Immune checkpoint inhibitors (ICIs), which are increasingly used in cancer pharmacotherapy, can induce myocarditis. ESC guidelines recommend cardiac MRI and myocardial biopsy as diagnostic methods, but these examinations are not readily available in all patients with suspected ICI myocarditis. One minor criterium is decline in left ventricular (LV) function, but precise details of parameters are not outlined. This may cause confusion with the diagnostic criteria for cancer therapeutic-related cardiac dysfunction (CTRCD) and may lead to difficulties in diagnosis of ICI myocarditis. The purpose of this study was to compare echocardiographic parameters and biomarkers in ICI myocarditis and non-ICI myocarditis patients, and moreover, to evaluate their usefulness as diagnostic tools for ICI myocarditis. Twelve patients receiving ICI therapy developed ICI myocarditis at our cancer hospital between March 2021 and November 2023. These were compared to a group of 35 patients without ICI induced myocarditis. Echocardiography was performed prior to ICI therapy (baseline) and after starting ICI therapy according to guidelines with median follow-up interval of 87 days. Echocardiographic findings and biomarkers were retrospectively analyzed. In the ICI myocarditis group ICI therapy was discontinued, while in the non-ICI myocarditis group ICI therapy was continued. Echocardiographic parameters were compared between baseline and follow-up for each group (Table 1). In the ICI myocarditis group, there were significant decreases in LVEF and GLS and worsening of TEI index, but no significant changes in LVMI, E/e', and E/A. In the non-ICI myocarditis group, there were no significant changes in LVEF, TEI index, LVMI, E/e' and E/A, however, GLS decreased significantly. Categorical data were compared between the two groups at follow-up (Table 2). Pericardial effusion, ECG changes, increased high-sensitivity Troponin I (hsTnI), increased BNP, and immune-related adverse effects (irAE) in other organs were significantly more prevalent in the ICI myocarditis group. However, there were no significant differences in CPK elevation, prior chemotherapy, dual ICI, prior CTRCD or CVD, and ICI-cardiotoxic combination therapy. By multinomial logistic regression analysis between the two groups, changes in hsTnI and LVEF were significant predictors to determine diagnosis, but not changes in GLS, with hsTnI being the strongest. LVEF and hsTnI are the most useful and available tools for the diagnosis of ICI myocarditis. However, GLS is not useful, as it is also decreasing in the non-ICI myocarditis patients. Therefore, reduction in GLS alone is not a feasible parameter for determining decline in LV function. This would differ from the approach used for the diagnosis of CTRCD.Changes of echocardiographic indices Comparison of clinical parameters

BACKGROUND:Pressure-volume (PV) analysis is the gold standard for evaluating left ventricular (LV) function but is rarely used clinically due to its invasiveness. We validated a noninvasive method for PV analysis by three-dimensional (3D) echocardiography against invasive reference measurements and a novel index of LV efficiency against LV efficiency derived from metabolism by positron emission tomography-computed tomography (PET-CT). METHODS:In 22 canines, LV volume was measured invasively using piezoelectric crystals and LV pressure by micromanometer. Echocardiography and peak pressure were used to obtain 3D LV volume traces and LV pressure trace estimates. Stroke work, single-beat contractility indices, arterial elastance, and an index of LV efficiency were derived from echocardiography and compared with their invasively measured counterparts at baseline and different interventions. In 12 sheep, the LV efficiency index was compared with efficiency calculated as stroke work divided by total LV glucose metabolism from PET-CT. The sheep underwent 8 weeks of rapid dyssynchronous pacing to induce heart failure (HF). Recordings were performed during synchronous and dyssynchronous electrical activation, at baseline, and after 8 weeks of pacing-induced HF. RESULTS:In canines, there was a very good correlation and agreement between noninvasive and invasive measurements of LV stroke work (r = 0.98, P < .0001; difference 237 ± 212 mm Hg × mL, mean ± SD). The noninvasive and invasive efficiency indices also showed very good agreement (r = 0.95, P < .0001; difference 0.4% ± 3.4%). The changes in LV function by the different interventions resulted in similar changes in the noninvasive and invasive PV indices (all P < .001). In sheep, the efficiency index showed similar decline compared to efficiency by PET-CT after induction of HF and after switching from synchronous to dyssynchronous electrical activation (r = 0.67, P < .001 for all interventions). CONCLUSIONS:Noninvasive PV analysis by three-dimensional echocardiography is feasible and accurate, making PV loop parameters for evaluating LV function accessible for clinical use. Further studies should explore the clinical utility of this method.

