Pellikka, Patricia A.

Abstract Background In patients with hemodynamically-significant chronic aortic valve regurgitation (AR), the prognostic significance of routinely-measured diastolic blood pressure (DBP), resting heart rate (RHR) and physical examination signs of heart failure (HF), is unknown. Purpose To investigate the association of DBP, RHR and HF signs, with all-cause mortality. Methods This retrospective cohort study included all consecutive patients with moderately-severe or severe AR within a tertiary-referral center from 2006–2017. Patients with ≥moderate aortic stenosis and those with ≥moderate mitral stenosis/regurgitation were excluded. Results Of 820 patients (age 59±17 years; 82% men) with DBP 64±13mmHg and RHR 64±12bpm, followed for 5.5±3.5 years, 104 died under medical management and 400 underwent aortic valve surgery (AVS). In multivariable analysis, DBP (adjusted-hazard ratio [HR] 0.82 [0.68–0.98] p=0.031, per 10mmHg increase), RHR (adjusted HR 1.2 [1.01–1.41] p=0.034 per 10bpm increase), and any HF signs (adjusted HR 1.66 [1.04–2.61] p=0.032) were associated with all-cause death independently of demographics, comorbidities, and guideline-derived surgical triggers. Mortality increased in a J-curve fashion for DBP starting at 70 mmHg and peaking at 55 mmHg (Fig A,C), and in a linear fashion for RHR starting at 60bpm (Fig B, D). The association persisted after additional adjustment for medications, presence of hypertension and time-dependent AVS. A clinical score combining DBP, RHR and any HF signs increased the mortality risk-discrimination of demographics and comorbidities from 74% to 79% (p=0.01), and from 79% to 82% after addition of surgical triggers (p=0.04). Figure. Risk of death by DBP and RHR Conclusions In patients with AR, routinely-measured vital signs and physical examination are strongly associated with all-cause mortality; lower DBP, higher RHR and any HF signs are independent predictors of mortality, and provide incremental mortality risk-discriminating value to baseline demographics, comorbidities and guideline-derived surgical triggers. These findings represent a clinical paradigm shift and have guideline implications.

Abstract Background Functional mitral regurgitation (MR) is expected to improve after aortic valve replacement (AVR) in patients with severe aortic stenosis (sAS) and MR. However, little is unknown about the impact of AVR on organic MR and whether concomitant mitral valve surgery (MVS) improves outcomes in patients with sAS and MR. Purpose We assessed the impact of AVR on MR severity according to MR mechanism. We also assessed the clinical outcomes in patients with sAS and MR that underwent AVR with vs without MVS. Methods We retrospectively investigated patients who received surgical AVR or transcatheter aortic valve implantation (TAVI) from 2008 to 2017. We identified patients with effective mitral regurgitant orifice area (ERO) ≥10 mm2 by the proximal isovelocity surface area method with transthoracic echocardiography. The change in MR after AVR was considered significant when there was at least one grade difference. We compared the all-cause mortality of patients with sAS and MR that underwent AVR with vs without MVS according to MR mechanism and patient age. Results We included 326 patients with sAS and MR (age 80 [Interquartile range 72–85] years, 53% male, 21% history of myocardial infarction). Organic and functional MR were present in 69% and 31%, respectively. Of these, 240 underwent AVR alone (AVR group) including TAVI in 112 while 86 underwent AVR and MVS (MVS group) including mitral valve replacement in 38 and mitral valve repair in 48. The median ERO at baseline was 17 (14–21) mm2 in AVR and 24 (19–33) mm2 in MVS (p<0.001). Improvement in MR was observed in 58% of AVR and 91% of MVS (p<0.001). In AVR group, organic MR improved as frequently as functional MR (58% vs. 59%, p=0.96). Predictors for improvement in organic MR were absence of atrial fibrillation and moderate or greater MR, and in functional MR, the only predictor was decrease in LV end-systolic diameter after AVR. During mean follow-up of 2.4±2.3 years, moderate or greater MR was observed in 23% of AVR and 7% of MVS (p=0.002). All-cause mortality was similar in AVR and MVS groups for organic and functional MR (hazard ratio for MVS group 0.68, 95% CI: 0.40–1.10, p=0.13 in organic MR and 0.62, 95% CI 0.29–1.22, p=0.68 in functional MR). All-cause mortality was lower in MVS group compared with AVR group in patients <80 years, and was similar in patients ≥80 years (Figure). Conclusion In patients with sAS and MR, MR improves after AVR, even in the majority of patients with organic MR. Compared with isolated AVR, concomitant MVS was associated with better prognosis in patients <80 years.

