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Background: During cardiac resynchronization therapy (CRT) device implantation, the pacing lead is usually positioned in the coronary sinus (CS) to stimulate the left ventricular (LV) epicardium. Transvenous LV endocardial pacing via transseptal puncture has been proposed as an alternative method. In the present study, we evaluated the acute hemodynamic effects of CRT through LV endocardial pacing in heart failure patients by analyzing LV pressure-volume relationships., Methods and Results: LV pressure and volume data were determined via conductance catheter during CRT device implantation in 10 patients. In addition to the standard epicardial CS pacing, the following endocardial LV sites were systematically assessed: the site transmural to the CS lead, the LV apex, the septal midwall, the basal lateral free wall, and the midlateral free wall. Four atrioventricular delays were tested. There was a significant improvement of systolic function with CRT in all LV pacing configurations, whereas no differences in systolic or diastolic function were detected between LV epicardial and endocardial transmural sites. The optimal pacing site varied among patients but was rarely related to relatively longer activation delays, as assessed by analyzing endocardial electric activation maps. Nonetheless, positioning the pacing lead at the optimal endocardial LV site in each patient significantly improved LV performance in comparison with conventional CS site stimulation (stroke volume, 83 [79-112] mL versus 73 [62-89] mL; P=0.034)., Conclusions: Pacing at the optimal individual LV endocardial site yields enhanced LV performance in comparison with conventional CS site stimulation. Endocardial LV pacing might constitute an alternative approach to CRT, when CS pacing is not viable.

Aims: It has been shown that atrioventricular (AV) delay optimization improves cardiac resynchronization therapy (CRT) response. Recently, an automatic algorithm (QuickOpt™, St Jude Medical), able to quickly identify the individual optimal AV interval, has been developed. The algorithm suggests an AV delay based on atrial intracavitary electrogram (IEGM) duration. We hypothesized that the difference between electrical and mechanical atrial delays could affect the effectiveness of QuickOpt method. The aim of this study was to test this hypothesis in 23 CRT patients who were recipients of St. Jude Medical devices., Methods and Results: Using echocardiography, aortic flow velocity time integral (VTI) was evaluated at baseline, at QuickOpt suggested AV delay and after reducing it by 25 and 50%. Mechanical inter-atrial delay (MIAD) derived from echo/Doppler and electrical inter-atrial delay (EIAD) derived from IEGM were also analysed. Optimal AV delay was identified by the maximal VTI. In 11 patients (Group 1) the maximal VTI was achieved at the AV delay suggested by the algorithm, in 6 patients (Group 2) after a 25% reduction, and in 6 patients (Group 3) after a 50% reduction. While EIAD was similar among the three groups, MIAD was significantly different (P< 0.001). MIAD was longer than EIAD in Group 1 (P= 0.028) and shorter than EIAD in Groups 2 (P= 0.028) and 3. (P< 0.001). Mechanical inter-atrial delay was the only independent predictor of the AV interval associated with the best VTI (R(2) = 0.77; P< 0.001)., Conclusion: Our results show that MIAD plays the main role in determining the optimal AV delay, thus caution should be taken when optimizing AV by IEGM-based methods.

Background: The Seattle Heart Failure Model (SHFM) is a multimarker risk assessment tool able to predict outcome in heart failure (HF) patients., Aim: To assess whether the SHFM can be used to risk-stratify HF patients who underwent cardiac resynchronization therapy with (CRT-D) or without (CRT) an implantable defibrillator., Methods and Results: The SHFM was applied to 342 New York Heart Association class III-IV patients who received a CRT (23%) or CRT-D (77%) device. Discrimination and calibration of SHFM were evaluated through c-statistics and Hosmer-Lemeshow (H-L) goodness-of-fit test. Primary endpoint was a composite of death from any cause/cardiac transplantation. During a median follow-up of 24 months (25th-75th percentile [pct]: 12-37 months), 78 of 342 (22.8%) patients died; seven patients underwent urgent transplantation. Median SHFM score for patients with endpoint was 5.8 years (25th-75th pct: 4.25-8.7 years) versus 8.9 years (25th-75th pct: 6.6-11.8 years) for those without (P < 0.001). Discrimination of SHFM was adequate for the endpoint (c-statistic always ranged around 0.7). The SHFM was a good fit of death from any cause/cardiac transplantation, without significant differences between observed and SHFM-predicted survival., Conclusion: The SHFM successfully stratifies HF patients on CRT/CRT-D and can be reliably applied to help clinicians in predicting survival in this clinical setting., (©2011, The Authors. Journal compilation ©2011 Wiley Periodicals, Inc.)

