Differential effects of left ventricular pacing sites in an acute canine model of contraction dyssynchrony

The goal of the present study was to assess the effects of left ventricular (LV) pacing sites (apex vs. free wall) on radial synchrony and global LV performance in a canine model of contraction dyssynchrony. Ultrasound tissue Doppler imaging and hemodynamic (LV pressure-volume) data were collected in seven anesthetized, opened-chest dogs. Right atrial (RA) pacing served as the control, and contraction dyssynchrony was created by simultaneous RA and right ventricular (RV) pacing to induce a left bundle-branch block-like contraction pattern. Cardiac resynchronization therapy (CRT) was implemented by adding simultaneous LV pacing to the RV pacing mode at either the LV apex (CRTa) or free wall (CRTf). A new index of synchrony was developed via pair-wise cross-correlation analysis of tissue Doppler radial strain from six midmyocardial cross-sectional regions, with a value of 15 indicating perfect synchrony. Compared with RA pacing, RV pacing significantly decreased radial synchrony (11.1 +/- 0.8 vs. 4.8 +/- 1.2, P < 0.01) and global LV performance (cardiac output: 2.0 +/- 0.3 vs. 1.4 +/- 0.1 l/min and stroke work: 137 +/- 22 vs. 60 +/- 14 mJ, P < 0.05). Although both CRTa and CRTf significantly improved radial synchrony, only CRTa markedly improved global function (cardiac output: 2.1 +/- 0.2 l/min and stroke work: 113 +/- 13 mJ, P < 0.01 vs. RV pacing). Furthermore, CRTa decreased LV end-systolic volume compared with RV pacing without any change in LV end-systolic pressure, indicating an augmented global LV contractile state. Thus, LV apical pacing appears to be a superior pacing site in the context of CRT. The dissociation between changes in synchrony and global LV performance with CRTf suggests that regional analysis from a single plane may not be sufficient to adequately characterize contraction synchrony.     

Biventricular pacing in the early postoperative period after cardiac surgery

Cardiac resynchronization therapy is not commonly used in the early postoperative period in patients undergoing cardiac surgery who have left ventricular (LV) dysfunction and a history of heart failure. We performed a prospective randomized clinical trial to compare atrial synchronous right ventricular (DDD RV) and biventricular (DDD BIV) pacing within 72 hours after cardiac surgery in patients with an EF ≤35 %, a QRS interval longer than 120 msec and who had LV dyssynchrony detected by real-time three-dimensional echocardiography (RT3DE). Epicardial pacing was provided by a modified Medtronic INSYNC III pacemaker. An LV epicardial pacing lead was implanted on the latest activated segment of the LV based on RT3DE. The study included 18 patients with ischemic heart disease, with or without valvular heart disease (14 men, 4 women, average age 71 years). Patients undergoing DDD BIV pacing had a statistically significant greater CO and CI (CO 6.7±1.8 l/min, CI 3.4±0.7 l/min/m(2)) than patients undergoing DDD RV pacing (CO 5.5±1.4 l/min, CI 2.8±0.7 l/min/m(2)), p<0.001. DDD BIV pacing in the early postoperative period after cardiac surgery corrects LV dyssynchrony and has better hemodynamic results than DDD RV pacing.     

Tailoring cardiac resynchronisation therapy to non-left bundle branch block: Successful cardiac resynchronisation for right bundle branch block with left posterior fascicular block without implantation of a left ventricular lead

