300 Years of Vernooy Family by W Vernooy
Abstract
Aims
Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational–experimental–clinical report.
Methods and results
Computer simulations were performed in the CircAdapt model of the normal and declining homo heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical written report, left ventricular (LV) pressure and book were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left package branch block QRS complex. Computer simulations and animate being studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10–15%. In computer simulations of failing hearts and in HF patients, reducing PR interval past biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± xxx ms) resulted in significant increases in LV stroke book and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated comeback of LV pump function coincided with both larger mitral arrival (E- and A-wave expanse) and reduction of diastolic mitral regurgitation.
Conclusion
Restoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, simply not RV pacing, may ameliorate cardiac function in patients with HF and prolonged PR interval.
Graphical Abstract
Graphical Abstract
What's new?
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Normalizing atrioventricular (AV) coupling using biventricular pacing in conditions of prolonged AV conduction times improves left ventricular pump function significantly, both in normal creature hearts and in failing human hearts.
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Increasing ventricular dyssynchrony past right ventricular pacing attenuates the beneficial effect of normalizing AV-coupling.
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Normalizing AV-coupling creates its haemodynamic benefit by both reducing diastolic mitral regurgitation and increasing mitral inflow.
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The similarity of the preclinical and clinical results with those from the computer simulations indicates that the mechanism of haemodynamic improvement by optimizing AV-delay tin exist explained past the well-established physical and physiological principles that are incorporated in the model, such as conservation of free energy, inertia of blood, and length-dependent activation of myocytes.
Introduction
Atrioventricular (AV) conduction filibuster (or: AV dromotropathy), as evidenced by a prolonged PR interval (>200 ms) on the electrocardiogram (ECG), is present in 15–51% of patients with heart failure (HF) and increases the risk of poor clinical effect. 1 A few minor studies in the 1990s suggested that shortening the AV-delay past ventricular pacing could improve cardiac pump office. 2 , three These studies were among the first to use ventricular pacing as a treatment for HF. Notably, these studies employed correct ventricular (RV) pacing, considering these were performed before the era of biventricular (BiV) pacing. In subsequent years, the attending for treatment of a prolonged PR interval faded equally it became overruled by cardiac resynchronization therapy (CRT). All the same, recent sub-analyses of clinical trials investigating the do good of CRT revitalized the interest in this topic. four While patients without left packet branch block (LBBB) generally bear witness piffling clinical improvement from CRT, a meaning benefit was observed in non-LBBB patients with prolonged PR interval. v Similarly, in a sub-study of the ReThinQ trial, which investigated the do good of CRT in patients with QRS duration <130 ms, but patients with a prolonged PR interval (>180 ms) showed a significant increase in maximum oxygen uptake. 6 The 2021 ESC guidelines on pacing and CRT recommend the use of pacing in patients with a PR interval >300 (Class II1, Level C) without recommending a pacing site. 7
Therefore, we hypothesized that restoring proper AV-coupling by pacing significantly improves cardiac pump function. Nosotros investigated this hypothesis and revealed the mechanisms of activeness using a three-step arroyo. First, the haemodynamic benefits of restoring AV-coupling were studied in a porcine model and a computational model of the non-declining middle with prolonged PR interval. Second, the confounding upshot of pacing-induced ventricular dyssynchrony and HF on the potential haemodynamic benefit of restoring AV-coupling was studied in the computational model. Third, a proof-of-principle clinical study was performed in patients with HF and a prolonged PR interval. In this study, a cut-off value for prolonged PR interval of 230 ms was chosen based on the subanalysis of the MADIT-CRT study. 5
Methods
Studies were performed in the CircAdapt computer model of the human being heart and circulation, in a porcine model of AV-block and in patients with HF and a prolonged PR interval (PR interval >230 ms).
Computer simulations
Previously, CircAdapt simulations of electro-mechanical and haemodynamic interventricular and atrioventricular interactions accept been extensively validated and practical nether physiological and pathophysiological conditions, including dyssynchronous HF and its treatment with pacing therapy (see Supplementary fabric online). In the CircAdapt model, a prolonged PR interval was simulated by increasing AV-delay from 150 ms to 300 ms in the reference simulation of the normal human heart with synchronous ventricular activation. Starting from this reference simulation, the following simulations were performed: (i) gradual shortening of the AV-delay from 300 to 50 ms (in steps of 25 ms) with synchronous ventricular activation (SYNC) and normal myocardial contractility, and (ii) gradual shortening of the AV-delay in a simulation of HF (LVEF < 35%) with synchronous ventricular activation and dyssynchronous ventricular activation, resembling BiV and RV pacing. Cardiac output (CO), transmitral flow patterns, mean arterial pressure (MAP), and ventricular volumes were obtained for all simulations. More methodological details about the model simulations are provided as Supplementary material online.
Fauna experiments
Animal handling was performed in compliance with the Guide for the Care and Use of Laboratory Animals and in accord with the European Community recommendations. The protocol was approved by the Dutch National Ethical Committee for Beast Handling.
Experiments were performed in seven female landrace pigs weighing 61 ± 3 kg. Animals were pre-medicated with intramuscular Zoletil (five mg/kg). Subsequently consecration with intravenous sodium thiopental (v–xv mg/kg), amazement was maintained by continuous infusion of Propofol (ten mg/kg/h), Sufentanyl (5 µg/kg/h), and Rocuronium (0.1 µg/kg/h). Details of the experimental model are provided in Figure ane. Complete AV-block was created by radiofrequency ablation of the AV-node. Subsequently, the animals were paced at the right atrial appendage and at the RV apex and left ventricular (LV) epicardial lateral wall. A seven-Fr conductance catheter (CD Leycom, Zoetermeer, The Netherlands) was introduced into the LV cavity via the femoral artery. A 4F Millar Mikro-Tip pressure catheter (Millar, Houston, TX, USA) was used to mensurate left atrial (LA) pressure level. A vascular flow probe (Transonic Europe B.V., Elsloo, Holland) was mounted around the ascending aorta to asses aortic flow and later calculate CO. Measurements were performed after instrumentation and haemodynamic stabilization using BiV pacing at 10 b.p.m. above intrinsic atrial rhythm with an AV-delay of 300 ms, mimicking prolonged PR interval, every bit baseline status. After, during BiV pacing the AV-delay was programmed between 50 and 250 ms in randomized steps of 50 ms. Baseline recordings were performed before every footstep. Each recording lasted for at to the lowest degree two respiratory cycles.
Figure 1
Schematic representation of the creature experimental ready-upwards. (A) Overview of the porcine model. Pacemaker leads were transvenously inserted in the right atrial (RA) bagginess and correct ventricular (RV) apex and attached to the left ventricular (LV) epicardium. Complete atrioventricular (AV) block was created by radiofrequency ablation of the AV-node. The LV force per unit area and book were measured using a conductance catheter and RV and left atrial (LA) pressure were measured using a cathetertip manometer. (B) Signal analysis. The first derivative of LV volume was used to calculate forwards menstruation over the mitral valve (blue area under E and A wave) and diastolic mitral regurgitation (MR, reddish area). The integral of aortic flow, measured by a flow probe, was used to quantify forward stroke volume and cardiac output (purple area).
