Electrical Inhomogeneity in Left Ventricular Hypertrophy

Recent studies designed to assess the relationship between aortic compliance and heterogeneity of heart electrical activity has shown that hypertrophy aggravates repolarization disturbances in the myocardium. Numerous mechanisms of electrical instability and inhomogeneity associated with left ventricular hypertrophy are now under investigation. Most of the studies have been found to be focused on ventricular Gradient, QT dispersion, amplitudes of isointegral maps during ventricular repolarization, abnormally low-QRST areas, dispersion of the QT interval, and spatial QRS-T _angle. These studies point to marked repolarization abnormalities in left ventricular hypertrophy and the dispersion of the QT interval as a valuable index for inhomogeneity of repolarization and the subsequent heart rate variability. The heart rate-corrected QT dispersion and QT apex dispersion seem to be significantly longer in the patients with left ventricular hypertrophy than in normal individuals. The review study has also identified QRST isointegral map as a valuable technique in assessment of the electro-cardiac events in LVH.     

Methods of assessment and clinical relevance of QT dynamics

The dependence on heart rate of the QT interval has been investigated for many years and several mathematical formulae have been proposed to describe the QT interval/heart rate (or QT interval/RR interval) relationship. While the most popular is Bazett's formula, it overcorrects the QT interval at high heart rates and under-corrects it at slow heart rates. This formulae and many others similar ones, do not accurately describe the natural behaviour of the QT interval. The QT interval/RR interval relationship is generally described as QT dynamics. In recent years, several methods of its assessment have been proposed, the most popular of which is linear regression. An increased steepness of the linear QT/RR slope correlates with the risk of arrhythmic death following myocardial infarction. It has also been demonstrated that the QT interval adapts to heart rate changes with a delay (QT hysteresis) and that QT dynamics parameters vary over time. New methods of QT dynamics assessment that take into account these phenomena have been proposed. Using these methods, changes in QT dynamics have been observed in patients with advanced heart failure, and during morning hours in patients with ischemic heart disease and history of cardiac arrest. The assessment of QT dynamics is a new and promising tool for identifying patients at increased risk of arrhythmic events and for studying the effect of drugs on ventricular repolarisation.     

Electrocardiogram,vectocardiogram and body surface maps in patients with panic disorder

An increased risk of myocardial ischemic changes was demonstrated in patients suffering from panic disorder (PD). Using classical ECG methods, this risk cannot be evaluated in most patients. We measured the vectocardiogram (VCG) using Frank orthogonal leads and body surface maps (BSM) including 12-lead ECG. In our study of 11 PD patients (2 men, 9 women), without any seizures and pharmacological treatment and without cardiovascular symptoms, we found marked sinus tachycardia (heart rate 90.1 +/- 12.2 min(-1)) and a shorter R-R interval (678 +/- 93.6 ms) than in 27 controls (heart rate 73.6 +/- 7.7min(-1), R-R 822.7 +/- 86.4 ms) (5 men, 22 women) (p<0.001). The VCG measured spatial QRS-STT angle was more opened (70.3 +/- 24.5 degrees) than in the control group (49.5 +/- 19.5 degrees) (p<0.05). The maximum (extremum) in depolarization (DIAM max 30, 40) and repolarization (RIAM max 35) of body surface isoarea and isointegral (RIIM max) maps was less positive (p<0.001) and the minimum (DIAM min 40) was less negative than in the controls (p<0.05) even in the period free of a panic attack. Our results showed the changes in the heart electric field parameters occurred in PD patients when compared to the control group.     

Effects of changing heart rate on electrophysiological and hemodynamic function in the dog

Cardiovascular parameters were measured in dogs after RR interval was changed from 0.25 s to 1.2 s with atropine and graded doses of zatebradine, an I(f)-channel blocker. Left ventricular (LV) pre-ejection period (PEP), systemic vascular resistance, tau (an estimate of myocardial stiffness), PQ, QTc, dLVP/dt(max) and dLVP/dt(min), aortic pressure, and right atrial pressure did not change when each parameter was plotted against RR interval (r(2)'s < or = 0.5). LV end-diastolic pressure, stroke volume index, LV ejection time (ET), and QT all increased either linearly or curvilinearly as RR interval prolonged. Cardiac output index and PEP/ET decreased curvilinearly. When heart rate (HR) was fixed by pacing, and graded doses of zatebradine were given, changes in cardiovascular function were minimal. Thus zatebradine affects cardiovascular function principally by changing HR and not by affecting function directly. This study provides data on the effects of changing HR, alone, on cardiovascular parameters measured frequently during pharmacological and toxicological studies. It should prove useful when physiological variables, including HR, change, and there is need to know what change in HR, alone, contributes.     

