Rationale and design of an implant procedure and pivotal study to evaluate safety and effectiveness of Medtronic's tibial neuromodulation device.

Percutaneous tibial neuromodulation is a medical guideline recommended therapy for treating symptoms of overactive bladder. Stimulation is delivered to the tibial nerve via a thin needle placed percutaneously for 30 min once a week for 12-weeks, and monthly thereafter. Studies have shown that this therapy can effectively relieve symptoms of overactive bladder; however, the frequent office visits present a barrier to patients and can impact therapy effectiveness. To mitigate the burden of frequent clinic visits, small implantable devices are being developed to deliver tibial neuromodulation. These devices are implanted during a single minimally invasive procedure and deliver stimulation intermittently, similar to percutaneous tibial neuromodulation. Here, we describe the implant procedure and design of a pivotal study evaluating the safety and effectiveness for an implantable tibial neuromodulation device. The Evaluation of Implantable Tibial Neuromodulation (TITAN 2) pivotal study is a prospective, multicenter, investigational device exemption study being conducted at up to 30 sites in the United States and enrolling subjects with symptoms of overactive bladder.

Does change in device detected frequency of non-sustained or diverted episodes serve as a marker for inappropriate shock therapy? Analyses from the INTRINSIC RV and ALTITUDE-REDUCES Trials.

AIMS: Implantable cardioverter-defibrillators (ICDs) treat ventricular tachycardia or fibrillation but may also deliver unnecessary shocks. We sought to determine if the frequency of ICD-detected non-sustained or diverted (NSD) episodes increases before appropriate or inappropriate ICD shocks. METHODS AND RESULTS: We evaluated NSD episodes in the INTRINSIC RV Trial and their relationship to ICD shocks (appropriate and inappropriate). Time from NSD to shock was analysed. Results were validated by utilizing 1495 adjudicated ICD and cardiac resynchronization therapy-defibrillator shocks following NSD episodes collected through the LATITUDE remote monitoring system as part of the ALTITUDE-REDUCES Study. In INTRINSIC RV, 185 participants received 373 shocks; 148 had at least 1 NSD episode. Non-sustained or diverted frequency increased 24 h before the first shock for those receiving an inappropriate (P < 0.01) but not an appropriate shock (P = 0.17). Patients with NSD episodes within 24 h of a shock were significantly more likely to receive inappropriate therapy [odds ratio (OR) = 3.12, P < 0.01]. At the receiver operator curve determined optimal cutoff, an NSD episode within 14 min before shock strongly predicted inappropriate therapy (sensitivity 48%, specificity 91%; OR = 8.8, and P < 0.001). The 14 min cut-off evaluated on an independent dataset of 1495 shock episodes preceded by an NSD in the ALTITUDE-REDUCES Study confirmed these results (sensitivity = 47%, specificity = 85%, OR = 5.0, and P < 0.001). CONCLUSION: Device-detected NSD episodes increase before inappropriate but not appropriate shocks. Novel alerts or automated algorithms based on NSD episodes may reduce inappropriate shocks.

Atrial support pacing in heart failure: results from the multicenter PEGASUS CRT trial.

INTRODUCTION: Cardiac resynchronization therapy (CRT) efficacy trials to date used atrial-synchronous biventricular pacing wherein there is no or minimal atrial pacing. However, bradycardia and chronotropic incompetence are common in this patient population. This trial was designed to evaluate the effect of atrial support pacing among heart failure patients receiving a CRT defibrillator. METHODS AND RESULTS: PEGASUS CRT was a multicenter, 3-arm, randomized study. At 6 weeks, patients were randomized to DDD mode at a lower rate of 40 bpm (DDD-40; control arm), or one of the following 2 treatment arms: DDD-70, or DDDR-40. The primary endpoint was a clinical composite endpoint that included all-cause mortality, heart failure events, NYHA functional class, and patient global self-assessment. Subjects were classified as improved, unchanged, or worsened at 12 months. There were 1,433 patients randomized, of whom 66% were male, mean age was 67 ± 11 years, and mean left ventricular ejection fraction was 23 ± 7%. The average follow-up time was 10.5 ± 3.5 months and 1,309 patients contributed to the primary endpoint. No significant differences were observed in the composite endpoint between either of the 2 treatment arms compared to the control arm (P>0.05 for both comparisons). Additionally, there were no differences among the groups in mortality or heart failure events. CONCLUSION: In advanced heart failure patients treated with CRT, atrial support pacing did not improve clinical outcomes compared to atrial tracking. However, atrial pacing did not adversely affect mortality or heart failure events.

