The use of impedance cardiography for optimizing the interventricular stimulation interval in cardiac resynchronization therapy—a comparison with left ventricular contractility

The present study aimed to assess whether impedance cardiography (IC) can correctly identify the optimal interventricular (VV) pacing interval in cardiac resynchronization therapy (CRT). Twenty four patients received a biventricular pacemaker and underwent IC for cardiac output (CO) measurements to identify the optimal VV interval. Invasive measurements of left ventricular (LV) dP/dt_max were used as a reference. During optimization the VV interval was changed with 20 ms steps from +80 (LV pre-excitation) to−80 ms (RV pre-excitation). The optimal VV interval was defined as the one that resulted in the highest LV dP/dt_max value and the highest CO obtained by IC, respectively. During simultaneous biventricular pacing both LV dP/dt_max and CO increased (mean 16.6% and 16.2%, respectively) as compared to baseline. Biventricular pacing with optimized VV intervals resulted in a further absolute increase of LV dP/dt _max and CO (5.6% and 41.3%, respectively). The average decrease in LV dP/dt_max was 79.6 ± 51.6 mmHg/s when the optimal VV interval was programmed according to the IC measurements. Cross spectral analysis showed no correlation between the optimal VV intervals identified by the two methods (p > 0.05) and identical optimal VV intervals were identified in only six of the 24 patients. When broader VV time intervals were compared the correlation between the two methods was statistically significant (p = 0,0166). In conclusion, the use of IC for VV interval optimization is questionable since these optimized time intervals do not seem to correlate well with those obtained by measuring LV dP/dt.     

Upgrading to biventricular pacing guided by pressure-volume loop analysis during implantation

Pressure–Volume Loop Analyses during CRT Implants. Introduction: cardiac resynchronization therapy (CRT) may improve prognosis in patients with chronic right ventricular (RV) pacing, and optimal lead position can decrease nonresponders. We evaluated the clinical and echocardiographic response to CRT in patients with previous chronic RV pacing, using pressure–volume loop analyses to determine the optimal left ventricular (LV) lead position during implantation. Methods and Results: In this single‐blinded, randomized, controlled crossover study, 40 patients with chronic RV apical pacing and symptoms of heart failure, decreased LV ejection fraction (LVEF) or dyssynchrony were included. During implantation, stroke work (SW), LVEF, cardiac output, and LV dP/dt_max were assessed by a conductance catheter. Clinical and echocardiographic response was studied during a 3‐month period of RV pacing (RV period, LV lead inactive) and a 3‐month period of biventricular pacing (CRT period). At the optimal LV lead position, SW (37 ± 41%), LVEF (16 ± 13%), cardiac output (29 ± 16%), and LV dP/dt_max increased (11 ± 11%) significantly during biventricular pacing compared to baseline. Additional benefit could be achieved by pressure–volume loop guided selection of the best left‐sided pacing location. RV outflow tract pacing did not improve hemodynamics. During follow‐up, symptoms improved during CRT, VO_2,max increased 10% and significant improvements in LVEF, LV volumes, and mitral regurgitation were observed as compared to the RV period. Conclusions: CRT in patients with chronic RV pacing causes significant improvement of both LV function as measured by pressure–volume loops during implantation and clinical and echocardiographic improvement during follow‐up. Pressure–volume loops during implantation may facilitate selection of the most optimal pacing site . (J Cardiovasc Electrophysiol, Vol. 22, pp. 677‐683, June 2011)     

Design of an Acute dP/dt Hemodynamic Measurement Protocol to Isolate Cardiac Effect of Pacing

BackgroundInvasively measured maximum increase in left ventricular pressure (LV dP/dt_max) has been used to assess biventricular (BiV) pacing. We quantified extracardiac factors contributing to its variability, and developed a protocol to minimize these effects in an acute pacing experiment.Methods and ResultsContinuous pressure was recorded by a guidewire sensor placed in the LV. Four to six test pacing interventions were performed, each repeated 3 times and followed by a baseline pacing configuration. Maximum increase in LV dP/dt_max from any measurement of BiV pacing was median 20.3% in 25 patients, compared with BiV pacing off. When directly comparing sequential measurements with BiV pacing on and off, median increase was 7.4%. Noncardiac sources of modulation included respiratory variation (6.4%), drift from first to last baseline measurement (5.0%), and discrepancy among repeated recordings of the same pacing intervention (3.3%). Comparing test interventions to interleaved baseline measurements reduced discrepancy among recordings to 2.1%; P < .001.ConclusionsWith repeated measurements of baseline state, and by comparing test interventions only to baseline measurements performed before and after, it is possible to minimize extracardiac factors and focus on the effects of test pacing interventions.     

