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Objectives: Our aim was to study the relationship between T-wave alternans (TWA) and rate-response (restitution) of repolarization in subjects with and without ventricular systolic dysfunction., Background: T-wave alternans is a promising predictor of sudden death, yet the mechanisms linking it with human ventricular arrhythmias are unclear. From theoretic considerations, we hypothesized that abnormal TWA is linked with steep restitution of action potential duration (APD) and that both predict arrhythmic outcome., Methods: We studied 53 subjects with left ventricular ejection fraction (LVEF) < or =40% and 18 control subjects. At electrophysiologic study, we recorded APD at 90% repolarization (APD(90)) in the right (n = 62) or left (n = 9) ventricle during pacing while measuring TWA from the body surface., Results: As expected, TWA (at <109 beats/min) was more likely to be abnormal in study than in control subjects (p < 0.01). However, study (LVEF 28 +/- 8%) and control (LVEF 58 +/- 12%) subjects did not differ in APD(90) restitution slope maxima (1.2 +/- 0.6 vs. 1.3 +/- 0.6, respectively; p = 0.82) or numbers with steep slope (>1; 58% vs. 67%). T-wave alternans and simultaneous APD alternans always occurred at diastolic intervals where APD restitution was not steep (p < 0.001), and there was no relationship between maximum restitution slope and TWA magnitude. Over 829 +/- 473 days, TWA (p = 0.02), but not restitution slope >1, predicted ventricular arrhythmias in subjects with LVEF < or =40%., Conclusions: The mechanism by which TWA predicts arrhythmic mortality does not reflect the maximum slope of ventricular APD restitution. Better understanding of the mechanisms underlying TWA may enable improved prediction and prevention of ventricular arrhythmias.

Objectives: The purpose of this study was to compare left ventricular (LV) dyssynchrony assessment by gated myocardial perfusion single-photon emission computed tomography (SPECT) (GMPS) and tissue Doppler imaging (TDI)., Background: Recently, it has been suggested that LV dyssynchrony is an important predictor of response to cardiac resynchronization therapy (CRT); dyssynchrony is predominantly assessed by TDI with echocardiography. Information on LV dyssynchrony can also be provided by GMPS with phase analysis of regional LV maximal count changes throughout the cardiac cycle, which tracks the onset of LV thickening., Methods: In 75 patients with heart failure, depressed LV function, and wide QRS complex, GMPS and 2-dimensional echocardiography, including TDI, were performed as part of clinical screening for eligibility for CRT. Clinical status was evaluated with New York Heart Association functional classification, 6-min walk distance, and quality-of-life score. Different parameters (histogram bandwidth, phase SD, histogram skewness, and histogram kurtosis) of LV dyssynchrony were assessed from GMPS and compared with LV dyssynchrony on TDI with Pearson's correlation analyses., Results: Histogram bandwidth and phase SD correlated well with LV dyssynchrony assessed with TDI (r = 0.89, p < 0.0001 and r = 0.80, p < 0.0001, respectively). Histogram skewness and kurtosis correlated less well with LV dyssynchrony on TDI (r = -0.52, p < 0.0001 and r = -0.45, p < 0.0001, respectively)., Conclusions: The LV dyssynchrony assessed from GMPS correlated well with dyssynchrony assessed by TDI; histogram bandwidth and phase SD showed the best correlation with LV dyssynchrony on TDI. These parameters seem most optimal for assessment of LV dyssynchrony with gated SPECT. Outcome studies after CRT are needed to further validate the use of GMPS for assessment of LV dyssynchrony.

Objectives: This study was designed to evaluate the role of cardiac resynchronization therapy (CRT) in heart failure (HF) patients with narrow QRS complexes (<120 ms) and echocardiographic evidence of mechanical asynchrony., Background: Cardiac resynchronization therapy is currently recommended to advanced HF patients with prolonged QRS duration. Echocardiographic assessment of systolic mechanical asynchrony has been proven useful to predict a favorable response after CRT., Methods: A total of 102 HF patients with New York Heart Association (NYHA) functional class III or IV were enrolled. Among them, 51 had wide QRS (>120 ms) and 51 had narrow QRS (<120 ms). Tissue Doppler imaging (TDI) was employed to select patients with systolic asynchrony (increased asynchrony index) in the narrow-QRS group. Clinical and echocardiographic assessments were performed at baseline and 3 months after CRT., Results: There was a significant reduction of left ventricular (LV) end-systolic volume in both narrow (122 +/- 42 cc vs. 103 +/- 47 cc, p < 0.001) and wide (148 +/- 74 cc vs. 112 +/- 64 cc, p < 0.001) QRS groups. Improvement of NYHA functional class (both p < 0.001), maximal exercise capacity (both p < 0.05), 6-min hall-walk distance (both p < 0.01), ejection fraction (both p < 0.001), and mitral regurgitation (both p < 0.005) was also observed. In both groups, the degree of baseline mechanical asynchrony determined LV reverse remodeling to a similar extent, as shown by the superimposed regression lines. Withholding CRT for 4 weeks resulted in loss of echocardiographic benefits., Conclusions: Cardiac resynchronization therapy for HF patients with narrow QRS complexes and coexisting mechanical asynchrony by TDI results in LV reverse remodeling and improvement of clinical status. The amplitude of benefit is similar to the wide-QRS group provided that similar extent of systolic asynchrony is selected.

