Adverse effects of atrioventricular synchronous right ventricular pacing on left ventricular sympathetic activity, efficiency, and hemodynamic status

Right ventricular (RV) pacing is now recognized to play a role in the development of heart failure in patients with and without underlying left ventricular (LV) dysfunction. We used the cardiac norepinephrine spillover method to test the hypothesis that RV pacing is associated with cardiac sympathetic activation. We studied 8 patients with normal LV function using temporary right atrial and ventricular pacing wires. All measurements were carried out during a fixed atrial pacing rate. The radiotracer norepinephrine spillover technique was employed to measure total body and cardiac sympathetic activity while changes in LV performance were evaluated with a high-fidelity manometer catheter. Atrioventricular synchronous RV pacing, compared with atrial pacing alone, was associated with a 65% increase in cardiac norepinephrine spillover, an increase in LV end-diastolic pressure, and a reduction in myocardial efficiency. These responses may play a role in the development of heart failure and poor outcomes that are associated with chronic RV pacing.     

Left ventricular pacing in patients with congestive heart failure

Cardiac resynchronisation therapy (CRT) using biventricular (BIV) pacing has proved its effectiveness to correct myocardial asynchrony and improve clinical status of patients with severe congestive heart failure (CHF) and widened QRS. Despite a different effect on left ventricular electrical dispersion, left univentricular (LV) pacing is able to achieve the same mechanical synchronisation as BIV pacing in experimental studies and in humans. This results in clinical benefits of LV pacing at mid-term follow-up, with significant improvement in functional class, quality of life and exercise tolerance at the same extent as those observed with BIV stimulation in non randomised studies. Furthermore these benefits are obtained at lesser costs and with conventional dual-chamber devices. However, LV pacing has to be compared to BIV pacing in randomised trials before being definitely considered as a cost-effective alternative to BIV pacing.     

An Approach to the Stepwise Management of Severe Mitral Regurgitation with Optimal Cardiac Pacemaker Function

Right ventricular apical pacing may cause or worsen mitral regurgitation (MR). Potential mechanisms for this adverse sequelae include intraventricular dyssynchrony, altered papillary muscle function, pacing-induced cardiomyopathy with left ventricular dilation, and annular dilation. In contrast, biventricular (BiV) pacing may improve MR presumably by opposing the negative effects. Whether or not left ventricular lead location is important in treating mitral regurgitation in patients with pacemakers is unknown.We report a case of severe MR and left ventricular (LV) systolic failure in a patient with right ventricular pacing. Multiple potential etiologies for the worsening valve function were noted, and a stepwise iterative optimizing scheme that included basal lateral LV pacing improved mitral valve function and ameliorated heart failure symptoms.     

Biventricular pacing in the early postoperative period after cardiac surgery

Cardiac resynchronization therapy is not commonly used in the early postoperative period in patients undergoing cardiac surgery who have left ventricular (LV) dysfunction and a history of heart failure. We performed a prospective randomized clinical trial to compare atrial synchronous right ventricular (DDD RV) and biventricular (DDD BIV) pacing within 72 hours after cardiac surgery in patients with an EF ≤35 %, a QRS interval longer than 120 msec and who had LV dyssynchrony detected by real-time three-dimensional echocardiography (RT3DE). Epicardial pacing was provided by a modified Medtronic INSYNC III pacemaker. An LV epicardial pacing lead was implanted on the latest activated segment of the LV based on RT3DE. The study included 18 patients with ischemic heart disease, with or without valvular heart disease (14 men, 4 women, average age 71 years). Patients undergoing DDD BIV pacing had a statistically significant greater CO and CI (CO 6.7±1.8 l/min, CI 3.4±0.7 l/min/m(2)) than patients undergoing DDD RV pacing (CO 5.5±1.4 l/min, CI 2.8±0.7 l/min/m(2)), p<0.001. DDD BIV pacing in the early postoperative period after cardiac surgery corrects LV dyssynchrony and has better hemodynamic results than DDD RV pacing.     