Blood pressure regulation in diabetic patients with and without peripheral neuropathy

Cardiac and vascular dysfunctions resulting from autonomic neuropathy (AN) are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure (BP) regulation in patients with peripheral neuropathy and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. We continuously measured electrocardiogram, arterial BP, and respiration during supine rest and 70° head-up tilt in 12 able-bodied subjects, 7 diabetics without, 7 diabetics with possible, and 8 diabetics with definite, sensory, and/or motor neuropathy (D2). During the first 3 min of tilt, systolic BP (SBP) of D2 decreased [-10.9 ± 4.5 (SE) mmHg] but increased in able-bodied (+4.8 ± 5.4 mmHg). Compared with able-bodied, D2 had smaller low-frequency (0.04-0.15 Hz) spectral power of diastolic BP, lower baroreflex effectiveness index (BEI), and more SBP ramps. Except for low-frequency power of SBP, D2 had greater SBP and smaller RR interval harmonic and nonharmonic components at rest across the 0.003- to 0.45-Hz region. In addition, our results support previous findings of smaller HF RR interval power, smaller numbers of baroreflex sequences, and lower baroreflex sensitivity in D2. We conclude that diabetic peripheral neuropathy is accompanied by diminished parasympathetic and sympathetic control of heart rate and peripheral vasomotion and diminished baroreflex regulation. A novel finding of this study lies in the sensitivity of BEI to detect AN, presumably because of its combination of parameters that measure reductions in both sympathetic control of vasomotion and parasympathetic control of heart rate.     

P-wave body surface isointegral maps in children and in young adults

Only limited data are available on body surface potential distribution during atrial activation. The aim of this study was to establish the distributions and to analyze chosen quantitative parameters of atrial isointegral maps recorded using a limited 24-lead system in a young healthy population. A total of 166 subjects underwent a procedure of body surface potential mapping. Isointegral maps during the P wave were constructed and qualitatively and quantitatively evaluated. Three types of atrial activation in individual maps were found according to the different shape of the zero isointegral line and to mutual positions of extrema. The most frequently occurring type resembled the group mean maps and was in good agreement with published data obtained from full lead systems. The highest extrema were found in the young men group, while, surprisingly, the lowest values in the young women group. All minima and the majority of maxima were recorded outside the ranges of standard chest leads. The usefulness of the limited lead system to record isointegral P wave maps was shown and new data were presented that can be useful in noninvasive evaluation of atrial pathologies.     

Subject-specific profiles of QT/RR hysteresis

The time lag of the QT interval adaptation to heart rate changes (QT/RR hysteresis) was studied in 40 healthy subjects (18 females; mean age, 30.4+/-8.1 yr) with 3 separate daytime (>13 h) 12-lead electrocardiograms (ECG) in each subject. In each recording, 330 individual 10-s ECG segments were measured, including 100 segments preceded by 2 min of heart rate varying greater than +/-2 beats/min. Other segments were preceded by a stable heart rate. In segments preceded by variable rate, QT/RR hysteresis was characterized by lambda parameters of the exponential decay models. The intrasubject SDs of lambda values were compared with the intersubject SD of the individual means. The lambda values were also correlated to individually optimized parameters of heart rate correction. Intrasubject SDs of lambda were substantially smaller than the population SD of individual means (0.390+/-0.197 vs. 0.711, P<0.0001). The lambda values were unrelated to the QT/RR correction parameters. When compared with the corrected QT (QTc) for averaged RR intervals in 10-s ECGs and with the averaged RR intervals in 2-min history, QTc for QT/RR hysteresis led to a substantially smaller SD of QTc values (11.4+/-2.00, 6.33+/-1.31, and 4.66+/-0.85 ms, respectively, P<0.0001). Thus the speed with which the QT interval adapts to heart rate changes is highly individual with intrasubject stability and intersubject variability. QT/RR hysteresis is independent of the static QT/RR relationship and should be considered as a separate physiological process. The combination of individual heart rate correction with individual hysteresis correction of the QT interval is likely to lead to substantial improvements of cardiac repolarization studies.     

