Left Ventricular Peak Systolic Pressure Research Articles

Non-invasive estimation of left ventricular systolic peak-pressure: a prerequisite to calculate of myocardial work in hypertrophic obstructive cardiomyopathy

Abstract Introduction Myocardial work (MW) is an echocardiographic parameter to estimate global and regional myocardial performance. This method utilizes pressure strain loops derived from global longitudinal strain (GLS) and left ventricular systolic pressure (LVSP) estimated by brachial blood pressure (BP). Purpose Since LVSP cannot be equated with BP in pts with HOCM, we investigated whether the LVSP can be calculated non-invasively by combining Doppler echo parameters and the BP. This estimation is mandatory to make MW applicable for HOCM-pts. Methods We studied 20 consecutive pts (8 women, 12 men; mean age 57.0±13.9 years; NYHA class 2.1±0.8) with indication for first alcohol septal ablation. 6 pts had hypertension and 2 pts unexplained syncope. 18 (90%) pts were in sinus rhythm. NTproBNP was 1431 pg/ml (1912 IQR). Echo baseline measurements showed subaortic septal (IVS) thickness of 21.0±5.0 mm and maximal IVS thickness of 24.7±6.3 mm. Pts showed high-normal left ventricular ejection fraction (70.4±10.1%). Left atrial (LA) volume was 101.2±26 ml. All measurements of pressures and gradients were performed in the catheterization laboratory after placement of a 5F Judkins JR4 in the ascending aorta and a 5.2F special pigtail catheter in the apex of LV beyond the obstruction. Simultaneous measurements of BP at left upper arm, echo intraventricular gradients (instantaneous and mean) with CW Doppler (GE Vivid E70), and invasive pressures and gradients (peak-to-peak and mean) of the LV and ascending aorta were performed. Echo and invasive gradients were averaged over 3 cardiac cycles. Finally, we tried to identify an estimation of invasively measured LV systolic pressure by combining systolic BP and echo measured gradients. Results Systolic BP was 143±21 mmHg. Max. CW Doppler gradient was 65±29 mmHg and mean gradient was 31±14 mmHg. Invasive simultaneous measurements at rest showed peak-to-peak gradient of 55±24 mmHg and mean gradient of 34±13 mmHg between apical LV and ascending aorta. Mean LVSP was 190±40 mmHg. Systolic pressure of the ascending aorta was 134±28 mmHg. Adding systolic peripheral BP and maximal echo-gradient mean value was 208±38 mmHg. Adding systolic peripheral BP and echo-mean gradient mean value was 174±26 mmHg. Correlating these values with the invasively measured systolic LV pressure we found a slightly higher correlation of the sum of systolic BP and mean-echo gradient (Pearson correlation coefficient: 0.867 p<0.001) compared with the sum of systolic BP and maximal echo-gradient (Pearson correlation coefficient: 0.851; p<0.001). Bland–Altman plots demonstrated good levels of agreements between invasively measured LVSP and both non-invasively estimated LVSP. Conclusions Non-invasive estimation of LVSP is feasible by combining conventional BP and CW Doppler measured mean LV outflow tract gradient in HOCM. Hereby estimation of MW in pts with HOCM is applicable.

Abstract 11310: T Helper 1 Lymphocytes Promote Diastolic Dysfunction and Fibrosis in a Non-Hypertensive Angiotensin II Mouse Model of Heart Failure

Introduction: Angiotensin (Ang) II induces cardiac fibrosis and diastolic dysfunction, also in absence of hypertension (HTN). We found that a non-HTN AngII infusion fails to induce dysfunction and fibrosis in T cell receptor α deficient mice ( Tcrα -/- , bereft of T cells). Hypothesis: Since T helper 1 (Th1) lymphocytes promote adverse remodeling in models of heart failure (HF), we hypothesized that Th1 cells are sufficient to induce diastolic dysfunction and fibrosis in a non-HTN AngII model. Methods: Naïve CD4+ cells were isolated from wild type (WT) mice lymph nodes (LNs) and spleens (MACS columns) and differentiated into Th1 cells over 7 days using plates coated with anti-CD3 antibody (5 μg/ml) plus IL-12 (10 ng/ml) and anti-IL-4 (1 μg/ml) and from day 4, IL-2 (20 ng/ml). Adoptive transfer (AT) of 10 7 Th1 cells/500 μl PBS, naïve CD4+ cells, or PBS alone was performed into Tcrα -/- mice (3-11 months old, N=8-16/group) implanted with AngII (0.2 μg/kg/day) osmotic pumps for 4 wks. AT was repeated two weeks later. LV dimensions, ejection fraction (EF), and diastolic function (isovolumetric relaxation time - IRT) were measured with Doppler echocardiography. LV end-diastolic pressure (EDP) and peak systolic pressure (PSP) were measured with a Millar catheter. Heart slides were stained with picrosirius red to measure interstitial fibrosis. Results: All groups had similar LV dimensions, EF, and PSP (not shown). AT of naïve CD4+ cells or PBS did not increase the IRT vs baseline (7.3±0.9 vs 7.6±0.6 and 9.9±0.7 vs 8.8±0.7 ms). AT of Th1 cells significantly increased the IRT (15.6±0.9 vs 9.0±0.7 ms, all p<0.0001). EDP was significantly higher in Th1 mice (11.5±0.8 mmHg) vs naïve CD4+ mice (4.6±0.8 mmHg) or PBS (5.2±0.6 mmHg) (all p<0.0001). Interstitial fibrosis in Th1 mice (1.4±0.2%) was significantly higher than in naïve CD4+ mice (0.7±0.1%) or PBS (0.8±0.1%) (all p<0.001). Conclusions: Th1 cells are sufficient to induce diastolic dysfunction and fibrosis in a non-HTN AngII HF mouse model.