Despite advances, cardiac resynchronisation therapy (CRT) remains fundamentally orientated to the dyssynchrony of left bundle branch block (LBBB), in which septo-lateral electrical and mechanical delays predominate. For non-LBBB patients response rates to conventional CRT are lower and mortality and rehospitalisation rates are not reduced. Despite this, alternative approaches which tailor CRT to the differing dyssynchrony patterns of non-LBBB have yet to be developed. In the specific non-LBBB subgroup of right bundle branch block (RBBB) with left posterior fascicular block (LPFB), ventricular conduction via the left anterior fascicle results in a unique early lateral, and late septal depolarisation, or lateral to septal left ventricular (LV) delay, an electrical sequence which is followed mechanically. This latero-septal delay is somewhat the reverse of LBBB and was overcome by fusing right ventricular (RV) septal pacing with intrinsic conduction via the left anterior fascicle, achieving successful resynchronisation without implantation of a left ventricular lead. A stable fusion pattern was achieved via the ‘Negative AV Hysteresis with Search’ algorithm (Abbott, St Paul, Minnesota). Improvement in all standard CRT response indices was achieved at 3 months: QRS duration was reduced from 153 to 106 ms, ejection fraction increased from 14 to 32%, and LV end-systolic and end-diastolic diameters reduced by 19% and 12.5% respectively. NYHA class improved from III-IV to class II. Cardiac resynchronisation for RBBB with LPFB can be successfully achieved with a standard pacemaker or defibrillator without left ventricular lead implantation by fusing RV septal-only pacing with intrinsic conduction.     

Quantification of left and right ventricular kinetic energy using four-dimensional intracardiac magnetic resonance imaging flow measurements

We aimed to quantify kinetic energy (KE) during the entire cardiac cycle of the left ventricle (LV) and right ventricle (RV) using four-dimensional phase-contrast magnetic resonance imaging (MRI). KE was quantified in healthy volunteers (n = 9) using an in-house developed software. Mean KE through the cardiac cycle of the LV and the RV were highly correlated (r(2) = 0.96). Mean KE was related to end-diastolic volume (r(2) = 0.66 for LV and r(2) = 0.74 for RV), end-systolic volume (r(2) = 0.59 and 0.68), and stroke volume (r(2) = 0.55 and 0.60), but not to ejection fraction (r(2) < 0.01, P = not significant for both). Three KE peaks were found in both ventricles, in systole, early diastole, and late diastole. In systole, peak KE in the LV was lower (4.9 ± 0.4 mJ, P = 0.004) compared with the RV (7.5 ± 0.8 mJ). In contrast, KE during early diastole was higher in the LV (6.0 ± 0.6 mJ, P = 0.004) compared with the RV (3.6 ± 0.4 mJ). The late diastolic peaks were smaller than the systolic and early diastolic peaks (1.3 ± 0.2 and 1.2 ± 0.2 mJ). Modeling estimated the proportion of KE to total external work, which comprised ～0.3% of LV external work and 3% of RV energy at rest and 3 vs. 24% during peak exercise. The higher early diastolic KE in the LV indicates that LV filling is more dependent on ventricular suction compared with the RV. RV early diastolic filling, on the other hand, may be caused to a higher degree of the return of the atrioventricular plane toward the base of the heart. The difference in ventricular geometry with a longer outflow tract in the RV compared with the LV explains the higher systolic KE in the RV.     

Mechanical discoordination rather than dyssynchrony predicts reverse remodeling upon cardiac resynchronization

By current guidelines a considerable part of the patients selected for cardiac resynchronization therapy (CRT) do not respond to the therapy. We hypothesized that mechanical discoordination [opposite strain within the left ventricular (LV) wall] predicts reversal of LV remodeling upon CRT better than mechanical dyssynchrony. MRI tagging images were acquired in CRT candidates (n = 19) and in healthy control subjects (n = 9). Circumferential strain (epsilon(cc)) was determined in 160 regions. From epsilon(cc) signals we derived 1) an index of mechanical discoordination [internal stretch fraction (ISF), defined as the ratio of stretch to shortening during ejection] and 2) indexes of mechanical dyssynchrony: the 10-90% width of time to onset of shortening, time to peak shortening, and end-systolic strain. LV end-diastolic volume (LVEDV), end-systolic volume (LVESV), and ejection fraction (LVEF) were determined before and after 3 mo of CRT. Responders were defined as those patients in whom LVESV decreased by >15%. In responders (n = 10), CRT increased LVEF and decreased LVEDV and LVESV (11 +/- 6%, 21 +/- 16%, and 30 +/- 16%, respectively) significantly more (P < 0.05) than in nonresponders (1 +/- 6%, 3 +/- 4%, and 5 +/- 10%, respectively). Among mechanical indexes, only ISF was different between responders and nonresponders (0.53 +/- 0.25 vs. 0.31 +/- 0.16; P < 0.05). In patients with ISF >0.4 (n = 10), LVESV decreased by 31 +/- 18% vs. 5 +/- 11% in patients with ISF <0.4 (P < 0.05). We conclude that mechanical discoordination, as estimated from ISF, is a better predictor of reverse remodeling after CRT than differences in time to onset and time to peak shortening. Therefore, discoordination rather than dyssynchrony appears to reflect the reserve contractile capacity that can be recruited by CRT.     

