Fifty years of cardiac pacing: the dark side of the moon?

Fifty years after its introduction, cardiac pacing has evolved from an experimental medical treatment to an expanding field in today's cardiology. Only recently there is accumulating evidence that prolonged stimulation of the right ventricular apex is associated with clinically significant adverse effects. In this commentary, the potential adverse effects are summarised and potential modifications in contemporary pacing are discussed. (Neth Heart J 2008;16(suppl 1):S12-S14.)     

Ventricular pacing – Electromechanical consequences and valvular function

Although great strides have been made in the areas of ventricular pacing, it is still appreciated that dyssynchrony can be malignant, and that appropriately placed pacing leads may ameliorate mechanical dyssynchrony. However, the unknowns at present include:1. The mechanisms by which ventricular pacing itself can induce dyssynchrony;2. Whether or not various pacing locations can decrease the deleterious effects caused by ventricular pacing;3. The impact of novel methods of pacing, such as atrioventricular septal, lead-less, and far-field surface stimulation;4. The utility of ECG and echocardiography in predicting response to therapy and/or development of dyssynchrony in the setting of cardiac resynchronization therapy (CRT) lead placement;5. The impact of ventricular pacing-induced dyssynchrony on valvular function, and how lead position correlates to potential improvement.This review examines the existing literature to put these issues into context, to provide a basis for understanding how electrical, mechanical, and functional aspects of the heart can be distorted with ventricular pacing. We highlight the central role of the mitral valve and its function as it relates to pacing strategies, especially in the setting of CRT. We also provide future directions for improved pacing modalities via alternative pacing sites and speculate over mechanisms on how lead position may affect the critical function of the mitral valve and thus overall efficacy of CRT.     

Phospholamban phosphorylation in ischemia-reperfused heart. Effect of pacing during ischemia and response to a β-adrenergic challenge

The status of phospholamban (PLB) phosphorylation in the ischemia-reperfused hearts remains controversial. Although a decrease in the phosphorylation of both PLB residues (Ser¹⁶, PKA site, and Thr¹⁷, CaMKII site) was previously reported, experiments from our laboratory failed to detect this decrease. In an attempt to elucidate the cause for this discrepancy, experiments were performed in Langendorff-perfused rat hearts with two main goals: (1) To determine whether keeping pacing during ischemia, a protocol followed in other ischemia-reperfusion models, decreases the phosphorylation of PLB residues, below pre-ischemic values; (2) To investigate whether a maximal -adrenergic challenge allows to detect a decrease in the ability of PLB to be phosphorylated in ischemia-reperfused hearts. Hearts were submitted to a global ischemia/reperfusion protocol (20/30 min) with (P) or without (NP) pacing during ischemia, and phosphorylation of PLB residues was assessed by immunodetection. The recovery of contractility upon reperfusion was lower in P vs. NP hearts. Ser¹⁶ of PLB, was phosphorylated at the end of ischemia in NP hearts. This increase appeared earlier in P hearts and was significantly diminished by catecholamine depletion and -blockade. Thr¹⁷ site was phosphorylated at the beginning of ischemia and the onset of reperfusion. The ischemia-induced phosphorylation of Thr¹⁷ was higher and more sustained in P vs. NP hearts, and inhibited by the calcium channel blocker, nifedipine, whereas the reperfusion-induced increase in Thr¹⁷ phosphorylation was similar in P and NP hearts and was significantly diminished by the Na⁺/Ca²⁺ exchanger inhibitor KB-R7943. Phosphorylation of PLB residues did not decrease below basal levels at any time during ischemia and reperfusion. However, the phosphorylation, inotropic and lusitropic response to -adrenergic stimulation was significantly decreased both in P and NP hearts.     

Rapid pacing of embryoid bodies impairs mitochondrial ATP synthesis by a calcium-dependent mechanism—A model of in vitro differentiated cardiomyocytes to study molecular effects of tachycardia

