. In the awake dog, ACh caused a triphasic change in HR—a rise, fall and secondary rise. The BP showed an initial gradual fall followed by a secondary precipitous fall coinciding with the fall in HR, and then return to base line. Anesthesia accentuated the precipitous fall in HR due to ACh, and narrowed the pulse pressure during the initial fall in BP due to ACh. The effects of atropine sulphate, propranolol and d-tubacurarine on the above were studied, indicating the roles of the sympathetic and parasympathetic systems in mediating the HR and BP reactions to ACh in the awake state and under pentobarbital sodium anesthesia.     

Single unit activity in the medial prefrontal cortex during Pavlovian heart rate conditioning: Effects of peripheral autonomic blockade

Electrical activity was recorded from single neurons in the medial prefrontal cortex of rabbits during differential Pavlovian heart rate (HR) conditioning. A heterogeneous population of cells were found, some of which showed CS-evoked increases and others CS-evoked decreases in discharge, while some cells were biphasic. A subset of cells also showed trial-related changes in discharge that were related to acquisition of the HR discrimination between the reinforced CS+ and non-reinforced CS-. Administration of the peripheral cholinergic antagonist, methylscopolamine, and the andrenergic antagonist, atenolol, either increased or decreased maintained baseline activity of many cells, but had little or no effect on the CS-evoked activity of these cells. Waveform changes also did not result from administration of these drugs. This finding suggests that CS-evoked mPFC activity is not being driven by cardiac afferent input to CNS cardiac control centers. Previous studies have shown that ibotenic acid lesions of this area greatly decreases the magnitude of decelerative heart rate conditioned responses; the latter finding, plus the results of the present study, suggest that processing of CS/US contingencies by the prefrontal cortex contributes to the acquisition of autonomic changes during Pavlovian conditioning.     

Differential preparatory cardiovascular responses to aversive and appetitive behavioral conditioning

Dogs were required to press a response panel either to avoid shock or obtain food. During a one-hour interval immediatelypreceding performance on the avoidance task, blood pressure increased while heart rate decreased. In contrast, both blood pressure and heart rate increased during the one-hour interval immediatelypreceding performance on the food task. During both the shock-avoidance and food performancesper se, however, elevations in heart rate and blood pressure were observed, though the avoidance task produced less consistent heart rate changes. These effects were observed (1) with different individual dogs on each of the two training procedures, and (2) with the same dogs exposed successively to both aversive and appetitive behavioral conditioning.     

Going beyond heart rate: autonomic space and cardiovascular assessment of mental workload

Psychophysiological assessment of pilot mental workload using heart rate should be augmented with an autonomic space model of cardiovascular function. This model proposes that autonomic nervous system influences on the heart may change with psychological processing in ways that are not evident in heart rate. A method of mental-workload assessment was proposed that used multiple psychophysiological measures of cardiovascular responsivity to derive the underlying sympathetic and parasympathetic information needed to represent the autonomic space for heart rate. Principal-components analysis was used to extract Sympathetic and Parasympathetic components from heart period, residual heart period. respiratory sinus arrhythmia, and Traube-Hering-Mayer wave in three experiments that manipulated perceptual/central processing and physical task demands. This initial evaluation of the method concluded that the autonomic components were valid and that the components had greater diagnosticity, and for some manipulations greater sensitivity, than heart rate. These results support the contention that the Sympathetic and Parasympathetic components provided increased precision for mental-workload assessment.     

QT & RR variability spots the earliest autonomic deregulation in diabetes. Fading of vagal sino-atrial drive but not of sympathetic ventricular responsiveness to life challenges.

27 consecutive insulin-dependent diabetic patients (pts), under 50 years, with blood glucose controlled within normal limits and no significant or multiple cardiovascular/neurological complications in the lights of clinical tests, went through a protocol as follows: laiddown at relaxed rest for 10 min, then stood-up quietly for 7 min, and finally experienced a stress-interview for 10 min while supine. A thoracic ECG lead was digitized at I ms (Codas, Dataq Instr.), RR and QT intervals were software-detected, resampled at 500 ms, and Fourier-transformed over 3 min epochs to get auto-or cross-spectra. RR-by-QT mean square coherence detached the RR-independent fraction of QT low fequency (LF) spectral power, called idioventricular QT-LF. We detected autonomic impairment of three types (discriminant score = 92.31%), presumably differentiated upon the locus of lesion, using RR's basal variance and mean RR shortening when standing as follows: (I) RR shortening > 200 ms in 10 pts; (II) normal RR shortening but no RR variance in 4 pts; (III) stiff RR around 600 ms and no RR variance in 2 pts. The above pts have been excluded from further analysis. The remaining 11 pts with no such impairments (5M and 6F, 36.4 y +/- 4.4 SD, history of 6.0 y +/- 5.2) have been compared with 11 normal subjects in an age and gender-paired control group in two steps. Step 1: Preliminary MANOVA/ANOVA showed significant effects on the ensemble of spectral variables of every single factor (status: normal or patient group; intervention; gender) with no significant factor interactions. Significant effects of intervention or status on main RR spectral variables and on a few QT spectral variables were also documented. Step 2: Non-parametric tests showed that diabetics had (mildly to moderately) shorter mean RR, while their RR-LF was always significantly lower than those found in normals--a difference propagated to QT-LF but not to idioventricular QT-LF. In the intra-group there were similar responses to interventions except stress with respect to mean RR. Consistent reduction in RR-LF under moderate or no change in mean RR suggests vagal down- regulation that, judging by idioventricular QT-LF showing, goes perhaps before a similar process with sympathetic control of ventricles. This phase delay may introduce an early arrhythmic risk worth dealing with in secondary prevention.     