Effigy i
Schematic representation of the animal experimental set-up. (A) Overview of the porcine model. Pacemaker leads were transvenously inserted in the right atrial (RA) appendage and right ventricular (RV) apex and attached to the left ventricular (LV) epicardium. Consummate atrioventricular (AV) cake was created past radiofrequency ablation of the AV-node. The LV force per unit area and volume were measured using a conductance catheter and RV and left atrial (LA) force per unit area were measured using a cathetertip manometer. (B) Signal analysis. The first derivative of LV volume was used to calculate forward catamenia over the mitral valve (blue area nether Due east and A wave) and diastolic mitral regurgitation (MR, red area). The integral of aortic menstruum, measured by a flow probe, was used to quantify forward stroke book and cardiac output (purple area).
Patient studies
The patient study was performed according to the principles of the Declaration of Helsinki and the study protocol was approved by the ethics committee of the Maastricht University Medical Center+ (registration number NL60764.068.17/METC 171013). All patients gave written informed consent prior to investigation, and the study was monitored by the Clinical Trial Center Maastricht. The study has been registered at clinicaltrials.gov (https://clinicaltrials.gov/ct2/bear witness/NCT03973944).
Patients were included in the Maastricht University Medical Eye+ (due north = 20), the Academy Medical Center Utrecht (due north = v), and the Amsterdam University Medical Center (n = one) from June 2018 to February 2020. Inclusion criteria were the presence of sinus rhythm, stable prolonged PR interval >230 ms, LV ejection fraction (LVEF) <35%, New York Heart Association (NYHA) functional class 2 to III, optimal HF medication, and indication for an implantable cardioverter-defibrillator (ICD). Patients were implanted with a CRT-D and LV atomic number 82 for this report, considering that this additional implantation creates minimal additional risk to the patient while the selection to provide CRT therapy was offered after the haemodynamic data of this study showed significant improvement. Patients were excluded when they already had a CRT device, in the presence of a class I CRT indication (LBBB or QRS duration >150 ms). Also, a resting middle rate >90 b.p.thou., chronic renal failure requiring dialysis, moderate to severe aortic stenosis, frequent premature ventricular complexes (≥2 complexes on a standard ECG), pregnant peripheral vascular disease, age beneath eighteen years or recent (<iii months) myocardial infarction, coronary artery featherbed graft, or valve surgery were exclusion criteria.
All participants underwent CRT device implantation co-ordinate to routine clinical practice. The atrial lead was positioned in the correct atrial bagginess, the RV lead in the RV upmost septum, and a quadripolar LV pb in a suitable vein on the posterolateral LV wall. A 7-Fr pressure–volume loop conductance catheter (CD Leycom, Zoetermeer, Kingdom of the netherlands) was introduced into the LV cavity via the femoral avenue.
The ECG and LV pressure and volume were recorded during BiV and RV pacing at four paced AV-delays. The paced AV-filibuster was set to ∼100%, 75%, 50%, and 25% of patient'south PR interval during baseline AAI pacing −30 ms to ensure capture at the longest AV-filibuster. 8 The pacing protocol (in DDD mode) was performed at ±10 b.p.m. to a higher place intrinsic sinus charge per unit. Interventricular pacing delay was set to −40 ms (LV starting time). Baseline measurements were performed during atrial pacing (AAI style) at the same pacing rate before and after each fashion of ventricular pacing. Pressure level–book loops were recorded for 60 s during the ventricular pacing protocol and 30 south before and after each setting in AAI mode. The latter were averaged and are referred to as baseline.
Data analysis
The acute haemodynamic effect of pacing at the unlike AV-delays in animals and patients was evaluated by invasive measurement of LV stroke volume and stroke work (area of the pressure–volume loop) too as the diastolic flow pattern, derived from the first derivative of the LV volume signal (menstruation; right console of Effigy 1) using a combination of the Conduct NT software (CD Leycom, Zoetermeer, Holland) and customized software programmed in MATLAB R2019b (MathWorks, Natick, MA, The states). Diastolic mitral regurgitation (MR) volume was quantified as the area below nix of the flow curve during diastole. Forwards period over the mitral valve was quantified as the combined expanse under the E- and A-waves (encounter also Figures one and 2). The diastolic MR fraction was divers every bit diastolic MR as a percentage of frontwards catamenia. In the animals, stroke volume was derived from the aortic catamenia probe. To account for spontaneous changes in baseline haemodynamic consequence parameters, each ventricular pacing setting was compared with the corresponding baseline. Ectopic ventricular beats and the two subsequent center beats were excluded from the analysis. Conductance catheter measurements were volume calibrated by adjusting baseline stroke volume to stroke volume measured using Swan Ganz thermodilution catheters in animals and to pre-procedural echocardiography in patients.
Figure 2
Haemodynamic event of improving atrioventricular (AV)-coupling in pig experiments and reckoner simulations during biventricular pacing. (Top row) LV and LA pressures, (second row) flow, and (third row) ECG from a representative experiment. (Quaternary and 5th row) Pressures and flow calculated from figurer simulations.
Figure ii
Haemodynamic upshot of improving atrioventricular (AV)-coupling in hog experiments and calculator simulations during biventricular pacing. (Top row) LV and LA pressures, (second row) flow, and (third row) ECG from a representative experiment. (Fourth and 5th row) Pressures and menstruation calculated from figurer simulations.
Statistical analysis of clinical and experimental written report
Statistical analysis was performed using Statistical Packet for Social Sciences version 24.0 (SPSS Inc., Chicago, IL, USA). Continuous data are presented as mean ± standard divergence (SD). The relative change of the haemodynamic variables at various AV-delays was evaluated using a one-way repeated measures ANOVA. If significant, a Pupil'south paired samples T-exam and Bonferroni correction was used to test significance of the change at individual AV-delays. To evaluate differences between unlike pacing modes, two-way ANOVA for repeated measurements was used, followed past Student's paired samples T-test. A ii-sided probability value of <0.05 was considered statistically significant.
Results
Restoring atrioventricular-coupling in normal hearts: animal experimental and computational analyses
Results from beast experiments and computer simulations showed proficient qualitative and quantitative agreement (Figure 2). Under baseline conditions at long AV-delay, the filibuster of ventricular activation resulted in (i) suboptimal LV filling with the early filling moving ridge (E) existence fused with or prematurely interrupted past the atrial filling wave (A), and (2) diastolic MR due to atrial relaxation and related atrial pressure drib occurring before the onset of ventricular activation and, hence, papillary muscle contraction. At intermediate AV-delays (150 ms) separated E- and A-waves were observed. At brusk AV-delays, A-moving ridge truncation occurred as well as increases in acme and mean LA force per unit area, presumably caused by atrial wrinkle confronting a airtight mitral valve.
Effigy 3 depicts that in the computer simulations and the animal studies, the largest increase in LV end-diastolic volume was observed at the AV-filibuster leading to the LV filling pattern with well-nigh pronounced East–A wave separation (175 ms in the simulations, 157 ± 7 ms in the animals) and leading to minimal diastolic MR. At this setting, MAP and CO were likewise increased (both ∼xv% in simulations and ∼10% in animals). Chiefly, in the beast studies, the largest increment in LVEDV (at AV-filibuster 150 ms) was achieved without a pregnant modify in mean LA pressure compared with the baseline condition with long AV-filibuster (Tabular array i).
Figure 3
Haemodynamic response to improving atrioventricular (AV) coupling in pig experiments and computer simulations during biventricular pacing. Relative changes in haemodynamic role by shortening AV-delay in all hog experiments (meridian panel) and simulations (bottom panel) when compared with a baseline PR interval of 300 ms. For the pig experiments hateful±SD are presented. * indicates P < 0.05 when compared with baseline. MAP, mean arterial pressure; LAPhateful, mean left atrial force per unit area; LVEDV, left ventricular end diastolic volume.
