Prolonged Atrioventricular Conduction Research Articles

Leucocyte telomere length and conduction system ageing

BackgroundDeterioration of the cardiac conduction system is an important manifestation of cardiac ageing. Cellular ageing is accompanied by telomere shortening and telomere length (TL) is often regarded as a marker...

Vascular function assessed by flow-mediated vasodilation and nitroglycerine-induced vasodilation in subjects with first-degree atrioventricular block

First-degree atrioventricular block (AVB) is a common electrocardiogram finding in clinical practice. Vascular dysfunction is associated with cardiovascular disease and events. There is no information on the association of AVB with vascular function. The purpose of this study was to evaluate the associations of PR interval with vascular function assessed in well-characterized subjects. A total of 2220 subjects were enrolled in this study. We evaluated endothelium-dependent vasodilatation assessed by flow-mediated vasodilation (FMD) and endothelium-independent vasodilatation assessed by nitroglycerine-induced vasodilation (NID) in 106 subjects with first-degree AVB (70 men; mean age, 64.3 ± 12.9 years) and 1241 subjects with normal PR interval (531 men; mean age, 56.1 ± 13.9 years). Subjects with first-degree AVB had a lower FMD value than that in subjects with normal PR interval (3.5 ± 2.4% vs. 4.9 ± 3.3%, P < 0.001). FMD was significantly lower in subjects with first-degree AVB than in subjects with normal PR interval even after adjustment of confounding factors for assessment of endothelium-dependent vasodilatation (OR: 1.73, 95% CI: 1.11–2.70; P = 0.015). Although NID was significantly lower in subjects with first-degree AVB than in subjects with normal PR interval (11.1 ± 6.0% vs. 13.6 ± 6.1%, P < 0.001), there was no significant difference in NID between the two groups in multivariate analysis (OR: 1.48, 95% CI: 0.91–2.41; P = 0.117). Both endothelium-dependent and endothelium-independent vasodilation in the brachial artery are impaired in parallel with the prolongation of atrioventricular conduction. After adjustments of confounding factors for vascular function, first-degree AVB is associated with impaired endothelium-dependent vasodilatation but not with impaired endothelium-independent vasodilatation. From the aspect of vascular function, it is unlikely that first-degree AVB is an electrocardiography abnormality with a good prognosis.

Doppler-derived cardiac performance and evaluation of alternative measures of AV conduction to predict unvfavuorable haemodynamics in patients with long PR (DEEPER PR Study)

Abstract Funding Acknowledgements Type of funding sources: None. Background Prolonged atrio-ventricular (AV) conduction has been shown to compromise cardiac performance. Long PR relates to unfavorable clinical outcome and even increased mortality. The PR interval is traditionally used to describe AV conduction, but this parameter comprises inter-atrial and AV conduction delays and may therefore not optimally reflect hemodynamic consequences of prolonged AV conduction. Ventricular conduction delay also impacts ventricular filling and cardiac performance, while delayed inter-atrial activation may alleviate LV hemodynamic compromise. It is unknown, which parameter of AV conduction relates closest to cardiac performance. The objective of this study is to characterize segments of the PR interval in patients with long PR vs. matched controls with normal PR and to investigate the association of various measures of AV conduction to Doppler-derived cardiac performance. Methods 52 hospitalized pts with AVB I° (group A), and 52 controls (matched according to age, gender, LVEF, group B) were studied in detail by digitalized 12 lead ECG and 2-D, Doppler, and tissue Doppler echocardiography. Segments of PR were compared between matched groups. Seven measures of AV conduction were correlated to LV and RV filling fraction, total isovolumic times, and Tei indices and ranked by logistic regression and ROC-AUC in the combined patient cohort. Results PR was 227.5 (212;251)ms (A) vs. 182 (164;190)ms (B); p&amp;lt;0.001). P wave duration was 127(114;136)ms (A) vs. 113(102.5;126.8)ms (B); p&amp;lt;0.001 with longer RA and LA activation in group A. Reduced LV filling fraction (PQ Δ0.045, PePV6 Δ0.050, AUC 0.681 vs. 0.719), prolonged combined LV isovolumic times (PR: Δ19ms, 15.8%, PePV6: Δ31ms, 26.9%, AUC 0.619 vs 0.698), and higher LV Tei indices (PR: Δ0.045, 10.3%, PePV6: Δ0.083, 19.8%, AUC 0.566 vs 0.626) were best predicted by the variable PePV6 (interval between the end of P in V1 and Rpeak in V6) according to bivariate correlations, logistic regression analyses, and ROC-AUC. Applying PePV6 instead of PR re-categorized 20% of pts as having prolonged vs normal AV conduction. Prolonged PePV6 was also best suited to predict worse RV hemodynamics. Although significant linear correlations were demonstrated, a non-linear component of the association between AV timing and LV filling appeard to be present with pronounced impairment of cardiac performance beyond the 3rd quartile of PePV6 (148ms), respectively. Conclusion Prolonged PR comprises prolonged atrial activation (30%) and delayed AV conduction (70%). In this study, PePV6, a novel parameter eliminating P wave duration and accounting for initial LV activation, was best suited to identify compromise of Doppler-derived LV and RV hemodynamics by delayed AV conduction. PePV6 prolongation beyond the 3rd quartile may particularly affect cardiac performance. These findings inform future clinical studies and should give rise to investigation of PePV6 in larger patient populations.