Tailoring cardiac resynchronization therapy using interventricular asynchrony. Validation of a simple model

This study explores the use of interventricular asynchrony (interVA) for optimizing cardiac resynchronization therapy (CRT), an idea emerging from a simple pathway model of conduction in the ventricles. Measurements were performed in six dogs with chronic left bundle branch block (LBBB) and in 29 patients of the Pacing Therapies for Congestive Heart Failure (PATH-CHF)-I study. In the dogs, intraventricular asynchrony (intraVA) was determined using left ventricular (LV) endocardial activation maps. In dogs and patients, the maximum rate of rise of LV pressure (LV dP/dt(max)) and the pulse pressure (PP) and interVA [time delay between upslope of LV and right ventricular (RV) pressure curves] were measured during LV, RV, and biventricular (BiV) pacing with various atrioventricular (AV) delays. Measurements in the canine hearts supported the pathway model in that optimal resynchronization occurred at approximately 50% reduction of intraVA and at an interVA value halfway that during LBBB and LV pacing. In patients with significant hemodynamic response during pacing (n = 22), intrinsic interVA and interVA at peak improvement (interVA(p)) varied widely between patients (from -83 to -15 ms and from -42 to +31 ms, respectively). However, the model predicted individual interVA(p) accurately (SD of +/-6 ms and +/-12 ms for LV dP/dt(max) and PP, respectively). At equal interVA, LV and BiV pacing produced equal hemodynamic response, but in 11 of 22 responders, BiV pacing reduced interVA insufficiently to reach the maximum hemodynamic response. LV pacing at short AV delay proved to result in better hemodynamics than predicted by the model, indicating that additional factors determine hemodynamics during LV preexcitation. Guided by a simple pathway model, interVA measurements accurately predict optimal hemodynamic performance in individual CRT patients.     

Anodal stimulation: an underrecognized cause of nonresponders to cardiac resynchronization therapy

Objective

The purpose of this study was to determine if anodal stimulation accounts for failure to benefit from cardiac resynchronization therapy (CRT) in some patients.

Background

Approximately 30-40% of patients with moderate to severe heart failure do not have symptomatic nor echocardiographic improvement in cardiac function following CRT. Modern CRT devices allow the option of programming left ventricular (LV) lead pacing as LV tip to right ventricular (RV) lead coil to potentially improve pacing thresholds. However, anodal stimulation can result in unintentional RV pacing (anode) instead of LV pacing (cathode).

Methods

Patients enrolled in our center''s CRT registry had an echocardiogram, 6-minute walk (6MW), and Minnesota Living with HF Questionnaire (MLHFQ) pre-implant and 6 months after CRT. Electrocardiograms (12 lead) during RV, LV, and biventricular (BiV) pacing were obtained at the end of the implant in 102 patients. Anodal stimulation was defined as LV pacing QRS morphology on EKG being identical to RV pacing or consistent with fusion with RV and LV electrode capture. LV end systolic volume (LVESV) was measured by echo biplane Simpson''s method and CRT responder was defined as 15% or greater reduction in LVESV.