Figure 3
Haemodynamic response to improving atrioventricular (AV) coupling in pig experiments and figurer simulations during biventricular pacing. Relative changes in haemodynamic function by shortening AV-delay in all squealer experiments (top panel) and simulations (bottom console) when compared with a baseline PR interval of 300 ms. For the pig experiments mean±SD are presented. * indicates P < 0.05 when compared with baseline. MAP, mean arterial pressure level; LAPmean, mean left atrial pressure; LVEDV, left ventricular terminate diastolic volume.
Table one
Haemodynamic data of AV-optimization in porcine hearts during BiV pacing
| AV-delay | ||||||
|---|---|---|---|---|---|---|
| 50 ms | 100 ms | 150 ms | 200 ms | 250 ms | 300 ms (BL) | |
| PQ interval (ms) | 53 ± 2 * | 102 ± 2 * | 151 ± 1 * | 202 ± ii * | 254 ± 2 * | 304 ± 1 |
| MAP (mmHg) | 79 ± 25 * | 87 ± 23 | 91 ± 24 * | 91 ± 23 * | 88 ± 25 | 84 ± 24 |
| Cardiac output aorta (50/min) | iii.0 ± 0.iii | 3.three ± 0.3 | 3.4 ± 0.iv | 3.4 ± 0.4 | 3.2 ± 0.three | 3.one ± 0.3 |
| Stroke work (mmHg⋅mL) | 3732 ± 1146 | 4316 ± 1012 | 4437 ± 1042 | 4379 ± 1123 | 4169 ± 1239 | 3828 ± 1266 |
| LV dP/dt max (mmHg/s) | 1225 ± 311 * | 1297 ± 282 | 1274 ± 259 | 1308 ± 282 | 1275 ± 295 | 1265 ± 311 |
| LV SP (mmHg) | 95 ± 21 * | 102 ± twenty | 106 ± 22 * | 105 ± 21 * | 103 ± 22 | 99 ± 21 |
| LV EDP (mmHg) | 7.0 ± 2.8 | 8.7 ± 2.6 | ix.5 ± 2.i * | vii.8 ± ii.4 | 7.four ± ii.9 * | 6.9 ± 3.0 |
| LAPmean (mmHg) | 8.4 ± 2.4 * | 7.8 ± 2.iv * | six.8 ± ii.3 | vi.six ± 2.2 | vi.6 ± ii.4 | 6.5 ± 2.two |
| LV EDV (mL) | 78 ± 39 | 83 ± 39 | ninety ± 36 * | 87 ± 36 * | 83 ± 39 * | lxxx ± 40 |
| Diastolic MR (mL/crush) | 0.three ± 0.5 | 2.5 ± 1.9 | 4.four ± two.9 | 4.5 ± 3.3 | four.3 ± 3.iii | vi.1 ± four.0 |
| Forward flow (mL/vanquish) | 50 ± ix | 53 ± 8 | 53 ± 6 | 53 ± half dozen | 51 ± 7 | 51 ± 8 |
| MR fraction (%-point) | 0.ix ± i.v | five.ii ± iv | ix.5 ± half-dozen.2 | 10 ± vii.2 | 10 ± seven.7 | 15 ± ten.ii |
| AV-delay | ||||||
|---|---|---|---|---|---|---|
| 50 ms | 100 ms | 150 ms | 200 ms | 250 ms | 300 ms (BL) | |
| PQ interval (ms) | 53 ± 2 * | 102 ± two * | 151 ± ane * | 202 ± 2 * | 254 ± 2 * | 304 ± 1 |
| MAP (mmHg) | 79 ± 25 * | 87 ± 23 | 91 ± 24 * | 91 ± 23 * | 88 ± 25 | 84 ± 24 |
| Cardiac output aorta (l/min) | 3.0 ± 0.3 | 3.3 ± 0.three | 3.4 ± 0.iv | 3.four ± 0.4 | 3.two ± 0.3 | 3.1 ± 0.iii |
| Stroke work (mmHg⋅mL) | 3732 ± 1146 | 4316 ± 1012 | 4437 ± 1042 | 4379 ± 1123 | 4169 ± 1239 | 3828 ± 1266 |
| LV dP/dt max (mmHg/s) | 1225 ± 311 * | 1297 ± 282 | 1274 ± 259 | 1308 ± 282 | 1275 ± 295 | 1265 ± 311 |
| LV SP (mmHg) | 95 ± 21 * | 102 ± 20 | 106 ± 22 * | 105 ± 21 * | 103 ± 22 | 99 ± 21 |
| LV EDP (mmHg) | 7.0 ± 2.8 | 8.vii ± ii.6 | 9.5 ± 2.1 * | vii.8 ± 2.4 | 7.4 ± two.nine * | 6.9 ± 3.0 |
| LAPmean (mmHg) | eight.4 ± two.iv * | 7.eight ± ii.4 * | half-dozen.8 ± 2.3 | 6.half dozen ± two.2 | six.six ± 2.4 | half-dozen.v ± 2.2 |
| LV EDV (mL) | 78 ± 39 | 83 ± 39 | ninety ± 36 * | 87 ± 36 * | 83 ± 39 * | 80 ± xl |
| Diastolic MR (mL/beat) | 0.3 ± 0.5 | ii.5 ± 1.9 | 4.4 ± 2.nine | 4.5 ± iii.3 | four.three ± 3.3 | half dozen.1 ± four.0 |
| Frontward catamenia (mL/trounce) | 50 ± 9 | 53 ± 8 | 53 ± 6 | 53 ± six | 51 ± 7 | 51 ± eight |
| MR fraction (%-point) | 0.ix ± one.5 | five.2 ± 4 | ix.5 ± 6.2 | 10 ± 7.two | 10 ± vii.7 | 15 ± ten.2 |
Results are presented as hateful ± SD (due north = 7).
BL, baseline; EDP, end diastolic force per unit area; EDV, terminate diastolic volume; ESV, end systolic volume; LAPmean, hateful left atrial pressure; LV, left ventricular; LVSP, LV systolic pressure; MAP, hateful arterial pressure; MR, mitral regurgitation.
* P < 0.05 compared with 300 ms (BL) using 1-way repeated measures ANOVA followed past Pupil's paired samples T-test and Bonferroni correction.
