Concomitant Bradycardia Research Articles

PO-03-011 LEFT BUNDLE BRANCH AREA DEFIBRILLATION (LBBAD): EVALUATION OF ACUTE DEFIBRILLATION PERFORMANCE

Conduction system Pacing (CSP) is a promising technique to prevent pacing-induced cardiomyopathy and is a valuable additional tool in cardiac-resynchronization therapy. Patients requiring an ICD for underlying structural heart disease often have a concomitant bradycardia pacing indication. As RV pacing is to be avoided in these patients, CSP is a promising option. A combined left bundle branch area (LBBA) pacing/defibrillation lead would be desirable over an additional CSP pacing lead. We evaluated defibrillation threshold testing (DFT) with a classical ICD lead (Boston Scientific Reliance 4-Front 0693/64cm) positioned in the LBBA. In our LBBAD feasibility pilot trial we evaluated the implantability of an ICD lead in the LBBA and looked at the acute performance of an ICD lead temporarily implanted in this position. One of the tests performed was DFT testing by VF induction using a shock-on-T with decreasing energy (ULV). This value was subsequently used to program the energy of the first shock to treat the induced VF (see Figure). After all tests were performed the lead was removed from the septum and implanted in a conventional location. We present the DFT results of the first 3 successfully implanted LBBAD leads. All three patients received an ICD in primary prevention for ischemic cardiomyopathy (mean EF of 25 ± 3.3%). Induction shock to initiate VF (ULV) was 14 ± 2.4 J (mean induced VF heart rate of 259 ± 13.9 bpm). Time to VF detection was 5.5 ± 1.2 s with a mean capacitor charging time of 4.9 ± 1.0 s to deliver 28 ± 4.7 J. All VF episodes were successfully terminated by the first programmed shock. The impedance over the shock-lead measured 68 ± 4,99 Ω. No complications occurred. Our LBBAD pilot trial is the first experience in man with ICD leads (temporarily) implanted in an LBBA position. Besides evaluation of the implant feasibility of an ICD lead in the LBBA, we also looked at the acute electrical performance of the lead in this position.

Acute Efficacy of a Traditional Chinese Medicine for Treatment of Frequent Premature Ventricular Contractions in Patients with Concomitant Sinus Bradycardia: Results from a Double-Blind, Placebo-Controlled, Multicentre, Randomized Clinical Trial.

Pharmacological antiarrhythmic therapy such as beta-blockers in patients with frequent premature ventricular contractions (PVCs) and concomitant bradycardia is challenging. A traditional Chinese medicine, Shensong Yangxin (SSYX), has been effective in treatment of frequent PVCs and sinus bradycardia (SB) in separate patient cohorts. This double-blind, placebo-controlled, multicentre, randomized clinical trial investigates the acute efficacy of SSYX in reducing PVCs burden in patients with concomitant SB. Patients with symptomatic, frequent PVCs, and SB, defined as mean heart rate (MHR) of 45 to 59 beats per min (bpm), were recruited at 33 medical centres in mainland China and randomly assigned by computer to either SSYX or matching placebo for eight weeks. Patients, investigators, and trial personnel were masked to treatment allocation. Primary endpoints were changes in PVCs burden and MHR as assessed by 24-hour Holter monitoring relative to baseline. Secondary efficacy endpoints were subjective symptom score, ECG, and biochemical parameters. Analysis was based on intention-to-treat principles. 333 patients were randomized, of which 166 received SSYX and 167 placebo. Baseline characteristics did not differ. SSYX reduced PVCs burden by 68.2% (p < 0.001) and increased MHR by 10.9% (p < 0.001) compared to 32.2% and 4.7%, respectively, in the placebo group. SSYX group experienced greater symptomatic improvement (p < 0.001). No differences in reported adverse events were seen (20 versus 23). SSYX is an effective antiarrhythmic therapy for symptomatic, frequent PVCs uniquely suited patients with concomitant SB. Clinical trial number was NCT01750775.

Cardiac parasympathetic activity and ventricular diastolic interactions in individuals with spinal cord injury.