Results

Of the 102 patients, 46 (45.1%) had the final LV lead pacing configuration programmed LV (tip or ring) to RV (coil or ring). 3 of the 46 subjects (6.5%) had EKG findings consistent with anodal stimulation, not corrected intraoperatively. All anodal stimulation patients were nonresponders to CRT by echo criteria (reduction in LVESV 13.3 ± 0.6%, increase in EF 5.0 ± 1.4%) compared to 46% responders for those without anodal stimulation, (change in LVESV 18.7 ± 25.6%, EF 7.6 ±10.9%). None of the anodal stimulation patients were responders for the 6 minute walk, compared to 32 of 66 (48%) of those without anodal stimulation.

Conclusion

Anodal stimulation is a potential underrecognized and ameliorable cause of poor response to CRT.     

Quantification of interventricular asynchrony during LBBB and ventricular pacing

The quantification of mechanical interventricular asynchrony (IVA) was investigated. In 12 dogs left bundle branch block (LBBB) was induced by radio frequency ablation. Left ventricular (LV) and right ventricular (RV) pressures were recorded before and after induction of LBBB and during LBBB + LV apex pacing at different atrioventricular (AV) delays. Four IVA measures were validated using computer simulations on experimentally obtained pressure signals. The most robust measure for IVA was the time delay between the upslope of the LV and RV pressure signals (DeltaT(up)), estimated by cross correlation. The induction of experimental LBBB decreased DeltaT(up) from -6.9 +/- 7.0 ms (RV before LV) to -33.9 +/- 7.6 ms (P < 0.05) in combination with a significant decrease of LV maximal first derivative of pressure development over time (dP/dt(max)). During LV apex pacing, DeltaT(up) increased with decreasing AV delay up to +20.9 +/- 14.6 ms (P < 0.05). Interventricular resynchronization (DeltaT(up) = 0 ms) significantly improved LV dP/dt(max) by 15.1 +/- 5.9%. QRS duration increased significantly after induction of LBBB but did not change during LV apex pacing. In conclusion, DeltaT(up) is a reliable measure of mechanical IVA, which adds valuable information concerning the nature of asynchronous activation of the ventricles.     

Cardiac resynchronization therapy modulation of exercise left ventricular function and pulmonary O₂ uptake in heart failure

To better understand the mechanisms contributing to improved exercise capacity with cardiac resynchronization therapy (CRT), we studied the effects of 6 mo of CRT on pulmonary O(2) uptake (Vo(2)) kinetics, exercise left ventricular (LV) function, and peak Vo(2) in 12 subjects (age: 56 ± 15 yr, peak Vo(2): 12.9 ± 3.2 ml·kg(-1)·min(-1), ejection fraction: 18 ± 3%) with heart failure. We hypothesized that CRT would speed Vo(2) kinetics due to an increase in stroke volume secondary to a reduction in LV end-systolic volume (ESV) and that the increase in peak Vo(2) would be related to an increase in cardiac output reserve. We found that Vo(2) kinetics were faster during the transition to moderate-intensity exercise after CRT (pre-CRT: 69 ± 21 s vs. post-CRT: 54 ± 17 s, P < 0.05). During moderate-intensity exercise, LV ESV reserve (exercise - resting) increased 9 ± 7 ml (vs. a 3 ± 9-ml decrease pre-CRT, P < 0.05), and steady-state stroke volume increased (pre-CRT: 42 ± 8 ml vs. post-CRT: 61 ± 12 ml, P < 0.05). LV end-diastolic volume did not change from rest to steady-state exercise post-CRT (P > 0.05). CRT improved heart rate, measured as a lower resting and steady-state exercise heart rate and as faster heart rate kinetics after CRT (pre-CRT: 89 ± 12 s vs. post-CRT: 69 ± 21 s, P < 0.05). For peak exercise, cardiac output reserve increased significantly post-CRT and was 22% higher at peak exercise post-CRT (both P < 0.05). The increase in cardiac output was due to both a significant increase in peak and reserve stroke volume and to a nonsignificant increase in heart rate reserve. Similar patterns in LV volumes as moderate-intensity exercise were observed at peak exercise. Cardiac output reserve was related to peak Vo(2) (r = 0.48, P < 0.05). These findings demonstrate the chronic CRT-mediated cardiac factors that contribute, in part, to the speeding in Vo(2) kinetics and increase in peak Vo(2) in clinically stable heart failure patients.     