Noninvasive evaluation of contractile state by left ventricular dP/dtmax divided by end-diastolic volume using continuous-wave doppler and M-mode echocardiography

The maximum rate of left ventricular (LV) pressure rise (dP/dt_max) is commonly used in the assessment of directional change in LV contractility and, recently, estimated by analyzing continuous-wave Doppler ultrasound velocity curve of mitral regurgitation. As an alteration in ventricular preload is known to affect dP/dt_max, normalized dP/dt_max for preload might be more reliable to assess LV contractile state. To investigate the usefulness of a new index of LV contractile state determined by continuous-wave Doppler analysis of mitral regurgitation and M-mode echocardiogram-derived LV end-diastolic volume, we studied 18 patients with mild mitral regurgitation. The continuous-wave Doppler velocity curves of mitral regurgitation were digitized and converted to instantaneous pressure gradient between the LV and left atrium using the simplified Bernoulli equation. The maximum value of its first derivative (Doppler-derived dP/dt_max) correlated well with LV dP/dt_maxusing simultaneously recorded LV pressures by manometer-tipped catheter (n = 20, r = 0.97, p < 0.001). Corrected Doppler-derived dP/dt_max for LV end-diastolic volume using Teichholz's method significantly increased by inotropic stimulation with dobutamine (p < 0.01); however, it remained unchanged by augmentation of afterload with angioteasin II. Thus, the LV dP/dt_max can be accurately estimated in humans by analyzing the continuous wave Doppler velocity curve of mitral regurgitation, and corrected Doppler-derived dP/dt_max for LV end-diastolic volume is relatively independent of loading alteration and sensitive to inotropic stimulation. We concluded that echocardiographic assessment by combined Doppler- and M-mode measurements provides a useful and sensitive index of LV contractile state noninvasively.     

对心肌病晚期心力衰竭患者行左心室和双心室起搏的血流动力学研究

目的　了解左心室和双心室起搏的急性期血流动力学效应。方法　对 16例心电图呈左束支传导阻滞 (LBBB)的晚期心肌病患者行左室游离壁和双心室起搏 ,记录左室、双心室和基础状态下的左室腔内最大压力上升速率 (dP dtmax)、主动脉根部压力和心电图QRS波宽度。结果　左室和双心室起搏分别使左室dP dtmax提高 2 1%和 18% (P <0 0 1) ,左室和双心室起搏组间无显著差异 ;左室起搏和双心室起搏使主动脉收缩压较基础状态升高 6 %和 5 % (P <0 0 1) ,左室和双心室起搏组间差异不显著 ;左室起搏心电图QRS间期缩短不明显 ,而双心室起搏QRS间期明显缩短。结论　对于心电图呈LBBB型的心肌病终末期心力衰竭患者 ,行双心室起搏和左室游离壁起搏均使患者的急性期血流动力学得到显著改善 ,两者的效果相当     

The ECG in Cardiac Resynchronization Therapy: Influence of Left and Right Ventricular Preactivation and Relation to Acute Response

Influence of Preactivation on the ECG in CRT. Introduction: The aims of this study were to compare ECG signs of biventricular electrical resynchronization during cardiac resynchronization therapy (CRT) with various interventricular (VV) delays and to correlate these and other ECG characteristics with the acute hemodynamic benefit of CRT. Methods and Results: Thirty‐four patients with heart failure and a left bundle branch block (LBBB) pattern were prospectively enrolled. A 12‐lead surface ECG and the relative improvement in left ventricular (LV) dP/dt_max (the maximum rate of pressure rise) were recorded at baseline and during CRT with VV delays varying from 80 ms LV preactivation to 40 ms right ventricular (RV) preactivation. Rightward QRS‐axis shift occurred in 71–80% among all VV delays. Activation reversal to dominant negative in leads I/aVL was progressively observed at increasing LV preactivation (53–65%) and less (18–22%) during RV preactivation. Activation reversal to dominant positive in leads V1/V2 was observed in 21–27% during LV preactivation and in 6–15% during RV preactivation. Higher acute response to CRT was independently predicted by a complete LBBB at baseline (regression coefficient B = 7.7 [0.3–15.0], P = 0.042), later timing of LV depolarization within the QRS at baseline (Q‐LVsense: B = 0.2 [0.1–0.3], P = 0.002), and biventricular electrical resynchronization during CRT as evidenced by activation reversal in leads I/aVL (B = 9.9 [3.2–16.6], P = 0.005). Conclusion: ECG signs of biventricular electrical resynchronization are present over a wide range of LV preactivated VV delays but to a lesser extent during RV preactivation. The presence of complete LBBB and longer Q‐LVsense at baseline and signs of biventricular electrical resynchronization during CRT predict higher acute hemodynamic response. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1237–1245, November 2012)     

Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption,but increase cardiac function more than proportionally

Background

The mechanoenergetic effects of atrioventricular delay optimization during biventricular pacing (“cardiac resynchronization therapy”, CRT) are unknown.

Methods

Eleven patients with heart failure and left bundle branch block (LBBB) underwent invasive measurements of left ventricular (LV) developed pressure, aortic flow velocity-time-integral (VTI) and myocardial oxygen consumption (MVO₂) at 4 pacing states: biventricular pacing (with VV 0 ms) at AVD 40 ms (AV-40), AVD 120 ms (AV-120, a common nominal AV delay), at their pre-identified individualised haemodynamic optimum (AV-Opt); and intrinsic conduction (LBBB).

Results

AV-120, relative to LBBB, increased LV developed pressure by a mean of 11(SEM 2)%, p = 0.001, and aortic VTI by 11(SEM 3)%, p = 0.002, but also increased MVO2 by 11(SEM 5)%, p = 0.04.AV-Opt further increased LV developed pressure by a mean of 2(SEM 1)%, p = 0.035 and aortic VTI by 4(SEM 1)%, p = 0.017. MVO2 trended further up by 7(SEM 5)%, p = 0.22.Mechanoenergetics at AV-40 were no different from LBBB.The 4 states lay on a straight line for Δexternal work (ΔLV developed pressure × Δaortic VTI) against ΔMVO2, with slope 1.80, significantly > 1 (p = 0.02).

Conclusions

Biventricular pacing and atrioventricular delay optimization increased external cardiac work done but also myocardial oxygen consumption. Nevertheless, the increase in cardiac work was ~ 80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechanoenergetics. Finally, the incremental effect of optimization on external work was approximately one-third beyond that of nominal AV pacing, along the same favourable efficiency trajectory, suggesting that AV delay dominates the biventricular pacing effect — which may therefore not be mainly “resynchronization”.     

Preferred left ventricular lead position for upgrade from right ventricular pacing to cardiac resynchronization therapy

Introduction

Cardiac resynchronization therapy (CRT) is well-established for treating symptomatic heart failure with electrical dyssynchrony. The left ventricular (LV) lead position is recommended at LV posterolateral to lateral sites in patients with left bundle branch block; however, its preferred region remains unclear in patients being upgraded from right ventricular (RV) apical pacing to CRT. This study aimed to identify the preferred LV lead position for upgrading conventional RV apical pacing to CRT.

Methods

We used electrode catheters positioned at the RV apex and LV anterolateral and posterolateral sites via the coronary sinus (CS) branches to measure the ratio of activation time to QRS duration from the RV apex to the LV anterolateral and posterolateral sites during RV apical pacing. Simultaneous biventricular pacing was performed at the RV apex and each LV site, and the differences in QRS duration and LV dP/dt_max from those of RV apical pacing were measured.

Results

Thirty-seven patients with anterolateral and posterolateral LV CS branches were included. During RV apical pacing, the average ratio of activation time to QRS duration was higher at the LV anterolateral site than at the LV posterolateral site (0.90 ± 0.06 vs. 0.71 ± 0.11, p < .001). The decreasing ratio of QRS duration and the increasing ratio of LV dP/dt_max were higher at the LV anterolateral site than at the posterolateral site (45.7 ± 18.0% vs. 32.0 ± 17.6%, p < .001; 12.7 ± 2.9% vs. 3.7 ± 8.2%, p < .001, respectively) during biventricular pacing compared with RV apical pacing.

Conclusion

The LV anterolateral site is the preferred LV lead position in patients being upgraded from conventional RV apical pacing to CRT.     