GDF5 deficiency prevents cardiac rupture following acute myocardial infarction in mice

BackgroundWe previously showed that growth differentiation factor 5 (GDF5) limits infarct expansion post-myocardial infarction (MI). We now examine the acute post-MI role of GDF5 in cardiac rupture. Methods and ResultsFollowing permanent ligation of the left anterior descending artery, GDF5 deficiency (i.e., GDF5 knockout mice) reduced the incidence of cardiac rupture (4/24 vs. 17/24; P < .05), and improved survival over 28-d compared to wild-type (WT) mice (79% vs. 25%; P < .0001). Moreover, at 3-d post-MI, GDF5-deficient mice manifest: (a) reduced heart weight/body weight ratio (P < .0001) without differences in infarct size or cardiomyocyte size; (b) increased infarct zone expression of Col1a1 (P < .05) and Col3a1 (P < .01), suggesting increased myocardial fibrosis; and (c) reduced aortic and left ventricular peak systolic pressures (P ≤ .05), suggesting reduced afterload. Despite dysregulated inflammatory markers and reduced circulating monocytes in GDF5-deficient mice at 3-d post-MI, reciprocal bone marrow transplantation (BMT) failed to implicate GDF5 in BM-derived cells, suggesting the involvement of tissue-resident GDF5 expression in cardiac rupture. ConclusionsLoss of GDF5 reduces cardiac rupture post-MI with increased myocardial fibrosis and lower afterload, albeit at the cost of chronic adverse remodeling.

Non-invasive estimation of left ventricular systolic peak pressure: a prerequisite to calculate myocardial work in hypertrophic obstructive cardiomyopathy.

Myocardial work (MyW) is an echocardiographically derived parameter to estimate myocardial performance. The calculation of MyW utilizes pressure strain loops from global longitudinal strain and brachial blood pressure (BP) as a surrogate of left ventricular systolic pressure (LVSP). Since LVSP cannot be equated with BP in hypertrophic obstructive cardiomyopathy (HOCM), we explored whether LVSP can be derived non-invasively by combining Doppler gradients and BP. We studied 20 consecutive patients (8 women, 12 men; mean age 57.0 ± 13.9 years; NYHA 2.1 ± 0.8; maximal septal thickness 24.7 ± 6.3 mm) with indication for first alcohol septal ablation. All measurements were performed simultaneously in the catheterization laboratory (CathLab)-invasively: ascending aortic and LV pressures; non-invasively: BP, maximal (CWmax) and mean (CWmean) Doppler gradients.LVSP was 188.9 ± 38.5 mmHg. Mean gradients of both methods were comparable (CathLab 34.3 ± 13.4 mmHg vs. CW 31.0 ± 13.7 mmHg). Maximal gradient was higher in echocardiography (64.5 ± 28.8 mmHg) compared with CathLab (54.8 ± 24.0 mmHg; P < 0.05). Adding BP (143.1 ± 20.6 mmHg) to CWmax resulted in higher (207.7 ± 38.0 mmHg; P < 0.001), whereas adding BP to CWmean in lower (174.1 ± 26.1 mmHg; P < 0.01) derived LVSP compared with measured LVSP. However, adding BP to averaged CWmax and CWmean resulted in comparable results for measured and derived LVSP (190.9 ± 31.6 mmHg) yielding a favourable correlation (r = 0.87, P < 0.001) and a good level of agreement in the Bland-Altman plot. Non-invasive estimation of LVSP in HOCM is feasible by combining conventional BP and averaged CWmean and CWmax gradients. Hereby, a more reliable estimation of MyW in HOCM may be feasible.

Novel use of an irrigated ablation catheter to monitor real-time hemodynamics during ablation.

Hemodynamic decompensation during catheter ablation occurs due to prolonged procedure time and irrigant delivery directly into the cardiac chambers. Real-time hemodynamic monitoring of patients undergoing catheter ablation procedures may identify patients at risk of decompensation; we set out to assess the feasibility of a novel, real-time, intracardiac pressure monitoring system using a standard irrigated ablation catheter. We studied 13 consecutive who underwent pressure measurement of the left atrium (LA) and left ventricle (LV) via transeptal access with a Swan Ganz (SG) catheter followed by two commercially available irrigated ablation catheters. Pressure waveform data was extracted to compare LA peak pressure, LV peak systolic pressure, LV end-diastolic pressure, and waveform analysis. Comparison between the SG and ablation catheters (AblA; AblB) demonstrated that LV systolic pressure (0.61-16.8 mmHg; 1.32-18.2 mmHg), and LV end-diastolic pressure (-3.4 to 2.8 mmHg; -3.0 to 3.35 mmHg) were well correlated and had accepted repeatability. Ablation waveforms demonstrated an 89.9 ± 6.4% correlation compared to SG waveforms. Pressure measurements derived from an irrigated ablation catheter are accurate and reliable when compared to an SG catheter. Further studies are needed to determine how real-time pressure monitoring can improve outcomes during ablation procedures.