Mechanism of prolonged electromechanical delay in late activated myocardium during left bundle branch block

During left bundle branch block (LBBB), electromechanical delay (EMD), defined as time from regional electrical activation (REA) to onset shortening, is prolonged in the late-activated left ventricular lateral wall compared with the septum. This leads to greater mechanical relative to electrical dyssynchrony. The aim of this study was to determine the mechanism of the prolonged EMD. We investigated this phenomenon in an experimental LBBB dog model (n = 7), in patients (n = 9) with biventricular pacing devices, in an in vitro papillary muscle study (n = 6), and a mathematical simulation model. Pressures, myocardial deformation, and REA were assessed. In the dogs, there was a greater mechanical than electrical delay (82 ± 12 vs. 54 ± 8 ms, P = 0.002) due to prolonged EMD in the lateral wall vs. septum (39 ± 8 vs.11 ± 9 ms, P = 0.002). The prolonged EMD in later activated myocardium could not be explained by increased excitation-contraction coupling time or increased pressure at the time of REA but was strongly related to dP/dt at the time of REA (r = 0.88). Results in humans were consistent with experimental findings. The papillary muscle study and mathematical model showed that EMD was prolonged at higher dP/dt because it took longer for the segment to generate active force at a rate superior to the load rise, which is a requirement for shortening. We conclude that, during LBBB, prolonged EMD in late-activated myocardium is caused by a higher dP/dt at the time of activation, resulting in aggravated mechanical relative to electrical dyssynchrony. These findings suggest that LV contractility may modify mechanical dyssynchrony.     

Left ventricle pacing challenges in cardiac resynchronization therapy systems

Left ventricle (LV) pacing can be considered peculiar due to its different lead/tissue interface (epicardial pacing) and the small vein wedging lead locations with less reliable lead stability. The current technologies available for LV capture automatic confirmation adopt the evoked response (ER), as well as “LV pace to right ventricular (RV) sense” algorithms. The occurrence of anodal RV capture is today completely solved by the use of bipolar LV leads, while intriguing data are recently published regarding the unintentional LV anodal capture beside the cathodal one, which may enlarge the front wave of cardiac resynchronization therapy (CRT) delivery. The LV threshold behavior over time leading to ineffective CRT issues (subthreshold stimulation or concealed loss of capture), the extracardiac capture with phrenic nerve stimulation (PNS), the flexible electronic cathode reprogramming and the inadequate CRT delivery related to inadequate AV and VV pace timing (and its management by LV “dromotropic pace-conditioning”) are discussed.Moreover, recently, His bundle pacing (HBP) and left bundle branch pacing (LBBP) have shown growing interest to prevent pacing-induced cardiomyopathy as well as for direct intentional CRT.The purpose of the present review is to explore these new challenges regarding LV pacing starting from old concepts.     

Visual LV motion and invasive LVdP/dtmax for selection and optimisation of cardiac resynchronisation therapy

Echocardiography shows that multiphasic septal movement and a septal to lateral apical systolic left ventricular (LV) motion have a high predictive value for dyssynchrony and the response to cardiac resynchronisation therapy (CRT). Presence of dyssynchrony is also the major marker for CRT response in the presence of scar tissue, provided the interventricular (V-V) pacing interval is optimalised. For atrioventricular (AV) interval optimisation, the velocity-time integral of the transmitral flow has an excellent correlation with invasive LVdP/dt_max. In acute haemodynamic measurements, LVdP/dt_max shows strongly the effect of AV and V-V optimisation. It also illustrates that the haemodynamic effect of LV pacing when associated with intrinsic conduction over the right bundle is equal to or better than biventricular pacing. We found that once AV and V-V interval were optimised, QRS morphology could be used as a template for optimal therapy. Automated continuous optimisation of the pacing intervals will be the big challenge for the future. (Neth Heart J 2008;16(suppl 1):S32-S35).     