Alteration of left ventricular performance by left bundle branch block simulated with atrioventricular sequential pacing

The effects of atrioventricular (AV) sequential pacing-induced left bundle branch block (LBBB) on left ventricular (LV) performance were evaluated during cardiac catheterization in 9 randomly selected patients being investigated for chest pain. All patients were in normal sinus rhythm with a normal P-R interval and QRS duration. LV performance was assessed by both hemodynamic and angiographie measurements. The maximal rate of LV pressure increase (dP/dt), rate of maximal LV pressure decrease ($\text{?dP}\text{dt}$), LV end-diastolic pressure (LVEDP), end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume and percent ejection (EF) were measured during right atrial and AV sequential pacing at a constant pacing rate. The average pacing rate was 97 ± 3 beats/min (mean ± standard error of the mean). In each patient, both dP/dt and $\text{?}\text{dP}\text{dt}$ decreased significantly (p < 0.001) during AV sequential pacing compared with atrial pacing at the same rate, from 1,541 ± 68 to 1,319 ± 56 mm Hg/s for dP/dt and from 1,506 ± 86 to 1,276 ± 92 for $\text{?dP}\text{dt}$. LVEDP did not change significantly when atrial (17 ± 3 mm Hg) and AV sequential pacing (16 ± 2 mm Hg) were compared. Mean LVEDV did not change during atrial (135 ± 13 ml) or AV sequential pacing (137 ± 14 ml). In contrast, the LVESV during AV sequential pacing was higher by 15 ml (23 % ) (from 48 ± 10 to 63 ± 12 ml) (p < 0.001); as a result, the stroke volume was lower by 13 ml (15%) and the EF decreased by 10 %, from 66 to 56 % (?15 %).These changes in LV performance during acutely induced LBBB by AV sequential pacing as compared with atrial pacing at the same rate were independent of altered preload, because both LVEDP and LVEDV were similar during the 2 different pacing modes. Peak systolic pressure during AV sequential pacing was significantly lower than that during atrial pacing (161 ± 10 vs 145 ± 10 mm Hg, p < 0.01), and thus afterload was presumably altered during the different pacing modes. However, because the observed change in systolic pressure (afterload) was lower during AV sequential pacing, this change should improve rather than result in deterioration of ejection phase indexes. Because the opposite was observed, it is concluded the deterioration in LV function noted during AV sequential pacing must be due in part to the asynchronous pattern of ventricular activation induced by this intervention.     

The reliability of cardiogenic impedance and correlation with echocardiographic and plethysmographic parameters for predicting CRT time intervals post implantation

Aims

Encouraging data have been reported on the use of cardiogenic impedance (CI) in cardiac resynchronization therapy (CRT) optimization. The purposes of this study were to: evaluate the stability of certain CI vectors 24 h postimplantation, study the correlation between these CI signals and selected echocardiographic parameters, and examine the possibility of non-invasive calibration of the patient-specific impedance-based prediction model.

Methods and results

Thirteen patients received a CRT–defibrillator device with monitor capability of the dynamic impedance between several electrodes. At implantation, a patient-specific impedance-based prediction model was created for identification of optimal atrioventricular and interventricular (VV) delays and calibrated on invasive measurements of left ventricular contractility (LV dP/dt_max). Simultaneously, non-invasive measurements of LV dP/dt_max and stroke volume (SV) were obtained using a finger plethysmograph. Patients were re-evaluated with echocardiography and new CI measurements the day after implantation. The hemodynamic benefit achieved by optimal VV setting according to the patient-specific impedance-based prediction model at follow-up was not as large as the one obtained at implantation. In a multivariate partial least square regression analysis, a correlation was found between aortic velocity time integral (VTI) and a generic linear combination of CI features (P?<?0,005). No correlation was found between the patient-specific impedance-based prediction models and the non-invasive measurements of LV dP/dt_max and SV.

Conclusion

Cardiogenic impedance signals can be used to optimize CRT settings but seem less feasible as an ambulatory tool since calibration is required. The positive correlation between aortic VTI and CI measurements seems promising, although a larger cohort is required to create an echocardiography-based patient-specific model.     

