Daily exercise reduces measures of heart rate and blood pressure variability in hypertensive rats.

This study was designed to test the hypothesis that daily spontaneous running (DSR) reduces measures of heart rate and blood pressure variability in spontaneously hypertensive rats (SHR). After 8 weeks of DSR or sedentary control, rats were chronically instrumented with arterial catheters. Daily exercise reduced most measures of heart rate (HR) and blood pressure variability. Specifically DSR decreased heart rate, Low Frequency Power (LF: 0.19-0.61 Hz), and Low Frequency/High Frequency (HF: 1.2-2.5 Hz) ratio of HR. Furthermore, Total Power (TP), LF power, and LF/HF ratio of systolic blood pressure were reduced by daily spontaneous running. Finally, TP, LF and HF powers and LF/HF ratios of diastolic blood pressure were reduced by daily spontaneous running. These data demonstrate that daily exercise reduces sympathetic activity and possibly increases cardiac reserve in hypertensive animals.

Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy is characterized by an imbalance between left ventricular performance and myocardial energy consumption. Experimental models suggest that oxidative stress resulting from increased xanthine oxidase (XO) activity contributes to this imbalance. Accordingly, we hypothesized that XO inhibition with intracoronary allopurinol improves left ventricular efficiency in patients with idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Patients (n=9; ejection fraction, 29+/-3%) were instrumented to assess myocardial oxygen consumption (MVO(2)), peak rate of rise of left ventricular pressure (dP/dt(max)), stroke work (SW), and efficiency (dP/dt(max)/MV O(2) and SW/MVO(2)) at baseline and after sequential infusions of intracoronary allopurinol (0.5, 1.0, and 1.5 mg/min, each for 15 minutes). Allopurinol caused a significant decrease in MVO(2) (peak effect, -16+/-5%; P<0.01; n=9) with no parallel decrease in dP/dt(max) or SW and no change in ventricular load. The net result was a substantial improvement in myocardial efficiency (peak effects: dP/dt(max)/MVO(2), 22+/-9%, n=9; SW/MVO(2), 40+/-17%, n=6; both P<0.05). These effects were apparent despite concomitant treatment with standard heart failure therapy, including ACE inhibitors and beta-blockers. XO and its parent enzyme xanthine dehydrogenase were more abundant in failing explanted human myocardium on immunoblot. CONCLUSIONS: These findings indicate that XO activity may contribute to abnormal energy metabolism in human cardiomyopathy. By reversing the energetic inefficiency of the failing heart, pharmacological XO inhibition represents a potential novel therapeutic strategy for the treatment of human heart failure.

Electrical induction of ventricular fibrillation for resuscitation from postcountershock pulseless and asystolic cardiac arrests.

BACKGROUND: There is increasing evidence that defibrillation from prolonged ventricular fibrillation (VF) before CPR decreases survival. It remains unclear, however, whether harmful effects are due primarily to initial countershock of ischemic myocardium or to resultant postdefibrillation rhythms (ie, pulseless electrical activity [PEA] or asystole). METHODS AND RESULTS: We induced 15 dogs into 12 minutes of VF and randomized them to 3 groups. Group 1 was defibrillated at 12 minutes and then administered advanced cardiac life support (ACLS); group 2 was allowed to remain in VF and was subsequently defibrillated after 4 minutes of ACLS; group 3 was defibrillated at 12 minutes, electrically refibrillated, and then defibrillated after 4 minutes of ACLS. All group 1 and 3 animals were defibrillated into PEA/asystole at 12 minutes. After 4 minutes of ACLS, group 2 and 3 animals were effectively defibrillated into sinus rhythm. The extension of VF in group 2 and 3 subjects paradoxically resulted in shorter mean resuscitation times (251+/-15 and 245+/-7 seconds, respectively, versus 459+/-66 seconds for group 1; P<0.05) and improved 1-hour survival (10 of 10 group 2 and 3 dogs versus 1 of 5 group 1 dogs; Fisher's exact, P<0.005) compared with more conservatively managed group 1 subjects. CONCLUSIONS: Precountershock CPR during VF appears more conducive to resuscitation than CPR during postcountershock PEA or asystole. The intentional induction of VF may prove useful in the management of PEA and asystolic arrests.

Lead configuration for defibrillator implantation in a patient with congenital heart disease and a mechanical prosthetic tricuspid valve.