Background: "Cardiac memory" (CM) refers to a change in repolarization induced by an altered pathway of activation. The effects of biventricular pacing on CM induction have not been investigated., Objective: To investigate the development of CM during cardiac resynchronization therapy (CRT) through vectorcardiography (VCG)., Methods: Eleven patients undergoing CRT were enrolled. VCG was acquired during spontaneous ventricular activation at baseline and during AAI and DDD pacing immediately after and 7, 14, 21 and 60 days after the implantation., Results: At 1-week follow-up, during AAI pacing T vector angles significantly changed (azimuth 23 ± 19°; p = 0.002; elevation 23 ± 27°; p = 0.019) and magnitude significantly increased (baseline 1.13 ± 0.69 mV; 7 days: 1.77 ± 1.27 mV; p = 0.026). T angle changes remained stable throughout the follow-up period while a further significant increase in magnitude was observed at 60 days (2.21 ± 1.50 mV; p = 0.01 vs. baseline and p = 0.04 vs. 7 days). Paced T vector magnitude at implant (2.24 ± 1.25 mV) decreased significantly at 7 days (1.64 ± 1.26 mV; p = 0.030) with a further significant decrease at 60 days (1.40 ± 1.18 mV; p = 0.003 vs. baseline; p = 0.02 vs. 7 days)., Conclusion: CRT induces a significant change in T vector magnitude, azimuth, and elevation after resumption of spontaneous ventricular activation after 7 days from implantation. While further changes in T vector angle were not observed, after 2 months of CRT a significant decrease of paced T vector magnitude and a significant increase of spontaneous T vector magnitude were observed.

Background: The effect of cardiac resynchronization therapy (CRT) on systemic inflammation and neurohormonal alterations associated with heart failure is not well characterized. Accordingly, we aimed to assess the long term effects of CRT on systemic inflammation and neurohormonal factors in heart failure patients., Methods and Results: In 47 HF patients (NYHA III-IV) we evaluated, at baseline and after one year of CRT: TNF-alpha, TNF soluble receptors (sTNFR1 and sTNFR2), insulin-like growth factor-1alpha (IGF-1alpha), adiponectin, norepinephrine, pro-atrial natriuretic peptide (pro-ANP), N-terminal-pro-brain natriuretic peptide (NT-proBNP) and angiotensin II, NYHA functional class, quality of life (the Minnesota Living with Heart Failure questionnaire), a 6-minute walk test and an echocardiogram. Long-term CRT decreased activation of renin-angiotensin system (RAS) only in patients with reverse remodelling. It failed to prevent a decline in adiponectin levels, regardless of reverse remodelling. NT-proBNP remained unchanged in patients with reverse remodelling, whereas its levels increased in those without reverse remodelling. IGF-1alpha increased with CRT, whereas CRT had no effect on pro-ANP and inflammatory markers., Conclusions: Long-term CRT is associated with decreased RAS activation and stabilization of NT-proBNP in heart failure patients with reverse remodelling. Long-term CRT, with or without reverse remodelling, does not affect systemic inflammation and fails to prevent a decline in adiponectin.

