The right ventricular annular velocity reduction caused by coronary artery bypass graft surgery occurs at the moment of pericardial incision.

BACKGROUND: Right ventricular (RV) long-axis function is known to be depressed after cardiac surgery, but the mechanism is not known. We hypothesized that intraoperative transesophageal echocardiography could pinpoint the time at which this happens to help narrow the range of plausible mechanisms. METHOD: Transthoracic echocardiography was conducted in 33 patients before and after elective coronary artery bypass graft. In an intensively monitored cohort of 9 patients, we also monitored RV function intraoperatively using serial pulsed wave tissue Doppler (PW TD) transesophageal echocardiography. RESULTS: There was no significant difference in myocardial velocities from the onset of the operation up to the beginning of pericardial incision, change in RV PW TD S' velocities 3% +/- 2% (P = not significant). Within the first 3 minutes of opening the pericardium, RV PW TD S' velocities had reduced by 43% +/- 17% (P < .001). At 5 minutes postpericardial incision, 2 minutes later, the velocities had more than halved, by 54% +/- 11% (P < .0001). Velocities thereafter remained depressed throughout the operation, with final intraoperative S' reduction being 61% +/- 11% (P < .0001). One month after surgery, in the full 33-patient cohort, transthoracic echocardiogram data showed a 55% +/- 12% (P < .0001) reduction in RV S' velocities compared with preoperative values. CONCLUSIONS: Minute-by-minute monitoring during cardiac surgery reveals that, virtually, all the losses in RV systolic velocity occurs within the first 3 minutes after pericardial incision. Right ventricular long-axis reduction during coronary bypass surgery results not from cardiopulmonary bypass but rather from pericardial incision.

Report on a national echocardiography quality-control exercise.

AIMS: To assess the feasibility of conducting a large-scale quality-control exercise on the echocardiographic grading of mitral regurgitation (MR). METHODS AND RESULTS: One hundred and fifty-two practising cardiologist and sonographer echocardiographers attended a dedicated session within a national meeting and were asked to review echocardiographic images of five case studies and evaluate the severity of MR using a six-point scale. The group's overall evaluation was analysed together with the variation in grading of severity. The proportion of gradings of MR more than one grade either side of the mode was <10% in all but one case, and <10% were inaccurately evaluated as inside categories of severe when the modal grading was outside and vice versa. However in a case where a single grading difference had important clinical implications, substantial variability was seen. CONCLUSIONS: Conducting a large-scale quality-control exercise in the assessment of mitral regurgitation is feasible. Overall results suggesting reasonable consistency in reporting may hide substantial clinically relevant variability. It is essential that increasing importance is attached to the development, conduct, and analysis of quality control within echocardiography if it is to maintain and extend its role as a key investigation for patients with heart disease.

Intraobserver variability in grading severity of repeated identical cases of mitral regurgitation.

BACKGROUND: In clinical practice, mitral regurgitation (MR) is often assessed from the visual impression of the color Doppler image. It is recognized that repeated scanning can give different images and that different observers may grade the same images differently. In this study, we focus on a more intrinsic source of variability-intraobserver variability in grading of identical images, presented more than once at the same sitting. Furthermore, we look for evidence that observer grading is influenced by the severity of the immediately preceding case viewed. METHODS: Anonymous, 4-chamber color Doppler 2-dimensional video clips of MR were obtained from 60 unselected patients with MR. Six clips were identified by 2 observers as of contentious severity (either between mild and moderate or between moderate and severe). A 72-clip sequence was constructed from the 54 "uncontentious" selected cases of MR intermingled with 3 presentations of each of the 6 "contentious" images. Each contentious image was shown once without a designed order, once preceded by 3 clips of less severe MR, and once preceded by 3 clips of more severe MR. RESULTS: Only 1 (8%) of 12 observers gave consistent gradings for the triply presented images. More than 90% (11/12) of the observers reported a different grading of the same clip of MR in at least 1 of the 6 cases. The MR severity was changed in 51.4% of the triplets of identical images shown. Of 12 reporters, 5 (42%) showed classification variability between severe and nonsevere grades in at least 1 of the 6 cases. The direction of change showed no sign of consistency between observers (P = .375). CONCLUSION: Even a skilled observer cannot be relied upon to give an identical grading to an identical simple video clip of MR, when re-presented surreptitiously within a few minutes. Interobserver variability cannot therefore simply be blamed on differential levels of skill. Because, even under these ideal and dramatically simplified conditions, visual assessment is so variable, the future emphasis of echocardiographic MR grading may lie in integrating qualitative analysis with simple quantification methods.

