Pellikka, Patricia A.

Background First-phase ejection fraction (EF1), the left ventricular (LV) ejection fraction (EF) until the time of peak transaortic velocity, is a novel marker of subclinical LV dysfunction able to predict adverse events in aortic stenosis (AS). This study investigated the association between end-systolic wall stress (ESWS) and EF1 in severe AS, as well as the prognostic value of EF1 in severe asymptomatic AS. Methods Two prospectively gathered cohorts of 94 asymptomatic patients and 108 symptomatic patients scheduled for aortic valve replacement (AVR), all with severe AS (aortic valve area <1 cm2) were stratified according to the median value of EF1 (33%). EF1 was defined as the EF at peak transaortic velocity. Asymptomatic patients were followed up for 3 years for the combined end-point of death, AVR or admission with heart failure. Results EF1 correlated with EF and was inversely associated with ESWS. In multivariate regression analysis, ESWS (p<0.001) and replacement fibrosis measured by MRI (p=0.02) were associated with EF1. Among asymptomatic patients, EF1 above the median was associated with the combined primary endpoint (HR=0.53 (95% CI 0.33 to 0.87)), while global longitudinal strain and EF were not. Among 42 patients with discordant AS (mean gradient <40 mm Hg), EF1 above median was associated with the primary endpoint (HR 0.28 (95% CI 0.12 to 0.61)). Conclusion EF1 is an afterload-dependent measure that is associated with events in patients with asymptomatic severe AS. The afterload dependency of EF1 may be useful in timing of risk stratification in patients with discordant AS. Trial registration numbers NCT02395107 and NCT02316587.

AbstractBackgroundA subset of patients with hypertrophic cardiomyopathy (HCM) is at high risk of sudden cardiac death (SCD). Practice guidelines endorse use of a risk calculator, which requires entry of left atrial (LA) diameter. However, American Society of Echocardiography (ASE) guidelines recommend the use of LA volume index (LAVI) for routine quantification of LA size. The aims of this study were to (a) develop a model to estimate LA diameter from LAVI and (b) evaluate whether substitution of measured LA diameter by estimated LA diameter derived from LAVI reclassifies HCM‐SCD risk.MethodsThe study cohort was comprised of 500 randomly selected HCM patients who underwent transthoracic echocardiography (TTE). LA diameter and LAVI were measured offline using digital clips from TTE. Linear regression models were developed to estimate LA diameter from LAVI. A European Society of Cardiology endorsed equation estimated SCD risk, which was measured using LA diameter and estimated LA diameter derived from LAVI.ResultsThe mean LAVI was 48.5 ± 18.8 mL/m2. The derived LA diameter was 45.1 mm (SD: 5.5 mm), similar to the measured LA diameter (45.1 mm, SD: 7.1 mm). Median SCD risk at 5 years estimated by measured LA diameter was 2.22% (interquartile range (IQR): 1.39, 3.56), while median risk calculated by estimated LA diameter was 2.18% (IQR: 1.44, 3.52). 476/500 (95%) patients maintained the same risk classification regardless of whether the measured or estimated LA diameter was used.ConclusionsSubstitution of measured LA diameter by estimated LA diameter in the HCM‐SCD calculator did not reclassify risk.

