End-diastolic Volume Index Research Articles

Myocardial inflammation in Fabry disease: correlations between myocardial histology, T2 mapping, and troponin

Abstract Background Myocardial inflammation likely plays a key role in cardiac Fabry disease (FD), supported by the frequent observation using cardiac MRI (CMR) of high T2 mapping values, mainly in areas of late gadolinium enhancement, LGE), typically representing oedema, and increased troponin (myocardial injury). Purpose To characterize inflammation in FD cardiomyopathy by comparing myocardial histology, T2 mapping and troponin. Methods Fifteen FD patients (67% females; 51 years old, range 39-62), undergoing 3 tests: biopsy (either RV endomyocardial biopsy, n=10, or myectomy, n=5); CMR (1.5T: cines, LGE, native T1/T2 mapping quantified in the sampling area); and troponin assessment (high sensitivity TnI). Mapping values were compared to local healthy volunteers. Left ventricle hypertrophy (LVH) was defined as either MWT ≥12mm or indexed LV mass above sex specific reference ranges. Tissue was stained using Haematoxylin-Eosin and Azan Mallory trichrome. Inflammatory cell staining used CD68 and CD3 antibodies. An abnormal inflammatory infiltrate was defined according to ESC criteria as ≥14 leukocytes/mm2 (up to 4monocytes/mm2, CD3+T-lymphocytes>7cells/mm2) and its distribution classified as focal (<30% of the specimen), multifocal (30-60%), diffuse (>60%). Results Median LV ejection fraction was 63% (58-67); indexed end diastolic volume 83ml/m2 (68-91). Seven patients had LVH. 8 patients had low native T1 and 6 had infero-lateral LGE. Median septal T2 value was 50ms (47-52) with 3 (all females) above local upper limit value (ULV). TnI was increased in 6 pts (40%; median value 54ng/L [38-128]). Histology showed mild inflammatory infiltrates in 8 pts (46%), none diffuse (focal 4, multifocal 4). Seven were mixed - T lymphocytes and macrophages, one was exclusively macrophages. Inflammatory foci were quiescent (n=5), or associated to myocytes injury not typical of ischemic damage and fibrosis (n=3). None had histologically visible myocardial oedema. Patients with inflammatory infiltrates had higher T2 values (52ms [50-54] vs 47ms [46-51]; p=0.043) but the same troponin (18ng/L [3-82] vs 14ms [3-24], p=0.215) (figure 1). The 3 patients with high T2 all had inflammatory cells associated to histologic myocyte injury (figure 2). Conclusion For the first time we correlate histology with T2 and myocardial injury in FD. In this small study, mild myocardial macrophage/lymphocyte infiltrates are common in FD and are associated to higher T2 values. Abnormal T2 septal elevation is less common (it is known common in the basal inferolateral wall however) and when present, infiltration with histological myocyte damage is found.

Epicardial adipose tissue is associated with an increased risk of mortality and hospitalizations in patients with heart failure with preserved ejection fraction

Abstract Background Accumulating evidence suggests that epicardial adipose tissue (EAT) plays a critical role in heart failure (HF). Previous studies raised the possibility of an association with mortality and hospitalizations, but data in preserved ejection fraction (HFpEF) is sparse. Purpose To investigate the association of epicardial fat measured by cardiac magnetic resonance imaging (CMR) with the combined end point of heart failure hospitalizations and cardiovascular death in patients with heart failure with preserved ejection fraction Methods In this secondary analysis of a prospective cohort study recruiting participants with HFpEF between July 2012 and March 2018 at a tertiary care centre. Patients with cardiac amyloidosis were excluded. The combined primary endpoint of this analysis consists of heart failure hospitalizations and cardiovascular mortality. The statistical analysis plan consisted of a Cox proportional hazard regression adjusted for multiple potential confounders. Adjustments were predefined and selected by their clinical relevance. EAT volume was measured using a modified Simpson rule, EAT area was measured in the four-chamber view. EAT was defined from visceral (immediately adhering the myocardium) to the parietal layer of the pericardium. Epi-pericardial tissue was excluded. We used dark blood steady-state free precision (SSFP) at end-diastole. If unavailable we used bright blood SSFP or true fast imaging with steady-state free precession. Results We studied 206 patients (69% women, mean age 71±9 years, median N-terminal prohormone of brain natriuretic peptide [NT-proBNP]: 1090 IQR 420 – 1997pg/mL). During mean follow-up of 78±35 months, 78 patients (37%) died of a cardiovascular cause. In multivariate analysis adjusting for age, gender, atrial fibrillation, left-ventricular ejection fraction (EF), right ventricular (RV) end-diastolic volume index, RVEF and NT-proBNP, EAT was significantly associated with a higher risk of the composite outcome (HR 1.07 [95% CI 1.02-1.12], P = 0.007). Additional adjustments for hepatic-, renal- and pulmonary function as well as metabolic biomarkers did not materially change the results. There was no statistically significant association with pulmonary pressures on right heart catheterization. Conclusions EAT accumulation is associated with increased risk for mortality and hospitalizations in patients with HF with preserved ejection fraction. This finding supports the rational for future interventional studies of EAT in HFpEF. Conclusions EAT accumulation is associated with increased risk for mortality and hospitalizations in patients with HF with preserved ejection fraction. This finding supports the rational for future interventional studies of EAT in HFpEF.

Determinants of NT-proBNP Levels in patients with a systemic right ventricle: a new cut-off level for risk stratification?