Tachycardia may cause substantial molecular and ultrastructural alterations in cardiac tissue. The underlying pathophysiology has not been fully explored. The purpose of this study was (I) to validate a three-dimensional in vitro pacing model, (II) to examine the effect of rapid pacing on mitochondrial function in intact cells, and (III) to evaluate the involvement of L-type-channel-mediated calcium influx in alterations of mitochondria in cardiomyocytes during rapid pacing. In vitro differentiated cardiomyocytes from P19 cells that formed embryoid bodies were paced for 24 h with 0.6 and 2.0 Hz. Pacing at 2.0 Hz increased mRNA expression and phosphorylation of ERK1/2 and caused cellular hypertrophy, indicated by increased protein/DNA ratio, and oxidative stress measured as loss of cellular thiols. Rapid pacing additionally provoked structural alterations of mitochondria. All these changes are known to occur in vivo during atrial fibrillation. The structural alterations of mitochondria were accompanied by limitation of ATP production as evidenced by decreased endogenous respiration in combination with decreased ATP levels in intact cells. Inhibition of calcium inward current with verapamil protected against hypertrophic response and oxidative stress. Verapamil ameliorated morphological changes and dysfunction of mitochondria. In conclusion, rapid pacing-dependent changes in calcium inward current via L-type channels mediate both oxidative stress and mitochondrial dysfunction. The in vitro pacing model presented here reflects changes occurring during tachycardia and, thus, allows functional analyses of the signaling pathways involved.     

The protective effects of 17beta-estradiol against ischemia–reperfusion injury and its effect on pacing postconditioning protection to the heart

The role of pacing postconditioning (PPC) in the heart protection against ischemia–reperfusion injury is not completely understood. The aim of this study was to investigated if 17-β-estradiol (estrogen, E2), endogenous atrial natriuretic peptide (ANP), endogenous brain natriuretic peptide (BNP), and tumor necrosis factor-alpha (TNF-α) are involved in PPC-mediated protection. Langendorff perfused female Wistar rat hearts were used for this study. Hearts challenged with regional ischemia for 30 min subjected to no further treatment served as a control. The PPC protocol was 3 cycles of 30 s pacing alternated between the right atrium and left ventricle (LV). Protection was assessed by recovery of LV contractility and coronary vascular–hemodynamics. Ischemia induced a significant (P?<?0.05) deterioration in the heart function compared with baseline data. PPC alone or in combination with short-term E2 treatment (E2 infusion at the beginning of reperfusion) significantly (P?<?0.05) improved the heart functions. Short-term E2 treatment post-ischemically afforded protection similar to that of PPC. However, long-term E2 substitution for 6 weeks completely attenuated the protective effects of PPC. Although no changes were noted in endogenous ANP levels, PPC significantly increased BNP expression level and decreased TNF-α in the cardiomyocyte lysate and coronary effluent compared to ischemia and controls. Our data suggested a protective role for short-term E2 treatment similar to that of PPC mediated by a pathway recruiting BNP and downregulating TNF-α. Our study further suggested a bad influence for long-term E2 substitution on the heart as it completely abrogated the protective effects of PPC.     

The effects of right ventricular apical pacing on left ventricular function. Stimulation of the right ventricular apex: should it still be the gold standard?

Current pacing practice is undergoing continuous and substantial changes. Initially pacing had an exclusively palliative role, since it was reserved for patients developing complete heart block or severe symptomatic bradycardia. With the appearance of novel pacing indications such as pacing for heart failure and atrial fibrillation, the effect of pacing site on cardiac function has become a critically important issue and a subject for consideration. It seems that the classical pacing site in the right ventricular apex is no longer the gold standard because of possible disadvantageous effects on cardiac function. The aim of this review article is to discuss the effect of right ventricular apical pacing on cardiac function including cellular and hemodynamic changes. We also aim to discuss the role of alternative pacing sites in the light of cardiac function.     

Conventional single-chamber pacemakers versus transcatheter pacing systems in a “real world” cohort of patients: A comparative prospective single-center study

PurposeDespite the developments in conventional transvenous pacemakers (VVI-PM), the procedure is still associated with significant complications. Although there are no prospective clinical trials that compared VVI-PM with transcatheter pacemaker systems (TPS).MethodsThis is a prospective, observational, single-center study that included all patients with an indication for a single-chamber pacemaker implant within a 4-year period. All clinical, ECG and echocardiographic characteristics at implant, electrical parameters, associated complications and mortality were analyzed. A Cox survival model and a Bayesian cohort analysis were performed for differences in complication rates between groups.ResultsThere were 443 patients included (198 TPS and 245 VVI-PM). The mean age was 81.5 years (TPS group, 79.2 ± 6.6 years; VVI-PM group, 83.5 ± 8.9 years). There was a male predominance in TPS group (123, 62.1% vs. 67, 27.3%; p < 0.001). The presence of systolic dysfunction and renal insufficiency were more frequent in VVI-PM group than in TPS patients. Mean follow-up was 22.3 ± 15.9 months. In a multivariable paired data the TPS group presented fewer complications than VVI-PM group (HR = 0.39 [0.15–0.98], p-value 0.013), but major complications were not different (6, 3% vs 14, 5.6% respectively, p = 0.1761). There was no difference in the mortality rate between the groups. The TPS group had less risk than VVI-PM group to have a complication, with a 96% of probability.ConclusionsTPS patients had a lower overall complication rate than VVI-PM patients including matched-pair samples using a Bayesian analysis. These results confirm the safety profile of TPS in clinical practice.     