Background Left bundle branch block (LBBB) causes left atrial (LA) dyssynchrony. It is unknown if LA dyssynchrony impacts long-term prognosis. Objectives The purpose of this study was to determine mechanisms of LA dyssynchrony in LBBB and if LA dyssynchrony impacts long-term prognosis. Methods In a prospective multicenter study of 168 heart failure patients with LBBB, echocardiographic strain imaging was done before and after 6 months with cardiac resynchronization therapy (CRT). Outcome was assessed after 6 years. Dyssynchrony was measured relative to septum as delay in left ventricular (LV) lateral wall shortening and LA lateral wall stretch. Response to CRT was defined as at least 15% reduction in LV end-systolic volume. Results Before CRT, there was marked LA dyssynchrony of 105 ± 76 ms, which decreased to 37 ± 68 ms in CRT-responders (P < 0.001), whereas nonresponders showed only a modest reduction in LA dyssynchrony (P < 0.05). There was strong association between LA and LV dyssynchrony (r = 0.70), consistent with direct LV-LA mechanical interaction. CRT caused modest increase in LA reservoir strain (P < 0.01) and marked increase of LV filling time (P < 0.001) in responders. Mortality after 6 years was 21% (35 deaths). LA dyssynchrony did not independently predict mortality. However, the combination of preserved LA reservoir strain (≥18%) and resolved LA dyssynchrony (≤53 ms) after 6 months with CRT was associated with excellent long term-prognosis: HR: 0.11 (95% CI: 0.03-0.42) vs preserved reservoir strain and persistent LA dyssynchrony. Conclusions LA dyssynchrony in LBBB was attributed to direct LV-LA mechanical interactions. CRT improved diastolic function by increasing LV filling time. Patients with preserved LA reservoir strain and resolution of LA dyssynchrony by CRT had excellent long-term prognosis. (Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy [CRID-CRT]; NCT02525185)

Background: Left ventricular (LV) efficiency is a key pathophysiological marker in heart failure (HF). LV pressure curve estimation and three-dimensional (3D) volumes via echocardiography allows for non-invasive pressure-volume (PV) analysis and calculation of an index of efficiency (Figure 1). Aim: Validate efficiency index by 3D echocardiography by comparing it to invasive measurements and efficiency derived from Positron Emission Tomography (PET) metabolism. Methods: Two experimental models were utilized - one with canines (n=21) and another with sheep (n=12). In canines, echocardiography provided 3D LV volumes and valve event timings. The pressure curve was estimated by adjusting the time axis of a reference pressure curve to the valve events and its amplitude to measured peak LV pressure, which in clinical practice would be approximated as systolic brachial cuff pressure. Invasive pressure was measured by micromanometer and volume by subendocardial piezoelectric crystals. Non-invasive and invasive efficiency indices, calculated as the ratio of stroke work to total mechanical energy (Figure 1), were compared during baseline, right ventricular pacing, aortic constriction and dobutamine infusion. Twelve sheep implanted with a pacemaker underwent 8 weeks of rapid dyssynchronous DDD pacing to induce dilated HF. LV efficiency index was calculated as in Figure 1, using measurements from a PV-catheter calibrated to end-diastolic volume by cardiac MRI, and compared to efficiency calculated as stroke work divided by total LV glucose metabolism via PET/CT. Recordings were performed during AAI and DDD pacing, at baseline (n=3) and following 8 weeks pacing-induced HF (n=12). Results: In canines, non-invasive and invasive efficiency indices showed excellent agreement (r=0.95, p<0.0001; mean difference 0.4%, SD 3.4%) (Figure 2). In sheep, the efficiency index showed similar decline compared to efficiency by PET/CT after induction of HF and after switching from AAI to DDD pacing (p<0.05 for all interventions). Overall correlation between the methods was moderate (r=0.67, p=0.0001) but excellent in animals with longitudinal data (r=0.89, p=0.0001) (Figure 3). Conclusions: Efficiency index by 3D echocardiography is accurate and reflects changes in efficiency measured by PET/CT. It may thus be of interest for clinical use.

Background: Early diagnosis and triage of patients with ischemic stroke is essential for rapid reperfusion therapy. The prehospital delay may be substantial and patients from rural districts often arrive at their local hospital too late for disability-preventing thrombolytic therapy due to prolonged transport times. Methods: Hallingdal District Medical Centre (HDMC) is located in a rural area of Norway and is equipped with a computed tomography (CT) scanner. We established emergency pathways of CT imaging and thrombolytic treatment of patients with acute ischemic stroke at HDMC. During office hours these pathways were managed by a radiographer and a general physician supported by videoconference from the Primary Stroke Centre. Outside office hours we remotely controlled the CT exam and supported telestroke guided paramedics handling and examining the patients. With a primary aim of demonstrating the feasibility of this de novo concept we enrolled patients in the period 2017-2021 into a comparative cohort observational study. We compared patients treated at HDMC (the Rural CT group) to patients from two other rural regions in Norway with similar distances to their local hospital but without access to a rural CT scanner (the Reference group). Results: A total of 86 patients were included in the Rural CT group (mean age 74, 52% male, 43% stroke mimics), and 69 patients were included in the Reference group (mean age 70, 42% male, 28% stroke mimics). Median time from onset of symptoms to completed CT examination was 93 min in the Rural CT group as compared to 240 min in the Reference group (p < 0.05). In patients receiving intravenous thrombolysis time from onset of symptoms to treatment was median 124 min in the Rural CT group and 213 min in the Reference group, p < 0.05. The frequency of thrombolysis for ischemic stroke did not significantly differ between the two groups. Conclusion: Combining prehospital rural CT examination with telestroke guided diagnosis and thrombolytic treatment by paramedics may facilitate earlier initiation of thrombolysis for patients with ischemic stroke.