Abstract Introduction The role of N-terminal natriuretic peptide (NT-proBNP) in the risk prediction of patients with a systemic left ventricle is indisputable. However, its value in patients with a systemic right ventricle (sRV) is not well defined. Method Ninety-eight patients with NT-proBNP values at baseline from the randomized clinical trial SERVE were included. The correlation between baseline NT-proBNP values and parameters of bi-ventricular volumes and function quantified by cardiac magnetic resonance was assessed by means of adjusted linear regression models. The prognostic value of NT-proBNP and other established prognostic markers were assessed by means of adjusted cox proportional hazards model, survival analysis and c-statistic. The primary outcome was defined as the occurrence of either clinically relevant arrhythmia, heart failure or death. Results Median age [interquartile range, IQR] at baseline was 39 years [32,48] and 32% were female. Median NT-proBNP was 238 [137,429] ng/L. Coefficients of determination for the relationship between NT-proBNP levels and right ventricular end-systolic and end-diastolic volume index, and ejection fraction (RVEF) were +0.481, p<0.001; +0.427, p<0.001; and -0.561, p<0.001, respectively. The sex and age adjusted hazard ratio [95% confidence interval, CI] for NT-proBNP values above the 75th percentile (429ng/L) showed an exponential increase (Figure) and there was a significant difference in survival comparing the group above our cut-off value and the group below it (Table). After adjusting for age and sex, the prognostic value of NT-proBNP was comparable to the prognostic value of RVEF and predicted VO2 max (C-statistic: 0.71, 0.72 and 0.71, respectively). Conclusion NT-proBNP levels correlated significantly with right ventricular parameters assessed by means of CMR. Measurement of NT-proBNP is a reliable and convenient tool for the prediction of adverse outcomes in patients with a sRV and using the cut-off value of 429ng/L could assist in the risk stratification for this population.

Impact of ventricular interaction and ventricular afterload on biventricular diastolic dysfunction in heart failure with preserved ejection fraction

Abstract Background Pressure-volume (PV) loop analyses recently identified two different hemodynamic phenotypes in response to exercise in heart failure with preserved ejection fraction (HFpEF). In addition to a rightward shift (RS) along the end-diastolic PV relation, a cohort of HFpEF patients characterised by a straight upward shift (US) of the PV relation with markedly increased systolic and diastolic stiffness and impaired left ventricular (LV) stroke volume (SV) was identified. Whether this is an effect of RV-LV interdependence or an alternative mechanism remains elusive. Purpose To invasively study biventricular exercise physiology in patients with HFpEF to decode cardiac mechanisms underlying exercise intolerance. Methods HFpEF was diagnosed according to the 2016 ESC guidelines. Patients underwent cardiac magnetic resonance imaging prior to invasive hemodynamic characterisation including sequential biventricular PV loop analysis during preload reduction and handgrip exercise. HFpEF patients were grouped according to LV hemodynamic phenotypes into RS cohort (change in indexed end-diastolic volume, ∆EDVi >0ml/m²) and US cohort (∆EDVi ≤0 ml/m²). Results A total of 37 HFpEF patients (n=20 RS and n=17 US, median age 71 years [68, 78], 70% female) were included. Clinical presentation did not differ between cohorts regarding age (p=0.22), functional NYHA class (p=0.52) and NTproBNP (p=0.57). In PV loop analysis, diastolic stiffness (EDP/EDVi ratio) was higher in the US cohort as compared to the RS cohort in both the LV (0.31 vs. 0.23 mmHg/ml, p<0.01) and the RV (0.14 vs. 0.10 mmHg/ml, p=0.03). This difference was even more pronounced during handgrip exercise (LV: 0.45 vs. 0.29 mmHg/ml/m², p<0.01; RV: 0.18 vs. 0.12 mmHg/ml/m², p=0.02). Similarly, exertional systolic stiffness was increased in US cohort compared to the RS cohort in both the LV (V120i 21.1 vs. 30.6 ml/m², p=0.04) and RV (V40i 27.8 vs. 40.5 ml/m², p<0.01). LV and RV volumes were closely correlated at rest (EDVi r=0.77, p<0.01; end-systolic volume, ESVi r=0.54, p<0.01; SVi r=0.95 p<0.01). The US of the LV PV relations could not be explained by ventricular interaction since exercise-induced increases (∆) in RV-EDVi did not correlate with increases in LV diastolic stiffness (∆LV-EDP/EDVi, p=0.58). However, the change in LV afterload from baseline to peak exercise (∆LV-Ea) did correlate with ∆LV-EDP/EDVi (r=0.61, p<0.01). A similar correlation was also found for RV afterload and RV diastolic stiffness (r=0.50, p<0.01). Conclusion Biventricular hemodynamic profiles closely resemble one another. The pathological LV US of the PV relations in response to exercise could not be explained by ventricular interdependence but was rather related to excess of biventricular afterload. Therefore, these findings indicate HFpEF to be a biventricular disease, which should be incorporated in future considerations about pathomechansims and potential therapeutic targets.Schematic biventricular PV-Loops

Prevalence of pulmonary hypertension in reduced left ventricular systolic function and its influence on outcomes

