Non-invasive myocardial work in aortic stenosis: validation and improvement in left ventricular pressure estimation.

AIMS: The non-invasive myocardial work index (MWI) has been validated in patients without aortic stenosis (AS). A thorough assessment of methodological limitations is warranted before this index can be applied to patients with AS. METHODS AND RESULTS: We simultaneously measured left ventricular pressure (LVP) by using a micromanometer-tipped catheter and obtained echocardiograms in 20 patients with severe AS. We estimated LVP curves and calculated pressure-strain loops using three different models: (i) the model validated in patients without AS; (ii) the same model, but with pressure at the aortic valve opening (AVO) adjusted to diastolic cuff pressure; and (iii) a new model based on the invasive measurements from patients with AS. Valvular events were determined by echocardiography. Peak LVP was estimated as the sum of the mean aortic transvalvular gradient and systolic cuff pressure. In same-beat comparisons between invasive and estimated LVP curves, Model 1 significantly overestimated early systolic pressure by 61 ± 5 mmHg at AVO compared with Models 2 and 3. However, the average correlation coefficients between estimated and invasive LVP traces were excellent for all models, and the overestimation had limited influence on MWI, with excellent correlation (r = 0.98, P < 0.001) and good agreement between the MWI calculated with estimated (all models) and invasive LVP. CONCLUSION: This study confirms the validity of the non-invasive MWI in patients with AS. The accuracy of estimated LVP curves improved when matching AVO to the diastolic pressure in the original model, mirroring that of the AS-specific model. This may sequentially enhance the accuracy of regional MWI assessment.

Detection of inflow obstruction in left ventricular assist devices by accelerometer: A porcine model study.

BACKGROUND: Left ventricular assist devices (LVAD) provide circulatory blood pump support for severe heart failure patients. Pump inflow obstructions may lead to stroke and pump malfunction. We aimed to verify in vivo that gradual inflow obstructions, representing prepump thrombosis, are detectable by a pump-attached accelerometer, where the routine use of pump power (PLVAD) is deficient. METHOD: In a porcine model (n = 8), balloon-tipped catheters obstructed HVAD inflow conduits by 34% to 94% in 5 levels. Afterload increases and speed alterations were conducted as controls. We computed nonharmonic amplitudes (NHA) of pump vibrations captured by the accelerometer for the analysis. Changes in NHA and PLVAD were tested by a pairwise nonparametric statistical test. Detection sensitivities and specificities were investigated by receiver operating characteristics with areas under the curves (AUC). RESULTS: NHA remained marginally affected during control interventions, unlike PLVAD. NHA elevated during obstructions within 52-83%, while mass pendulation was most pronounced. Meanwhile, PLVAD changed far less. Increased pump speeds tended to amplify the NHA elevations. The corresponding AUC was 0.85-1.00 for NHA and 0.35-0.73 for PLVAD. CONCLUSION: Elevated NHA provides a reliable indication of subclinical gradual inflow obstructions. The accelerometer can potentially supplement PLVAD for earlier warnings and localization of pump.

Microcirculatory Resistance Predicts Allograft Rejection and Cardiac Events After Heart Transplantation.

BACKGROUND: Single-center data suggest that the index of microcirculatory resistance (IMR) measured early after heart transplantation predicts subsequent acute rejection. OBJECTIVES: The goal of this study was to validate whether IMR measured early after transplantation can predict subsequent acute rejection and long-term outcome in a large multicenter cohort. METHODS: From 5 international cohorts, 237 patients who underwent IMR measurement early after transplantation were enrolled. The primary outcome was acute allograft rejection (AAR) within 1 year after transplantation. A key secondary outcome was major adverse cardiac events (MACE) (the composite of death, re-transplantation, myocardial infarction, stroke, graft dysfunction, and readmission) at 10 years. RESULTS: IMR was measured at a median of 7 weeks (interquartile range: 3-10 weeks) post-transplantation. At 1 year, the incidence of AAR was 14.4%. IMR was associated proportionally with the risk of AAR (per increase of 1-U IMR; adjusted hazard ratio [aHR]: 1.04; 95% confidence interval [CI]: 1.02-1.06; p < 0.001). The incidence of AAR in patients with an IMR ≥18 was 23.8%, whereas the incidence of AAR in those with an IMR <18 was 6.3% (aHR: 3.93; 95% CI: 1.77-8.73; P = 0.001). At 10 years, MACE occurred in 86 (36.3%) patients. IMR was significantly associated with the risk of MACE (per increase of 1-U IMR; aHR: 1.02; 95% CI: 1.01-1.04; P = 0.005). CONCLUSIONS: IMR measured early after heart transplantation is associated with subsequent AAR at 1 year and clinical events at 10 years. Early IMR measurement after transplantation identifies patients at higher risk and may guide personalized posttransplantation management.