Cohort cross-sectional study. To investigate the relationship between cardiac vagal activity and left ventricular filling at rest and during vagal stimulation, via the cold face test (CFT), in individuals with spinal cord injury (SCI). University-based laboratory at Brock University, St. Catharines, ON, Canada. A total of 12 able-bodied (age: 40 ± 8.5 years) and 13 SCI individuals (age: 41 ± 8.5 years; C4-T6; AIS: A-D) were recruited. Cardiac parasympathetic activity was assessed via heart rate variability (HRV) while LV filling was assessed by conventional echocardiography. All indices of HRV and diastolic function were obtained at rest and during cardiac vagal stimulation via the CFT. At baseline, the able-bodied group demonstrated strong positive correlations between HRV and early diastolic filling; however, such correlations were absent in the SCI group. The CFT resulted in elevated HRV with concomitant bradycardia in the able-bodied group, while the SCI group experienced no change in HRV or heart rate during the CFT. Able-bodied individuals showed a positive correlation between the change in HRV and the change in LV diastole during the CFT, which was attributed to increased cardiac vagal tone and not the change in heart rate, however, no relationships were observed in the SCI group. In able-bodied individuals, cardiac parasympathetic activity is associated with LV filling at rest and during elevated cardiac vagal tone. After SCI, there is a discord between vagal and LV diastolic activity, where changes in autonomic function do not influence LV filling, suggesting a disconnect between parasympathetic and cardiac function.

Repolarisation anomalies and rhabdomyolysis

Acute rhabdomyolysis is a rare but potentially severe disease in childhood. Inherited metabolic disorders have to be searched for. Significant repolarisation abnormalities have been described in patients with acute rhabdomyolysis and TANGO2 mutation involved in the Golgi apparatus. Between 12/2013 and 01/2017, 4 children (mean age 3,5 years at first crisis) presented in our department with 1 to 3 acute severe rhabdomyolysis crises (CPK > 10,000 UI/L) associated with significant ECG anomalies. All 4 had neurodevelopmental delay (from mild speech delay to spastic tetraparesia, with microcephaly). Rhabdomyolysis occurred after acute viral illnesses or unusual fasting and were associated with neurological deterioration. Cardiac anomalies included significant lengthening of QT and QTc interval in all 4, concomitant bradycardia and life-threatening “torsades de pointe” in patient 1, left bundle branch bloc in patient 3 and ventricular arrhythmia and cardiac arrest in patient 4 ( Fig. 1 ). ECG anomalies were maximal around 10 days after the beginning of crisis and slightly delayed from the peak CPK level. Ventricular dysfunction was associated in patient 2 (mild) and in patient 3 (severe requiring inotrope support). Cardiac anomalies regressed completely in all between the rhabdomyolysis crises. Patient 1 died while admitted for her 3rd rhabdomyolysis crisis, with severe neurological worsening, prolonged QT but no ventricular arrhythmia. TANGO2 mutation was confirmed in patient 1, suspected but not yet confirmed for the 3 others. Ventricular conduction and function have to be explored in children with acute rhabdomyolysis in the setting of neurodevelopmental delay. TANGO2 mutations may be responsible. The cardiac disorders are rapidly progressive, potentially life-threatening but reversible. The mechanism and treatment are poorly defined.

Influence of increased heart rate and aortic pressure on resting indices of functional coronary stenosis severity