Abstract Background/Introduction Reduced left ventricular (LV) systolic function can lead to pulmonary hypertension (PHT). However, the significance of PHT complicating reduced LV systolic function remains poorly characterised. Purpose We aimed to describe the prevalence and prognostic importance of PHT in a large cohort of adults with at reduced left ventricular ejection fraction (LVEF). Methods We analysed the National Echocardiography Database of Australia (data from 2000-2019). Adults with a recorded tricuspid regurgitation (TR) peak velocity and LVEF <50% were included. Patients with moderate or greater left sided valvular pathology were excluded, as were patients with prior aortic or mitral valve replacements. These subjects (n= 23675) were then categorised according to their TR peak velocity. The relationship between PHT severity and mortality outcomes were evaluated (median follow-up of 2.9 years, interquartile range 1.0-5.4years). Results Subjects were aged 70±15years and 31.7% were female. Overall, 8801 (37.2%), 7061 (29.8%), 5676 (24.0%), and 2137 (9.0%) patients had normal (TR peak velocity <2.5m/sec), borderline (2.5-2.8m/sec), intermediate (2.9-3.4m/sec), or high risk PHT (>3.4m/sec), respectively. An echocardiographic phenotype for ‘left heart disease’ was evident with worsening PHT, showing rising E:e’ ratio and a greater proportion of right ventricular (RV) dilation and dysfunction (p<0.0001 for all). Left and right atrial sizes increased from low-intermediate risk, before plateauing at high risk PHT (p<0.0001). With increasing risk of PHT, 1- and 5-year actuarial mortality increased from 13.3% and 43.8%, to 41.5% and 81.4% respectively (p<0.0001). After adjustment for age, sex, LVEF, LV end diastolic diameter and LA volume index, the risk of mortality increased as TR peak velocity increased (adjusted hazard ratio (aHR) 1.31, 95% confidence interval 1.23-1.38 in borderline risk, to aHR2.38, 95%CI 2.21-2.56 in high risk PHT) (Figure 1). The cohort was also assessed in two groups based on LVEF severity according to guidelines. The sub-group of patients with mildly reduced LVEF (40-49%, n = 12495) showed that mortality risk increased as risk of PHT increased; (aHR 1.38, 95%CI 1.27-1.50 in borderline risk, to aHR2.82, 95%CI 2.52-3.15 in high risk PHT). Similarly, those with reduced LVEF (<40%, n = 11180) mirrored these trends (aHR 1.23, 95%CI 1.14-1.33 in borderline risk, to aHR2.07, 95%CI 1.88-2.28 in high risk PHT). There was a mortality threshold seen from TR peak velocity 2.41m/sec onwards (aHR1.18, 95%CI 1.04-1.33) (Figure 2). Conclusion(s) In this large cohort study, we demonstrate that PHT risk is common in patients with reduced LV systolic function and mortality increases as PHT becomes more severe. A threshold for higher mortality lies within the range of "borderline-intermediate" risk PHT.Adjusted Risk for All-Cause MortalityThreshold for Mortality

Cardiosphere derived cell secretome therapy after experimental myocardial infarction: effects of intracoronary administration on ventricular tachycardia inducibility and cardiac function

Abstract Background Myocardial infarction (MI) carries high risk of sudden cardiac death due to the development of ventricular tachycardia (VT) which is caused by viable myocytes located within the infarct scar tissue [1]. Cardiosphere derived cell secretome (S-CDCs) has been demonstrated to possess antiarrhythmic properties when delivered transendocardially [2]. Further, S-CDCs has been proven to reduce scar size and increase viable myocardial mass in chronic MI [3]. Purpose The objective of this study was to evaluate the effects of an intracoronary (IC) administration of S-CDCs on VT inducibility and cardiac function in a porcine MI model. Methods After obtaining the approval of the Institutional Animal Care and Use Committee, 14 Large White swine were subjected to closed chest MI induction carrying out balloon occlusion of the left anterior descending coronary artery (below the second diagonal branch) for 150 minutes. One month after MI creation, pigs received an IC administration of saline (CON; 5mL; n=7) or S-CDCs (S-CDCs; 9.16 mg of protein in 5mL of saline; n=7). VT inducibility and magnetic resonance (MR) studies were performed pre- and four months post-injection determining ejection fraction (EF), infarct size (IS) and indexed end diastolic and systolic volumes (EDVi, ESVi). Results Before injection VT was inducible in all cases and no differences were observed between groups in any MR-derived parameter (figure). IC infusion was successful in all swine. At four months VT inducibility study revealed lower inducibility rates in S-CDCs compared to CON (57% versus 100%; p=0.05). At this timepoint EF was higher in S-CDCs (35±10% versus 29±10%) although differences between groups were not statistically significant. Conversely, IS was significantly lower in S-CDCs (12±3% versus 16±2% (p=0.03)). Moreover, a trend towards lower ventricular volumes (EDVi: 83±18mL/m² versus 88±29mL/m² and ESVi: 56±20mL/m² versus 64±27mL/m²) was detected in this group. Conclusions The IC administration of S-CDCs suggests a potential reduction on post-MI VT development as well as a beneficial effect on cardiac function. This therapy seems to reduce IS in this porcine MI model.MR derived parameters

Echocardiographic characterization of patients with supranormal ejection fraction: pooled core laboratory analysis of the TOPCAT and PARAGON-HF trials

Abstract Background Patients with heart failure and supranormal ejection fraction (HFsnEF) may be phenotypically distinct from those with normal or below normal left ventricular ejection fraction (LVEF), and may demonstrate different prognostic trajectories or treatment responses. Purpose To characterize clinical features, cardiac structure and function among patients with HF with preserved EF (defined as 45% ≤ LVEF ≤ 65%) and supranormal EF (defined as LVEF>65%). Methods Baseline clinical characteristics and key echocardiographic parameters from patients enrolled in the echocardiographic substudies of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist)-Americas and PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARB [angiotensin-receptor blocker] Global Outcomes in Heart Failure with Preserved Ejection Fraction) were compared between patients with and without HFsnEF. Results Among 1,751 participants (mean age 73 years old, 51% women) in this pooled core laboratory analysis, 265 (15%) had HFsnEF. Participants in HFsnEF group were more likely to be women, and less likely to have prior myocardial infarction and atrial fibrillation (Table 1). Compared with those with LVEF ≤ 65%, those with LVEF > 65% had lower LV end-diastolic and end-systolic volume indices, lower LV mass index, higher LV relative wall thickness, and higher right ventricular fractional area change. LV geometry and measures of LV diastolic function were similar in both groups (Table 1). Global longitudinal strain (GLS) was abnormal (absolute GLS <16%) in 28% in those with HFsnEF compared with 53% in those with LVEF ≤ 65%. After adjusting for baseline LV ejection fraction and sex, and stratified by trial, abnormal GLS was associated with a higher risk of composite of first heart failure hospitalization or cardiovascular death (overall hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.23 – 1.98, P < 0.001), cardiovascular death (overall HR 2.06, 95% CI 1.35 – 3.13, P = 0.001), and heart failure hospitalization (overall HR 1.49, 95% CI 1.15 – 1.93, P = 0.003) in both HFsnEF and non-HFsnEF groups (P-interaction > 0.05 for all, Figure 1). Conclusions Among participants in the TOPCAT-Americas and PARAGON-HF trials, those with LVEF > 65% were predominantly women, had less LV remodeling, and had better RV function based on echocardiographic measures. Nevertheless, despite supranormal LVEF, GLS was abnormal in over a quarter of patients and remained an important predictor of adverse clinical outcomes in this cohort.Table 1Figure 1

