Alberto Malliani

Cardiovascular variability signals: towards the identification of a closed-loop model of the neural control mechanisms

The authors consider parametric methods for processing cardiovascular signals and try to provide a global, although indirect evaluation of some neural regulatory activities. In particular, the variability signals of the heart rate (under the form of interval tachogram) and arterial blood pressure (systogram) together with respiratory movement signal (respirogram) are considered as inputs to a closed-loop model which describes a few aspects of the physiological interactions among the signals themselves. The identifiability of the transfer function of the model is demonstrated from the joint process black-box description of the signals. A direct identification procedure is proposed dividing the system into two dynamic adjustment models. A few suggestions are deduced on how and where the respirogram enters the model and on the genesis of the 10-s rhythm, parameters relevant to the Starling effect, Windkessel model, and the gain of baroreceptor mechanisms. The approach presented is intended also to provide a general frame for closed-loop identification in different pathophysiological conditions.<<ETX>>

Model for the assessment of heart period and arterial pressure variability interactions and of respiration influences

A model which assesses the closed-loop interaction between heart period (HP) and arterial pressure (AP) variabilities and the influence of respiration on both is applied to evaluate the sources of low frequency (LF∼0·1 Hz) and high frequency (HF, respiratory rate ∼0·25 Hz) in conscious dogs (n=18) and humans (n=5). A resonance of AP closed-loop regulation is found to amplify LF oscillations. In dogs, the resonance gain increases slightly during baroreceptor unloading (mild hypotension obtained with nitroglycerine (NTG) i.v. infusion, n=8) and coronary artery occlusion ((CAO), n=6), and it is abolished by ganglionic transmission blockade ((ARF), Arfonad i.v. infusion, n=3). In humans, this gain is considerably increased by passive tilt. Different, possibly central, sources of LF oscillations are also evaluated, finding a strong rhythmic modulation of HP during CAO. At HF, a direct respiratory arrhythmia is dominant in dogs at control, while it is considerably reduced during CAO. On the contrary, in humans, a strong influence of respiration on AP is shown which induces a reflex respiratory arrhythmia. An index of the gain of baroreceptive response, αcl, was decreased by NTG and CAO, and virtually abolished by chronic arterial baroreceptive denervation (TABD, n=4) and ARF.

A positive feedback sympathetic pressor reflex during stretch of the thoracic aorta in conscious dogs.

The role of pressor sympathetic reflexes in circulatory control was investigated in conscious dogs. Animals were previously instrumented with a 6- to 8-cm rigid core cannula covered by an inflatable rubber cylinder in the thoracic aorta, a pressure catheter implanted in the aorta above the cannula, and a second catheter inserted into the aorta below the cannula through a femoral artery. Two piezoelectric crystals were positioned at opposing adventitial sites to measure aortic distension with ultrasound techniques. After recovery from surgery, the diameter of the aortic segment surrounding the cannula was increased by 9.6 ± 0.4% from 16 ± 1 mm by inflating the rubber cylinder, without obstructing blood flow. Mean aortic pressure rose 31 ± 3% from 100 ± 3 mm Hg and heart rate 20 ± 3% from 91 ± 3 beats/min (P < 0.01). The pressor response was abolished by α-adrenergic blockade (phentolamine 1 mg/kg, iv). The heart rate response was reduced either by β-blockade (propranolol 1 mg/kg, iv) or muscarinic blockade (atropine 0.2 mg/kg, iv) and abolished by their combination. During aortic stretch, the sensitivity of the baroreflex was reduced 57 ± 7% from 18 ± 2 msec/mm Hg (P < 0.01). The pressor response was increased to 49 ± 8% after bilateral carotid sinus nerve section and vagotomy. These excitatory reflex responses were obtained in absence of any pain reaction. Thus, in the conscious dog, aortic distension within physiological ranges induces a potent pressor sympathetic reflex with positive feedback characteristics. Such a pressor reflex not only occurs in the presence of functioning baroreflexes, but is also capable of reducing their sensitivity.