Lung ultrasound: a new tool for the cardiologist

Background

We have previously reported strain dyssynchrony index assessed by two-dimensional speckle tracking strain, and a marker of both dyssynchrony and residual myocardial contractility, can predict response to cardiac resynchronization therapy (CRT). A newly developed three-dimensional (3-D) speckle tracking system can quantify endocardial area change ratio (area strain), which coupled with the factors of both longitudinal and circumferential strain, from all 16 standard left ventricular (LV) segments using complete 3-D pyramidal datasets. Our objective was to test the hypothesis that strain dyssynchrony index using area tracking (ASDI) can quantify dyssynchrony and predict response to CRT.

Methods

We studied 14 heart failure patients with ejection fraction of 27 ± 7% (all≤35%) and QRS duration of 172 ± 30 ms (all≥120 ms) who underwent CRT. Echocardiography was performed before and 6-month after CRT. ASDI was calculated as the average difference between peak and end-systolic area strain of LV endocardium obtained from 3-D speckle tracking imaging using 16 segments. Conventional dyssynchrony measures were assessed by interventricular mechanical delay, Yu Index, and two-dimensional radial dyssynchrony by speckle-tracking strain. Response was defined as a ≥15% decrease in LV end-systolic volume 6-month after CRT.

Results

ASDI ≥ 3.8% was the best predictor of response to CRT with a sensitivity of 78%, specificity of 100% and area under the curve (AUC) of 0.93 (p < 0.001). Two-dimensional radial dyssynchrony determined by speckle-tracking strain was also predictive of response to CRT with an AUC of 0.82 (p < 0.005). Interestingly, ASDI ≥ 3.8% was associated with the highest incidence of echocardiographic improvement after CRT with a response rate of 100% (7/7), and baseline ASDI correlated with reduction of LV end-systolic volume following CRT (r = 0.80, p < 0.001).

Conclusions

ASDI can predict responders and LV reverse remodeling following CRT. This novel index using the 3-D speckle tracking system, which shows circumferential and longitudinal LV dyssynchrony and residual endocardial contractility, may thus have clinical significance for CRT patients.     

Six months clinical outcome comparison between quadripolar and bipolar left ventricular leads in cardiac resynchronization therapy: A prospective,non-randomized,single-centre observational study

Background and objectivesQuadripolar left ventricular (LV) leads in cardiac resynchronization therapy (CRT) offer multi-vector pacing with different pacing configurations and hence enabling LV pacing at most suitable site with better lead stability. We aim to compare the outcomes between quadripolar and bipolar LV lead in patients receiving CRT.MethodsIn this prospective, non-randomized, single-center observational study, we enrolled 93 patients receiving CRT with bipolar (BiP) (n = 31) and quadripolar (Quad) (n = 62) LV lead between August 2016 to August 2019. Patients were followed for six months, and outcomes were compared with respect to CRT response (defined as ≥5% absolute increase in left ventricle ejection fraction), electrocardiographic, echocardiographic parameters, NYHA functional class improvement, and incidence of LV lead-related complication.ResultsAt the end of six months follow up, CRT with quadripolar lead was associated with better response rate as compared to bipolar pacing (85.48% vs 64.51%; p = 0.03), lesser heart failure (HF) hospitalization events (1.5 vs 2; p = 0.04) and better improvement in HF symptoms (patients with ≥1 NYHA improvement 87.09% vs 67.74%; p = 0.04). There were fewer deaths per 100 patient-year (6.45 vs 9.37; p = 0.04) and more narrowing of QRS duration (Δ12.56 ± 3.11 ms vs Δ7.29 ± 1.87 ms; p = 0.04) with quadripolar lead use. Lead related complications were significantly more with the use of bipolar lead (74.19% vs 41.94%; p = 0.02).ConclusionsOur prospective, non-randomized, single-center observational study reveals that patients receiving CRT with quadripolar leads have a better response to therapy, lesser heart failure hospitalizations, lower all-cause mortality, and fewer lead-related complications, proving its superiority over the bipolar lead.     