Abstract Background Anthracyclines are one of the most effective chemotherapeutic agents but can lead to a decline in cardiac function. Two-dimensional (2D) speckle tracking echocardiography derived strain can predict cancer therapeutics-related cardiac dysfunction (CTRCD). However, little is known about the role of three-dimensional (3D) strain imaging in this setting. Purpose To evaluate different methods of Left Ventricular Ejection Fraction (LVEF) and strain, and to identify the best strain parameter for the prediction of CTRCD in this group of patients during treatment with anthracycline based chemotherapy. Methods Patients with Hodgkin's or non-Hodgkin's lymphoma receiving anthracycline based chemotherapy were enrolled. 2D-and 3D echocardiography was performed at 3 time points: baseline, at the completion of chemotherapy and at 1 year. 2D- and 3D LVEF (2D Modified Quinones, M-mode, 2D Biplane, 3D Philips, 3D GE and 3D TomTec), peak systolic left and right ventricular longitudinal, radial and circumferential strain and strain rate were measured. CTRCD was defined as a decrease in LVEF >10% to an absolute value of <53%. Lin's Concordance Correlation Coefficient (CCC) was calculated to compare LVEF methods. ANOVA, uni and multivariate analysis was performed. Results A total of 130 patients (79 males, mean age 57±16 years) were enrolled; 104 non-Hodgkin.3D Philips and GE (CCC 0.88 [0.84, 0.92]), 3D Philips and biplane (CCC 0.84 [0.79, 0.89]), 3D Philips and Modified Quinones (CCC 0.86 [0.82, 091]) as well as 3D Philips and M-mode (CCC 0.77 [0.70, 0.85]) showed strong correlation for LVEF. 15 patients (12%) developed CTRCD. Mean cumulative anthracycline dose was 263±65 mg/m2. 2D and 3D global longitudinal and circumferential peak systolic strain, 2D global longitudinal systolic and early diastolic strain rate, 2D global early diastolic strain rate, 2D right ventricular longitudinal peak systolic strain and systolic strain rate, 2D global radial peak systolic strain and systolic strain rate measured at the completion of chemotherapy were independent predictors of the development of CTRCD at 1 year post-chemotherapy. The strongest predictors of CTRCD were 3D global longitudinal and circumferential strain either individually (area under the curve, 0.90 and 0.95 respectively) or combined (area under the curve, 0.95) at the completion of chemotherapy; a cutoff value of <-18% in 3D global longitudinal strain had a sensitivity of 82% and specificity of 99%, while for 3D global circumferential peak systolic strain of <-24% had a sensitivity of 82% and specificity of 95%. Conclusions To our knowledge this is the first prospective trial that shows that 3D EF correlates well with other EF methods and 3D strain predicts cardiac toxicity in this group of patients with a very good sensitivity and specificity. Acknowledgement/Funding Department of Cardiovascular Medicine-Mayo Clinic Rochester MN

Abstract Background Currently data on the risk stratification of patients with moderate aortic stenosis (AS) are very limited. Method Patients diagnosed with moderate AS in 2012 (aortic valve area [AVA]: >1 and ≤1.5cm2) were identified. Patients were stratifying by LV diastolic function (normal vs high filling pressure), left ventricular ejection fraction (LVEF ≥50 vs <50%) and stroke volume index (SVI ≥35 vs <35 ml/m2). High filling pressure was defined as average E/e' ≥14 or septal E/e' ≥11 when atrial fibrillation was present. The prognosis was compared to age- and sex-matched general population. Results 898 patients were included (age 74 years, 58% male, AVA 1.25 cm2). During a median follow-up of 2.9 years, there were 346 deaths. In patients with moderate AS, mortality was higher than expected (P<0.001, Fig 1A). LV high filling pressure, LVEF<50% and SVI<35ml/m2 were present in 416 (55%), 140 (17%) and 81 (9%) patients, respectively. Those with normal filling pressure had similar prognosis when compared to controls (Fig 1C, P=0.35); whereas mortality rates remained higher than reference even when LVEF≥50% or SVI≥35ml/m2 (Fig 1E, 1G, P<0.001). Amongst all groups, mortality rates were the highest in patients with LVEF <50% or SVI <35 ml/m2 (Fig 1D, 1F, P<0.001); mortality ratios were 3.78 (95% CI 3.01–4.67) and 6.91 (95% CI 5.13–9.11), respectively. Noteworthy, high filling pressure allowed further risk stratification when LVEF or SVI was preserved (Fig 2, P<0.001). Figures 1 & 2 Conclusions Patients with moderate AS showed poor survival. A clinical trial examining role of aortic valve replacement would be beneficial not only in patients with reduced LVEF or SVI but also in those with high LV filling pressures.

