Incidence and characteristics of far-field R-wave sensing in low right atrial septum pacing.

BACKGROUND: Although low atrial septal (LAS) pacing may prevent atrial tachyarrhythmias in selected patients, far-field R-wave (FFRW) sensing in this region seems more likely than in the right atrial appendage. METHODS AND RESULTS: We compared the clinical characteristics and prevalence of FFRW sensing in 31 recipients (mean age, 74 ± 10 years) of dual-chamber pacemakers, randomly assigned to 10.0 mm (n=15) vs. 1.1mm (n=16) tip-ring electrode spacing of bipolar atrial leads implanted in the LAS for management of bradyarrhythmias. The pacemakers were programmed to DDD mode with backup rates at 50-60 beats/min. FFRW sensing was measured with atrial sensitivity set at 0.1 mV, and increased in 0.1 mV steps. Predictors of FFRW sensing were examined by multiple variable regression analysis, and hazard ratios (HR) and confidence intervals (CI) were calculated. At atrial sensitivities of 0.1 and 0.5 mV, FFRW was sensed in 24 (77%) and 9 (29%) patients, respectively. A 10.0-mm tip-ring electrode spacing of the atrial lead (HR 10.3; 95%CI 1.0-102.7; P=0.047), and presence of left ventricular hypertrophy (LVH) on 12-lead ECG (HR 14.5, 95%CI 1.2-180.0; P=0.037) were independent predictors of FFRW sensing. CONCLUSIONS: The prevalence of FFRW sensing in the LAS region was high. A narrow spacing of the tip-ring electrodes is recommended in the LAS, particularly in the presence of LVH on ECG.

Reliability and characteristics of atrial tachyarrhythmias detection in dual chamber pacemakers.

BACKGROUND: Although atrial high rate episodes (AHRE) have been commonly used to detect atrial tachyarrhythmias (AT/AF) in pacemaker patients, its reliability and characteristics are unclear. METHODS AND RESULTS: 39 patients with implanted dual chamber pacemakers (mean age 79.7 ± 6.6 years), who had no history of AT/AF and were programmed in the setting of AHRE at > 190 beats/min in DDD mode, were studied. An atrial overdrive pacing (AOP) algorithm was randomly programmed "ON" in 19 and "OFF" in 20 patients. AHRE were detected in 20 patients (51%), consisting of AT/AF in 15 and repetitive non-reentrant ventriculoatrial synchrony (RNRVAS) in 8 patients, all included in the AOP "ON" group. A total of 257 of 1,528 episodes of AHRE were available for analysis, including 181 and 76 episodes in the AOP "ON" and "OFF" groups, respectively. Among 181 episodes in the AOP "ON" group, 72 (40%) were RNRVAS, whereas all episodes in the AOP "OFF" group (100%) were AT/AF. Detection of RNRVAS was closely associated with a high cumulative % atrial pacing. The specificity of AT/AF detection by AHRE was 40% when the AOP algorithm was activated, vs. 100% when not in use. CONCLUSIONS: AT/AF was common in pacemaker patients without a history of AT/AF. The increase in cumulative % atrial pacing and the use of an AOP algorithm might be closely associated with RNRVAS, non-AT/AF, detected by AHRE.

Allyl isothiocyanates and cinnamaldehyde potentiate miniature excitatory postsynaptic inputs in the supraoptic nucleus in rats.

Allyl isothiocyanates (AITC) and cinnamaldehyde are pungent compounds present in mustard oil and cinnamon oil, respectively. These compounds are well known as transient receptor potential ankyrin 1 (TRPA1) agonists. TRPA1 is activated by low temperature stimuli, mechanosensation and pungent irritants such as AITC and cinnamaldehyde. TRPA1 is often co-expressed in TRPV1. Recent study showed that hypertonic solution activated TRPA1 as well as TRPV1. TRPV1 is involved in excitatory synaptic inputs to the magnocellular neurosecretory cells (MNCs) that produce vasopressin in the supraoptic nucleus (SON). However, it remains unclear whether TRPA1 may be involved in this activation. In the present study, we examined the role of TRPA1 on the synaptic inputs to the MNCs in in vitro rat brain slice preparations, using whole-cell patch-clamp recordings. In the presence of tetrodotoxin, AITC (50µM) and cinnamaldehyde (30µM) increased the frequency of miniature excitatory postsynaptic currents without affecting the amplitude. This effect was significantly attenuated by previous exposure to ruthenium red (10µM), non-specific TRP channels blocker, high concentration of menthol (300µM) and HC-030031 (10µM), which are known to antagonize the effects of TRPA1 agonists. These results suggest that TRPA1 may exist at presynaptic terminals to the MNCs and enhance glutamate release in the SON.