Arrhythmia rate distribution and tachyarrhythmia therapy in an ICD population: results from the INTRINSIC RV trial.

BACKGROUND: Appropriate implantable cardioverter-defibrillator (ICD) therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) depends, in part, on the programming of tachycardia zones. OBJECTIVE: We assessed events treated with ICD shocks or antitachycardia pacing (ATP) in the Inhibition of Unnecessary RV Pacing with AV Search Hysteresis in ICDs (INTRINSIC RV) trial. METHODS: ATP and shock episodes from 1530 patients with dual-chamber ICDs were analyzed. RESULTS: For episodes in which electrograms were stored and adjudicated, ATP was delivered for 763 episodes (182 patients), shock-only was delivered for 300 episodes (146 patients), and shock following ATP was delivered for 81 episodes (56 patients). ATP was delivered appropriately for 507 episodes (130 patients), with 93% success, and inappropriately for 256 episodes (89 patients). For ATP episodes, appropriate (VT: 170 ± 28 bpm) and inappropriate (not VT: 165 ± 21 bpm) rates did not differ (P = .16). When the initial therapy was shock, onset rates were higher for appropriate therapy than for inappropriate therapy (224 ± 46 bpm vs 187 ± 31 bpm; P <.001). Inappropriate ATP was more likely to be followed by a shock (odds ratio 2.49; 95% confidence interval 1.56-3.97; P <.001). Fifty-eight percent (225 of 381) of shocked episodes had rates <200 bpm. For episodes between 200 and 250 bpm, 20% (23 of 113) were polymorphic VT or VF, 59% were monomorphic VT, 19% were supraventricular, and <1% was artifact. For episodes >250 bpm, 37% were VF, 28% polymorphic VT, 23% monomorphic VT, 7% supraventricular, and 5% artifact. CONCLUSIONS: In a general ICD population, ATP treated VT effectively or obviated the need for shock. Most ventricular arrhythmias <250 bpm were not VF. Proper zone programming may identify and treat VT without shock.

Design and rationale of the assessment of proper physiologic response with rate adaptive pacing driven by minute ventilation or accelerometer (APPROPRIATE) trial.

Rate-adaptive sensors are designed to restore a physiologic heart rate response to activity, in particular for patients that have chronotropic incompetence (CI). Limited data exist comparing two primary types of sensors; an accelerometer (XL) sensor which detects activity or motion and a minute ventilation (MV) sensor, which detects the product of respiration rate and tidal volume. The APPROPRIATE study will evaluate the MV sensor compared with the XL sensor for superiority in improving functional capacity (peak VO(2)) in pacemaker patients that have CI. This study is a double-blind, randomized, two-arm trial that will enroll approximately 1,000 pacemaker patients. Patients will complete a 6-min walk test at the 2-week visit to screen for potential CI. Those projected to have CI will advance to a 1-month visit. At the 1-month visit, final determination of CI will be done by completing a peak exercise treadmill test while the pacemaker is programmed to DDDR with the device sensors set to passive. Patients failing to meet the study criteria for CI will not continue further in the trial. Patients that demonstrate CI will be randomized to program their rate-adaptive sensors to either MV or XL in a 1:1 ratio. The rate-adaptive sensor will be optimized for each patient using a short walk to determine the appropriate response factor. At a 2-month visit, patients will complete a CPX test with the rate-adaptive sensors in their randomized setting.

Heart rate predicts outcomes in an implantable cardioverter-defibrillator population.