Abstract 11446: Impact of Higher Synchronized Left Ventricular Pacing Rate for Prognosis on Cardiac Resynchronization Therapy

Background: The adaptive cardiac resynchronization therapy (aCRT) algorithm provides synchronized left ventricular pacing (sLVP) to produce fusion with the intrinsic right ventricular activation in normal atrioventricular (AV) conduction. Although sLVP has benefits over biventricular pacing (BiV), the adequate sLVP rate for better clinical outcome is still unclear. Purpose: The aim of this study was to assess the association between sLVP rate and clinical outcome. Methods: Among our cohort of 271 consecutive patients who had CRT implantation between April 2016 and August 2021, we evaluated 63 CRT patients without considerably prolonged AV conduction to whom we applied the aCRT algorithm (48 males, mean age: 64±14 years old, and the median follow up period: 316 days [interquartile range: 212-809days]). Results: At follow-up 6 months after CRT implantation, the frequency of CRT responder was 71% (n=45). The sLVP rate was significantly higher in responder compared to non-responder (75±30 vs 47±40 %, p=0.003). Receiving operating characteristics (ROC) curve analysis revealed that optimal cut-off value during sLVP rate was 59.4% for prediction of CRT responder (an area under the curve: 0.70, sensitivity: 80%, specificity: 61%, positive predictive value: 84%, and negative predictive value: 55%). Kaplan-Meier analysis demonstrated that higher sLVP group (sLVP≥59.4%, n=43) had better prognosis (cardiac death and heart failure hospitalization) compared to lower sLVP group (sLVP&lt;59.4%, n=20) (log-rank p&lt;0.001) (Figure) and multivariate Cox hazard analysis revealed that higher rate was associated with good prognosis (p&lt;0.001). Conclusion: sLVP was associated with CRT response and higher sLVP rate (≥59.4%) may be important for good prognosis in patient with aCRT.

Pacing therapy for atrioventricular dromotropathy: a combined computational-experimental-clinical study.

AimsInvestigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational–experimental–clinical study.Methods and resultsComputer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10–15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± 30 ms) resulted in significant increases in LV stroke volume and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated improvement of LV pump function coincided with both larger mitral inflow (E- and A-wave area) and reduction of diastolic mitral regurgitation.ConclusionRestoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, but not RV pacing, may improve cardiac function in patients with HF and prolonged PR interval.