TRPV1 gene deficiency attenuates miniature EPSC potentiation induced by mannitol and angiotensin II in supraoptic magnocellular neurons.

The release of arginine vasopressin (AVP) from the magnocellular neurosecretory cells (MNCs) in the supraoptic nucleus (SON) is crucial for body fluid homeostasis. The MNC activity is modulated by synaptic inputs and humoral factors. A recent study demonstrated that an N-terminal splice variant of the transient receptor potential vanilloid type 1 (TRPV1) is essential for osmosensory transduction in the SON. In the present study, we examined the effects of mannitol and angiotensin II on miniature EPSCs (mEPSCs) in the supraoptic MNCs using whole-cell patch-clamp recording in in vitro slice preparation. Mannitol (60 mm) and angiotensin II (0.1 microm) increased the frequency of mEPSCs without affecting the amplitude. These effects were attenuated by pre-exposure to a nonspecific TRPV channel blocker, ruthenium red (10 microm) and enhanced by pre-exposure to cannabinoid type1 receptor antagonist, AM251 (2 microm). Mannitol-induced potentiation of mEPSCs was not attenuated by angiotensin II receptor antagonist, losartan (10 microm), indicating independent pathways of mannitol and angiotensin II to the TRPV channels. The potentiation of mEPSCs by mannitol was not mimicked by a TRPV1 agonist, capsaicin, and also not attenuated by TRPV1 blockers, capsazepine (10 microm). PKC was involved in angiotensin II-induced potentiation of mEPSCs. The effects of mannitol and angiotensin II on the supraoptic MNCs in trpv1 knock-out mice were significantly attenuated compared with those in wild-type mice counterparts. The results suggest that hyperosmotic stimulation and angiotensin II independently modulate mEPSCs through capsaicin-insensitive TRPV1 channel in the presynaptic terminals of the SON.

Electromagnetic interference with a bipolar pacemaker by an induction heating (IH) rice cooker.

Electromagnetic fields may interfere with normal pacemaker function. Despite new device designs and bipolar leads, electromagnetic interference (EMI) remains a concern when pacemaker recipients are exposed to various household appliances. We report the observation of EMI by an induction heating (IH) rice cooker in a patient with sick sinus syndrome who was the recipient of a bipolar dual chamber-pacing system. Stored electrograms revealed episodes of inappropriate ventricular pacing, all coinciding with the opening of an IH rice cooker. Recipients of implantable medical devices must be warned to handle IH rice cookers with caution.

Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3.

AIMS: In the type 3 long QT syndrome (LQT3), shortening of the QT interval by overdrive pacing is used to prevent life-threatening arrhythmias. However, it is unclear whether accelerated heart rate induced by beta-adrenergic agents produces similar effects on the late sodium current (I(Na)) to those by overdrive pacing therapy. We analyzed the beta-adrenergic-like effects of protein kinase A and fluoride on I(Na) in R1623Q mutant channels. MAIN METHODS: cDNA encoding either wild-type (WT) or R1623Q mutant of hNa(v)1.5 was stably transfected into HEK293 cells. I(Na) was recorded using a whole-cell patch-clamp technique at 23 degrees C. KEY FINDINGS: In R1623Q channels, 2 mM pCPT-AMP and 120 mM fluoride significantly delayed macroscopic current decay and increased relative amplitude of the late I(Na) in a time-dependent manner. Modulations of peak I(Na) gating kinetics (activation, inactivation, recovery from inactivation) by fluoride were similar in WT and R1623Q channels. The effects of fluoride were almost completely abolished by concomitant dialysis with a protein kinase inhibitor. We also compared the effect of pacing with that of beta-adrenergic stimulation by analyzing the frequency-dependence of the late I(Na). Fluoride augmented frequency-dependent reduction of the late I(Na), which was due to preferential delay of recovery of late I(Na). However, the increase in late I(Na) by fluoride at steady-state was more potent than the frequency-dependent reduction of late I(Na). SIGNIFICANCE: Different basic mechanisms participate in the QT interval shortening by pacing and beta-adrenergic stimulation in the LQT3.