Left atrial haemodynamic evaluation using 4D flow cardiac magnetic resonance imaging: application to hypertension and hypertrophic cardiomyopathy

Abstract Introduction Changes in left atrial (LA) hemodynamics have been suggested reflective of left ventricular (LV) disease progression. Kinetic energy (KE), viscous energy loss, and vorticity could be promising indices for the assessment of left atrial dynamics by time resolved four-dimensional cardiac magnetic resonance (4D flow CMR). Hypertrophic cardiomyopathy (HCM) patients are at risk of developing mitral regurgitation and left ventricular outflow tract obstruction, with poor outcome (1). Hypertensive myocardial remodelling has been suggested to be due to complex flow and tissue interactions leading to hypertrophy and diastolic dysfunction (2). Early detection of altered LA hemodynamic abnormalities may help non-invasive assessment, improving their long-term outcome (3). Purpose Quantitative and qualitative evaluation of left atrial hemodynamic metrics by 4D flow CMR in a cohort of HCM patients, hypertensive patients, and healthy controls with no known cardiovascular disease. Methods Eighteen HCM patients (50.0 [±18.2] years, 8 females), twenty-one hypertensive patients (55.2 [±6.2] years, 11 females), and seventeen controls (36.7 [±12.8] years, 1 female) underwent 4D flow CMR. Both patient groups had significantly higher LV-indexed mass, end-diastolic volume, and end-systolic volumes (P < 0.05). A semi-automated pipeline was used to segment the LA including pulmonary inflow and mitral outflow tracts using phase contrast magnetic resonance images derived from the 4D flow acquisition's phase and magnitude images. LA KE, viscous energy loss and vorticity were computed throughout the cardiac cycle. Results The HCM and hypertensive groups demonstrated significantly higher average KE integrated across the cardiac cycle (1.58 ± 0.79 and 1.32 ± 0.50 mJ respectively) compared to controls (1.20 ± 0.47 mJ) (P < 0.05), with the systolic curve in HCM showing the highest peak KE. Qualitatively, KE in the diastolic portion of the cardiac cycle appeared less variable between groups (Figure 1). Vorticity in HCM showed different configurations with loss of the central atrial vortex core (Figure 2). Viscous energy loss was also significantly higher in HCM patients confirming the increase in energy loss (Figure 2). Average KE across the cardiac cycle highly correlated with LA volume and pulmonary capillary wedge pressure calculated by a previously published regression method (4) (Pearson correlation: r= 0.76 and 0.71 respectively P < 0.05). There were also significant correlations with cardiac metrics such as indexed end-diastolic and indexed end-systolic volumes (Pearson correlation: r= 0.54 and 0.52 respectively P < 0.05) as well as indexed LV mass (r= 0.59 P < 0.05). Conclusion Hemodynamic metrics derived from 4D flow CMR may be valuable in establishing valuable predictive metrics of ventricular function. Integration of 4D flow MRI in clinical workflows could provide information that may be indicative of pathological onset before abnormal remodelling.Kinetic energy and viscous energy lossParticle pathlines and vorticity

Outcome of transcatheter mitral valve repair in heart failure patients with reduced ejection fraction and severe left ventricular dilatation

Abstract Introduction The COAPT trial demonstrated the benefit of transcatheter edge­to­edge mitral valve repair (TEER) for heart failure patients who had reduced ejection fraction (HFrEF) with symptomatic secondary mitral regurgitation (MR). However, patients with severe left ventricular (LV) dilatation were not included in the COAPT trial. Furthermore, disproportionate LV dilatation was suggested as a possible explanation for the lack of benefit in the MITRA­FR trial. Purpose The purpose of this study was to assess the safety and efficacy of TEER in HFrEF patients with severe LV dilatation. Methods We studied 75 HFrEF patients who underwent mitral valve repair between 2018-2021. Reduced LV ejection fraction (LVEF) was defined as LVEF of 40% or less. These patients were categorized with and without severe LV dilatation based on left ventricular end-diastolic volume index (LVEDVI) using a median cut­off value of >139ml/m2 in men and >128cm/m2 in women. Results There were 37 patients with severe LV dilatation (D) and 38 without (ND). Median LVEDVI was 172 [149-190] ml/m2 in the D group vs 120 [105-127] ml/m2 in the ND group. Compared to the ND patients, patients with severe LV dilatation were more treated with SGLT2-inhibitor (rate 24% vs 3%), had lower LVEF (30 [25-31] % vs 32 [30-36] %), and higher BNP (1160 [683-2586] vs 619 [396-1253] pg/ml). There was no significant difference in MR grade (4 [3-4] vs 4 [3-4]), EROA (0.32 [0.22-0.66] vs 0.34 [0.24-0.48] cm2), NYHA class (3 [2-4] vs 3 [2-3]) and mean systolic pulmonary pressure (31 [20-43] vs 34 [25-41] mmHg). Peri­procedural adverse events were rare in both groups. 1 patient had pseudoaneurysm in the ND group, and 1 patient had cardiogenic shock and 1 patient had stroke after the procedure in the D group. At discharge, there was marked improvement in MR grade (1 [1-2] vs 1 [1-2] for both). D group had a tendency of higher reduction in LVEDVI (-12 [-24--1] vs -5[-13-4] ml/m2) than ND group. BNP level of the D group had a significantly higher degree of decline before discharge (-458 [-141--1566] to -102 [+51--306] pg/ml) than that of ND group. No differences were noted in mortality between two groups (Figure). Conclusion TEER in HFrEF patients with severe LV dilatation seems to provide similar outcomes compared to patients with less severe dilatation. Further studies are needed to clarify the indication and establish the effectiveness of TEER in these patients.