Objectives: We evaluated the ability of delayed enhancement magnetic resonance imaging (DE-MRI) to predict clinical response to cardiac resynchronization therapy (CRT)., Background: Cardiac resynchronization therapy reduces morbidity and mortality in selected heart failure patients. However, up to 30% of patients do not have a response. We hypothesized that scar burden on DE-MRI predicts response to CRT., Methods: The DE-MRI was performed on 28 heart failure patients undergoing CRT. Patients with QRS > or =120 ms, left ventricular ejection fraction < or =35%, New York Heart Association functional class II to IV, and dyssynchrony > or =60 ms were studied. Baseline and 3-month clinical follow-up, wall motion, 6-min walk, and quality of life assessment were performed. The DE-MRI was performed 10 min after 0.20 mmol/kg intravenous gadolinium. Scar measured by planimetry was correlated with response criteria., Results: Twenty-three patients completed the protocol (mean age 64.9 +/- 11.7 years), with 12 (52%) having a history of myocardial infarction. Thirteen (57%) patients met response criteria. Percent total scar was significantly higher in the nonresponse versus response group (median and interquartile range of 24.7% [18.1 to 48.7] vs. 1.0% [0.0 to 8.7], p = 0.0022) and predicted nonresponse by receiver-operating characteristic analysis (area = 0.94). At a cutoff value of 15%, percent total scar provided a sensitivity and specificity of 85% and 90%, respectively, for clinical response to CRT. Similarly, septal scar < or =40% provided a 100% sensitivity and specificity for response. Regression analysis showed linear correlations between percent total scar and change in each of the individual response criteria., Conclusions: The DE-MRI accurately predicted clinical response to CRT. This technique offers unique information in the assessment of patients referred for CRT.

Objectives: We attempted to assess the efficacy of combined cardiac resynchronization therapy-implantable cardioverter-defibrillator (CRT-ICD) in heart failure patients with and without ventricular arrhythmias., Background: Because CRT and ICDs both lower all-cause mortality in patients with advanced heart failure, combination of both therapies in a single device is challenging., Methods: A total of 191 consecutive patients with advanced heart failure, left ventricular ejection fraction <35%, and a QRS duration >120 ms received CRT-ICD. Seventy-one patients had a history of ventricular arrhythmias (secondary prevention); 120 patients did not have prior ventricular arrhythmias (primary prevention). During follow-up, ICD therapy rate, clinical improvement after 6 months, and mortality rate were evaluated., Results: During follow-up (18 +/- 4 months), primary prevention patients experienced less appropriate ICD therapies than secondary prevention patients (21% vs. 35%, p < 0.05). Multivariate analysis revealed, however, no predictors of ICD therapy. Furthermore, a similar, significant, improvement in clinical parameters was observed at 6 months in both groups. Also, the mortality rate in the primary prevention group was lower than in the secondary prevention group (3% vs. 18%, p < 0.05)., Conclusions: As 21% of the primary prevention patients and 35% of the secondary prevention patients experienced appropriate ICD therapy within 2 years after implant, and no predictors of ICD therapy could be identified, implantation of a CRT-ICD device should be considered in all patients eligible for CRT.

Objectives: We aimed to determine whether intensive statin therapy reduces hospitalization for heart failure (HF) in high-risk patients., Background: While the relationship between intensive statin therapy and ischemic events is well established, its relationship to the risk of HF after an acute coronary syndrome (ACS) is not well defined., Methods: The Pravastatin or Atorvastatin Evaluation and Infection Trial-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) study randomized 4,162 patients, stabilized after ACS, to either intensive statin therapy (atorvastatin 80 mg) or moderate statin therapy (pravastatin 40 mg). Hospitalization for HF occurring more than 30 days after randomization was determined during a mean follow-up of 24 months. B-type natriuretic peptide (BNP) levels were measured at baseline (median seven days after randomization)., Results: Treatment with atorvastatin 80 mg significantly reduced the rate of hospitalization for HF (2.3% vs. 3.9%, [corrected] hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.45 to 0.91, p = 0.012) [corrected] independently of a recurrent myocardial infarction or prior history of HF. The risk of HF increased steadily with increasing quartiles of BNP (HR 2.45, 95% CI 1.33 to 4.52, p = 0.004 [corrected] for the highest quartile compared with the lowest). Among patients with elevated levels of BNP (>80 pg/ml), treatment with atorvastatin significantly reduced the risk of HF compared with pravastatin (HR 0.50, 95% CI 0.27 to 0.93, p = 0.028). [corrected]. A meta-analysis of four trials that included 27,546 patients demonstrates a 27% reduction in the odds of hospitalization for HF with intensive statin therapy., Conclusions: Intensive statin therapy reduces the risk of hospitalization for HF after ACS with the most gain in patients with elevated levels of BNP.