Baseline assessment of functional stenosis severity has been proposed as a practical alternative to hyperemic indices. However, intact autoregulation mechanisms may affect intracoronary hemodynamics. The aim of this study was to investigate the effect of changes in aortic pressure (Pa) and heart rate (HR) on baseline coronary hemodynamics and functional stenosis assessment. In 15 patients (55 ± 3% diameter stenosis) Pa, intracoronary pressure (Pd) and flow velocity were obtained at control, and during atrial pacing at 120 bpm, increased Pa (+30 mmHg) with intravenous phenylephrine (PE), and elevated Pa while pacing at sinus heart rate (PE + sHR). We derived rate pressure product (RPP = systolic Pa × HR), baseline microvascular resistance (BMR = Pd/velocity), and stenosis resistance [BSR = (Pa − Pd)/velocity] as well as whole-cycle Pd/Pa. Tachycardia (120 ± 1 bpm) raised RPP by 74% vs. control. Accordingly, BMR decreased by 27% (p < 0.01) and velocity increased by 36% (p < 0.05), while Pd/Pa decreased by 0.05 ± 0.02 (p < 0.05) and BSR remained similar to control. Raising Pa to 121 ± 3 mmHg (PE) with concomitant reflex bradycardia increased BMR by 26% (p < 0.001) at essentially unchanged RPP and velocity. Consequently, BSR and Pd/Pa were only marginally affected. During PE + sHR, velocity increased by 21% (p < 0.01) attributable to a 46% higher RPP (p < 0.001). However, BMR, BSR, and Pd/Pa remained statistically unaffected. Nonetheless, the interventions tended to increase functional stenosis severity, causing Pd/Pa and BSR of borderline lesions to cross the diagnostic threshold. In conclusion, coronary microvascular adaptation to physiological conditions affecting metabolic demand at rest influences intracoronary hemodynamics, which may lead to altered basal stenosis indices used for clinical decision-making.

Divergent cardio-ventilatory and locomotor effects of centrally and peripherally administered urotensin II and urotensin II-related peptides in trout.

The urotensin II (UII) gene family consists of four paralogous genes called UII, UII-related peptide (URP), URP1 and URP2. UII and URP peptides exhibit the same cyclic hexapeptide core sequence (CFWKYC) while the N- and C-terminal regions are variable. UII, URP1, and URP2 mRNAs are differentially expressed within the central nervous system of teleost fishes, suggesting that they may exert distinct functions. Although the cardiovascular, ventilatory and locomotor effects of UII have been described in teleosts, much less is known regarding the physiological actions of URPs. The goal of the present study was to compare the central and peripheral actions of picomolar doses (5–500 pmol) of trout UII, URP1, and URP2 on cardio-ventilatory variables and locomotor activity in the unanesthetized trout. Compared to vehicle, intracerebroventricular injection of UII, URP1 and URP2 evoked a gradual increase in total ventilation (VTOT) reaching statistical significance for doses of 50 and 500 pmol of UII and URP1 but for only 500 pmol of URP2. In addition, UII, URP1 and URP2 provoked an elevation of dorsal aortic blood pressure (PDA) accompanied with tachycardia. All peptides caused an increase in locomotor activity (ACT), at a threshold dose of 5 pmol for UII and URP1, and 50 pmol for URP2. After intra-arterial (IA) injection, and in contrast to their central effects, only the highest dose of UII and URP1 significantly elevated VTOT and ACT. UII produced a dose-dependent hypertensive effect with concomitant bradycardia while URP1 increased PDA and heart rate after injection of only the highest dose of peptide. URP2 did not evoke any cardio-ventilatory or locomotor effect after IA injection. Collectively, these findings support the hypothesis that endogenous UII, URP1 and URP2 in the trout brain may act as neurotransmitters and/or neuromodulators acting synergistically or differentially to control the cardio-respiratory and locomotor systems. In the periphery, the only physiological actions of these peptides might be those related to the well-known cardiovascular regulatory actions of UII. It remains to determine whether the observed divergent physiological effects of UII and URPs are due to differential interaction with the UT receptor or binding to distinct UT subtypes.

Severe unexplained relative hypotension and bradycardia in the emergency department.

A precipitous episode of hypotension with concomitant bradycardia is a true medical emergency especially in patients with chronic hypertension and often requires hospitalization for detailed interrogation of the underlying causes. We describe herein a case of a patient with chronic labile hypertension who presented to the ED with a sharp drop in blood pressure and heart rate which was not simply explained by an antihypertensive overdose but more so by an aggregate of the patient's multiple chronic medical conditions. This report highlights the complexities of treating simultaneous hypotension and bradycardia and the importance of discerning the underpinnings of the causes including past medical issues, patient medications, and the timeline of key events leading to the issue at hand.

How should propranolol be initiated for infantile hemangiomas: Inpatient versus outpatient?

How should propranolol be initiated for infantile hemangiomas: Inpatient versus outpatient?