Moderate functional mitral regurgitation: difference between atrial and ventricular mechanism of the regurgitation

Abstract Background/Introduction In severe functional mitral regurgitation (MR), further distinction of the mechanism of MR in atrial functional MR (aFMR) and ventricular functional MR (vFMR) has shown prognostic importance. However, no data are available on moderate functional MR, whose characteristics and prognosis are largely unknown. Purpose To assess clinical and echocardiographic characteristics of patients with moderate aFMR and vFMR and their potential difference in outcome. Methods Patients with moderate functional MR were retrospectively included. aFMR was defined as isolated mitral annulus dilatation in combination with preserved left ventricular ejection fraction (LVEF≥50%) without ischemic heart disease or LV dilatation. Patients were classified as vFMR when LVEF was reduced, LV was dilated and/or wall motion abnormalities were present. Mitral valve intervention and all-cause mortality were used as combined endpoint. Results In total 474 patients with moderate functional MR (mean age 67 ±12, 57% male) were evaluated, of which 136 (29%) had aFMR and 338 (71%) had vFMR as underlying mechanism. Among the clinical variables, patients with aFMR had more atrial fibrillation (77% vs. 35%; p<0.001), were less symptomatic (NYHA class ≥ III: 6% vs. 18%; p<0.001) and had better renal function (eGFR 73 ±23 ml/min/1,73m2 vs. 65 ±23 ml/min/1,73m2; p=0.005) as compared to vFMR. In the vFMR group, 49% of patients had ischemic heart disease. Among the echocardiographic variables, as expected in aFMR, LVEF was higher (42 ±14% vs. 55 ±13%; p<0.001), while LV volumes (LV end-diastolic volume index 55 ±13 mL/m2 vs. 82 ±38 mL/m2; p<0.001) and E/E’ ratio were smaller (10 ±4 vs. 15 ±4; p<0.001) as compared to vFMR. However left atrial (LA) volume index was similar between both groups (43 ±14 mL/m2 vs. 41 ±18 mL/m2; p=0.271). For the echocardiographic measures of the right heart, significant difference was observed only for TAPSE which was higher for the aFMR group (22 ±4mm vs. 20 ±5mm; p<0.001). During a median follow-up of 74 months [IQR: 46.8-107.0], 132 (30%) patients died and 30 (6%) underwent mitral valve intervention. Event-free survival analysis for the combined endpoint was significantly better for aFMR patients (Figure 1). Based on significant variables from the univariable Cox regression analysis, multivariable Cox regression analysis showed that the mechanism of functional MR (with aFMR being protective as compared to vFMR), age, male gender, impaired renal function, NYHA class, severe LA dilatation and TAPSE were independently associated with the combined endpoint (Table 1). Conclusion In patients with moderate functional MR, aFMR is independently associated with better event-free survival as compared to vFMR. Therefore, clear identification of the mechanism of MR implies a better risk stratification and may be helpful for the management of patients with moderate MR.

Anthracycline therapy induces an early decline of cardiac contractility with transient edema in low risk patients with breast cancer

Abstract Background Cancer therapy-related cardiac dysfunction (CTRCD) is a dreaded complication of anthracycline therapy in the treatment of breast cancer. CTRCD most frequently appears in patients with cardiovascular risk factors or known cardiovascular disease. There is limited evidence of incidence and prospective course of anthracycline-induced CTRCD in young patients without common risk factors for CTRCD. Purpose To longitudinally investigate a cohort of young women on anthracycline treatment due to breast cancer without cardiovascular risk factors or known cardiovascular disease. Methods 59 women with first-diagnosed breast cancer and planned anthracycline regime-based therapy were enrolled. Exclusion criteria were cardiovascular risk factors or known cardiovascular disease. We conducted a longitudinal assessment before, immediately after- and 12 months after cancer therapy with general laboratory, electrocardiograms, echocardiography and cardiovascular magnetic resonance (CMR), including myocardial relaxometry with T1, T2 and extracellular volume mapping. Results Every single patient experienced a drop in CMR-measured left ventricular ejection fraction (LVEF) of 6 ± 3 % immediately after cancer therapy. According to the novel definition 32 patients (54.2%) developed CTRCD after 12 months defined by reduction in LVEF, global longitudinal strain (GLS) and/or biomarkers elevation (Figure 1). LVEF reduction was accompanied by a decrease in stroke volume and cardiac power index while enddiastolic volume index remained stable. Global myocardial T2 relaxation times as well as myocardial mass increased coincidently with a decline in wall-thickening. While T2 values and myocardial mass normalized after 12 months, LVEF and GLS remained impaired. Conclusion Among breast cancer patients without pre-existing risk factors for CTRCD anthracyclines induce a decline of myocardial contractility in every single patient, which may lead to an increased risk of future cardiovascular diseases in these patients. Figure 1: Patients with diagnosed CTRCD directly after CT and after 12 months follow up stratified by underlying CTRCD criteria. Boldness of arrows proportionally represents the number of patients changing between the criteria. Some patients fulfilled more than one criterium for CTRCD.Graphical Abstract Figure 1

Cardiac magnetic resonance for prophylactic implantable-cardioVerter defibrillator therapy international registry in patients with ischemic cardiomyopathy