Effects of a sinus node inhibitor on the normal and failing rabbit heart

The effects on cardiac function of slowed frequency produced by a sinus node inhibitor (zatebradine, or UL-FS 49) were studied in the conscious rabbit under control conditions (n=16) and after heart failure was produced by rapid atrial pacing for an average of 18.5 days (n=8). Echocardiography was used to verify severe left ventricular (LV) dysfunction, and high-fidelity micromanometry and cardiac output measurements (Doppler echo) were performed. Echocardiographic fractional shortening was 40.3±4.1% (SD) in controls; in heart failure it was 18.0±1.6%, and the LV was enlarged. In controls, as heart rate (HR) was decreased from 279 beats per minute (bpm) by incremental doses of zatebradine (up to 0.75 mg/kg), maximal changes occurred when the heart reached 218 bpm with a maximum decrease of the first derivative of LV pressure (LV dP/dt_max) of 15.9%; LV enddiastolic pressure (EDP) increased from 4.3 to 8.4 mmHg along with a significant decrease in cardiac index (CI) of 15.2%, while LV systolic pressure (SP) was stable. In heart failure, LV dP/dt_max and CI were markedly reduced compared to controls and with reduction of HR from 257 to 221 with reduction of HR from 257 to 221 bpm LV dP/dt_max was unchanged, LVEDP increased slightly (NS), LVSP was unchanged and CI fell by 13.5% at the highest dose. In subgroups (control n=9, failure n=6), in order to eliminate the hemodynamic effects of cardiac slowing by zatebradine the sinus rate present before zatebradine was matched by atrial pacing; this procedure eliminated all hemodynamic abnormalities accompanying cardiac slowing in both groups. In conclusion, slowed HR due to a sinus node inhibitor was well tolerated in severe heart failure, and all negative hemodynamic responses in both controls and in heart failure were due entirely to a negative forcefrequency effect, without a direct depressant action of zatebradine on the myocardium.Supported in part by grand HL-53733 awarded by the National Heart, Lung and Blood Institute and an endowed chair awarded to Dr. Ross by the San Diego County Affiliate of the American Heart Association.     

Maximum derivative of left ventricular pressure predicts cardiac mortality after cardiac resynchronization therapy

Background

Cardiac resynchronization therapy (CRT) has been reported to improve cardiac performance. However, CRT in patients with advanced heart failure is not always accompanied by an improvement in survival rates. We investigated the association between hemodynamic studies and long‐term prognosis after CRT.

Methods

A total of 68 consecutive patients receiving CRT devices due to advanced heart failure were assessed by hemodynamic study and long‐term outcome after implantation of the device. Hemodynamic parameters were measured both with the CRT on and off.

Results

Patients demonstrated significant improvement in the maximum first derivative of left ventricular (LV) pressure (LV dP/dt_max) and QRS duration after periods with the CRT on. During the follow‐up period of 34.9 ± 17.6 months, basal LV dP/dt_max and isovolemic LV pressure half‐time (T_1/2), but not percent change in LV dP/dt_max, were independent predictors of cardiac mortality or hospitalization due to heart failure after multivariate Cox regression analysis. The Kaplan‐Meier survival analysis revealed that patients in the lowest basal LV dP/dt_max tertile or the longest basal T_1/2 tertile exhibited a significantly higher cardiac‐caused mortality or heart failure hospitalization.

Conclusions

Lower LV dP/dt_max or longer T_1/2 independently predicts cardiac mortality or heart failure hospitalization in patients receiving CRT. The assessment of the basal LV dP/dt_max and T_1/2 could provide useful information in long‐term prognosis after CRT. Copyright © 2010 Wiley Periodicals, Inc. This work was supported by grant from the Grant‐in‐Aid for Young Scientists, the Nakashima Foundation, and the Kowa Life Science Foundation to RS. Hirohiko Suzuki, MD and Masayuki Shimano, MD equally contributed to the work.     

Effects of different inotropic interventions on myocardial function in the developing rabbit heart

The development of the mammalian heart is characterized by substantial changes in myocardial performance. We studied the ontogeny of myocardial function with and without various inotropic interventions in the developing isolated, antegrade-perfused rabbit heart (2d, 8d, 14d, 28d, n = 96). Myocardial function was related to the protein expression of the sarcolemmal Na⁺-Ca²⁺ exchanger and to the sarcoplasmic Ca²⁺-ATPase. In neonatal hearts an age-dependent increase in maximal developed pressure velocity (dP/dt_max) by 45 % and peak negative pressure velocity (dP/dt_min) by 75 % within days 2 to 8 were observed. In response to inotropic intervention with isoproterenol, ouabain, calcium and the Na⁺-channel modulator BDF 9148, dP/dt_max and dP/dt_min increased in a concentration dependent manner. Significant differences between neonatal, juvenile and adult hearts could be demonstrated in a repeated measurement ANOVA model on the concentration-response curves for BDF 9148 (dP/dt_max and dP/dt_min), ouabain (dP/dt_min) and calcium (dP/dt_min), but not for isoproterenol. At the maximum isoproterenol concentration of 1 μmol/l, the increase in dP/dt_max and dP/dt_min was significantly higher in adult compared to neonatal hearts (t-test, p < 0.01). The significant decline of the Na⁺-Ca²⁺ exchanger protein expression from neonatal (1822 ± 171) to adult hearts (411 ± 96 S.E.M. [units per 20 μg protein], p < 0.01) was related to an increase in myocardial function (dP/dt_max r = 0.63, p < 0.01, dP/dt_min r = 0.62, p < 0.01). Contractility, relaxation and the observed positive inotropic effects were in general significantly lower in neonatal compared to adult hearts. In the individual heart an increase in contractility and relaxation was related to a decrease in Na⁺-Ca²⁺ exchanger expression. Received: 22 May 2000, Returned for 1. revision: 21 June 2000, 1. Revision received: 27 November 2000, Returned for 2. revision: 19 December 2000, 2. Revision received: 2 January 2001, Returned for 3. revision: 17 January 2001, 3. Revision received: 25 May 2001, Accepted: 11 June 2001     

