Distinct impacts of heart rate and right atrial-pacing on left atrial mechanical activation and optimal AV delay in CRT.

BACKGROUND: Controversy exists regarding how atrial activation mode and heart rate affect optimal atrioventricular (AV) delay in cardiac resynchronization therapy. We studied these questions using high-reproducibility hemodynamic and echocardiographic measurements. METHODS: Twenty patients were hemodynamically optimized using noninvasive beat-to-beat blood pressure at rest (62 ± 11 beats/min), during exercise (80 ± 6 beats/min), and at three atrially paced rates: 5, 25, and 45 beats/min above rest, denoted as Apaced,r+5 , Apaced,r+25 , and Apaced,r+45 , respectively. Left atrial myocardial motion and transmitral flow were timed echocardiographically. RESULTS: During atrial sensing, raising heart rate shortened optimal AV delay by 25 ± 6 ms (P < 0.001). During atrial pacing, raising heart rate from Apaced,r+5 to Apaced,r+25 shortened it by 16 ± 6 ms; Apaced,r+45 shortened it 17 ± 6 ms further (P < 0.001). In comparison to atrial-sensed activation, atrial pacing lengthened optimal AV delay by 76 ± 6 ms (P < 0.0001) at rest, and at ∼20 beats/min faster, by 85 ± 7 ms (P < 0.0001), 9 ± 4 ms more (P  =  0.017). Mechanically, atrial pacing delayed left atrial contraction by 63 ± 5 ms at rest and by 73 ± 5 ms (i.e., by 10 ± 5 ms more, P < 0.05) at ∼20 beats/min faster. Raising atrial rate by exercise advanced left atrial contraction by 7 ± 2 ms (P  =  0.001). Raising it by atrial pacing did not (P  =  0.2). CONCLUSIONS: Hemodynamic optimal AV delay shortens with elevation of heart rate. It lengthens on switching from atrial-sensed to atrial-paced at the same rate, and echocardiography shows this sensed-paced difference in optima results from a sensed-paced difference in atrial electromechanical delay. The reason for the widening of the sensed-paced difference in AV optimum may be physiological stimuli (e.g., adrenergic drive) advancing left atrial contraction during exercise but not with fast atrial pacing.

Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure.

RATIONALE: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited. OBJECTIVES: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance "strength") rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects. METHODS: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation. MEASUREMENTS AND MAIN RESULTS: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain-consequent to increased chemosensitivity and delay-the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = -0.68) oscillations (P < 0.001 for all, both groups combined). CONCLUSIONS: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population.

Fully automatable, reproducible, noninvasive simple plethysmographic optimization: proof of concept and potential for implantability.

BACKGROUND: Hemodynamic optimization of cardiac resynchronization therapy (CRT) can be achieved reproducibly and--with bulky, nonimplantable equipment--noninvasively. We explored whether a simple photoplethysmogram signal might be used instead. METHOD: Twenty patients (age 65 ± 12) with CRT underwent automatic atrioventricular (AV) delay optimization, using a multiple-transitions protocol, at two atrially paced heart rates: just above sinus rate ("slow ApVp," 77 ± 11 beats per minute [bpm]) and 100 bpm ("fast ApVp"). We then retested to assess short-term reproducibility. RESULTS: All 80 optimizations identified an optimum (correctly oriented parabola). At 100 bpm, the simple photoplethysmogram had wider scatter between repeat optimizations than did Finometer: standard deviation of difference (SDD) 22 ms versus 14 ms, respectively, P = 0.028. The simple photoplethysmogram improved in reproducibility when slope (instead of peak) of its signal was used for optimization, becoming as reproducible as Finometer (SDD 14 ms vs 14 ms, P = 0.50). At slow heart rate, reproducibility of simple photoplethysmogram-based optimization worsened from 14 to 22 ms (P = 0.028), and Finometer-based optimization from 14 to 26 ms (P = 0.005). Increasing the number of replicates averaged improved reproducibility. For example, SDD of simple photoplethysmogram optimization (using peak) fell from 62 ms with two replicates to 22 ms with eight replicates (P < 0.0001). At 100 bpm, the eight-replicate protocol takes ∼12 minutes. CONCLUSIONS: A 12-minute protocol of simple photoplethysmographic AV optimization can be processed fully automatically. Blinded test-retest reproducibility of the optimum AV is good and improves with more replicates. If benefits to some patients are not to be neutralized by harm to others, endpoint studies should first test check narrowness of "within-patient error bars."