Attenuation of reflected waves in man during retrograde propagation from femoral artery to proximal aorta.

BACKGROUND: Wave reflection may be an important influence on blood pressure, but the extent to which reflections undergo attenuation during retrograde propagation has not been studied. We quantified retrograde transmission of a reflected wave created by occlusion of the left femoral artery in man. METHODS: 20 subjects (age 31-83 years; 14 male) underwent invasive measurement of pressure and flow velocity with a sensor-tipped intra-arterial wire at multiple locations distal to the proximal aorta before, during and following occlusion of the left femoral artery by thigh cuff inflation. A numerical model of the circulation was also used to predict reflected wave transmission. Wave reflection was measured as the ratio of backward to forward wave energy (WRI) and the ratio of peak backward to forward pressure (Pb/Pf). RESULTS: Cuff inflation caused a marked reflection which was largest at 5-10 cm from the cuff (change (Δ) in WRI=0.50 (95% CI 0.38, 0.62); p<0.001, ΔPb/Pf=0.23 (0.18-0.29); p<0.001). The magnitude of the cuff-induced reflection decreased progressively at more proximal locations and was barely discernible at sites>40 cm from the cuff including in the proximal aorta. Numerical modelling gave similar predictions to those observed experimentally. CONCLUSIONS: Reflections due to femoral artery occlusion are markedly attenuated by the time they reach the proximal aorta. This is due to impedance mismatches of bifurcations traversed in the backward direction. This degree of attenuation is inconsistent with the idea of a large discrete reflected wave arising from the lower limb and propagating back into the aorta.

Novel cardiac pacemaker-based human model of periodic breathing to develop real-time, pre-emptive technology for carbon dioxide stabilisation.

BACKGROUND: Constant flow and concentration CO2 has previously been efficacious in attenuating ventilatory oscillations in periodic breathing (PB) where oscillations in CO2 drive ventilatory oscillations. However, it has the undesirable effect of increasing end-tidal CO2, and ventilation. We tested, in a model of PB, a dynamic CO2 therapy that aims to attenuate pacemaker-induced ventilatory oscillations while minimising CO2 dose. METHODS: First, pacemakers were manipulated in 12 pacemaker recipients, 6 with heart failure (ejection fraction (EF)=23.7±7.3%) and 6 without heart failure, to experimentally induce PB. Second, we applied a real-time algorithm of pre-emptive dynamic exogenous CO2 administration, and tested different timings. RESULTS: We found that cardiac output alternation using pacemakers successfully induced PB. Dynamic CO2 therapy, when delivered coincident with hyperventilation, attenuated 57% of the experimentally induced oscillations in end-tidal CO2: SD/mean 0.06±0.01 untreated versus 0.04±0.01 with treatment (p<0.0001) and 0.02±0.01 in baseline non-modified breathing. This translated to a 56% reduction in induced ventilatory oscillations: SD/mean 0.19±0.09 untreated versus 0.14±0.06 with treatment (p=0.001) and 0.10±0.03 at baseline. Of note, end-tidal CO2 did not significantly rise when dynamic CO2 was applied to the model (4.84±0.47 vs 4.91± 0.45 kPa, p=0.08). Furthermore, mean ventilation was also not significantly increased by dynamic CO2 compared with untreated (7.8±1.2 vs 8.4±1.2 L/min, p=0.17). CONCLUSIONS: Cardiac pacemaker manipulation can be used to induce PB experimentally. In this induced PB, delivering CO2 coincident with hyperventilation, ventilatory oscillations can be substantially attenuated without a significant increase in end-tidal CO2 or ventilation. Dynamic CO2 administration might be developed into a clinical treatment for PB. TRIAL REGISTRATION NUMBER: ISRCTN29344450.

Influence of gender on clinical outcomes following transcatheter aortic valve implantation from the UK transcatheter aortic valve implantation registry and the National Institute for Cardiovascular Outcomes Research.

