Severe bradyarrhythmia linked to left atrial dysfunction in Fabry disease-A cross-sectional study.

BACKGROUND: Fabry disease (FD) is a lysosomal storage disorder caused by an enzymatic deficiency. Conduction abnormalities and bradyarrhythmias are common and can occur prior to the onset of left ventricular (LV) hypertrophy. We aimed to describe the clinical, electrocardiographic and echocardiographic, including left atrial (LA) function, determinants of bradyarrhythmic events in FD. HYPOTHESIS: Bradyarrhythmic events are frequent in patients with FD and are associated with LA dysfunction. METHODS: We designed a cross-sectional study that includes 53 FD patients (mean age, 45 years; 42% male). Clinical characteristics and electrocardiographic and echocardiographic data were collected. LA function was measured using biplane volumes and 2D speckle-tracking echocardiography. Bradyarrhythmic events were defined as pause of more than 2 seconds (sinus pause or atrioventricular block) recorded on Holter, severe bradycardia (≤ 40 bpm on ECG) or implantation of a permanent pacemaker. RESULTS: Six (11%) patients had installation of a pacemaker, 4 (8%) patients had cardiac pause and 2 (4%) patients had an episode of severe bradycardia. Patients with bradyarrhythmic events were older and had a lower resting heart rate. On echocardiography, a significantly higher LV mass, a lower LV ejection fraction, and a more affected LA reservoir function were found in those with bradyarrhythmic events. Patients also experienced tachyarrhythmias frequently. Atrial fibrillation occurred in 11 (21%) patients and ventricular tachycardia in 4 (8%) patients. CONCLUSIONS: Bradyarrhythmia are common manifestations of cardiac involvement in FD. Age, LV mass, LV ejection fraction and LA reservoir dysfunction can be useful markers associated with bradyarrhythmia.

Estimation of the QT-RR relation: trade-off between goodness-of-fit and extrapolation accuracy.

Correction of the QT interval in the ECG for changes in heart rate (RR interval) is needed to compare groups of patients and assess the risk of sudden cardiac death. The QTc represents the QT interval at 60 bpm, although most patients typically have a faster heart rate, thus requiring extrapolation of the QT-RR relationship. OBJECTIVE: This paper investigates the ability of QT-RR models with increasing number of parameters to fit beat-to-beat variations in the QT interval and provide a reliable estimate of the QTc. APPROACH: One-, two- and three-parameter functions generalising the Bazett and Fridericia formulas were used in combination with hysteresis reduction (memory) obtained by time-averaging the history of RR intervals with exponentially-decaying weights. In normal men and women datasets of Holter recordings in normal subjects (24 h monitoring), two measures were computed for each model: the root mean square error (RMSE) of fitting and the difference between the estimated QTc and a reference QTc obtained by collecting data points around RR = 1000 ms. MAIN RESULTS: The two- and three-parameter functions all gave similar low RMSE with uncorrelated residues. An optimal memory parameter was found that still minimized the RMSE and could be used for all functions and subjects. This reduction in RMSE resulted from changes in the parameters linked to the increased steepness of the QT-RR relation after hysteresis reduction. At optimal memory, the two and three-parameter models provided poorer prediction of the QTc as compared to the Fridericia's model in subjects with fast heart rates, since accurate representation of the steeper QT-RR relation worsened the extrapolation that was then needed to determine the QTc. SIGNIFICANCE: As a result, among all models investigated, the Fridericia formulation offered the best trade-off for QTc prediction robust to memory and fast heart rates.

Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction.

AIMS: To quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies. METHODS: Twenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT-RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation. RESULTS: Moxifloxacin prolonged the QTc by 10.6 ± 6.6 ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87 ± 0.13 vs. 0.82 ± 0.12, p<0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91 ± 0.11 (p<0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7 ± 1.1 ms vs. 8.8 ± 1.2 ms for Fridericia). CONCLUSION: The ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.