When is an optimization not an optimization? Evaluation of clinical implications of information content (signal-to-noise ratio) in optimization of cardiac resynchronization therapy, and how to measure and maximize it.

Impact of variability in the measured parameter is rarely considered in designing clinical protocols for optimization of atrioventricular (AV) or interventricular (VV) delay of cardiac resynchronization therapy (CRT). In this article, we approach this question quantitatively using mathematical simulation in which the true optimum is known and examine practical implications using some real measurements. We calculated the performance of any optimization process that selects the pacing setting which maximizes an underlying signal, such as flow or pressure, in the presence of overlying random variability (noise). If signal and noise are of equal size, for a 5-choice optimization (60, 100, 140, 180, 220 ms), replicate AV delay optima are rarely identical but rather scattered with a standard deviation of 45 ms. This scatter was overwhelmingly determined (ρ = -0.975, P < 0.001) by Information Content, [Formula: see text], an expression of signal-to-noise ratio. Averaging multiple replicates improves information content. In real clinical data, at resting, heart rate information content is often only 0.2-0.3; elevated pacing rates can raise information content above 0.5. Low information content (e.g. <0.5) causes gross overestimation of optimization-induced increment in VTI, high false-positive appearance of change in optimum between visits and very wide confidence intervals of individual patient optimum. AV and VV optimization by selecting the setting showing maximum cardiac function can only be accurate if information content is high. Simple steps to reduce noise such as averaging multiple replicates, or to increase signal such as increasing heart rate, can improve information content, and therefore viability, of any optimization process.

Maximizing efficiency of alternation algorithms for hemodynamic optimization of the AV delay of cardiac resynchronization therapy.

BACKGROUND: During optimization of the atrioventricular (AV) delay of cardiac resynchronization therapy (CRT), it is not known exactly which windows of time around the transition are most informative for identification of the optimum. METHOD AND RESULTS: IN 22 patients with CRT, we performed AV delay optimization using continuous noninvasive hemodynamics. We used signal-to-noise ratio to determine the most efficient averaging window location and width. We found that it is most efficient to position the averaging windows immediately before and immediately after the transition in AV delay. For example, skipping five beats after the transition decreases signal-to-noise ratio by 17.5% (P < 0.0001). Similarly, skipping five beats immediately before the transition reduces signal-to-noise ratio by 11.7% (P < 0.0001). The best choice of "fixed" averaging window width was found to be six beats, with signal-to-noise ratio falling by, for example, 41% for a one-beat window (P = 0.0002). However, even better was to set the window width for each patient to match one respiratory cycle. We observed that the pre- and posttransition signal-to-noise ratio traces begin to diverge three beats after the transition in AV delay. We believe this represents the time taken for the peripheral response to pacing-induced changes in stroke volume to occur. CONCLUSIONS: THE most efficient way to use alternating transitions for the hemodynamic optimization of CRT is to use an averaging window of one respiratory cycle, and not to skip any beats between the pretransition and posttransition averaging windows.

Dynamic CO2 therapy in periodic breathing: a modeling study to determine optimal timing and dosage regimes.

We examine the potential to treat unstable ventilatory control (seen in periodic breathing, Cheyne-Stokes respiration, and central sleep apnea) with carefully controlled dynamic administration of supplementary CO(2), aiming to reduce ventilatory oscillations with minimum increment in mean CO(2). We used a standard mathematical model to explore the consequences of phasic CO(2) administration, with different timing and dosing algorithms. We found an optimal time window within the ventilation cycle (covering approximately 1/6 of the cycle) during which CO(2) delivery reduces ventilatory fluctuations by >95%. Outside that time, therapy is dramatically less effective: indeed, for more than two-thirds of the cycle, therapy increases ventilatory fluctuations >30%. Efficiency of stabilizing ventilation improved when the algorithm gave a graded increase in CO(2) dose (by controlling its duration or concentration) for more severe periodic breathing. Combining gradations of duration and concentration further increased efficiency of therapy by 22%. The (undesirable) increment in mean end-tidal CO(2) caused was 300 times smaller with dynamic therapy than with static therapy, to achieve the same degree of ventilatory stabilization (0.0005 vs. 0.1710 kPa). The increase in average ventilation was also much smaller with dynamic than static therapy (0.005 vs. 2.015 l/min). We conclude that, if administered dynamically, dramatically smaller quantities of CO(2) could be used to reduce periodic breathing, with minimal adverse effects. Algorithms adjusting both duration and concentration in real time would achieve this most efficiently. If developed clinically as a therapy for periodic breathing, this would minimize excess acidosis, hyperventilation, and sympathetic overactivation, compared with static treatment.