Simultaneous stimulation of 2 left ventricular (LV) sites could enhance the effectiveness of cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the acute hemodynamic response to dual-site LV CRT. Two LV pacing leads were successfully implanted in 12 CRT candidates (New York Heart Association classes III to IV, QRS >or=120 ms). Target positions were the lateral or posterolateral vein (site A) and anterior or anterolateral vein (site B). A conductance catheter was placed in the left ventricle for pressure-volume measurements. Tested CRT configurations were alternated by atrial overdrive pacing at a fixed rate and included site A and B single-site CRT and dual-site LV CRT (2 LV sites plus right ventricular apex) at 4 atrioventricular intervals. Overall, single-site LV CRT significantly enhanced stroke volume, stroke work, maximum pressure derivative, and conductance-derived indexes of LV synchrony when delivered in site A, whereas no significant changes were noticed with pacing in site B. Specifically, site-A pacing resulted in a higher stroke volume increase (LV pacing site associated with the best hemodynamic response [best-LV]) in 8 patients, and site-B pacing, in 4 patients. At intermediate atrioventricular intervals, dual-site LV CRT resulted in improved stroke volume, stroke work, maximum pressure derivative, and LV synchrony with respect to single-site CRT when delivered at the best-LV (all p <0.05). However, single-site CRT at best-LV produced results similar to dual-site LV CRT when the atrioventricular interval was optimized in each patient. In conclusion, adding a second LV lead does not result in further improvement in acute hemodynamic response with respect to standard CRT when the single LV pacing site and atrioventricular interval are optimal.

Background: Inflammatory markers are involved in heart failure (HF) pathophysiology. However, the link between these markers and reverse remodeling as well as major adverse cardiac events (HF death, sudden death, and unplanned cardiac rehospitalizations) in patients who undergo cardiac resynchronization therapy (CRT) has not been evaluated., Methods and Results: We recorded major adverse cardiac events of 140 patients (on optimized medical therapy, left ventricular ejection fraction 29.9 +/- 9.6%, New York Heart Association Class III-IV, with intraventricular dyssynchrony) who underwent CRT (enrolled since April 2004). Moreover, we evaluated before and after 6 months of CRT: interleukin-6, high-sensitivity C-reactive protein, New York Heart Association class, quality of life (score on Minnesota Living with Heart Failure questionnaire), 6-minute walking test, left ventricular end-diastolic and end-systolic volumes (nonindexed and indexed by body surface area), and left ventricular ejection fraction. Adverse cardiac events were observed in 40 patients (28.6%): 22 deaths and 18 cardiac unplanned rehospitalizations. Only patients without adverse events during follow-up showed a significant reduction of inflammatory markers and left ventricular volumes (reverse remodeling), despite a significant improvement of clinical status observed in both groups of patients., Conclusions: The reduction of inflammatory status seems to be linked to reverse remodeling as well as to a better clinical prognosis in patients with HF who underwent CRT.

Background: Cardiac resynchronization therapy (CRT) is an emerging treatment for heart failure patients with left bundle branch block; in these patients left ventricle filling pattern (LVFP) abnormalities are recognized as cause of symptoms and predictors of outcome. We investigated the effects of CRT on diastolic function and the prognostic value of LVFP in patients on CRT., Methods: 65 patients treated with CRT were studied over a 12 months period. At baseline, according to defined echocardiographic criteria, restrictive LVFP (RFP) was present in 25 patients, whereas 40 patients showed no-RFP., Results: After CRT, opposite changes occurred in the two groups. In no-RFP patients, early-to-atrial filling velocity ratio (E/A) increased from 0.8+/-0.3 to 1.0+/-0.6 (p=0.006) and E wave deceleration time (DT) decreased from 234+/-83 ms to 196+/-51 ms (p=0.028). In 13 RFP patients, E/A decreased from 2.2+/-0.9 to 0.8+/-0.5 and DT increased from 128+/-43 ms to 205+/-52 ms (both p<0.001), leading to reversal of RFP. In both groups, clinical, functional and echographic benefits were evident, with mortality rates of 5% (2/40) and 15% (2/13) respectively. The remaining patients showed persistence of RFP (E/A and DT unchanged), no improvement and a mortality rate of 42% (5/12) (p=0.005, versus no-RFP)., Conclusions: CRT improves diastolic function, inducing also reversal of LVFP in a consistent number of RFP patients. The persistence of RFP after CRT is associated to an extremely poor prognosis.