Effects of pacing modes on cardiac baroreflex function in permanently paced patients with sinus node dysfunction.

OBJECTIVES: We compared, in patients with sick sinus syndrome, the effects of various pacing modes on baroreceptor (BR)-stroke volume (SV) reflex sensitivity, a method we have closely correlated with BR-heart rate (HR) reflex sensitivity. BACKGROUND: Impaired autonomic nervous function, such as decreased BR-HR reflex sensitivity, predicts sudden cardiac death. However, in patients with sick sinus syndrome, the effects of various pacing modes on autonomic function are unknown, since chronotropic incompetence precludes its evaluation by measurements of BR-HR reflex sensitivity. METHODS: We studied 12 recipients of dual-chamber pacemakers with sick sinus syndrome (mean age = 73 +/- 8 years; 8 men). Beat-by-beat blood pressure (BP) and SV were measured during 5-minute runs of AAI, DDD, and VVI pacing, and spectrally analyzed to assess BR-SV reflex sensitivity. RESULTS: Systolic BP was significantly lower (P < 0.01) during VVI (109 +/- 24 mmHg) than during DDD (124 +/- 22 mmHg) or AAI (125 +/- 41 mmHg) pacing. SV was significantly smaller during VVI (36 +/- 23 mL) than during DDD (49 +/- 31 mL) pacing (P < 0.05). BR-SV reflex sensitivity was significantly lower (P < 0.05) during VVI (9.3 +/- 5.7% per mmHg) than during DDD (15.0 +/- 6.5% per mmHg) or AAI (15.5 +/- 6.2% per mmHg) pacing. CONCLUSIONS: BR-SV reflex sensitivity was significantly lower during VVI than during AAI or DDD pacing. Atrioventricular synchrony plays an important role in the preservation of BR-SV reflex sensitivity in pacemaker recipients.

Angiotensin receptor blocker improves coronary flow velocity reserve in hypertensive patients: comparison with calcium channel blocker.

Large-scale clinical studies have indicated that angiotensin receptor blockers (ARBs) have beneficial effects against cardiovascular diseases. We designed this study to compare the effects of an ARB and a calcium channel blocker (CCB) on coronary flow velocity reserve (CFVR), a predictor of cardiovascular events, as estimated using transthoracic Doppler echocardiography. Sixteen hypertensive patients (63.1+/-9.6 years old; 10 males) were randomly allocated in a double-blind fashion to valsartan (n=8, 40-80 mg/day) or nifedipine (n=8, 20-40 mg/day) groups. Age- and gender-matched subjects without hypertension were enrolled as a control group (n=12). CFVR was calculated by dividing the adenosine triphosphate-induced hyperemic flow velocity by the basal flow velocity in the left anterior descending coronary artery. Baseline characteristics and reduction in systolic and diastolic blood pressure after 6 months were similar in both groups. CFVR in the valsartan group increased from 2.34+/-0.38 to 3.10+/-0.84 at 2 months (p<0.05), and to 3.04+/-1.09 at 6 months (p<0.01). Both values became comparable to that in the control group (2.81+/-0.60). CFVR in the valsartan group was significantly higher (p<0.001) than that in the nifedipine group, which was little changed at 6 months. This discrepancy was derived from the significant increase of hyperemic velocity in the valsartan group, from 36.6+/-17.3 cm/s to 41.1+/-12.7 cm/s at 2 months, and to 48.1+/-20.2 cm/s at 6 months. We concluded that the ARB valsartan not only reduced high blood pressure but improved CFVR in hypertensive patients. However, these effects were not seen with the CCB nifedipine.