Effects of gabapentin on muscle spasticity and both induced as well as spontaneous autonomic dysreflexia after complete spinal cord injury

We recently reported that the neuropathic pain medication, gabapentin (GBP; Neurontin), significantly attenuated both noxious colorectal distension (CRD)-induced autonomic dysreflexia (AD) and tail pinch-induced spasticity compared to saline-treated cohorts 2–3 weeks after complete high thoracic (T4) spinal cord injury (SCI). Here we employed long-term blood pressure telemetry to test, firstly, the efficacy of daily versus acute GBP treatment in modulating AD and tail spasticity in response to noxious stimuli at 2 and 3 weeks post-injury. Secondly, we determined whether daily GBP alters baseline cardiovascular parameters, as well as spontaneous AD events detected using a novel algorithm based on blood pressure telemetry data. At both 14 and 21 days after SCI, irrespective of daily treatment, acute GBP given 1 h prior to stimulus significantly attenuated CRD-induced AD and pinch-evoked tail spasticity; conversely, acute saline had no such effects. Moreover, daily GBP did not alter 24 h mean arterial pressure (MAP) or heart rate (HR) values compared to saline treatment, nor did it reduce the incidence of spontaneous AD events compared to saline over the three week assessment period. Power spectral density (PSD) analysis of the MAP signals demonstrated relative power losses in mid frequency ranges (0.2–0.8 Hz) for all injured animals relative to low frequency MAP power (0.02–0.08 Hz). However, there was no significant difference between groups over time post-injury; hence, GBP had no effect on the persistent loss of MAP fluctuations in the mid frequency range after injury. In summary, the mechanism(s) by which acute GBP treatment mitigate aberrant somatosensory and cardiophysiological responses to noxious stimuli after SCI remain unclear. Nevertheless, with further refinements in defining the dynamics associated with AD events, such as eliminating requisite concomitant bradycardia, the objective repeatability of automatic detection of hypertensive crises provides a potentially useful tool for assessing autonomic function pre- and post-SCI, in conjunction with experimental pharmacotherapeutics for neuropathic pain, such as GBP.

Life-threatening bradycardia after bilateral paramedian thalamic and midbrain infarction

Dear Sirs,Bilateral symmetric thalamic infarcts are uncommon pre-sentations of ischemic stroke that mostly occur in the ter-ritories of the paramedian thalamic arteries [1]. Thesearteries arise either separately from the posterior cerebralarteries (PCAs) or exceptionally from a single commontrunk the artery of Percheron [2]. In this article, a case ofbithalamic paramedian and midbrain stroke presenting withdrowsiness, ophtalmoplegia, and life-threatening brady-cardia is presented. Despite it is known that different stroketopographic patterns can produce slowing of heart rate andasystolia, this is the first report of acute bradycardia inconcomitance to bilateral midbrain infarction [3–5].A 51-year-old man with a 3-year history of idiopathicarterial hypertension (on zofenopril) was admitted to ouremergency room after being found unresponsive in bed. Onadmission he showed fluctuating level of consciousness,dysarthria, anisocoria, and vertical gaze palsy (NIHSS 7,GCS 9). During examination, the patient suddenly devel-oped severe sinus bradycardia (pulse rate \30 beats perminute (bpm), for 3 minutes) that improved only afteratropine administration. Arterial blood pressure (BP),blood exams, toxicological screening, and brain CT scanwere all normal. Within 1 h, another self-limiting episodeof drowsiness and concomitant bradycardia ensued. Dif-fusion-weighted (DW) sequences on brain MRI demon-strated symmetric bilateral thalamic, hypothalamic, andmidbrain acute infarctions, thus, advocating the occlusionof a putative artery of Percheron (Fig. 1a). Top-of-the-basilar syndrome was ruled out documenting patency ofthe basilar artery and both PCAs by MRI angiography.Extensive cardiological workup showed no signs ofhypertensive cardiomyopathy both on ECG and echocar-diography, but revealed a patent foramen ovale (PFO) withsevere right-to-left atrial shunt. Anticoagulant therapy was,therefore, started and PFO closure suggested. In the fol-lowing days, episodes of bradycardia (nadir of 38 bpm,without major alterations of BP) tended to recur duringdrowsiness and night sleep. Particularly, diurnal fluctua-tions of vigilance paralleled recurrent sleep spindle patternson electroencephalography (Fig. 1b). Sinus bradycardiaoccurred less often and heart rate gradually increased in thefollowing weeks. At the 3-month follow-up, despite fullresolution of gaze palsy and arrhythmia, the patient stillpresented recurring episodes of hypersomnolence andimportant disability due to long-lasting apathy.Infarcts at the mesencephalic–diencephalic junctionresult in complex clinical syndromes contingent on thedeep brain structures involved. Supranuclear vertical gazepalsy and associated abnormal ocular reflexes are related tolesions of the rostral interstitial and Edinger–Westphalnuclei [6]. Fluctuating level of consciousness, coma, andhypersomnolence are attributed to the involvement ofintralaminar nuclei and reticular mesencephalic formation[7]. Notably, while presenting symptoms usually reverseover time, cognitive dysfunctions caused by limbic loopinterruption lead to long-term disability [8]. In our patient