Objectives: We evaluated the impact of treatment crossovers on study results in the Mode Selection Trial (MOST)., Background: The MOST study, a 2,010-patient, 6-year trial comparing dual-chamber pacing (DDDR) and ventricular pacing (VVIR) in sinus node dysfunction, demonstrated no difference in death or stroke and modest reductions in heart failure hospitalization (HFH) and atrial fibrillation (AF) with DDDR pacing. However, a moderate proportion of VVIR-randomized patients were temporarily or permanently crossed over to DDDR pacing., Methods: Intent-to-treat (ITT) analyses compared treatment arms by randomized pacing mode. On-treatment analyses used time-dependent covariates to account for all crossovers. All analyses used Cox proportional hazards models and included covariates prespecified in the study design: age, gender, Charlson index, and prior stroke, heart failure, myocardial infarction, supraventricular tachyarrhythmia, and ventricular tachycardia or fibrillation., Results: Of 996 VVIR-randomized patients, 375 (38%) were DDDR paced at some time, accounting for 27% of follow-up days among all VVIR-randomized patients. Of 1,014 DDDR-randomized patients, 53 (5%) were VVIR paced at some time, accounting for 1.5% of follow-up days among all DDDR-randomized patients. On-treatment analyses showed slightly lower hazard ratios favoring DDDR versus VVIR compared with ITT: death or stroke 0.88 (on-treatment) versus 0.91 (ITT); death 0.94 versus 0.95; stroke 0.74 versus 0.81; HFH 0.72 versus 0.73; and AF 0.72 versus 0.77. Interpretation of treatment effects was unchanged., Conclusions: Although treatment crossovers accounted for >25% of follow-up time in the VVIR-randomized group, this did not affect study results. End point comparisons between randomized modes are accurate reflections of DDDR versus VVIR pacing in this study population.

Objectives: This study was designed to investigate the loss of well-being, in terms of life-years, overall and in patients randomized to metoprolol versus carvedilol in the Carvedilol Or Metoprolol European Trial (COMET)., Background: The ultimate objectives of treating patients with heart failure are to relieve suffering and prolong life. Although the effect of treatment on mortality is usually described in trials, the effects on patient well-being throughout the trials' courses are rarely reported., Methods: A total of 3,029 patients randomized in the COMET study were included in the analysis. "Patient journey" was calculated by adjusting days alive and out of hospital over four years using a five-point score completed by the patient every four months, adjusted according to the need for intensification of diuretic therapy. Scores ranged from 0% (dead or hospitalized) to 100% (feeling very well)., Results: Over 48 months, 17% of all days were lost through death, 1% through hospitalization, 23% through impaired well-being, and 2% through the need for intensified therapy. Compared with metoprolol, carvedilol was associated with fewer days lost to death, with no increase in days lost due to impaired well-being or days in hospital. The "patient journey" score improved from a mean of 54.8% (SD 26.0) to 57.4% (SD 26.3%) (p < 0.0068)., Conclusions: Despite treatment with beta-blockers, heart failure remains associated with a marked reduction in well-being and survival. Loss of quality-adjusted life-years through death and poor well-being seemed of similar magnitude over four years, and both were much larger than the loss that could be attributed to hospitalization.

Objectives: The purpose of this research was to evaluate right ventricular (RV) remodeling after six months of cardiac resynchronization therapy (CRT)., Background: Cardiac resynchronization therapy is beneficial in patients with end-stage heart failure. The effect of CRT on RV size is currently unknown. Accordingly, the effects of CRT on RV size, severity of tricuspid regurgitation, and pulmonary artery pressure were evaluated., Methods: Fifty-six consecutive patients with end-stage heart failure (52% ischemic cardiomyopathy), left ventricular (LV) ejection fraction (EF) < or =35%, QRS duration >120 ms, and left bundle branch block were included. Clinical parameters, LV volumes, LVEF, LV dyssynchrony, and RV chamber size were assessed at baseline and after six months of CRT; LV dyssynchrony was assessed using tissue Doppler imaging., Results: Clinical parameters improved significantly; LV dyssynchrony was acutely reduced after CRT and remained unchanged at six-month follow-up. Left ventricular EF improved significantly from 19 +/- 6% to 26 +/- 8% (p < 0.001), and LV end-diastolic volume decreased from 257 +/- 98 ml to 227 +/- 86 ml (p < 0.001). Right ventricular annulus decreased significantly from 37 +/- 9 mm to 32 +/- 10 mm, RV short-axis from 29 +/- 11 mm to 26 +/- 7 mm, and RV long-axis from 89 +/- 11 mm to 82 +/- 10 mm (all p < 0.001). Left ventricular and RV reverse remodeling were only observed in patients with substantial LV dyssynchrony at baseline. Finally, significant reductions in severity of tricuspid regurgitation and pulmonary artery pressure were observed., Conclusions: Cardiac resynchronization therapy results in significant reverse LV and RV remodeling after six months of CRT in patients with LV dyssynchrony. Moreover, CRT leads to a reduction of the severity of tricuspid regurgitation and a decrease in pulmonary artery pressure.