Prognostic role of global work efficiency in patients undergoing transcatheter aortic valve implantation

Abstract Background Non-invasive myocardial work (MW) quantification has emerged in the last years as an alternative echocardiographic tool for myocardial function assessment. Its role in patients with severe aortic stenosis (AS) after aortic valve implantation (TAVI) has not been adequately investigated. Purpose We aimed to evaluate MW indices as early echocardiographic markers of LV reverse remodeling within a month after TAVI and their prognostic value. Methods and results We conducted a single-centre prospective study, enrolling 88 consecutive patients (mean age 79.9±6.4 years, 35% males) with AS undergoing TAVI between April 2018 and 2021, selected from the EffecTAVI registry. Exclusion criteria were prior valve surgery, atrial fibrillation, left bundle branch block (LBBB) at baseline and and suboptimal quality of imaging. Echocardiographic assessment was performed before TAVI and at 30-day follow-up, including quantification of 2D global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE). LV peak systolic pressure was estimated non-invasively from the sum of systolic blood pressure and trans-aortic mean gradient. One month after the procedure, there was a significant improvement of LV GLS (−18.4±4.2 vs −19.5±4.2%, before and after TAVI respectively, p=0.006), a significant reduction of GWI (2406±567 vs 1908±479 mmHg%, p&amp;lt;0.001), GCW (2783±616 vs 2202±463 mmHg%, p&amp;lt;0.001), and GWW (238±203 vs 173±127 mmHg%, p=0.002). Conversely, MWE did not change early after intervention (90.4±6.2 vs 91.4±5.1%, p=0.113). After TAVI, 32 patients (36.4%) developed LV dyssynchrony due to LBBB or pacemaker implantation. When the population was divided according to the presence or absence of LV dyssynchrony at 30-day follow-up, a significant reduction in GWW was found only in the those without dyssynchrony (241±229 vs 142±103 mmHg% before and after TAVI, p&amp;lt;0.001). Consistently, in this subgroup, MWE significantly improved after TAVI (90±7 vs 93±5%, p=0.001), while a trend of MWE reduction was observed in patients who developed dyssynchrony after TAVI (91±5 vs 89±5%, p=0.110). In the overall population, a 30-day value of MWE≤92% was associated with an increased rate of cardiovascular events (composite of all-cause death and rehospitalization for heart failure) at 1-year follow-up (29.5% vs 4.8%, long rank p=0.003). In multivariable Cox-regression analysis, adjusted for confounders, GWE after TAVI (HR: 0.892, CI: 0.817–0.974; p=0.011) was independently associated with events at 1-year follow-up. Conclusions In patients with severe AS undergoing TAVI a significant reduction of GWW and improvement of MWE can be detected only in those who do not develop LV dyssynchrony. In this setting, MWE≤92% early after TAVI is associated with poor outcome. Thus, MWE could represent an alternative tool for myocardial function assessment and prognostic evaluation in patients receiving TAVI. Funding Acknowledgement Type of funding sources: None.

Normal ranges of non-invasive left ventricular myocardial work indices in healthy young people.

ObjectivesEchocardiographic global myocardial work (GMW) indices recently emerged to non-invasively evaluate left ventricular (LV) myocardial performance with less load-dependence than LV ejection fraction (LVEF) or global longitudinal strain (GLS). Yet, few data exist on the descriptions of LV GMW indices in young people. We therefore aimed to provide normal reference values of LV GMW in a healthy young cohort, and simultaneously to investigate factors associated with non-invasive GMW indices.Materials and methodsA total of 155 healthy young people (age 10–24 years, 59% male) underwent transthoracic echocardiography were recruited and further stratified for age groups and divided by gender. Two-dimensional speckle-tracking echocardiography (2D-STE) were performed to determine LV GLS, peak strain dispersion (PSD) and GMW indices, which include global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). LV peak systolic pressure was assumed to be equal to the systolic brachial artery cuff blood pressure.ResultsAge and gender specific normal ranges for LV GMW indices were presented. On multivariable analysis, GWI and GCW correlated more closely with systolic blood pressure (SBP) than LV GLS, while both GWW and GWE independently correlated with PSD (P < 0.05 for all). There were no associations between any of the GMW indices with age, sex, body mass index, heart rate, left ventricular mass index as well as LV sizes or LVEF. Of noted, LV GMW indices had good intra-observer and inter-observer reproducibility.ConclusionWe reported echocardiographic reference ranges for non-invasive LV GMW indices in a large group of healthy young subjects, which are reproducible and reliable, and thus can be further used when assessing subclinical dysfunction in young people with myocardial diseases.

Left ventricular venting during extracorporeal membrane oxygenation; the effects on cardiac performance in a porcine model of critical post-cardiotomy failure.