Evaluation of a subject-specific transfer-function-based nonlinear QT interval rate-correction method.

The QT interval in the electrocardiogram (ECG) is a measure of total duration of depolarization and repolarization. Correction for heart rate is necessary to provide a single intrinsic physiological value that can be compared between subjects and within the same subject under different conditions. Standard formulas for the corrected QT (QTc) do not fully reproduce the complexity of the dependence in the preceding interbeat intervals (RR) and inter-subject variability. In this paper, a subject-specific, nonlinear, transfer function-based correction method is formulated to compute the QTc from Holter ECG recordings. The model includes five parameters: three describing the static QT-RR relationship and two representing memory/hysteresis effects that intervene in the calculation of effective RR values. The parameter identification procedure is designed to minimize QTc fluctuations and enforce zero correlation between QTc and effective RR. Weighted regression is used to better handle unbalanced or skewed RR distributions. The proposed optimization approach provides a general mathematical framework for further extensions of the model. Validation, robustness evaluation and comparison with existing QT correction formulas is performed on ECG signals recorded during sinus rhythm, atrial pacing, tilt-table tests, stress tests and atrial flutter (29 subjects in total). The resulting average modeling error on the QTc is 4.9 ± 1.1 ms with a sampling interval of 2 ms, which outperforms correction formulas currently used. The results demonstrate the benefits of subject-specific rate correction and hysteresis reduction.

Extraction and analysis of T waves in electrocardiograms during atrial flutter.

Analysis of T waves in the ECG is an essential clinical tool for diagnosis, monitoring, and follow-up of patients with heart dysfunction. During atrial flutter, this analysis has been so far limited by the perturbation of flutter waves superimposed over the T wave. This paper presents a method based on missing data interpolation for eliminating flutter waves from the ECG during atrial flutter. To cope with the correlation between atrial and ventricular electrical activations, the CLEAN deconvolution algorithm was applied to reconstruct the spectrum of the atrial component of the ECG from signal segments corresponding to TQ intervals. The locations of these TQ intervals, where the atrial contribution is presumably dominant, were identified iteratively. The algorithm yields the extracted atrial and ventricular contributions to the ECG. Standard T-wave morphology parameters (T-wave amplitude, T peak-T end duration, QT interval) were measured. This technique was validated using synthetic signals, compared to average beat subtraction in a patient with a pacemaker, and tested on pseudo-orthogonal ECGs from patients in atrial flutter. Results demonstrated improvements in accuracy and robustness of T-wave analysis as compared to current clinical practice.

Atrial tachyarrhythmias and repolarization changes induced by discrete activation of dorsal mediastinal cardiac nerves in canines.

BACKGROUND: Chronotropic "vagal responses" elicited by high-frequency stimulation have been used to identify atrial targets for ablative treatment of atrial tachyarrhythmias (AT), whereas an anatomic approach consisting of extensive ablation of the ganglionated plexus areas has been proposed as an alternative. Therefore, there is a need for precise delineation of juxtacardiac nerves involved in AT initiation and clarification of their regional influences throughout the atria in relation to AT sites of origin, beyond chronotropic effects related to sinus node modulation. METHODS AND RESULTS: Unipolar electrograms were recorded from 191 biatrial epicardial sites in 13 anesthetized canines, with concomitant left atrial endocardial recording from 63 sites in 5 of 13 animals. When electric stimuli were delivered to dorsal mediastinal nerves during the atrial refractory period, atrial premature depolarizations initiating AT were elicited in all animals, most frequently without prior sinus cycle length modification. Among 63 episodes, the sites of origin of early AT beats were localized to (1) the posterolateral left atrial wall in the pulmonary vein region (33%), (2) superior left atrial loci along the Bachmann bundle (55%), and (3) the region of Bachmann bundle insertion into the superior right atrial wall (11%). Moreover, the AT sites of origin were spatially concordant with regional waveform changes during the repolarization phase of unipolar recordings. AT induction and repolarization changes were abolished after atropine administration. CONCLUSIONS: Activation of individual dorsal mediastinal nerves induces AT arising from distinct sites of origin which are spatially concordant with regional atrial repolarization changes.