Background: During left bundle branch block (LBBB), tachycardia causes marked elevation of left ventricular (LV) filling pressures due to insufficient time for LV relaxation. Cardiac resynchronization therapy (CRT) may reduce pulmonary congestion during exercise by facilitating more time for LV filling, thereby reducing the need for increased left atrial (LA) pressures to accelerate blood into the LV. Purpose: Investigate if successful CRT increases LV filling time and if this is reflected in shorter LA reservoir phase duration. Methods: In a multicenter study of 168 patients, LA and LV global strain was measured by speckle-tracking echocardiography before and 7 ± 1 months after CRT. LA reservoir phase duration was measured from onset shortening in the LV to peak global LA strain, and LV filling time from mitral valve opening to closure. A volumetric response was defined as ≥ 15% decrease in LV end-systolic volume at follow-up. Results: The patient in Figure 1 exemplifies LV/LA mechanical interactions in a volumetric responder. In the LV, resynchronization increases filling time (four areas shaded in gray in Figure 1). This is mirrored in the LA, where resynchronization reduces LA reservoir phase duration (white arrows, upper panels). In all responders, resynchronization was associated with increased LV filling time (p<0.0001) and decreased LA reservoir phase duration (p<0.0001), regardless of heart rate (Figure 2). Reduction in LA reservoir phase duration correlated with a reduction in LV filling time (β=–0.302, p<0.0001 corrected for change in heart rate). These improvements in filling dynamics were not observed in non-responders. Conclusions: LA reservoir phase duration mirrors LV filling time and may be an important diastolic marker of successful CRT.

Background: Recent observations suggest that residual left atrial (LA) dyssynchrony after cardiac resynchronization therapy (CRT) may have prognostic significance. Since LA dyssynchrony implies prolongation of the LA reservoir phase, measuring the duration of the LA reservoir phase should offer similar prognostic information. Purpose: To investigate the impact of LA reservoir phase duration on long-term survival after CRT. Methods: In a recent prospective multicenter study of 168 patients, LA strain was measured by speckle-tracking echocardiography before and 7±1 months after CRT. LA reservoir strain was measured as the difference between peak and minimum global strain during the atrial cycle and LA reservoir phase duration as the time from onset shortening in the left ventricle to peak LA reservoir strain. Since LA reservoir strain <18% is associated with elevated LV filling pressure, we used 18% as cutoff and for LA reservoir phase duration 516 ms in accordance with a Receiver Operating Curve. All-cause mortality was used as clinical endpoint during follow-up. Results: After 6.0±1.8 years follow-up, 35 (21%) patients had died. LA reservoir strain ≥18% after CRT was associated with favorable long-term survival (HR: 0.51, 95% CI: 0.26–0.98) (upper panel in the Figure). LA reservoir phase duration was not independently associated with survival. However, when used in patients with LA reservoir strain ≥18% after CRT, LA reservoir phase duration ≤516 ms identified patients with particularly excellent long-term survival (HR: 0.18, 95% CI: 0.05–0.63 vs patients with reservoir strain ≥18% and LA reservoir phase duration >516 ms) (lower panel in the Figure). Patients with preserved LA reservoir strain but prolonged LA reservoir phase duration had similar outcome as patients with reduced LA reservoir strain (HR 1.10, 95% CI: 0.49–2.51). Conclusions: LA reservoir strain ≥18% combined with reservoir phase duration ≤516 ms is associated with excellent long-term survival after CRT. Prolonged reservoir phase duration is linked to adverse long-term outcomes in patients with preserved LA reservoir strain. Therefore, reservoir phase duration provides added value for risk prediction after CRT that may be clinically important.