Left ventricular distension is a major concern with postcardiotomy veno-arterial extracorporeal membrane oxygenation (VA-ECMO) supporting a critical heart failure after cardiac surgery. This porcine study evaluates the effects of left ventricular venting on cardiac function during ECMO-supported circulation and after weaning from ECMO. Twenty anaesthetised open-chest pigs were put on cardiopulmonary bypass with aortic cross-clamping and suboptimal cardioplegic arrest for 40min. After declamping and defibrillation, the animals were supported by VA-ECMO for 180min either with or without additional left ventricular venting. Continuous haemodynamic evaluations were performed at baseline and at cardiac arrest, during VA-ECMO and for 120min after weaning from circulatory support. Left ventricular perfusion and function were evaluated with microspheres, pressure-volume loops and epicardial echocardiography at baseline and after 1 and 2h with unsupported circulation. In vented animals both mean aortic and left ventricular peak systolic pressure increased at the end of the ECMO-supported period compared to those not vented and remained increased also after weaning. Both at 60 min and 120min after weaning from circulatory support, left ventricular stroke work and pressure-volume area were increased in vented compared to not vented animals. At 120min left ventricular stroke volume was increased in vented compared to not vented animals, myocardial perfusion did not differ. The left ventricular mechanical efficiency, defined as the ratio between pressure volume area and myocardial perfusion, was increased (53.2 ± 5 vs 36.2 ± 2.1J/mL/g, p = 0.011) in vented- compared to not vented hearts. This experimental study demonstrate that left ventricular venting during post-cardiotomy veno-arterial ECMO for 3h attenuates deterioration of left ventricular function and haemodynamics early after weaning from circulatory support.

652 Myocardial work in patients undergoing transcatheter aortic valve implantation: clinical value and implications for outcome

Abstract Aims Non-invasive myocardial work (MW) quantification has emerged in the last years as an alternative echocardiographic tool for myocardial function assessment. This new parameter provides a less loading-dependent evaluation of myocardial performance through the combined assessment of global longitudinal strain (GLS) and non-invasive left ventricle (LV) pressures. The role of MW as a marker of cardiac dysfunction and reverse remodelling in patients with severe aortic stenosis (AS) after aortic valve implantation (TAVI) has not been adequately investigated. This study aims to evaluate MW indices as early echocardiographic markers of LV reverse remodelling within a month after TAVI and their prognostic value. Methods and results We conducted a single-centre prospective study, enrolling 70 consecutive patients (mean age 80.1 ± 5.5 years) with severe AS undergoing TAVI between 2018 and 2020, selected from the EffecTAVI registry. Exclusion criteria were prior valve surgery, severe mitral stenosis, permanent atrial fibrillation, left bundle branch block (LBBB) at baseline, and suboptimal quality of speckle-tracking image analysis. Echocardiographic assessment was performed before TAVI and at 30-day follow-up. Clinical, demographic, and resting echocardiographic data were recorded, including quantification of 2D global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). LV peak systolic pressure was estimated non-invasively from the sum of systolic blood pressure and trans-aortic mean gradient. One month after the procedure, there was a significant improvement of LV GLS (−17.94 ± 4.24% vs. −19.35 ± 4.31%, before and after TAVI respectively, P = 0.002), as well as a significant reduction of GWI (2430 ± 586 mmHg% vs. 1908 ± 472 mmHg%, P &amp;lt; 0.001), GCW (2828 ± 626 mmHg% vs. 2206 ± 482 mmHg%, P &amp;lt; 0.001), and GWW (238 ± 207 mmHg% vs. 171 ± 118 mmHg%, P = 0.006). Conversely, MWE did not significantly change early after intervention (90.53 ± 6.05% vs. 91.45 ± 5.05%, P = 0.204). After TAVI, 30 patients (42.8%) developed LV dyssynchrony due to LBBB or pacemaker implantation. When the population was divided according to the presence or absence of LV dyssynchrony at 30-day follow-up, a significant reduction in GWW was found only in those without dyssynchrony (244 ± 241 vs. 141 ± 110 mmHg% with and without dyssynchrony respectively, P = 0.002). Consistently, in this subgroup, MWE significantly improved post-TAVI (90 ± 7 vs. 93 ± 5%, P = 0.002), while a trend of MWE reduction was observed in patients who developed dyssynchrony post-TAVI (91 ± 4 vs. 89 ± 5%, P = 0.164). In the overall population, a baseline value of MWE&amp;lt; 92% was associated with an increased rate of cardiovascular events (composite of all-cause death and rehospitalization for heart failure) at 1-year follow-up (22.2 vs. 3.1%, long rank, P = 0.016). Conclusions In patients with severe AS undergoing TAVI a significant reduction of GWW and improvement of MWE can be detected only in those who did not develop LV dyssynchrony. In this setting, MWE lower than 92% at baseline is associated with poor outcome. Thus, MWE could represent an alternative tool for myocardial function assessment in patients receiving TAVI.

Cardiac abnormalities after induction of endoplasmic reticulum stress are associated with mitochondrial dysfunction and connexin43 expression.