Prospective evaluation of psychological distress and psychiatric morbidity in recurrent vasovagal and unexplained syncope.

UNLABELLED: Syncope is experienced by a third of the population, and in the absence of cardiac pathology is most commonly of vasovagal (VVS) or unexplained origin (US). Psychiatric morbidity has been observed in up to 81% of patients with US but findings with VVS are contradictory. Little is known regarding the chronicity of their psychiatric morbidity. OBJECTIVE: To determine the psychological profile of patients with recurrent syncope prior to and following diagnostic head-up tilt testing (HUT), and whether it predicts syncope recurrence. METHOD: Seventy-three women and 43 men (mean age=48+/-16.6) were recruited from all consenting patients referred for HUT. Psychological status (Psychiatric Symptom Index, Anxiety Sensitivity Index (ASI), Fear of Blood Injury Subscale) and presence of mood/anxiety disorders (Primary Care Evaluation of Mental Disorders) were evaluated 1 month prior to and 6 months following HUT. Follow-up data were collected for 83 patients (mean age=48+/-17.34). RESULTS: At baseline, clinically significant levels of distress were observed in 60% of patients. Those with US (negative HUT) had a fivefold greater risk of suffering from a depressive or anxiety disorder compared to VVS (positive HUT) after controlling for significant covariates. There was no significant change in distress level over follow-up, although psychiatric morbidity dropped from 33% to 22% (P=.049). Syncope recurrence was predicted by elevations in baseline psychological distress (OR=1.544, P=.013) independently of lifetime number of syncopes. CONCLUSIONS: Patients exhibited high levels of psychological distress and psychiatric morbidity despite reassurance and education received after HUT. Improved screening for and treatment of psychological distress in these patients is critical.

Attenuation of autonomic nervous system functions in hypertensive patients at rest and during orthostatic stimulation.

The effect of age on autonomic nervous system was assessed at rest and while standing using systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate, and power spectral analysis of the time duration between 2 consecutive R waves of an electrocardiogram (RR) interval variability, as well as on plasma norepinephrine and epinephrine levels in mild to moderate hypertensive patients (DBP, 90-110 mm Hg). Patients younger than 60 years (n=57) and older than 60 years (n=32), were evaluated after a 3- to 4-week placebo period. Plasma catecholamines were measured in the supine position at rest and after 10 minutes of standing. Power spectral analysis of the RR interval variability was performed in each condition using the high-frequency (HF) band (0.15-0.4 Hz) as an index of parasympathetic activity and the low-frequency (LF) band (0.05-0.15 Hz) and LF-HF ratio to estimate sympathetic activity. The total power was calculated as the sum of LF and HF power. supine SBP was significantly higher in older patients (P<.05). SBP and DBP increased significantly only in younger patients during standing (P<.05), while the changes were smaller and nonsignificantly lower in older patients. HR was similar in both groups at rest and increased similarly during standing. Norepinephrine and epinephrine levels were similar at rest and increased similarly in both groups of patients during standing. At rest, lower LF and HF components were observed in older patients. The LF component increased less and the HF component decreased less in older patients during standing. A lower sympathetic and parasympathetic basal cardiac tone was observed at rest in older hypertensive patients. Moreover, reduced hemodynamic and sympathetic responses to standing as assessed by SBP, DBP, and the LF component of HR variability were observed in older hypertensives in the presence of a normal catecholamine response. These observations could reflect a decreased sensitivity of cardiac beta-adrenoceptors with aging.

Diagnosis and discrimination of remote antero- and inferoseptal non-Q wave myocardial infarctions with body surface potential mapping.