Concomitant hypertension, bradycardia, and loss of transcranial electric motor evoked potentials during pedicle hook removal: report of a case

Neurophysiologic monitors in the form of transcranial electric motor evoked potentials (tceMEPs) and somatosensory evoked potentials (SSEPs) have become widely used modalities to monitor spinal cord function during major orthopedic spine procedures. In combination with invasive and non-invasive clinical monitoring and an anesthesia information management system (AIMS), we promptly recognized an acute change in hemodynamic and neurophysiologic parameters, managed intraoperative spinal cord contusion, and successfully minimized iatrogenic injury to the spinal cord during corrective spine surgery.

Right ventricular pacing is associated with impaired overall survival, but not with an increased incidence of ventricular tachyarrhythmias in routine cardioverter/defibrillator recipients with reservedly programmed pacing

Data from previous defibrillator studies raised concern about right ventricular pacing (RVP) promoting heart failure progression and mortality in implantable cardioverter/defibrillator (ICD) patients. The present observational study re-examined the association of RVP, survival, and ventricular tachyarrhythmias/ventricular fibrillation (VT/VF) in routine ICD patients with restrictively programmed pacing. In 213 ICD patients [183 men, left ventricular ejection fraction (LVEF) 37 +/- 15%, follow-up 37 +/- 18 months, no advanced atrioventricular (AV) block], the RVP proportion, survival, and the time to a first appropriate VT/VF episode were assessed. Electrograms were validated and the overall survival was determined. The RVP prevalence was dichotomized at > or = 30% (high RVP) vs. <30% (low RVP). High RVP (RVP 94%, n = 24) and low RVP (RVP 0%, n = 189) patients had similar LVEF, underlying heart disease, ICD indication, and medication. Multivariate Cox regression showed no difference in survival without appropriate VT/VF treatment [odds ratio (OR): 0.92, 95% confidence interval (CI): 0.41-2.04, P = 0.83]. Overall survival was significantly more favourable in low RVP patients (OR: 0.34, CI: 0.13-0.91, P = 0.03). Frequent RVP is associated with impaired survival in ICD patients despite conservative pacing settings. Implantable cardioverter/defibrillator patients requiring concomitant bradycardia pacing should be cared for with particular attention to clinical worsening. Right ventricular pacing prevention and alternative modalities of ventricular pacing need prospective evaluation.

Abstract 4121: Clomipramine Infusion During Tilt Test To Imply The Neurocardiogenic Origin Of Syncopes And Presyncopes Of Unknown Aetiology