Table 1
Haemodynamic information of AV-optimization in porcine hearts during BiV pacing
| AV-delay | ||||||
|---|---|---|---|---|---|---|
| l ms | 100 ms | 150 ms | 200 ms | 250 ms | 300 ms (BL) | |
| PQ interval (ms) | 53 ± two * | 102 ± 2 * | 151 ± 1 * | 202 ± ii * | 254 ± ii * | 304 ± 1 |
| MAP (mmHg) | 79 ± 25 * | 87 ± 23 | 91 ± 24 * | 91 ± 23 * | 88 ± 25 | 84 ± 24 |
| Cardiac output aorta (l/min) | 3.0 ± 0.3 | three.3 ± 0.3 | three.4 ± 0.four | 3.four ± 0.4 | 3.two ± 0.three | 3.1 ± 0.3 |
| Stroke work (mmHg⋅mL) | 3732 ± 1146 | 4316 ± 1012 | 4437 ± 1042 | 4379 ± 1123 | 4169 ± 1239 | 3828 ± 1266 |
| LV dP/dt max (mmHg/southward) | 1225 ± 311 * | 1297 ± 282 | 1274 ± 259 | 1308 ± 282 | 1275 ± 295 | 1265 ± 311 |
| LV SP (mmHg) | 95 ± 21 * | 102 ± 20 | 106 ± 22 * | 105 ± 21 * | 103 ± 22 | 99 ± 21 |
| LV EDP (mmHg) | 7.0 ± 2.8 | viii.vii ± two.6 | 9.v ± ii.ane * | 7.8 ± two.4 | 7.4 ± ii.9 * | 6.9 ± 3.0 |
| LAPmean (mmHg) | eight.four ± 2.4 * | 7.8 ± 2.iv * | half dozen.viii ± 2.three | six.vi ± 2.2 | 6.6 ± 2.4 | vi.v ± 2.2 |
| LV EDV (mL) | 78 ± 39 | 83 ± 39 | 90 ± 36 * | 87 ± 36 * | 83 ± 39 * | 80 ± twoscore |
| Diastolic MR (mL/crush) | 0.3 ± 0.5 | 2.5 ± 1.9 | 4.4 ± 2.9 | 4.5 ± three.3 | 4.3 ± 3.3 | half dozen.1 ± iv.0 |
| Forward flow (mL/beat) | 50 ± ix | 53 ± 8 | 53 ± 6 | 53 ± six | 51 ± 7 | 51 ± 8 |
| MR fraction (%-point) | 0.9 ± 1.five | 5.2 ± iv | 9.5 ± 6.two | 10 ± seven.2 | ten ± seven.7 | 15 ± 10.2 |
| AV-delay | ||||||
|---|---|---|---|---|---|---|
| 50 ms | 100 ms | 150 ms | 200 ms | 250 ms | 300 ms (BL) | |
| PQ interval (ms) | 53 ± 2 * | 102 ± 2 * | 151 ± one * | 202 ± ii * | 254 ± two * | 304 ± i |
| MAP (mmHg) | 79 ± 25 * | 87 ± 23 | 91 ± 24 * | 91 ± 23 * | 88 ± 25 | 84 ± 24 |
| Cardiac output aorta (l/min) | 3.0 ± 0.three | iii.3 ± 0.iii | 3.four ± 0.4 | 3.4 ± 0.iv | 3.two ± 0.3 | iii.ane ± 0.3 |
| Stroke work (mmHg⋅mL) | 3732 ± 1146 | 4316 ± 1012 | 4437 ± 1042 | 4379 ± 1123 | 4169 ± 1239 | 3828 ± 1266 |
| LV dP/dt max (mmHg/southward) | 1225 ± 311 * | 1297 ± 282 | 1274 ± 259 | 1308 ± 282 | 1275 ± 295 | 1265 ± 311 |
| LV SP (mmHg) | 95 ± 21 * | 102 ± 20 | 106 ± 22 * | 105 ± 21 * | 103 ± 22 | 99 ± 21 |
| LV EDP (mmHg) | 7.0 ± 2.8 | viii.seven ± 2.6 | 9.5 ± 2.1 * | 7.8 ± 2.iv | 7.four ± 2.ix * | 6.9 ± 3.0 |
| LAPhateful (mmHg) | 8.iv ± 2.4 * | 7.eight ± 2.four * | six.8 ± 2.three | 6.vi ± 2.2 | half-dozen.six ± 2.4 | six.5 ± two.2 |
| LV EDV (mL) | 78 ± 39 | 83 ± 39 | 90 ± 36 * | 87 ± 36 * | 83 ± 39 * | 80 ± 40 |
| Diastolic MR (mL/vanquish) | 0.iii ± 0.5 | 2.5 ± 1.9 | 4.iv ± ii.ix | 4.v ± three.3 | 4.3 ± 3.3 | six.1 ± 4.0 |
| Forward flow (mL/beat) | 50 ± ix | 53 ± 8 | 53 ± 6 | 53 ± 6 | 51 ± vii | 51 ± 8 |
| MR fraction (%-point) | 0.9 ± one.five | 5.ii ± four | 9.5 ± vi.2 | 10 ± 7.2 | 10 ± 7.seven | fifteen ± 10.two |
Results are presented as mean ± SD (n = seven).
BL, baseline; EDP, terminate diastolic pressure level; EDV, finish diastolic book; ESV, finish systolic book; LAPmean, mean left atrial force per unit area; LV, left ventricular; LVSP, LV systolic pressure level; MAP, mean arterial pressure level; MR, mitral regurgitation.
* P < 0.05 compared with 300 ms (BL) using one-way repeated measures ANOVA followed by Student's paired samples T-test and Bonferroni correction.
Both the computer simulations and animal studies showed that the increased filling at intermediate AV-delays was achieved past a dual event: larger forward flow over the mitral valve (area nether the E- and A-waves) and reduction in diastolic MR (central figure, Tabular array one).
Modulating furnishings of ventricular dyssynchrony: computer simulations
While the aforementioned report results concerned manipulation of AV-coupling in normal hearts at a constant degree of ventricular dyssynchrony, a next stride was to investigate how dissimilar degrees of pacing-induced ventricular dyssynchrony would influence the haemodynamic response to changes of AV-coupling in the failing eye. The amount of haemodynamic comeback obtained with recovery of AV-coupling depended on the caste of pacing-induced ventricular dyssynchrony. The largest haemodynamic improvement was predicted with the simulations with synchronous ventricular activation, while RV pacing simulations showed the smallest improvement, in terms of stroke volume (Figure 4A), LVEDV (Figure 4B), and LV inflow pattern (Figure 4C). Most separated E- and A-waves and least diastolic MR occurred during synchronous pacing (Figure 4C).
Figure 4
Issue of interventricular desynchronization on haemodynamic benefits of restoring AV-coupling. Simulation data from the protocol where restoration of AV-coupling was achieved with unchanged synchronous ventricular activation (cerise) or with biventricular (BiV) pacing (orange) or right ventricular (RV) pacing (purple). (A) Modify in stroke volume. (B) Pressure volume loops at optimal pump function. (C) Mitral valve flow.
Figure 4
Result of interventricular desynchronization on haemodynamic benefits of restoring AV-coupling. Simulation data from the protocol where restoration of AV-coupling was achieved with unchanged synchronous ventricular activation (red) or with biventricular (BiV) pacing (orangish) or right ventricular (RV) pacing (purple). (A) Modify in stroke volume. (B) Pressure volume loops at optimal pump part. (C) Mitral valve period.
Patient study
Tabular array S1 (run into Supplementary material online) shows the baseline patient characteristics. The study accomplice consisted of patients with moderate to severe HF (NYHA II or Iii), mean LVEF of 29 ± 6%, mean PR interval of 261 ± 32 ms, QRS duration of 123 ± 19 ms, and a mix of ischaemic and dilated cardiomyopathy.
Similar to the computer simulations and animal studies (Figures two and 4), patients showed the characteristic pattern of E–A wave fusion and diastolic MR at baseline (Figure 5A). During BiV pacing, a articulate separation of the Eastward- and A-waves was seen at AV-delays of 50% and 75% of intrinsic PR interval, while truncation of the A-moving ridge occurred at shorter AV-filibuster (25% of intrinsic PR interval). Restoration of AV-coupling by BiV pacing at an AV-delay of fifty% of intrinsic PR interval (137 ± 30 ms) resulted in a significant increase of forward mitral flow (on average +8mL/beat) and reduction of MR fraction (on boilerplate −12%-bespeak), Figure 5B and C, Tabular array 2.