Improving haemodynamic optimization of cardiac resynchronization therapy for heart failure.

OBJECTIVE: Optimization of cardiac resynchronization therapy using non-invasive haemodynamic parameters produces reliable optima when performed at high atrial paced heart rates. Here we investigate whether this is a result of increased heart rate or atrial pacing itself. APPROACH: Forty-three patients with cardiac resynchronization therapy underwent haemodynamic optimization of atrioventricular (AV) delay using non-invasive beat-to-beat systolic blood pressure in three states: rest (atrial-sensing, 66 ± 11 bpm), slow atrial pacing (73 ± 12 bpm), and fast atrial pacing (94 ± 10 bpm). A 20-patient subset underwent a fourth optimization, during exercise (80 ± 11 bpm). MAIN RESULTS: Intraclass correlation coefficient (ICC, quantifying information content mean ±SE) was 0.20 ± 0.02 for resting sensed optimization, 0.45 ± 0.03 for slow atrial pacing (p  < 0.0001 versus rest-sensed), and 0.52 ± 0.03 for fast atrial pacing (p  = 0.12 versus slow-paced). 78% of the increase in ICC, from sinus rhythm to fast atrial pacing, is achieved by simply atrially pacing just above sinus rate. Atrial pacing increased signal (blood pressure difference between best and worst AV delay) from 6.5 ± 0.6 mmHg at rest to 13.3 ± 1.1 mmHg during slow atrial pacing (p  < 0.0001) and 17.2 ± 1.3 mmHg during fast atrial pacing (p  = 0.003 versus slow atrial pacing). Atrial pacing reduced noise (average SD of systolic blood pressure measurements) from 4.9 ± 0.4 mmHg at rest to 4.1 ± 0.3 mmHg during slow atrial pacing (p  = 0.28). At faster atrial pacing the noise was 4.6 ± 0.3 mmHg (p  = 0.69 versus slow-paced, p  = 0.90 versus rest-sensed). In the exercise subgroup ICC was 0.14 ± 0.02 (p  = 0.97 versus rest-sensed). SIGNIFICANCE: Atrial pacing, rather than the increase in heart rate, contributes to ~80% of the observed information content improvement from sinus rhythm to fast atrial pacing. This is predominantly through increase in measured signal.

The atrioventricular delay of cardiac resynchronization can be optimized hemodynamically during exercise and predicted from resting measurements.

BACKGROUND: Atrioventricular (AV) optimization of cardiac resynchronization therapy (CRT) is typically calculated at rest. However, patients often become symptomatic during exercise. OBJECTIVE: In this study, we use acute noninvasive hemodynamics to optimize the AV delay of CRT during exercise and investigate whether this exercise optimum can be predicted from a three-phase resting model. METHODS: In 20 patients with CRT, we adjusted the sensed AV delay while the patient exercised on a treadmill up to a heart rate of 100 bpm to identify the hemodynamically optimal value. Separately, at rest, by pacing with three different configurations and calculating the sensed-paced difference, we calculated an "expected" value for the exercise optimum. RESULTS: It was possible to perform AV delay optimization while a patient exercised. The resting three-phase model correlated well with the actual exercise optimal AV delay (r = 0.85, mean difference +/- standard deviation [SD] = 3.7 +/- 17 ms). Simply using measurements made at rest during atrial-sensed pacing showed a poorer correlation with exercise (r = 0.64, mean difference +/- SD = 2.2 +/- 24 ms). The three-phase resting model allows improved exercise hemodynamics to be achieved. Programming according to the three-phase resting model yields an exercise blood pressure of only 0.5 mmHg (+/-1.4 mmHg; P = NS) less than the true exercise optimum, whereas programming the resting sensed optimum yields an exercise blood pressure of 1.4 mmHg (+/-2.2 mmHg, P = .02) less than the true optimum. CONCLUSIONS: Using acute noninvasive hemodynamics and a protocol of alternations, it is possible to optimize the AV delay of cardiac resynchronization devices even while a patient exercises. In clinical practice, the exercise optimum AV delay could be determined from three phases of resting measurements, without performing exercise.