Abstract Background Sudden cardiac death (SCD) in patients with ischemic cardiomyopathy (ICM) remains a leading cause of death. Current guidelines provide a class I recommendation for implantable cardioverter–defibrillator (ICD) implantation in ICM patients with transthoracic echocardiographic (TTE) left ventricular ejection fraction (LVEF) ≤35%. and NYHA functional class II or III. The current paradigm is suboptimal in identifying patients who are likely to benefit. In fact, only a relatively small proportion of ICD recipients for SCD primary prevention receive appropriate device therapy and instead there is a not negligible percentage of patients who experienced SCD event despite not fulfilling criteria for implantation. Purpose The DERIVATE-ICM registry sought to evaluate the additional prognostic value for the indication of ICD implantation using cardiac magnetic resonance (CMR) as compared to standard of care based on TTE in a large cohort of ICM patients. Methods We enrolled 861 ICM patients (86% male, mean age 65±11 years) with chronic heart failure and TTE-LVEF<50%. Major adverse arrhythmic cardiac events (MAACE), defined as the combination of SCD, aborted SCD event, and sustained ventricular tachycardia. were the primary endpoint. Independent predictors were used to calculate a CMR risk score for each patient. Risk levels were defined as low (quantile 1 [Q1]), medium (Q2 and Q3) and high (Q4). Results During a median follow-up of 1054 days, MAACE occurred in 88 (10.2%). Left ventricular end-diastolic volume index (HR:1.007, 95%CI:1.000-1.011, p=0.05), CMR-LVEF (HR:0.972, 95%CI: 0.945-0.999, p=0.045) and late gadolinium enhancement (LGE) mass (HR:1.010, 95%CI: 1.002–1.018, p=0.015) were independent predictors of MAACE. Based on the multivariate analysis, CMR weighted risk score was developed according to the following equation [0.005 * EDV/BSA (mL/m2) – 0.029 * LVEF (%) + 0.010 * LGE ischemic mass (g)]. A multiparametric CMR weighted predictive derived score effectively identifies subjects at high risk for MAACE as compared to TTE-LVEF cut-off of 35% with a Continuous NRI: 31.7% (95%CI: 8.6%-54.8%, p=0.007) (Figure 1, Figure 2). Conclusions In this large multicenter registry, a multi-parametric CMR predictive model provides additional prognostic stratification for MAACE predictions in a large cohort of ICM patients as compared to standard of care. This model identifies a large number of patients with TTE-LVEF<35% at low risk of SCD event and on the other side it identifies a subset of patients who are at high risk of MAACE despite TTE-LVEF≥35% (i.e. the population currently not fulfilling the guideline-based criteria for ICD implantation). Further randomized trials to test a CMR guided strategy for ICD implantation versus standard of care are now needed.Kaplan-Meier curvesEvent rate redistribution

Abstract 17097: Carotid Artery Atherosclerosis and Mid-Life Cognitive Function: Evidence From Bogalusa Heart Study

Background: Little is known about the relationship between carotid plaque formation and cognitive function in a middle-aged population. Hypothesis: We hypothesize that there will be an association between carotid atherosclerotic burden and cognitive function in middle-aged adults. Aim: The purpose of the present study is to examine the relationship between carotid artery (CA) plaque and cognitive function in middle-aged white and black men and women from the Bogalusa Heart Study (BHS) cohort. Methods: We included a total of 1,107 BHS participants with echocardiography and carotid ultrasound performed between 2013 and 2016. Cognitive function was quantified in a global cognitive score (GCS) comprised of the z standardized sum of 7 neuropsychiatric tests. CA plaque was defined by carotid intima media thickness ≥1.5mm in any segment of the CA including right and left common artery (RCC/LCC), bulbs (RCB/LCB) as well as right and left internal carotid artery (RIC/LIC). We compared demographic, clinical, and echocardiographic characteristics in participants with or without CA plaque and used linear regression analysis for the association between CA and GCS adjusted for age, sex, race and education. Results: Among all, 373 (33.7%) of participants had one or more CA plaque. The most common locations of CA plaque formation differed according to laterality, with 230 (61.7%), 189 (50.7%), 108 (29.0%), 92 (24.7%), 83 (22.3%), 10 (2.7%) participants having plaque in the RCB, LCB, LCA, RIC, LIC, and RCA, respectively. Participants with CA plaque were likely to be older (49.9 vs. 47.2 years), male (52 vs.38.9%), white (70.2 vs.63.4%,), have larger left ventricular (LV) end-diastolic volume (97.4 vs.94 ml) and LV mass index (83.4 vs.76.3 g/m 2 , all p -value<0.01), but similar LV ejection fraction (60.1 vs.60.0%) as compared to those without CA plaque. Moreover, CA is associated with poorer cognitive function (GCS, standardized β coefficient=-0.07; p =0.02) adjusted for age, sex, and race. However, the association was attenuated after adjusting for education. Conclusion: CA plaque was highly prevalent and inversely associated with cognitive function. The association was attenuated by education emphasizing the importance of social determinants in cognitive health.

Abstract 12818: Clinical Significance of Myocardial Perfusion in Dilated Cardiomyopathy and Hypokinetic Non-Dilated Cardiomyopathy

Introduction: Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) systolic dysfunction with LV dilatation. Hypokinetic non-dilated cardiomyopathy (HNDC) characterized by LV dysfunction without LV dilatation is proposed as a new category of DCM. Microvascular dysfunction in DCM is associated with the degree of LV dysfunction. However, the association between myocardial perfusion and clinical spectrum of DCM has not been elucidated. Hypothesis: We assessed the hypothesis that myocardial perfusion is correlated with the clinical spectrum of DCM. Methods: Thirty-six subjects (20 non-ischemic cardiomyopathy (NICM) patients and 16 control subjects, mean age: 59 ± 2 years) underwent CMR at 3T. Cine imaging, adenosine stress perfusion, T1 mapping, and late gadolinium enhancement were performed. NICM group was divided into DCM (n=10) and HNDC (n=10). Native T1 and extracellular volume fraction (ECV) were measured as an averaged values in the septum of 3 short-axis slices of base-to-apex LV myocardium. Myocardial perfusion reserve (MPR) was calculated as the ratio of stress/rest myocardial blood flow. Results: LV ejection fraction was significantly lower in NICM compared to control (29.2±1.6% vs. 56.6±1.5%, p<0.001). Native T1 and ECV were significantly higher in NICM compared to control (native T1: 1296±12ms vs. 1228±8ms, p<0.001, ECV: 32.9±1.7% vs. 27.3±0.62%, p<0.001), but they showed no significant differences between DCM and HNDC. MPR in HNDC was significantly higher than that in DCM (2.0±0.51 vs. 1.5±0.27, p=0.026), and comparable to that in control (1.9±0.11, p=0.717, Fig 1). MPR was negatively correlated with LV end diastolic volume index (r=-0.333, p=0.047, Fig 2), but MPR showed no significant correlations with native T1 and ECV. Conclusions: HNDC showed preserved MPR in contrast to impaired MPR in DCM. Myocardial perfusion may be a promising factor for the clinical spectrum of DCM.