Effigy five
Haemodynamic consequence of improving atrioventricular (AV)-coupling in patients. (A) Left ventricular (LV) force per unit area (Superlative row) and flow (2nd row) and ECG (third row), as measured in a representative patient. Diastolic mitral regurgitation (MR) is presented in cherry. Accented changes in (B) diastolic mitral forward period, and (C) diastolic mitral regurgitant (MR) fraction when compared with baseline (AAI) in the entire cohort. In the ECG an atrial pacing fasten is present in all conditions, in the biventricular paced beats the LV pacing spike is indicted past a large vertical bar which is followed 40 ms later on by a pocket-sized spike representing the RV stimulus. Mean ± SD are presented. *P < 0.05 when compared with baseline.
Effigy five
Haemodynamic effect of improving atrioventricular (AV)-coupling in patients. (A) Left ventricular (LV) force per unit area (Top row) and period (Second row) and ECG (tertiary row), as measured in a representative patient. Diastolic mitral regurgitation (MR) is presented in scarlet. Accented changes in (B) diastolic mitral frontwards flow, and (C) diastolic mitral regurgitant (MR) fraction when compared with baseline (AAI) in the entire cohort. In the ECG an atrial pacing fasten is present in all weather, in the biventricular paced beats the LV pacing spike is indicted past a big vertical bar which is followed 40 ms later by a small spike representing the RV stimulus. Mean ± SD are presented. *P < 0.05 when compared with baseline.
Tabular array 2
Haemodynamic and electrocardiographic data in patients paced at various paced AV-delays (% of intrinsic PR interval—thirty ms)
| AV-filibuster (=PR 30 ms) | |||||
|---|---|---|---|---|---|
| 25% | 50% | 75% | 100% | AAI | |
| BiV pacing | Baseline | ||||
| AV-delay (ms) | seventy ± xiv * | 137 ± 30 * | 203 ± 40 * | 270 ± 51 * | 300 ± 61 |
| QRS duration (ms) | 147 ± 24 * , ** | 149 ± 22 * ,** | 142 ± 22 ** | 129 ± 29 | 128 ± 25 |
| LVPmax (mmHg) | 110 ± 22 * | 115 ± 23 | 117 ± 24 | 117 ± 25 | 118 ± 25 |
| Stroke book (mL) | 53 ± 19 ** | 58 ± 20 * , ** | 59 ± 21 * | 53 ± xviii * | 48 ± xvi |
| Stroke piece of work (mL⋅mmHg) | 4993 ± 2041 ** | 5605 ± 2263 * , ** | 5726 ± 2369 * | 5273 ± 2128 * | 4792 ± 1992 |
| LV dP/dt max (mmHg/s) | 896 ± 164 ** | 935 ± 153 ** | 965 ± 162 ** | 971 ± 165 * | 927 ± 166 |
| LV EDP (mmHg) | 11 ± 5 | 13 ± half-dozen * | thirteen ± 8 * | 11 ± 7 | 11 ± six |
| LV EDV (mL) | 208 ± 55 | 215 ± 56 | 215 ± 59 | 213 ± 55 | 215 ± 56 |
| Diastolic frontwards flow (mL/vanquish) | 65 ± 22 ** | 69 ± 23 * , ** | 68 ± 22 * | 66 ± 21 * | 61 ± 21 |
| MR fraction (%) | nine ± 9 * | 6 ± 6 * | nine ± 9 * | 12 ± nine * | eighteen ± 11 |
| Diastolic filling fourth dimension (ms) | 434 ± 104 * | 432 ± 104 | 429 ± 111 | 415 ± 93 | 417 ± 87 |
| RV pacing | Baseline | ||||
| AV-delay (ms) | 70 ± 14 | 137 ± 30 | 203 ± twoscore | 270 ± 51 | 300 ± 61 |
| QRS duration (ms) | 175 ± 20 * | 173 ± 20 * | 165 ± 22 * | 143 ± 25 | 128 ± 25 |
| LVPmax (mmHg) | 109 ± xix * | 115 ± 22 | 118 ± 24 | 120 ± 24 | 118 ± 25 |
| Stroke volume (mL) | 42 ± 17 | 46 ± 19 | 48 ± 19 | 48 ± eighteen | 48 ± xvi |
| Stroke work (mL⋅mmHg) | 3885 ± 1844 * | 4455 ± 2055 | 4811 ± 2254 | 4904 ± 2090 | 4792 ± 1992 |
| LV dP/dt max (mmHg/s) | 801 ± 145 * | 845 ± 144 * | 896 ± 163 | 951 ± 148 | 927 ± 166 |
| LV EDP (mmHg) | 11 ± seven | 12 ± 7 | 13 ± vii * | 11 ± vi | 11 ± 6 |
| LV EDV (mL) | 213 ± 51 | 220 ± 55 | 222 ± 56 | 219 ± 51 | 215 ± 56 |
| Diastolic forward menses (mL/trounce) | 55 ± 22 | 59 ± 23 | 61 ± 24 | 62 ± 24 | 61 ± 21 |
| MR fraction (%-point) | thirteen ± 12 | 11 ± 9 | 14 ± 10 | 17 ± 10 | 18 ± 11 |
| Diastolic filling time (ms) | 416 ± 99 | 409 ± 91 | 411 ± 95 | 414 ± 101 | 417 ± 87 |
| AV-delay (=PR 30 ms) | |||||
|---|---|---|---|---|---|
| 25% | 50% | 75% | 100% | AAI | |
| BiV pacing | Baseline | ||||
| AV-delay (ms) | 70 ± 14 * | 137 ± 30 * | 203 ± 40 * | 270 ± 51 * | 300 ± 61 |
| QRS elapsing (ms) | 147 ± 24 * , ** | 149 ± 22 * ,** | 142 ± 22 ** | 129 ± 29 | 128 ± 25 |
| LVPmax (mmHg) | 110 ± 22 * | 115 ± 23 | 117 ± 24 | 117 ± 25 | 118 ± 25 |
| Stroke volume (mL) | 53 ± 19 ** | 58 ± twenty * , ** | 59 ± 21 * | 53 ± 18 * | 48 ± 16 |
| Stroke work (mL⋅mmHg) | 4993 ± 2041 ** | 5605 ± 2263 * , ** | 5726 ± 2369 * | 5273 ± 2128 * | 4792 ± 1992 |
| LV dP/dt max (mmHg/s) | 896 ± 164 ** | 935 ± 153 ** | 965 ± 162 ** | 971 ± 165 * | 927 ± 166 |
| LV EDP (mmHg) | 11 ± five | 13 ± 6 * | xiii ± eight * | 11 ± 7 | xi ± half dozen |
| LV EDV (mL) | 208 ± 55 | 215 ± 56 | 215 ± 59 | 213 ± 55 | 215 ± 56 |
| Diastolic forward catamenia (mL/beat) | 65 ± 22 ** | 69 ± 23 * , ** | 68 ± 22 * | 66 ± 21 * | 61 ± 21 |
| MR fraction (%) | 9 ± 9 * | 6 ± half dozen * | 9 ± 9 * | 12 ± ix * | eighteen ± xi |
| Diastolic filling fourth dimension (ms) | 434 ± 104 * | 432 ± 104 | 429 ± 111 | 415 ± 93 | 417 ± 87 |
| RV pacing | Baseline | ||||
| AV-delay (ms) | 70 ± fourteen | 137 ± 30 | 203 ± forty | 270 ± 51 | 300 ± 61 |
| QRS elapsing (ms) | 175 ± twenty * | 173 ± 20 * | 165 ± 22 * | 143 ± 25 | 128 ± 25 |
| LVPmax (mmHg) | 109 ± 19 * | 115 ± 22 | 118 ± 24 | 120 ± 24 | 118 ± 25 |
| Stroke volume (mL) | 42 ± 17 | 46 ± 19 | 48 ± 19 | 48 ± 18 | 48 ± 16 |
| Stroke work (mL⋅mmHg) | 3885 ± 1844 * | 4455 ± 2055 | 4811 ± 2254 | 4904 ± 2090 | 4792 ± 1992 |
| LV dP/dt max (mmHg/s) | 801 ± 145 * | 845 ± 144 * | 896 ± 163 | 951 ± 148 | 927 ± 166 |
| LV EDP (mmHg) | xi ± 7 | 12 ± 7 | 13 ± vii * | eleven ± 6 | 11 ± 6 |
| LV EDV (mL) | 213 ± 51 | 220 ± 55 | 222 ± 56 | 219 ± 51 | 215 ± 56 |
| Diastolic forrad flow (mL/beat) | 55 ± 22 | 59 ± 23 | 61 ± 24 | 62 ± 24 | 61 ± 21 |
| MR fraction (%-point) | thirteen ± 12 | 11 ± nine | xiv ± x | 17 ± 10 | 18 ± 11 |
| Diastolic filling time (ms) | 416 ± 99 | 409 ± 91 | 411 ± 95 | 414 ± 101 | 417 ± 87 |
Results are presented as hateful±SD (n = 22).