Abstract Background There is a paucity of data about the prevalence and natural history of mitral annular calcification (MAC). Purposes In a large cohort of patients undergoing clinically-indicated echocardiography, we aimed to evaluate the prevalence and the natural history of MAC, and the frequency of associated mitral valve dysfunction (MVD). Methods Retrospective review of all patients who underwent echocardiographic evaluation at our institution between January 1st and December 31st 2015. The patients were stratified into 3 groups: MAC with MVD, MAC without MVD, no MAC. MVD was defined as moderate or greater mitral regurgitation (MR) or stenosis (MS). The 3 groups were compared for baseline clinical and echocardiographic characteristics and all-cause mortality during follow-up. Results Of 24,415 evaluated patients, 5478 (22%) had MAC. Patients with MAC were older (75±10 vs. 60±16 years, p&lt;0.01) and more often female (46% vs. 43%, p&lt;0.01). MVD was more frequently observed in patients with MAC (16% vs. 7%, p&lt;0.01); moderate or greater MR was found in 10% of patients with MAC vs. 6% without MAC (p&lt;0.01) and MS in 7% vs. 0.5% (p&lt;0.01). In patients with MAC, those with MVD were more often female and more frequently had creatinine ≥2mg/dl and moderate or greater aortic stenosis (AS) than those without MVD (Fig. A). Kaplan-Meier survivals at 1 year were 75% in patients with MAC and MVD, 87% in those with MAC without MVD, and 92% in those without MAC (Fig B). Adjusted for age, sex, diabetes, creatinine ≥2 mg/dl, coronary artery disease, left ventricular ejection fraction &lt;50%, and AS, MAC was associated with higher all-cause mortality (adjusted hazard ratio1.4, 95% confidence interval: 1.3–1.5, p&lt;0.01); combined MAC and MVD was associated with the highest mortality during follow-up of 2.5±1.8 years. Conclusion In a large cohort of patients undergoing echocardiographic evaluation, the prevalence of MAC was 22%. MV dysfunction was more than twice as prevalent in patients with MAC as without. Patients with MAC had higher all-cause mortality than patients without MAC. Among patients with MAC and mitral valvular dysfunction, adjusted mortality was two-fold higher compared to those without MAC. Funding Acknowledgement Type of funding source: None

Abstract Background Prevalence of calcific mitral stenosis (MS) increases with age. Mitral valve interventions for calcific MS are often delayed until symptoms are severely limiting because the natural history of calcific MS and its relation to cardiac symptoms or comorbidities have not been well assessed. Objectives We assessed the prevalence of symptoms, comorbidities and determinants of all-cause mortality in patients with severe calcific MS. Methods We retrospectively investigated adults with echocardiographic isolated severe MS, defined as mitral valve area (MVA by the continuity equation) ≤1.5 cm2, from July 2003 to December 2017. Among them, calcific MS was identified as obstruction of left ventricular inflow due to degenerative calcification of the mitral annulus using echocardiography and, whenever available, operative findings including histopathological examination. Inactivity was defined as requirement for assistance with activities of daily living. Follow up was obtained by review of medical records. Results Of 491 patients with isolated severe MS, calcific MS was present in 200 (41%; age 78±11 years, 18% men, 32% with atrial fibrillation). Charlson Comorbidity Index (CCI) was 5.1±1.7 and 14 (7%) were inactive. MVA and transmitral gradient (TMG) were 1.26±0.19 cm2 and 8.1±3.8 mmHg, respectively. Symptoms were present at baseline in 120 (60%) including dyspnea in 97, chest discomfort in 12, syncope in 3, lower extremity edema in 3, thrombosis in 3 and fatigue in 2. Of them, mitral valve interventions including surgical or transcatheter mitral valve replacement and mitral valve bypass were performed in 27 (23%): within 1 year after index TTE in 23 (19%) and at 2, 4, 5 and 6 years in 1 each. Of 80 patients without symptoms at index TTE, 20 (25%) developed symptoms at mean 2.9±3.2 years and interventions were performed in 5 (6%). Of 168 who did not receive interventions, 60 (36%) did not develop symptoms during follow up, 58 (35%) were considered to have moderate MS, 46 (27%) were not offered surgery because of high risk due to advanced age, multiple comorbidities or heavy calcification, and 2 (1%) declined interventions. During follow-up of 2.8±3.0 years, Kaplan-Meier survival at 1 and 3 years without intervention were 72% and 52%, respectively (Fig. A). Inactivity, CCI &gt;5, left ventricular ejection fraction (LVEF) &lt;50%, TMG ≥8 mmHg (the mean TMG) and right ventricular systolic pressure (RVSP) ≥50 mmHg were independently associated with mortality (Fig. B). Symptoms were associated with referral for interventions (OR 3.43, 95% CI 1.22–9.65; p=0.019), but not with mortality. Conclusion Patients with isolated severe calcific MS had a high burden of comorbidities and had high mortality without intervention. Symptoms were common (60%), but were not associated with mortality. TMG ≥8 mmHg, RVSP ≥50 mmHg, LVEF&lt;50%, CCI &gt;5 and inactivity were independently associated with mortality. Funding Acknowledgement Type of funding source: None