The aim of this study was to prospectively evaluate the diagnostic accuracy for neurocardiogenic syncopes (NCS) of two Head-Up Tilt table test (HUT) strategies in 991 patients with syncopes/presyncopes of unknown aetiology after negative clinical and non invasive investigations. HUT is a widely accepted tool in the evaluation of patients with evidence of VVS but questions remain about the sensitivity and the use of provocative agents.Clomipramine (CP), a serotonin re-uptake inhibitor, was recently proposed as a new drug challenge test for the diagnosis of neurocardiogenic syncope (NCS). Group A : the first 341 pts (207 male ; mean age = 49,9 ± 23 years) were passively tilted at 60° for 30 minutes (min), then for 15 min with 2 μg/min isoproterenol infusion rate. Group B : the following 650 pts (383 male ; mean age = 48,3 ± 21 years) were tilted at 60° for 20 min with 5 mg CP infused during the first 5 min of tilt. A positive HUT was defined as reproducting the patient’s syncope or presyncope, associated with an abrupt fall in blood pressure (systolic blood pressure &lt;80 mmHg) and/or concomitant bradycardia (&lt;50 beats/min). Positives responses were classified in 3 types according to the Brignole’s modification of the VASIS classification. There was no significant difference between group A/B in sex or age. Group A : Positive HUT* : 103 (Sensitivity : 30,2%) Group B : Positive HUT* : 382 (Sensitivity : 58,8 %) (*) type 1 : 36 vs 157 ; type 2A : 8 vs 13 ; Type 2B: 9 vs 57 (14,9%) ; Type 3 : 50 vs 155. No adverse effect was noticed. CP during HUT increase significantly the accuracy of the test for NCS diagnosis, especially for type 2B answers, and patients &lt;30 yo. The duration of the test is notably shortened, and the tolerance is remarkable. If previously reported specificity (87 to 94%) was confirmed, CP-HUT might be the most valuable tool in the evaluation of pts with syncopes/presyncopes of unknown aetiology.

Ventilatory and cardiovascular actions of centrally administered trout tachykinins in the unanesthetized trout

The brains of teleost fish contain members of the tachykinin family that are the products of orthologous genes expressed in mammalian nervous tissues, but little is known regarding the physiological effects of these peptides in their species of origin. The present study compares the central actions of trout neuropeptide gamma (NPgamma), substance P (SP) and neurokinin A (NKA) (5-250 pmol) on ventilatory and cardiovascular parameters in the unanesthetized rainbow trout Oncorhynchus mykiss. Intracerebroventricular (ICV) injection of NPgamma evoked a dose-dependent elevation of the ventilation rate (f(V)) but a reduction of the ventilation amplitude (V(AMP)) that was caused by a reduction of the magnitude of the adduction phase of the ventilatory signal. The net effect of NPgamma was to produce an hypoventilatory response since the total ventilation (V(TOT)) was significantly reduced. The minimum effective dose for a significant effect of NPgamma on f(V) and V(AMP) was 50 pmol. SP evoked a significant elevation of f(V), a concomitant depression of V(AMP), and a resultant decrease in V(TOT) but only at the highest dose (250 pmol). NKA was without action on f(V) but significantly decreased V(AMP) at only the highest dose tested. In this case also, the net effect of NKA was to reduce V(TOT). When injected centrally, none of the three peptides, at any dose tested, produced changes in heart rate or mean dorsal aortic blood pressure (P(DA)). Intra-arterial injection of the three tachykinins (250 pmol) produced a significant (P<0.05) increase in P(DA), but only SP and NKA induced concomitant bradycardia. None of the three peptides produced any change in f(V) or V(AMP). In conclusion, our results demonstrate that centrally injected tachykinins, particularly NPgamma, produce a strong hypoventilatory response in a teleost fish and so suggest that endogenous tachykinins may be differentially implicated in neuroregulatory control of ventilation.

Progression of paroxysmal atrial fibrillation to persistent atrial fibrillation in patients with bradyarrhythmias