Left ventricular endocardial or triventricular pacing to optimize cardiac resynchronization therapy in a chronic canine model of ischemic heart failure

Cardiac resynchronization therapy (CRT) is a proven treatment for heart failure but ~30% of patients appear to not benefit from the therapy. Left ventricular (LV) endocardial and multisite epicardial [triventricular (TriV)] pacing have been proposed as alternatives to traditional LV transvenous epicardial pacing, but no study has directly compared the hemodynamic effects of these approaches. Left bundle branch block ablation and repeated microembolizations were performed in dogs to induce electrical dysynchrony and to reduce LV ejection fraction to <35%. LVdP/dt(max) and other hemodynamic indexes were measured with a conductance catheter during LV epicardial, LV endocardial, biventricular (BiV) epicardial, BiV endocardial, and TriV pacing performed at three atrioventricular delays. LV endocardial pacing was obtained with a clinically available pacing system. The optimal site was defined as the site that increased dP/dt(max) by the largest percentage. Implantation of the endocardial lead was feasible in all canines (n = 8) without increased mitral regurgitation seen with transesophageal echocardiography and with full access to the different LV endocardial pacing sites. BiV endocardial pacing increased dP/dt(max) more than BiV epicardial and TriV pacing on average (P < 0.01) and at the optimal site (P < 0.01). There were no significant differences between BiV epicardial and TriV pacing. BiV endocardial pacing was superior to BiV epicardial and to TriV pacing in terms of acute hemodynamic response. Further investigation is needed to confirm the chronic benefit of this approach in humans.     

Transesophageal left ventricular posterior wall potential in heart failure patients with biventricular pacing.

INTRODUCTION: Biventricular (BV) pacing is an established therapy for heart failure (HF) patients with intraventricular conduction delay, but not all patients improved clinically. We investigated the interventricular delay (IVD) by means of the transesophageal left ventricular posterior wall potential (LVPWP). MATERIALS AND METHODS, AND RESULTS: A total of 18 HF patients (age 62+/-9 years; 15 males) with NYHA class 3.1+/-0.3, LV ejection fraction 22+/-7%, left bundle branch block and a QRS duration (QRSD) of 171+/-27 ms were analyzed using transesophageal LVPWP before implantation of a BV pacing device. The median follow up was 14+/-14 months. In 14 responders, IVD was 81+/-25 ms with a QRSD/IVD ratio of 2.2+/-0.3 with reclassification of NYHA class 3.1+/-0.3 to 2.0+/-0.5 (p<0.001) and an increase in LV ejection fraction from 22+/-7% to 36+/-11% (p=0.001) during long-term BV pacing. In four non-responders, transesophageal IVD was significantly smaller at 30+/-11 ms (p=0.001). CONCLUSION: Transesophageal IVD may be a useful method to detect responders to BV pacing. Transesophageal LVPWP may be a simple and useful technique to detect clinical responders to BV pacing in HF patients.     

Anodal stimulation: an underrecognized cause of nonresponders to cardiac resynchronization therapy

Objective

The purpose of this study was to determine if anodal stimulation accounts for failure to benefit from cardiac resynchronization therapy (CRT) in some patients.

Background

Approximately 30-40% of patients with moderate to severe heart failure do not have symptomatic nor echocardiographic improvement in cardiac function following CRT. Modern CRT devices allow the option of programming left ventricular (LV) lead pacing as LV tip to right ventricular (RV) lead coil to potentially improve pacing thresholds. However, anodal stimulation can result in unintentional RV pacing (anode) instead of LV pacing (cathode).

Methods

Patients enrolled in our center''s CRT registry had an echocardiogram, 6-minute walk (6MW), and Minnesota Living with HF Questionnaire (MLHFQ) pre-implant and 6 months after CRT. Electrocardiograms (12 lead) during RV, LV, and biventricular (BiV) pacing were obtained at the end of the implant in 102 patients. Anodal stimulation was defined as LV pacing QRS morphology on EKG being identical to RV pacing or consistent with fusion with RV and LV electrode capture. LV end systolic volume (LVESV) was measured by echo biplane Simpson''s method and CRT responder was defined as 15% or greater reduction in LVESV.