Cardiac resynchronization therapy has been shown to be an effective treatment for patients with systolic ventricular dysfunction, prolonged (>120 ms) QRS duration, and New York Heart Association (NYHA) functional class III or IV symptoms despite optimal medical therapy. However, studies show that a majority of heart failure patients have QRS duration <120 ms. We have been investigating the potential utility of cardiac contractility modulating (CCM) signals as a treatment option for such patients. Cardiac contractility modulating signals are non-excitatory signals applied during the absolute refractory period using a pacemaker-like device that connects to the heart with pacemaker leads. Acute studies carried out in animals and humans with heart failure suggest that CCM signals can enhance the strength of left ventricular contraction. Results of initial long-term studies designed mainly to demonstrate feasibility and provide preliminary indication of safety in patients with medically refractory NYHA functional class III heart failure are summarized. The results of these preclinical and clinical studies formed the basis for proceeding with two prospective, randomized clinical studies currently underway to definitively test the safety and efficacy of this treatment.

Cardiac resynchronization therapy (CRT) devices have been studied clinically since 1998, and have been on the U.S. market since the Food and Drug Administration (FDA) approval of the first product in 2001. Since that time, the FDA has approved many different models from three different manufacturers, representing the first and second generations of these products. All of these products have undergone the FDA pre-market approval process, which examines the safety and effectiveness of the devices for their intended use. Over the last several years, the FDA has adapted recommendations for CRT clinical trials based on an evolving understanding of what these devices can achieve. This paper will outline the dynamic nature of the FDA's approval process for CRT devices and briefly review the clinical trial designs for the first generation devices.

Patients with chronic heart failure might benefit from electrical therapy with a view to resynchronize the heart and improve its mechanical performance by cardiac resynchronization therapy (CRT) or to prevent the risk of sudden death by automatic defibrillation. These two therapies can be applied separately or with a combined device, the biventricular implantable cardioverter-defibrillator (CRT-D). There is currently no strong scientific evidence indicating that a CRT-D must be offered to all candidates for CRT. Plain common sense should limit the prescription of these costly devices for patients in need of secondary prevention or for younger patients without major comorbidities. The preferential choice of CRT pacemakers in the remainder of patients is currently a logical one.

Objectives: This study compared cardiac resynchronization therapy's (CRT) impact on ventricular tachyarrhythmia susceptibility in patients who, due to worsening heart failure (HF) symptoms, underwent a replacement of a conventional implantable cardioverter-defibrillator (ICD) with a CRT-ICD., Background: Cardiac resynchronization therapy is an effective addition to conventional treatment of HF in many patients with left ventricular systolic dysfunction. However, whether CRT-induced improvements in HF status also reduce susceptibility to life-threatening arrhythmias is less certain., Methods: Clinical and ICD electrogram data were evaluated in 18 consecutive ICD patients who underwent an upgrade to CRT-ICD. Pharmacologic HF therapy was not altered during follow-up. The definition of ventricular tachycardia (VT) and ventricular fibrillation (VF) for each patient was as determined by device programming. Statistical comparisons used paired t tests., Results: Findings were recorded during two time periods: 47 +/- 21 months (range 24 to 70 months) before and 14 +/- 2 months (range 9 to 18 months) after CRT upgrade. At time of upgrade, patient age was 69 +/- 11 years and ejection fraction was 21 +/- 8%. Before CRT the frequency of VT, VF, and appropriate ICD shocks was 0.31 +/- 1.23, 0.047 +/- 0.083, and 0.048 +/- 0.085 episodes/month/patient, respectively. After CRT-ICD, VT and VF arrhythmia burdens and frequency of shocks were respectively 0.13 +/- 0.56, 0.001 +/- 0.004, and 0.003 +/- 0.016 episodes/month/patient (p = 0.59, 0.03, and 0.05 vs. pre-CRT)., Conclusions: Arrhythmia frequency and number of appropriate ICD treatments were reduced after upgrade to CRT-ICD for HF treatment. Thus, apart from hemodynamic benefits, CRT may also ameliorate ventricular tachyarrhythmia susceptibility in HF patients.

Cardiac resynchronization therapy (CRT) is an established adjunctive treatment for patients with systolic heart failure (HF) and ventricular dyssynchrony. The majority of recipients respond to CRT with improvements in quality of life, New York Heart Association functional class, 6-min walk test, and ventricular function. Management of HF after CRT may include up-titration of neurohormonal blockade and an exercise prescription through cardiac rehabilitation to further improve and sustain clinical outcomes. Diagnostic data provided by the CRT device may help to facilitate and optimize treatment. Initial nonresponder rates remain problematic. We suggest a simple step-by-step management and troubleshooting strategy that integrates device function with advanced HF therapy in patients who do not initially respond to CRT. This algorithm represents a new, comprehensive, collaborative approach between the HF and electrophysiology specialists to further improve and sustain outcomes in the field of CRT.