BACKGROUND: Previous studies have shown that the diagnosis and localization of previous non-Q wave myocardial infarction (NQMI) is possible by body surface potential mapping (BSPM), but the criteria for the discrimination between anteroseptal and inferoseptal middle regions remain to be determined. METHODS: BSPM using 63 unipolar leads was recorded in 119 patients with previous NQMI (36 to 76 years of age, average 61 years; 85 men). Localization of anteroseptal or inferior middle NQMI occurred in 70 cases (44 to 76 years of age, average 61 years, 53 men) by determining early anterior minimum potential with only slight negativity. In these cases, isopotential maps obtained at additional time points were investigated to discriminate between anteroseptal and inferoseptal NQMI. The clinical localization was based on the concordance of two of the following tests: wall motion disturbances on echocardiography, coronary angiogram and repolarization changes in the acute-phase electrocardiogram. RESULTS: Two milliseconds before the appearance of the first anterior minimum, a more accentuated superior negativity indicated anteroseptal NQMI (32 of 70 cases), while a more pronounced inferior negativity indicated inferoseptal NQMI (38 of 70 cases). Fisher's exact test showed statistically significant associations between the above BSPM localizations and the clinical localizations (P<0.001). Occlusion or stenosis of the expected infarct-related coronary artery was detected in all patients either as a single lesion or together with other coronary artery lesions. CONCLUSIONS: The BSPM criteria proposed here are suitable to detect the most frequent NQMI localizations. The narrowing of the infarct-related coronary arteries, the left anterior descending or the posterior descending coronary artery, can be thus differentiated.

Cervical vagosympathetic and mediastinal nerves activation effects on atrial arrhythmia formation.

In anesthetized dogs both epi-and endocardial atrial activation maps and corresponding isointegral repolarization maps were created before and during right or left mediastinal nerve (RMN and LMN) and cervical vagus nerve (CVN) stimulation. Right mediastinal nerve stimulation typically caused sinus slowing, atrial tachycardia (AT), followed by atrial fibrillation (AF). Activation maps during AT showed epicardial breakthroughs from the right atrial free wall or Bachmann's bundle. Left mediastinal nerve stimulation (LMN) rarely caused sinus slowing and ATs originated mostly from Bachmann's bundle or from the pulmonary vein ostial region. Atrial repolarization changes induced by neural stimulation were measured by integrating the area subtended by 161 epicardial unipolar electrograms. Atrial tachycardia epicardial breakthrough sites were closely associated with the border zone where repolarization changes occurred. Both AT and AF were abolished by I.V. atropine, as were sinus bradycardia and atrial repolarization effects of nerve stimulation. Shortening of latency of onset and duration of AT by I.V. timolol suggest concurrent activation of adrenergic efferent neurons. In conclusion, juxta-cardiac mediastinal nerve stimulation can induce atrial fibrillation from multiple, discrete right and left atrial sites, which correspond to localized repolarization changes. Secondly, sinus bradycardia is not a necessary index of parasympathetic neurally induced atrial fibrillation.

Understanding ST depression in the stress-test ECG.

OBJECTIVE: The electrocardiogram (ECG) obtained during stress testing often shows a typical pattern of primary ST depression. A similar pattern can occur in unstable angina. Current textbooks consider ST depression as a direct result of partial occlusion of a coronary artery. However, animal models could not reproduce this phenomenon. An alternative explanation for ST depression specific to stress testing involves global subendocardial ischemia. In this study, we evaluated both explanations with a realistic mathematical model of the human heart. METHODS: The ECG was simulated with an anisotropic reaction-diffusion model of the human heart and an inhomogeneous boundary-element model of the human torso. RESULTS: Limited subendocardial ischemic zones caused small ST depression in ECG leads not overlying the ischemic region. An ischemic zone of 50% transmural extent covering the entire left ventricular subendocardium caused an ST-depression pattern similar to that observed during stress test. CONCLUSION: In contrast to regional subendocardial ischemia, global subendocardial ischemia can explain ST depression in our model.