Nonexcitatory stimulus delivery improves left ventricular function in hearts with left bundle branch block

INTRODUCTION: Preliminary data in a heart failure animal model and isolated muscle preparation have suggested that nonexcitatory stimulation (NES) improves left ventricular (LV) function. METHODS AND RESULTS: We compared biventricular (BV) pacing with NES in an animal model with left bundle branch block (LBBB). The left bundle branch (LBB) was ablated in eight normal heart pigs and led to >50% increase in QRS duration (mean 100 +/- 15 msec). End-diastolic LV pressure, end-systolic LV pressure, LV pressure (LV dP/dtmax), aortic pulse pressure, and LV ejection fraction were measured before pre-LBB ablation and compared with post-LBB ablation (AAI pacing), BV pacing, NES delivery, and BV+NES. Moreover, to evaluate LV diastolic function, we measured the early (E wave) and late flows (A wave) through the mitral valve using spectral Doppler. Compared with post-LBB ablation, NES led to a significant increase in LV dP/dtmax (1,047 +/- 224 mmHg/sec vs 897 +/- 116 mmHg/sec; P < 0.05), LV ejection fraction (64% +/- 18% vs 49% +/- 17%; P < 0.05), and aortic pulse pressure (18 +/- 3.6 mmHg vs 16 +/- 2.8 mmHg; P < 0.05). Moreover, improvement in LV hemodynamic parameters was significantly higher during NES delivery when compared with BV pacing. No significant changes in E wave, A wave, and E/A were recorded during NES, NES+BV, and BV pacing. CONCLUSION: Our preliminary data demonstrate that NES is superior to BV pacing in improving LV function in an animal model with LBBB. Moreover, we demonstrated that NES does not affect transmitral valve flow and subsequently LV diastolic function.     

Hemodynamic Effects of Late Sodium Current Inhibitors in a Swine Model of Heart Failure

ObjectivesTo evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls.BackgroundRanolazine and mexiletine potently inhibit depolarizing late Na⁺ current (I_Na,late) and Na⁺ entry into cardiomyocytes_. Blocking Na⁺ entry may increase forward-mode Na/Ca exchange and reduce cellular Ca⁺² load, further compromising systolic contraction during HF.Methods and ResultsAnesthetized tachypaced HF swine received ranolazine (n = 9) or mexiletine (n = 7) as boluses, then as infusions; the same experiments were performed in 10 nonpaced controls. The swine with HF had characteristic elevated left ventricular end-diastolic pressure (LVEDP) and reduced maximal left ventricular pressure rise (+dP/dt_max) and left ventricular peak systolic pressure (LVSP). No significant change occurred after ranolazine dosing for any parameter: LVEDP, +dP/dt_max, LVSP, heart rate, maximal LV pressure fall rate (–dP/dt_max), or time constant for isovolumic relaxation. Similar results seen in additional swine with HF: 7 were given mexiletine, and 7 others were given ranolazine after a 27% rate decrement to maximize I_Na,late. Patch-clamped HF cardiomyocytes confirmed drug-induced I_Na,late blockade.ConclusionsRanolazine or mexiletine blocking I_Na,late neither worsened nor improved hemodynamics during advanced HF. Although results must be clinically confirmed, they suggest inhibition of I_Na,late by ranolazine or mexiletine may not exacerbate HF in patients.     