The authors devised a nonthoracotomy defibrillation system for a patient with a prosthetic tricuspid valve using existing technology and previously established implantation techniques. Their lead configuration deviates substantially from existing designs in its primary use of a coronary sinus defibrillation coil and a left-sided subcutaneous array to distribute current across the ventricular myocardium.

Usefulness of magnesium sulfate in stabilizing cardiac repolarization in heart failure secondary to ischemic cardiomyopathy.

Experimental heart failure is associated with cardiac magnesium loss, causing increased beat-to-beat variability in the action potential. Unstable repolarization contributes to sudden death, but no therapy has been shown to reduce repolarization variability safely. We sought to test whether a prolonged infusion of magnesium sulfate (MgSO(4); 40 mmol/24 hours) would normalize QT interval variability in patients with compensated heart failure. Fifteen patients (New York Heart Association class II to III; mean age 63 years) were enrolled in a placebo-controlled, double-blind study. Surface electrocardiograms were recorded and digitized at entry and at 48 and 168 hours (drug washout). Repolarization stability was assessed using an automated method measuring each QT interval in a 5-minute epoch. The QT variability index was derived as the ratio of normalized QT-to-normalized heart rate variability. Seven of 15 patients received MgSO(4). Mean heart rate and QT did not change in either group. The QT variability index was stable in the placebo group (-0.69 +/- 0.15 at entry, -0.71 +/- 0.22 at 48 hours, -0.70 +/- 0.18 at 168 hours), but decreased significantly in the treated group at 48 hours (-0.95 +/- 0.19 to -1.36 +/- 0.13, p <0.05 repeated-measures analysis of variance), returning to baseline at 168 hours (-0.84 +/- 0.18). Regression analyses showed that administration of MgSO(4) resulted in a stronger correlation between the QT and RR interval (p <0.01). Thus, MgSO(4) stabilizes cardiac repolarization in patients with compensated heart failure due to ischemic heart disease. Magnesium therapy may be useful in altering the proarrhythmic substrate in heart failure.

Prospective randomized comparison of the safety and effectiveness of placement of endocardial pacemaker and defibrillator leads using the extrathoracic subclavian vein guided by contrast venography versus the cephalic approach.

The purpose of this prospective randomized study was to compare the safety and efficacy of the cephalic approach versus a contrast-guided extrathoracic approach for placement of endocardial leads. Despite an increased incidence of lead fracture, the intrathoracic subclavian approach remains the dominant approach for placement of pacemaker and implantable defibrillator leads. Although this complication can be prevented by lead placement in the cephalic vein or by lead placement in the extrathoracic subclavian or axillary vein, these approaches have not gained acceptance. A total of 200 patients were randomized to undergo placement of pacemaker or implantable defibrillator leads via the contrast-guided extrathoracic subclavian vein approach or the cephalic approach. Lead placement was accomplished in 99 of the 100 patients randomized to the extrathoracic subclavian vein approach as compared to 64 of 100 patients using the cephalic approach. In addition to a higher initial success rate, the extrathoracic subclavian vein medial approach was determined to be preferable as evidenced by a shorter procedure time and less blood loss. There was no difference in the incidence of complications. In conclusion, these results demonstrate that lead placement in the extrathoracic subclavian vein guided by contrast venography is effective and safe. It was also associated with no increased risk of complications as compared with the cephalic approach. These findings suggest that the contrast-guided approach to the extrathoracic portion of the subclavian vein should be considered as an alternative to the cephalic approach.

Laser ablation of the pulmonary veins by using a fiberoptic balloon catheter: implications for treatment of paroxysmal atrial fibrillation.

BACKGROUND AND OBJECTIVE: Focal sources of paroxysmal atrial fibrillation may be treatable by electrical isolation of the pulmonary veins from the left atrium. A new fiberoptic balloon catheter was tested as an alternative to radiofrequency catheter ablation for creation of circumferential thermal lesions at the pulmonary vein orifice. STUDY DESIGN/MATERIALS AND METHODS: In vitro and in vivo experiments were conducted in canine hearts to demonstrate efficacy and optimize ablation dosimetry. Continuous-wave, 1.06-microm, Nd:YAG laser radiation was delivered radially through diffusing optical fiber tips enclosed in a balloon catheter. During in vivo studies, the catheter was placed at the pulmonary vein orifice through a left atrial appendage sheath under X-ray fluoroscopic guidance during an open-chest procedure. Additionally, circumferential lesions in the left atrial appendage were correlated with epicardial electrograms demonstrating elimination of electrical activity. RESULTS: The pulmonary veins were successfully ablated by using laser powers of 30--50 W and irradiation times of 60--90 seconds. Transmural, continuous, and circumferential lesions were produced in the pulmonary veins in a single application without evidence of tissue vaporization or endothelial disruption. CONCLUSION: Laser ablation by using a fiberoptic balloon catheter may represent a promising alternative to radiofrequency catheter ablation for electrical isolation of the pulmonary veins from the left atrium during treatment of paroxysmal atrial fibrillation. Further development and testing of the fiberoptic catheter is warranted for possible clinical studies.