Results

Of the 102 patients, 46 (45.1%) had the final LV lead pacing configuration programmed LV (tip or ring) to RV (coil or ring). 3 of the 46 subjects (6.5%) had EKG findings consistent with anodal stimulation, not corrected intraoperatively. All anodal stimulation patients were nonresponders to CRT by echo criteria (reduction in LVESV 13.3 ± 0.6%, increase in EF 5.0 ± 1.4%) compared to 46% responders for those without anodal stimulation, (change in LVESV 18.7 ± 25.6%, EF 7.6 ±10.9%). None of the anodal stimulation patients were responders for the 6 minute walk, compared to 32 of 66 (48%) of those without anodal stimulation.

Conclusion

Anodal stimulation is a potential underrecognized and ameliorable cause of poor response to CRT.     

Improvement in pump function with endocardial biventricular pacing increases with activation time at the left ventricular pacing site in failing canine hearts

Recently, attention has been focused on comparing left ventricular (LV) endocardial (ENDO) with epicardial (EPI) pacing for cardiac resynchronization therapy. However, the effects of ENDO and EPI lead placement at multiple sites have not been studied in failing hearts. We hypothesized that differences in the improvement of ventricular function due to ENDO vs. EPI pacing in dyssynchronous (DYSS) heart failure may depend on the position of the LV lead in relation to the original activation pattern. In six nonfailing and six failing dogs, electrical DYSS was created by atrioventricular sequential pacing of the right ventricular apex. ENDO was compared with EPI biventricular pacing at five LV sites. In failing hearts, increases in the maximum rate of LV pressure change (dP/dt; r = 0.64), ejection fraction (r = 0.49), and minimum dP/dt (r = 0.51), relative to DYSS, were positively correlated (P < 0.01) with activation time at the LV pacing site during ENDO but not EPI pacing. ENDO pacing at sites with longer activation delays led to greater improvements in hemodynamic parameters and was associated with an overall reduction in electrical DYSS compared with EPI pacing (P < 0.05). These findings were qualitatively similar for nonfailing hearts. Improvement in hemodynamic function increased with activation time at the LV pacing site during ENDO but not EPI pacing. At the anterolateral wall, end-systolic transmural function was greater with local ENDO compared with EPI pacing. ENDO pacing and intrinsic activation delay may have important implications for management of DYSS heart failure.     

Dynamic three-dimensional echocardiography combined with semi-automated border detection offers advantages for assessment of resynchronization therapy

Simultaneous electrical stimulation of both ventricles in patients with interventricular conduction disturbance and advanced heart failure improves hemodynamics and results in increased exercise tolerance, quality of life. We have developed a novel technique for the assessment and optimization of resynchronization therapy. Our approach is based on transthoracic dynamic three-dimensional (3D) echocardiography and allows determination of the most delayed contraction site of the left ventricle (LV) together with global LV function data. Our initial results suggest that fast reconstruction of the LV is feasible for the selection of the optimal pacing site and allows identifying LV segments with dyssynchrony.     

Biventricular / left ventricular pacing in hypertrophic obstructive cardiomyopathy: an overview

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory pathological left ventricle (LV) hypertrophy due to sarcomere dysfunction. In an important proportion of patients with HCM, the site and extent of cardiac hypertrophy results in severe obstruction to LV outflow tract (LVOT), contributing to disabling symptoms and increasing the risk of sudden cardiac death (SCD). In patients with progressive and/or refractory symptoms despite optimal pharmacological treatment, invasive therapies that diminish or abolish LVOT obstruction relieve heart failure-related symptoms, improve quality of life and could be associated with long-term survival similar to that observed in the general population. The gold standard in this respect is surgical septal myectomy, which might be supplementary associated with a reduction in SCD. Percutaneous techniques, particularly alcohol septal ablation (ASA) and more recently radiofrequency (RF) septal ablation, can achieve LVOT gradient reduction and symptomatic benefit in a large proportion of HOCM patients at the cost of a supposedly limited septal myocardial necrosis and a 10-20% risk of chronic atrioventricular block. After an initial period of enthusiasm, standard DDD pacing failed to show in randomized trials significant LVOT gradient reductions and objective improvement in exercise capacity. However, case reports and recent small pilot studies suggested that atrial synchronous LV or biventricular (biV) pacing significantly reduce LVOT obstruction and improve symptoms (acutely as well as long-term) in a large proportion of severely symptomatic HOCM patients not suitable to other gradient reduction therapies. Moreover, biV/LV pacing in HOCM seems to be associated with significant LV reverse remodelling.     