An integrated approach based on uniform quantization for the evaluation of complexity of short-term heart period variability : Application to 24 h holter recordings in healthy and heart failure humans

We propose an integrated approach based on uniform quantization over a small number of levels for the evaluation and characterization of complexity of a process. This approach integrates information-domain analysis based on entropy rate, local nonlinear prediction, and pattern classification based on symbolic analysis. Normalized and non-normalized indexes quantifying complexity over short data sequences ( approximately 300 samples) are derived. This approach provides a rule for deciding the optimal length of the patterns that may be worth considering and some suggestions about possible strategies to group patterns into a smaller number of families. The approach is applied to 24 h Holter recordings of heart period variability derived from 12 normal (NO) subjects and 13 heart failure (HF) patients. We found that: (i) in NO subjects the normalized indexes suggest a larger complexity during the nighttime than during the daytime; (ii) this difference may be lost if non-normalized indexes are utilized; (iii) the circadian pattern in the normalized indexes is lost in HF patients; (iv) in HF patients the loss of the day-night variation in the normalized indexes is related to a tendency of complexity to increase during the daytime and to decrease during the nighttime; (v) the most likely length L of the most informative patterns ranges from 2 to 4; (vi) in NO subjects classification of patterns with L=3 indicates that stable patterns (i.e., those with no variations) are more present during the daytime, while highly variable patterns (i.e., those with two unlike variations) are more frequent during the nighttime; (vii) during the daytime in HF patients, the percentage of highly variable patterns increases with respect to NO subjects, while during the nighttime, the percentage of patterns with one or two like variations decreases.

Analysis of the pressor sympathetic reflex produced by intracoronary injections of bradykinin in conscious dogs.

The reflex hemodynamic effects of intracoronary bradykinin were tested in 20 conscious instrumented dogs. When the experiments were performed after full recovery from surgery and anesthesia, graded doses (10–300 ng/kg) of bradykinin always produced graded pressor responses, in the absence of any pain reaction. At the maximum pressor response obtained with 100 ng/kg, mean arterial pressure rose 28 ± 3% from 89 ± 4 mm Hg, left ventricular pressure 20 ± 3% from 121 ± 2 mm Hg, heart rate 30 ± 4% from 88 ± 5 beats/min, rate of change of left ventricular pressure 18 ± 3% from 2812 ± 65 mm Hg/sec (P < 0.01). Higher doses of bradykinin did not produce greater responses. The magnitude of the response was similar when the injection was performed in either the left anterior descending (change in mean arterial pressure 29 ± 3%) or circumflex (change in mean arterial pressure 27 ± 2%) coronary artery. The reflex nature of the response was proved by its disappearance after appropriate pharmacological blockades; moreover, after vagotomy, the pressor rise was maintained, the heart rate response was reduced (change in heart rate 10 ± 2%), and the inotropic response was enhanced (rate of change of left ventricular pressure 24 ± 3%). This suggested that the afferent pathway of the pressor reflex was in the sympathetic nerves and that a subordinate vagal depressor reflex was also operative. No pain reaction was obtained even when injecting very large amounts (1000–2000 ng/kg) of bradykinin, which, instead, induced arterial hypotension. Pain reactions (as inferred by agitation and vocalization) were observed in three out of nine dogs studied during the first week after surgery. This reaction was no longer present when the same animals were tested later on, at the time of complete recovery. In five of the nine dogs studied during the first week after surgery, the intracoronary injection of bradykinin produced a depressor (change in mean arterial pressure −31 ± 6%) response, which, however, reverted to a pressor effect (change in mean arterial pressure 22 ± 4%) later, when recovery was complete. In five additional dogs, the pressor response observed after full recovery from surgery was no longer present when the injection of bradykinin was repeated under anesthesia. The present experiments in conscious dogs show that the chemical stimulation of the fully innervated heart with intracoronary bradykinin can initiate pressor reflexes independent of pain and in the presence of intact buffering mechanisms.