Gamma-irradiated ceruloplasmin affords antifibrillatory protection against ischemia/reperfusion damage in the isolated rat heart.

PURPOSE: Ceruloplasmin (CP), an important serum antioxidant, was previously found to reduce the incidence of ventricular fibrillation (VF) induced by ischemia and reperfusion in isolated rat hearts. The present study investigated whether CP sterilized by gamma-irradiation maintains its antiarrhythmic capacity and in vitro antioxidant properties. MATERIALS AND METHODS: Isolated rat hearts submitted to regional ischemia (15 min), were reperfused (10 min) with native CP or with CP irradiated at various doses (1-3 kGy) in the absence or presence of tyrosine (Tyr). RESULTS: All untreated hearts showed VF at reperfusion, which were all irreversible ventricular fibrillation (IVF). No IVF were found in hearts treated with native CP or gamma-irradiated CP. Cardioprotection afforded by irradiated CP (with or without Tyr) was slightly higher than that obtained with native CP. No VF at all (100% prevention) was found in hearts treated with CP irradiated alone or in the presence of tyrosine at 3 kGy. Tyrosine and irradiated tyrosine had no cardiotoxic or protective effects on reperfusion-induced arrhythmias. The Oxygen Radical Absorbing Capacity (ORAC), measured in vitro with beta-phycoerythrin (beta-PE) fluorescent indicator, was slightly higher for gamma-irradiated CP in the presence of Tyr. CONCLUSIONS: Ceruloplasmin sterilized by gamma-irradiation maintains antioxidant and antiarrhythmic effects in the post-ischemia reperfused isolated rat heart.

Effects of valsartan or amlodipine alone or in combination on plasma catecholamine levels at rest and during standing in hypertensive patients.

To compare the effects of valsartan and amlodipine alone or in combination on plasma norepinephrine (NE) at rest and standing for 10 minutes in patients with hypertension, 47 patients with a sitting diastolic blood pressure (BP) (DBP)>95 mm Hg and<110 mm Hg were randomized in a double-blind fashion to either valsartan or amlodipine. During the first 4 weeks of treatment, patients received a low dose of either valsartan (80 mg) or amlodipine (5 mg). The patients were force-titrated to the high dose of either drug (160 or 10 mg) for 4 weeks. After 8 weeks of therapy, those who still had a DBP>90 mm Hg (nonresponders) received combination therapy with the other drug, whereas patients with a DBP<90 mm Hg (responders) continued on monotherapy. Decreases in ambulatory BP and clinic systolic BP and DBP were significant (P<.05) after 8 weeks' therapy with no difference between the 2 groups. Amlodipine but not valsartan as monotherapy consistently increased NE levels at rest and enhanced NE levels during standing. Valsartan decreased basal NE in responders. Combination therapy with valsartan and amlodipine did not attenuate the rise in NE levels induced by amlodipine. This study indicates that therapy with amlodipine increases peripheral sympathetic basal tone and reactivity to standing in patients with hypertension, whereas valsartan does not. Combined therapy with amlodipine/valsartan did not attenuate the sympathetic activation induced by amlodipine. The hypotensive action of valsartan may be mediated in part by an inhibition of the sympathetic baroreflex in patients with hypertension.

Differential effects of cervical vagosympathetic and mediastinal nerve activation on atrial arrhythmia formation in dogs.