BACKGROUND: Elevated heart rate (HR) is associated with adverse cardiovascular events and total mortality in the general population and in individuals with heart disease. Our hypothesis was that mean HR predicts total mortality and heart failure hospitalization in patients undergoing implantable cardioverter-defibrillator (ICD) implantation. METHODS AND RESULTS: The Inhibition of Unnecessary RV Pacing With AV Search Hysteresis in ICDs (INTRINSIC RV) trial included 1530 patients undergoing ICD implantation. After implantation of a dual-chamber ICD, patients were followed for a mean of 10.4 months. The mean HR for 1436 patients over the follow-up period was determined from device histograms. Patients were grouped into strata by mean HR, and the relationship between the primary end point and mean HR was analyzed with Mantel-Haenszel ordinal chi(2) tests. Higher intrinsic (unpaced) HR was associated with greater risk of achieving the primary end point of death or heart failure hospitalization (P<0.001). Of patients with a mean HR <75 bpm, 5.8% died or were hospitalized for heart failure, whereas 20.9% with a mean HR >90 bpm achieved the same end point, a 3.6-fold difference (P<0.0001). In a multivariate model with the use of Cox regression, HR was a significant predictor with a hazard ratio of 1.34 (P=0.0001; 95% confidence interval, 1.19 to 1.50), as were age, New York Heart Association functional class, and percent right ventricular pacing, but it was independent of gender and beta-blocker dosing. When considered as continuous or discrete variables grouped by 5-bpm increments, HR remained a significant predictor. CONCLUSIONS: In this ICD population, the mean intrinsic HR was strongly associated with outcomes. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Identifier: NCT00148967.

Newly detected atrial fibrillation in patients with an implantable cardioverter-defibrillator is a strong risk marker of increased mortality.

BACKGROUND: Atrial fibrillation (AF) has been associated with higher rates of all-cause mortality in patients with heart failure (HF). The risk of newly detected AF in patients receiving implantable cardioverter-defibrillator (ICD) therapy is unknown. METHODS: Newly detected AF was evaluated in all patients enrolled in the Inhibition of Unnecessary RV Pacing with AV Search Hysteresis in ICDs (INTRINSIC RV) study. The relationships between AF and endpoints (total mortality, ICD shocks, and HF hospitalizations) were analyzed retrospectively with proportional-hazards models. RESULTS: At 108 centers, 1530 patients meeting VITALITY AVT ICD indications were followed for 12 months. Of these, 1356 (89%) had no history of AF at the time of implant. Patients with a history of AF had a higher prevalence of HF (52% vs. 36%; P <.01) and had higher rates of HF hospitalization (hazard ratio [HR] 2.14 [1.29-3.54], P <.01), death (HR 2.22 [1.26-3.92], P <.01), and any ICD shock (HR 1.75 [1.19-2.58], P <.01) compared with those with no history. AF incidence during the first 3 months of implant was available in 1317 (86%; 1170 no AF, 147 history of AF) patients. New-onset AF during the first 3 months of implant (45 of 1170, 4%) was associated with a significant increased risk of death (HR 2.86 [1.02-8.05], P = .05) but not with inappropriate ICD shock (HR 2.43 [0.87-6.75], P = .09) or HF hospitalization (HR 1.17 [0.28-4.82], P = .83). CONCLUSION: History of AF at the time of ICD implant identifies additional risk of HF and death. Newly detected AF is associated with significantly higher rates of death. The relationship between newly detected AF and inappropriate ICD shock or HF hospitalization is uncertain and requires further study.

A blended sensor restores chronotropic response more favorably than an accelerometer alone in pacemaker patients: the LIFE study results.

BACKGROUND: Adaptive rate sensors used in permanent pacemakers incorporate an accelerometer (XL) to increase heart rate with activity. Limited data exists regarding the relative benefit of a blended sensor (BS) (XL and minute ventilation) versus XL alone in restoring chronotropic response (CR) in chronotropically incompetent (CI) patients. METHODS: One thousand five hundred thirty-eight patients from the limiting chronotropic incompetence for pacemaker recipients (LIFE) study were implanted with a pacemaker and 1,256 patients had data collected at 1 month. Patients performed a treadmill test 1-month postimplant while programmed in nonrate responsive mode (DDD-60) to determine CI. Only patients who completed at least three exercise stages and achieved a peak perceived exertion >or=16 were included in the analyses. The metabolic chronotropic relationship (MCR) slope was used to evaluate CR in 547 patients. Patients were randomized to XL or BS with a conservative fixed rate response factor (XL = 8, MV = 4). CI patients performed a follow-up 6-month treadmill test. RESULTS: CI prevalence in this patient population (n = 547) was 34%. No differences in baseline characteristics existed between groups. Although both groups showed significant within-group improvements in MCR slope from 1 to 6 months (both P < 0.001), the BS group had a significantly higher MCR slope at 6 months compared to the XL group (P = 0.011). Improvement in quality of life (QOL) did not differ between groups. CONCLUSIONS: In this general pacemaker population with CI, a BS programmed empirically restores CR more favorably than an XL sensor programmed nominally. Further studies are needed to determine if individual sensor optimization would lead to improvement in functional capacity, higher MCR slopes, and QOL.