The experimental concept that "atrial fibrillation (AF) begets AF" implies that atrial tachyarrhythmia (AT)/AF burden uniformly increases over time. However, the temporal patterns of paroxysmal AT/AF burden progression, its conversion to persistent AF, and the relationship to underlying disease in humans are unknown. We analyzed the average daily AT/AF burden in patients with concomitant bradycardia and paroxysmal AF to examine these issues. Three hundred thirty patients with a history of paroxysmal AF (mean age 70 +/- 10 years; 61% male) were implanted with a pacemaker that automatically recorded the cumulative daily AT/AF burden. Persistent AT/AF was defined as 7 consecutive days with >23 hours of AT on the device data logs. Antiarrhythmic drug therapy was required to be stable for at least 7 months. Average follow-up was 401 +/- 123 days. Seventy-eight patients (24%) progressed to persistent AT/AF during the follow-up period with a mean interval of 147 +/- 149 days. Mean AT/AF burden increased progressively (slope 14 s/d, P < .001) over 500 days after implant, and median AT/AF burden also increased (P < .01) in this subgroup of patients. This increase was highly correlated with the presence of structural heart disease (P < .001). There was a concomitant decrease in atrial premature beat (APB) frequency. Most patients transitioning to persistent AF were in sinus rhythm with minimal AT/AF burden in the days immediately before persistent AF. Neither mean nor median AT/AF burden increased over time in patients remaining in paroxysmal AF (slope 0 s/d, P = .7) despite a higher APB frequency than in patients with heart disease (P =.003) and a higher likelihood of daily AT/AF events (P < .001). Temporal patterns of AT/AF burden in patients developing persistent AF show a progressive increase with a sudden transition to persistent AF. This is more consistent with substrate changes, rather than increased density of triggering APBs or paroxysmal AT/AF events. Thus, progression to persistent AF is probably related to an AF substrate, which is undergoing progressive structural remodeling owing to heart disease and other factors and is now suddenly capable of sustaining prolonged or multiple ATs. Therapies directed at the atrial substrate may be needed to prevent persistent AF.

PHARMACOKINETICS AND PHARMACODYNAMICS OF A NITRIC OXIDE‐RELEASING DERIVATIVE OF ENALAPRIL IN MALE BEAGLES

1. Pharmacological compounds that release nitric oxide (NO) have been useful tools in the evaluation of the broad role of NO in physiopathology and therapeutics. The present study compared the pharmacokinetics and pharmacodynamics of enalapril and an NO-releasing enalapril molecule (NCX899) in conscious male beagles. The effects of both enalapril and NCX899 in the arterial hypertension and bradycardia induced by acute NO inhibition in anaesthetized dogs were also investigated. 2. Dogs received either NCX899 (4 micromol/kg, i.v.) or enalapril (4 micromol/kg, i.v.), after which plasma concentrations of the analytes and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). 3. In the NCX899 group, the area under the time-course curve (AUC(0-24h)) was 29.18 +/- 4.72, 229.37 +/- 51.32 and 5159.23 +/- 514.88 microg.h/L for the analytes nitro-enalapril, enalapril and enalaprilat, respectively. In the enalapril group, the AUC(0-24h) was 704.53 +/- 158.86 and 4149.27 +/- 847.30 microg.h/L for the analytes enalapril and enalaprilat, respectively. Statistical analysis of data from both groups showed a significant difference for the analyte enalapril, but not for enalaprilat. Moreover, NCX899 and enalapril were equally effective in inhibiting the activity of serum angiotensin-converting enzyme. 4. In anaesthetized dogs, i.v. administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 0.1-10 mg/kg) significantly elevated arterial blood pressure, with concomitant bradycardia. The compound NCX899 significantly attenuated both arterial hypertension and bradycardia, whereas enalapril had no significant effect. 5. In conclusion, the present results showed that the NO-releasing derivative of enalapril NCX899 presents a pharmacokinetic/pharmacodynamic relationship similar to its parent compound enalapril. Moreover, NCX899 (but not enalapril) was effective in protecting against the cardiovascular changes induced by acute NOS inhibition.

Cardiovascular effects of the essential oil of Croton zehntneri leaves and its main constituents, anethole and estragole, in normotensive conscious rats

Cardiovascular effects of the essential oil of Croton zehntneri (EOCZ) were investigated in conscious rats. In these preparations, intravenous (i.v.) injections of EOCZ (1–20 mg kg − 1 ) and its main constituents anethole and estragole (both at 1–10 mg kg − 1 ) elicited brief and dose-dependent hypotension and bradycardia (phase I) that were followed by a significant pressor effect associated with a delayed bradycardia (phase II). The initial hypotension and bradycardia (phase I) of EOCZ were unchanged by atenolol (1.5 mg kg − 1 , i.v.) or l-NAME (20 mg kg − 1 , i.v.) pretreatment, but were respectively reversed into pressor and tachycardic effects by methylatropine (1 mg kg − 1 , i.v.) pretreatment. The subsequent pressor effect and the delayed bradycardia (phase II) remained unaffected by atenolol, but were abolished by l-NAME and methylatropine pretreatment, respectively. In rat endothelium-containing aorta preparations, the vasoconstrictor responses to phenylephrine were enhanced and reduced, respectively, by the lower (1–30 μg mL − 1 ) and higher (300–1000 μg mL − 1 ) concentrations of EOCZ. Only the enhancement of phenylephrine-induced contraction was abolished by either the incubation with l-NAME (50 μM) or in the absence of the endothelium. These data show, for the first time, that i.v. administration EOCZ induces an initial hypotension followed by a pressor response, two effects that appear mainly attributed to the actions of anethole and estragole. The EOCZ-induced hypotension (phase I) is mediated by a cholinergic mechanism and seems to result mainly from the concomitant bradycardia. The pressor response of EOCZ (phase II) seems to be caused by an indirect vasoconstrictive action of EOCZ most likely through inhibition of endothelial nitric oxide production.