Abstract Background Cardiac power output-to-mass (CPOM) ratio is a measure of myocardial performance that incorporates both pressure and flow output, normalized to left ventricular (LV) mass generating that cardiac work. Prior small studies have shown that CPOM predicts outcomes in patients with ischemic cardiomyopathy and reduced LV ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise CPOM and power reserve (increase from rest to peak exercise) in patients with normal EF. Methods and results Retrospective study in 24,783 patients (age 59±13 years, 45% females) with EF≥50% and no significant valve disease or right ventricular (RV) dysfunction, undergoing exercise stress echocardiography between 2004–2018. CPOM was calculated as previously described (0.222 x cardiac output x mean blood pressure / LV mass) and expressed in Watts/100g myocardium. Power reserve was calculated as difference in CPOM between peak stress and rest. All-cause mortality was the primary endpoint. Patients were divided into quartiles of power reserve. Patients with higher power reserve were younger, had higher blood pressure and heart rate, lower LV mass, and lower prevalence of prior myocardial infarction. (Table). During follow-up (median (IQR) 3.9 (0.6–8.3) years), 931 (3.8%) patients died. Progressively lower power reserve was associated with increasing mortality (Figure A). Compared to patients with abnormal stress test, patients with the lowest power reserve but otherwise normal stress test had the same survival as those with infarction/cardiomyopathy or ischemia on stress test (Figure B). Resting CPOM had lower predictive value. After adjusting for age, sex, METs achieved, ischemia/infarction on stress test results, and diastolic function grade, both peak exercise CPOM and power reserve were independent predictors of mortality (p<0.0001), incremental to conventional measures. Conclusion Cardiac power output and reserve measured during exercise stress echo provides independent prognostic information in patients with normal resting EF and no significant valve disease or RV dysfunction. The survival of patients with low power reserve but normal stress test was similar to patients with prior infarction/ cardiomyopathy or ischemia on stress test.

Abstract Background Left ventricular ejection fraction (LVEF), end diastolic, end systolic volumes (EDV, ESV) and global longitudinal strain (GLS) are very important parameters that are frequently reported in cardiology. Normal cardiac geometry was not considered in articles that published normal values. It is important to know normal parameters for population studies. Our hypothesis is to analyze how EF, volumes and GLS may vary by age groups, gender and BMI in a population with normal cardiac geometry. Purpose To define the values in EF, volumes and GLS measurements in a healthy population with normal cardiac geometry stratified by age groups, gender and body mass index (BMI). Methods This is a single center retrospective study conducted from 2008 to 2018. We selected 4557 subjects (2605 females, 1952 males) >18 years with ≤ mild valvular heart disease, who underwent 2D-echocardiography (2DE) at Mayo clinic, Rochester. All selected subjects had normal LV geometry (i.e., LV mass index≤88g/m2 in females and ≤102g/m2 in males and relative wall thickness ≤0.42 measured by 2DE) and without any cardiovascular risk factors or structural or functional abnormality determined by 2DE. Based on age groups, gender and BMI, we assessed the variability in volumes indexed to body surface area, EF and GLS by Mean ± SD and two sample t-test. Results Mean age was 54±15 years (females = 53±15, males = 56±16), body surface area was 1.9 m2±0.2 (females = 1.8±0.2, males = 2.1±0.2), LV GLS −20.7% ±2 SD (females = −21.2±2, males= −20.2±1.9) ranging −16.1 to −27.6 in both genders (Figure); LVEF by Biplane volume method 62.6% ± 4 SD (females = 63±4.3, males=62±4.5). The end diastolic volume 63.6±11.7 cc/m2 (female = 59.9±10.3, males = 68.1±11.8) and end systolic volume 23.9 cc/m2±5.4 (female = 22.3±4.8, males = 25.9±5.5). LV GLS, Biplane EF values were higher in females and EDV and ESV values were higher in males. LV GLS values decreased with age in females (P<0.0001). While EF increased with age in both genders (P<0.0001), EDV and ESV values decreased with age (P<0.0001). When each gender is sub-divided based on their BMI (<25 and ≥25), GLS, EDV and ESV values were higher in population with BMI <25 (P<0.0001). Normal geometry variables Conclusion To our knowledge, this is the biggest single center study to evaluate LV GLS values, LV EF, ED, ES volumes. These results can be used as reference values in a normal population. Acknowledgement/Funding None