Factors determining the magnitude of the pre-ejection leftward septal motion in left bundle branch block.

AIMS: An abnormal large leftward septal motion prior to ejection is frequently observed in left bundle branch block (LBBB) patients. This motion has been proposed as a predictor of response to cardiac resynchronization therapy (CRT). Our goal was to investigate factors that influence its magnitude. METHODS AND RESULTS: Left (LVP) and right ventricular (RVP) pressures and left ventricular (LV) volume were measured in eight canines. After induction of LBBB, LVP and, hence, the transmural septal pressure (PLV-RV = LVP-RVP) increased more slowly (P < 0.01) during the phase when septum moved leftwards. A biventricular finite-element LBBB simulation model confirmed that the magnitude of septal leftward motion depended on reduced rise of PLV-RV. The model showed that leftward septal motion was decreased with shorter activation delay, reduced global or right ventricular (RV) contractility, septal infarction, or when the septum was already displaced into the LV at end diastole by RV volume overload. Both experiments and simulations showed that pre-ejection septal hypercontraction occurs, in part, because the septum performs more of the work pushing blood towards the mitral valve leaflets to close them as the normal lateral wall contribution to this push is lost. CONCLUSIONS: Left bundle branch block lowers afterload against pre-ejection septal contraction, expressed as slowed rise of PLV-RV, which is a main cause and determinant of the magnitude of leftward septal motion. The motion may be small or absent due to septal infarct, impaired global or RV contractility or RV volume overload, which should be kept in mind if this motion is to be used in evaluation of CRT response.

Non-invasive myocardial work index identifies acute coronary occlusion in patients with non-ST-segment elevation-acute coronary syndrome.

AIMS: Acute coronary artery occlusion (ACO) occurs in ∼30% of patients with non-ST-segment elevation-acute coronary syndrome (NSTE-ACS). We investigated the ability of a regional non-invasive myocardial work index (MWI) to identify ACO. METHODS AND RESULTS: Segmental strain analysis was performed before coronary angiography in 126 patients with NSTE-ACS. Left ventricular (LV) pressure was estimated non-invasively using a standard waveform fitted to valvular events and scaled to systolic blood pressure. MWI was calculated as the area of the LV pressure-strain loop. Empirical cut-off values were set to identify segmental systolic dysfunction for MWI (<1700 mmHg %) and strain (more than -14%). The number of dysfunctional segments was used in ROC analysis to identify ACO. The presence of ≥4 adjacent dysfunctional segments assessed by MWI was significantly better than both global strain and ejection fraction at detecting the occurrence of ACO (P < 0.05). Regional MWI had a higher sensitivity (81 vs. 78%) and especially specificity (82 vs. 65%) compared with regional strain. Logistic regression demonstrated that elevated systolic blood pressure significantly decreased the probability of actual ACO in a patient with an area of impaired regional strain. CONCLUSION: The presence of a region of reduced MWI in patients with NSTE-ACS identified patients with ACO and was superior to all other parameters. The regional MWI was able to account for the influence of systolic blood pressure on regional contraction. We therefore propose that MWI may serve as an important clinical tool for selecting patients in need of prompt invasive treatment.

Cardiac responses to left ventricular pacing in hearts with normal electrical conduction: beneficial effect of improved filling is counteracted by dyssynchrony.

Cardiac resynchronization therapy (CRT) has been proposed in heart failure patients with narrow QRS, but the mechanism of a potential beneficial effect is unknown. The present study investigated the hypothesis that left ventricular (LV) pacing increases LV end-diastolic volume (LVEDV) by allowing the LV to start filling before the right ventricle (RV) during narrow QRS in an experimental model. LV and biventricular pacing were studied in six anesthetized dogs before and after the induction of LV failure. Function was evaluated by pressures and dimensions, and dyssynchrony was evaluated by electromyograms and deformation. In the nonfailing heart, LV pacing gave the LV a head start in filling relative to the RV (P < 0.05) and increased LVEDV (P < 0.05). The response was similar during LV failure when RV diastolic pressure was elevated. The pacing-induced increase in LVEDV was attributed to a rightward shift of the septum (P < 0.01) due to an increased left-to-right transseptal pressure gradient (P < 0.05). LV pacing, however, also induced dyssynchrony (P < 0.05) and therefore reduced LV stroke work (P < 0.05) during baseline, and similar results were seen in failing hearts. Biventricular pacing did not change LVEDV, but systolic function was impaired. This effect was less marked than with LV pacing. In conclusion, pacing of the LV lateral wall increased LVEDV by displacing the septum rightward, suggesting a mechanism for a favorable effect of CRT in narrow QRS. The pacing, however, induced dyssynchrony and therefore reduced LV systolic function. These observations suggest that detrimental effects should be considered when applying CRT in patients with narrow QRS.

