Optical mapping of activation patterns in an animal model of congenital heart block.
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Congenital heart block (CHB) is associated with high mortality and affects children of mothers with autoantibodies (IgG) to ribonucleoproteins SSB/La and SSA/Ro. IgG from mothers of children with CHB (positive IgG) was used to assess activation patterns in both the right atrium (RA) and right ventricle (RV) of Langendorff-perfused young rabbit hearts. Optical action potentials (AP) were obtained by using a 124-site photodiode array with 4-[-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium. Optical APs were recorded to simultaneously image activation patterns from the RA and RV. Perfusion of positive IgG (800--1,200 micro resulted in sinus bradycardia and varying degrees of heart block. Activation maps revealed marked conduction delay at the sinoatrial junction but only minor changes in overall atrial and ventricular activation patterns. No conduction disturbances were seen in the presence of IgG from mothers with healthy children. In conclusion, besides atrioventricular (AV) block, positive IgG induces sinus bradycardia. These results establish that the sequelae of CHB are associated with impaired intrasinus and/or sinoatrial conduction. The findings raise the possibility that sinus bradycardia in the developing heart may indicate the potential for AV conduction disturbances. (+info)
Hypotension, autonomic failure, and cardiac hypertrophy in transgenic mice overexpressing the alpha 1B-adrenergic receptor.
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alpha(1)-Adrenergic receptors (alpha(1A), alpha(1B), and alpha(1D)) are regulators of systemic arterial blood pressure and blood flow. Whereas vasoconstrictory action of the alpha(1A) and alpha(1D) subtypes is thought to be mainly responsible for this activity, the role of the alpha(1B)-adrenergic receptor (alpha(1B)AR) in this process is controversial. We have generated transgenic mice that overexpress either wild type or constitutively active alpha(1B)ARs. Transgenic expression was under the control of the isogenic promoter, thus assuring appropriate developmental and tissue-specific expression. Cardiovascular phenotypes displayed by transgenic mice included myocardial hypertrophy and hypotension. Indicative of cardiac hypertrophy, transgenic mice displayed an increased heart to body weight ratio, which was confirmed by the echocardiographic finding of an increased thickness of the interventricular septum and posterior wall. Functional deficits included an increased isovolumetric relaxation time, a decreased heart rate, and cardiac output. Transgenic mice were hypotensive and exhibited a decreased pressor response. Vasoconstrictory regulation by alpha(1B)AR was absent as shown by the lack of phenylephrine-induced contractile differences between ex vivo mesenteric artery preparations. Plasma epinephrine, norepinephrine, and cortisol levels were also reduced in transgenic mice, suggesting a loss of sympathetic nerve activity. Reduced catecholamine levels together with basal hypotension, bradycardia, reproductive problems, and weight loss suggest autonomic failure, a phenotype that is consistent with the multiple system atrophy-like neurodegeneration that has been reported previously in these mice. These results also suggest that this receptor subtype is not involved in the classic vasoconstrictory action of alpha(1)ARs that is important in systemic regulation of blood pressure. (+info)
Potentiation of baroreceptor reflex response by heat shock protein 70 in nucleus tractus solitarii confers cardiovascular protection during heatstroke.