Abstract Background While the presence left ventricular (LV) remodelling after ST-segment elevation myocardial infarction (STEMI) is known to worsen prognosis, the impact of progressive vs. stable LV remodelling on outcome has not been established. Purpose To investigate the impact of progressive LV remodelling on outcome in STEMI patients who were treated with primary percutaneous coronary intervention (PCI) and optimal pharmacotherapy. Methods Baseline, 3-, 6- and 12-month echocardiograms were analysed. Early LV remodelling (ER) was defined as a ≥20% increase in LV end-diastolic volume (EDV) during the first 3 months post-STEMI, and mid-term remodelling (MTR) as ≥20% LVEDV change by 6 months. Progressive LV remodelling was defined according to spline curve analyses: ≥0% LVEDV increase by 6 months (i.e. further increase after 3 months) for ER, and ≥20% by 12 months (i.e. an additional increase after 6 months) for MTR. The impact of progressive LV remodelling on outcome was evaluated with a Log rank test. Results 589 STEMI patients (mean age 61±12 years, 78% male) who demonstrated LV remodelling in the first 6 months post-infarct, were analysed: 408 (69%) ER and 181 (31%) MTR. Progressive LV remodelling occurred in 146 (36%) ER and in 12 (7%) MTR. After a median follow-up of 90 (IQR 64–117) months, 39 (10%) ER were hospitalised for heart failure. 25 (14%) MTR remodellers died after a median follow-up of 86 (IQR 66–112) months. Progressive LV remodelling in ER led to a higher rate of heart failure hospitalisation (P=0.017 vs. non-progressive ER, Fig. 1A) but no mortality difference (P=0.10 vs. non-progressive ER). In contrast, MTR with progressive LV remodelling experienced worse survival (P=0.01 vs. non-progressive MTR, Fig. 1B) but no increase in heart failure hospitalisation (P=0.65 vs. non-progressive MTR). Conclusions Progressive LV remodelling causes an increased risk of heart failure in ER post-infarct, vs. higher mortality in MTR. These two patterns of progressive, post-infarct LV remodelling possibly represent different underlying pathophysiological mechanisms: i.e. evolution of true post-infarct remodelling in ER, vs. natural history of established heart failure in MTR. Figure 1 Funding Acknowledgement Type of funding source: None

Abstract Background Transmitral gradient (TMG) is highly dependent on hemodynamic state, leading to discordance between TMG and mitral valve area (MVA). The effect of heart rate (HR) and stroke volume (SV) on TMG among patients with mitral stenosis (MS) is poorly understood. Purposes We aimed to (1) develop a formula for projected TMG (proTMG) for assessment of MS severity under varying hemodynamics; (2) assess the prognostic value of proTMG in patients with MS. Methods All patients evaluated for suspected MS without ≥moderate other valve disorder at our tertiary center between 2001 and 2017 were analyzed. Projected TMG is the expected gradient under normal flow (SV 80–94 ml and HR 60–79 bpm), and was modeled based on the observed impact of HR and SV on TMG by multiple regression analysis. The data were randomly split (2:1) into training and testing sets. The improvement in agreement between MVA and proTMG was evaluated. Composite cardiac events including all-cause death and mitral valve interventions were compared according to TMG grade using TMG and proTMG. Severe and moderate MS were defined as MVA ≤1.5 cm2 and 1.5–2.0 cm2 respectively, by the continuity equation. MVA ≤1.0 cm2 was considered as very severe MS. Results Of 4973 patients with suspected MS (age 73±12 years, 33% male), severe MS was present in 437 (9%, including 98 with very severe MS) and moderate MS in 934 (19%). In 838 patients with normal HR and SV, very severe, severe and moderate MS corresponded to TMG ≥12 mmHg, ≥6 mmHg and 4–6 mmHg, respectively. In the training set (n=3315), the median [interquartile range] of HR and SV were 70 [61–80] bpm and 97 [83–113] mL in men (n=1120), and 72 [63–82] bpm and 84 [71–97] mL in women (n=2195), respectively. The impact of HR and SV on TMG for men and women were 0.07 and 0.08 mmHg per 1 bpm increase in HR (95% confidence interval [CI] 0.06–0.07 and 0.07–0.08), and 0.03 and 0.05 mmHg per 1 mL increase in SV (95% CI 0.03–0.03 and 0.04–0.05), respectively. Therefore, the final formula to calculate proTMG was: proTMG=TMG-0.07(HR-70)-0.03(SV-97) in men and proTMG=TMG-0.08(HR-72)-0.05(SV-84) in women. In the testing set (n=1658), the proTMG (kappa=0.63, 95% CI 0.60–0.66) had better agreement with MS severity by MVA than TMG (kappa=0.28, 95% CI 0.24–0.32). To explore the prevalence of patients reclassified using proTMG, in 98 with TMG ≥12 mmHg, proTMG remained ≥6 mmHg. Of 657 with TMG 6–12 mmHg, proTMG remained ≥6 mmHg in 356 (54%), and decreased to &lt;6 mmHg in 301 (46%). In patients with TMG 6–12 mmHg, proTMG ≥6 mmHg was associated with higher probability of cardiac events compared with &lt;6 mmHg during follow-up of 2.8±3.1 years (Figure). Conclusion We propose a novel concept of projected TMG defined as the expected transmitral gradient at normal HR and SV levels. This improved the diagnostic yield of Doppler TMG measurements for MS severity assessment and identified a low-risk subset of patients with elevated TMG due to high HR or SV. Funding Acknowledgement Type of funding source: None