High defibrillation energy requirements are encountered rarely with modern dual-chamber implantable cardioverter-defibrillator systems.

AIMS: Defibrillation conversion testing to assure a 10 J safety margin is a standard practice during implantable cardioverter-defibrillator (ICD) implantation. Little data are available on the number of patients who do not have a 10 J margin initially and therefore require system revisions, further testing, or a higher energy output device. METHODS AND RESULTS: The INTRINSIC RV study enrolled 1530 new ICD recipients who were not in permanent atrial fibrillation who received a VITALITY AVT (Guidant, St Paul, MN, USA) standard energy (31 J maximum) ICD and underwent defibrillation conversion testing at the time of implantation from 108 centres. Among enrolled patients, 59 (3.9%) did not initially meet the 10 J safety margin criterion. In these 59 patients, a 10 J safety margin was achieved by making at least one system revision: reversing shocking polarity (n = 33, 56%), right ventricular lead repositioning (n = 19, 32%), repeat testing at a later date (n = 1, 2%), adding a subcutaneous array (n = 1, 2%), or other means (n = 10, 17%). Only New York Heart Association class (P = 0.001) and no previous myocardial infarction (P = 0.044) predicted a failed initial conversion test. There were no reported complications from ICD shock testing. CONCLUSION: Successful defibrillation conversion criteria with the first configuration tested with a standard energy device is almost always met with modern dual-chamber ICD systems. The need for revising the initial ICD shock configuration to achieve a 10 J safety margin appears extremely low and of low risk.

Eliminating right ventricular pacing may not be best for patients requiring implantable cardioverter-defibrillators.

BACKGROUND: Excessive right ventricular (RV) pacing has been associated with adverse clinical outcomes in patients receiving pacemakers or implantable cardioverter-defibrillators (ICDs). It remains uncertain how much RV pacing is clinically deleterious. OBJECTIVE: This retrospective analysis assessed the relationship between the amount of RV pacing and the composite of all-cause mortality and heart failure hospitalization in all patients programmed DDDR in the Inhibition of Unnecessary RV Pacing with AV Search Hysteresis in ICDs (INTRINSIC RV) study. METHODS: Seven hundred fifteen patients consistently programmed to DDDR mode throughout follow-up (mean 11.6 months) were examined. The relationship between RV pacing tier and death and heart failure hospitalization was determined and compared with patient characteristics. RESULTS: Across the six RV pacing tiers, patients differed significantly with respect to age, clinical history of ventricular tachycardia, atrial fibrillation, and atrial flutter, and amiodarone use. When controlling for these baseline differences, the best outcome was seen in the group with RV pacing between 10% and 19% (2.8% event rate; n = 106). Increasing levels of RV pacing were generally predictive of higher event rates (death or heart failure hospitalization; P = 0.003), except for the group (n = 344) with the least amount of RV pacing (0-9%). This group exhibited poorer outcomes than otherwise expected (P = 0.016), with 8.1% of these patients experiencing an event. CONCLUSIONS: High levels of RV pacing are associated with heart failure hospitalization and mortality in a large ICD population. However, ICD patients with some RV pacing (10%-19%) exhibit lower event rates compared with those with very low levels (0-9%), possibly due to the physiologically appropriate nature of that RV pacing.

Myocardial perfusion, oxidative metabolism, and free fatty acid uptake in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-tropomyosin gene: a positron emission tomography study.