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BACKGROUND: Whereas hypotension and bradycardia seen during the onset of heatstroke may be protected by prior induction of heat shock protein 70 (HSP70) in the brain, the underlying mechanism is not fully understood. We evaluated the hypothesis that HSP70 may confer cardiovascular protection during heatstroke by potentiating the baroreceptor reflex (BRR) control of peripheral hemodynamic performance. METHODS AND RESULTS: Adult male Sprague-Dawley rats subjected to a brief hyperthermic heat shock (HS; 42 degrees C for 15 minutes) induced discernible expression of HSP70 in the bilateral nucleus tractus solitarii (NTS), the terminal site in the brain stem for primary baroreceptor afferents. This HSP70 expression was detected at 8 hours, peaked at 24 hours, and returned to baseline by 48 hours after HS. Brief hyperthermia also significantly potentiated the BRR response in a temporal profile that correlated positively with changes in HSP70 expression at the NTS. Prior HS also appreciably alleviated hyperthermia, severe hypotension, and bradycardia manifested during the onset of heatstroke (45 degrees C for 60 minutes) elicited 24 hours later. Microinjection bilaterally of anti-HSP70 antiserum (1:20) into the NTS or denervation of the sinoaortic baroreceptor afferents significantly reversed the enhancement of BRR response and cardiovascular protection during heatstroke induced by prior HS. CONCLUSIONS: These results suggest that HS-induced expression of HSP70 in the NTS may alleviate severe hypotension and bradycardia exhibited during the onset of heatstroke by potentiating both the sensitivity and capacity of BRR response. (+info)
Autonomic origins of a nonsignal stimulus-elicited bradycardia and its habituation in humans.
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The purposes of the present study were to determine the autonomic origins of a bradycardiac response to a moderate intensity nonsignal auditory stimulus and the changes in autonomic cardiac control of this response as a function of habituation. Pure tone stimuli were repeatedly presented to participants while phasic changes in heart period (HP), preejection period (PEP), and respiratory sinus arrhythmia (RSA) were observed. Tone stimuli initially elicited an increase in HP, an increase in RSA, and a decrease in PEP, suggesting a coactivation of the parasympathetic and sympathetic inputs mediating changes in the bradycardiac HP response. As expected, HP responses habituated with repeated presentations of the tones. PEP and RSA responses, however, demonstrated different habituation rates than HP. These data demonstrate that cardiodeceleratory responses to nonsignal stimuli can arise from changes in activity of both autonomic divisions and document the importance of considering the autonomic origins of habituating cardiac responses in order to fully understand the process of response habituation. (+info)
Autosomal recessive catecholamine- or exercise-induced polymorphic ventricular tachycardia: clinical features and assignment of the disease gene to chromosome 1p13-21.
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BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death in response to physiological or emotional stress. In 2 families with autosomal dominant inheritance, the disease gene was mapped to chromosome 1q42-43. The objectives of this study were to characterize the clinical features of the disease in a Bedouin tribe from Israel and to map the disease gene. METHODS AND RESULTS: In this Bedouin tribe, 9 children (age, 7+/-4 years) from 7 related families have died suddenly during the past decade, and 12 other children suffered from recurrent syncope and seizures starting at the age of 6+/-3 years. Parents of affected individuals were asymptomatic and were all related (first-, second-, or third-degree cousins). Segregation analysis suggested autosomal recessive inheritance. All 12 symptomatic patients and 1 asymptomatic sibling (mean age, 13+/-7 years) were found to have a relative resting bradycardia (64+/-13 bpm, versus 93+/-12 bpm in the unaffected siblings), as well as PVT induced by treadmill or isoproterenol infusion and appearing at a mean sinus rate of 110+/-10 bpm. Patients responded favorably to treatment with beta-blockers. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 16-megabase interval on chromosome 1p13-21. A maximal lod score of 8.24 was obtained with D1S189 at theta=0.00. Sequencing of KCND3, a gene that encodes an I(tO) potassium channel transporter, did not reveal any significant sequence alterations. CONCLUSIONS: This unique form of autosomal recessive PVT affects young children and may be lethal if left untreated. Linkage analysis maps this disorder to chromosome 1p13-21. (+info)
Relationship between pacemaker dependency and the effect of pacing mode on cardiovascular outcomes.