Abstract Background The left ventricle (LV) undergoes different types of remodeling to normalize its wall stress. There has been an increase in the trend in research regarding the process of remodeling but little is known about how LV volumes and global longitudinal strain (GLS) may vary depending upon the type of remodeling. Purpose To define the values of LV volumes and GLS in patients with different types of LV remodeling with normal ejection fraction (EF). Methods Single center retrospective study conducted from 2008 to 2018. We selected 10,356 subjects >18 years (5808 females, 4548 males) with normal EF and who underwent 2D echocardiography (2DE) at Mayo clinic, Rochester. They were categorized into 4 groups (Figure) i.e., group 1 = normal geometry, group 2 = concentric remodeling, group 3 = concentric hypertrophy, group 4 = eccentric hypertrophy based on their LV mass index (102 g/m2 in males, 88 g/m2 in females) and relative wall thickness (0.42) values measured by 2DE (figure). The patterns of LV GLS, end diastolic and end systolic volumes (EDV, ESV) indexed to body surface area were analyzed in these four groups by gender and body mass index (BMI). Mean±SD, One-way Anova, two sample t-test and Tukey- Kramer HSD were applied. Results The mean age of the selected population is 57.9 years ±14.9 (females=57.7±14.7, males=58.2±15.1) and the body surface area of 1.9 m2±0.2 (females=1.8±2 and males=2.1±0.2). The LV GLS values (Figure) of groups 1, 2, 3 and 4 were −20.7, −18.9, −17.5 and −19.9 and their EDV cc/m2 values were 63.6, 58.5, 61.2 and 68.2 respectively. LV GLS and Biplane EF values were higher in females while Biplane EDV and ESV were higher in males. When each gender is sub-divided based on their BMI (<25 and ≥25), the LV GLS, EDV and ESV values were higher in all groups with BMI<25 except in males with concentric remodeling and females with concentric hypertrophy where they were low. Remodeling distribution Conclusion To our knowledge, this is the biggest single center study to evaluate LV GLS and volumes based on type of remodeling by gender and BMI. When compared with normal geometry, LV volumes and GLS values were statistically different among each type of remodeling as well as for gender and BMI. These results can be used as reference values in patient population studies where remodeling is being analyzed in subjects with normal LV EF. Acknowledgement/Funding None

Objectives To test the relationship between increasing severity of obesity, calculated risk and observed outcomes. Methods Patients with symptoms suggestive of coronary artery disease (CAD) (n=10 003) were stratified according to body mass index (BMI). We compared risk factors, pooled risk scores and physicians’ perception of risk. Cox regression tested the association between BMI and (1) presence of obstructive CAD and (2) composite clinical endpoints (death, cardiovascular death, unstable angina hospitalisation and myocardial infarction). Results BMI was ≥30 kg/m2 in 48% of patients and ≥35 in 20%. Increasingly obese patients were younger, female and non-smoking but with higher prevalence of hypertension, diabetes, black race and sedentary lifestyle. Pooled risk estimates of CAD were highest in those with mid-range BMI. In contrast, physicians’ estimation of the likelihood of significant CAD based on clinical impression increased progressively with BMI. For a 10% increase in the Diamond-Forrester probability of CAD, the adjusted OR for obstructive CAD was 1.5 (95% CI 1.4 to 1.5) in patients with BMI <35, but only 1.2 (95% CI 1.1 to 1.3) in those with BMI ≥35 (interaction p<0.001). Framingham Risk Score increased across increasing BMI categories. However, there was a strong and consistent inverse relationship between degree of obesity and all three composite clinical endpoints over a median 25 months of follow-up. Conclusions Despite perceptions of higher risk and higher risk scores, increasingly obese patients had obstructive CAD less frequently than predicted and had fewer adverse clinical outcomes. There is a need for risk assessment tools and guidelines that account for obesity. Trial registration number NCT01174550.