BiV, biventricular; AV, atrioventricular; LV, left ventricular; EDP, cease diastolic pressure; EDV, stop diastolic volume; MR, mitral regurgitation; RV, right ventricular.
* P < 0.05 compared with baseline.
** P < 0.05 compared with RV pacing with corresponding AV-delay, using 1- and two-style repeated measures ANOVA, respectively, followed by Pupil'south paired samples T-test and Bonferroni correction.
Table two
Haemodynamic and electrocardiographic data in patients paced at diverse paced AV-delays (% of intrinsic PR interval—thirty ms)
| AV-delay (=PR 30 ms) | |||||
|---|---|---|---|---|---|
| 25% | 50% | 75% | 100% | AAI | |
| BiV pacing | Baseline | ||||
| AV-filibuster (ms) | seventy ± xiv * | 137 ± thirty * | 203 ± xl * | 270 ± 51 * | 300 ± 61 |
| QRS duration (ms) | 147 ± 24 * , ** | 149 ± 22 * ,** | 142 ± 22 ** | 129 ± 29 | 128 ± 25 |
| LVPmax (mmHg) | 110 ± 22 * | 115 ± 23 | 117 ± 24 | 117 ± 25 | 118 ± 25 |
| Stroke book (mL) | 53 ± 19 ** | 58 ± 20 * , ** | 59 ± 21 * | 53 ± xviii * | 48 ± 16 |
| Stroke work (mL⋅mmHg) | 4993 ± 2041 ** | 5605 ± 2263 * , ** | 5726 ± 2369 * | 5273 ± 2128 * | 4792 ± 1992 |
| LV dP/dt max (mmHg/s) | 896 ± 164 ** | 935 ± 153 ** | 965 ± 162 ** | 971 ± 165 * | 927 ± 166 |
| LV EDP (mmHg) | 11 ± five | 13 ± 6 * | 13 ± 8 * | 11 ± 7 | 11 ± 6 |
| LV EDV (mL) | 208 ± 55 | 215 ± 56 | 215 ± 59 | 213 ± 55 | 215 ± 56 |
| Diastolic forward flow (mL/beat) | 65 ± 22 ** | 69 ± 23 * , ** | 68 ± 22 * | 66 ± 21 * | 61 ± 21 |
| MR fraction (%) | nine ± 9 * | 6 ± half-dozen * | nine ± ix * | 12 ± 9 * | eighteen ± 11 |
| Diastolic filling time (ms) | 434 ± 104 * | 432 ± 104 | 429 ± 111 | 415 ± 93 | 417 ± 87 |
| RV pacing | Baseline | ||||
| AV-filibuster (ms) | 70 ± 14 | 137 ± 30 | 203 ± xl | 270 ± 51 | 300 ± 61 |
| QRS elapsing (ms) | 175 ± twenty * | 173 ± 20 * | 165 ± 22 * | 143 ± 25 | 128 ± 25 |
| LVPmax (mmHg) | 109 ± xix * | 115 ± 22 | 118 ± 24 | 120 ± 24 | 118 ± 25 |
| Stroke volume (mL) | 42 ± 17 | 46 ± xix | 48 ± 19 | 48 ± eighteen | 48 ± 16 |
| Stroke work (mL⋅mmHg) | 3885 ± 1844 * | 4455 ± 2055 | 4811 ± 2254 | 4904 ± 2090 | 4792 ± 1992 |
| LV dP/dt max (mmHg/south) | 801 ± 145 * | 845 ± 144 * | 896 ± 163 | 951 ± 148 | 927 ± 166 |
| LV EDP (mmHg) | eleven ± 7 | 12 ± 7 | 13 ± vii * | 11 ± 6 | 11 ± 6 |
| LV EDV (mL) | 213 ± 51 | 220 ± 55 | 222 ± 56 | 219 ± 51 | 215 ± 56 |
| Diastolic forward menstruum (mL/beat) | 55 ± 22 | 59 ± 23 | 61 ± 24 | 62 ± 24 | 61 ± 21 |
| MR fraction (%-point) | thirteen ± 12 | 11 ± 9 | 14 ± ten | 17 ± 10 | 18 ± 11 |
| Diastolic filling fourth dimension (ms) | 416 ± 99 | 409 ± 91 | 411 ± 95 | 414 ± 101 | 417 ± 87 |
| AV-delay (=PR 30 ms) | |||||
|---|---|---|---|---|---|
| 25% | fifty% | 75% | 100% | AAI | |
| BiV pacing | Baseline | ||||
| AV-delay (ms) | 70 ± 14 * | 137 ± xxx * | 203 ± 40 * | 270 ± 51 * | 300 ± 61 |
| QRS duration (ms) | 147 ± 24 * , ** | 149 ± 22 * ,** | 142 ± 22 ** | 129 ± 29 | 128 ± 25 |
| LVPmax (mmHg) | 110 ± 22 * | 115 ± 23 | 117 ± 24 | 117 ± 25 | 118 ± 25 |
| Stroke book (mL) | 53 ± 19 ** | 58 ± 20 * , ** | 59 ± 21 * | 53 ± 18 * | 48 ± xvi |
| Stroke work (mL⋅mmHg) | 4993 ± 2041 ** | 5605 ± 2263 * , ** | 5726 ± 2369 * | 5273 ± 2128 * | 4792 ± 1992 |
| LV dP/dt max (mmHg/s) | 896 ± 164 ** | 935 ± 153 ** | 965 ± 162 ** | 971 ± 165 * | 927 ± 166 |
| LV EDP (mmHg) | 11 ± 5 | 13 ± six * | xiii ± 8 * | 11 ± vii | eleven ± 6 |
| LV EDV (mL) | 208 ± 55 | 215 ± 56 | 215 ± 59 | 213 ± 55 | 215 ± 56 |
| Diastolic forward catamenia (mL/beat) | 65 ± 22 ** | 69 ± 23 * , ** | 68 ± 22 * | 66 ± 21 * | 61 ± 21 |
| MR fraction (%) | 9 ± nine * | 6 ± 6 * | ix ± 9 * | 12 ± nine * | xviii ± 11 |
| Diastolic filling time (ms) | 434 ± 104 * | 432 ± 104 | 429 ± 111 | 415 ± 93 | 417 ± 87 |
| RV pacing | Baseline | ||||
| AV-filibuster (ms) | 70 ± 14 | 137 ± 30 | 203 ± xl | 270 ± 51 | 300 ± 61 |
| QRS duration (ms) | 175 ± 20 * | 173 ± 20 * | 165 ± 22 * | 143 ± 25 | 128 ± 25 |
| LVPmax (mmHg) | 109 ± nineteen * | 115 ± 22 | 118 ± 24 | 120 ± 24 | 118 ± 25 |
| Stroke volume (mL) | 42 ± 17 | 46 ± xix | 48 ± xix | 48 ± 18 | 48 ± sixteen |
| Stroke work (mL⋅mmHg) | 3885 ± 1844 * | 4455 ± 2055 | 4811 ± 2254 | 4904 ± 2090 | 4792 ± 1992 |
| LV dP/dt max (mmHg/s) | 801 ± 145 * | 845 ± 144 * | 896 ± 163 | 951 ± 148 | 927 ± 166 |
| LV EDP (mmHg) | 11 ± 7 | 12 ± 7 | 13 ± seven * | xi ± 6 | 11 ± 6 |
| LV EDV (mL) | 213 ± 51 | 220 ± 55 | 222 ± 56 | 219 ± 51 | 215 ± 56 |
| Diastolic forward flow (mL/beat) | 55 ± 22 | 59 ± 23 | 61 ± 24 | 62 ± 24 | 61 ± 21 |
| MR fraction (%-point) | xiii ± 12 | eleven ± 9 | 14 ± 10 | 17 ± 10 | 18 ± 11 |
| Diastolic filling time (ms) | 416 ± 99 | 409 ± 91 | 411 ± 95 | 414 ± 101 | 417 ± 87 |
Results are presented every bit mean±SD (n = 22).