The effects of rust and anthracnose on the photosynthetic competence of diseased bean leaves.

ABSTRACT The effects of rust (caused by Uromyces appendiculatus) and anthracnose (caused by Colletotrichum lindemuthianum) and their interaction on the photosynthetic rates of healthy and diseased bean (Phaseolus vulgaris) leaves were determined by gas-exchange analysis, in plants with each disease, grown under controlled conditions. The equation P(x)/P(0) = (1 - x)() was used to relate relative photosynthetic rate (P(x)/P(0)) to proportional disease severity (x), where beta represents the ratio between virtual and visual lesion. The beta values obtained for rust were near one, indicating that the effect of the pathogen on the remaining green leaf area was minimal. The high values of beta obtained for anthracnose (8.46 and 12.18) indicated that the photosynthesis in the green area beyond the necrotic symptoms of anthracnose was severely impaired. The impact of anthracnose on bean leaf photosynthesis should be considered in assessments of the proportion of healthy tissue in diseased leaves. The accurate assessment of the healthy portion of the leaf could improve the use of concepts such as healthy leaf area duration and healthy leaf area absorption, which are valuable predictors of crop yield. The equation used to analyze the interaction between rust and anthracnose on the same leaf was P(z) = P(0) (1 - x)(x) x (1 - y)(y), where P(z) is the relative photosynthetic rate of any given leaf, P(0) is the maximum relative photosynthetic rate, x is anthracnose severity, y is rust severity, betax is the beta value for anthracnose in the presence of rust, and betay is the beta value for rust in the presence of anthracnose. From the resulting response surface, no interaction of the two diseases was observed. Dark respiration rate increased on diseased leaves compared with control leaves. The remaining green leaf area of leaves with both diseases was not a good source to estimate net photosynthetic rate because the effect of anthracnose extended far beyond the visual lesions, whereas the effect of rust on photosynthesis was essentially limited to the pustule plus halo.

Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.

The KvLQT1 gene encodes a voltage-gated potassium channel. Mutations in KvLQT1 underlie the dominantly transmitted Ward-Romano long QT syndrome, which causes cardiac arrhythmia, and the recessively transmitted Jervell and Lange-Nielsen syndrome, which causes both cardiac arrhythmia and congenital deafness. KvLQT1 is also disrupted by balanced germline chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth and cancer. Because of the diverse human disorders and organ systems affected by this gene, we developed an animal model by inactivating the murine Kvlqt1. No electrocardiographic abnormalities were observed. However, homozygous mice exhibited complete deafness, as well as circular movement and repetitive falling, suggesting imbalance. Histochemical study revealed severe anatomic disruption of the cochlear and vestibular end organs, suggesting that Kvlqt1 is essential for normal development of the inner ear. Surprisingly, homozygous mice also displayed threefold enlargement by weight of the stomach resulting from mucous neck cell hyperplasia. Finally, there were no features of BWS, suggesting that Kvlqt1 is not responsible for BWS.

Linear lesions in myocardium created by Nd:YAG laser using diffusing optical fibers: in vitro and in vivo results.