Abstract Background Left atrial (LA) reservoir strain after CRT has been linked to long-term outcome, but the role of LA function in response to cardiac resynchronization therapy (CRT) is incompletely understood. LA dyssynchrony during left bundle branch block has negative effects on LA function beyond LA reservoir strain. We hypothesized that correction of LA dyssynchrony after CRT has added value to LA reservoir strain as a marker of long-term outcome. Purpose To explore the role of LA function in long-term survival after CRT. Methods In a recent prospective multicenter study of 168 patients, LA segmental and global strains were measured by speckle-tracking echocardiography before and 7 ± 1 months after CRT. LA reservoir strain was measured as the difference between peak and minimum global strain during the atrial cycle and LA dyssynchrony as the time delay between onset systolic stretch of the interatrial septum and LA lateral wall. Since LA reservoir strain < 18% is associated with elevated LV filling pressure, we used 18% as cutoff and for LA dyssynchrony 43 ms (mean after CRT in the present study). All-cause mortality was used as clinical endpoint during follow-up. Results After 6 years ± 21 months (mean ± SD) follow-up, 35 (21%) patients died. LA reservoir strain was significantly lower (15 ± 9% vs 20 ± 10%, p = 0.003) and LA dyssynchrony numerically higher (61 ± 68 ms vs 39 ± 69 ms, p = 0.099) in patients who died compared to survivors. LA reservoir strain ≥ 18% after CRT was associated with favorable long-term survival (HR: 0.51, 95% CI: 0.26 - 0.98) (upper panel in the Figure). LA dyssynchrony was not independently associated with mortality. However, when used in concert with LA reservoir strain ≥ 18% after CRT, it identified patients with perticularly excellent long-term survival (HR: 0.17, 95% CI: 0.05 - 0.58 vs patients with reservoir strain ≥ 18% and persistent LA dyssynchrony) (lower panel in the Figure). Patients with preserved LA reservoir strain but persistent LA dyssynchrony had similar outcome as patients with reduced LA reservoir strain (HR: 0.98, 95% CI: 0.45 - 2.12). Conclusion LA reservoir strain ≥ 18% and absence of LA dyssynchrony is associated with excellent long-term survival after CRT.LA strain after CRT and survival

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian Research Council. Background/Introduction The timing of left ventricular pressure rise (Td) relative to QRS-onset is associated with dispersion of regional work distribution and prolongs with dyssynchrony and dyssynergistic contractions. Td is short in normal conduction and shortening of Td can be achieved with effective biventricular pacing (BIVP). The effect of endocardial compared to epicardial pacing on Td is unknown and could be important for the interpretation of Td when different pacing strategies are utilized for CRT. Purpose We wanted to analyze the measurement from QRS-onset to onset of LV pressure rise identified as the peak double derivative of LV pressure rise (Onset of Synergy, OoS) and to the peak pressure rise (Td), and test the effects of cardiac resynchronization therapy with endocardial vs epicardial pacing electrodes in a large animal model of LBBB. Methods 5 mongrel dogs were included in the study and handled according to ethics committee approved protocol/GLP. Pacing electrodes were placed epicardial on the left ventricular (LVepi) and right ventricular (RVepi) free wall, and endocardial electrodes were positioned at the right ventricular septum (RVsept) and in the LV endocardial free wall (LVendo). The atrial electrode was placed on the left atrial appendage. Pressure was measured with a Micro-tip pressure sensor (Millar Inc.) in the LV and sampled at 1000Hz. LBBB was created with a retrograde placed 7F standard ablation catheter and confirmed by surface ECG and four endocardial electrodes. Td was measured from 10 consecutive beats. Mixed models were utilized for the repeated measurements. Results Td was measured to 115±2ms at baseline in LBBB. Td decreased by 5ms from RVepi (114±3ms) to RVendo (109±3ms) regardless of LV electrode position. We then compared the effects of using LV endocardial and epicardial pacing in CRT and found that Td was 6ms higher (p<0.01) in LVepi (115±3ms) vs LVendo (109±3ms) regardless of RV electrode position. The interaction between RV RV and LV revealed that RVepi/LVendo (105±3ms) was significant shorter than RVendo/LVendo (110±3ms, p0.01) and RVepi/LVepi (115±3ms, p<0.01). OoS with RVepi/LVendo was 71±2ms, and a significant relationship between OoS and Td were found (R=0.62, p<0.01) to indicate that the myocardial contraction is affected by pacing already at 71ms after QRS-onset early during the pre-ejection period. Conclusion(s) In this study we demonstrate how endocardial and epicardial pacing applied with CRT may affect contraction patterns of the heart differently. The different effects from pacing can be measured as early as 71ms after QRS-onset. Shortening of Td occurs to a larger extent with pacing from the endocardial LV and epicardial RV, while pacing at two endocardial sites did not result in synergistic effects on Td. This may indicate that there might be an interaction between endocardial pacing sites when applied in combination.