Effects of atrial tachypacing on symptoms and blood pressure in severe orthostatic hypotension.

UNLABELLED: The treatment of severe orthostatic hypotension (OH) is currently unsatisfactory and usually includes various pharmaceuticals to expand the blood volume and promote peripheral vasoconstriction. This study examined the short- and intermediate-term effects of atrial tachypacing (ATP) in patients with severe OH. We implanted dual chamber pacemakers in five patients (mean age 64 +/- 7 years; four men), presenting with drug refractory, recurrent syncope, and OH due to panautonomic failure with severe chronotropic incompetence and absence of rate acceleration upon assuming the upright posture. The blood pressure (BP) was measured in the supine and passive upright postures, during sinus rhythm, and during atrial pacing at 90, 100, and 110 ppm, at 1 week and at discharge and/or 3 months after pacemaker implantation. Alleviation of symptoms and a delay in the fall in upright BP were observed in a single patient at 1 week, while at discharge and/or 3 months, all patients were markedly improved. The mean fall in systolic/diastolic BP between supine and upright position decreased from 73 +/- 17/46 +/- 13 mmHg before, to 56 +/- 27/41 +/- 30 mmHg during ATP. Although these changes did not reach statistical significance, the time required for the fall in BP lengthened significantly from 2.1 +/- 0.2 minutes during sinus rhythm to 9.3 +/- 1.5 minutes during ATP (P < 0.001). CONCLUSIONS: At discharge and/or 3 months of follow-up, ATP conferred beneficial effects on orthostatic BP and alleviated symptoms in patients with severe OH. The short-term effects of ATP did not reflect its longer-term effects in four of the five patients.

Comparison of HERG channel blocking effects of various beta-blockers-- implication for clinical strategy.

beta-Blockers are widely used in the treatment of cardiovascular diseases. However, their effects on HERG channels at comparable conditions remain to be defined. We investigated the direct acute effects of beta-blockers on HERG current and the molecular basis of drug binding to HERG channels with mutations of putative common binding site (Y652A and F656C). beta-Blockers were selected based on the receptor subtype. Wild-type, Y652A and F656C mutants of HERG channel were stably expressed in HEK293 cells, and the current was recorded by using whole-cell patch-clamp technique (23 degrees C). Carvedilol (nonselective), propranolol (nonselective) and ICI 118551 (beta(2)-selective) inhibited HERG current in a concentration-dependent manner (IC(50) 0.51, 3.9 and 9.2 microM, respectively). The IC(50) value for carvedilol was a clinically relevant concentration. High metoprolol (beta(1)-selective) concentrations were required for blockade (IC(50) 145 microM), and atenolol (beta(1)-selective) did not inhibit the HERG current. Inhibition of HERG current by carvedilol, propranolol and ICI 118551 was partially but significantly attenuated in Y652A and F656C mutant channels. Affinities of metoprolol to Y652A and F656C mutant channels were not different compared with the wild-type. HERG current block by all beta-blockers was not frequency-dependent. Drug affinities to HERG channels were different in beta-blockers. Our results provide additional strategies for clinical usage of beta-blockers. Atenolol and metoprolol may be preferable for patients with type 1 and 2 long QT syndrome. Carvedilol has a class III antiarrhythmic effect, which may provide the rationale for a favourable clinical outcome compared with other beta-blockers as suggested in the recent COMET (Carvedilol Or Metoprolol European Trial) substudy.

Blockade of HERG cardiac K+ current by antifungal drug miconazole.