Analytical identification of ideal pulmonary-systemic flow balance in patients with bidirectional cavopulmonary shunt and univentricular circulation: oxygen delivery or tissue oxygenation?

BACKGROUND: In the present study, we extended previous mathematical modeling work on patients with bidirectional cavopulmonary ("bidirectional Glenn") anastomosis to assess the potential utility of several descriptors of oxygen status. We set out to determine which of these descriptors best represents the overall tissue oxygenation. We also introduce a new descriptor, SO2min, defined as the lower of the superior and inferior vena cava oxygen saturations. METHODS AND RESULTS: The application of differential calculus to a model of oxygen physiology of patients with bidirectional Glenn allowed simultaneous assessment of all possible distributions of blood flow and metabolic rate between upper and lower body, across all cardiac outputs, total metabolic rates, and oxygen-carrying capacities. When total cardiac output is fixed, although it may intuitively seem best to distribute flow to maximize oxygen delivery (total, upper body, or lower body), we found that for each variable, there are situations in which its maximization seriously deprives flow to the upper or lower circulation. In contrast, maximizing SO2min always gives physiologically sensible results. If the majority of metabolism is in the upper body (typical of infancy), then oxygenation is optimized when flow distribution matches metabolic distribution. In contrast, if the majority of metabolism is in the lower body (typical of older children and during exercise), oxygenation is optimal when flows are equal. CONCLUSIONS: In patients with bidirectional cavopulmonary anastomosis, because there is a tradeoff between flow distribution and saturation, it is unwise to concentrate on maximizing oxygen delivery. Maximizing systemic venous saturations (especially SO2min) is conceptually different and physiologically preferable for tissue oxygenation.

Evidence of a dominant backward-propagating "suction" wave responsible for diastolic coronary filling in humans, attenuated in left ventricular hypertrophy.

BACKGROUND: Coronary blood flow peaks in diastole when aortic blood pressure has fallen. Current models fail to completely explain this phenomenon. We present a new approach-using wave intensity analysis-to explain this phenomenon in normal subjects and to evaluate the effects of left ventricular hypertrophy (LVH). METHOD AND RESULTS: We measured simultaneous pressure and Doppler velocity with intracoronary wires in the left main stem, left anterior descending, and circumflex arteries of 20 subjects after a normal coronary arteriogram. Wave intensity analysis was used to identify and quantify individual pressure and velocity waves within the coronary artery circulation. A consistent pattern of 6 predominating waves was identified. Ninety-four percent of wave energy, accelerating blood forward along the coronary artery, came from 2 waves: first a pushing wave caused by left ventricular ejection-the dominant forward-traveling pushing wave; and later a suction wave caused by relief of myocardial microcirculatory compression-the dominant backward-traveling suction wave. The dominant backward-traveling suction wave (18.2+/-13.7 x 10(3) W m(-2)s(-1), 30%) was larger than the dominant forward-traveling pushing wave (14.3+/-17.6 x 10(3) W m(-2) s(-1), 22.3%, P =0.001) and was associated with a substantially larger increment in coronary blood flow velocity (0.51 versus 0.14 m/s, P <0.001). In LVH, the dominant backward-traveling suction wave percentage was significantly decreased (33.1% versus 26.9%, P =0.01) and inversely correlated with left ventricular septal wall thickness (r =-0.52, P <0.02). CONCLUSIONS: Six waves predominantly drive human coronary blood flow. Coronary flow peaks in diastole because of the dominance of a "suction" wave generated by myocardial microcirculatory decompression. This is significantly reduced in LVH.