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BACKGROUND: A recently completed trial, the Canadian Trial of Physiological Pacing (CTOPP), showed that physiological pacing did not significantly reduce mortality, stroke, or heart failure hospitalization, but it did show that atrial fibrillation occurred less frequently in patients with physiological pacing. Many pacemaker patients experience only transient bradyarrhythmias with an adequate unpaced heart rate (UHR) and are not pacemaker-dependent. The purpose of the present analysis was to determine if pacemaker-dependent patients have an increased benefit from physiological pacing compared with non-pacemaker-dependent patients. METHODS AND RESULTS: Of 2568 patients included in the CTOPP trial, 2244 patients had a pacemaker dependency test performed at the first follow-up visit. The yearly event rate of cardiovascular death or stroke steadily increased with decreasing UHR in the ventricular pacing group, but it remained constant in the physiological pacing group. When the patients were subdivided to UHR 60 bpm, there was an interaction between pacing mode treatment and UHR subgroup. The Kaplan-Meier plot confirmed a physiological pacing advantage only in the UHR +info)
Reflex nature of the cardiorespiratory response to primary thoracic blast injury in the anaesthetised rat.
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Blast injuries represent a problem for civilian and military populations. Primary thoracic blast injury causes a triad of bradycardia, hypotension and apnoea. The objective of this study was to investigate the reflex nature of this response and its modulation by vagotomy or administration of atropine. The study was conducted on terminally anaesthetised (alphadolone/alphaxalone, 18-24 mg x kg x h(-1), I.V.) male Wistar rats randomly allocated to the groups indicated below. Blast injuries were produced with compressed air while sham blast involved the sound of a blast only. Primary blast injury to the thorax resulted in a bradycardia (measured as an increase in the interval between beats, or heart period (HP) to 489 +/- 37 ms from 133 +/- 3 ms with a latency of onset of 4.3 +/- 0.3 s, mean +/- S.E.M.), hypotension (fall in mean arterial blood pressure (MBP) from 128.1 +/- 3.7 mmHg to 34.8 +/- 4.1 mmHg, latency of onset 2.0 +/- 0.1 s) and apnoea lasting 28.3 +/- 2.3 s. Sham blast had no effect. The bradycardia and apnoea following thoracic blast were abolished by cervical vagotomy while the hypotension was attenuated. Atropine (0.3 mg x kg(-1), I.V.) caused a significant reduction in the bradycardia (HP increasing from 124 +/- 3 ms to 142 +/- 4 ms) but did not modulate either the hypotension or apnoea. It is concluded that a reflex involving the vagus nerve mediates the bradycardia, apnoea and a component of the hypotension associated with thoracic blast. The pattern of this response is similar to effects that follow stimulation of the pulmonary afferent C-fibres. (+info)
Randomized assessment of syncope trial: conventional diagnostic testing versus a prolonged monitoring strategy.
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BACKGROUND: Establishing a diagnosis in patients with unexplained syncope is complicated by infrequent and unpredictable events. Prolonged monitoring may be an alternative strategy to conventional testing with short-term monitoring and provocative tilt and electrophysiological testing. METHODS AND RESULTS: Sixty patients (aged 66+/-14 years, 33 male) with unexplained syncope were randomized to "conventional" testing with an external loop recorder and tilt and electrophysiological testing or to prolonged monitoring with an implantable loop recorder with 1 year of monitoring. If patients remained undiagnosed after their assigned strategy, they were offered crossover to the alternate strategy. A diagnosis was obtained in 14 of 27 patients randomized to prolonged monitoring compared with 6 of 30 patients undergoing conventional testing (52% versus 20%, P=0.012). Crossover was associated with a diagnosis in 1 of 6 patients undergoing conventional testing compared with 8 of 13 patients who completed monitoring (17% versus 62%, P=0.069). Overall, prolonged monitoring was more likely to result in a diagnosis than was conventional testing (55% versus 19%, P=0.0014). Bradycardia was detected in 14 patients undergoing monitoring compared with 3 patients undergoing conventional testing (40% versus 8%, P=0.005). CONCLUSIONS: A prolonged monitoring strategy is more likely to provide a diagnosis than conventional testing in patients with unexplained syncope. Consideration should be given to earlier implementation of a monitoring strategy. (+info)