Conduction and refractory disorders in the diabetic atrium

Diabetes mellitus (DM) is an independent risk of atrial fibrillation. However, its arrhythmogenic substrates remain unclear. This study sought to examine the precise propagation and the spatiotemporal dispersion of the action potential (AP) in the diabetic atrium. DM was induced by streptozotocin (65 mg/kg) in 8-wk-old male Wister rats. Optical mapping and histological analysis were performed in the right atrium (RA) from control (n = 26) and DM (n = 27) rats after 16 wk. Rate-dependent alterations of conduction velocity (CV) and its heterogeneity and the spatial distribution of AP were measured in RA using optical mapping. The duration of atrial tachyarrhythmia (AT) induced by rapid atrial stimulation was longer in DM (2.4 ± 0.6 vs. 0.9 ± 0.3 s, P < 0.05). CV was decreased, and its heterogeneity was greater in DM than control. Average action potential duration of 80% repolarization (APD(80)) at pacing cycle length (PCL) of 200 ms from four areas within the RA was prolonged (53 ± 2 vs. 40 ± 3 ms, P < 0.01), and the coefficient of variation of APD(80) was greater in DM than control (0.20 ± 0.02 vs. 0.15 ± 0.01%, P < 0.05). The ratio of APD(80) at PCL shorter than 200 ms to that at 200 ms was smaller (P < 0.001), and the incidence of APD alternans was higher in DM than control (100 vs. 0%, P < 0.001). Interstitial fibrosis was greater and connexin 40 expression was lower in DM than control. The remodeling of the diabetic atrium was characterized as follows: greater vulnerability to AT, increased conduction slowing and its heterogeneity, the prolongation of APD, the increase in spatial dispersion and frequency-dependent shortening of APD, and increased incidence of APD alternans.     

Diastolic dysfunction and intraventricular dyssynchrony are restored by low intensity exercise training in obese men

The aim of this study was to evaluate the impact of a low-intensity training program on subclinical cardiac dysfunction and on dyssynchrony in moderately obese middle aged men. Ten obese and 14 age-matched normal-weight men (BMI: 33.6 ± 1.0 and 24.2 ± 0.5 kg/m(2)) were included. Obese men participated in an 8-week low-intensity training program without concomitant diet. Cardiac function and myocardial synchrony were assessed by echocardiography with tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). At baseline, obese men showed diastolic dysfunction on standard echocardiography, lower strain values (systolic strain: 15.9 ± 0.9 vs. 18.8 ± 0.3%, diastolic strain rate: 0.81 ± 0.09 vs. 1.05 ± 0.06 s(-1)), and significant intraventricular dyssynchrony (systolic: 13.3 ± 2.1 vs. 5.4 ± 2.1 ms, diastolic: 17.4 ± 3.2 vs. 9.1 ± 2.1 ms) (P < 0.05 vs. controls for all variables). Training improved aerobic fitness, decreased systolic blood pressure and heart rate, and reduced fat mass without weight loss. Diastolic function, strain values (systolic strain: 17.4 ± 0.9%, diastolic strain rate: 0.96 ± 0.12 s(-1)) and intraventricular dyssynchrony (systolic: 3.3 ± 1.7 ms, diastolic: 5.5 ± 3.4 ms) improved significantly after training (P < 0.05 vs. baseline values for all variables), reaching levels similar to those of normal-weight men. In conclusion, in obese men, a short and easy-to-perform low intensity training program restored diastolic function and cardiac synchrony and improved body composition without weight loss.     

Diastolic dysfunction in volume-overload hypertrophy is associated with abnormal shearing of myolaminar sheets