Response to atrial overdrive pacing during narrow QRS tachycardia. What is the mechanism?

A 35-year old lady with no pre-excitation on surface electrocardiogram underwent EP study for recurrent palpitation and documented adenosine responsive narrow QRS tachycardia. Regular narrow QRS tachycardia was induced with critical AH delay on programmed atrial stimulation. An atrial overdrive pacing (AOD) was performed during the tachycardia (Fig: 1 & 2). What is the response to AOD and what is the mechanism of tachycardia?     

Should all patients receive dual chamber pacing ICDs? The rationale for the DAVID trial

All of the prospective multicenter trials that support the use of implantable defibrillators have used single chamber pacemakers/implantable cardiovertor defibrillators (ICDs). Despite the significantly increased cost of dual chamber pacemaker/ICD devices and the lack of outcome data, these devices accounted for approximately two-thirds of the ICDs implanted in the United States during the 12 months ending April 2001. Dual chamber pacemaker trials have not provided data that would support this trend, but the high incidence of atrial fibrillation, bradycardia, and congestive heart failure, as comorbid conditions, suggest that the situation could be different in the defibrillator patient population. The DAVID (Dual Chamber and VVI Implantable Defibrillator) trial is designed to measure the incremental benefit of dual chamber pacemaker/ICDs.     

Do gap junctions play a role in nerve transmissions as well as pacing in mouse intestine?

Varicosities of nitrergic and other nerves end on deep muscular plexus interstitial cells of Cajal or on CD34-positive, c-kit-negative fibroblast-like cells. Both cell types connect to outer circular muscle by gap junctions, which may transmit nerve messages to muscle. We tested the hypotheses that gap junctions transmit pacing messages from interstitial cells of Cajal of the myenteric plexus. Effects of inhibitors of gap junction conductance were studied on paced contractions and nerve transmissions in small segments of circular muscle of mouse intestine. Using electrical field stimulation parameters (50 V/cm, 5 pps, and 0.5 ms) which evoke near maximal responses to nitrergic, cholinergic, and apamin-sensitive nerve stimulation, we isolated inhibitory responses to nitrergic nerves, inhibitory responses to apamin-sensitive nerves and excitatory responses to cholinergic nerves. 18beta-Glycyrrhetinic acid (10, 30, and 100 microM), octanol (0.1, 0.3, and 1 mM) and gap peptides (300 microM of (40)Gap27, (43)Gap26, (37,43)Gap27) all failed to abolish neurotransmission. 18beta-Glycyrrhetinic acid inhibited frequencies of paced contractions, likely owing to inhibition of l-type Ca(2+) channels in smooth muscle, but octanol or gap peptides did not. 18beta-Glycyrrhetinic acid and octanol, but not gap peptides, reduced the amplitudes of spontaneous and nerve-induced contractions. These reductions paralleled reductions in contractions to exogenous carbachol. Additional experiments with gap peptides in both longitudinal and circular muscle segments after N(G)-nitro-l-arginine and TTX revealed no effects on pacing frequencies. We conclude that gap junction coupling may not be necessary for pacing or nerve transmission to the circular muscle of the mouse intestine.     

Interesting response to ventricular overdrive pacing during regular narrow QRS tachycardia. What is the mechanism?

33 year old gentleman has undergone an electrophysiology study for recurrent paroxysmal palpitation. During one of the episodes of palpitation a regular narrow QRS tachycardia was documented which has terminated with intravenous adenosine. Baseline electrocardiogram did not show any pre-excitation. Atrial-His (AH) and His-Ventricular (HV) intervals were normal at baseline. There was no evidence of dual atrioventricular (AV) nodal physiology. Earliest atrial electrogram during ventricular pacing was recorded at coronary sinus (CS) 9,10 dipoles placed at CS OS region. Narrow QRS tachycardia with cycle length (TCL) of 400 ms and earliest retrograde atrial activation at CS 9,10 dipoles was induced with programmed ventricular stimulation. Ventricular overdrive (VOD) pacing was performed at 30 ms shorter than TCL during the tachycardia (Fig: 1). What is the mechanism of tachycardia?     

Right bundle branch block pattern during right ventricular permanent pacing: Is it safe or not?