Assessment of autonomic cardiovascular indices in non-stationary data in rats

The analysis of heart rate in the frequency domain has become increasingly important in physiological studies, and supports the use of heart rate variability as an index of autonomic cardiovascular control. A new index, the instant centre frequency (ICF) has been proposed as a global index of the instantaneous relationship between sympathetic and vagal modulation. The aim of this study was to assess ICF, RR intervals, and heart rate variability measures as indices of sympathovagal balance during a pharmacological blockade of the autonomic nervous system in normotensive rats. RR intervals and arterial blood pressure of 10 conscious Wistar rats equipped with telemetry probes, were evaluated before, during, and after injection of: (1) saline (100 microl kg(-1) i.v.); (2) phentolamine (5 mg kg(-1) i.v.); (3) atropine methyl nitrate (0.5 mg kg(-1) i.v.); and (4) atenolol (1 mg kg(-1) i.v.). RR interval series were analysed by the smoothed pseudo-Wigner-Ville distribution. A general linearised model was used to evaluate the parameters. ICF was calculated in the same way as the peak power frequency by use of the first moment of instant spectrum. We calculated the ICF of the whole spectrum (ICF(T)), ICF in high frequency (ICF(H)) and ICF in low frequency (ICF(L)). The RR intervals and ICF indexes varied similarly and presented the lowest coefficient of variation among animals exposed to the same autonomic conditions. ICF(T)-ICF(L) and ICF(H)-ICF(T) were strongly correlated with normalised HF and normalised LF. In normotensive rats, RR intervals and ICF indices may reliably capture the effects of the sympathetic and parasympathetic nervous system on the sinus node.     

ECG body surface mapping (BSM) in type 1 diabetic patients

Diabetes mellitus is a risk factor of cardiovascular diseases. ECG of patients with diabetes mellitus type 1 (DM 1) shows tachycardia (block of parasympathetic innervation) and abnormal repolarization (increased QT interval and QT dispersion (QTd)) indicating a risk of ventricular tachycardia and sudden death in young people with DM 1. The aim of the present report was to measure 145 parameters of the heart electric field in 22 patients (14 men, 8 women) with DM 1 without complications (mean age 32.8+/-11.4 years) and in 22 controls (11 men, 11 women, mean age 30.1+/-3.4 years). The duration of diabetes was 13.9+/-7.8 years. The parameters were registered by the diagnostic system Cardiag 112.2 and statistically evaluated by the Student and Mann-Whitney test. Tachycardia (86.3+/-2.7 beats.min(-1)), shortening of both QRS (79.9+/-1.6 ms) and QT (349.0+/-5.9 ms) and increased QT dispersion (115+/-36 ms) were observed in DM 1 when compared with the controls (75.0+/-2.1 beats. min.(-1), QRS 89.9+/-2.7 ms, QT 374.0+/-4.4 ms, QTd 34.0+/-12.0 ms, p<0.01). The QTc was 415.2+/-4.1 ms in DM 1 and 401.4+/-6.6 ms in controls (NS). Other significant findings in DM 1 were: higher maximum of depolarization isopotential maps (DIPMmax) in the initial phase of QRS and less positive in the terminal phase, more negative minimum (DIPMmin) during QRS similarly as the minimum in depolarization isointegral maps (DIIMmin) and the minimum in isointegral map of the Q wave (Q-IIMmin), lower maximum in repolarization isopotential maps (RIPMmax) and less negative minimum (RIPMmin), more negative amplitude of Q wave (Q-IPMAM) and more pronounced spread of depolarization (activation time). Our results confirmed a decreased parasympathetic to sympathetic tone ratio (tachycardia, shortening of the activation time) and revealed different depolarization and repolarization patterns in DM 1. The differences in heart electric field parameters measured by the BSPM method in DM 1 and in the controls indicate the importance of ECG examination of diabetic patients type 1 in the prevention of cardiovascular diseases.     