The endoplasmic reticulum (ER) is responsible for protein synthesis and calcium storage. ER stress, reflected by protein unfolding and calcium handling abnormalities, has been studied as a pathogenic factor in cardiovascular diseases. The aim of this study is to examine the effects of ER stress on mechanical and electrophysiological functions in the heart and explore the underlying molecular mechanisms. A total of 30 rats were randomly divided into control, ER stress inducer (tunicamycin[TN]) and ER stress inhibitor (tunicamycin+4-phenylbutyric acid [4-PBA]) groups. ER stress induction led to significantly systolic and diastolic dysfunction as reflected by maximal increasing/decreasing rate of left intraventricular pressure (±dp/dt), left ventricular peaksystolic pressure(LVSP) and LV end-diastolic pressure(LVEDP). Epicardial mapping performed in vivo revealed reduced conduction velocity and increased conduction heterogeneity associated with the development of spontaneous ventricular tachycardia. Masson's trichrome staining revealed marked fibrosis in the myocardial interstitial and sub-pericardial regions, and thickened epicardium. Western blot analysis revealed increased pro-fibrotic factor transforming growth factor-β1 (TGF-β1), decreased mitochondrial biogenesis protein peroxlsome proliferator-activated receptor-γ coactlvator-1α （PGC-1a）, and decreased mitochondrial fusion protein mitofusin-2 (MFN2). These changes were associated with mitochondria dysfunction and connexin 43(CX43)translocation to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Our study shows that ER stress induction can produce cardiac electrical and mechanism dysfunction as well as structural remodelling. Mitochondrial function alterations are contributed by CX43 transposition to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA.

Assessment of left ventricular systolic function by non-invasive pressure-strain loop area in young male strength athletes

BackgroundThe health of athletes has been recognized as a worldwide public concern with more reported sudden cardiac deaths (SCD). Therefore, early detection of abnormal heart function in athletes can help reduce the risk of exercise. A novel valid non-invasive method to evaluate left ventricular (LV) myocardial work (MW) using LV pressure-strain loop (PSL), was used in this paper to explore LV systolic function in young male strength athletes.MethodsThirty-six professional young male strength athletes (the athlete group) and 32 healthy, age-matched young men (the control group) were involved in the study. The LVMW parameters were calculated as the area of PSL by two-dimensional speckle tracking echocardiography (2D-STE) and peak systolic LV pressure. The differences between two groups of data and the predictive efficacy of MW parameters for LV systolic function were analyzed.ResultsThe athlete group had significantly higher values of global wasted myocardial work (GWW) and peak strain dispersion (PSD) than did the control group (P<0.05). Global myocardial work index (GWI), global constructive myocardial work (GCW) and global longitudinal strain (GLS) were lower in the athlete group than that in the control group, although statistical significance was not reached (P>0.05). Due to the proportion of GWW and GCW, statistically significant reduction was found in global myocardial work efficiency (GWE) in the athlete group. Conventional echocardiography parameters were well correlated with GWW and GWE (P<0.05). The best predictor of LV myocardial contractile performance in the athletes using receiver operating characteristic curve (ROC) was GWE, with the area under ROC (AUC) of 0.733, sensitivity of 83.3% and specificity of 59.4%.ConclusionsSubclinical changes have appeared in the hearts of young male strength athletes after long-term intensive exercise and LVMW parameters by PSL play an important role in the evaluation of athlete’s LV contractile performance.

P1575 Preserved myocardial work efficiency after transcatheter aortic valve implantation-induced left bundle branch block

Abstract Background Left bundle branch block (LBBB) frequently complicates transcatheter aortic valve implantation (TAVI), but may not induce classical mechanical dyssynchrony typically observed in heart failure patients with LBBB. Non-invasive estimated myocardial work by pressure strain-loops is a novel method for evaluation of left ventricular (LV) performance including loading conditions and identifies responders to cardiac resynchronization therapy. Assessment of myocardial work in TAVI-induced LBBB has, however, not been performed earlier. Purpose We aimed to evaluate myocardial performance in TAVI-induced LBBB by myocardial work. Methods Patients with severe aortic stenosis (AS) and normal ventricular conduction undergoing transfemoral TAVI were included. TAVI-induced LBBB was defined according to strict ECG criteria. In addition to standard echocardiographic parameters, we performed speckle tracking echocardiography (STE) within 2 days post procedure. Post-procedural myocardial work was estimated by commercially available software, combining LV strain by STE and a non-invasively estimated LV pressure curve. Peak systolic LV pressure was assumed to be equal to the sum of peak arterial cuff pressure and mean aortic valve pressure gradient. The proportion of constructive work relative to the sum of wasted and constructive work was expressed as myocardial work efficiency (Figure). A global work efficiency &amp;lt; 90 % was considered abnormal according to the recently published EACVI NORRE study. Results We included 109 consecutive patients undergoing TAVI (83 ± 7 years old, 54 % women, logistic Euroscore 16 ± 10) with severe AS (valve area 0.7 ± 0.2 cm2, mean transvalvular gradient 54 ± 18 mmHg), QRS duration 94 ± 10 ms, and a relatively preserved LV ejection fraction (54 ± 9%). New-onset LBBB was observed in 28 patients (26 %) after TAVI. Although post-procedural myocardial work efficiency was slightly better in patients who retained normal ventricular conduction than those with TAVI-induced LBBB (93.6 ± 2.5% vs 91.2 ± 3.4%, p = 0.004), both groups of patients had global myocardial work efficiency within the normal reference range. Conclusions Patients with TAVI-induced LBBB have preserved work efficiency despite gross electrical block satisfying strict ECG criteria. The reduced myocardial work efficiency in TAVI-induced LBBB was within the reference range of normal in the recently published EACVI NORRE study. The preservation of myocardial work in TAVI-induced LBBB may explain why LBBB as a complication to TAVI does not necessarily imply poor prognosis. Abstract P1575 Figure.