BACKGROUND AND OBJECTIVE: Linear lesions may be necessary for successful catheter ablation of cardiac arrhythmias such as atrial fibrillation. This study uses laser energy delivered through diffusing optical fibers as an alternative to radiofrequency energy for the creation of linear lesions in cardiac tissue in a single application. STUDY DESIGN/MATERIALS AND METHODS: Samples of canine myocardium were placed in a heated, circulating saline bath and irradiated with a 1.06-microm, continuous-wave Nd:YAG laser during in vitro studies. Laser ablation was then performed in vivo on the epicardial surface of the right ventricle during an open-chest procedure by using similar ablation parameters. Laser energy was delivered to the tissue by being diffused radially through flexible optical fiber tips oriented parallel to the tissue surface. Histology and temperature measurements verified transmurality, continuity, and linearity of the lesions. RESULTS: Peak tissue temperatures measured in vitro remained low (51 +/- 1 degrees C at the endocardial surface, 61 +/- 6 degrees C in the mid-myocardium, and 55 +/- 6 degrees C at the epicardial surface) with no evidence of tissue charring or vaporization. Lesion dimensions produced in vitro and in vivo were similar (depth, 6 mm; width, 8-10 mm; length, 16-22 mm), demonstrating that tissue perfusion in vivo did not significantly alter the heating. CONCLUSION: Long linear lesions, necessary for duplication of the surgical maze procedure during catheter ablation of atrial fibrillation, may be created by using laser radiation delivered through flexible diffusing optical fiber tips. Further development of steerable catheters for endocardial atrial ablation and studies correlating thermal damage zones with electrophysiologic indicators of irreversible conduction block are warranted.

Visualization and temporal/spatial characterization of cardiac radiofrequency ablation lesions using magnetic resonance imaging.

BACKGROUND: The purpose of this study was to describe a system and method for creating, visualizing, and monitoring cardiac radiofrequency ablation (RFA) therapy during magnetic resonance imaging (MRI). METHODS AND RESULTS: RFA was performed in the right ventricular apex of 6 healthy mongrel dogs with a custom 7F nonmagnetic ablation catheter (4-mm electrode) in a newly developed real-time interactive cardiac MRI system. Catheters were positioned to intracardiac targets by use of an MRI fluoroscopy sequence, and ablated tissue was imaged with T2-weighted fast spin-echo and contrast-enhanced T1-weighted gradient-echo sequences. Lesion size by MRI was determined and compared with measurements at gross and histopathological examination. Ablated areas of myocardium appeared as hyperintense regions directly adjacent to the catheter tip and could be detected 2 minutes after RF delivery. Lesions reached maximum size approximately 5 minutes after ablation, whereas lesion signal intensity increased linearly with time but then reached a plateau at 12.2+/-2.1 minutes. Lesion size by MR correlated well with actual postmortem lesion size and histological necrosis area (55.4+/-7.2 versus 49.7+/-5.9 mm(2), r=0.958, P<0.05). CONCLUSIONS: RFA can be performed in vivo in a new real-time interactive cardiac MRI system. The spatial and temporal extent of cardiac lesions can be visualized and monitored by T2- and T1-weighted imaging, and MRI lesion size agrees well with actual postmortem lesion size. MRI-guided RFA may be a useful approach to help facilitate anatomic lesion placement and to provide insight into the biophysical effects of new ablation techniques and technologies.

Resuscitation after prolonged ventricular fibrillation with use of monophasic and biphasic waveform pulses for external defibrillation.

BACKGROUND: Survival after prolonged ventricular fibrillation (VF) appears severely limited by 2 major factors: (1) low defibrillation success rates and (2) persistent post-countershock myocardial dysfunction. Biphasic (BP) waveforms may prove capable of favorably modifying these limitations. However, they have not been rigorously tested against monophasic (MP) waveforms in clinical models of external defibrillation, particularly where rescue from prolonged VF is the general rule. METHODS AND RESULTS: We randomized 26 dogs to external countershocks with either MP or BP waveforms. Hemodynamics were assessed after shocks applied during sinus rhythm, after brief VF (>10 seconds), and after resuscitation from prolonged VF (>10 minutes). Short-term differences in percent change in left ventricular +dP/dt(max) (MP -16+/-28%, BP +9.1+/-24%; P=0.03) and left ventricular -dP/dt(max) (MP -37+/-26%, BP -18+/-20%; P=0.05) were present after rescue from brief VF, with BP animals exhibiting less countershock-induced dysfunction. After prolonged VF, the BP group had lower mean defibrillation thresholds (107+/-57 versus 172+/-88 J for MP, P=0.04) and significantly shorter resuscitation times (397+/-73.7 versus 488+/-74.3 seconds for MP, P=0.03). CONCLUSIONS: External defibrillation is more efficacious with BP countershocks than with MP countershocks. The lower defibrillation thresholds and shorter resuscitation times associated with BP waveform defibrillation may improve survival after prolonged VF arrest.

Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay.