BACKGROUND: The relationship between myocardial metabolic changes and the severity of left ventricular (LV) hypertrophy in patients with hypertrophic cardiomyopathy (HCM) is largely unknown. We characterized metabolic abnormalities in patients with a genetically identical cause for HCM but with variable LV hypertrophy. METHODS AND RESULTS: Eight patients with HCM attributable to the Asp175Asn mutation in the alpha-tropomyosin gene underwent myocardial perfusion, oxidative, and free fatty acid (FFA) metabolism measurements via positron emission tomography and oxygen 15-labeled water, carbon 11 acetate, and fluorine 14(R,S)-[18F] Fluoro-6-thia-heptadecanoic acid (18 FTHA). LV mass, work, and efficiency were assessed by echocardiography. Thirty-six healthy volunteers served as control subjects. Compared with control subjects, HCM patients had increased myocardial oxidative metabolism and FFA uptake (P < .05). However, in patients, LV mass was inversely related to global myocardial perfusion, oxidative metabolism, and FFA uptake (all P < .03), and regional wall thickness was inversely related to regional perfusion (P < .01), oxidative metabolism (P < .001), and FFA uptake (P < .01). Therefore patients with mild (LV mass less than median of 177 g) but not advanced LV hypertrophy were characterized by increased perfusion, oxidative metabolism, and LV efficiency as compared with control subjects (P < .05). CONCLUSIONS: In HCM attributable to the Asp175Asn mutation in the alpha-tropomyosin gene, myocardial oxidative metabolism and FFA metabolism are increased and inversely related to LV hypertrophy at both the whole heart and regional level. Increased metabolism and efficiency characterize patients with mild myocardial hypertrophy. These hypermetabolic alterations regress with advanced hypertrophy.

Pacing Evaluation-Atrial SUpport Study in Cardiac Resynchronization Therapy (PEGASUS CRT): design and rationale.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been demonstrated to be an effective heart failure (HF) therapy. All pivotal trials of CRT to date have used atrial-synchronous biventricular pacing wherein there is no or minimal atrial pacing. In clinical practice, however, physicians often program CRT devices to have atrial rate support pacing, either by increasing the lower rate limit or by activating the rate sensor. OBJECTIVE: The purpose of this study is to evaluate the effect of empiric atrial support pacing in patients with HF who have received a CRT defibrillator (CRT-D) device. METHODS: PEGASUS CRT is a multicenter, 3-arm, randomized clinical trial of approximately 1200 patients receiving a CRT-D device. For the first 6 weeks after implant, devices are programmed to DDD with a lower rate limit of 40 beats/min. At 6 weeks, patients are randomized to DDD-40, DDD-70, or DDDR-40. All randomized patients are followed for 1 year, and at each visit, mortality, HF events, quality of life, New York Heart Association class, and atrial and ventricular arrhythmic episodes are evaluated. An exercise substudy will also be conducted, enrolling a minimum of 375 patients. Patients in this substudy will complete 2 cardiopulmonary exercise tests to evaluate the effect pacing mode has on exercise capacity. This randomized controlled trial will address whether empiric atrial support pacing is of clinical benefit to patients with HF who receive a CRT-D device.

Assessment of right ventricular oxidative metabolism by PET in patients with idiopathic dilated cardiomyopathy undergoing cardiac resynchronization therapy.

PURPOSE: Right ventricular (RV) performance is known to have prognostic value in patients with congestive heart failure (CHF). Cardiac resynchronization therapy (CRT) has been found to enhance left ventricular (LV) energetics and metabolic reserve in patients with heart failure. The interplay between the LV and RV may play an important role in CRT response. The purpose of the study was to investigate RV oxidative metabolism, metabolic reserve and the effects of CRT in patients with CHF and left bundle brach block. In addition, the role of the RV in the response to CRT was evaluated. METHODS: Ten patients with idiopathic dilated cardiomyopathy who had undergone implantation of a biventricular pacemaker 8+/-5 months earlier were studied under two conditions: CRT ON and after CRT had been switched OFF for 24 h. Oxidative metabolism was measured using [11C]acetate positron emission tomography (Kmono). The measurements were performed at rest and during dobutamine-induced stress (5 microg/kg per minute). LV performance and interventricular mechanical delay (interventricular asynchrony) were measured using echocardiography. RESULTS: CRT had no effect on RV Kmono at rest (ON: 0.052+/-0.014, OFF: 0.047+/-0.018, NS). Dobutamine-induced stress increased RV Kmono significantly under both conditions but oxidative metabolism was more enhanced when CRT was ON (0.076+/-0.026 vs 0.065+/-0.027, p=0.003). CRT shortened interventricular delay significantly (45+/-33 vs 19+/-35 ms, p=0.05). In five patients the response to CRT was striking (32% increase in mean LV stroke volume, range 18-36%), while in the other five patients no response was observed (mean change +2%, range -6% to +4%). RV Kmono and LV stroke volume response to CRT correlated inversely (r=-0.66, p=0.034). None of the other measured parameters, including all LV parameters and electromechanical parameters, were associated with the response to CRT. In responders, RV Kmono with CRT OFF was significantly lower than in non-responders (0.036+/-0.01 vs 0.058+/-0.02, p=0.047). CONCLUSION: CRT appears to enhance RV oxidative metabolism and metabolic reserve during stress. Patients responding to CRT appear to have lower RV oxidative metabolism at rest, suggesting that the RV plays a significant role in the response to CRT.