Gender differences exist in outcomes after percutaneous coronary intervention and coronary artery bypass graft surgery but have yet to be fully explored after transcatheter aortic valve implantation. We aimed to investigate gender differences after transcatheter aortic valve implantation in the UK National Institute for Cardiovascular Outcomes Research registry. A retrospective analysis was performed of Medtronic CoreValve and Edwards SAPIEN implantation in 1,627 patients (756 women) from January 2007 to December 2010. Men had more risk factors: poor left ventricular systolic function (11.9% vs 5.5%, p <0.001), 3-vessel disease (19.4% vs 9.2%, p <0.001), previous myocardial infarction (29.5% vs 13.0%, p <0.001), peripheral vascular disease (32.4% vs 23.3%, p <0.001), and higher logistic EuroSCORE (21.8 ± 14.2% vs 21.0 ± 13.4%, p = 0.046). Thirty-day mortality was 6.3% (confidence interval 4.3% to 7.9%) in women and 7.4% (5.6% to 9.2%) in men and at 1 year, 21.9% (18.7% to 25.1%) and 22.4% (19.4% to 25.4%), respectively. There was no mortality difference: p = 0.331 by log-rank test; hazard ratio for women 0.91 (0.75 to 1.10). Procedural success (96.6% in women vs 96.4% in men, p = 0.889) and 30-day cerebrovascular event rates (3.8% vs 3.7%, p = 0.962) did not differ. Women had more major vascular complications (7.5% vs 4.2%, p = 0.004) and less moderate or severe postprocedural aortic regurgitation (7.5% vs 12.5%, p = 0.001). In conclusion, despite a higher risk profile in men, there was no gender-related mortality difference; however, women had more major vascular complications and less postprocedural moderate or severe aortic regurgitation.

A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial).

BACKGROUND: Restoring sinus rhythm in patients with heart failure (HF) and atrial fibrillation (AF) may improve left ventricular (LV) function and HF symptoms. We sought to compare the effect of a catheter ablation strategy with that of a medical rate control strategy in patients with persistent AF and HF. METHODS AND RESULTS: Patients with persistent AF, symptomatic HF, and LV ejection fraction <50% were randomized to catheter ablation or medical rate control. The primary end-point was the difference between groups in LV ejection fraction at 6 months. Baseline LV ejection fraction was 32±8% in the ablation group and 34±12% in the medical group. Twenty-six patients underwent catheter ablation, and 24 patients were rate controlled. Freedom from AF was achieved in 21/26 (81%) at 6 months off antiarrhythmic drugs. LV ejection fraction at 6 months in the ablation group was 40±12% compared with 31±13% in the rate control group (P=0.015). Ablation was associated with better peak oxygen consumption (22±6 versus 18±6 mL/kg per minute; P=0.014) and Minnesota living with HF questionnaire score (24±22 versus 47±22; P=0.001) compared with rate control. CONCLUSIONS: Catheter ablation is effective in restoring sinus rhythm in selected patients with persistent AF and HF, and can improve LV function, functional capacity, and HF symptoms compared with rate control. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01411371.

Basal septal hypertrophy.

A significant clinical problem is patients presenting with exercise-limiting dyspnoea, sometimes with associated chest pain, in the absence of detectable left ventricular (LV) systolic dysfunction, coronary artery disease, or lung disease. Often the patients are older, female, and have isolated basal septal hypertrophy (BSH), frequently on a background of mild hypertension. The topic of breathlessness in patients with clinical heart failure, but who have a normal ejection fraction (HFNEF) has attracted significant controversy over the past few years. This review aims to analyse the literature on BSH, identify the possible associations between BSH and HFNEF, and consequently explore possible pathophysiological mechanisms whereby clinical symptoms are experienced.

Contrasting effect of different cardiothoracic operations on echocardiographic right ventricular long axis velocities, and implications for interpretation of post-operative values.

BACKGROUND: Patients undergoing coronary artery bypass grafting (CABG) experience a reduction in right ventricular long axis velocities post surgery. OBJECTIVES: We tested whether the phenomenon of right ventricular (RV) long axis velocity decline depends on the chest being opened fully by mid-line sternotomy, pericardial incision, or on the type of operation performed. METHOD: By intraoperative transoesophageal echocardiography (TEE) we recorded serial right ventricular (RV) systolic pulse-wave tissue Doppler velocities during 6 types of elective procedure: 53 CABG surgery, 15 robotic-assisted minimally-invasive CABG (RCABG), 28 aortic valve replacement (AVR), 8 minimally-invasive aortic valve replacement (mini-AVR), 5 mediastinal mass excision, and 1 left atrial myxoma excision. Pre and post operative transthoracic echocardiography (TTE) were also conducted. RESULTS: Surgery without substantial opening of the pericardium did not significantly reduce RV systolic velocities (RCABG 13 ± 1.8 versus 12.4 ± 2.7 cm/s post; mini-AVR 11.9 ± 2.3 versus 11.1 ± 2.3 cm/s; mediastinal mass excision 13.9 ± 3.1 versus 13.8 ± 4 cm/s). In contrast, within 5 min of pericardial incision those whose surgery involved full opening of the pericardium had large reductions in RV velocities: 54 ± 11% decline with CABG (11.3 ± 1.9 to 5.1 ± 1.6 cm/s, p<0.0001), 54 ± 5% with AVR (12.6 ± 1.4 to 5.7 ± 0.6 cm/s, p<0.001) and 49% with left atrial myxoma excision (11.3 to 15.8 cm/s). This persisted immediately after pericardial opening to the end of surgery (61 ± 11%, p<0.0001; 58 ± 7%, p<0.0001; 59% respectively). CONCLUSIONS: It is full opening of the pericardium, and not cardiac surgery in general, which causes RV long axis decline following cardiac surgery. The impact is immediate (within 5 min) and persistent.