BACKGROUND: VDD pacing can enhance systolic function in patients with dilated cardiomyopathy and discoordinate contraction; however, identification of patients likely to benefit is unclear. We tested predictors of systolic responsiveness on the basis of global parameters as well as directly assessed mechanical dyssynchrony. METHODS AND RESULTS: Twenty-two DCM patients with conduction delay were studied by cardiac catheterization with a dual-sensor micromanometer to measure LV and aortic pressures during sinus rhythm and LV free-wall pacing. Pacing enhanced isovolumetric (dP/dt(max)) and ejection-phase (pulse pressure, PP) systolic function by 35+/-21% and 16.4+/-11%, respectively, and these changes correlated directly (r=0.7, P=0.001). %DeltadP/dt(max) was weakly predicted by baseline QRS (r=0.6, P<0.02), more strongly by baseline dP/dt(max) (r=0.7, P=0.001), and best by bidiscriminate analysis combining baseline dP/dt(max) < or =700 mm Hg/s and QRS > or =155 ms to predict %DeltadP/dt(max) > or =25% and %DeltaPP > or =10% (P<0.0005, chi(2)), with no false-positives. Benefit could not be predicted by %DeltaQRS. To test whether basal mechanical dyssynchrony predicted responsiveness to LV pacing, circumferential strains were determined at approximately 80 sites throughout the LV by tagged MRI in 8 DCM patients and 7 additional control subjects. Strain variance at time of maximal shortening indexed dyssynchrony, averaging 28.0+/-7.1% in normal subjects versus 201.4+/-84.3% in DCM patients (P=0.001). Mechanical dyssynchrony also correlated directly with %DeltadP/dt(max) (r=0.85, P=0.008). Conclusions-These results show that although mechanical dyssynchrony is a key predictor for pacing efficacy in DCM patients with conduction delay, combining information about QRS and basal dP/dt(max) provides an excellent tool to identify maximal responders.

Temporal repolarization lability in hypertrophic cardiomyopathy caused by beta-myosin heavy-chain gene mutations.

BACKGROUND: Certain genetic mutations associated with hypertrophic cardiomyopathy (HCM) carry an increased risk of sudden death. QT variability identifies patients at a high risk for sudden death from ventricular arrhythmias. We tested whether patients with HCM caused by beta-myosin heavy-chain (beta-MHC) gene mutations exhibit labile ventricular repolarization using beat-to-beat QT variability analysis. METHODS AND RESULTS: We measured the QT variability index and heart rate-QT interval coherence from Holter monitor recordings in 36 patients with HCM caused by known beta-MHC gene mutations and in 26 age- and sex-matched controls. There were 7 distinct beta-MHC gene mutations in these 36 patients; 9 patients had HCM caused by the malignant Arg(403)Gln mutation and 8 patients had HCM caused by the more benign Leu(908)Val mutation. The QT variability index was higher in HCM patients than in controls (-1.24+/-0.17 versus -1. 58+/-0.38, P<0.01), and the greatest abnormality was detected in patients with the Arg(403)Gln mutation (-0.99+/-0.49 versus -1. 46+/-0.43 in controls, P<0.05). In keeping with this finding, coherence was lower for the entire HCM group than for controls (P<0. 001). Coherence was also significantly lower in patients with the Arg(403)Gln mutation compared with controls (P<0.05). CONCLUSIONS: These findings suggest that (1) patients with HCM caused by beta-MHC gene mutations exhibit labile repolarization quantified by QT variability analysis and, hence, may be more at risk for sudden death from ventricular arrhythmias, and (2) indices of QT variability may be particularly abnormal in patients with beta-MHC gene mutations that are associated with a poor prognosis.

Prospective comparison of lesions created using a multipolar microcatheter ablation system with those created using a pullback approach with standard radiofrequency ablation in the canine atrium.

The aim of this study was to compare the lesions created using a multipolar microcatheter (MICRO) ablation system in the right canine atrium to a pullback approach with a standard radiofrequency (STND RF) ablation and to determine the value of electrogram amplitude and pacing threshold in predicting transmurality of lesions. Ten dogs underwent right atrial ablation using a MICRO (6 dogs) or STND RF (4 dogs) ablation system in each animal. Attempts were made to create linear RF lesions at four predetermined atrial sites. RF energy was delivered for 60 seconds using closed-loop, temperature control to achieve a target temperature of 60 degrees C for STND RF and 50 degrees C for MICRO. Unipolar atrial electrogram amplitude and atrial pacing threshold were obtained before and after ablation. Pathological analysis was determined at 4 weeks after ablation. Lesions created with MICRO were narrower, more likely to be continuous, and more likely to be anchored to an anatomic structure than those lesions which were created using a STND RF. No difference was observed in overall lesion length or in the proportion of lesions that were transmural over at least 50% of their length. Of lesions created using MICRO, a significant relation was observed between transmurality of lesion and unipolar electrogram amplitude as well as pacing threshold. Further studies are needed to determine if this type of ablation technique and parameters during ablation may facilitate a successful catheter-based MAZE procedure.

Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block.

BACKGROUND: Left ventricular or biventricular pacing/stimulation can acutely improve systolic function in patients with dilated cardiomyopathy (DCM) and intraventricular conduction delay by resynchronizing contraction. Most heart failure therapies directly enhancing systolic function do so while concomitantly increasing myocardial oxygen consumption (MVO(2)). We hypothesized that pacing/stimulation, in contrast, incurs systolic benefits without raising energy demand. METHODS AND RESULTS: Ten DCM patients with left bundle-branch block (ejection fraction 20+/-3%, QRS duration 179+/-3 ms, mean+/-SEM) underwent cardiac catheterization to measure ventricular and aortic pressure, coronary blood flow, arterial-coronary sinus oxygen difference (DeltaAVO(2)), and MVO(2). Data were measured under sinus rhythm or with left ventricular or biventricular pacing/stimulation at the same heart rate. These results were then contrasted to intravenous dobutamine (n=7) titrated to match systolic changes during LV pacing. Systolic function rose quickly and substantially from LV pacing (18+/-4% rise in arterial pulse pressure, which correlates with cardiac output, and 43+/-6% increase in dP/dt(max); both P<0.01). However, DeltaAVO(2) and MVO(2) declined -4+/-2% and -8+/-6.5%, respectively (both P<0.05). Similar results were obtained with biventricular activation. In contrast, dobutamine raised dP/dt(max) 37+/-6%, accompanied by a 22+/-11% rise in per-beat MVO(2) (P<0.05 versus pacing). CONCLUSIONS: Ventricular resynchronization by left ventricular or biventricular pacing/stimulation in DCM patients with left bundle-branch block acutely enhances systolic function while modestly lowering energy cost. This should prove valuable for treating DCM patients with basal dyssynchrony.

Ventricular pacing with premature excitation for treatment of hypertensive-cardiac hypertrophy with cavity-obliteration.

BACKGROUND: Hypertensive left ventricular hypertrophy with supranormal systolic ejection and distal cavity obliteration (HHCO) can result in debilitating exertional fatigue and dyspnea. Dual-chamber pacing with ventricular preactivation generates discoordinate contraction, which can limit cavity obliteration and thereby increase potential ejection reserve. Accordingly, we hypothesized that pacing may improve exercise tolerance long-term in this syndrome. METHODS AND RESULTS: Dual-chamber pacemakers were implanted in 9 patients with exertional dyspnea caused by HHCO. Intrinsic atrial rate was sensed, and ventricular preactivation was achieved by shortening the atrial-ventricular delay. Pacing was on or off for successive 3-month periods (randomized, double-blind, crossover design), followed by 6 additional pacing-on months. Metabolic exercise testing, quality-of-life assessment, and rest and dobutamine-stress echocardiographic/Doppler data were obtained. After 3 months of pacing-on, exercise duration rose from 324+/-133 to 588+/-238 s (mean+/-SD; P=0.001, with 7 of 9 patients improving >/=30%), and maximal oxygen consumption increased from 13.6+/-2.9 to 16.7+/-3.3 mL of O(2). min(-1). kg(-1) (P<0.02). Both parameters were little changed from baseline during the pacing-off period. Improved exercise capacity persisted at 1-year follow-up. Clinical symptoms and activities of daily living improved during the pacing-on period and stayed improved at 1 year, but they were little changed during the pacing-off period. Despite similar basal values, stroke volume (P<0.001) and cardiac output (P<0.02) increased with dobutamine stimulation 2 to 3 times more after 1 year of follow-up as compared with baseline. CONCLUSIONS: Long-term dual-chamber pacing can improve exercise capacity, cardiac reserve, clinical symptoms, and activities of daily living in patients with HHCO. This therapy may provide a novel alternative for patients in whom traditional pharmacological treatment proves inadequate.