Abstract Introduction Intraventricular vortices facilitate efficient blood flow in a healthy heart. Changes in the blood flow pattern can cause energy loss and inefficient filling or ejection. Thus changes, or reduction in vorticity may therefore be of importance for cardiac function. Blood speckle imaging (BSI) is a novel blood flow visualization tool based on echocardiography, partially overcoming the angel dependency of conventional colour Doppler. BSI tracks speckles generated by the moving blood cells, similar to myocardial speckle tracking, but requires a very high frame rate limiting penetration. Dyssynchrony in left bundle branch block (LBBB) affects the systolic functions but there is limited insight into how LBBB alters the blood flow vorticity. Purpose We investigated the effect of dyssynchrony on blood flow hemodynamics using blood speckle imaging. Methods In eight anesthetized canine mongrels, left ventricular flow was visualized using BSI. A qualitative visual assessment of vortices during the cardiac cycle, together with a quantitative assessment based on kinetic energy loss and vorticity were made. Regional myocardial function parameters were measured by sonomicrometry. Peak septal flash strain in isovolumetric contraction (IVC) was measured by sonomicrometry (figure) as an indicator of dyssynchrony. Assessments were made at baseline, under right ventricular free wall pacing (RV pacing) mimicking LBBB, after induced LBBB by ablation and under cardiac resynchronization therapy (CRT). Results During IVC at baseline all animals had a central ventricular vortex. However during RV pacing and LBBB it was distorted in various patterns. RV pacing significantly reduced the number of vortices in systole and disrupted the central vortex in IVC (1.0±0.0 vs 0.4±0.5, p=0.01). Energy loss (EL) in systole increased (40.2±12.5 vs 55.3±23.3 mW/m, p<.05). Septal end systolic strain was significantly reduced (-8.8±5.1 vs -1.9±7.3 %, p<0.01) and septal flash strain was significantly increased (1.0±1.4 vs 7.7±3.6 and 6.6±3.8 [ER1] [ER2] %, p<0.01) in RV pacing and LBBB. CRT caused a realignment of the central vortex (0.8±0.5 vs0.3±0.5, p=0.03). The change in energy loss was not significant, but numerically reduced (55.4±38.8 vs 76.4±48.9 mW/m, p=0.06). See table and figure 1. Conclusions The main systolic vortex in IVC was disrupted during septal flash by RV pacing and LBBB, altering the flow pattern compared to baseline. The resultant unstructured flow pattern had increased energy loss in systole, indicating a less efficient flow pattern and less preservation of energy. It should be further explored if this is of importance to understand the reduced LV function and LV remodelling during dyssynchrony.Figure 1Table 1

AbstractAimsSuccessful cardiac resynchronization therapy (CRT) shortens the pre-ejection period (PEP) which is prolonged in the left bundle branch block (LBBB). In a combined animal and patient study, we investigated if changes in the pulse arrival time (PAT) could be used to measure acute changes in PEP during CRT implantation and hence be used to evaluate acute CRT response non-invasively and in real time.Methods and resultsIn six canines, a pulse transducer was attached to a lower limb and PAT was measured together with left ventricular (LV) pressure by micromanometer at baseline, after induction of LBBB and during biventricular pacing. Time-to-peak LV dP/dt (Td) was used as a surrogate for PEP. In twelve LBBB patients during implantation of CRT, LV and femoral pressures were measured at baseline and during five different pacing configurations. PAT increased from baseline (277 ± 9 ms) to LBBB (313 ± 16 ms, P < 0.05) and shortened with biventricular pacing (290 ± 16 ms, P < 0.05) in animals. There was a strong relationship between changes in PAT and Td in patients (r2 = 0.91). Two patients were classified as non-responders at 6 months follow-up. CRT decreased PAT from 320 ± 41 to 298 ± 39 ms (P < 0.05) in the responders, while PAT increased by 5 and 8 ms in the two non-responders.ConclusionThis proof-of-concept study indicates that PAT can be used as a simple, non-invasive method to assess the acute effects of CRT in real time with the potential to identify long-term response in patients.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian Research Council. Background/Introduction The timing of left ventricular pressure rise (Td) is associated with dispersion of regional work distribution and prolongs with dyssynchrony and dyssynergistic contractions. Synergistic contractions shorten Td and result from effective biventricular pacing (BIVP). Attempts have been made to optimize right ventricular (RV) lead position with septal lead placement away from the apex. In this study we attempted to study the effects from RV free wall (RVfw) compared to septal/ apical RV (RVsept) lead positioning on Td. Purpose RVfw pacing results in activation of RVfw before LV activation with a delay that may hamper the myocardial synergy resulting from biventricular pacing. This effect has not yet been demonstrated and may play an important role to understand non-response to CRT. Methods 9 mongrel dogs were included in the study and handled according to ethics committee approved protocol/GLP. Pacing electrodes were placed epicardial on the left atrial appendage, the RVfw and LV, and endocardial in the septum. Pressure was measured with a Micro-tip pressure sensor (Millar Inc.) in the LV. BIVP was performed from LV combined with RVsept or RVfw. Td was measured from 10 consecutive beats. Mixed models were utilized for the repeated measurements. Results The average Td with BiVP-RVfw, BIVP-RVsept and LV pacing only was 116ms (95% CI: 110, 122), 114ms (95% CI: 108, 120), and 118ms (95% CI: 112, 124) respectively (p<0.001). BiVP with RVsept shortened Td by 4.1 ms (95% confidence interval (CI): -5.3, -2.9, p<0.001), whereas BiVP with RVfw pacing location shorten Td by 1.8 ms (95% CI: -2.8, -0.8, p<0.001), compared to LVP. The SD from 10 beats was on average 0.8ms (range 0-1.6ms). Conclusion(s) Myocardial Synergy with shortening of Td compared to LV only pacing was demonstrated with BIVP regardless of RV position. The synergistic effect from BIVP is more pronounced with BIVP-RVsept than from BIVP-RVfw. RV lead position may play an important role in cardiac resynchronization therapy that can be revealed when measuring the time-course of LV pressure rise.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian Research Council. Background/Introduction The timing of left ventricular pressure rise (Td) relative to QRS-onset is associated with dispersion of regional work distribution and prolongs with dyssynchrony and dyssynergistic contractions. Td is short in normal conduction and shortening of Td can be achieved with effective biventricular pacing (BIVP). The effect of atrial pacing on Td is unknown and could be important for the interpretation of Td when utilized for cardiac resynchronization therapy. Purpose We wanted to test the effects from atrial pacing (AP) compared to sinus rhythm (SR) on Td in animals with narrow QRS (nQRS) complexes and after the creation of LBBB. Methods 9 mongrel dogs were included in the study and handled according to ethics committee approved protocol/GLP. Pacing electrodes were placed epicardial on the left atrial appendage. Pressure was measured with a Micro-tip pressure sensor (Millar Inc.) in the LV and sampled at 1000Hz. LBBB was created with a retrograde placed 7F standard ablation catheter and confirmed by surface ECG and four endocardial electrodes. Td was measured from 10 consecutive beats. Mixed models were utilized for the repeated measurements. Results Analysis of the marginal means in pooled data showed that the average Td with AP was 96.7ms (95% CI: -195.7, 388.7), and in SR 96.5ms (95% CI: - 195.5, 389.0). The analysis with the Bonferroni correction for multiple comparisons revealed that the differences between pacing configurations were not statistically significant (p=0.80). The analysis revealed that AP on average lengthens Td by 0.3ms (95% confidence interval (CI): - 1.7, 2.2, p=0.8), compared to no pacing. The difference in Td in nQRS between AP and SR was 82.4ms (95% CI: 76.8, 88.1) and 82.1ms (95% CI: 76.4, 87.8) respectively (p=0.02) while the difference in Td in LBBB between AP and SR was 111.1ms (95% CI: 104.8, 117.4) and 110.9ms (95% CI: 104.581, 117.197) respectively (p=0.48). Standard deviation within 10 consecutive beats was 1.0ms (max 3.7ms, min 0.4ms, median 0.95ms), and AP did not influence Td measurement variability (p=0.53). Conclusion(s) We did not find any influence from atrial pacing in Td in this study. The significant difference between AP and SR in nQRS was extremely small and less than the sample interval of 1ms. The significance of this difference is attributed to the robustness of the Td measurement and does not represent a meaningful clinical significance. Td can be measured without being influenced by atrial pacing in both native conduction and with LBBB.