Objectives: The analysis goal was to estimate incremental cost-effectiveness ratios (ICERs) for the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial patients who received cardiac resynchronization therapy (CRT) via pacemaker (CRT-P) or pacemaker-defibrillator (CRT-D) in combination with optimal pharmacological therapy (OPT) relative to patients with OPT alone., Background: In the COMPANION trial, CRT-P and CRT-D reduced the combined risk of all-cause mortality or first hospitalization among patients with advanced heart failure and intraventricular conduction delays, but the cost effectiveness of the therapy remains unknown., Methods: In this analysis, intent-to-treat trial data were modeled to estimate the cost effectiveness of CRT-D and CRT-P relative to OPT over a base-case seven-year treatment episode. Exponential survival curves were derived from trial data and adjusted by quality-of-life trial results to yield quality-adjusted life-years (QALYs). For the first two years, follow-up hospitalizations were based on trial data. The model assumed equalized hospitalization rates beyond two years. Initial implantation and follow-up hospitalization costs were estimated using Medicare data., Results: Over two years, follow-up hospitalization costs were reduced by 29% for CRT-D and 37% for CRT-P. Extending the cost-effectiveness analysis to a seven-year base-case time period, the ICER for CRT-P was 19,600 dollars per QALY and the ICER for CRT-D was 43,000 dollars per QALY relative to OPT., Conclusions: For the COMPANION trial patients, the use of CRT-P and CRT-D was associated with a cost-effectiveness ratio below generally accepted benchmarks for therapeutic interventions of 50,000 dollars per QALY to 100,000 dollars per QALY. This suggests that the clinical benefits of CRT-P and CRT-D can be achieved at a reasonable cost.

Objectives: To determine the short-term effects of cardiac resynchronization therapy (CRT) on measurements of left ventricular (LV) diastolic function in patients with severe heart failure., Background: Cardiac resynchronization therapy improves systolic performance; however, the effects on diastolic function by load-dependent pulsed-wave Doppler transmitral indices has been variable., Methods: Fifty patients with severe heart failure were evaluated by two-dimensional Doppler echocardiography immediately prior to and 4 +/- 1 month after CRT. Measurements included LV volumes and ejection fraction (EF), pulsed-wave Doppler (PWD)-derived transmitral filling indices (E- and A-wave velocities, E/A ratio, deceleration time [DT], diastolic filling time [DFT], and isovolumic relaxation time). Tissue Doppler imaging was used for measurements of systolic and diastolic (Em) velocities at four mitral annular sites; mitral E-wave/Em ratio was calculated to estimate LV filling pressure. Color M-mode flow propagation velocities were also obtained., Results: After CRT, LV volumes decreased significantly (p < 0.001) and LVEF increased >5% in 28 of 50 patients (56%) and were accompanied by reduction in PWD mitral E-wave velocity and E/A ratio (both p < 0.01), increased DT and DFT (both p < 0.01), and lower filling pressures (i.e., E-wave/Em septal; p < 0.01). Patients with LVEF response < or =5% after CRT had no significant changes in measurements of diastolic function; LV relaxation (i.e., Em velocities) worsened in this group., Conclusions: In heart failure patients receiving CRT, improvement in LV diastolic function is coupled to the improvement in LV systolic function.

Encouraged by the clinical success of cardiac resynchronization therapy (CRT), the implantation rate has increased exponentially, although several limitations and unresolved issues of CRT have been identified. This review concerns issues that are encountered during implantation of CRT devices, including the role of electroanatomical mapping, whether CRT implantation should be accompanied by simultaneous atrioventricular nodal ablation in patients with atrial fibrillation, procedural complications, and when to consider surgical left ventricular lead positioning. Furthermore, (echocardiographic) CRT optimization and assessment of CRT benefits after implantation are highlighted. Also, controversial issues such as the potential value of CRT in patients with mild heart failure or narrow QRS complex are addressed. Finally, open questions concerning when to combine CRT with implantable cardioverter-defibrillator therapy and the cost-effectiveness of CRT are discussed.

Despite the numerous documented benefits of cardiac resynchronization therapy (CRT), a significant proportion of patients undergoing CRT do not demonstrate symptomatic or morphologic improvement, triggering the search to improve targeting of this therapy. Many studies now support direct assessment of mechanical dyssynchrony as a method to better identify CRT responders. Among the methods used, echo-Doppler imaging has taken center stage and is covered in other articles in this special issue; however, these methods have several inherent limitations, and other alternatives are also being explored such as magnetic resonance imaging (MRI). This review discusses the concepts and clinical use of MRI methods for quantitative assessment of mechanical dyssynchrony, highlighting newer acquisition and analysis methods and focusing on how the data can be synthesized into robust indexes of dyssynchronous heart failure.

Objectives: The InSync III study evaluated sequential cardiac resynchronization therapy (CRT) in patients with moderate-to-severe heart failure and prolonged QRS., Background: Simultaneous CRT improves hemodynamic and clinical performance in patients with moderate-to-severe heart failure (HF) and a wide QRS. Recent evidence suggests that sequentially stimulating the ventricles might provide additional benefit., Methods: This multicenter, prospective, nonrandomized, six-month trial enrolled a total of 422 patients to determine the effectiveness of sequential CRT in patients with New York Heart Association (NYHA) functional class III or IV HF and a prolonged QRS. The study evaluated: whether patients receiving sequential CRT for six months experienced improvement in 6-min hall walk (6MHW) distance, NYHA functional class, and quality of life (QoL) over control group patients from the reported Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial; whether sequential CRT increased stroke volume compared to simultaneous CRT; and whether an increase in stroke volume translated into greater clinical improvements compared to patients receiving simultaneous CRT., Results: InSync III patients experienced greater improvement in 6MHW, NYHA functional class, and QoL at six months compared to control (all p < 0.0001). Optimization of the sequential pacing increased (median 7.3%) stroke volume in 77% of patients. No additional improvement in NYHA functional class or QoL was seen compared to the simultaneous CRT group; however, InSync III patients demonstrated greater exercise capacity., Conclusions: Sequential CRT provided most patients with a modest increase in stroke volume above that achieved during simultaneous CRT. Patients receiving sequential CRT had improved exercise capacity, but no change in functional status or QoL.