First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study.

BACKGROUND: Sympathetic overactivation, is reduced by renal denervation in drug-resistant hypertension. A similar role for renal denervation in heart failure remains unstudied, partly due to the concern about potential concomitant deleterious blood pressure reductions. This pilot study evaluated the safety of renal denervation for heart failure using an intensive follow-up protocol. METHOD: 7 patients (mean age 69 years) with chronic systolic heart failure (mean BP on referral 112/65 mmHg) on maximal tolerated heart failure therapy underwent bilateral renal denervation May-July 2011. Patients were admitted for pre-procedure baseline assessments and in-patient observation for 5 days following denervation. Follow-up was weekly for 4 weeks, and then monthly for 6 months. RESULTS: No significant haemodynamic disturbances were noted during the acute phase post renal denervation. Over 6 months there was a non-significant trend to blood pressure reduction (Δsystolic -7.1 ± 6.9 mmHg, p=0.35; Δdiastolic -0.6 ± 4.0 mmHg, p=0.88). No hypotensive or syncopal episodes were reported. Renal function remained stable (Δcreatinine -5.7 ± 8.4 µmol/l, p=0.52 and Δurea -1.0 ± 1.0 mmol/l, p=0.33). All 7 patients described themselves as symptomatically improved. The six minute walk distance at six months was significantly increased (Δ=27.1 ± 9.7 m, p=0.03), with each patient showing an increase. CONCLUSIONS: This study found no procedural or post procedural complications following renal denervation in patients with chronic systolic heart failure in 6 months of intensive follow-up. Results suggested improvements in both symptoms and exercise capacity, but further randomised, blinded sham-controlled clinical trials are required to determine the impact of renal denervation on morbidity and mortality in systolic heart failure. These data suggest such trials will be safe. ClinicalTrial.gov NCT01584700

A systematic approach to designing reliable VV optimization methodology: assessment of internal validity of echocardiographic, electrocardiographic and haemodynamic optimization of cardiac resynchronization therapy.

BACKGROUND: In atrial fibrillation (AF), VV optimization of biventricular pacemakers can be examined in isolation. We used this approach to evaluate internal validity of three VV optimization methods by three criteria. METHODS AND RESULTS: Twenty patients (16 men, age 75 ± 7) in AF were optimized, at two paced heart rates, by LVOT VTI (flow), non-invasive arterial pressure, and ECG (minimizing QRS duration). Each optimization method was evaluated for: singularity (unique peak of function), reproducibility of optimum, and biological plausibility of the distribution of optima. The reproducibility (standard deviation of the difference, SDD) of the optimal VV delay was 10 ms for pressure, versus 8 ms (p=ns) for QRS and 34 ms (p<0.01) for flow. Singularity of optimum was 85% for pressure, 63% for ECG and 45% for flow (Chi(2)=10.9, p<0.005). The distribution of pressure optima was biologically plausible, with 80% LV pre-excited (p=0.007). The distributions of ECG (55% LV pre-excitation) and flow (45% LV pre-excitation) optima were no different to random (p=ns). The pressure-derived optimal VV delay is unaffected by the paced rate: SDD between slow and fast heart rate is 9 ms, no different from the reproducibility SDD at both heart rates. CONCLUSIONS: Using non-invasive arterial pressure, VV delay optimization by parabolic fitting is achievable with good precision, satisfying all 3 criteria of internal validity. VV optimum is unaffected by heart rate. Neither QRS minimization nor LVOT VTI satisfy all validity criteria, and therefore seem weaker candidate modalities for VV optimization. AF, unlinking interventricular from atrioventricular delay, uniquely exposes resynchronization concepts to experimental scrutiny.