A long-term follow-up of patients with prolonged asystole of greater than 15s on head-up tilt testing.

BACKGROUND: Head-up tilt (HUT) is used for diagnosis of vasovagal syncope (VVS), and can provoke cardioinhibition. VVS is usually considered benign, however pacemaker insertion may be indicated in some patients. We sought to characterize the long-term outcomes of patients with prolonged asystole (>15s) on HUT. METHODS: We conducted a retrospective study on patients with asystole >15s on HUT identified from 5133 patients who were investigated between 1998 and 2012 at our institution. Patients were mailed questionnaires or telephoned to ascertain outcomes. Where contact was not possible, the patients' general practitioners were contacted to request up-to-date information. RESULTS: A total of 26 patients with a mean age of 45 ± 18 years and a mean duration of asystole on HUT of 26 ± 7s were successfully followed up from a total of 77 patients identified. The follow-up duration was 99 ± 39 months. Six patients had undergone pacemaker (PPM) implantation. Of the patients without PPM, 16 reported spontaneously improved symptoms. Ten patients sustained injury prior to HUT compared with one after HUT, when a clear diagnosis was made and management advice was given. There were no major injuries or deaths after HUT. The 6 patients with PPMs had a mean age of 60 ± 16 (67% male) at HUT. Four patients had no further syncope after PPM and two demonstrated improvement but still experienced recurrent syncope. CONCLUSIONS: Prolonged asystole (>15s) on tilt does not necessarily predict adverse outcomes with most patients improving spontaneously over the long-term. Pacemaker insertion in selected patients may reduce syncope recurrence but does not always abolish it.

Defining the real-world reproducibility of visual grading of left ventricular function and visual estimation of left ventricular ejection fraction: impact of image quality, experience and accreditation.

Left ventricular function can be evaluated by qualitative grading and by eyeball estimation of ejection fraction (EF). We sought to define the reproducibility of these techniques, and how they are affected by image quality, experience and accreditation. Twenty apical four-chamber echocardiographic cine loops (Online Resource 1-20) of varying image quality and left ventricular function were anonymized and presented to 35 operators. Operators were asked to provide (1) a one-phrase grading of global systolic function (2) an "eyeball" EF estimate and (3) an image quality rating on a 0-100 visual analogue scale. Each observer viewed every loop twice unknowingly, a total of 1400 viewings. When grading LV function into five categories, an operator's chance of agreement with another operator was 50% and with themself on blinded re-presentation was 68%. Blinded eyeball LVEF re-estimates by the same operator had standard deviation (SD) of difference of 7.6 EF units, with the SD across operators averaging 8.3 EF units. Image quality, defined as the average of all operators' assessments, correlated with EF estimate variability (r = -0.616, p < 0.01) and visual grading agreement (r = 0.58, p < 0.01). However, operators' own single quality assessments were not a useful forewarning of their estimate being an outlier, partly because individual quality assessments had poor within-operator reproducibility (SD of difference 17.8). Reproducibility of visual grading of LV function and LVEF estimation is dependent on image quality, but individuals cannot themselves identify when poor image quality is disrupting their LV function estimate. Clinicians should not assume that patients changing in grade or in visually estimated EF have had a genuine clinical change.

Abnormal temporal dynamics of blood pressure and RR interval regulation in patients with chronic heart failure: relationship to baroreflex sensitivity.

It is not known whether the temporal relationship between blood pressure (BP) and RR interval is modulated by the same mechanisms in normal controls and patients with chronic heart failure (CHF). We investigated this under conditions of controlled slow breathing. Fifty patients with CHF and 17 age-matched normals underwent recordings of BP and RR interval during 0.1 Hz controlled breathing. Fourier analysis was used to determine the phase relationships between the oscillations in respiration, BP and RR interval. There was no significant difference between patients and normals in the distribution of phase angle between respiration and BP (P=0.06) or between respiration and RR interval (P=0.21). There was, however, a significant difference in the phase relationship between BP and RR interval (P=0.03): in normals, BP led RR interval by a mean phase angle of 48.4 degrees (S.D. 16.8 degrees ). In patients with CHF, the distribution of phase difference was much wider [34.4 degrees (S.D. 62.8 degrees )]. The source of this wide distribution was patients with attenuated baroreflex sensitivity (BRS), with those with preserved BRS showing a relationship between BP and RR interval similar to the normal group. During controlled respiration, normal subjects exhibit a stereotyped relationship between oscillations in BP and RR interval, which is mediated by the baroreflex. This relationship is maintained in those patients with CHF who have a preserved BRS. In contrast, patients with an attenuated BRS show a wide distribution in the relationship between BP and RR interval ranging from completely in phase, to anti-phase. This may have important implications for the measurement and interpretation of BRS in patient groups where BRS is weak.