Effect of changes in aortic pressure and in coronary arterial pressure on left ventricular geometry and function Anrep vs. gardenhose effect

Summary Sudden increases in aortic pressure (AoP, mmHg) are associated with increases in left ventricular (LV) function which persist even after diastolic volume has returned to its initial value (Anrep effect). Likewise, increases in coronary arterial pressure (CAP, mmHg) are associated with improved LV function (gardenhose effect). In situ, increases in AoP are paralleled by increases in both CAP and coronary blood flow, i.e., oxygen supply. We investigated the individual contributions of AoP and CAP increases on function (peak systolic pressure: LVP_max, mm Hg; dP/dt_max, mm Hg/s; end-diastolic pressure: LVP_ed, mm Hg) and end-diastolic geometry (inner diameter: ID_ed, mm; wall thickness: WT_ed, mm; sonomicrometry). CAP-induced increases in coronary flow were prevented by admixing dextran to the perfusate. The experiments were performed on isolated, saline-perfused, working rabbit hearts. Increasing CAP from 60 to 80 mm Hg (n=11) resulted in improved function: LVP_max 89±3 vs. 94±3, dP/dt_max 1160±50 vs. 1250±50, LVP_ed 17±1 vs. 16±1 (mean±SEM). ID_ed decreased from 9.96±0.25 to 9.64±0.33 and WT_ed increased from 6.02±0.16 to 6.15±0.17. In a second series, AoP was increased from 60 to 80 (n=9). Both LVP_max, dP/dt_max and LVP_ed increased (90±4 vs. 97±3, 1170±70 vs. 1270±90 and 18±1 vs. 19±1). ID_ed increased from 9.76±0.39 to 9.99±0.37 and WT_ed decreased from 6.08±0.22 to 5.86±0.25. After additionally increasing CAP to 80, function further improved (LVP_max: 101±3, dP/dt_max: 1310±80) while LVP_ed decreased (18±1). This time, ID_ed decreased to 9.71±0.36 and WT_ed increased to 6.03±0.26. Increases in CAP improve LV function via the gardenhose effect and likely do not depend on simultaneous increases in coronary flow or oxygen supply. On the other hand, increases in AoP alone improve systolic function via the Frank-Starling mechanism. Increases in both pressures together amplify this effect. Increases in CAP and in AoP have opposing effects on ID_ed and WT_ed. In conclusion, the homeometric Anrep effect-at least in part — can be viewed as synergistic action of the Frank-Starling mechanism and the gardenhose effect for this experimental model.Part of the results was presented at the 70th Meeting of the German Physiologic Society, 1991, Freiburg, FRG     

Novel Means to Monitor Cardiac Performance: The Impact of the Force-frequency and Force-interval Relationships on Recirculation Fraction and Potentiation Ratio

Insights into intracellular calcium regulation and contractile state can be accomplished by changing pacing rate. Steady-state increases in heart rate (HR) (force-frequency relationship, FFR), and introduction of extrasystoles (ES) (force-interval relationship, FIR) have been used to investigate this relationship. This study focused on the recirculation fraction (RF) and potentiation ratio (PR), obtained from the recovery of the FFR and FIR. These parameters may provide insight on intracellular Ca²⁺ regulation. Left ventricular (LV) pressures and HR were assessed in anesthetized canines (n = 7). Intrinsic data were collected prior to and following HR increases to 150, 180, and 200 bpm, as well as following delivery of an ES at 280 ms. The RF was calculated as the slope of dP/dt_{max(n + 1)} vs. dP/dt_max(n), where n = beat number. The PR was calculated by normalizing dP/dt_max from the first beat following the ES (or the last paced beat) to the steady-state dP/dt_max. The RF due to an ES was not significantly different than that from a HR of 200 bpm. The PR from an ES was not significantly different than from a HR of 150 bpm. The impact of an ES delivered at an interval of 280 ms produces a PR similar to that from a HR of 150 bpm; yet, it recovers similarly to the termination of pacing at 200 bpm, eliciting a similar RF value. The method of measuring RF by an ES versus an increased HR may provide a safer and more feasible approach to collecting diagnostic information.     

Cardiac resynchronization therapy cures dyssynchronopathy in canine left bundle-branch block hearts.