The acute effects of changes to AV delay on BP and stroke volume: potential implications for design of pacemaker optimization protocols.

BACKGROUND: The AV delay optimization of biventricular pacemakers (cardiac resynchronization therapy) may maximize hemodynamic benefit but consumes specialist time to conduct echocardiographically. Noninvasive BP monitoring is a potentially automatable alternative, but it is unknown whether it gives the same information and similar precision (signal/noise ratio). Moreover, the immediate BP increment on optimization has been reported to decay away: it is unclear whether this is the result of an (undesirable) decrease in stroke volume or a (desirable) compensatory relief of peripheral vasoconstriction. METHODS AND RESULTS: To discriminate between these alternative mechanisms, we measured simultaneous beat-to-beat stroke volume (flow) using Doppler echocardiography, and BP using finger photoplethysmography, during and after AV delay changes from 40 to 120 ms in 19 subjects with cardiac pacemakers. BP and stroke volume both increased immediately (P<0.001, within 1 heartbeat). BP showed a clear decline a few seconds later (average rate, -0.65 mm Hg/beat; r=0.95 [95% CI, 0.86-0.98]); in contrast, stroke volume did not decline (P=0.87). The immediate BP increment correlated strongly with the stroke volume increment (r=0.74, P<0.001). The signal/noise ratio was 3-fold better for BP than stroke volume (6.8±3.5 versus 2.3±1.4; P<0.001). CONCLUSIONS: Improving AV delay immediately increases BP, but the effect begins to decay within a few seconds. Reassuringly, this is because of compensatory vasodilatation rather than reduction in cardiac function. Pacemaker optimization will never be reliable unless there is an adequate signal/noise ratio. Using BP rather than Doppler minimizes noise. The early phase (before vascular compensation) has the richest signal lode.

Selective right ventricular impairment following coronary artery bypass graft surgery.

BACKGROUND: The right ventricle (RV) may be selectively impaired following coronary artery bypass graft (CABG) surgery. We tested this hypothesis in two study parts: a prospective cohort undergoing CABG, and a retrospective cross-sectional cohort of heart-failure patients with and without a history of CABG. METHODS: In the prospective study, 20 patients undergoing CABG had echocardiography prior to surgery and 3 months postoperatively. In the retrospective study, 101 patients with established heart failure underwent echocardiography, 40 of whom had undergone previous CABG and 61 of whom had not. Myocardial tissue Doppler velocities were used as a measure of left and right ventricular function. To adjust for varying degrees of overall cardiac impairment, we calculated the ratio between the velocities of the RV and left ventricle (LV). RESULTS: In the prospective study, there was a significant fall in RV:LV ratio following CABG surgery. For S', the ratio fell from 2.27 to 1.13 (50%, p<0.0001), for E' from 1.49 to 0.94 (37%, p<0.0001) and for A' from 1.66 to 1.05 (37%, p<0.0001). In the retrospective study, the RV:LV ratio was lower in the CABG group compared with the non-CABG group for S' (by 32%, p<0.001), E' (by 39%, p<0.001) and A' (by 37%, p<0.001). In the retrospective study, even when the CABG patients were compared with the ischaemic aetiology heart-failure patients without CABG, a similar relative impairment was seen: 25% in S' (p<0.001), 34% in E' (p<0.001) and by 38% in A' (p<0.002). CONCLUSIONS: Both prospectively and cross-sectionally, there is evidence of substantial, selective right ventricular impairment following CABG. These features cannot be explained simply by some general feature of ischaemia and, therefore, must be a consequence of surgery.

Usefulness of a Z-score of E' versus raw E' velocities to detect left ventricular dysfunction in patients with mitral or aortic regurgitation or dilated cardiomyopathy.