New advances in nonpharmacologic therapy for atrial fibrillation

Atrial fibrillation (AF) is the most commonly occurring cardiac arrhythmia. Due to the low clinical efficacy of current antiarrhythmic agents, various nonpharmacologic approaches including catheter ablation, permanent cardiac pacing and surgical procedure, alone or in combination, have been developed for the treatment of AF. Except in patients who require open heart surgery, surgical procedures have a very limited role in the treatment of AF. Pacing therapy alone, except in patients with concomitant bradycardia, has a very limited role for the treatment of AF. The incremental benefit of alternate- or multiple-site pacing and different pacing algorithms remains to be defined. Catheter ablation procedures may prove to provide curative therapy for AF in selected but widening patient populations. However, issues concerning the optimal ablation technique and safety of the procedure remain to be resolved. Currently, most of the nonpharmacologic methods of AF treatment are more or less experimental and need to b...

Cardiovascular effects of peptide kinin B2 receptor antagonists in rats

Bradykinin (BK) is a vasoactive peptide reputed to play an important role in cardiovascular homeostasis. In this study, we describe the cardiovascular changes (mean blood pressure (BP) and heart rate (HR)) induced by the i.v. administration (left jugular vein) of two selective kinin B2 receptor antagonist, namely icatibant (0.1-1 micromol/kg as a bolus) and MEN1 1270 (0.1-1 micromol/kg as a bolus or 1 micromol/kg infused in 15 or 60 min), in urethane-anaesthetized or conscious rats with an indwelling catheter implanted in the right carotid artery for BP measurements. In conscious rats, icatibant at 0.1 or 0.3 micromol/kg did not change BP but at 0.1 micromol/kg increased HR at 30 min from administration. MEN1 1270 at 0.1 or 0.3 micromol/kg induced a dose-related increase in BP and a concomitant bradycardia (significant at 0.3 micromol/kg) lasting for 5 or 30 min, respectively. Icatibant at 1 micromol/kg induced a slight (P < 0.05) increase in BP that resolved in 5 min and a biphasic tachycardia (peaks at 30 and 90 min from administration). MEN1 1270 at 1 micromol/kg induced a triphasic change in HR (tachycardia in the first 5 min, bradycardia at 30 min, and tachycardia at 90 and 120 min) and a biphasic change in BP (hypotension at 15 min and hypertension at 30 min). The i.v. infusion of MEN1 1270 (1 micromol/kg in 15 or 60 min) produced hypertension, whereas HR was increased only following the 15-min infusion. In urethane-anaesthetized rats, both icatibant and MEN1 1270 (0.1 micromol/kg as a bolus) increased BP and the onset for this effect was correlated with the time course of the antagonism of BK-induced hypotension, where the effect of MEN1 1270 was more rapid than that of icatibant. These results indicate that kinin B2 receptor antagonists can induce acute cardiovascular effects, and the reason for the different haemodynamic profile between icatibant and MEN1 1270 could be putatively attributed to kinetic characteristics.

The Hemodynamic and Holter-Electrocardiogram Changes During Halothane and Sevoflurane Anesthesia for Adenoidectomy in Children Aged One to Three Years

The Hemodynamic and Holter-Electrocardiogram Changes During Halothane and Sevoflurane Anesthesia for Adenoidectomy in Children Aged One to Three Years