Abstract Background The left ventricle (LV) in obese patients undergoes different patterns of remodeling in order to normalize wall stress. However, little is known about how LV volume indices, LV global longitudinal strain and right ventricular free wall strain (GLS) vary according to the pattern of LV remodeling. Aim To define the echocardiographic reference values of LV volumes and biventricular GLS across the different LV remodeling patterns in obese patients with a preserved ejection fraction. Methods 2393 adult obese patients (1428 females, 965 males) with a normal ejection fraction who underwent echocardiography from January 2008 to December 2018 were selected. They were categorized according to 4 cardiac remodeling groups defined by LV mass index (102g/m2 in males, 88g/m2 in females) and relative ventricular wall thickness (0.42): normal geometry (NG), eccentric hypertrophy (EH), concentric remodeling (CR) and concentric hypertrophy (CH). Obese subjects were further categorized by BMI class (30–35, 35–40, &gt;40 kg/m2). Obese subjects were gender matched to controls with a normal BMI (18.5–25 kg/m2) and normal cardiac geometry. Mean ± SD, One-way Anova and Tukey- Kramer HSD were applied. P&lt;0.05 is considered significant. Results The mean age of controls and obese patients' were 50±16 and 57±13.6 years respectively (P&lt;0.0001). LV GLS for controls compared to obese subjects with NG, EH, CR and CH was −21.1±2 vs. −20.2±1.9, −19.6±2.8, −18.5±2.9, −17.5±3.4 respectively (p&lt;0.0001 for all), and for RV GLS it was −27.9±4 vs −26.7±3.9, −25.1±5, −23.5±5.5, −24.1±5.2 respectively (p&lt;0.01 for all, except for NG where p=0.2). The distribution of LV indices according to cardiac remodeling subtypes is shown in the figure. Indexed end diastolic and end systolic volumes were smaller in NG, CH and CR compared to controls (p&lt;0.001 for each respectively). LV GLS and ejection fraction were higher in females, while indexed LV volumes were higher in males within each remodeling category (P&lt;0.0001). No significant difference in LV GLS or indexed LV volume was seen across BMI categories within each remodeling pattern (P&gt;0.05). Obese subjects with CH had the highest incidence of the cardiovascular risk factors hyperlipidemia, hypertension and history of myocardial infarction or stroke, compared to those with other remodeling patterns (p&lt;0.0001 for each, vs. NG, EH and CR). Conclusion To our knowledge, this is the largest study to define LV volumes and left and right ventricular GLS according to LV remodeling pattern and BMI category. The Lowest GLS was noted in CH. Ejection fraction was similar across the LV remodeling patterns. There were no differences in GLS and LV indexed volumes across BMI categories within each remodeling group. These results can be applied as a reference values for the obese population with a normal LV ejection fraction. Funding Acknowledgement Type of funding source: None