Despite their potential as a sensitive measure of ventricular performance, tissue Doppler velocities vary with normal aging. This is inconvenient for nonspecialists to interpret and makes it difficult to use as an entry criterion for clinical studies. The age-adjusted tissue Doppler Z-scores might avoid these disadvantages and be more discriminant for myocardial impairment than the raw velocities. We conducted a meta-regression of studies reporting age-specific normal tissue Doppler velocities to determine a consensus formula for Z-scores (8 studies, 1,867 patients) that we then tested in an independent study at our institution. We next compared the Z-scores head-to-head with the raw velocities for their ability to distinguish a fresh set of 81 healthy subjects from groups in whom subtle ventricular dysfunction might be expected, including 50 patients with dilated cardiomyopathy, 50 with aortic regurgitation, and 50 with mitral regurgitation. The discriminant capacity, assessed by the area under the receiver operating characteristic curves, was higher for the Z-scores than for the raw velocities in each patient group. At the septal angle of the mitral annulus: dilated cardiomyopathy 0.95 versus 0.92 (p = 0.03), aortic regurgitation 0.83 versus 0.78 (p = 0.02), mitral regurgitation 0.85 versus 0.81 (p = 0.04). At the lateral angle: dilated cardiomyopathy 0.94 versus 0.88 (p = 0.005), aortic regurgitation 0.92 versus 0.83 (p = 0.001), mitral regurgitation 0.87 versus 0.85 (p = 0.31). In conclusion, the Z-scores of the tissue Doppler velocities were better than the raw velocities at detecting myocardial impairment in valvular or heart muscle disease. The calculation needs only the raw velocity and patient age. Tissue Doppler Z-scores could be used to create a novel, more sensitive, definition of ventricular dysfunction and might make it easier for nonspecialists to interpret the reports.

Reduced confounding by impaired ventilatory function with oxygen uptake efficiency slope and VE/VCO2 slope rather than peak oxygen consumption to assess exercise physiology in suspected heart failure.

Heart failure and ventilatory disease often coexist; both create abnormalities in cardiopulmonary exercise test measurements. The authors evaluated the relative dependency of a well-recognized index of heart failure, peak oxygen consumption (VO(2)), and 2 newer indices, the minute ventilation (VE)/carbon dioxide production (VCO(2)) slope and oxygen uptake efficiency slope (OUES), on standard markers of impaired cardiac and ventilatory function. One hundred twenty-four patients (median age, 65.8; range, 22.6-84.9), with functional limitation from clinical heart failure were exercised. Peak VO(2) was 17.14 ± 7.58 mL/kg/min, VE/VCO(2) slope 50.1 ± 20.1, OUES 1.46 ± 0.68 L/min, and forced expiratory volume in 1 second (FEV(1) ) 1.88 ± 0.75 L. Peak VO(2) is substantially more sensitive to FEV(1) than ejection fraction (4.0 mL/kg/min difference between above- and below-median FEV(1) and 1.5 mL/kg/min between above- and below-median ejection fraction). OUES does not share this peculiar excess sensitivity to FEV(1) (0.12 L/min difference between above- and below-median FEV(1) and 0.01 L/min between above- and below-median ejection fraction). VE/VCO(2) slope has a borderline effect by FEV(1) (7.07 difference between above- and below-median FEV(1) and 2.07 between above- and below-median ejection fraction). Although widely used as a marker of heart failure severity, peak VO(2) is very sensitive to spirometry status and is indeed more affected by FEV(1) than by ejection fraction. OUES in contrast does not show this preferential sensitivity to impaired FEV(1).

Novel use of cardiac pacemakers in heart failure to dynamically manipulate the respiratory system through algorithmic changes in cardiac output.

BACKGROUND: Alternation of heart rate between 2 values using a pacemaker generates oscillations in end-tidal CO(2) (et-CO(2)). This study examined (a) whether modulating atrioventricular delay can also do this, and (b) whether more gradual variation of cardiac output can achieve comparable changes in et-CO(2) with less-sudden changes in blood pressure. METHODS AND RESULTS: We applied pacemaker fluctuations by adjusting heart rate (by 30 bpm) or atrioventricular delay (between optimal and nonoptimal values) or both, with period of 60 s in 19 heart failure patients (age 73+/-11, EF 29+/-12%). The changes in cardiac output, by either heart rate or atrioventricular delay or both, were made either as a step ("square wave") or more gradually ("sine wave"). We obtained changes in cardiac output sufficient to engender comparable oscillations in et-CO(2) (P=NS) in all 19 patients either by manipulation of heart rate (14), or by atrioventricular delay (2) or both (3). The square wave produced 191% larger and 250% more sudden changes in blood pressure than the sine wave alternations (22.4+/-11.7 versus 13.6+/-4.5 mm Hg, P<0.01 and 19.8+/-10.0 versus 7.9+/-3.2 mm Hg over 5 s, P<0.01), but peak-to-trough et-CO(2) elicited was only 45% higher (0.45+/-0.18 versus 0.31+/-0.13 kPa, P=0.01). CONCLUSIONS: This study shows that cardiac output is the key to dynamically manipulating the respiratory system with pacing sequences. When manipulating respiration by this route, a sine wave pattern may be preferable to a square wave, because it minimizes sudden blood pressure fluctuations.