Objectives: The aim of this study was to test the hypothesis that a longer septal-to-posterior wall motion delay (SPWMD) would predict greater reverse remodeling and an improved clinical response in heart failure patients randomized to cardiac resynchronization therapy (CRT) in the CONTAK-CD trial., Background: The SPWMD predicted clinical benefit with CRT in two previous studies from the same center., Methods: In this retrospective analysis of the CONTAK-CD trial, SPWMD was measured from the baseline echocardiogram of 79 heart failure patients (ejection fraction 22 +/- 7%, QRS duration 159 +/- 27 ms, 72% ischemic, 84% male) randomized to CRT and compared with six-month changes in echocardiographic and clinical parameters. Patients with a left ventricular end-systolic volume index (LVESVI) reduction of at least 15% were considered responders., Results: The feasibility and reproducibility of performing the SPWMD measurements were poor. Larger values for SPWMD did not correlate with six-month changes in left ventricular end-diastolic volume index (p = 0.26), LVESVI (p = 0.41), or left ventricular ejection fraction (p = 0.36). Responders did not have a significantly different SPWMD than non-responders (p = 0.26). The SPWMD did not correlate with measures of clinical improvement. At a threshold of SPWMD >130 ms, the test characteristics to predict reverse remodeling or a clinical response were inadequate., Conclusions: The previous findings that SPWMD predicts reverse remodeling or clinical improvement with CRT were not reproducible in patients randomized in the CONTAK-CD trial.

Objectives: The aim of this study was to evaluate the mode of death in patients with advanced chronic heart failure (HF) and intraventricular conduction delay treated with optimal pharmacologic therapy (OPT) alone or OPT with biventricular pacing to provide cardiac resynchronization therapy (CRT) or CRT + an implantable defibrillator (CRT-D)., Background: Limited data are available on mode of death in advanced HF. No data have existed on mode of death in these patients who also have an intraventricular conduction delay and are treated with CRT or CRT-D., Methods: Using prespecified definitions and source materials, seven cardiologists assessed mode of death among the 313 deaths that occurred in the Comparison of Medical, Pacing, and Defibrillation Therapies in Heart Failure (COMPANION) trial., Results: A primary cardiac cause was present in 78% of deaths. Pump failure (44.4%) was the most common mode of death followed by sudden cardiac death (SCD) (26.5%). Compared with OPT, CRT-D significantly reduced the number of cardiac deaths (38%, p = 0.006), whereas CRT alone was associated with a non-significant 14.5% reduction (p = 0.33). Both CRT and CRT-D tended to reduce pump failure deaths (29%, p = 0.11 and 27%, p = 0.14, respectively). The CRT-D significantly reduced SCD (56%, p = 0.02), but CRT alone did not., Conclusions: Pump failure deaths are the predominant mode of death in patients with advanced HF and are modestly reduced by both CRT and CRT-D. Only CRT-D reduced SCD and thus produced a favorable effect on cardiac mortality.

Objectives: The purpose of this study was to evaluate the safety of implanting a cardiac resynchronization therapy (CRT) system., Background: Clinicians and patients require data on the safety of the CRT implant procedure to estimate procedural risk., Methods: We evaluated outcomes of transvenous CRT system implantation in 2,078 patients from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study, the MIRACLE Implantable Cardioverter-Defibrillator (ICD) study, and the InSync III study. We compared the MIRACLE study to the InSync III study and the MIRACLE ICD study randomized phase to its general phase to evaluate the effect of new technologies., Results: The implant attempt succeeded in 1,903 of 2,078 (91.6%) patients. Implant time decreased from 2.7 h in the MIRACLE study to 2.3 h in the InSync III study (p < 0.001), and from 2.8 h in the MIRACLE ICD study randomized phase to 2.4 h in the general phase (p < 0.001). The implant procedure produced 62 perioperative complications in 53 (9.3%) MIRACLE trial patients; 159 in 135 (21.1%) MIRACLE ICD study randomized phase patients and 71 in 62 (13.9%) general phase patients (p < 0.05 vs. randomized); and 41 in 37 (8.8%) InSync III study patients (p = NS vs. the MIRACLE study). We observed 73 postoperative complications in 62 (11.7%) MIRACLE trial patients, 77 in 68 (11.9%) MIRACLE ICD study randomized phase patients and 56 in 45 (11.0%) general phase patients (p = NS), and 37 in 34 (8.6%) InSync III study patients (p = NS). A total of 8% of patients required reoperation to treat lead dislodgement, extracardiac stimulation, or infection during follow-up., Conclusions: Transvenous CRT system implantation appears safe, well-tolerated, has a high success rate, and improves with operator experience and the addition of new technologies.