Autonomic effects on QT-RR interval dynamics after exercise

This study was designed to assess autonomic effects on the QT interval during recovery from exercise. Exercise is associated with an acute increased risk of sudden cardiac death. Evidence of impaired parasympathetic activity, such as low heart rate variability and heart rate recovery, and an increased QT interval are also associated with increased mortality. However, there is no clear pathophysiological link among these findings. Bicycle exercise testing was performed serially in 33 healthy volunteers (19 men; ages, 54 +/- 7 yr) under four conditions: 1) baseline, 2) beta-adrenergic blockade-intravenous propranolol (0.2 mg/kg) administered during exercise, 3) parasympathetic blockade-intravenous atropine (0.04 mg/kg) administered during exercise, and 4) double blockade with propranolol and atropine. ECGs were obtained every minute in recovery for 10 min and then at the 15th and 20th min, from which the QT and RR intervals were measured. Linear regression analyses were used to assess the individual QT-RR relationships for each subject for each condition. Relative to baseline, the QT-RR relationship with parasympathetic blockade was shifted to the left and had a steeper slope. In contrast, the QT-RR relationship with beta-adrenergic blockade was shifted to the right and had a less steep slope. The baseline and double-blockade QT-RR relationships were in the middle and essentially superimposable. There was a negative relationship between QT-RR slope and heart rate or RR interval recoveries, but it was significant only for the 1- and 2-min RR interval recoveries with low R(2) values of 0.124 and 0.114. The main parasympathetic effect in the postexercise recovery period is to counteract the sympathetically mediated QT prolongation. These data support the concept that parasympathetic tone may provide a natural antiarrhythmic effect during this time.     

Roles of the AV junction in determining the ventricular response to atrial fibrillation.

The statistical properties of RR interval sequences during cholinergic atrial fibrillation were studied in anesthetized dogs both in control conditions and after the selective injection of dromotropic agents into the atrioventricular (AV) node artery. It was observed that RR interval histogram configurations depended mainly on the mean heart rate, regardless of whether it was a control or a post-injection sequence. The sequences were found to vary from almost regular at fast rates to highly irregular at slow rates, covering all intermediate possibilities. Since the injections of dromotropic agents into the AV node artery were carried out during sinus rhythm between the episodes of fibrillation, their influences on the AV junction, as reflected both on the length of the PR interval during sinus rhythm and on the RR interval dispersion during fibrillation, could be compared. The dispersion of RR intervals was found to increase as the PR interval duration became longer. In addition, it was observed that the generally random character of the RR interval sequences during fibrillation was not affected by the injection of dromotropic agents into the AV node artery. These results were interpreted as an indication that, for a well-established atrial fibrillation, the degree of ventricular irregularity (dispersion of RR intervals) is related to the conductivity within the AV junction and that the random character of RR interval sequences is related to the atrial fibrillatory activity itself.     

Heart rate and heart rate variability in pregnant warmblood and Shetland mares as well as their fetuses

Heart rate (HR) is an important parameter of fetal well-being. In horses, HR and heart rate variability (HRV) can be determined by fetomaternal electrocardiography (ECG) from mid-pregnancy to foaling. Normal values for physiological parameters in larger breeds are often used as reference values in ponies. However, HR increases with decreasing size of the animal and in ponies is higher than in warmblood horses. It is not known if fetal HR is affected by breed and if values obtained in larger breeds can be used to assess Shetland fetuses. We have determined fetomaternal beat-to-beat (RR) interval (inversely correlated to HR) and HRV in warmblood (n=6) and Shetland pregnancies (n=7) at days 280 and 300 of gestation by ECG. Maternal RR interval was lower in pony than in warmblood mares (day 280: Shetland: 958±110, warmblood: 1489±126ms, p<0.01) The SDRR (standard deviation of RR interval) and the RMSSD (root mean square of successive RR differences) did not differ between breeds at any time. Also RR interval as well as HRV did not differ between warmblood and pony fetuses (RR interval day 280: Shetland: 606±39, warmblood: 589±38ms). In conclusion, although maternal RR interval is clearly higher in Shetland than in warmblood mares, fetal RR interval in the two breeds is on the same level.     

QT-RR hysteresis is caused by differential autonomic states during exercise and recovery

QT-RR hysteresis is characterized by longer QT intervals at a given RR interval while heart rates are increasing during exercise and shorter QT intervals at the same RR interval while heart rates are decreasing during recovery. It has been attributed to a lagging QT response to different directional changes in RR interval during exercise and recovery. Twenty control subjects (8 males, age 51 ± 6 yr), 16 subjects with type 2 diabetes (12 males, age 56 ± 8 yr), 71 subjects with coronary artery disease (CAD) and preserved left ventricular ejection fraction (LVEF) (≥50%) (51 males, age 59 ± 12 yr), and 17 CAD subjects with depressed LVEF (<50%) (13 males, age 57 ± 10 yr) underwent two 16-min exercise tests followed by recovery. In session 2, parasympathetic blockade with atropine (0.04 mg/kg) was achieved at end exercise. QT-RR hysteresis was quantified as: 1) the area bounded by the QT-RR relationships for exercise and recovery in the range of the minimum RR interval at peak exercise to the minimum RR interval + 100 ms and 2) the difference in QT interval duration between exercise and recovery at the minimum RR interval achieved during peak exercise plus 50 ms (ΔQT). The effect of parasympathetic blockade was assessed by substituting the QT-RR relationship after parasympathetic blockade. QT-RR hysteresis was positive in all groups at baseline and reversed by parasympathetic blockade (P < 0.01). We conclude that QT-RR hysteresis is not caused by different directional changes in RR interval during exercise and recovery. Instead, it is predominantly mediated by differential autonomic nervous system effects as the heart rate increases during exercise vs. as it decreases during recovery.     