BiV, biventricular; AV, atrioventricular; LV, left ventricular; EDP, end diastolic pressure; EDV, end diastolic volume; MR, mitral regurgitation; RV, right ventricular.
* P < 0.05 compared with baseline.
** P < 0.05 compared with RV pacing with corresponding AV-filibuster, using one- and two-way repeated measures ANOVA, respectively, followed by Student's paired samples T-examination and Bonferroni correction.
Effigy 6A presents LV force per unit area–volume loops of a patient during BiV (left) and RV pacing (right). When compared with baseline, BiV pacing increased LV stroke book and stroke work (width and surface area of the loop, respectively), with the nigh pronounced benefit at an AV-delay of fifty% of intrinsic PR interval. In dissimilarity, RV pacing tend to reduce stroke volume and stroke work, especially at shorter AV-delays. It can also be observed that elevation LV pressure macerated during RV pacing.
Figure vi
Haemodynamic consequence of improving atrioventricular (AV)-coupling in patients during biventricular (BiV) and right ventricular (RV) pacing. (A) Left ventricular (LV) pressure–volume loops in a representative patient at baseline (dashed line) and at tested AV-delay settings (solid lines) during BiV pacing (left) and right ventricular pacing (right). Relative changes in stroke volume (B) and stroke work (C) when compared with baseline (AAI) for BiV (black) and RV pacing (greyness) in the entire cohort. Mean ± SD are presented. *P < 0.05 when compared with baseline.
Figure 6
Haemodynamic consequence of improving atrioventricular (AV)-coupling in patients during biventricular (BiV) and right ventricular (RV) pacing. (A) Left ventricular (LV) pressure–volume loops in a representative patient at baseline (dashed line) and at tested AV-delay settings (solid lines) during BiV pacing (left) and right ventricular pacing (correct). Relative changes in stroke book (B) and stroke work (C) when compared with baseline (AAI) for BiV (black) and RV pacing (gray) in the entire cohort. Mean ± SD are presented. *P < 0.05 when compared with baseline.
In the unabridged accomplice of patients, BiV pacing increased QRS duration moderately, whereas a more pronounced prolongation occurred by applying RV pacing (Table 2). BiV pacing at an AV-delay of 50% of intrinsic PR interval significantly increased LV stroke book by 34 ± 40% (Figure 6B) and LV stroke work by 26 ± 31% (Figure 6C), when compared with baseline. The increase in LV stroke piece of work provided by BiV pacing coincided with slight but significant increases in LV end-diastolic force per unit area (on average 2 mmHg) and LV dP/dt max and largely unchanged systolic LV pressure (Table two). In dissimilarity, restoration of the AV-filibuster with RV pacing did not alter or even decreased stroke volume and stroke piece of work compared with baseline (Table 2). The decrease in stroke work during RV pacing at short AV-delays coincided with significant reductions in stroke volume, systolic LV pressure, and LV dP/dt max (Table 2).
Give-and-take
The presented combination of computational, experimental, and clinical proof-of-principle studies provides strong evidence that restoration of AV-coupling by BiV pacing results in pregnant haemodynamic benefit in hearts with AV dromotropathy (evidenced by a prolonged PR interval). This do good is caused past (i) increased ventricular filling, established by a larger forward menses across the mitral valve and less late-diastolic MR, but (ii) is attenuated by ventricular desynchronization due to RV pacing. These results point that the current guidelines on pacing and CRTvii may demand revision, because the lower limit of PR interval for recommending pacing therapy may be decreased (from >300 to >230 ms) and that BiV pacing is recommended. In club to avoid ventricular desynchronization, too BiV pacing, also recently proposed modes of physiological ventricular pacing, such equally His bundle, left bundle co-operative, and LV septum pacing 9 , x may be used to this purpose.
Restoring atrioventricular coupling provides haemodynamic improvement
A few studies in the 1990s used DDD RV pacing to restore AV-coupling. two , 3 These studies showed benign effects of normalization of AV-coupling in terms of reduction of diastolic MR, 2 longer filling times and larger CO 2 , and higher LVEF and arterial blood force per unit area. three Notably, these studies were performed in small-scale (12–24 patients) cohorts with variable baseline characteristics (broad and narrow QRS complex, normal, and depressed cardiac part). The results from the present study non merely corroborate these findings using state-of-the-art measurements, only besides extend them and provide a comprehensive understanding of mechanisms involved. The complicated interaction betwixt (intrinsic or paced) AV-delay and ventricular dyssynchrony on haemodynamics may explain why other (unpublished) studies were not able to reproduce these results, in detail when single site pacing was used.
Improving AV-coupling is an integral part of 'conventional CRT' in patients with LBBB and/or QRS duration >150 ms (class I CRT indication) and its benefit can therefore exist considered as bear witness-based. Interestingly, recent analysis using the same computer model as used in the present written report, and information from CRT patients indicated that improving AV-coupling in 'conventional' CRT may be responsible for more than two-thirds of the do good of this therapy while simply one-3rd was accounted for past ventricular resynchronization. xi Nevertheless, the feasibility, safety, and long-term efficacy of pacing-based AV-coupling in patients without LBBB and with narrow QRS complex requires farther investigation in prospective clinical trials. Such studies should also provide a more precise definition of the category patients that qualify for this therapy, such as the optimal cutting-off of PR interval, caste of separation of E and A wave on the mitral valve Doppler velocity recording, NYHA class, ischaemic or non-ischaemic cardiomyopathy, and LVEF. In addition, elapsing of the (intrinsic and paced) P-moving ridge may exist important to take into business relationship, considering big inter-atrial filibuster may safeguard LV filling in the presence of a long PR interval.