Assessment of wasted myocardial work: a novel method to quantify energy loss due to uncoordinated left ventricular contractions.

Left ventricular (LV) dyssynchrony reduces myocardial efficiency because work performed by one segment is wasted by stretching other segments. In the present study, we introduce a novel noninvasive clinical method that quantifies wasted energy as the ratio between work consumed during segmental lengthening (wasted work) divided by work during segmental shortening. The wasted work ratio (WWR) principle was studied in 6 anesthetized dogs with left bundle branch block (LBBB) and in 28 patients with cardiomyopathy, including 12 patients with LBBB and 10 patients with cardiac resynchronization therapy. Twenty healthy individuals served as controls. Myocardial strain was measured by speckle tracking echocardiography, and LV pressure (LVP) was measured by micromanometer and a previously validated noninvasive method. Segmental work was calculated by multiplying strain rate and LVP to get instantaneous power, which was integrated to give work as a function of time. A global WWR was also calculated. In dogs, WWR by estimated LVP and strain showed a strong correlation (r = 0.94) and good agreement with WWR by the LV micromanometer and myocardial segment length by sonomicrometry. In patients, noninvasive WWR showed a strong correlation (r = 0.96) and good agreement with WWR using the LV micromanometer. Global WWR was 0.09 ± 0.03 in healthy control subjects, 0.36 ± 0.16 in patients with LBBB, and 0.21 ± 0.09 in cardiomyopathy patients without LBBB. Cardiac resynchronization therapy reduced global WWR from 0.36 ± 0.16 to 0.17 ± 0.07 (P < 0.001). In conclusion, energy loss due to incoordinated contractions can be quantified noninvasively as the LV WWR. This method may be applied to evaluate the mechanical impact of dyssynchrony.

A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work.

AIMS: Left ventricular (LV) pressure-strain loop area reflects regional myocardial work and metabolic demand, but the clinical use of this index is limited by the need for invasive pressure. In this study, we introduce a non-invasive method to measure LV pressure-strain loop area. METHODS AND RESULTS: Left ventricular pressure was estimated by utilizing the profile of an empiric, normalized reference curve which was adjusted according to the duration of LV isovolumic and ejection phases, as defined by timing of aortic and mitral valve events by echocardiography. Absolute LV systolic pressure was set equal to arterial pressure measured invasively in dogs (n = 12) and non-invasively in patients (n = 18). In six patients, myocardial glucose metabolism was measured by positron emission tomography (PET). First, we studied anaesthetized dogs and observed an excellent correlation (r = 0.96) and a good agreement between estimated LV pressure-strain loop area and loop area by LV micromanometer and sonomicrometry. Secondly, we validated the method in patients with various cardiac disorders, including LV dyssynchrony, and confirmed an excellent correlation (r = 0.99) and a good agreement between pressure-strain loop areas using non-invasive and invasive LV pressure. Non-invasive pressure-strain loop area reflected work when incorporating changes in local LV geometry (r = 0.97) and showed a strong correlation with regional myocardial glucose metabolism by PET (r = 0.81). CONCLUSIONS: The novel non-invasive method for regional LV pressure-strain loop area corresponded well with invasive measurements and with directly measured myocardial work and it reflected myocardial metabolism. This method for assessment of regional work may be of clinical interest for several patients groups, including LV dyssynchrony and ischaemia.

The role of echocardiography in quantification of left ventricular dyssynchrony: state of the art and future directions.

This article discusses how echocardiography can be applied to quantify dyssynchrony in patients who are evaluated for cardiac resynchronization therapy (CRT). A number of echocardiographic indices have been proposed as markers of success of CRT. However, when tested against QRS width in prospective clinical trials, none of the echocardiographic indices are proven to give clinical benefit. One important message in this review is that future studies should focus on approaches which can differentiate between electrical and non-electrical aetiologies of dyssynchrony, since only electrical dyssynchrony is likely to respond to CRT. Just measuring velocity indices does not identify the aetiology. Myocardial strain appears more promising, but one should be aware that timing of peak systolic strain is determined not only by electrical conduction. It is proposed to use onset septal shortening during pre-ejection for timing of earliest left ventricular (LV) electrical activation. One should take into account potential ischaemia, scarring, and other structural changes as contributors to dyssynchrony. As a method to identify electrical dyssynchrony, the authors propose to use time of active force generation as defined by LV pressure-strain loops. A non-invasive method to measure segmental pressure-strain loops is also proposed as a means to quantify the impact of dyssynchrony on distribution of myocardial work. Furthermore, it is important to be aware that LV dyssynchrony may have a combination of aetiologies, not all amenable for CRT.

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.

Echocardiographic evaluation of hemodynamics in patients with decompensated systolic heart failure.