QT interval variability and cardiac norepinephrine spillover in patients with depression and panic disorder

Suggestions were made that increased myocardial sympathetic activity is reflected by elevated QT variability (dynamic changes in QT interval duration). However, the relationship between QT variability and the amount of norepinephrine released from the cardiac sympathetic terminals is unknown. We thus attempted to assess this relationship. The study was performed in 17 subjects (12 with major depressive disorder and 5 with panic disorder). Cardiac norepinephrine spillover (measured by direct catheter technique coupled with norepinephrine isotope dilution methodology) was assessed before and 4 mo after treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants. The distribution of the cardiac norepinephrine spillover was bimodal, with the majority of patients having values of < or =10 ng/min. There was a positive correlation between cardiac norepinephrine spillover and corrected QT interval (r = 0.7, P = 0.03) but not with any of the QT variability measures. However, in a subgroup of five patients who had high levels of cardiac norepinephrine spillover (>20 ng/min) a tendency for a strong positive correlation with variance of QT intervals (r = 0.9, P = 0.08) was observed. There were significant correlations between the severity of depression and QT variability indexes normalized to the heart rate [QTVi and QT interval/R-R interval (QT/RR) coherence] and between the severity of anxiety and the QT/RR residual and regression coefficient, respectively. Treatment with SSRI antidepressants substantially reduced depression score but did not affect any of the QT variability indexes. We conclude that in depression/panic disorder patients with near-normal cardiac norepinephrine levels QT variability is not correlated with cardiac norepinephrine spillover and is not affected by treatment with SSRI.     

Systemic NO synthase inhibition blunts the chronotropic, but not the inotropic response to isoprenaline in man.

There is evidence that nitric oxide (NO) is involved in the chronotropic, the inotropic, and the vasodilator response to beta-adrenoceptor agonists. In the present study we hypothesized that inhibition of NO synthase may modulate the systemic vascular and cardiac effects of isoprenaline, a beta-adrenoceptor agonist, in healthy subjects. Subjects received stepwise increasing doses of isoprenaline (0.1-0.8 microg/min) in the absence or presence of systemic NO-synthase inhibition using two intravenous doses of N-monomethyl-L-arginine (L-NMMA; dosage 1, 3.0 mg/kg over 5 min, followed by 30 microg/kg/min over 75 min; dosage 2, 6.0 mg/kg over 5 min, followed by 60 microg/kg/min over 75 min) or peripheral vasoconstriction using exogenous endothelin-1 (ET-1; 5.0 ng/kg/min for 80 min). The chronotropic (RR interval) and the inotropic (QS2c) responses were assessed by noninvasive measurement of systolic time intervals. L-NMMA alone did not influence QS2c, but did increase the RR interval (P < 0.001) and the mean arterial blood pressure (P = 0.003). L-NMMA did not attenuate the blood pressure and the QS2c responses to isoprenaline, but significantly and dose-dependently blunted the heart rate response to beta-adrenoceptor stimulation (P = 0.029). ET-1 decreased the RR interval (P < 0.001) and increased the mean arterial blood pressure (P = 0.028). Our results indicate that beta-adrenoceptor mediated effects on the heart rate are much more susceptible to NOS inhibition than inotropic responses. This indicates that NO has an important role in heart rate control during beta-adrenoceptor stimulation.     

Properties of fetal heartbeat intervals during labour

This study was designed to investigate the range of beat-to-beat changes in fetal inter-beat (RR) intervals during routine clinical monitoring in labour. Fetal RR intervals were automatically measured and collected from 10 fetuses. Intervals which were incorrectly measured were excluded, and the remaining 23510 intervals were used to compile the distribution of beat-to-beat changes. The inter-quartile range of this distribution was 23 ms and the 99th centile fell at approximately 50 ms. No relationship could be established between beat-to-beat changes and the absolute RR interval. These findings differ from the results published by other workers on the basis of data obtained antenatally or during early labour. In addition, the results suggest possibilities for improving algorithms designed to enhance data quality in fetal heart rate monitoring.     