P5438Cardiac abnormalities after induction of endoplasmic reticulum stress are associated with mitochondrial dysfunction and connexin43 expression

Abstract Background The endoplasmic reticulum (ER) is responsible for protein synthesis and calcium storage. ER stress, reflected by protein unfolding and calcium handling abnormalities, has been studied as a pathogenetic factor in cardiovascular diseases. Purpose The aim of this study is to examine the effects of ER stress on mechanical and electrophysiological functions in the heart and explore the underlying molecular mechanisms. Methods A total of 30 rats were randomly divided into control, ER stress induction (tunicamycin) and ER stress inhibition (4-phenylbutyric acid, 4-PBA) groups. Results ER stress induction led to significantly systolic and diastolic dysfunction as reflected by maximal increasing/decreasing rate of left intraventricular pressure (±dp/dt), LV peak systolic pressure, LV development pressure and LV end-diastolic pressure. Epicardial electrical mapping performed in vivo revealed reduced conduction velocity, increased conduction heterogeneity and spontaneous ventricular tachycardia. Masson's trichrome staining revealed marked fibrosis in the myocardial interstitium and sub-pericardium and thickened epicardium. Western blot analysis revealed increased pro-fibrotic factor TGF-β1, decreased mitochondrial biogenesis protein PGC-1a, decreased mitochondrial fusion protein MFN2. These changes were associated with decreased mitochondrial membrane potential (MMP) and connexin 43 translocation to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Conclusions Our study shows that ER stress induction can produce cardiac electrical and mechanism dysfunction as well as structural remodeling. Mitochondrial function alterations are contributed by CX43 transposition to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Acknowledgement/Funding National Natural Science Foundation of China (No. 81570298 to T.L.)

P1609Adverse left ventricular remodeling in descending thoracic vs ascending aorta banding in novel porcin model. cMRI study

Abstract Background Based on differences in the timing of left ventricular (LV) peak systolic pressure, distinction between early from late LV systolic loading is made. Reduced ascending aortic compliance results with chronic early LV systolic loading. Chronic late LV systolic loading associates with end-systolic wave refection's and developing earlier heart failure. The LV remodeling in chronic late vs early systolic loading has not been studied previously in a porcine model. Objective To develop novel porcin model and to study the LV hypertrophic remodeling in chronic late vs early LV systolic loading, during thoracic aorta banding. Methods Domestic male pigs (28±3.4kg, n=14) underwent thoracic aorta banding. Ascending aorta banding (PB, n=6) induced chronic early LV systolic loading. Descending thoracic aorta banding (DB n=8) provoked chronic late LV systolic loading. 3T cMRI with T1 mapping was performed at baseline, 4 and 8 weeks. Hemodynamic measurements were obtained using 5Fr Millar P-V catheter in LabChart, after 4 and 8 weeks. ANOVA two-way for repeated measurements was performed (R studio 3.5.1). Leven and Shapiro-Wilk normality testing was done. Analysis of variance of aligned rank transformed data was performed. Linear regression showed correlation between relevant parameters. Results Hemodynamic measurements are presented as means±se and means±sd for cMRI, for significant p&lt;0.05. After 8 weeks of thoracic aorta banding, the timing of peak systolic LV pressure was prolonged in DB (PB 159±6 msec; DB 329±16 msec; p&lt;0.01), correlating with LV dPdtmax (p=0.017, r=−0.8), Ea (p=0.04, r=0.73), LVEF (p=0.035, r=−0.74) and native T1 (p=0.01, r=−0.83) in DB. Tau was not different (p=0.8), correlated with the timing of peak LV pressure in DB (p=0.015, r=0.81). The gradients were not different (PB 25±5mmHg; DB 16±1mmHg; p=0.88) and LV systolic pressure (p=0.61). The isovolumic contraction phase was prolonged in DB (PB 34±4msec; DB 56±4msec, p&lt;0.01). LV mass index increased (p=0.013) and was not different between the groups (PB 95±14g/m2; DB 89±12g/m2; p=0.89). RWT was different within (p&lt;0.01) and between the groups (p=0.02),correlating with LVEFas dPdtmax (p=0.013, r=−0.82), whilst with dPdtmin (p=0.018, r=0.8) in DB. There was an interaction for site of aortic constriction and LV remodeling (RWT 0.067±0.08 in PB; 0.45±0.04 in DB, p=0.004; posterior LV wall thickness (PWT) p=0.012). RWT correlated with native T1 in PB (p=0.04) and DB (p&lt;0.01, r=−0.8). Des. aorta banding in late LV loadining Conclusion The LV hypertrophic remodeling, defined by RWT, PWT and hemodynamic correlates is different between chronic late and early LV systolic loading, in this novel porcine model. The timing of peak LV afterload associates with increased LV afterload and adverse LV remodeling in presence of chronic late LV systolic loading, in the porcin model of descending thoracic aorta banding. Increased RWT ratio associates with adverse LV remodeling in the porcine model of descending thoracic aortic constriction.