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Institute for Surgical Research, Oslo University Hospital. Introduction Left ventricular pressure-volume analysis is a powerful method to quantify left ventricular function. A major limitation of its clinical utility, however, is the need for invasive pressure and volume measurements. We hypothesized that accurate non-invasive left ventricular (LV) stroke work analysis is feasible by combining continuous 3-dimensional (3D) echocardiographic LV volume measurements with non-invasive LV pressure curve estimation. Purpose To investigate if LV stroke work can be estimated non-invasively by combining 3D echocardiographic volume measurements with non-invasive pressure curve estimation. Methods In 21 open-chest anesthetized canines, piezoelectric crystals were placed in the LV subendocardium for volume measurements and a micromanometer catheter was placed in the LV cavity for pressure measurements. Echocardiography was performed directly on the heart to acquire 3D LV volumes and timings of mitral and aortic valve events. The estimated LV pressure curve was obtained by adjusting the cardiac phases of an LV reference pressure curve to these valve events and adjusting its amplitude to measured peak LV pressure. Stroke work was calculated as the area under the pressure-volume curve from mitral valve closure to mitral valve opening. Non-invasively estimated and invasively measured stroke work were compared. Recordings were done during baseline, aortic constriction, dobutamine infusion and after induction of left bundle branch block by ablation. Results Panel A in the Figure illustrates non-invasive (left) and invasive (right) pressure-volume loops from a representative experiment. Baseline and the different interventions are colour-coded allowing visual comparison of the similar non-invasive and invasive stroke work. Panel B shows the pooled data from all experiments. There was a strong correlation (r=0.98, p<0.0001) and good agreement between the non-invasive and invasive stroke work. Furthermore, the non-invasive method captured similar changes in stroke work during interventions as compared to the invasive method (Panel C). Conclusions Non-invasive pressure-volume analysis by combining 3D echocardiography and estimated pressure for stroke work evaluation, is feasible and accurate.