1. Miconazole, an imidazole antifungal agent, is associated with acquired long QT syndrome and ventricular arrhythmias. Miconazole increases the plasma concentration of QT-prolonging drugs by inhibiting the hepatic cytochrome P450 metabolic pathway, but whether it has direct effects on cardiac ion channels has not been elucidated. 2. To determine the mechanism underlying these clinical findings, we investigated the effect of miconazole on human ether-a-go-go-related gene (HERG) K+ channels. 3. HERG channels were heterologously expressed in human embryonic kidney 293 (HEK293) cells and whole-cell currents were recorded using a patch-clamp technique (23 degrees C). 4. Miconazole inhibited HERG peak tail current in a concentration-dependent manner (0.4-40 microM) with an IC50 of 2.1 microM (n=3-5 cells at each concentration, Hill coefficient 1.2). HERG block was not frequency-dependent. It required channel activation, occurred rapidly, and had very slow dissociation properties. 5. The activation curve was shifted in a negative direction (V(1/2): -9.5+/-2.3 mV in controls and -15.3+/-2.4 mV after 4 microM miconazole, P<0.05, n=6). Miconazole did not change other channel kinetics (activation, deactivation, onset of inactivation, recovery from inactivation, steady-state inactivation). 6. The S6 domain mutation, F656C, abolished the inhibitory action of miconazole on HERG current indicating that miconazole preferentially binds to an aromatic amino-acid residue within the pore-S6 region. 7. Our findings indicate that miconazole causes HERG channel block by binding to a common drug receptor, and this involves preferential binding to activated channels. Thus, miconazole prolongs the QT interval by direct inhibition of HERG channels.

Intrinsic mechanism of the enhanced rate-dependent QT shortening in the R1623Q mutant of the LQT3 syndrome.

OBJECTIVE: In the type 3 long QT syndrome (LQT3), arrhythmia events tend to occur at rest or during sleep. One of the mutations, R1623Q, is located in the voltage sensor of the cardiac sodium channel (hH1), and patients with R1623Q mutation have been also reported to show bradycardia-dependent cardiac events. Although the mutant channel has been characterized by inactivation gating defects, the intrinsic mechanism(s) that might explain why arrhythmia attack is most prevalent at slower heart rates has not been investigated. METHODS: cDNA encoding either the wild-type or the R1623Q mutant of hH1 was stably transfected into HEK293 cells. I(Na) was recorded using a whole-cell patch-clamp technique at 23 degrees C. RESULTS: A train of 50 depolarizing pulses from holding potentials (-120 and -80 mV) to -20 mV or a train of 50 action potential waveforms was applied at different frequencies. When using a rectangular waveform voltage clamp protocol, rate-dependent reduction of I(Na) was holding voltage-dependent but was not different between peak I(Na) and late I(Na). However, using the action potential clamp, preferential rate-dependent reduction of the phase 3 I(Na) was obvious as compared with peak I(Na). The discrepancy in the rate-dependent reduction between protocols was attributed to accelerated recovery from inactivation under non-equilibrium condition. CONCLUSION: The rate dependency of phase 3 I(Na) under non-equilibrium gating is a novel mechanism to explain the enhanced rate-dependent QT-shortening in LQT3 patients. Our findings are important for genotype-phenotype correlations in LQT3 mutants as well as for understanding the function of S4 segment of domain IV region in the cardiac Na(+) channel.

New onset of pacemaker dependency after permanent pacemaker implantation.

Pacemaker dependency has dangerous consequences under conditions of electromagnetic interference, unrecognized lead dysfunction, and battery depletion, and has been associated with cardiovascular and overall mortality. The aim of this study was to examine the incidence of new onset of pacemaker dependency during long-term follow-up after pacing system implantation. The study included 518 patients (mean age 72.9 +/- 10.4 years) who presented with intrinsic rhythms at the time of implantation. Indications for pacing were sick sinus syndrome (SSS) in 275 (53%) patients, AV block in 209 (40%), and AF with bradycardia in 34 (7%) patients. The mean follow-up was 3.7 +/- 2.7 years (range 1-17). Pacemaker dependency was defined as the absence of an intrinsic rhythm during backup pacing at 30 beats/min for 30 seconds. New onset of pacemaker dependency was observed in 23 (4.4%) of the 518 patients at a mean of 3.1 +/- 2.7 years of follow-up. Pacing indications were SSS in 6 (2.2%) of 275 patients, AV block in 15 (7.2%) of 209, and AF with bradycardia in 2 (5.9%) of 34. Patients with AV block had a significantly higher incidence of pacemaker dependency than patients with SSS (odds ratio 3.51; 95% CI 1.3 to 9.3; P = 0.012). The average annual rate of new pacemaker dependency was 1.6% during an 8-year follow-up. The incidence of new onset of pacemaker dependency varied among pacing indications, and was significantly higher in patients with AV block than patients with SSS.