Transcatheter Aortic Valve Implantation and Complications Regarding Cardiac Conductance

Degenerative aortic stenosis is an inflammatory process, affecting up to 12% of patients aged over 85 years. Transcatheter aortic valve implantation (TAVI) has become the preferred option for symptomatic, high and intermediate risk patients, including those denied for surgical valve replacement. Aortic stenosis is associated with prolonged atrio-ventricular (AV) conduction time, as well as higher degree of AV conduction disorders. In addition, it was observed that TAVI patients have a higher incidence of conduction abnormalities during the procedure, as well as during the following days, many of them requiring the implantation of a permanent pacemaker. Definitive guidelines for management of the conduction disorders are not yet available, the burden of choosing the best approach being put on each individual clinician.

A randomized controlled trial of cardiac resynchronization therapy in patients with prolonged atrioventricular interval: the REAL-CRT pilot study.

A prolonged PR interval is known to be associated with increased mortality and a higher risk of developing atrial fibrillation (AF). We tested the hypothesis that cardiac resynchronization therapy (CRT) is superior to conventional dual-chamber pacing with algorithms for right ventricular pacing avoidance (DDD-VPA) in preserving systolic and diastolic function and in preventing new-onset AF in patients with normal systolic function, indication for pacing and prolonged atrioventricular conduction (PR interval ≥220 ms). We randomly assigned 82 patients with ejection fraction >35%, indication for pacing and PR interval ≥220 ms to CRT or to DDD-VPA. On 12-month follow-up examination, the study and control arms did not differ in terms of left ventricular end-systolic volume (44 ± 17 mL vs. 47 ± 16 mL, P = 0.511) or ejection fraction (55 ± 6% vs. 57 ± 8%, P = 0.291). The E to A mitral wave amplitude ratio was higher in the CRT arm (1.3 ± 1.3 vs. 0.8 ± 0.4, P = 0.046) and the E wave deceleration time was longer (262 ± 83 ms vs. 205 ± 51 ms, P = 0.027). Left atrial volume was smaller in the CRT arm (64 ± 17 mL vs. 84 ± 25 mL, P = 0.035). Moreover, the functional class was lower in CRT patients (1.4 ± 0.6 vs. 1.8 ± 0.5, P = 0.010). During follow-up, CRT was associated with a lower risk of new-onset AF [hazard ratio = 0.37 (0.13-0.98), P = 0.046]. Cardiac resynchronization therapy proved superior to DDD-VPA in terms of better diastolic function, less left atrial enlargement and lower risk of new-onset AF, at 12 months. These data need to be confirmed in a larger trial with longer follow-up. URL: http://clinicaltrials.gov/ Identifier: NCT02150538.

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues

Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba2+ current through Cav1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite.

Continuous optimization of cardiac resynchronization therapy reduces atrial fibrillation in heart failure patients: Results of the Adaptive Cardiac Resynchronization Therapy Trial

Data from randomized trials have suggested a modest or no effect of conventional cardiac resynchronization therapy (convCRT) on the incidence of atrial fibrillation (AF). AdaptivCRT (aCRT, Medtronic, Mounds View, MN) is a recently described algorithm for synchronized left ventricular (LV) pacing and continuous optimization of cardiac resynchronization therapy (CRT). We compared the long-term effects of aCRT with convCRT pacing on the incidence of AF. The Adaptive CRT trial randomized CRT-defibrillator (CRT-D)-indicated patients (2:1) to receive either aCRT or convCRT pacing. The aCRT algorithm evaluates intrinsic conduction every minute, providing LV-only pacing during normal atrioventricular (AV) conduction and AV and ventriculoventricular timing adjustments during prolonged AV conduction. The primary outcome of this subanalysis was an episode of AF >48 consecutive hours as detected by device diagnostics. Over a follow-up period with a mean and standard deviation of 20.2 ± 5.9 months, 8.7% of patients with aCRT and 16.2% with convCRT experienced the primary outcome (hazard ratio [HR] = 0.54; 95% confidence interval [CI] = 0.31-0.93; P= .03). In patients with prolonged baseline AV, the incidence of the primary outcome was 12.8% in patients randomized to aCRT compared with 27.4% in convCRT patients (HR = 0.45; 95% CI = 0.24-0.85; P = .01). Also, patients with AF episodes adjudicated as clinical adverse events were less common with aCRT (4.3%) than with convCRT (12.7%) (HR = 0.39; 95% CI = 0.19-0.79; P = .01). Patients receiving aCRT had a reduced risk of AF compared with those receiving convCRT. Most of the reduction in AF occurred in subgroups with prolonged AV conduction at baseline and with significant left atrial reverse remodeling.