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

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

Luteolin improves heart preservation through inhibiting hypoxia-dependent L-type calcium channels in cardiomyocytes.

The current study aimed to evaluate whether luteolin could improve long-term heart preservation; this was achieved by evaluating the heart following long-term storage in University of Wisconsin solution (the control group) and in solutions containing three luteolin concentrations. The effects of different preservation methods were evaluated with respect to cardiac function while hearts were in custom-made ex vivo Langendorff perfusion systems. Different preservation methods were evaluated with respect to the histology, ultrastructure and apoptosis rate of the hearts, and the function of cardiomyocytes. In the presence of luteolin, the rate pressure product of the left ventricle was increased within 60 min of reperfusion following a 12-h preservation, coronary flow was higher within 30 min of reperfusion, cardiac contractile function was higher throughout reperfusion following 12- and 18-h preservations, and the left ventricle peak systolic pressure was significantly higher compared with the control group (all P<0.05). The expression levels of apoptosis regulator Bax and apoptosis regulator Bcl-2 in the luteolin groups were significantly decreased and increased, respectively. Lactate dehydrogenase, creatine kinase and malondialdehyde enzymatic activity was increased following long-term storage, while the activity of superoxide dismutase was significantly decreased. Furthermore, luteolin inhibited L-type calcium currents in ventricular myocytes under hypoxia conditions. Thus, luteolin demonstrated protective effects during long-term heart preservation in what appeared to be a dose-dependent manner, which may be accomplished through inhibiting hypoxia-dependent L-type calcium channels.

Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling.

Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles. Tamoxifen treated wild-type (WT-TAM; n=5) and vehicle treated AlK-1-cKO mice (cKO-CON; n=5) served as controls for tamoxifen treated AlK-1-cKO mice (cKO-TAM; n=15). AlK-1 cKO-TAM mice demonstrated reduced 14-day survival compared to cKO-CON controls (13 vs 100%, respectively, p<0.01). Seven days after treatment, cKO-TAM mice exhibited reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14days total body mass was reduced, but LV and lung mass increased in cKO-TAM not cKO-CON mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume were increased in cKO-TAM, not cKO-CON mice. LV AlK-1 mRNA levels were reduced in cKO-TAM, not cKO-CON mice. LV levels of other TGFβ-family ligands and receptors (AlK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFβ1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-TAM mice, but LV levels of β-MHC and SERCA were unchanged. No increase in markers of cardiac fibrosis, Type I collagen, CTGF, or PAI-1, were observed between groups. No differences were observed for any variable studied between cKO-CON and WT-TAM mice. Global deletion of AlK-1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of AlK-1 in cardiac remodeling independent of systemic AVMs are required.

Cardiac rupture in takotsubo cardiomyopathy treated surgically.

A 74-year-old woman, without a history of cardiological problems or risk factors of cardiovascular diseases, was admitted to the emergency room of our hospital after 2 h of chest pain. During the transport, the patient received 5000 U of unfractionated heparin, aspirin (300 mg) and clopidogrel (600 mg). The patient had suffered from an anxiety syndrome for several years. At admission, the patient was in a serious condition generally, was vomiting, and had severe chest pain with signs of cardiogenic shock (skin pale and wet, blood presure (BP) and heart rate (HR) undetectable). Electrocardiogram demonstrated a sinus rhythm of 58 per minute with QS complex and ST segment elevation in precordial leads (V2–V6). Laboratory results revealed increased troponin I concentration (2.041 ng/ml). Following hemodynamic stabilization, the patient was transported to the catheterization laboratory. Coronarography did not reveal any significant stenosis. Left ventricle angiography (LVA) showed normal volume with contractile disturbances of apex and hyperkinesis of the basement segments, with ejection fraction (EF) of 56%. Contrast outflow to the epicardium was observed within the area of the apex, through the perforated wall of the left ventricle (Figures 1 A–C). Echo confirmed the presence of fluid in the pericardium and cardiac tamponade. The patient was supported with intra-aortic balloon contra-pulsation and transported to the cardiac surgery for urgent intervention. During transport, the patient lost consciousness. After urgent cardiac tamponade decompression, the pulse and arterial pressure increased. Active bleeding through the ruptured left ventricle was observed in the area of the apex during the operation. Left ventricular plication with sutures on a double layered Teflon pad was performed. The lines of the sutures were conducted through healthy tissues. Examination of the supported ruptured region showed left ventricle tightness and complete hemostasis. No significant complications were observed during the perioperative period. On the first day after the operation the patient was extubated, and on the fifth day the intra-aortic balloon contra-pulsation was removed. The patient was transported to the regional hospital on day 11 to continue the therapeutic and rehabilitation procedures. A discharge echocardiogram revealed akinesis of the apex and hypokinesis of the septum, with an EF of 50%. The patient was under cardiosurgical follow-up for the next 3 months. She was in good general condition without any chest pain, and the wounds from the sternotomy were healing properly. In a 2.5-year long study the patient was in good condition and the echocardiogram conformed normokinesis of the left ventricle apex. She has been treated with bisoprolol 5 mg and aspirin 75 mg since hospitalization. Figure 1 A – ventriculography (left ventricular systole – normal volume of the left ventricle, contractile disturbances of the apex and hyperkinesis of the basement segments), B – ventriculography (left ventricular diastole), C – ... Most cases of takotsubo cardiomyopathy (TTC) have a good prognosis. However, occasionally the clinical outcome is complicated by cardiogenic shock, serious ventricular rhythm abnormalities or even cardiac rupture [1–3]. The mechanism of cardiac rupture in TTC is not as well understood as the causes of mechanical complications in other cases without significant coronary artery stenosis, i.e. dissolving thrombus, embolization, vessel spasm and myocardial bridging [4]. According to Kumar et al. [1] the risk factors for cardiac rupture in takotsubo patients are female gender, older age, persistent ST elevation, ST elevations in inferior leads (especially in II), higher systolic blood pressure and diastolic blood pressure, low EF and LV peak systolic pressure. The present case provides evidence of the significance of monitoring patients during the first days of the TTC syndrome. Only immediate diagnosis and urgent cardiosurgical intervention leads to a favorable prognosis in patients with TTC cardiomyopathy complicated by cardiac rupture.