Previous trials of cardiac resynchronization therapy (CRT) have suggested that this therapy can significantly improve functional class and exercise capacity during short-term follow-up. The impact of this therapy on morbidity and mortality has only recently been reported. The Cardiac Resynchronization-Heart Failure (CARE-HF) study has definitively shown that CRT significantly reduces mortality (36%, p < 0.002) in patients with NYHA functional class III and IV heart failure and ventricular dyssynchrony. This study also shows that CRT reverses ventricular remodeling and improves myocardial performance progressively for at least 18 months. In heart failure patients, the CARE-HF and Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) (the earlier major morbidity/mortality trial) studies together show the unequivocal benefit for CRT therapy and CRT therapy with back-up defibrillation to significantly reduce mortality and hospitalization compared with optimal medical therapy. Both studies suggest the benefit of adding the implantable cardiac defibrillator to CRT devices, as over one-third of deaths in the CRT-pacemaker arm of both the COMPANION and CARE-HF studies were sudden.

Cardiac resynchronization therapy (CRT) has been used extensively over the last years in the therapeutic management of patients with end-stage heart failure. Data from 4,017 patients have been published in eight large, randomized trials on CRT. Improvement in clinical end points (symptoms, exercise capacity, quality of life) and echocardiographic end points (systolic function, left ventricular size, mitral regurgitation) have been reported after CRT, with a reduction in hospitalizations for decompensated heart failure and an improvement in survival. However, individual results vary, and 20% to 30% of patients do not respond to CRT. At present, the selection criteria include severe heart failure (New York Heart Association functional class III or IV), left ventricular ejection fraction <35%, and wide QRS complex (>120 ms). Assessment of inter- and particularly intraventricular dyssynchrony as provided by echocardiography (predominantly tissue Doppler imaging techniques) may allow improved identification of potential responders to CRT. In this review a summary of the clinical and echocardiographic results of the large, randomized trials is provided, followed by an extensive overview on the currently available echocardiographic techniques for assessment of LV dyssynchrony. In addition, the value of LV scar tissue and venous anatomy for the selection of potential candidates for CRT are discussed.

Objectives: The purpose of this research was to investigate the effect of using rate-adaptive pacing and atrioventricular interval (AVI) adaptation on exercise performance during cardiac resynchronization therapy (CRT)., Background: The potential incremental benefits of using rate-adaptive pacing and AVI adaptation with CRT during exercise have not been studied., Methods: We studied 20 patients with heart failure, chronotropic incompetence (<85% age-predicted heart rate [AP-HR] and <80% HR reserve), and implanted with CRT. All patients underwent a cardiopulmonary exercise treadmill test using DDD mode with fixed AVI (DDD-OFF), DDD mode with adaptive AVI on (DDD-ON), and DDDR mode with adaptive AVI on (DDDR-ON) to measure metabolic equivalents (METs) and peak oxygen consumption (VO2max)., Results: During DDD-OFF mode, not all patients reached 85% AP-HR during exercise, and 55% of patients had <70% AP-HR. Compared to patients with >70% AP-HR, patients with <70% AP-HR had significantly lower baseline HR (66 +/- 3 beats/min vs. 80 +/- 5 beats/min, p = 0.015) and percentage HR reserve (27 +/- 5% vs. 48 +/- 6%, p = 0.006). In patients with <70% AP-HR, DDDR-ON mode increased peak exercise HR, exercise time, METs, and VO2max compared with DDD-OFF and DDD-ON modes (p < 0.05), without a significant difference between DDD-OFF and DDD-ON modes. In contrast, there were no significant differences in peak exercise HR, exercise time, METs, and VO2max among the three pacing modes in patients with >70% AP-HR. The percentage HR changes during exercise positively correlated with exercise time (r = 0.67, p < 0.001), METs (r = 0.56, p < 0.001), and VO2max (r = 0.55, p < 0.001)., Conclusions: In heart failure patients with severe chronotropic incompetence as defined by failure to achieve >70% AP-HR, appropriate use of rate-adaptive pacing with CRT provides incremental benefit on exercise capacity during exercise.

Prolongation of QRS (> or =120 ms) occurs in 14% to 47% of heart failure (HF) patients. Left bundle branch block is far more common than right bundle branch block. Left-sided intraventricular conduction delay is associated with more advanced myocardial disease, worse left ventricular (LV) function, poorer prognosis, and a higher all-cause mortality rate compared with narrow QRS complex. It also predisposes heart failure patients to an increased risk of ventricular tachyarrhythmias, but the incidence of cardiac or sudden death remains unclear because of limited observations. A progressive increase in QRS duration worsens the prognosis. No electrocardiographic measure is specific enough to provide subgroup risk categorization for excluding or selecting HF patients for prophylactic implantable cardioverter-defibrillator (ICD) therapy. In ICD patients with HF, a wide underlying QRS complex more than doubles the cardiac mortality compared with a narrow QRS complex. There is a high incidence of an elevated defibrillation threshold at the time of ICD implantation in patients with QRS > or =200 ms. Mechanical LV dyssynchrony potentially treatable by ventricular resynchronization occurs in about 70% of HF patients with left-sided intraventricular conduction delay, a fact that would explain the lack of therapeutic response in about 30% of patients subjected to ventricular resynchronization according to standard criteria relying on QRS duration. The duration of the basal QRS complex does not reliably predict the clinical response to ventricular resynchronization, and QRS narrowing after cardiac resynchronization therapy does not correlate with hemodynamic and clinical improvement. Mechanical LV dyssynchrony is best shown by evolving echocardiographic techniques (predominantly tissue Doppler imaging) currently in the process of standardization.