Background: Mitral stenosis frequently coexists in patients with severe aortic stenosis. Mitral stenosis severity evaluation is challenging in the setting of combined aortic stenosis and mitral stenosis because of hemodynamic interactions between the 2 valve lesions. The impact of aortic valve replacement (AVR) for severe aortic stenosis on mitral stenosis is unknown. This study aimed to assess the effect of AVR on mitral stenosis hemodynamics and the clinical outcomes of patients with severe aortic stenosis with and without mitral stenosis. Methods: We retrospectively investigated patients who underwent surgical AVR or transcatheter AVR for severe aortic stenosis from 2008 to 2015. Mean transmitral gradient by Doppler echocardiography ≥4 mm Hg was identified as mitral stenosis; patients were then stratified according to mitral valve area (MVA, by continuity equation) as >2.0 cm 2 or ≤2.0 cm 2 . MVA before and after AVR in patients with mitral stenosis were evaluated. Clinical outcomes of patients with and without mitral stenosis were compared using 1:2 matching for age, sex, left ventricular ejection fraction, method of AVR (surgical AVR versus transcatheter AVR) and year of AVR. Results: Of 190 patients with severe aortic stenosis and mitral stenosis (age 76±9 years, 42% men), 184 were matched with 362 with severe aortic stenosis without mitral stenosis. Among all mitral stenosis patients, the mean MVA increased after AVR by 0.26±0.59 cm 2 (from 2.00±0.50 to 2.26±0.62 cm 2 , P <0.01). MVA increased in 105 (55%) and remained unchanged in 34 (18%). Indexed stroke volume ≤45 mL/m 2 (odds ratio [OR] 2.40; 95% CI, 1.15–5.01; P =0.020) and transcatheter AVR (OR, 2.36; 95% CI, 1.17–4.77; P =0.017) were independently associated with increase in MVA. Of 107 with significant mitral stenosis (MVA ≤2.0 cm 2 ), MVA increased to >2.0 cm 2 after AVR in 52 (49%, pseudo mitral stenosis) and remained ≤2.0 cm 2 in 55 (51%, true mitral stenosis). During follow-up of median 2.9 (0.7–4.9) years, true mitral stenosis was an independent predictor of all-cause mortality (adjusted hazard ratio, 1.88; 95% CI, 1.20–2.94; P <0.01). Conclusions: MVA improved after AVR in nearly half of patients with severe aortic stenosis and mitral stenosis. MVA remained ≤2.0 cm 2 (true mitral stenosis) in nearly half of patients with severe aortic stenosis and significant mitral stenosis; this was associated with worse survival among patients undergoing AVR for severe aortic stenosis.

Abstract Background: Sarcoidosis is a systemic granulomatous disease that may affect the myocardium. This study evaluated the diagnostic and prognostic value of 2-dimensional speckle tracking echocardiography in cardiac sarcoidosis (CS). Methods: Eighty-three patients with extracardiac, biopsy-proven sarcoidosis and definite/probable diagnosis of cardiac involvement diagnosed from January 2005 through December 2016 were included. In order to analyze the alteration of strain parameters in early stages of CS, a subgroup of 23 CS patients with left ventricular ejection fraction (LVEF) within normal limits (LVEF>52% for men: >54% for women, mean value: 57.3%±3.8%) and no wall motion abnormalities was compared with 97 controls (1:4) without cardiac disease. LV and right ventricular (RV) global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain and strain rate (SR) analyses were performed with TomTec software and correlated with cardiac outcomes (including heart failure and arrhythmias). This study was approved by the Mayo Clinic Institutional Review Board, and all patients gave informed written consent to participate. Results: Mean age of CS patients was 53.6±10.8 years, and 34.9% were women. Mean LVEF was 43.2%±12.4%; LV GLS, -12.4%±3.7%; LV GCS, -17.1%±6.5%; LV GRS, 29.3%±12.8%; and RV wall GLS, 14.6%±6.3%. In the 23 patients with early stage CS with normal LVEF and RV systolic function, strain parameters were significantly reduced when compared with controls (respectively: LV GLS, -15.9%±2.5% vs -18.2%±2.7% [ P =.001]; RV GLS, -16.9%±4.5% vs -24.1%±4.0% [ P <.001]). A LV GLS value of -16.3% provided 82.2% sensitivity and 81.2% specificity for the diagnosis of CS (AUC 0.91), while a RV value of -19.9% provided 88.1% sensitivity and 86.7% specificity (AUC 0.93). Hospital admission and heart failure significantly correlated to impaired LV GLS (> -14%). Conclusion: Reduced strain values in the LV GLS and RV GLS can be used in the diagnostic algorithm in patients with suspicion of cardiac sarcoidosis. These values also correlate with adverse cardiovascular events.