Abstract 16636: Superior Vena Caval Occlusion: A Novel Approach to Improve Cardiac Function in Heart Failure

Cardiac preload is a primary target of drug therapy for heart failure. No device based approaches to limit preload in heart failure exist. The inferior (IVC) and superior vena cava (SVC) provide two-thirds and one-third of venous return, respectively. We hypothesized that mechanical occlusion of the SVC improves biventricular function in heart failure by reducing ventricular preload. Methods and Results: To test this hypothesis, 4 adult swine underwent 60 minutes of left anterior descending artery occlusion followed by 60 minutes of reperfusion. 1 animal expired due to ventricular fibrillation after reperfusion. The acute hemodynamic effects of transient sequential percutaneous balloon occlusion of the SVC or IVC (n=4) were studied using conductance catheters before the onset of left ventricular (LV) injury. Transient IVC occlusion significantly reduced biventricular volumes, reduced LV stroke volume, and reduced LV peak-systolic pressure (Figure). In contrast, transient SVC occlusion reduced biventricular volumes but increased LV stroke volume, without decreasing LV peak-systolic pressure (Figure). IVC occlusion increased renal vein pressure from 10 to 24 mmHg, whereas SVC occlusion did not alter renal vein pressure. One week after LV injury, the hemodynamics of prolonged SVC occlusion were studied (n=3). Full SVC occlusion for 2 hours reduced biventricular volumes, and increased LV stroke volume, without decreasing LV peak-systolic or systemic blood pressure. Conclusions: SVC occlusion represents a novel device based approach that targets cardiac preload. In contrast to IVC occlusion, transient and prolonged full SVC occlusion was well tolerated. SVC occlusion reduces biventricular volume, while increasing cardiac output and sustaining systemic blood pressure, without adversely affecting renal hemodynamics. Future studies will test the clinical utility of continuous and intermittent SVC occlusion in acute and chronic heart failure.

Abstract 64: Conditional Knockout of Activin Like Kinase-1 (ALK-1) Leads to Heart Failure Without Maladaptive Remodeling

Activin like kinase 1 (ALK1) mediates signaling via the TGFb family of ligands. ALK1 activity promotes endothelial proliferation and migration. Reduced ALK1 activity is associated with arteriovenous malformations. No studies have examined the effect of global ALK1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of ALK1 promote maladaptive cardiac remodeling. Methods: We employed an ALK1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase mediated excision of floxed ALK1 alleles. Tamoxifen treated wild-type (WT-Tam; n=5) and vehicle treated ALK1-cKO mice (cKO-Veh; n=5) served as controls for tamoxifen treated ALK1-cKO mice (cKO-Tam; n=15). Results: ALK1 cKO-Tam mice demonstrated reduced 14-day survival compared to cKO-Veh controls (33% vs 100%, respectively, p&lt;0.01). Seven days after treatment, ALK1 cKO mice began to exhibit reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14 days total body mass was reduced, but LV and lung mass increased in cKO-Tam not cKO-Veh mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume increased in cKO-Tam, not cKO-Veh mice. LV ALK1 mRNA and protein levels were reduced in cKO-Tam, not cKO-Veh mice. LV levels of other TGFb-family ligands and receptors (ALK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFB1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-Tam mice, but LV levels of b-MHC, SerCA, and calcineurin were unchanged. No increase in cardiac fibrosis Type I collagen, CTGF, or PAI-1 levels were observed between groups. No differences were observed for any variable studied between cKO-Veh and WT-Tam mice. Conclusion: Global deletion of ALK1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of ALK1 in cardiac remodeling are required.