179-02: First-degree atrioventricular Block, Atrioventricular (Dys)synchrony and Dual-chamber pacing. A long PR interval or a wide QRS? That is the dilemma

Background: In modern DDD pacemakers, strategies to minimize artificial right ventricular activation seek to avoid the potential but well-studied deleterious effects of cardiac pacing. While these mechanisms maintain electrical atrioventricular (AV) sequence, if significant 1st. degree AV block (1st.AVB) coexists, paradoxically AV mechanical dyssynchrony could be promoted. Apparently, atrioventricular sequence differs from atrioventricular synchrony. The purpose of this study was to elucidate clinical and hemodynamic results of long AV delays - narrow intrinsic QRS against DDD pacing with optimized AV interval - paced wide QRS. Methods: Prospectively included 32 adult patients with DDD pacemakers implanted for sick sinus node disease (SSND) and 1st.AVB. Study protocol demanded septal right ventricular lead, demonstrated <5% of ventricular pacing overall since implantation, normal QRS duration, preserved left ventricular ejection fraction (LVEF), no prosthetic valves and no history of atrial fibrillation (AF). Using Doppler echocardiography diastolic and systolic performances were verified in AAI pacing 10 beats/min faster than sinus rhythm, intrinsic long AV delay and native QRS (Ap-Vs), against the hemodynamic results (VTi, LVEF and Mitral regurgitation obtained by iteratively shortening the programmed AV delay (DDD pacing - Ap-Vp) at same cardiac rate. By Mitral valve inflow analysis (E/A waves measurements) optimal diastolic function (AV synchrony) was verified. Best left ventricular contractility and function was assessed by means of higher aortic flow time velocity integral (VTi) and LVEF. Optimal AV delay was defined by maximal separation of E/A waves, higher VTi and best LVEF with less Mitral valve regurgitation. AV dyssinchrony was determined by fused E + A waves, or E + A duration <40% of cardiac cycle. This patients were kept to ventricular pacing at the optimal AV interval (optimized AV – OAV group) for further comparison. The non-optimized AV (NOAV) group was formed by those whose best cardiac function was found at the intrinsic PR interval-native QRS. This group was kept to minimal ventricular pacing at the baseline PR interval. Follow-up included clinical evaluation and cardiac structure and function assessment at 3 and 6 months for both groups of patients. Results: Our cohort so far (mean= 73,6 + /-11,8 years) confirmed the existence of 2 separate groups from the diastolic function point of view: those showing AV dyssynchrony requiring AV optimization (OAV group: 18/32) and those with no AV dyssynchrony (no need for AV optimization - NOAV group: 14/32); p= 0.003. No other statistical differences were found in age, gender, symptoms, NYHA functional class, medication use, and structural heart disease, baseline PR interval or LVEF between groups. AAI pacing rate for echo measurements was 65 + /-9bpm for the OAV group vs. 67,5 + /-6,7bpm of their counterparts (p= NS). Remarkably, the AV interval when exceeded 263ms in the OAV group was 72% sensitive and 73% specific to demonstrate AV dyssynchrony. Moreover, in the OAV group, under optimized AV delay and artificial ventricular pacing, after 6 months of follow-up, LVEF is noticed to significantly decline (p= 0.002) and detrimental changes of cardiac structure with significant increase in left ventricular systolic (p= 0.04) and diastolic (p= 0.02) dimensions are noticed. No other statistical differences at follow-up were found in clinical outcomes (incidence of new AF episodes, electronic arrhythmias, pacemaker syndrome-like symptoms, NYHA functional class or hospitalizations) between groups. Conclusion: Our results preliminarily suggest that 1st.AVB with non-physiologically prolonged AV conduction (when ≥263ms) is highly associated with disturbed AV synchrony. However, this AV dyssynchrony when corrected by echocardiographycally optimized AV delays and forced ventricular pacing is negatively affected by the detrimental consequences of continual right ventricular artificial activation. Alternative-pacing strategies such as biventricular-pacing in this scenario merit further investigation.