Myocardial perfusion reserve and oxidative metabolism contribute to exercise capacity in patients with dilated cardiomyopathy.

BACKGROUND: Exercise intolerance is a hallmark symptom in patients with heart failure; however, myocardial factors contributing to the limited exercise capacity are not fully characterized. METHODS: Twenty patients with stable heart failure resulting from idiopathic dilated cardiomyopathy (DCM) and 13 controls were studied. Myocardial perfusion, biventricular oxidative metabolism, and insulin-stimulated glucose uptake were measured using positron emission tomography and [(15)O]H(2)O, [(11)C]acetate, and [(18)F]FDG. RESULTS: Hyperemic perfusion and perfusion reserve were significantly lower in the DCM patients compared with the healthy subjects. There was no difference in left ventricular oxidative metabolism between the 2 groups; however, the patients had a 19% higher right ventricular oxidative metabolism (P=.005). Consequently, the ratio of right to left ventricular oxidative metabolism was also higher (31%) in the patients. There was a strong inverse association between decreased exercise capacity and the ratio of right to left ventricular oxidative metabolism (r=-.68, P<.01) and a positive association with myocardial perfusion reserve (r=.62, P<.01) in the patient group. These 2 parameters along with resting left ventricular work explained 57% of the variability in peak exercise capacity. CONCLUSIONS: Impaired perfusion reserve and an exaggerated imbalance in right to left ventricular oxidative metabolism appear to significantly contribute to the impaired exercise capacity in these DCM patients.

The effects of cardiac resynchronization therapy on left ventricular function, myocardial energetics, and metabolic reserve in patients with dilated cardiomyopathy and heart failure.

OBJECTIVES: The effects of long-term cardiac resynchronization therapy (CRT) on left ventricular (LV) energetics and metabolic reserve were evaluated. BACKGROUND: Cardiac resynchronization therapy is a new therapy for patients with drug-refractory severe heart failure (HF). METHODS: Ten patients with idiopathic dilated cardiomyopathy who had undergone implantation of biventricular pacemaker 8 +/- 5 months earlier were studied during two conditions: CRT switched on, and after CRT was switched off for 24 h. Left ventricular function was measured using echocardiography and oxidative metabolism using [(11)C]acetate positron emission tomography. Both measurements were performed at rest and during dobutamine-induced stress (5 microg/kg/min). Basal- and adenosine-stimulated (140 microg/kg/min) myocardial blood flow were quantitated using [(15)O]water. RESULTS: During CRT off, LV stroke volume was significantly reduced at rest (72 +/- 18 ml vs. 63 +/- 15 ml, p < 0.05), but LV oxidative metabolism (K(mono)) remained unchanged (0.046 +/- 0.008 vs. 0.054 +/- 0.016 min(-1)) leading to a significant deterioration of myocardial efficiency of forward work (from 48.2 +/- 16.7 to 36.6 +/- 11.7 mm Hg.l/g, p < 0.05). During dobutamine-induced stress, stroke volume and K(mono) values were not different whether CRT was on or off. However, myocardial efficiency (56.1 +/- 16.1 vs. 49.8 +/- 18.0 mm Hg.ml.g(-1).min(-1), p = 0.099) and metabolic reserve, the response of K(mono) to dobutamine (0.023 +/- 0.014 vs. 0.013 +/- 0.014 min(-1), p = 0.09), tended to reduce when CRT was switched off. Cardiac resynchronization therapy had no effects on myocardial perfusion. Natriuretic peptides increased significantly during CRT-off period. CONCLUSIONS: Long-term CRT has beneficial effects on LV function and myocardial efficiency at rest in patients with HF. These effects are not associated with changes in myocardial perfusion or oxygen consumption. During dobutamine-induced stress, CRT does not affect functional parameters, but myocardial efficiency and metabolic reserve may be increased.

Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy.