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Institute for Surgical Research, Oslo University Hospital. Introduction It was recently shown that left bundle branch block (LBBB) is associated with risk of developing atrial fibrillation. A potential mechanism is abnormal left atrial (LA) loading caused by LA dyssynchrony. Purpose To investigate if LBBB is associated with abnormal LA loading as reflected in non-uniform segmental strains. Methods In a prospective study of 143 heart failure patients with LBBB, myocardial strain was measured by speckle-tracking echocardiography prior to and after 7±2 months on cardiac resynchronization therapy (CRT). As indicated by brackets in the lower panels in the Figure, LA strain amplitudes were calculated as the difference between minimum and peak strain during the reservoir phase. Results In the Figure, the upper panel shows segmental and average LA strain traces in a representative LBBB patient. This patient illustrates marked spatial non-uniformity in strain amplitude between the interatrial septum and the LA lateral wall during the reservoir phase. For the entire study population, strain amplitudes were 19±9% (mean±SD) for the interatrial septum and 24±11% for the LA lateral wall (p<0.0001). In the quartile of patients with largest differences, strain amplitudes were 16±9 and 32±12%, respectively (p<0.0001). CRT abolished these differences (p = NS). Conclusions Patients with LBBB showed marked spatial non-uniformity of LA strains. Potentially, the excessive LA lateral wall strain amplitudes may stimulate atrial adverse remodelling. Future studies should investigate if abnormal LA strains may be a trigger mechanism for atrial fibrillation in patients with LBBB.

Abstract Introduction Left atrial (LA) dyssynchrony is a predictor of response to cardiac resynchronization therapy (CRT). It is unknown, however, if LA resynchronization contributes to response to CRT. We hypothesize that there is a relationship between correction of LA dyssynchrony and response to CRT. Purpose To investigate the association between LA resynchronization and response to CRT. Methods In a prospective study of 171 heart failure patients with LBBB, myocardial strain was measured by speckle-tracking echocardiography, before and 6 months after CRT. As indicated by the white arrows in Figure 1, LA dyssynchrony was measured as the time delay between onset systolic stretch of the interatrial septum and the LA lateral wall. Response to CRT was defined as at least 15% reduction in left ventricular (LV) end systolic volume at 6 months follow up. Results 119 (70%) patients responded to CRT. The panels in Figure 1 shows LA strain traces in a representative LBBB patient that did respond (upper panels), and a patient that did not respond (lower panels). The white arrows in the left panels indicate that both the responder and the non-responder had marked LA dyssynchrony before CRT (198 and 171 ms, respectively). However, after 6 months with CRT, there was recovery of LA synchrony only in the responder (time delay −40 ms), and still marked LA dyssynchrony of 191 ms in the non-responder (right panels). Figure 2 confirms similar results for the whole study population: CRT response was associated with marked reduction of LA dyssynchrony (p=0.0001). In the CRT non-responders there was, however, only a modest, non-significant reduction of LA dyssynchrony. Conclusions Positive CRT response was associated with resynchronization of the left atrium. These findings suggest LA resynchronization as a potential additional target for CRT. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Institute for Surgical Research, Oslo University HospitalThe Intervention Centre, Oslo University Hospital

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Institute for Chirurgical Research - Oslo University Hospital Introduction Left bundle branch block (LBBB) leads to left ventricular (LV) mechanical dyssynchrony. Since the left atrium (LA) and the left ventricle (LV) are anatomically connected, dyssynchronous LV contractions may be transmitted to the LA causing LA dyssynchrony and disturbed LA function. Purpose To investigate if LA dyssynchrony induced by LBBB predicts LV reverse remodelling after cardiac resynchronization therapy (CRT). Methods In a prospective study, myocardial strain was measured by speckle-tracking echocardiography in 171 heart failure patients with LBBB, before and 6 months after CRT. LA dyssynchrony was measured as the time delay between onset systolic stretch of the interatrial septum and the LA lateral wall (white arrows in Figure), and LV dyssynchrony as the time from onset septal shortening to onset lateral wall shortening. Septal flash was assessed visually. Response to CRT was defined as at least 15 % reduction in LV end systolic volume at 6 months follow up. Results The figure shows a representative LBBB patient with LA and LV dyssynchrony which was abolished by CRT. For the whole study population, LA dyssynchrony was 104 ± 77 ms (mean ± SD) before CRT, and decreased to 43 ± 70 ms (p < 0.0001) after CRT. There was a significant correlation between LA and LV dyssynchrony (r = 0.68, p < 0.0001). LA dyssynchrony correlated with LV reverse remodelling after CRT (p = 0.009), and multivariable analysis revealed that LA dyssynchrony was an independent predictor of CRT response (β=-0.046, p = 0.04) when combined with septal flash, QRS duration and QRS morphology (Table). Conclusions Patients with LBBB had marked LA dyssynchrony which was attributed to direct LV-LA mechanical interaction. Furthermore, LA dyssynchrony was an independent predictor of LV reverse remodelling after CRT. These findings suggest that assessment of LA dyssynchrony should be part of the echocardiographic evaluation in patients with dyssynchronous heart failure. Abstract Figure.