Multivariate time-variant identification of cardiovascular variability signals: a beat-to-beat spectral parameter estimation in vasovagal syncope

In this paper a bivariate, time-variant model able to continuously measure the mutual interactions between heart rate and systolic blood pressure variability signals is presented. A recursive identification of the model parameters makes it possible to estimate, on a beat-to-beat basis, spectral low-frequency (LF) and high-frequency (HF) power (LF/HF ratio) and cross-spectral (coherence and phase relationships between spectral peaks) indexes during nonstationary events. These indexes can be helpful in: 1) physiological study of autonomic nervous system mechanisms of cardiovascular control and 2) quantification and clinical evaluation of the neural and mechanical links between the two signals. In addition, an estimate of baroreceptive activation (/spl alpha/-gain) is continuously extracted. Before applying the model to cardiovascular signals, the reliability of the estimated parameters was tested on simulated signals. Subsequently, the model was applied to investigating vasovagal syncope episodes, aiming at the assessment of autonomic nervous system status and autonomic role in the dynamic phenomena which lead to syncope. The proposed model, which provides noninvasive beat-to-beat evaluation of the autonomic events, may be useful in the description of the syncopal episodes and in the comprehension of the complex physiological mechanisms of syncope.

Excitatory Effect of Adenosine on Cardiac Sympathetic Afferent Fibers

Sensory innervation of the heart seems capable of perceiving the occurrence of transient myocardial ischemia. As a result, neural reflexes and pain can originate from the heart. However, while the link existing between myocardial ischemia and pain is elusive [1], as nonpainful episodes are a common clinical and experimental feature, complex cardiovascular reflexes seem to accompany experimental occlusion of a coronary artery [2–4] and transient myocardial ischemia in humans [5, 6]. Their consequences range from simple changes in heart rate and arterial pressure to the precipitation of malignant arrhythmias [7, 8]. Two hypotheses have been advanced to explain the independence of neural reflexes from pain: 1) Two sets of different afferent fibers could be responsible for mediating neural reflexes and pain, with the latter arising only concomitantly with the recruitment of high-threshold cardiac nociceptors, specifically devoted to signaling tissue damage [9]; 2) the same population of low-threshold afferent fibers would transmit different impulse codes, giving rise, respectively, to cardiovascular reflexes and pain [1].

Presence or Absence of Angina Pectoris During Myocardial Ischemia

If we had to organize a sense of pain that could subserve a finalistic function in the most adequate manner, we would have to demand extreme precision on the following two issues: a) tissue damage should always represent a “nocuous” [24] stimulus and cause pain without ambiguity; b) particularly, the experience of pain should only correspond to tissue damage. In short, we would like to organize the sensation of pain as a specific and unequivocal sense, like vision [23]. Probably, this is not the case.

Time and frequency domain analysis of heart rate variability after myocardial infarction

Despite the significant reduction in mortality which has been obtained over the last few years, the identification of patients at risk after a myocardial infarction remains one of the most important objectives for clinical cardiology. In addition to the more traditional techniques based upon the evaluation of residual left ventricular dysfunction or ischemia and upon the characterization of cardiac electrical instability, as indicated by the presence of ventricular arrhythmias or ventricular late potentials, new approaches have been recently proposed to evaluate the alterations of neural regulatory mechanisms and to identify patients at risk. Among them, the study of heart rate variability has provided the most relevant clinical results.

Heart Rate Variability and Nonlinear Dynamics

Heart rate variability (HRV) is in part the result of numerous and complex rhythmical oscillations that can be extracted from time series with spectral methodology (1,2,3). This approach in the frequency domain has made it possible to indirectly explore the neural regulation of cardiovascular function and in particular to assess the changes in sympathovagal balance (2,3).