Aims: The majority of tissue Doppler indexes proposed to predict left ventricular (LV) reverse remodelling in cardiac resynchronization therapy (CRT) reflects LV asynchrony as assessed in ejection phase. We evaluated the predictive value of a new strain-imaging parameter reflecting the total amount of time spent by 12 LV segments in contracting after aortic valve closure., Methods and Results: Fifty-nine patients who fulfilled current treatment recommendations were studied before and 6 months after CRT. Time to tissue Doppler systolic peak velocity (Ts) and time exceeding aortic closure (ExcT) in strain curves were measured in 12 LV segments. Ts standard deviation (Ts-SD) and sum of ExcT of overall 12 LV segments (oExcT) were analysed. After 6 months, responders were defined according to > or =15% LV end-systolic volume reduction. Responders (47%) when compared with non-responders (53%) had significantly higher baseline Ts-SD and oExcT values. Receiver operating characteristic (ROC) curve analysis demonstrated that an optimal cutoff value of 760 ms for oExcT yielded 93.5% sensitivity and 82.8% specificity. For Ts-SD at the cutoff of 32 ms, 82% sensitivity and 39% specificity were obtained. Area under ROC was significantly larger for oExcT than for Ts-SD., Conclusion: o-ExcT is able to predict LV reverse remodelling after CRT.

Aims: Functional mitral regurgitation (FMR) improvement induced by cardiac resynchronization therapy (CRT) has been related to left ventricular (LV) remodeling reversal and contractility enhancement. The effects induced by the changes of LV synchronicity indexes on FMR severity have not been investigated., Methods and Results: In 30 patients with CRT for heart failure (HF) and QRS>130 ms, LV function parameters, FMR severity as mitral jet regurgitation/left atrial area ratio (JA/LAA) and standard deviation (SD) of the time to the systolic peak velocity at 6-basal and mid-LV segments as asynchrony indexes were evaluated (echo/tissue Doppler) before and 6 months after implant. At follow-up, 15 patients resulted responders to LV reverse remodeling with > or =15% end-systolic volume (ESV) and LV systolic function improvement. Improvement of FMR with > or =15% JA/LAA reduction was observed in 19 patients, 7 were nonresponders to LV reverse remodeling. In patients with > or =15% JA/LAA reduction a significant decrease of LV asynchrony indexes was observed as compared to patients without > or =15% JA/LAA reduction in whom LV asynchrony indexes were increased. Reduction of LV mid-segmental asynchrony was the variable most strongly related to JA/LAA reduction (r(2)=0.697, P<0.01), with good agreement between observed and predicted values (only 1 patient outside the mean+/-2SD)., Conclusion: These data reveal that CRT can reduce FMR irrespective to LV remodeling reversal; this effect is related to LV asynchrony reduction and further support CRT employment in patients with HF and FMR.

Atrial fibrillation (AF) and congestive heart failure (CHF) share several characteristics and often coexist in the same patient. Both are responsible for significant morbidity and mortality, are increasing in prevalence, and are major sources of health expenditure. The Management of Atrial fibrillation Suppression in AF-HF COmorbidity Therapy (MASCOT) study is a European, single-blind, prospective, controlled, multicentre, randomized clinical trial designed to examine whether adding the AF Suppression Algorithm to cardiac resynchronization therapy (CRT) improves the prognosis of patients with CHF. The patients will be randomly assigned to a CRT-only group, with the AF Suppression algorithm programmed OFF (control group), versus a CRT+AF Suppression group, with the algorithm programmed ON (treatment group). The primary study endpoint is development of permanent AF, and secondary endpoints are safety of the AF Suppression algorithm, and evolution of multiple clinical variables over 24 months of follow-up. CRT combined with a refined atrial tachyarrhythmia prevention pacing algorithm may represent a major advance in the management of AF and CHF by electrical stimulation.