Abstract 13478: Causes of Long-Term Mortality in Patients With Microvascular Obstruction Following ST-Segment Elevation Myocardial Infarction

Introduction: The presence of microvascular obstruction (MVO) following ST-segment elevation myocardial infarction (STEMI) portends a poor prognosis and is associated with adverse left-ventricular (LV) remodeling and an increase in mortality in the subsequent year of follow-up. However, the long-term effects of MVO on mortality have not been previously described. Methods: We analyzed the long-term follow-up and cardiac MRIs of 475 patients (Average age = 60 years, 76% male) for the presence (n=337) or absence (n=138) of MVO at a single institution following STEMI and successful reperfusion with primary percutaneous intervention (PCI). Causes of death were determined from the patient's electronic medical record or death certificate. Results: The infarct-related artery was more likely to be the LAD in patients with MVO and the RCA in patients without MVO. Patients with MVO had greater ischemic times (159 vs. 141 mins; p = 0.012) and were more likely to have TIMI 0 flow on presentation (71 vs 54%; p <0.002). Patients with MVO had greater infarct size by cardiac enzymes resulting in greater LV end-diastolic volume index (LVEDVI) (80 vs.75 ml/m2), LV end-systolic volume index (LVESVI) (39 vs 30 ml/m2) and LV mass (146 vs 134 g) and reduced LVEF (48 vs 58 %; all p < 0.01) by cardiac MRI performed 1-3 days following STEMI and PCI . During long-term follow-up a total of 56 patients with MVO died compared to 18 patients without MVO. Patients with MVO died sooner after STEMI (5.9 vs 7.8 years) and were more likely to die from cardiovascular causes such as progressive heart failure or sudden cardiac death (Table). LVEF before death was lower in the MVO group (46 vs 52%). Conclusions: There is significant long-term mortality associated with MVO following STEMI with the majority of patients dying from cardiovascular causes. In contrast, patients with STEMI without MVO rarely died from a cardiac etiology but from cancer and natural causes.

Abstract 13830: Pheochromocytoma in a Patient With Tetralogy of Fallot and Chromosome 17p12 Duplication

Description of Case: A 22-year-old male with Tetralogy of Fallot (TOF) status post transannular patch repair, hypothyroidism, and known partial duplication of chromosome 17p12 concerning for Charcot-Marie-Tooth disease (CMT), presented to his cardiologist with exertional angina and dyspnea, difficulty gaining weight, and diaphoresis. Cardiac MRI demonstrated moderate to severe pulmonic regurgitation with regurgitation fraction of 35% and RV end-diastolic volume index of 150 cc/m 2 . He was referred for pulmonic valve replacement surgery. While awaiting surgical evaluation, he presented to an ER with new hypertension with blood pressure to 240/140 and tachycardia to 107. A CT scan demonstrated a 4.3 x 5.0 x 4.4 cm mass in the right adrenal gland. On admission he was started on phenoxybenzamine and carvedilol. Workup revealed elevated catecholamines and metanephrines ( Table ). He underwent surgical adrenalectomy without complications. Immunohistochemical staining was consistent with pheochromocytoma. Post-procedurally, he was normotensive off medications. He was seen in clinic three weeks after surgery with significant improvement in symptoms. Discussion: We report on a novel genetic association of chromosome 17p12 duplication and pheochromocytoma. The region transcribes peripheral myelin protein-22, which has associations with CMT. Overlap has been demonstrated in other CMT-associated mutations and pheochromocytoma syndromes (e.g. kinesin family member 1B). In congenital heart disease, risk for pheochromocytoma is felt to be driven by hypoxia causing catecholamine secretion, adrenal hyperplasia, and eventual neoplasia. Further study is needed to characterize genetic associations between pheochromocytoma, neuropathy, and congenital heart disease. This patient’s presentation is a lesson in maintaining a high index of suspicion for pheochromocytoma in congenital heart disease, especially with associated genetic syndromes.

Abstract 14625: Association of Eicosanoid Metabolites With Cardiac Structure and Function

Introduction: Eicosanoids are bioactive lipids that govern the upstream initiation of pro- and anti-inflammatory activity. They may serve as important pathways by which obesity and cardiometabolic disease lead to the development of heart failure with preserved ejection fraction (HFpEF). Objective: We sought to examine the association of plasma circulating eicosanoid metabolites with subclinical cardiac remodeling as ascertained by cardiac magnetic resonance imaging (CMR) as important determinants of HFpEF risk. Methods: We studied 3880 MESA study participants (mean age 63±10 years, 53% women) who underwent plasma metabolite profiling using a mass spectrometry-based platform and CMR. We used multivariable linear regression to examine the association of eicosanoid metabolites with left ventricular mass index (LVMI, primary outcome), LV end-diastolic volume index (LVEDV), and left atrial volume (LAV). Results: Of 811 eicosanoids, 158 were associated with LVMI (Figure; FDR q <0.05 for all). Specifically, derivatives of eicosadienoic acid (15 oxoEDE), linoleic acid (9,10 diHOME), and arachidonic acid (12(R) HETE) were negatively associated with LVMI and prostaglandin 19R-hydroxy-PGE1 was positively associated with LVMI. Of 158 metabolites, 65 were are also associated with LVEDV including derivatives of linoleic acid (13(S) HOTrE), oxylipin 11-HETE and 15 oxoEDE. Of 158 metabolites, Adrenic acid is also associated with LAV. Conclusions: We found that specific eicosanoids including 15 oxoEDE, 9,10 diHOME, and 12(R) HETE were associated with LVMI, an important measure of subclinical cardiac remodeling and precursor to HFpEF. As causal drivers of HFpEF are poorly characterized, a better understanding of pro- and anti-inflammatory eicosanoid pathways that contribute to cardiac remodeling may have important implications for the prevention of HFpEF.