The aim of this study was to assess the relation between peripheral endothelial function and myocardial perfusion reserve in patients with mild heart failure due to idiopathic dilated cardiomyopathy (IDC). Myocardial perfusion and brachial artery flow mediated dilation (FMD) were measured in 20 clinically stable patients with IDC (New York Heart Association classes I to III, ejection fraction 35 +/- 9%) and 13 apparently healthy subjects who were matched for age and lipid profile. Resting and hyperemic (dipyridamole; 0.56 mg/kg/min) perfusion were measured using oxygen-15-labeled water and positron emission tomography (PET). Perfusion reserve was calculated as the ratio of hyperemic to resting perfusion. FMD was assessed by measuring the change in brachial artery diameter in response to reactive hyperemia. Patients with IDC had lower hyperemic perfusion (1.73 +/- 0.83 vs 3.01 +/- 1.20 ml/min/g, p <0.001) and perfusion reserve (2.01 +/- 0.91 vs 3.08 +/- 1.35, p <0.01) compared with healthy subjects. Brachial artery FMD, however, was not different from that of the healthy subjects. Furthermore, neither hyperemic perfusion nor perfusion reserve was correlated with FMD in the patients with IDC, whereas the healthy subjects demonstrated a positive correlation between FMD and perfusion reserve (r = 0.57; p = 0.04). Thus, abnormal myocardial perfusion characterizes patients with IDC. Myocardial perfusion reserve and peripheral endothelial function do not parallel each other in patients with IDC.

Exercise training improves insulin-stimulated myocardial glucose uptake in patients with dilated cardiomyopathy.

BACKGROUND: The effects of exercise training on myocardial substrate utilization have not previously been studied in patients with idiopathic dilated cardiomyopathy and mild heart failure. METHODS AND RESULTS: Myocardial glucose uptake was studied in 15 clinically stable patients with dilated cardiomyopathy (New York Heart Association class I-II, ejection fraction 34% +/- 8%) with the use of 2-[fluorine 18]fluoro-2-deoxy-d-glucose ([F-18]FDG) and positron emission tomography under euglycemic hyperinsulinemia. Eight of these patients participated in a 5-month endurance and strength training program, whereas seven patients served as nontrained subjects. Left ventricular function was assessed by 2-dimensional echocardiography before and after the intervention. After the training period, insulin-stimulated myocardial fractional [F-18]FDG uptake and glucose uptake rates were significantly increased in the anterior, lateral, and septal walls (P <.01) in the trained subjects but remained unchanged in the nontrained subjects. In the trained patients, whole-body insulin-stimulated glucose uptake was enhanced and serum free fatty acid levels were suppressed during hyperinsulinemia compared with the baseline study (P <.05). No changes were observed in the nontrained group. CONCLUSIONS: These results indicate that exercise training in patients with dilated cardiomyopathy improves insulin-stimulated myocardial glucose uptake. This improvement in glucose uptake may be indicative of a switch in myocardial preference to a more energy-efficient substrate.

Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy.

OBJECTIVES: The aim of this study was to determine the effect of exercise training on myocardial oxidative metabolism and efficiency in patients with idiopathic dilated cardiomyopathy (DCM) and mild heart failure (HF). BACKGROUND: Exercise training is known to improve exercise tolerance and quality of life in patients with chronic HF. However, little is known about how exercise training may influence myocardial energetics. METHODS: Twenty clinically stable patients with DCM (New York Heart Association classes I through III) were prospectively separated into a training group (five-month training program; n = 9) and a non-trained control group (n = 11). Oxidative metabolism in both the right and left ventricles (RV and LV) was measured using [(11)C]acetate and positron emission tomography. Myocardial work power was measured using echocardiography. Myocardial efficiency for forward work was calculated as myocardial work power per mass/LV oxidative metabolism. RESULTS: Significant improvements were noted in exercise capacity (VO(2)) and ejection fraction in the training group, whereas no changes were observed in the non-trained group. Exercise training reduced both RV and LV oxidative metabolism and elicited a significant increase in LV forward work efficiency, although no significant changes were observed in the non-trained group. CONCLUSIONS: Exercise training improves exercise tolerance and LV function. This is accompanied by a decrease in biventricular oxidative metabolism and enhanced forward work efficiency. Therefore, exercise training elicits an energetically favorable improvement in myocardial function and exercise tolerance in patients with DCM.