To investigate the influence of the thoracic autonomic neuronal hierarchy on atrial arrhythmia formation, we compared the characteristics of atrial tachyarrhythmias induced by electrical stimulation of 1) the right vagosympathetic nerve complex at the cervical level and 2) the more caudal juxta-cardiac mediastinal nerves located on the anterior surface of the superior vena cava. Unipolar electrograms were recorded from 191 sites on the entire epicardial atrial surface and, in some experiments, from 63 right atrial endocardial sites. The sites of origin of initial beats at the onset of atrial tachyarrhythmias so induced were investigated analysing atrial activation maps. Neural effects on repolarization were determined by computing the integral surface subtended by unipolar recordings under basal conditions and at maximum neurally induced bradycardia, and calculating differences at each recording site. The mean area affected by nerve stimulation in all animals was significantly greater in response to vagosympathetic than mediastinal nerve stimulation. Atrial cycle length prolongation prior to tachyarrhythmia onset was more pronounced in response to vagosympathetic than mediastinal nerve stimulation. The earliest epicardial activations in early tachyarrhythmia beats were localized in the right atrial free wall and Bachmann bundle region in both cases, but with a higher incidence of double breakthroughs from septal sites of origin in response to vagosympathetic versus mediastinal nerve stimulation. Sites of early activation were associated with the areas of neurally induced repolarization changes. Thus, differential contributions are made to the electrophysiologic substrate of neurally induced atrial tachyarrhythmias depending on the pattern of engagement of neural elements within the autonomic neuronal hierarchy.

Menopause, hormone replacement and RR and QT modulation during sleep.

BACKGROUND AND PURPOSE: Sleep affects the RR interval in electrocardiogram (ECG) recordings and ventricular repolarization differentially in men and women. Compared to men, pre-menopausal women have a more pronounced shortening of RR interval and prolongation of QT and QT corrected (QTc, by Bazett's formula) ECG waves during rapid eye movement (REM) sleep. The aim of the present study was to evaluate sleep-related RR and QT changes: (1) with the physiological decline in female hormones occurring with menopause, and (2) after hormone replacement therapy with estrogen and progesterone (HRT). PATIENTS AND METHODS: We analyzed ECG recordings from 14 post-menopausal women (48-61 years old) who underwent polysomnography before HRT (T1) and after 6 months of HRT (T2) with estrogen and progesterone. Eight of the post-menopausal women (48-54 years) were also compared to eight age-matched pre-menopausal women. In all subjects, mean RR interval, mean QT interval and QTc, were obtained from 1-min recordings selected from wakefulness, stage 2 and REM sleep. RESULTS: Pre-menopausal and post-menopausal women showed similar changes in RR, QT and QTc intervals from wakefulness through sleep. Specifically, in both pre-menopausal and post-menopausal women the RR interval was shorter during REM sleep compared to wakefulness (P=0.009) and stage 2 sleep (P=0.001); the QT interval was more prolonged during stage 2 (P=0.002) and REM (P=0.006); and the QTc interval was significantly prolonged during stage 2 (P=0.01) and REM (P=0.0003) sleep compared to wakefulness. Among post-menopausal women, both before and after HRT (T1 and T2), RR interval shortened significantly during REM compared to wakefulness (P=0.03) and to stage 2 (P=0.002); the absolute QT interval was longer during stage 2, compared to both wakefulness (P<0.001) and REM (P<0.001); the QTc interval was increased during REM sleep compared to wakefulness (P=0.003). CONCLUSIONS: Sleep-related RR and QT changes in women are not altered by menopausal status nor by post-menopausal hormonal replacement with estrogen and progesterone.

Neuroprotective and cardioprotective actions of an association of pyruvate, vitamin E and fatty acids.