A direct analytical demonstration of the essential equivalence of detrended fluctuation analysis and spectral analysis of RR interval variability.

Detrended fluctuation analysis (DFA) of heart rate variability appears to yield improved prognostic power in cardiovascular disease, through calculation of the fractal scaling exponent alpha. We have recently used Taylor series approximations to propose that DFA is closely related to standard spectral analysis measures. We now present a direct analytical approach using integration and explicit expressions for the steps involved in DFA. This demonstrates clearly how DFA corresponds to standard spectral analysis.

Relationship between detrended fluctuation analysis and spectral analysis of heart-rate variability.

The recently-introduced technique of detrended fluctuation analysis (DFA) for heart-rate variability appears to yield improved prognostic power in cardiovascular disease through calculation of the fractal scaling exponent alpha. However, the physiological meaning of alpha remains unclear. In DFA, the signal is segmented into lengths from 4 to 64 beats. For each segmentation length (n), the individual segments are cumulated, detrended and the sum of the squares (F2) of residuals calculated. Alpha is the slope of log(F) against log(n). We show mathematical equivalence between alpha calculated by DFA and by a novel alternative method using frequency-weighted power spectra. We show F2 (and thus alpha) can be obtained from a frequency-weighted power spectrum without DFA. To do this, we cumulate and detrend the Taylor series of individual Fourier components. F2 is found to depend on the relationship between the signal period and segment length. F2 can therefore be expressed in terms of frequency-weighted power spectra. From this, the alpha coefficient of DFA can then be described in power-spectral terms, which facilitates exploration of its physiological basis. We confirm these findings using samples from 20 healthy volunteers and 40 patients with heart failure.

Automated speckle tracking algorithm to aid on-axis imaging in echocardiography.

Obtaining a "correct" view in echocardiography is a subjective process in which an operator attempts to obtain images conforming to consensus standard views. Real-time objective quantification of image alignment may assist less experienced operators, but no reliable index yet exists. We present a fully automated algorithm for detecting incorrect medial/lateral translation of an ultrasound probe by image analysis. The ability of the algorithm to distinguish optimal from sub-optimal four-chamber images was compared to that of specialists-the current "gold-standard." The orientation assessments produced by the automated algorithm correlated well with consensus visual assessments of the specialists ([Formula: see text]) and compared favourably with the correlation between individual specialists and the consensus, [Formula: see text]. Each individual specialist's assessments were within the consensus of other specialists, [Formula: see text] of the time, and the algorithm's assessments were within the consensus of specialists 85% of the time. The mean discrepancy in probe translation values between individual specialists and their consensus was [Formula: see text], and between the automated algorithm and specialists' consensus was [Formula: see text]. This technology could be incorporated into hardware to provide real-time guidance for image optimisation-a potentially valuable tool both for training and quality control.

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.

Automated aortic Doppler flow tracing for reproducible research and clinical measurements.

In clinical practice, echocardiographers are often unkeen to make the significant time investment to make additional multiple measurements of Doppler velocity. Main hurdle to obtaining multiple measurements is the time required to manually trace a series of Doppler traces. To make it easier to analyze more beats, we present the description of an application system for automated aortic Doppler envelope quantification, compatible with a range of hardware platforms. It analyses long Doppler strips, spanning many heartbeats, and does not require electrocardiogram to separate individual beats. We tested its measurement of velocity-time-integral and peak-velocity against the reference standard defined as the average of three experts who each made three separate measurements. The automated measurements of velocity-time-integral showed strong correspondence (R(2) = 0.94) and good Bland-Altman agreement (SD = 1.39 cm) with the reference consensus expert values, and indeed performed as well as the individual experts ( R(2) = 0.90 to 0.96, SD = 1.05 to 1.53 cm). The same performance was observed for peak-velocities; ( R(2) = 0.98, SD = 3.07 cm/s) and ( R(2) = 0.93 to 0.98, SD = 2.96 to 5.18 cm/s). This automated technology allows > 10 times as many beats to be analyzed compared to the conventional manual approach. This would make clinical and research protocols more precise for the same operator effort.