ECG Response: October 1, 2013

HomeCirculationVol. 128, No. 14ECG Response: October 1, 2013 Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBECG Response: October 1, 2013 Originally published1 Oct 2013https://doi.org/10.1161/CIRCULATIONAHA.113.005949Circulation. 2013;128:1586–1587ECG Challenge: A 66-year-old woman with a history of diabetes mellitus, hyperlipidemia, and rheumatoid arthritis presents to her primary care physician with complaints of intermittent lightheadedness. She has not experienced syncope. With the lightheadedness, she has noted her heart rate to be slow, often at ≈40 bpm. She denies any other cardiac symptoms. While in the office, she has a sudden onset of lightheadedness, and an ECG is obtained.Download figureDownload PowerPointThere is a regular rhythm at a rate of 32 bpm. The QRS complex has a normal duration (0.08 second) and a normal morphology. The axis is extremely leftward between −30° and −90° (positive QRS complex in lead I and negative QRS complex in leads II and aVF with an rS morphology). Causes of an extreme left axis include an inferior wall myocardial infarction in which there is a deep Q wave in leads II and aVF or a left anterior fascicular block in which there is an rS morphology in leads II and aVF. This is a left anterior fascicular block. The QT/QTc intervals are normal (460/340 milliseconds). P waves are seen before each QRS complex (+), with a stable PR interval of 0.40 second. The P wave is positive in leads I, II, aVF, and V4 through V6. This represents a sinus rhythm with a first-degree atrioventricular (AV) block or prolonged AV conduction. A second sinus P wave is seen after each QRS complex (*); it is not followed by a QRS complex and hence is nonconducted. The presence of an occasional on time but not conducted P wave defines a second-degree AV block, and because every other P wave is nonconducted, this represents a 2:1 AV block or AV conduction. The second-degree AV block may be either Mobitz type I or Wenckebach, which is attributable to a conduction abnormality in the AV node, or Mobitz type II, which is attributable to a conduction abnormality within the His-Purkinje system. When there is a continuous pattern of 2:1 AV block, the block may be Mobitz type I or II. The etiology can only be established if there is a change in the pattern of conduction, ie two sequentially conducted P waves (if PR interval stable it is Mobitz II, if PR interval lengthens it is Mobitz I) or the development of complete heart block (escape junctional rhythm it is Mobitz I, escape ventricular rhythm it is Mobtiz II). It can be seen that the PP interval is not constant, but there is a repeating pattern such that the PP interval surrounding the QRS complex is slightly shorter (↔, 0.80 sec) than the PP interval without a QRS complex (└┘, 0.96 sec). This is called ventriculophasic arrhythmia. Proposed mechanisms include enhanced sinus node artery pulsatile blood flow with ventricular contraction that increased the automaticity of the sinus node, stretch of the right atrium and sinus node with ventricular contraction that augments sinus node automaticity, and changes in baroreceptor output resulting from the stroke volume caused by ventricular contraction.FootnotesCorrespondence to Philip J. Podrid, MD, West Roxbury VA Hospital, Section of Cardiology, 1400 VFW Pkwy, West Roxbury, MA 02132. E-mail [email protected] Previous Back to top Next FiguresReferencesRelatedDetails October 1, 2013Vol 128, Issue 14 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.113.005949PMID: 24081954 Originally publishedOctober 1, 2013 PDF download Advertisement

Revisiting diastolic filling time as mechanistic insight for response to cardiac resynchronization therapy