Effects of differentially modeled stimuli on vicarious autonomic arousal

The present study examined effects of variations in modeled pain cues on level of vicarious arousal, using heart rate and blood-volume amplitude as psychophysiological measures. Students were assigned randomly to one of four groups in which they either (a) underwent directly the cold-pressor test, (b) observed a model exposed to the cold-pressor test and expressing pain by facial and bodily movements, (c) heard only the modeled verbal expressions of pain, or (4) observed the model express neither verbal expressions nor physical movements while undergoing the painful stimulation. The results show aversive stimulation increases heart rate whereas vicarious aversive stimulation produces reductions in heart rate. The deceleration of heart rate was not found in response to all three forms of modeling. Both direct and vicarious aversive stimulation produced decreases in the amplitude of vasomotor responses. The size of the decrement between direct stimulation and the minimal modeling condition of vicarious arousal showed significant differences, but differences between direct stimulation and the maximal modeling condition were not significant. The vasoconstriction was found in response to two forms of modeling.     

Operant conditioning of large magnitude, 12-hour duration,heart rate elevations in the baboon

Two baboons were prepared with arterial and venous catheters and their heart rate and blood pressure were monitored continuously thereafter. Following a 2 to 3 week interval during which baseline cardiovascular levels were determined, the animals were exposed to daily 12 hr conditioning sessions (alternating with 12-hr “rest” or “Conditioning Off’ sessions) during which food reward and shockavoidance were programmed as contingent consequences of pre-specified increases in heart rate. Initially, the criterion heart rate was set at 10–15 bpm above the animal’s pre-experimental resting baseline level, with progressive increases programmed to occur at a rate approximating 7 bpm per week over a period of 8–10 weeks. Within this 2–3 month interval, heart rate doubled, reaching levels maintained above 160 bpm for more than 95 per cent of each daily 12-hour “Conditioning On” period. Propranolol selectively eliminated the conditioned heart rate increase but not the blood pressure elevation, indicating the contribution of sympathetic nervous activity to these operantly conditioned cardiovascular changes.     

Predictors of myocardial infarction over a span of 30 years in Roseto, Pennsylvania.

Predictors of myocardial infarction with or without survival were sought in a 30-year study of Roseto, Pennsylvania, a nearly exclusively Italian community of approximately 1,600, compared to the immediately adjacent town of Bangor with a population of approximately 5,000. At the start of the study the death rate from myocardial infarction among men in Roseto was less than half that in Bangor despite an equal prevalence of the usual risk factors, mainly smoking and diet. The communities were followed prospectively for 30 years during a striking social change in Roseto toward less family and community cohesion and more commitment to individual goals and adherence to materialistic values. During this period the prevalence of and mortality from myocardial infarction increased sharply to equal the situation in Bangor. The predictive values of measurements made of Rosetans during individual examinations in 1962-63 were tested against the outcome in 1990. Those who experienced fatal myocardial infarction and those who had a well documented infarction and survived were matched with and compared to controls. Although subjects with cholesterol concentration above 200 were twice as likely to experience myocardial infarction as those with concentrations below 200, less than 20% of those whose cholesterol concentration was above 200 experienced any evidence of myocardial infarction over the nearly 30-year period. Moreover, there were no significant differences between the coronary patients, with or without survival, and their sex, age, and cholesterol matched controls; nor were smoking, evidence of hypertension, diabetes, or obesity predictive of significant differences between the two groups. These data lead to the inference that while those with the conventional risk factors are more likely to develop myocardial infarction than are those without the risk factors, an even larger proportion of the population may have the risk factors and not succumb to myocardial infarction over a period of nearly three decades.