Abnormal cardiac wall motion and early matrix metalloproteinase activity

Activation of matrix metalloproteinases (MMPs) in the heart is known to facilitate cardiac remodeling and progression to failure. We hypothesized that regional dyskinetic wall motion of the left ventricle would stimulate activation of MMPs. Abnormal wall motion at a target site on the anterior lateral wall of the left ventricle was induced by pacing atrial and ventricular sites of five open-chest anesthetized dogs. Changes in shortening at the left ventricular (LV) pacing site and at a remote site at the anterior base of the left ventricle were monitored with piezoelectric crystals. Simultaneous atrial and ventricular pacing resulted in abnormal motion at the LV pacing site, yielding early shortening and late systolic lengthening, whereas the shortening pattern at the remote site remained unaffected. Assessment of global myocardial MMP activity showed a sevenfold increase in substrate cleavage (P < 0.02) at the LV pacing site relative to the remote site. Gelatin zymography revealed increases in 92-kDa MMP-9 activity and 86-kDa MMP-9 activity at the LV pacing site relative to the remote site, whereas MMP-2 activity was unaffected. Abnormal wall motion was associated with increases in collagen degradation (approximately 2-fold; P < 0.03), plasmin activity (approximately 1.5-fold; P < 0.05), nitrotyrosine levels (approximately 20-fold; P = 0.05), and inflammatory infiltrate (approximately 2-fold; P < 0.02) relative to the remote site. Results indicate that regional dyskinesis induced by epicardial activation is sufficient to stimulate significant MMP activity in the heart, suggesting that abnormal wall motion is a stimulus for MMP activation.     

Biventricular stimulation therapy in patients with heart failure and tachycardic arrhythmias. Indications--results--prospects]

Biventricular pacing (BV-P) therapy is a new therapeutic approach in patients (pts) with drug refractory congestive heart failure; the beneficial effects of implantable cardioverter defibrillator (ICD) without BV-P therapy in patients (pts) with life-threatening ventricular tachyarrhythmias and impaired left ventricular (LV) function is associated with a relatively high cardiac and total mortality. We studied the follow-up of 410 pts (368 males, 42 females, mean age 57 +/- 11 years) after ICD implant. The LV function was assessed by the New York Heart functional class of heart failure (NYHA). Fifty pts (12%) were in NYHA I-II, 151 pts (37%) in NYHA II, 117 pts (29%) in NYHA II-III and 92 pts (22%) in NYHA III. Epicardial ICD implantation was performed in 209 pts (51%) and 201 pts (49%) received nonthoracotomy ICDs. Perioperatively (within 30 days after implant), 12 pts (3%) died, significantly more frequent after epicardial (11 of 209 pts, 5%) than after transvenous ICD implant (1 of 201 pts, < 1%)(p < 0.05). During a mean follow-up of 28 + 24 months (range < 1 to 114 months), 90 pts (23%) died: 9 pts (2%) died from sudden arrhythmic death and 5 pts (1%) suddenly, but probably not from arrhythmic causes; 55 pts (14%) died from cardiac causes (congestive heart failure, myocardial reinfarction) and 21 pts (5%) from noncardiac causes. 338 pts (82%) received ICD shocks (mean incidence 21 +/- 43 shocks per pt). Our data show that pts with LV dysfunction benefit from ICD therapy and that these pts survive for a considerable time after the first shock. However, survival is clearly influenced by the degree of left ventricular dysfunction and, in addition to ICD therapy, aggressive treatment of heart failure is necessary. Therefore, BV-P is a very promising concept to improve the worse prognosis in pts with moderate or severe congestive heart failure.     