Oxidative stress may involve overproduction of hydrogen peroxide which can generate highly cytotoxic hydroxyl radicals in the presence of ferrous ions. This work demonstrates that TCAT (Tricomponent Antioxidant Therapy), an association of pyruvate, vitamin E and fatty acids, provides neuronal and cardiac protection in oxidative stress, ex vivo. Mouse P19 neuron cultures were exposed for 30 min to low millimolar H2O2 concentrations in the absence or presence of Fe2+. Concentrations 1X (10 mmol/L pyruvate, 0.1 U/mL vitamin E and 0.1% fatty acids) and 3X of TCAT, respectively, prevented neuronal death caused by these treatments. Analysis of the contribution of TCAT components to neuroprotection showed that vitamin E and fatty acids enhanced pyruvate action whereas they displayed no neuroprotection by themselves. In contrast, vitamin E and fatty acids were as potent antioxidants as pyruvate in an in vitro cell-free assay, indicating that TCAT protection is modulated by the existence of the cellular membrane barriers. Isolated rat hearts were perfused under electrolysis or subjected to regional ischemia-reperfusion. TCAT 1X prevented the electrolysis-induced decrease in left ventricular pressure, heart rate and coronary flow. At 0.25X concentration, TCAT abolished the incidence of irreversible ventricular fibrillation in ischemia-reperfusion. The results indicate that TCAT could have a broad therapeutic utility in neurological and cardiac injuries associated with oxidative stress. The protective action of TCAT can surpass that of its components, revealing a benefit of the association.

Effect of the renin-angiotensin system or calcium channel blockade on the circadian variation of heart rate variability, blood pressure and circulating catecholamines in hypertensive patients.

OBJECTIVE: To determine the effects of 8 weeks of therapy with amlodipine, ramipril or telmisartan on the autonomic system over 24 h in hypertensives. METHODS: After a placebo run-in, 57 patients were included in a prospective randomized open-label design protocol for therapy with amlodipine (5 mg for 4 weeks followed by 10 mg for 4 weeks, n = 22), or ramipril (2.5 mg for 1 week, 5.0 mg for 3 weeks and 10 mg for 4 weeks, n = 17) or telmisartan (80 mg for 8 weeks, n = 18). Autonomic functions were assessed by norepinephrine (NE) and epinephrine (E), as well as by the spectral analysis of heart rate variability (HRV). RESULTS: The 24-h ambulatory blood pressure, plasma NE and HRV demonstrated the characteristic day-night circadian rhythm in hypertensives. Higher values for SBP and DBP and for NE levels, as well as for spectral analysis components - low frequency band (LF) and low frequency/high frequency (LF/HF) ratio - were found during the day, whereas the HF was higher during the night. In patients treated with amlodipine, the HF decreased significantly during the night, while the LF and the LF/HF ratio increased during the day in association with the rise in NE. The therapy with telmisartan did increase the HF during the night and the day, while ramipril did not influence all HRV components during the night but significantly increased the HF, and decreased the LF/HF ratio during the day. No changes were observed in plasma NE with telmisartan or ramipril, but a 50% increase in NE levels throughout the 24-h period was found in amlodipine-treated patients. CONCLUSION: These data suggest a sympathetic activation during the day and a decrease in parasympathetic activity during the night after therapy with amlodipine, correlated with increases in plasma NE. In contrast, the therapy with telmisartan significantly increased parasympathetic activity without changes in NE during the night and day. The therapy with ramipril increased the parasympathetic activity only during the day.

Origin and pharmacological response of atrial tachyarrhythmias induced by activation of mediastinal nerves in canines.

We sought to determine the sites of origin of atrial tachyarrhythmias induced by activating mediastinal nerves, as well as the response of such arrhythmias to autonomic modulation. Under general anaesthesia, atrioventricular block was induced after thoracotomy in 19 canines. Brief trains of 5 electrical stimuli were delivered to right-sided mediastinal nerves during the atrial refractory period. Unipolar electrograms were recorded from 191 right and left atrial epicardial sites under several conditions, i.e. (i) with intact nervous systems and following (ii) acute decentralization of the intrathoracic nervous system or administration of (iii) atropine, (iv) timolol, (v) hexamethonium. Concomitant right atrial endocardial mapping was performed in 7 of these dogs. Mediastinal nerve stimulation consistently initiated bradycardia followed by atrial tachyarrhythmias. In the initial tachyarrhythmia beats, early epicardial breakthroughs were identified in the right atrial free wall (28/50 episodes) or Bachmann bundle region (22/50), which corresponded to endocardial sites of origin associated with the right atrial subsidiary pacemaker complex, i.e. the crista terminalis and dorsal locations including the right atrial aspect of the interatrial septum. Neuronally induced responses were eliminated by atropine, modified by timolol and unaffected by acute neuronal decentralization. After hexamethonium, responses to extra-pericardial but not intra-pericardial nerve stimulation were eliminated. It is concluded that concomitant activation of cholinergic and adrenergic efferent intrinsic cardiac neurons induced by right-sided efferent neuronal stimulation initiates atrial tachyarrhythmias that originate from foci anatomically related to the right atrial pacemaker complex and tissues underlying major atrial ganglionated plexuses.