Abstract Background Atrial fibrillation (Afib) leads to beat-to-beat variability in cycle length; however, whether there is associated beat-to-beat variability in the tricuspid annulus (TA) dimensions or variability in the time in cardiac cycle when TA reaches maximal size is unknown. Purpose We aim to assess the beat-to-beat variability in the TA dimensions in Afib compared with sinus rhythm (SR). Methods Images were obtained from 58 patients (29 in Afib, 29 in SR) undergoing either 3D TTE or TEE examination. We measured TA in 3–6 cardiac cycles per patient using commercially available software (TomTec 4MV). Results Median absolute difference in maximal TA area over 3–6 cardiac cycles was 1.60 cm2 (range 0.35 cm2 to 4.08 cm2) in Afib vs. 1.17 cm2 (range 0.32 cm2 to 2.19 cm2) in SR, p=0.0063. Median absolute difference in the maximal circumference was 0.79 cm (range 0.09 cm to 2.2 cm) in Afib vs 0.54 cm (range 0.12 cm to 1.43 cm) in SR, p=0.0175. A total of 118 cardiac cycles were analyzed in patients in SR and 147 in Afib. Timing of maximal TA area was most commonly recorded at end-diastole (80–100% of the R-R interval) in 62% of cycles in SR; however, it was distributed over a broad range in Afib, p&lt;0.0001, [Figure]. Conclusion Afib leads to significant beat-to-beat variability in the maximal TA area, minimal TA area, maximal TA circumference, and in the time of maximal TA area. These findings suggest that accurate assessment of TA dimensions should be based on continuous tracking of the TA over several cardiac cycles, especially in patients with Afib. These observations have significant implications for device sizing in percutaneous tricuspid valve interventions. Timing of Maximal TA Area Funding Acknowledgement Type of funding source: None

Abstract Background Bicuspid aortic valve (BAV) is an important cause of AR; these patients belong to a young and male predominant population and are distinctively different from tricuspid aortic valve (TAV). However, the differences between BAV and TAV in AR have not been completely explored. Purpose To explore differences between patients with BAV and TAV in hemodynamically significant aortic regurgitation (AR). Methods Consecutive patients with ≥moderate-severe AR were retrospectively identified from 2006 to 2017. Results Of 798 patients (502 with TAV, mean age 67±14 years; 296 with BAV, mean age 46±14 years) followed for 6.1±3.6 years, 403 underwent AV surgery (AVS); 154 died during follow-up. BAV men (94%) tended to become symptomatic when left ventricle enlarged; TAV patients became symptomatic before left ventricular (LV) enlargement. During follow-up, BAV patients had lower mortality (hazard ratio [HR], 0.19; P&lt;0.0001) and higher incidence of AVS (HR, 1.28; P=0.01) than TAV, which attenuated after adjusted on age, sex, comorbidities, LV ejection fraction (LVEF), functional class, and time-dependent AVS. In a propensity-matched cohort, differences of survival and incidence of AVS between BAV and TAV were not demonstrated. After a median of 6.3 (IQR: 3.3–9.3) years, 53 patients died post-AVS; TAV patients having class I surgical triggers had poor survival than TAV-non-class I patients and BAV patients with and without class I triggers (Figure). Class I triggers had no effect on BAV patients regarding post-AVS survival. LVEF&lt;60% was associated with increased mortality in both TAV and BAV. Conclusions The correlation between larger LV size and symptomatic status only applied in BAV men. Patients with BAV and significant AR tended to have better survival and higher incidence of AVS, likely driven by inherent younger age and less comorbidity than patients with TAV. Class I surgical triggers had heavier negative impact on poor survival in TAV patients. The cutoff of LV dysfunction in AR may be LVEF 60%. Figure 1. Kaplan-Meier curves post-AVS Funding Acknowledgement Type of funding source: None

Abstract Aims Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF. Methods and results We performed a retrospective analysis in 24 885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6–8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4–0.6, P &lt; 0.001] and HF at follow-up [adjusted HR, highest vs. lowest quartile, 0.4, 95% CI (0.3, 0.5), P &lt; 0.001]. Power reserve showed similar results. Conclusion The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.