BACKGROUND: Doppler echocardiography is currently applied for the assessment of left ventricular and right ventricular hemodynamics in patients with cardiovascular disease. However, there are conflicting reports about its accuracy in patients with unstable decompensated heart failure. The objective of this study was to evaluate the accuracy of the technique in patients with unstable heart failure. METHODS AND RESULTS: Consecutive patients with decompensated heart failure had simultaneous assessment of left ventricular and right ventricular hemodynamics invasively and by Doppler echocardiography. In 79 patients, the noninvasive measurements of stroke volume (r=0.83, P<0.001), pulmonary artery systolic (r=0.83, P<0.001) and diastolic pressure (r=0.51, P=0.009), and mean right atrial pressure (r=0.85, P<0.001) all had significant correlations with invasively acquired measurements. Several Doppler indices had good accuracy in identifying patients with pulmonary capillary wedge pressure >15 mm Hg (area under the curve, 0.86 to 0.92). The recent American Society of Echocardiography/European Association of Echocardiography guidelines were highly accurate (sensitivity, 98%; specificity, 91%) in identifying patients with increased wedge pressure. In 12 repeat studies, Doppler echocardiography readily detected the changes in mean wedge pressure (r=0.75, P=0.005) as well as changes in pulmonary artery systolic pressure and mean right atrial pressure. CONCLUSIONS: Doppler echocardiography provides reliable assessment of right and left ventricular hemodynamics in patients with decompensated heart failure.

Mechanisms of abnormal systolic motion of the interventricular septum during left bundle-branch block.

BACKGROUND: In a majority of patients with left bundle-branch block (LBBB), there is abnormal leftward motion of the interventricular septum during the preejection phase. This motion was considered to be passive, caused by early rise in right ventricular (RV) pressure, and has therefore been excluded from most indices of left ventricular (LV) dyssynchrony. If considered active, however, the leftward motion reflects onset of septal activation and should be included. We therefore investigated if the motion was a passive response to pressure changes or caused by active contraction. METHODS AND RESULTS: LBBB was induced in 8 anesthetized dogs with micromanometers. Cardiac dimensions were measured by sonomicrometry and echocardiography. Induction of LBBB resulted in preejection leftward motion of the septum, simultaneously with shortening of septal segments (P<0.01). In each experiment, preejection septal shortening occurred against rising LV pressure, consistent with active contraction. Furthermore, the LV pressure-segment length relationships were shifted upward (P<0.01) relative to the passive elastic curve, indicating stiffening of septal myocardium, confirming an active mechanism. Initially, RV pressure increased faster than LV pressure, suggesting that the leftward septal motion may have a passive pressure component. However, the passive component appeared to play a minor role. The magnitude of preejection septal shortening was modified by load alterations. CONCLUSIONS: Leftward preejection motion of the septum during LBBB is mainly a result of active septal contraction, whereas alterations in diastolic ventricular pressures modulate the amplitude of this motion. The findings imply that the preejection phase should be included when assessing LV dyssynchrony.

Evaluation of left ventricular dyssynchrony by onset of active myocardial force generation: a novel method that differentiates between electrical and mechanical etiologies.

BACKGROUND: Better clinical tools for measuring left ventricular electrical dyssynchrony are needed. The present study investigates if onset of active myocardial force generation (AFG) may serve as a measure of electrical dyssynchrony. METHODS AND RESULTS: In anesthetized dogs, we evaluated left ventricular mechanical dyssynchrony by 2 different approaches. First, we measured timing of peak myocardial shortening velocity and strain. Second, we measured the first sign of tension development by onset AFG as defined by the myocardial pressure-segment length loop upward shift from its passive-elastic state. Electrical dyssynchrony was measured by intramyocardial electromyograms (IM-EMG). Dyssynchrony was quantified as peak intersegment time difference and as standard deviation of timing for 6 to 8 myocardial segments. During baseline, reduced preload and myocardial ischemia shortening velocity and strain indicated segmental mechanical heterogeneity, whereas onset AFG and onset R in IM-EMG indicated synchronous activation of all segments. After induction of left bundle-branch block, all methods indicated dyssynchrony. Peak intersegment time difference for shortening velocity and strain showed weak correlations (r=0.17 and 0.16) and weak agreements (mean differences, -48+/-27 ms and -28+/-27 ms, respectively) with IM-EMG. Onset AFG by pressure-segment length loops, however, correlated well with IM-EMG (r=0.93), and agreement was good (mean difference, -0.6+/-6.8 ms). Results were similar for standard deviation of timing. Onset AFG from pressure-strain analysis by echocardiography showed accuracy similar to sonomicrometry. CONCLUSIONS: Onset AFG was an accurate marker of myocardial electrical activation and was superior to shortening velocity and strain. Identification of electrical dyssynchrony by onset AFG may be feasible clinically using left ventricular pressure-strain analysis.