The opposite polarity of the PQ segment compared to the P wave isointegral maps

The aim of our work was to study the opposite polarity of the PQ segment to the P wave body surface potential maps in different groups of patients. We constructed isointegral maps (IIM) in 26 healthy controls (C), 16 hypertensives (HT), 26 patients with arterial hypertension and left ventricular hypertrophy (LVH) and 15 patients with myocardial infarction (MI). We analyzed values and positions of map extrema and compared the polarity of maps using the correlation coefficient. The IIM P maxima appeared mainly over the precordium, the minima mainly in the right subclavicular area. The highest maxima were in the MI group, being significantly higher than in the HT and LVH groups. No differences concerning any values of other extrema were significant. The IIM PQ maxima were distributed over the upper half of the chest; the minima mainly over the middle sternum. A statistically significant opposite polarity between the IIM P and IIM PQ was found in 80 % of cases. The opposite polarity of the P wave and the PQ segment was proved in isointegral body surface maps. The extrema occurred in areas not examined by the standard chest leads. This has to be considered for diagnostic purposes.     

A circadian rhythm in heart rate variability contributes to the increased cardiac sympathovagal response to awakening in the morning

Morning hours are associated with a heightened risk of adverse cardiovascular events. Recent evidence suggests that the sleep-wake cycle and endogenous circadian system modulate cardiac function in humans and may contribute to these epidemiological findings. The aim of the present study was to investigate the interaction between circadian and sleep-wake-dependent processes on heart rate variability (HRV). Fifteen diurnally active healthy young adults underwent a 72-h ultradian sleep-wake cycle (USW) procedure (alternating 60-min wake episodes in dim light and 60-min nap opportunities in total darkness) in time isolation. The present study revealed a significant main effect of sleep-wake-dependent and circadian processes on cardiac rhythmicity, as well as a significant interaction between these processes. Turning the lights off was associated with a rapid increase in mean RR interval and cardiac parasympathetic modulation (high-frequency [HF] power), whereas low-frequency (LF) power and sympathovagal balance (LF:HF ratio) were reduced (p?≤?.001). A significant circadian rhythm in mean RR interval and HRV components was observed throughout the wake and nap episodes (p?≤?.001). Sleep-to-wake transitions occurring in the morning were associated with maximal shifts towards sympathetic autonomic activation as compared to those occurring during the rest of the day. Namely, peak LF:HF ratio was observed in the morning, coincidental with peak salivary cortisol levels. These results contribute to our understanding of the observed increase in cardiovascular vulnerability after awakening in the morning.     

Quantifying the strength of the linear causal coupling in closed loop interacting cardiovascular variability signals

 The coherence function measures the amount of correlation between two signals x and y as a function of the frequency, independently of their causal relationships. Therefore, the coherence function is not useful in deciding whether an open-loop relationship between x and y is set (x acts on y, but the reverse relationship is prevented) or x and y interact in a closed loop (x affects y, and vice versa). This study proposes a method based on a bivariate autoregressive model to derive the strength of the causal coupling on both arms of a closed loop. The method exploits the definition of causal coherence. After the closed-loop identification of the model coefficients, the causal coherence is calculated by switching off separately the feedback or the feedforward path, thus opening the closed loop and fixing causality. The method was tested in simulations and applied to evaluate the degree of the causal coupling between two variables known to interact in a closed loop mainly at a low frequency (LF, around 0.1 Hz) and at a high frequency (HF, at the respiratory rate): the heart period (RR interval) and systolic arterial pressure (SAP). In dogs at control, the RR interval and the SAP are highly correlated at HF. This coupling occurs in the causal direction from the RR interval to the SAP (the mechanical path), while the coupling on the reverse causal direction (the baroreflex path) is not significant, thus pointing out the importance of the direct effects of respiration on the RR interval. Total baroreceptive denervation, by opening the closed loop at the level of the influences of SAP on RR interval, does not change these results. In elderly healthy men at rest, the RR interval and SAP are highly correlated at the LF and the HF. At the HF, a significant coupling in both causal directions is found, even though closed-loop interactions are detected in few cases. At the LF, the link on the baroreflex pathway is negligible with respect to that on the reverse mechanical one. In heart transplant recipients, in which SAP variations do not cause RR interval changes as a result of the cardiac denervation, the method correctly detects a significant coupling only on the pathway from the RR interval to the SAP. Received: 28 June 2001 / Accepted in revised form: 23 October 2001