Objectives: We sought to identify whether home telemonitoring (HTM) improves outcomes compared with nurse telephone support (NTS) and usual care (UC) for patients with heart failure who are at high risk of hospitalization or death., Background: Heart failure is associated with a high rate of hospitalization and poor prognosis. Telemonitoring could help implement and maintain effective therapy and detect worsening heart failure and its cause promptly to prevent medical crises., Methods: Patients with a recent admission for heart failure and left ventricular ejection fraction (LVEF) <40% were assigned randomly to HTM, NTS, or UC in a 2:2:1 ratio. HTM consisted of twice-daily patient self-measurement of weight, blood pressure, heart rate, and rhythm with automated devices linked to a cardiology center. The NTS consisted of specialist nurses who were available to patients by telephone. Primary care physicians delivered UC. The primary end point was days dead or hospitalized with NTS versus HTM at 240 days., Results: Of 426 patients randomly assigned, 48% were aged >70 years, mean LVEF was 25% (SD, 8) and median plasma N-terminal pro-brain natriuretic peptide was 3,070 pg/ml (interquartile range 1,285 to 6,749 pg/ml). During 240 days of follow-up, 19.5%, 15.9%, and 12.7% of days were lost as the result of death or hospitalization for UC, NTS, and HTM, respectively (no significant difference). The number of admissions and mortality were similar among patients randomly assigned to NTS or HTM, but the mean duration of admissions was reduced by 6 days (95% confidence interval 1 to 11) with HTM. Patients randomly assigned to receive UC had higher one-year mortality (45%) than patients assigned to receive NTS (27%) or HTM (29%) (p = 0.032)., Conclusions: Further investigation and refinement of the application of HTM are warranted because it may be a valuable role for the management of selected patients with heart failure.

Objectives: We evaluated the six-month clinical trajectory of patients hospitalized for heart failure (HF) with preserved ejection fraction (EF), as the natural history of this condition has not been well established. We compared mortality, hospital readmission, and changes in functional status in patients with preserved versus depressed EF., Background: Although the poor prognosis of HF with depressed EF has been extensively documented, there are only limited and conflicting data concerning clinical outcomes for patients with preserved EF., Methods: We prospectively evaluated 413 patients hospitalized for HF to determine whether EF >or=40% was an independent predictor of mortality, readmission, and the combined outcome of functional decline or death., Results: After six months, 13% of patients with preserved EF died, compared with 21% of patients with depressed EF (p = 0.02). However, the rates of functional decline were similar among those with preserved and depressed EF (30% vs. 23%, respectively; p = 0.14). After adjusting for demographic and clinical covariates, preserved EF was associated with a lower risk of death (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.26 to 0.90; p = 0.02), but there was no difference in the risk of readmission (HR 1.01, 95% CI 0.72 to 1.43; p = 0.96) or the odds of functional decline or death (OR 1.01, 95% CI 0.59 to 1.72; p = 0.97)., Conclusions: Heart failure with preserved EF confers a considerable burden on patients, with the risk of readmission, disability, and symptoms subsequent to hospital discharge, comparable to that of HF patients with depressed EF.

Objectives: This study sought to compare the short- and long-term outcomes of elderly patients undergoing coronary artery stenting with those of younger patients and to determine the long-term clinical outcome and survival of elderly patients post stent implantation., Background: Elderly patients undergoing coronary revascularization are considered a high-risk group. Few data exist that relate the results of stenting in treating coronary artery disease in the elderly population., Methods: All elderly patients >75 years of age who underwent coronary artery stenting between March 1993 and July 1997 (n=137) at our center were compared to the patients <75 who underwent coronary artery stenting during the same time period (n=2,551). Long-term clinical follow-up and survival were determined for the elderly group., Results: Elderly patients presented with lower ejection fractions (54% vs. 58%, p=0.0001), more unstable angina (47% vs. 28%, p=0.0001), and more multivessel disease (78% vs. 62%, p= 0.0001) than younger patients. These older patients had higher rates of procedure related complications including procedural myocardial infarction (MI) (2.9% vs. 1.7%, p=0.2), emergency CABG (3.7% vs. 1.4%, p=0.04), and death (2.2% vs. 0.12%, p=0.0001). Angiographic follow-up, obtained in both groups, demonstrated significantly higher restenosis rates in the elderly versus younger patients (47% vs. 28%, p=0.0007). Longer term clinical follow-up, which was obtained only in the elderly group, showed that at a mean follow-up period of 12 months post coronary stenting, elderly survival free from death, MI, revascularization and angina was 54% and that their overall survival was 91%. Subanalysis of the elderly patients who died showed much higher incidence of combined unstable angina (80%), prior MI (60%), lower ejection fraction (46%), multivessel disease (100%) and complex lesions (100%) than the overall group., Conclusions: Elderly patients who undergo coronary artery stenting have significantly higher rates of procedural complications and worse six month outcomes than younger patients, especially those who present with combined unstable angina, history of MI, EF < 50%, multivessel disease and complex lesions. Overall survival in the elderly population at 12 months postcoronary artery stenting was 91% and event-free survival was 54%.