Intraventricular dyssynchrony and commonly associated prolonged atrioventricular conduction both reduce diastolic filling time (DFT), which can be improved by cardiac resynchronization therapy (CRT). Our aim was to investigate whether change in DFT corrected for RR interval (DFTC) after CRT might serve to assess the mechanistic response to CRT. Echocardiography data of consecutive patients in sinus rhythm (n = 91) were studied before and 6 months after implantation. Mortality and heart failure hospitalization data were collected. Patients with vs. without DFTC increase after 6 months were compared. The programmed atrioventricular delay, percentage of biventricular pacing, and change in PR interval were similar in both groups. DFTC increase after 6 months reflected favourable reverse left ventricular remodelling and was significantly associated with freedom from death or heart failure admission (P = 0.008). In multivariate analysis including guideline criteria for CRT (i.e. QRS width, presence of left bundle branch block, and ejection fraction), interventricular mechanical delay, and Tei index, baseline DFTC was the strongest predictor of adverse outcome. Notably, while patients with impaired relaxation had a large and highly significant reduction in all-cause mortality and heart failure admissions when DFTC increased [hazard ratio (HR), 95% confidence interval (CI) = 0.24, 0.08-0.73; P = 0.012], this benefit was less pronounced and did not reach statistical significance in patients with pseudonormal or restrictive filling (HR, 95% CI = 0.64, 0.23-1.77; P = 0.388). DFTC increase after CRT reflects favourable reverse remodelling and is associated with better clinical outcome.

2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities

Developed in Collaboration With the American Association for Thoracic Surgery, Heart Failure Society of America, and Society of Thoracic Surgeons

Prolongation of the Atrioventricular Conduction in Fetuses Exposed to Maternal Anti-Ro/SSA and Anti-La/SSB Antibodies Did Not Predict Progressive Heart Block: A Prospective Observational Study on the Effects of Maternal Antibodies on 165 Fetuses

We prospectively examined the prevalence and outcome of untreated fetal atrioventricular (AV) prolongation in the presence of maternal anti-Ro antibodies. It has been suggested that antibody-mediated congenital complete atrioventricular block (CAVB) may be preventable if detected and treated early when low-grade block is present. With this rationale in mind, dexamethasone has been advocated by others to treat prolonged fetal AV conduction >2 z-scores, consistent with first-degree heart block. Between July 2003 and June 2009, 165 fetuses of 142 anti-Ro/La antibody-positive women were referred to our center for serial echocardiography. Our protocol included weekly evaluation of the fetal AV conduction between 19 (range 17 to 23) and 24 (range 23 to 35) gestational weeks. AV times were compared with institutional reference data and with post-natal electrocardiograms. Of 150 fetuses with persistently normal AV conduction throughout the observation period, a diagnosis of CAVB was subsequently made in 1 at 28 weeks, after the serial evaluation had ended. Of 15 untreated fetuses either with AV prolongation between 2 and 6 z-scores or with type 1 second-degree block, progressive heart block developed in none of them. Three of these 15 fetuses (20%) had a neonatal diagnosis of first-degree block that spontaneously resolved (n = 2) or has not progressed (n = 1) on follow-up examinations. No other cardiac complications were detected. Fetal AV prolongation did not predict progressive heart block to birth. Our findings question the rationale of a management strategy that relies on the early identification and treatment of fetal AV prolongation to prevent CAVB.

Atrioventricular conduction and cardiovascular mortality: Assessment of recovery PR interval is superior to pre-exercise measurement

A prolonged electrocardiographic PR interval at rest has been considered a benign phenomenon until recently. We hypothesized that measurement of the PR interval during recovery from physical exertion could improve cardiovascular mortality risk stratification because it would track the dynamic influences of homeostatic mechanisms controlling atrioventricular (AV) conduction. A total of 1,979 consecutive patients (1,244 men and 735 women) with clinically indicated bicycle ergometer tests enrolled in FINCAVAS (the Finnish Cardiovascular Study) were included in the study. The PR interval was measured at 1 min before and at 2 min after exercise. During the mean follow-up period of 47 months (interquartile range: 37 to 59 months), 50 cardiovascular deaths (end point) were registered. The unadjusted hazard ratios (HR) in Cox regression analyses were significant for both continuous PR interval and first-degree atrioventricular (AV) block for pre- and post-exercise phases. After adjustment for standard markers, the PR interval for 20-ms increments (HR: 1.17, P = .117) and first-degree AV block (HR: 1.85, P = .138) during the pre-exercise phase were not prognostic. However, during recovery from exercise, prolonged AV conduction achieved significance both in continuous (HR: 1.29, P = .006) and dichotomized analyses (HR: 2.41, P = .045). The PR interval before exercise is not a robust risk stratifier for cardiovascular death during 4-year follow-up. Post-exercise assessment of AV conduction may offer improved prediction because of functional abnormalities that become manifest only during this physiologic challenge to the heart.