心室不同部位起搏对正常犬和扩张型心肌病心力衰竭犬模型在体心肌跨室壁复极离散的影响

实验以正常犬和扩张型心肌病心力衰竭犬(dilated cardiomyopathy congestive heart failure,DCM-CHF)模型为对象、以心肌跨室壁复极离散的相关参数为指标,研究左心室心外膜起搏、双心室起搏(模拟临床上心室再同步治疗的方法)后的心肌电生理特性变化。实验以快速右心室起搏的方法制备DCM-CHF犬模型;正常犬和DCM-CHF犬均经射频消融希氏束制备三度房室传导阻滞模型;采用同步记录犬体表心电图和内膜下、中层、外膜下三层心肌单相动作电位(monophasic action potentials,MAP)的方法,测定不同部位起搏时的QT间期、Tpeak-Tend(Tp-Te)间期和三层心肌的单相动作电位时程(MAP duration,MAPD)、跨室壁复极离散度(transmural dispersion of repolaization,TDR)。结果显示:在正常犬,左室心外膜与双心室起搏后三层心肌的MAPD均延长,同时TDR增大(左室心外膜起搏47.16 ms、双心室起搏37.54 ms、右室心内膜起搏26.75 ms,P<0.001),体表心电图Tp-Te间期的变化与之平行;在DCM-CHF犬较正常犬已表现出中层心肌MAPD延长(276.30 ms vs 257.35 ms,P<0.0001)和TDR(33.8 ms vs 27.58 ms,P=0.002)增大的基础上,左室心外膜参与起搏后仍进一步使三层心肌的MAPD延长和TDR增大。研究结果提示,左室心外膜起搏和双心室起搏后使内膜下、中层     

Non-invasive Determination of the Optimized Atrioventricular Delay in Patients with Implanted Biventricular Pacing Devices

Background

Biventricular (BiV) is extensively used in the treatment of congestive heart failure but so far no recommendations for optimized programming of atrioventricular-delay (AVD) settings have been proposed. Can AVD optimization be performed using a simple formula based on non-invasive doppler-echocardiography?

Methods

25 patients (ejection fraction 30±8%) received BiV ICDs. Doppler-echocardiographic evaluation of diastolic and systolic flow was performed for different AVDs (30ms to 150ms) and different stimulation sites (left ventricular (LV), right ventricular and BiV). The optimal atrioventricular delay was calculated applying a simple formula based on systolic and diastolic mechanical delays determined during doppler-echocardiography.

Results

The mean optimal AVD was calculated to be 112±29ms (50 to 180ms) for BiV, 95±30ms (65 to 150ms) for LV and 75±28ms (40 to 125ms) for right ventricular pacing with wide interindividual variations. Compared to suboptimal AVDs diastolic optimization improved preejection and ejection intervals independent to pacing site. Optimization of the AVD significantly increased ejection time during BiV pacing (279ms versus 266ms; p<0.05). Compared to LV or right ventricular pacing BiV pacing produced the shortest mean pre-ejection and longest ejection intervals as parameters of improved systolic ventricular contractile synchrony. Diastolic filling times were longest during BiV pacing compared to LV or RV pacing.

Conclusions

Individual programming of BiV pacing devices increases hemodynamic benefit when implementing the inter-individually widely varying electromechanical delays. Optimization applying a simple formula not only improves diastolic ventricular filling but also increases systolic functional parameters.     

Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure

Angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor (ACEI) each act in a different manner to prevent myocardial fibrosis and left ventricular (LV) stiffness in animals with pathways in the heart for generating ANG II as well as ACE. A model of pacing-induced congestive heart failure (CHF) was used to test the central hypothesis that ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness to a greater extent than ARB or ACEI alone. Thirty-five dogs were assigned to the following treatment protocols on the 8th day of a 4-wk pacing schedule: 1) rapid ventricular pacing, 2) ARB (candesartan cilexetil, 1.5 mg.kg(-1).day(-1)) with pacing, 3) ACEI (enalapril, 1.9 mg.kg(-1).day(-1)) with pacing, 4) ARB (candesartan cilexetil, 0.75 mg.kg(-1).day(-1)) + ACEI (enalapril, 0.95 mg.kg(-1).day(-1)) with pacing, and 5) sham operation. The LV stiffness coefficient was significantly increased after rapid pacing but was significantly lower with ARB + ACEI than with ARB or ACEI alone. The collagen volume fraction and mRNA levels of collagen I and III, which were increased by rapid pacing, were significantly lower with ARB + ACEI than with ARB or ACEI alone. Thus ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness during the progression of CHF compared with ARB or ACEI alone.     

Biventricular pacing in heart failure: update on results from clinical trials

Biventricular pacing or resynchronisation therapy is a non-pharmacological therapy for patients with chronic heart failure. Since being originally described in 1994, biventricular pacing has become a subject of intense interest and investigation. This review analyses the results reported in observational series and randomised trials, and seeks to answer two questions. If it works, why does it work? Which heart failure patients will it benefit?     

Alterations in cardiac adrenergic terminal function and beta-adrenoceptor density in pacing-induced heart failure

Congestive heart failure is associated with cardiac adrenergic nerve terminal changes and beta-adrenoceptor density downregulation. To study the temporal sequence of these changes, we performed studies in rabbits at 2, 4, and 8 wk of cardiac pacing (360 beats/min) and at 1, 2, and 4 wk after cessation of pacing. Rapid pacing produced left ventricular (LV) dysfunction and an increase in plasma norepinephrine (NE) in 1-2 wk. At week 2, NE uptake activity, NE uptake-1 density, and adenylyl cyclase responses to isoproterenol, 5'-guanylyl imidodiphosphate [Gpp(NH)p], and forskolin reduced. However, immunostained tyrosine hydroxylase profile, beta-adrenoceptor density, and NE histofluorescence did not reduce until 4-8 wk of pacing. After cessation of cardiac pacing, LV function normalized quickly, followed by return of tyrosine hydroxylase and NE profiles in 1 wk and adenylyl cyclase responses to agonists and NE uptake activity in 2 wk. Myocardial beta-adrenoceptor density returned to normal by 4 wk after cessation of pacing. Our results suggest that there is no permanent structural neuronal damage in the myocardium within the first 8 wk of rapid cardiac pacing. Abnormal myocardial NE reuptake mechanism may play an important pathophysiological role in heart failure.     

Cardiac dyssynchrony and response to cardiac resynchronisation therapy in heart failure: can genetic predisposition play a role?

Cardiac resynchronisation therapy (CRT) is an accepted treatment for heart failure patients with depressed left ventricular (LV) function and dyssynchrony. However, despite better clinical outcome and improved cardiac function after CRT in the majority of eligible heart failure patients, a large proportion of implanted patients do not seem to benefit clinically from this therapy. In this review we consider whether genetic factors may play a role in modulating response to CRT and summarise the few genetic studies that have investigated the role of genetic variation in candidate genes.     

Coenzyme Q10 treatment in serious heart failure.

Several noninvasive studies have shown the effect on heart failure of treatment with coenzyme Q10. In order to confirm this by invasive methods we studied 22 patients with mean left ventricular (LV) ejection fraction 26%, mean LV internal diameter 71 mm and in NYHA class 2-3. The patients received coenzyme Q10 100 mg twice daily or placebo for 12 weeks in a randomized double-blinded placebo controlled investigation. Before and after the treatment period, a right heart catheterisation was done including a 3 minute exercise test. The stroke index at rest and work improved significantly, the pulmonary artery pressure at rest and work decreased (significantly at rest), and the pulmonary capillary wedge pressure at rest and work decreased (significantly at 1 min work). These results suggest improvement in LV performance. Patients with congestive heart failure may thus benefit from adjunctive treatment with coenzyme Q10.