Unlabelled: Cardiac resynchronization therapy (CRT) by biventricular pacing is indicated in patients with severe heart failure and left bundle branch block who remain symptomatic despite optimal medical therapy. The relationship between baseline resting perfusion pattern and hemodynamic response to CRT has not been fully investigated. We tested the usefulness of perfusion gated SPECT for baseline evaluation and follow-up of these patients., Methods: In 20 patients, we performed gated SPECT before CRT and at the 3-mo follow up. Left ventricular (LV) ejection fraction (EF), end-diastolic (ED) and end-systolic (ES) volume indexes (VI), and wall motion score index (WMSI) were measured and compared with clinical outcome., Results: One patient died before follow-up. The 19 remaining patients were classified into 1 of 2 groups according to the presence (group A) or absence (group B) of a significant severe perfusion defect at baseline before CRT. At the 3-mo follow-up, 6 of 10 group A and 8 of 9 group B patients had an improvement in New York Heart Association class. In both groups, quality of life, 6-min walking distance, and WMSI significantly improved. In group A, no significant change was registered in LVEF, LVEDVI, or LVESVI. In group B, LVEF increased from 23.1% +/- 8% to 27.1% +/- 11% (P < 0.03) and LVEDVI and LVESVI decreased from 159 +/- 70 mL to 135 +/- 68 mL (P < 0.02) and from 127 +/- 67 mL to 104 +/- 65 mL (P < 0.01), respectively., Conclusion: Perfusion gated SPECT appears useful to characterize and follow up candidates for CRT. Despite clinical improvement, patients with severe resting perfusion defects do not show significant improvement in LVEF or reduction in LV volumes.

Aim: Gender related differences in epidemiology, treatment, and prognosis of heart failure (HF) have been reported. We examined the sex influence in patients treated with cardiac resynchronization therapy (CRT). Methods and Results: Out of 334 consecutive HF patients (19.7% women) who underwent CRT, 195 patients reached clinical and echocardiographic evaluation at six and 12 months and were selected for analysis. A reduction in left ventricular (LV) end-diastolic volume/m2 (EDVi) and end systolic volume/m2 (ESVi) was evident in the overall population at six months (P < 0.001) and from six to 12 months (P < 0.001). Compared to men, women showed significantly greater changes in LV volumes at mid (P < 0.05) and long-term (P < 0.001) follow-up and a significantly higher LV ejection fraction (EF) (40.8 ± 12.3 vs 34.1 ± 10.1, P < 0.01) at one year. Multiple regression analysis, including several demographic and clinical parameters, revealed that female gender is independently associated with greater reduction in LV ESVi. At the 12-month follow-up, the proportion of responders (defined in terms of ESV reduction by at least 10%) was higher in women than in men (76.1% vs 59.3%, P < 0.05). Conclusions: CRT induced a gender specific LV remodeling response. [ABSTRACT FROM AUTHOR]

Abstract: Background: Tailored atrioventricular delay (AVd) and interventricular delay (VVd) combination improves hemodynamics in patients treated with cardiac resynchronization therapy (CRT). Whether tailored AVd-VVd combination changes over time is not known. Methods and Results: Twenty-two patients (18 M, aged 69.9 ± 12.5 years, New York Heart Association class III, QRS ≥ 130 ms, ejection fraction 29.6 ± 8.8%) were implanted with a biventricular device with programmable VVd. Myocardial performance index (MPI) was evaluated during pacing at different VVds and AVds at baseline and after 6 and 12 months. The optimal AVd-VVd combination was identified by the minimum MPI. After optimization, the appropriate AVd-VVd combination was programmed in each patient. MPI at 6-month follow-up after optimization was significantly higher compared with baseline (.79 ± .21 vs. .59 ± .15, P < .05). Re-optimization of AVd-VVd combination was required after 6 months in 21 of 22 (95%) patients. Re-optimization significantly reduced MPI compared with the value prior to re-optimization (.56 ± .15 vs. .79 ± .21, P < .05). The MPI remained unchanged at 12-month compared with 6-month follow-up (.59 ± .19 vs. .56 ±.15, P = NS). Clinical symptoms and reverse left ventricular remodeling were sustained at 6-month and 12-month follow-up. Conclusion: Optimal AVd and VVd combination changes over time in patients with heart failure. Sustained improvement in clinical symptoms and reverse left ventricular remodeling after CRT are not temporally associated with improvement in MPI. [Copyright &y& Elsevier]