Aims The aim of this study is to investigate determinants of left atrial (LA) reservoir and pump strain and if these parameters may serve as non-invasive markers of left ventricular (LV) filling pressure. Methods and results In a multicentre study of 322 patients with cardiovascular disease of different aetiologies, LA strain and other echocardiographic parameters were compared with invasively measured LV filling pressure. The strongest determinants of LA reservoir and pump strain were LV global longitudinal strain (GLS) (r-values 0.64 and 0.51, respectively) and LV filling pressure (r-values -0.52 and -0.57, respectively). Left atrial volume was another independent, but weaker determinant of both LA strains. For both LA strains, association with LV filling pressure was strongest in patients with reduced LV ejection fraction. Left atrial reservoir strain <18% and LA pump strain <8% predicted elevated LV filling pressure better (P < 0.05) than LA volume and conventional Doppler parameters. Accuracy to identify elevated LV filling pressure was 75% for LA reservoir strain alone and 72% for pump strain alone. When combined with conventional parameters, accuracy was 82% for both LA strains. In patients with normal LV systolic function by GLS, LA pump strain >14% identified normal LV filling pressure with 92% accuracy. Conclusion Left atrial reservoir and pump strain are determined predominantly by LV GLS and filling pressure. Accuracy of LA strains to identify elevated LV filling pressure was best in patients with reduced LV systolic function. High values of LA pump strain, however, identified normal LV filling pressure with good accuracy in patients with normal systolic function.

Abstract Introduction Left bundle brach block (LBBB) leads to left ventricular (LV) mechanical dyssynchrony with septal flash and delayed lateral wall contractions. Since atrium and ventricle are anatomically connected, dyssynchronous LV contractions may be transmitted to the left atrium, thereby disturbing left (LA) function. Purpose To test the hypothesis that patients with LBBB have LA dyssynchrony induced by tethering to the dyssynchronous left ventricle. Methods Myocardial strain was measured by speckle-tracking echocardiography in 20 non-ischaemic heart failure patients with LBBB, before and 6 months after cardiac resynchronization therapy (CRT), and in 20 healthy controls. For the LA, dyssynchrony was measured as time delay between onset of the interatrial septum and the lateral wall, and for the LV, between onset septal flash and onset lateral wall contraction. White arrows in Figure indicate onset LA stretch. Results As shown in the Figure, patients with LBBB and HF had marked LA reservoir phase dyssynchrony. Before CRT time delay from onset LA septal stretch to onset lateral wall stretch was 125±71 ms (mean±SD), and decreased to 23±70 (p<0.0001) with CRT. In controls there was a small delay of 34±56 ms. The LA dyssynchrony correlated with LV dyssynchrony (r=0.50, p=0.033), supporting the hypothesis that LA dyssynchrony in LBBB represents mechanical interaction due to tethering between the respective walls. Conclusions Patients with LBBB had marked LA reservoir phase dyssynchrony, which was abolished with CRT. The LA dyssynchrony was attributed to direct LV-LA mechanical interaction. The observed LA resynchronization by CRT represent an additional benefit of CRT in patients with heart failure. Funding Acknowledgement Type of funding sources: None. Left atrial and ventricular dyssynchrony

Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority Elevated left ventricular (LV) filling pressure is an important diagnostic feature of heart failure. To investigate determinants of left atrial (LA) reservoir and pump strain and if these parameters may serve as markers of LV filling pressure. In a multicenter study of 322 patients with cardiovascular disease of different etiologies, LA strain by speckle tracking echocardiography was compared to conventional echocardiographic markers using invasive pressure as reference. Left ventricular filling pressure correlated well with LA reservoir and pump strain (r-values ‑0.52 and ‑0.57, respectively) (Figure). However, LV global longitudinal strain (GLS) was the strongest determinant of LA reservoir strain (r = 0.64), and correlated well with LA pump strain (r = 0.51).  For both LA strains, association with filling pressure was strongest in patients with reduced LV ejection fraction. In patients with normal GLS (≥18%), atrial strains provided no information regarding filling pressure (Figure). Reservoir strain <18% and pump strain <8% predicted elevated LV filling pressure better (p < 0.05) than the conventional indices LA volume, ratio of mitral early filling velocity/annular velocity and tricuspid regurgitation velocity. Accuracy to classify filling pressure as normal or elevated was 75% for both LA strains . When any one of the conventional indices were missing, and were replaced by LA strains, the combination of indices had accuracy 82% to correctly classify filling pressure. Left atrial reservoir and pump strain may serve as clinical markers of LV filling pressure, but will be useful predominantly in patients with reduced systolic function.  Due to limited diagnostic accuracy, LA strain should be used in combination with other indices. Abstract Figure