Abstract 13403: Age-Related Echocardiographic Characteristics in Patients With Heart Failure With Preserved Ejection Fraction in PARAGON-HF

Introduction: Heart failure with preserved ejection fraction (HFpEF) may have different characteristics by age groups. Aim Compare clinical and echocardiographic characteristics in patients with HFpEF enrolled in the PARAGON-HF echocardiography substudy by age groups. Methods: Echocardiography was performed in 1097 patients in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), where patients with left ventricular ejection fraction (LVEF) >=45% were enrolled. Clinical and echocardiographic characteristics were compared in patients who were <65, 65-74, and >75 years of age. Results: Younger patients were more likely to be male, obese, have prior myocardial infarction (MI) and diabetes, but less likely to have atrial fibrillation (AF, Table 1). Older patients had smaller left ventricular (LV) dimension indices, more likely to have concentric hypertrophy or remodeling, higher LVEF and better global longitudinal strain, and more likely to have left atrial enlargement and echocardiographic evidence of higher LV filling pressure (Table 1). Echocardiographic measures of pulmonary pressure and right ventricular function were similar across age groups. After adjusting for sex, race, region, history of MI, diabetes, AF, and body mass index, every 10 years of increase in age was associated with 5.1 mL/m 2 decrease in LV end-diastolic volume index (95% confidence interval [CI] 3.9 - 6.5, p < 0.001), 0.4% increase in absolute global longitudinal strain (95% CI 0.1% - 0.7%, p = 0.017), and 1.07 increase in E/e’ septal ratio (95% CI 0.42 - 1.73, p = 0.001). Conclusions: Compared with younger patients, older patients with HFpEF were more likely to be female with AF, have better systolic function and higher LV filling pressure. These findings demonstrated the heterogeneity in cardiac structure and function in HFpEF by age and may have implications for treatment and future clinical trial recruitment.

Abstract 12798: Cardiovascular Function and Prognostic Relevance of Cardiac Cachexia in Patients With Cancer; a Systematic Review and Meta Analysis

Introduction: Cardiac cachexia (CC), a severe muscle-wasting condition prevalent in advanced cancers, poses significant implications for heart health. Hypothesis: To evaluate the specific alterations in clinical and imaging parameters and assess their prognostic value. Methods: A systematic search was conducted on PubMed, Cochrane, and Embase, covering articles available until June 1, 2023. The outcomes were pooled using a random-effects model, and mean differences (MD) with 95% confidence intervals (CI). Results: Our analysis included a total of 873 patients (670 cancer patients and 203 controls) from five studies. Cancer patients exhibited a significant reduction in LV Ejection Fraction [MD, 2.61 (95% CI: 0.29 to 4.93), I2=82.05%, p=0.03], LV Mass [MD, 26.59 (95% CI: 13.57 to 39.61), I2=0.00%, p<0.001], Left Ventricular Mass Index for height [MD, 8.028 (95%CI: 4.257-11.800), I2=0.00%, p<0.001] and LV Mass Index for Body Surface Area [MD, 9.684 (95%CI: 4.233-15.135), I2=0.00%, p=0.0005] for cancer patients. However, no statistically significant differences were found in Right Ventricular Wall Thickness [MD, -0.065 (95%CI: -0.246 to 0.115), I2=9.88%, p=0.4770], LV Wall Thickness [MD, 0.511 (95% CI: -1.027 to 2.049), I2=78.48%, p=0.5150], Intraventricular Septal thickness [MD, 0.420 (95% CI: -0.804 to 1.644), I2=76.71%, p=0.50], and LV End-Diastolic Volume Index [MD, -0.186 (95% CI: -7.222 to 6.849), I2=74.09%, p=0.9586]. Qualitative analysis: CC causes remodeling and hence, alters cardiac parameters. It is associated with chemo- and radiotherapy, and tumor progression. Furthermore, it is also linked to increased all-cause mortality. Conclusions: The presence of CC is associated with notable changes in various parameters, detectable through routine imaging techniques. Screening for these alterations may hold clinical importance in guiding the selection of appropriate cancer regimens for affected patients.

Abstract 12559: Functional Autoantibodies Against Angiotensin II Receptor Type 1 and Endothelin-1 Receptor Type A Predict Adverse Remodeling and Cardiovascular Events After Acute Myocardial Infarction

Introduction: Myocardial infarction is a leading cause of death worldwide. Although advances have been made in acute treatment, an incomplete understanding of left ventricular (LV) remodeling (LVR) processes has limited the effectiveness of therapies to reduce late-stage mortality. Hypothesis: We hypothesized that autoantibodies (AAs) activating angiotensin II receptor type 1 (AT1R-AAs) and endothelin-1 receptor type A (ETAR-AAs) are associated with LVR after ST-elevation myocardial infarction (STEMI) and with recurrent major adverse cardiac events (MACE). Methods: We studied 131 STEMI patients (age 61±11 years, 112 males) treated with primary percutaneous coronary intervention between February 2021 and January 2022 at Padua University Medical Center. Within 48 hours of admission standard 2D echocardiography was performed and blood samples were obtained for AAs level measurement. Echocardiography was performed at 6 months repeatedly in all patients. The endpoint was LVR, defined as an increase of 20% or more of LV end-diastolic volume index. Results: Overall, 41 (32%) patients experienced LVR. The titer for the autoantibodies was significantly higher in patients with LVR (p=0.009 for AT1R-AAs; p=0.01 for ETAR-AAs). The prevalence of AT1R-AAs and ETAR-AAs seropositivity was higher in patients with LVR (39% vs. 11%, p<0.001 and 37% vs. 12%, p=0.001, respectively). At multivariable analysis, AT1R-AAs seropositivity was the strongest predictor of LVR (OR=4.25, p=0.002). Similarly, AT1R-AAs seropositivity was a strong predictor of recurrent MACE, both before (OR, 4.09; p = 0.006) and after (OR 19.6; p=0.002) adjusting for the confounding factors. Conclusions: Our results support the hypothesis that AT1R-AAs and ETAR-AAs concentration are a risk factor for LVR in STEMI patients. AT1R-AAs is also a predictor of recurrent MACE. These initial observations may set the stage for a better pathophysiological understanding of the mechanisms contributing to LVR.