Haemodynamic improvement relates to ameliorate ventricular filling
The crucial finding of the present study is that improving AV-coupling leads to increased LV filling, thereby increasing CO at unchanged (patients) or increased (simulations, animals) claret pressure. These improvements are likely explained by the length-dependent activation of the myocardium, the cellular basis of the well-known Frank–Starling mechanism. Notably, LV dP/dt max was hardly affected, whereas this is a very sensitive marker of CRT benefit in LBBB patients. 8 , 12 Yet, the overall haemodynamic benefit of AV-coupling in terms of CO seems at to the lowest degree as large as that of 'CRT'. Increases in stroke work, measured in this report using the conductance catheter technique, were on average slightly smaller than those measured during conventional CRT (28 vs. 43%). 13 However, this difference may be due to very small-scale pressure–volume loop areas in LBBB hearts that may be associated with an artefact of the conductance catheter technique. Another important finding is that the increased LV filling during optimal AV-coupling is achieved past both improved diastolic filling pattern (i.due east. larger and meliorate separated Eastward- and A-waves) and less diastolic MR. Finally, an of import finding from the animate being and simulation studies was that the improved filling was accomplished while mean LA pressure was equal to or lower than baseline, indicating that the amend forward pump role may even coincide with reduced astern failure.
In the past, several studies have shown similar results apropos parts of the parameters investigated in the present study. The importance of proper AV-coupling has already been addressed by fauna studies in the 1960s, 14 reporting that a properly timed effective atrial contraction is necessary for optimal LV systolic function. Similar findings were obtained in a small clinical study where echo-Doppler every bit well as invasive pressure and flow measurements were used. In eight patients with PR intervals >200 ms, AV-optimization using DDD RV pacing increased filling times, LV end-diastolic pressure level, and CO. xv Other clinical studies showed repeat-Doppler recordings of mitral E- and A-waves with A-moving ridge truncation at also curt AV-delays and East–A-wave fusion combined with diastolic MR at besides long AV-delays. 16 , 17
The results from the nowadays report provide the total moving-picture show with comprehensive invasive haemodynamic measurements in animals and patients, supplemented by computer simulations that enable control of experimental atmospheric condition that cannot be achieved in vivo (like disabled MR). Furthermore, the utilise of the offset derivative of the LV volume point of the conductance catheter provides diastolic ventricular inflow patterns, rather than velocities as is the case in echo-Doppler studies. Therefore, the forward and astern flows, determined in the present written report, represent the actual claret volume displaced.
The fact that the calculator model could replicate all the changes seen in the animals, indicates that the mechanism of haemodynamic improvement past optimizing AV-filibuster can be explained by the well-established concrete and physiological principles that are incorporated in the model, such as conservation of energy, inertia of claret, and length-dependent activation of myocytes (Frank–Starling effect).
Effects of ventricular pacing-induced dyssynchrony
The RV pacing is known to increase ventricular dyssynchrony and thereby to take a negative impact on cardiac pump office. 18 Our patient and simulation data testify that the benefit of normalizing AV-coupling should be weighed against the detrimental effect of pacing-induced ventricular dyssynchrony. In the present written report, BiV pacing was able to acutely increase cardiac pump function in 19 out of 22 patients, indicating that the functional gain achieved by improving AV-coupling is relatively large compared with the loss of function due to BiV pacing-induced ventricular dyssynchrony. On the other hand, severe ventricular dyssynchrony occurs during RV pacing abrogates the haemodynamic benefits of restoring AV-coupling. Interestingly, shortening the AV-delay using RV pacing did non ameliorate filling either, due to a lack of reduction in diastolic MR and no increase in diastolic filling fourth dimension or diastolic forward flow. These observations may be explained by a combination of factors, such as prolonged isovolumic contraction due to desynchronization and dyssynchronous contraction of the papillary muscles which increases the hazard of diastolic MR. Our study also suggests that the presence of LV filling abnormalities, such as E–A wave fusion and diastolic MR, may be important selection criteria for the use of BiV pacing in patients with prolonged PR interval.
The results from the present study may also explain the lack of benefit of algorithms aiming at minimization of ventricular pacing. After all, these algorithms exercise so by prolonging the AV-delay, thus inducing AV dromotropathy. 19 Our report supports the idea that likewise aggressive prolongation of PR interval may have agin furnishings on pump function and possibly clinical outcome.
Limitations
The nowadays patient report has all the characteristics of a proof-of-principle report, showing acute haemodynamic effects in a small cohort. For upstanding reasons, patients in this study all had the indication for ICD implant, and so that the implant of the LV lead was only a small-scale extension of the medically indicated procedure. Clearly, studies in a wider population (as well non-ICD indicated patients) and using long-term outcome as endpoint are required to provide further evidence for the benefit of improving AV-coupling in patients with a prolonged PR interval. Promising is that subanalyses in non-LBBB patients of the randomized MADIT-CRT xx and RethinQ 6 trials besides indicate that patients with long PR interval can benefit from BiV pacing when compared with their unpaced 'control group' counterparts.
The preclinical studies were performed in porcine hearts. While this species is oft used for cardiovascular research, a limitation is that the amount of dyssynchrony induced by (unmarried site) ventricular pacing is small. Therefore, for this study only BiV pacing was used to demonstrate the effect of AV-coupling at unchanged ventricular activation (BiV pacing being used for all AV-delays). Moreover, the lack of intra-thoracic negative force per unit area in these open-thorax experiments may take interfered with the effect of AV-interval on filling.
Conclusions
The combination of computational, experimental, and clinical studies provides strong confirmation of previous prove that normalizing AV-coupling by BiV pacing in hearts with prolonged PR interval improves cardiac pump function. This comeback is predominantly achieved past better ventricular filling, caused by a combined effect of reduction in diastolic MR and increment in diastolic forward flow. Pacing-induced ventricular dyssynchrony, caused by RV pacing, attenuates the do good of restored AV-coupling. Therefore, this report may pave the way for a novel pacing-based therapeutic arroyo in patients with HF and prolonged PR interval that is not office of current guidelines.
Supplementary textile
Supplementary cloth is available at Europace online.
Funding
This work was supported by research grants from Abbott (Veenendaal, The netherlands), the Dutch Heart Foundation [grant number 2015T082 to J.50.], the French Authorities Agence National de la Recherche au titre du plan investissements d'Avenir [grant number ANR-10-IAHU-04], the Netherlands Organisation for Scientific Inquiry [grant number 016.176.340 to J.Fifty.], and the European union's Horizon 2020 Research and Innovation programme under the Marie Sklodowska-Curie grant agreement No. 860745.
Conflict of involvement: J.Fifty. has received inquiry grants from Medtronic. F.W.P. has received research grants from Medtronic, Abbott, Microport CRM, and Biotronik. One thousand.V. has received research grants from Medtronic, Abbott and has a consultancy understanding with Medtronic and Abbott. C.P.A. received research grants from Biotronik and Boston Scientific. The remaining authors accept zippo to disembalm.
Information availability
The information underlying this article volition be shared on reasonable request to the corresponding author.
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Author notes
† Floor C.W.M. Salden, Peter R. Huntjens, Joost Lumens, Kevin Vernooy contributed equally to the study.
© The Author(southward) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
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