Diastolic dysfunction in volume-overload hypertrophy by aortocaval fistula is characterized by increased passive stiffness of the left ventricle (LV). We hypothesized that changes in passive properties are associated with abnormal myolaminar sheet mechanics during diastolic filling. We determined three-dimensional finite deformation of myofiber and myolaminar sheets in the LV free wall of six dogs with cineradiography of implanted markers during development of volume-overload hypertrophy by aortocaval fistula. After 9 +/- 2 wk of volume overload, all dogs developed edema of extremities, pulmonary congestion, elevated LV end-diastolic pressure (5 +/- 2 vs. 21 +/- 4 mmHg, P < 0.05), and increased LV volume. There was no significant change in systolic function [dP/dt(max): 2,476 +/- 203 vs. 2,330 +/- 216 mmHg/s, P = not significant (NS)]. Diastolic relaxation was significantly reduced (dP/dt(min): -2,466 +/- 190 vs. -2,076 +/- 166 mmHg/s, P < 0.05; time constant of LV pressure decline: 32 +/- 2 vs. 43 +/- 1 ms, P < 0.05), whereas duration of diastolic filling was unchanged (304 +/- 33 vs. 244 +/- 42 ms, P = NS). Fiber stretch and sheet shear occur predominantly in the first third of diastolic filling, and chronic volume overload induced remodeling in lengthening of the fiber and reorientation of the laminar sheet architecture. Sheet shear was significantly increased and delayed at the subendocardial layer (P < 0.05), whereas magnitude of fiber stretch was not altered in volume overload (P = NS). These findings indicate that enhanced filling in volume-overload hypertrophy is achieved by enhanced sheet shear early in diastole. These results provide the first evidence that changes in motion of radially oriented laminar sheets may play an important functional role in pathology of diastolic dysfunction in this model.     

Frequency-dependent left ventricular performance in women and men

We aimed to determine whether sex differences in humans extend to the dynamic response of the left ventricular (LV) chamber to changes in heart rate (HR). Several observations suggest sex influences LV structure and function in health; moreover, this physiology is also affected in a sex-specific manner by aging. Eight postmenopausal women and eight similarly aged men underwent a cardiac catheterization-based study for force-interval relationships of the LV. HR was controlled by right atrial (RA) pacing, and LV +dP/dt(max) and volume were assessed by micromanometer-tipped catheter and Doppler echocardiography, respectively. Analysis of approximated LV pressure-volume relationships was performed using a time-varying model of elastance. External stroke work was also calculated. The relationship between HR and LV +dP/dt(max) was expressed as LV +dP/dt(max) = b + mHR. The slope (m) of the relationship was steeper in women compared with men (11.8 ± 4.0 vs. 6.1 ± 4.1 mmHg·s(-1)·beats(-1)·min(-1), P = 0.01). The greater increase in contractility in women was reproducibly observed after normalizing LV +dP/dt(max) to LV end-diastolic volume (LVVed) or by measuring end-systolic elastance. LVVed and stroke volume decreased more in women. Thus, despite greater increases in contractility, HR was associated with a lesser rise in cardiac output and a steeper fall in external stroke work in women. Compared with men, women exhibit greater inotropic responses to incremental RA pacing, which occurs at the same time as a steeper decline in external stroke work. In older adults, we observed sexual dimorphism in determinants of LV mechanical performance.     

Effects of angiotensin (1-7) upon right ventricular function in experimental rat pulmonary embolism

Right ventricular (RV) dysfunction contributes to poor clinical prognosis after pulmonary embolism (PE). The present studies evaluate the effects of angiotensin (1-7) (ANG (1-7)) upon RV function during experimental PE in rats. Circulating ANG II increased 8-fold 6 hr after PE (47±13 PE vs. 6±3 pg/mL, control, p<0.05). ACE2 protein was uniformly localized in the RV myocardium of control rats, but showed a patchy distribution with some cells devoid of stain after 6 or 18 hr of PE. RV function decreased 18 hr after PE compared with control treated animals (19±4 vs. 41±1 mmHg, respectively, p<0.05; 669±98 vs. 1354±77 mmHg/sec, respectively, p<0.05), while left ventricular function (LV) was not significantly changed. Animals treated with ANG (1-7) during PE showed improved RV +dP/dt and peak systolic pressure development to values not significantly different from control animals. Protection of RV function by ANG (1-7) was associated with improved arterial blood sO2, base excess and pH. Supplemental delivery of ANG (1-7) reduced the development of RV dysfunction, suggesting a novel approach to protecting RV function in the setting of acute experimental PE.