Impact of sleep on arrhythmogenesis.

Sleep is generally considered to be a protected period, when the cardiovascular system benefits from the restorative influences of the sleeping brain. However, the dynamics of cardiovascular control during sleep can tax the capacity of the diseased coronary circulation and myocardium with surges in sleep-state–related autonomic activity and disruptions in airway function and central nervous system regulation. In this regard, sleep may constitute an autonomic stress test for the heart. The scope of sleep-related risk for atrial and ventricular arrhythmias is substantial. The major subgroups susceptible to adverse influences of surges in autonomic activity during sleep are those with ischemic heart disease, heart failure, and channelopathies (Table).1 It is significant that 20% of myocardial infarctions and 15% of sudden deaths occur at night in the United States.2 Most atrial arrhythmias in patients younger than 61 years of age have nocturnal onset.3 The young are not immune to risk, as sudden infant death syndrome (SIDS) claims 2500 lives in the United States annually.4 Cardiovascular risk is compounded by comorbid factors, most notably apnea, which affects an estimated 4% to 9% of the general population5 and is considerably more prevalent among obese individuals.6 The more common form is obstructive sleep apnea (OSA), with partial or complete collapse of the pharynx. Half of heart failure patients experience either OSA or central sleep apnea (CSA) with central nervous system–mediated periodic breathing, commonly referred to as Cheyne-Stokes respiration. Such cardiorespiratory disturbances profoundly alter autonomic nervous system activity and increase risk of arrhythmia, hypertension, and myocardial infarction. View this table: Table. Patient Groups at Potentially Increased Risk for Nocturnal Cardiac Events It is surprising, as recently underscored by Malhotra and Loscalzo,7 that the significance of cardiovascular risk during sleep may not be duly recognized within the cardiology community. The reasons are …

Effects of metabolic inhibition on conduction, Ca transients, and arrhythmia vulnerability in embryonic mouse hearts

Developing myocardium is more dependent on glycolysis than adult myocardium, yet the effects of selectively inhibiting glycolysis versus oxidative phosphorylation on embryonic heart function have not been well characterized. Accordingly, we investigated how selective metabolic inhibition affects membrane voltage and intracellular Ca (Ca(i)) transients in embryonic mouse hearts, including their susceptibility to arrhythmias. A total of 136 isolated embryonic mouse hearts were exposed to either 1) 2-deoxyglucose (2DG; 10 mM) or iodoacetate (IAA; 0.1 mM) with 10 mM pyruvate in place of glucose to selectively inhibit glycolysis or 2) the mitochondrial uncoupler protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP; 500 nM) with 10 mM glucose present to selectively inhibit oxidative phosphorylation. Using confocal imaging, we found that mitochondrial membrane potential monitored with tetramethylrhodamine methyl ester (200 nM) remained stable with 2DG or IAA but depolarized within 5 min after exposure to FCCP. IAA and FCCP decreased heart rate, inhibited Ca(i) transient amplitude, shortened action potential duration at 80% repolarization (APD(80)), and prolonged atrioventricular conduction time to similar extents. Although 2DG decreased heart rate and Ca(i) transient amplitude, it did not significantly affect APD(80) and AV conduction time. In addition, spontaneous arrhythmias occurred in 77 of 136 embryonic hearts (57%) after exposure to IAA (28/53) or FCCP (49/83). There were no significant differences in the types or incidence of arrhythmias induced by IAA and FCCP. These data support the idea that both glycolysis and oxidative phosphorylation play critical metabolic roles in regulating cardiac function in the embryonic mouse heart.