Guidance for accurate and consistent tissue Doppler velocity measurement: comparison of echocardiographic methods using a simple vendor-independent method for local validation.

BACKGROUND: Variability has been described between different echo machines and different modalities when measuring tissue velocities. We assessed the consistency of tissue velocity measurements across different modalities and different manufacturers in an in vitro model and in patients. Furthermore, we present freely available software tools to repeat these evaluations. METHODS AND RESULTS: We constructed a simple setup to generate reproducible motion and used it to compare velocities measured using three echocardiographic modalities: M-mode, speckle tracking, and tissue Doppler, with a straightforward, non-ultrasound, optical gold standard. In the clinical phase, 25 patients underwent M-mode, speckle tracking, and tissue Doppler measurements of s', e', and a' velocities. In vitro, the M-mode and speckle tracking velocities agreed with optical assessment. Of the three possible tissue Doppler measurement conventions (outer, middle, and inner edge) only the middle agreed with optical assessment (discrepancy -0.20 (95% CI -0.44 to 0.03) cm/s, P = 0.11, outer +5.19 (4.65 to 5.73) cm/s, P < 0.0001, inner -6.26 (-6.87 to -5.65) cm/s, P < 0.0001). A similar pattern occurred across all four studied manufacturers. M-mode was therefore chosen as the in vivo gold standard. Clinical measurements of s' velocities by speckle tracking and the middle line of the tissue Doppler showed concordance with M-mode, while the outer line overestimated significantly (+1.27(0.96 to 1.59) cm/s, P < 0.0001) and the inner line underestimated (-1.82 (-2.11 to -1.52) cm/s, P < 0.0001). CONCLUSIONS: Echocardiographic velocity measurements can be more consistent than previously suspected. The statistically modal velocity, found at the centre of the spectral pulsed wave tissue Doppler envelope, most closely represents true tissue velocity. This article includes downloadable, vendor-independent software enabling calibration of echocardiographic machines using a simple, inexpensive in vitro setup.

Comparison of different invasive hemodynamic methods for AV delay optimization in patients with cardiac resynchronization therapy: implications for clinical trial design and clinical practice.

BACKGROUND: Reproducibility and hemodynamic efficacy of optimization of AV delay (AVD) of cardiac resynchronization therapy (CRT) using invasive LV dp/dtmax are unknown. METHOD AND RESULTS: 25 patients underwent AV delay (AVD) optimisation twice, using continuous left ventricular (LV) dp/dtmax, systolic blood pressure (SBP) and pulse pressure (PP). We compared 4 protocols for comparing dp/dtmax between AV delays: We assessed for dp/dtmax, LVSBP and LVPP, test-retest reproducibility of the optimum. Optimization using immediate absolute dp/dtmax had poor reproducibility (SDD of replicate optima=41 ms; R(2)=0.45) as did delayed absolute (SDD 39 ms; R(2)=0.50). Multiple relative had better reproducibility: SDD 23 ms, R(2)=0.76, and (p<0.01 by F test). Compared with AAI pacing, the hemodynamic increment from CRT, with the nominal AV delay was LVSBP 2% and LVdp/dtmax 5%, while CRT with pre-determined optimal AVD gave 6% and 9% respectively. CONCLUSIONS: Because of inevitable background fluctuations, optimization by absolute dp/dtmax has poor same-day reproducibility, unsuitable for clinical or research purposes. Reproducibility is improved by comparing to a reference AVD and making multiple consecutive measurements. More than 6 measurements would be required for even more precise optimization--and might be advisable for future study designs. With optimal AVD, instead of nominal, the hemodynamic increment of CRT is approximately doubled.