AIMS: We investigated to what extent biventricular pacing (BVP) can normalize LV function and remodeling, induced by isolated left bundle branch block (LBBB). METHODS AND RESULTS: In 16 dogs LBBB was induced. Eight animals were followed for 16 weeks and in 8 animals BVP was started after 8 weeks. LV pressure, LV geometry (2Dechocardiography), systolic circumferential shortening (CSsys, MRI tagging) and myocardial blood flow (MBF, microspheres) was measured. * and # indicate P < 0.05 compared to pre-LBBB and 8 weeks of LBBB, respectively. Data is presented relative to pre-LBBB values (mean +/- SEM). BVP increased LV dP/dt|max from 78 +/- 5%* to 86 +/- 5%*# (immediately) and 89 +/- 6%# (after 8 weeks) and normalized regional differences in CSsys and MBF. After 8 weeks of BVP, LV end-diastolic volume (EDV) was reduced from 123 +/- 3%* to 109 +/- 6%# and LV lateral wall mass was reduced from 128 +/- 5%* to 113 +/- 3%*#. The acute increase in LV dP/dt|max upon BVP correlated with LV EDV and LV wall mass after 8 weeks of BVP. CONCLUSION: In canine hearts with long-term isolated LBBB, BVP largely reverses global and regional functional and structural abnormalities induced by LBBB.     

Vardenafil increases coronary flow response to hypercapnic acidosis in isolated guinea pig heart

The hypothesis was tested that vardenafil, a PDE5 inhibitor, specifically enhances coronary vasodilation during acidosis. In isolated constant pressure perfused guinea pig hearts, infusion of vardenafil (≤ 1 μM) increased coronary flow concentration-dependently 34 % above baseline. In parallel, cGMP release increased (0.44 ± 0.094 vs. 0.14 ± 0.017 pmol/min·g at 0.5 μM vardenafil vs. baseline). Flow increases occurred in the absence of changes in heart function (LVP, heart rate, dP/dt_max, heart rate – pressure product). Infusion of the NO synthase blocker L-NMMA (100 μM) caused a rightward shift of the dose-response curve of vardenafil. To test whether vardenafil treatment may enhance metabolic coronary vasodilation, arterial pCO₂ was raised from 38 to 61mmHg, which resulted in a steady state flow increase of 18.8 ± 4.5%. Infusion of vardenafil, given at a threshold flow enhancing concentration, doubled the coronary flow response during hypercapnic acidosis to 38.4 ± 4.2 % (p = 0.004). This flow amplification during acidosis was not shared by the K_ATP channel opener cromakalim, indicating a specific effect of vardenafil on flow control during myocardial acidosis. We conclude that vardenafil specifically relaxes coronary resistance vessels through NO/cGMP-dependent pathways and increases the coronary flow response toward hypercapnic acidosis. This finding further supports the importance of the NO-cGMP axis in mediation of this flow response.     

Intra-ventricular resynchronization for optimal left ventricular function during pacing in experimental left bundle branch block

oBJECTIVES: We sought to investigate to what extent intra-ventricular asynchrony (intraVA) and inter-ventricular asynchrony (interVA) determine left ventricular (LV) function in canine hearts with left bundle branch block (LBBB) during ventricular pacing. BACKGROUND: Pacing therapy improves LV pump function in patients with heart failure and abnormal ventricular conduction supposedly due to resynchronization. However, the relationship between LV pump function and measures of asynchrony is not well established. METHODS: In 15 experiments, LV (various sites) and biventricular (BiV) pacing was performed at atrioventricular (AV) delays of 20 to 140 ms. Measured were the maximum rate of increase (dP/dt(max)) of LV pressure and LV stroke work (SW) (conductance catheter), interVA (time delay between the upslope of LV and RV pressures), and intraVA (from endocardial electrical activation maps). RESULTS: Induction of LBBB increased interVA (-6.4 +/- 8.6 to -28.4 +/- 8.5 ms [RV earlier]) and intraVA (4.9 +/- 2.4 to 18.0 +/- 3.3 ms), whereas LV dP/dt(max) and SW decreased (-13 +/- 18% and -39 +/- 24%, respectively). During LBBB, LV and BiV pacing increased LV dP/dt(max) and SW (mean increases 14% to 21% and 11% to 15%, respectively) without changing diastolic function or preload. Optimal improvement in LV function was obtained consistently when intraVA returned to pre-LBBB values, while interVA remained elevated. Normalization of intraVA required AV delays shorter than the baseline PQ time during LV apex and BiV pacing, thus excluding endogenous LV activation, but AV delays virtually equal to the baseline PQ time (difference 4 +/- 9 ms, p = NS) during pacing at (mid)lateral LV sites to obtain fusion between pacing-induced and endogenous activation. CONCLUSIONS: In LBBB hearts, optimal restoration of LV systolic function by pacing requires intra-ventricular resynchronization. The optimal AV delay to achieve this depends on both the site of pacing and baseline PQ time.