The present case report describes a patient with dual chamber pacemaker whose surface ECG demonstrated paced right bundle branch block pattern suggesting a malpositioned ventricular lead in the left ventricle. However, diagnostic work-up revealed that the lead was appropriately located in the right ventricular apex. Diagnostic maneuvers and clues for differentiating safe right bundle branch block pattern during permanent pacing are thoroughly revisited and discussed within the article.     

Severe left ventricular systolic dysfunction after permanent pacemaker implantation: Should we pause before upgrading to biventricular pacing?

Left ventricular (LV) systolic dysfunction leading to heart failure (HF) is known to occur after permanent pacemaker implantation (PPI) in a subset of patients. They are often treated by upgradation of the pacemaker to cardiac resynchronisation therapy (CRT). We report a case of progressive LV dysfunction and HF after PPI. Cardiac ¹⁸FDG-PET-CT scan revealed abnormal myocardial FDG uptake suggestive of cardiac sarcoidosis (CS). Biopsy from FDG avid lymph node demonstrated non-caseating granuloma. Therapy with steroids resulted in resolution of HF symptoms accompanied by a significant improvement in LV function.     

A comparative analysis of karyotypes of three species of Macleaya—producers of a complex of isoquinoline alkaloids

Using a set of methods (C-banding, DAPI-staining, fluorescence hybridization in situ (FISH) with probes of 26S and 5S rDNA, and analysis of meiosis), the first comparative cytogenetic study of three species of Macleaya, producers of complex isoquinoline alkaloids, cordate Macleaya cordata (Willd.) R. Br. (2n = 20), small-fruited Macleaya microcarpa (Maxim.) Fedde (2n = 20) and Macleaya kewensis Turrill (2n = 20), was first carried out. On the basis of morphometric analysis, formulas of karyotypes were made for each species. Species ideograms for M. cordata, M. microcarpa, and M. kewensis were constructed taking into account the polymorphic variants of the C-banding patterns and indicating the location of 26S and 5S rDNA sites. A comparative study revealed that the karyotypes of M. microcarpa and M. kewensis have more in common with each other than with M. cordata. Analysis of meiotic chromosomes suggests of genetic stability of Macleaya genomes. The results of chromosome analysis were used to confirm the close relationship of Macleaya and to clarify their phylogenetic relationships.     

Effect of γ-Irradiation on Development of Lachrymator of Onion

A thermosensitive uracil requiring mutant of Bacillus subtilis Marburg 168 thy trp₂ ts42 was examined as to the colony forming ability at the permissive and nonpermissive temperatures. The viability of the mutant cells decreased rapidly at the restrictive temperature in the modified Woese’s (MW) medium. However, the cells retained viability when sodium succinate or potassium chloride was added to the medium at that temperature although uracil deficiency was unchanged. A little but significant incorporation of adenine-8-¹⁴C into RNA still continued even after the incorporation of N-acetyl-³H-d-glucosamine into acid insoluble fraction of the cells terminated in the MW medium at 48°C. Both incorporations as well as increase of absorbance were slowed down in the presence of sodium succinate at 48°C. This mutant, ts42, was more sensitive to deoxycholate (DOC) than the parent strain. The restoration of colony forming ability after the temperature shift back from 48 to 37°C was suppressed by the addition of DOC to the medium. However, the cell became resistant to DOC when uracil was added to the medium prior to the temperature shift.     

Mechanisms of action of the α-amylase of Micromonospora melanosporea

The -amylase of Micromonospora melanosporea was produced extracellularly during batch fermentation in a 5.0-1 fermentor. The absence of an organic nitrogen source in its growth medium facilitated subsequent purification of the enzyme by ammonium sulphate fractionation and two consecutive Superose-12 gel-filtration steps. The enzyme exhibited maxima for activity at pH 7.0 and 55° C and was 72% stable at pH 6.0–12.0 for 30 min at 40° C. It had a relative molecular mass of 45 000 and an isoelectric point at pH 7.6. The enzyme catalyses the conversion of starch to maltose (53%, w/w) as the predominant final end-product. Initial hydrolysis of this substrate, however, gave rise to the formation of maltooligosaccharides in the range maltotriose to maltohexaose. Maximum yields of these intermediate sugars accumulated to between 31 and 42% (w/w) as the reaction proceeded. The action of the M. melanosporea amylase on high concentrations of saccharides larger than maltotriose resulted in the formation of mainly maltose and maltotriose without concomitant glucose production. A combination of hydrolytic and transfer events is postulated to be responsible for this phenomenon and for the high maltose levels achieved. Correspondence to: C. T. Kelly