Simple, quantitative body surface potential map parameters in the diagnosis of remote Q wave and non-Q wave myocardial infarction.

BACKGROUND: Body surface potential mapping has been shown to be a useful tool in the diagnosis and localization of remote non-Q wave and Q wave myocardial infarction, but human expertise is required to interpret the maps. OBJECTIVE: To identify quantitative body surface potential mapping parameters that could enable a computer-based diagnosis. METHODS: Body surface isopotential maps (63 unipolar leads) were recorded in 86 patients with remote Q wave and 71 patients with remote non-Q wave myocardial infarction. Twenty-four healthy adults served as control subjects. Myocardial infarctions were classified using standard electrocardiogram leads in the acute and chronic phases, and were validated by coronary angiography, ventriculography and thallium scintigraphy. RESULTS: Two simple quantitative parameters with high diagnostic power were identified: the time interval between the peak minimum and the peak maximum potentials (time-shift), and the ratio of these potentials (maximum to minimum ratio [max/min]). Both parameters showed significant differences between infarction patients and normal control subjects, and optimum cut-off values were determined using receiver operating characteristic curves (anterior infarction: time-shift of -4 ms or less, max/min of 0.6 or less; posterior infarction: time-shift of 8 ms or greater, max/min of 1.25 or greater). The sensitivities of the two parameters were 100% and 97%, and the specificities were 99% and 100%, respectively, in the anterior Q wave infarction group, compared with sensitivities of 88% and 100%, and specificities of 94% and 95%, respectively, in the posterior Q wave infarction group. In the anterior non-Q wave infarction group, sensitivity was 35% for both parameters, specificity was 100% for both parameters, and only infarctions associated with a low ejection fraction were detected, indicating that infarction size may influence the power of the tests. CONCLUSIONS: Time-shift and max/min are two new, simple, powerful parameters for infarction diagnosis and may also be suitable for automated, computer-based processing.

Functional and autoradiographic characterization of dopamine D2-like receptors in the guinea pig heart.

Dopamine receptors include the D1- (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) families. D1-like receptors are positively and D2-like receptors negatively coupled to the adenylyl cyclase. Dopamine D2-like (D4 subtype) receptors have been identified in human and rat hearts. However the presence of D2 and D3 receptor subtypes is unclear. Furthermore, their role in cardiac functions is unknown. By autoradiographic studies of guinea pig hearts, we identified D3 and D4 receptors, using the selective radioligands [3H]-7-OH-DPAT and [3H]emonapride (YM-09151-2 plus raclopride). Western blot analysis confirmed D3 and D4 receptors in the right and left ventricle of the same species. Selective agonists of D3 and D4 receptors (+/-)-7-OH-DPAT and PD 168 077 (10(-9) to 10(-5) M, respectively) induced a significant negative chronotropic and inotropic effect in the isolated guinea pig heart preparation. Negative inotropic effect induced by PD 168 077 was associated with an inhibition in cyclase activity. No changes in cyclase activity were found with (+/-)-7-OH-DPAT. The aim of this study is to support the presence of D3 and D4 receptors in the heart. Although our results suggest that D3 and D4 receptors are functionally active in the heart, we need additional information with an antagonist and an agonist of improved potency and selectivity to understand the respective roles of D3 and D4 receptors in the cardiac functions.