Complete heart block and sudden death in mice overexpressing calreticulin.

The expression of calreticulin, a Ca(2+)-binding chaperone of the endoplasmic reticulum, is elevated in the embryonic heart, and because of impaired cardiac development, knockout of the Calreticulin gene is lethal during embryogenesis. The elevated expression is downregulated after birth. Here we have investigated the physiological consequences of continued high expression of calreticulin in the postnatal heart, by producing transgenic mice that overexpress the protein in the heart. These transgenic animals exhibit decreased systolic function and inward I(Ca,L), low levels of connexin43 and connexin40, sinus bradycardia, and prolonged atrioventricular (AV) node conduction followed by complete heart block and sudden death. We conclude that postnatal downregulation of calreticulin is essential in the development of the cardiac conductive system, in particular in the sinus and AV nodes, when an inward Ca(2+) current is required for activation. This work identifies a novel pathway of events, leading to complete heart block and sudden cardiac death, which involves high expression of calreticulin in the heart.

Cardiovascular Adverse Drug Reaction Associated with Combined β-Adrenergic and Calcium Entry-Blocking Agents

Numerous studies have shown a beneficial effect of combination therapy with beta-blockers and calcium antagonists in patients with anginal syndrome and/or hypertension. However, because both agents exert a negative chronotropic effect, their combined use may cause bradyarrhythmias with resultant symptoms of cerebral, coronary, and systemic hypoperfusion. We describe our clinical experience with patients who had cardiovascular adverse drug reactions (CVADRs) with combination therapy. This prospective study included 26 patients who had CVADRs among 2,574 admissions during a 2-year period. The study group included 14 men and 12 women with a median age of 73 years. Various combinations of calcium antagonists and beta-blockers were associated with the CVADRs. The most frequent pharmacologic combination was diltiazem plus propranolol. The CVADRs were the cause for hospital admission in 10 patients, an associated cause in nine patients, and developed during hospitalization in seven patients. Cardiac bradyarrhythmias were found in 22 patients. These rhythm abnormalities resolved within 24 h after discontinuation of the offending drugs. Temporary transvenous pacemaker insertion was necessary in only one patient with complete atrioventricular block. Twenty-two patients recovered, two patients died of pump failure not associated with CVADRs, and in two patients, the CVADRs contributed to the patients' death. CVADRs are not uncommon in elderly patients with ischemic heart disease and/or hypertension treated with the concomitant use of calcium antagonist and beta-adrenergic blocking drugs. Use of calcium antagonist plus beta-blocker may unpredictably cause serious hemodynamic events, marked suppression of sinus node activity, and prolongation of atrioventricular conduction in some patients. Enhanced therapeutic monitoring may be warranted when calcium antagonists are combined with beta-blockers.

Inhibition of ventricular stimulation in patients with dual chamber pacemakers and prolonged AV conduction.

Episodes of repetitive P wave undersensing have been described in dual chamber pacemakers due to automatic extension of the postventricular atrial refractory period (PVARP). Pacemaker stimulation was completely inhibited despite the presence of adequate P waves. This study sought to determine whether cycles of repetitive P wave undersensing occur even in the absence of PVARP extension. Two-hundred fifty-five patients were investigated after DDD or VDD pacemaker implantation for intermittent atrioventricular (AV) block. Forty-six episodes of repetitive atrial undersensing were found during 24-hour Holter ECG in nine patients. Pacemaker syndrome-like symptoms occurred. Episodes were elicited by atrial or ventricular premature contractions when (1) native AV conduction was present but considerably prolonged, (2) intrinsic sinus rate exceeded pacemaker intervention rate, and (3) native AV interval plus PVARP exceeded sinus cycle length. Programming of a particularly short AV interval and PVARP helped to reduce the incidence of repetitive P wave undersensing. Patients with dual chamber devices and prolonged native AV conduction are prone to develop episodes of output inhibition. Standard timing cycles may be inappropriate in these patients.