Sustained polymorphic ventricular tachycardia unassociated with QT prolongation or bradycardia in the Kearns-Sayre syndrome.

Cardiac dysfunction, including congestive heart failure and impulse conduction abnormalities, have been implicated in the sudden death of patients suffering from the Kearns-Sayre syndrome. This report describes a 29-year-old woman who suffered syncopal episodes due to sustained polymorphic VT. Sustained polymorphic VT was not associated with prolongation of the QT interval or bradycardia on the ECG. The implantation of a cardioverter defibrillator should be considered in this syndrome.

Microdislodgment: a likely mechanism of pacing failure with high impedence small area electrodes.

High impedance tined steroid-eluting leads, Medtronic CapSure Z family, incorporating a small surface (1.2 mm2) electrode made of porous platinum material are designed to reduce battery current drain. However, in some prior studies, an increased incidence of microdislodgment with this lead was reported thought to be due to the reduced electrode surface area. This article reports the experience that ventricular pacing failure due to microdislodgment occurred after CapSure Z lead implantation and the previous literature is reviewed. (

Clinical advantage of neutral anode positioning feature in recent pacemaker generator.

Recent advances in pacemaker technology such as a thinner lead body, smaller size of pacemaker generators and pacemaker pulse generators with the neutral anode positioning (NAP) feature, have made pacemaker implantation easier. To date, however, the clinical disadvantages of this NAP feature have not been investigated. We investigated whether there are any clinically disadvantages in pacing and sensing thresholds, myopotential tracking thresholds and myopotential inhibition thresholds in 62 pacemaker patients with the NAP feature. All measured data from the NAP devices when the pacemaker was set to the bipolar system were acceptable and normal. In the unipolar system with NAP feature, no differences were observed in the numerous parameters measured compared to previously reported measured data in the unipolar system without the NAP feature. We concluded that the physician can also benefit from this feature since any pulse generator with the NAP feature is suitable for implant on either side of the body, without any disadvantages. Therefore, left- or right-sided pacers need no longer be ordered, stocked, or specified at the time of implant.

Late Na currents affected by alpha subunit isoform and beta1 subunit co-expression in HEK293 cells.

Peak Na current underlies excitability and conduction in the heart, and late non-inactivating or slowly inactivating Na current plays a role in action potential duration. We hypothesized that different alpha subunit isoforms or beta1 subunit co-expression might affect late Na current. The human Na channel alpha subunits hNa(v)1.5 (hH1a) and hNa(v)1.4 (hSkM1) were transfected with and without the hNa(V)beta1 (beta1) subunit in HEK293 cells and studied by whole cell patch clamp. The inactivation relationship for hH1a was 28mV negative to that for hSkM1, and beta1 shifted the midpoint positively by 22mV for hH1a and 8mV for hSkM1. When pre-pulse duration was varied from 10ms to 10s, "steady-state" was approached more slowly for hH1a. beta1 caused hH1a but not hSkM1 to reach "steady-state" earlier. Both isoforms showed two recovery components but hH1a showed a "cardiac phenotype" with a smaller slow component that was unaffected by beta1. The amplitude of a late current (at 750ms) was significantly greater for hH1a than hSkM1, but beta1 decreased late current for hH1a and eliminated the difference. Under the study conditions the alpha subunit isoforms have distinct functional phenotypes and co-expression with beta1 tends to diminish these distinctions. These properties may provide mechanisms for regional and transmural distribution of late Na current and late Na current amplitudes during development and in disease states.